Indian Patents
Title of Invention

"5-SUBSTITUTED-2-PHENYLAMINO BENZAMIDE AS MEK INHIBITOR"
Abstract An objective of the present invention is to provide compounds that exhibit strong MEK-inhibiting activity and are stable in vivo and soluble in water, which can be used as preventive or therapeutic agents for proliferative diseases. The compounds of the present invention and pharmaceutically acceptable salts thereof are represented by the following formula
Full Text DESCRIPTION
5-SUBSTITUTED-2-PHENYLAMINO-BENZAMIDE AS MEK INHIBITOR
Technical Field
The present invention relates to novel compounds having MEK inhibitory activity and
pharmaceutically acceptable salts thereof, intermediates for synthesis of the compounds, andpharmaceutical compositions comprising the compounds or pharmaceutically acceptable salts
thereof.The compounds of the present invention can be used as MEK inhibitors. The
compounds can be used to treat proliferative diseases, for example, cancers, psoriasis, restenosis,
autoimmune diseases, and atherosclerosis, and other diseases such as sequelae of heart failure,
heterograft rejection, osteoarthritis, chronic rheumatoid arthritis, asthma, cystic fibrosis,
hepatomegalia, cardiac hypertrophy, Alzheimer's disease, diabetes, septic shock, and HIV
infection.
Background Art
Cell survival is regulated by various extracellular signals, for example, growth factors,
cytokines, and extracellular matrices (ECM), via cell surface receptors.
Two major signal transduction pathways regulate the process of signal transduction
from the cell surface to the nucleus. One is the Ras signaling pathway, and the other is the
PI3K (Phosphatidylinositol 3 kinase) pathway. The PI3K pathway is either activated via cell
surface receptors or indirectly by Ras. The present invention focuses on the Ras signaling
pathway.
The MAPK (mitogen-activated protein kinase) cascade which comprises three kinases,
namely, Raf, MEK (MAPK or ERK kinase), and ERK (extracellular stimulus regulated kinase),
is a key component of the Ras signaling pathway. The cascade starts with the activation of Ras
and in response to extracellular signals, plays an important role in regulating cell proliferation,
differentiation, and transformation (Person, G, F. Robinson, T. Beers Gibson, B. Xu, M.
Karandikar, K. Berman, and M. H. Cobb. Endocrine Rev., 22,153-183 (2001); Bryan A. Ballif
and John Blenis, Cell Growth & Differentiation, 12, 397-408 (2001); Cobb MH, Prog. Biophys.
Mol. Biol., 71 479-500 (1999); Lewis TS, Shapiro PS and AhnNG. Adv. Cancer Res., 74 49-139
(1998); Kolch W, Biochem. J., 351, 289-305 (2000); Judith S Sebolt-Leopold, Oncogene, 19,
6594-6599 (2000); Roman Herrera and Judith S. Sebolt-Leopold, Treds in Molecular Medicine,
8,827-831(2002)).Ras activation is regulated through the interplay between GTP-exchange factors (GEFs)
and GTPase-activating proteins (GAPs) (Giorgio Scita, Pierluigi Tenca, Emanuela Frittoli
Arianna Tocchetti, Metello Innocenti, Giuseppina Giardina and Pier Paolo Di Fiore, EMBO
Journal. 19, 2393-2398 (2000)). GEFs activate Ras through the formation of Ras-GTP complex,
and GAPs inactivate Ras through the formation of Ras-GDP complex. Ras activation results
from growth factor-mediated extracellular signals to cell surface receptors or from Ras mutations.
Ras mutations are found in many human cancer cells. It is known that such Ras mutations
result in sustained Ras activation (GTP complex) and play key roles in the proliferation of
human cancer cells.
Activated Ras interacts with Raf-1, a serine/threonine protein kinase, to activate Raf-1
(Daum G, Eisenmann-Tappe I, Fries HW, Troppmair J and Rapp UR, Trends Biochem. Sci., 19,
474-480 (1994); Stokoe D, Macdonald SG, Cadwallader K, Symons M and Hacock JF, Science,
264,1463-1467(1994)).
Activated Raf-1 then phosphorylates and activates MEK1 and MEK2. MEK is
phosphorylated on two serine residues (Ser218 and Ser222) (Dent P, Haser W, Haystead TA,
Vincent LA, Roberts TM and Sturgill TW, Science, 257, 1404-1407 (1992); Crews CM,
Alessandrini A and Erikson RL, Science, 258, 478-480 (1992); Her JH, Lakhani S, Zu K, Vila J,
Dent P, Sturgill TW and Weber MJ, Biochem. J., 296,25-31 (1993); Alessi, D. R., Y. Saito, D. G.
Campgell, P. Cohen, G. Sithanandam, U. Rapp, A. Ashworth, C. J. Marshall, and S. Cowley.
Trends Biochem. Sci. 21 373-372 (1994); Zheng, C. F., and K. L. Guan. J. Biol. Chem. 268,
23933-23939 (1993)).
MEK is a dual-specificity kinase. Activated MEK phosphorylates ERK1 and ERK2 on
tyrosine (185) and threonme (183) residues (Anderson NG, Mailer JL, Tonks NK and Sturgill TW,
Nature, 343, 651-653 (1990); Seger R and Krebs EG, FASEG J, 9 716-735 (1995)).
The MEK-mediated ERK phosphorylation results in not only ERK activation but also
translocation of ERK to the nucleus.
Activated ERK (MAPK) activates various substrates, for example, transcription factors
hi the cytoplasm and nucleus, and the result is that the activation leads to cellular changes
(proliferation, differentiation, and transformation) depending on the extracellular signal.
MEK has a strict substrate specificity. ERK1 and ERK2 are the only substrates of
MEK phosphorylation that have been identified (Seger R, Ahn NG, Posada J, Munar ES, Jensen
AM, Cooper JA, Cobb MH and Kregs EG, J. Biol. Chem., 267, 14373-14381 (1992)).
Strict substrate specificity (limited substrates: ERK1 and 2) and dual specificity
(phosphorylation on both tyrosine and threonine), which are unique properties of MEK bur
rarely found in other kinases, are suggested to play a central role in the MEK integration of
signals in the MAPK pathway.
Constitutive activation of the MEK/MAPK pathway is shown to be associated with the
neoplastic phenotypes of a relatively large number of cancer cell types (Hoshino R, Chatani Y,
Yamori T, Tsuruo T, Oka H, Yoshida O, Shimada Y, Ari-I S, Wada H, Fujimoto J, Kohno M,
oncogene, 18, 813 (1999); Kim SC, Hahn JS, Min YH, Yoo NC, Ko YW, Lee WJ, Blood, 93,
3893 (1999); Morgan MA, Dolp 0, Reuter CW, Blood, 97,1823 (2001)).
In addition, constitutive activation of MEK has been reported to result in cellular
alteration (transformation or canceration) (Cowley S, Paterson H, Kemp P and Marshall CJ, Cell,
77, 841-852 (1994); Mansour SJ, Marten WT, Hermann AS, Candia JM, Rong S, Fukasawa K,
Vande Woude GF and AhnNG, Science, 265, 966-970 (1994)).
Furthermore, studies of MEK inhibitors (PD98059 and others) have revealed that MEK
inhibition not only results in impaired cell proliferation, but also has impact on various cellular
events, including cell differentiation, apoptosis, and angiogenesis (Dudley DT, Pang L, Decker
SJ, Bridges AJ and Saltiel AR, Proc. Natl. Acad. Sci. USA, 92, 7686-7689 (1995); Alessi DR,
Cuenda A, Cohen P, Dudley DT and Saltiel AR, J. Biol. Chem., 270, 27489-27494 (1995); Pages
G, Lenorman D, L'Allemain G, Chambard JC, Meloche S and Puyssegur J, Proc. Natl. Acad. Sci.
USA., 90, 8319-8323 (1993); Pang L, Sawada T, Decker SJ and Saltiel AR., J. Biol. Chem., 270,
13585-13588 (1995); Finalay D, Healy V, Furlong F, O'Connell FC, Keon NK and Martin F, Cell
Death Differ. 7, 303-313 (2000); Holmstrom TH, Iran SE, Johnson VL, Ahn NG, Chow SC and
Eriksson JE, Mol. Cell. Biol., 19, 5991-6002 (1999); Elliceiri BP, Klemke R, Stromblad S and
Cherexh DA, J. Cell Biol., 141,1255-1263 (1998); Milanini J, Vinals F, Pouyssegur J and Pages
G, J. Biol. Chem., 273,18165-18172 (1998)).
The above-described findings suggest that MEK, one of the major mediators in the
MAPK cascade, can serves as a potential target for therapeutic agents used in treating diseases
caused by aberrant cell proliferation.
There are many previously reported MEK inhibitors including, for example, compounds
having the backbone structure of a 2-phenylaminobenzoic acid or a derivative thereof, and which
comprise various types of substituents at different positions (US Patent No. 6251943; US Patent
No. 6310060; US Patent No. 6506798; International Publication WO 98/37881; WO 99/01421;
WO 99/01426; WO 00/35435; WO 00/35436; WO 00/37141; WO 00/40235; WO 00/40237; WO
00/41505; WO 00/41994; WO 00/42002; WO 00/42003; WO 00/42022; WO 00/42029; WO
00/64856; WO 01/05390; WO 01/05391; WO 01/05392; WO 01/05393; WO 01/68619; WO
02/06213; WO 02/18319; WO 03/062189; WO 03/062191; WO 03/077855; WO 03/077914; WO
04/056789; and Japanese Patent Application Kokai Publication No. (JP-A) 2001-55376
(unexamined published Japanese patent application)). The previously reported compounds also
include N-alkoxy-2-phenylamino-benzamide derivatives which have an alkoxy residue as the
substituent on the amide nitrogen atom. Furthermore, the reported compounds also include
compounds which comprise as a substituent, a halogen atom, a carbamoyl group, a sulfamoyl
group, or such, at position 5 of the benzamide ring (International Publication WO 98/37881; WO
99/01426; WO 00/42003; WO 01/68619; and WO 02/06213).
Meanwhile, the anti-cancer effect of compounds comprising the feature of an MEK
inhibitor, as reported, has been drawing attention. Such compounds include, for example,
compound CI-1040 described below (in Example 95 of WO 99/01426). The result of a phase I
clinical trial of compound CI-1040 was reported in the American Society of Clinical Oncology
Annual Meeting in 2002 (American Society of Clinical Oncology Annual Meeting in 2002
(Abstract Nos. 320 and 321; May, 18-21, 2002)). However, various problems have been
pointed out, for example, rapid hydrolysis and inactivation of the compound in vivo; high lipid
solubility and low water solubility; and a wide interpatient variability in pharmacokinetic
parameters. The clinical trial for CM 040 was thus terminated. At present, PD0325901 (WO
02/06213) is currently at the stage of a phase II clinical trial in U.S.
Meanwhile, there are reports on methods of preventing or treating rheumatoid arthritis
or osteoarthritis using compounds having MEK-inhibiting activity (International Publication WO
00/35436; WO 01/68619; and JP-A2001-55376).
Disclosure of the Invention
An objective of the present invention is to provide preventive or therapeutic agents for
proliferative diseases, that have excellent safety, exhibit strong MEK inhibitory effect, and are
stable in vivo and soluble in water.
Through various intensive studies, the present inventors discovered that
N-alkoxy-2-phenylamino-benzamide derivatives which comprise a substituent at position 5 of
the ring have an unexpectedly strong MEK inhibitory effect and high water solubility, and are
highly stable in vivo. In addition, the inventors discovered that the compounds of the present
invention have effects of suppressing tumor growth and of suppressing the onset of arthritis, and
that they could serve as preventive or therapeutic agents for cancers and arthritis with improved
biological utility, thereby completing the present invention.
Specifically, the present invention includes:
[1 ] a compound represented by the following formula (1), or a pharmaceutically
acceptable salt thereof,
wherein
RI represents a halogen atom, an alkenyl group, or an alkynyl group;
Ra represents a halogen atom or an alkyl group; the alkyl group may be substituted by a hydroxyl
group;
RS represents a hydrogen atom or a halogen atom;
R4 represents a hydrogen atom, an alkyl group, an alkenyl group, or an alkynyl group; the alkyl
group, the alkenyl group, and the alkynyl group may have one to three substituents selected from
the group consisting of -ORa, -NRaRb, -NRaCORb, a heterocyclic group, and a heteroaryl
group; the heterocyclic group and the heteroaryl group may have one to three substituents
selected from the group consisting of a C 1.5 alkyl group, -ORa, and -NRaRb;
X represents a group represented by the following formula (i);
wherein
Y represents -O-, -NR8O-, -ONRg-, -NRgCO-, or -NRgSO2-;
Z represents an Ci-g alkylene chain which may be substituted by one to three
groups represented by W;
where Rg represents a hydrogen atom, an alkyl group, -ORa, or
-CORg; and the alkyl group may be substituted by a halogen atom,
-ORa, or -NRaRb;
Rg represents a hydrogen atom, an alkyl group, or -ORa; and the alkyl
group may be substituted by a halogen atom, -ORa, or -NRaRb;
Rg and Rg may be linked to the alkylene chain of Z or form a
heterocyclic group through a linkage to the substituent represented by
RaorRbofW)
or alternatively,
X represents a group represented by the following formula (ii):
wherein
YI and ¥2, which may be the same or different, each represent a single bond,
-CO-, -COO-, -O-, -OCO-, -NRa-, or -SO2-;
Z' represents a €1-5 chain which may be substituted by one to three groups
represented by W);
in the above formulae (i) and (ii),
W and W, which may be the same or different, each represent a Ci-s alkyl group, a
halogen atom , an oxo group, -ORa, -COORa, -COOCORa, -CO-halogen atom,
-OCORa, -CONRaRb, -SRa, -SORa, -SO2Ra, -NRaRb, -NRaCORb, -NRaSO2Rb,
-SO2NRaRb, a heterocyclic group, or a heteroaryl group; the heterocyclic group and the
heteroaryl group may have a substituent selected from the group consisting of a Ci-s
alkyl group, -ORa, and -NRaRb; the alkyl group may be substituted by a hydroxyl
group, a Ci-s alkoxy group, or an amino group;
the above substituents except the oxo group and the halogen may be linked to each other
to form a cycloalkyl group or a heterocyclic group; the cycloalkyl group or the
heterocyclic group may have a substituent selected from the group consisting of, -ORa,
-NRaRb, and a Ci-s alkyl group that may be substituted with -ORa;
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a
Ci-s alkyl group; the alkyl group may be substituted by one to three groups selected
from the group consisting of a hydroxyl group, a Ci.5 alkoxy group, and an amino
group;
provided that, when X is the group represented by the above formula (i) and Y is not -O-,
W may be a hydrogen atom;
Herein, the symbol "•" used in the formulae such as (i), (ii), (iii), and (iv) means the
site of bonding.
[2] the compound according to [1], or a pharmaceutically acceptable salt thereof,
wherein X represents the group -Y-Z-W of the formula (i) and Z represents a Ci-s alkylene
chain,
wherein the alkylene chain may have one to three substituents selected from the group
consisting of a Ci-s alkyl group, a halogen atom, -ORa, -NRaRb, and an oxo group; the
above substituents except the oxo group and the halogen atom may be linked to each
other to form a cycloalkyl group or a heterocyclic group;
the cycloalkyl group orthe heterocyclic group may have a substituent selected from the
group consisting of -ORa, -NRaRb, and a Ci-s alkyl group that may be substituted with
-ORa;
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a
Ci-s alkyl group; and the alkyl group may be substituted by a hydroxyl group, a Ci-s
alkoxy group, or an amino group;
[3] the compound according to [1] or [2], or a pharmaceutically acceptable salt thereof,
wherein X represents the group -Y-Z-W of the formula (i), wherein the alkylene chain of Z is any
one of the groups represented by the following formulae:
-CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -CH2CH(Me)-, -CH2C(Me)2-, -C(Me)2CH2-,
-(CH2)2CH(Me)-, -(CH2)2C(Me)2-, -CH(Me)(CH2) 2-, -C(Me)2(CH2)2-, -CH2CH(Me)CH2-,
-CH2C(Me)2CH2-, -CH2C(CH2CH2)CH2-, -CO-, -CH2CO-, -COCH2-, -(CH2)2CO-, -CO(CH2)2-,
-CHOH-, -CH2CH(OH)-, -CH(OH)CH2-, -CH2CH(OH)CH2-, -CH(OH)CH2CH2-, and
-CH2CH2CH(OH)-;
[4] the compound according to any one of [1] to [3], or a pharmaceutically acceptable
salt thereof, wherein X represents -Y-Z-W of the formula (i), wherein Rg represents a hydrogen
atom, a hydroxyl group, a Ci-s alkyl group, or -CORg;
R9 represents a hydrogen atom, a hydroxyl group, a Ci-s alkyl group, or a Ci-s alkoxy group;
the alkyl group and the alkoxy group represented byRg and Rg may be substituted by one to three
hydroxyl groups at arbitrary positions of the hydrocarbon moiety;
[5] the compound according to any one of [1] to [4], or a pharmaceutically acceptable
salt thereof, wherein X represents -Y-Z-W of the formula (i), wherein Rg represents a hydrogen
atom, a hydroxyl group, a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an
n-butyl group, an i-butyl group, a t-butyl group, a sec-butyl group, a 1,1-dimethylpropyl group, a
2,2-dimethylpropyl group, a 1,2-dimethylpropyl group, a pentyl group, a formyl group, an acetyl
group, a 2-methoxyacetyl group, a 2-ethoxyacetyl group, a 2-hydroxyacetyl group, a propionyl
group, a 2-methylpropionyl group, a 2-methoxypropionyl group, a 2-ethoxypropionyl group, a
2-hydroxypropionyl group, a 3-methoxypropionyl group, a 3-ethoxypropionyl group, a
3-hydroxypropionyl group, a methoxy group, an ethoxy group, an n-propyloxy group, an
i-propyloxy group, a hydroxymethyl group, or a 2-hydroxyethyl group;
[6] the compound according to any one of [1] to [5], or a pharmaceutically acceptable
salt thereof, wherein X represents -Y-Z-W of the formula (i), wherein Y represents -O-, -NHO-,
-N(COCH3)0-, -N(COCH2OH)0-, -N(COCH2CH3)O-, -N(COCH(OH)CH3)O-,
-N(COCH2CH2OH)0-, -N(COCH(OH)CH2OH)O-, -N(COCH2CH2CH3)O-,
-N(COCH2CH2CH2OH)0-, -N(COCH(OH)CH2CH3)O-, -N(COCH2CH(OH)CH3)O-, -NHCO-,
or -NHSO2-;
[7] the compound according to [1], or a pharmaceutically acceptable salt thereof,
wherein X represents a group represented by the formula (ii) and X is any one of the groups
represented by the following formulae:
o
wherein Z' represents a Ci-s alkylene chain which may be substituted by one to three
groups represented by W ;
W represents a Ci-s alkyl group, a halogen atom, an oxo group, -ORa, -CONRaRb,
-SRa, -SORa, -SO2Ra, -NRaRb, -NRaCORb, -NRaSO2Rb, -SO2NRaRb, a heterocyclic
group, or a heteroaryl group;
the heterocyclic group and the heteroaryl group may have substituents selected from the
group consisting of a CM alkyl group, -ORa, and -NRaRb; the alkyl group may be
substituted by a hydroxyl group, a €1.5 alkoxy group, or an amino group;
the above substituents except the oxo group and the halogen may be linked to each other
to form a cycloalkyl group or a heterocyclic group; the cycloalkyl group or the
heterocyclic group may have a substituent selected from the group consisting of -ORa,
-NRaRb, and a €1-5 alkyl group that may be substituted with -ORa;
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a
Ci-s alkyl group; and the alkyl group may be substituted by a hydroxyl group, a Ci-s
alkoxy group, or an amino group;
[8] the compound according to any one of [1] or [7], or a pharmaceutically acceptable
salt thereof, wherein X represents the group represented by the formula (ii), wherein W
represents any one of the groups represented by the formulae:
-Me, -Et, -n-Pr, -i-Pr, -CH2OH, -CH2CH2OH, -CH(OH)CH3, -OH, -OMe, -OEt, -OCH2OH,
-0(CH2)2OH, -O(i-Pr), -O(n-Pr), -CONH2, -CONHMe, -CONHEt, -CONH(n-Pr), -CONH(i-Pr),
-CONMe2, -CON(Et)Me, -SO2Me, -SOMe, -SMe, -NH2, -NHMe, -NHCH2OH, -NH(CH2)2OH,
-N(Me)CH2CH2OH, -NHEt, -NMe2, -N(Et)Me, -NHCOMe, -NMeCOMe, -NHCOEt,
-NHCO(n-Pr), and -NHCO(i-Pr);
[9] the compound according to any one of [1], [7], and [8], or a pharmaceutically
acceptable salt thereof, wherein X represents the group represented by the formula (ii), wherein
the alkylene chain of Z' is any one of the groups represented by the following formulae:
-CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -CH2CH(Me)-, -CH2C(Me)2-, -C(Me)2CH2-,
-(CH2)2CH(Me>, -(CH2)2C(Me)2-, -CH(Me)(CH2)2-, -C(Me)2(CH2)2-, -CH2CH(Me)CH2-,
-CH2C(Me)2CH2-, -CHOH-, -CH2CH(OH)-, -CH(OH)CH2-, -CH2CH(OH)CH2-,
-CH(OH)CH2CH2-, -CH2CH2CH(OH)-, -CO-, -CH2CO-, -COCH2-, -(CH2)2CO-, -CO(CH2)2-,
and-CH2CH(OH)CH2-; •
[10] the compound according to any one of [1], [7], [8], and [9], or a pharmaceutically
acceptable salt thereof, wherein X represents the group represented by the formula (ii) and X is
any one of the groups represented by the following formulae:
o o & o
wherein the alkylene chain may be substituted at arbitrary positions by one to three
substituents selected from the group consisting of a d-s alkyl group, a halogen atom,
-ORa, -NRaRb, and an oxo group; Ra and Rb, which may be the same or different, each
represent a hydrogen atom or a Ci-s alkyl group; the alkyl group may be substituted by a
hydroxyl group, a Ci-s alkoxy group, or an amino group; Ra represents a hydrogen atom
10
or a Ci-s alkyl group; and the alkyl group may be substituted by a hydroxyl group, a Ci.5
alkoxy group, or an amino group;
[11] the compound according to [1], or a pharmaceutically acceptable salt thereof,
wherein X represents the group represented by the following formula (iii) or (iv):
or
wherein n represents an integer ranging from 1 to 5 and n' represents an integer ranging
from 0 to 5; the repeated units represented by -(Ct^n- or -(CH2)n'- in the formulae
may be substituted at arbitrary positions in the hydrocarbon moiety by one to three
substituents selected from the group consisting of a Ci-s alkyl group, a halogen atom,
-ORa, -NRaRb, and an oxo group; Ra and Rb, which may be the same or different, each
represent a hydrogen atom or a Ci-s alkyl group; and the alkyl group may be substituted
by a hydroxyl group, a Ci-s alkoxy group, or an amino group;
[12] the compound according to [1], or a pharmaceutically acceptable salt thereof,
wherein X represents a group selected from the group consisting of a 2-hydroxyethoxy group, a
3-hydroxy-2-dimethylpropoxy group, a 3-hydroxypropoxy group, a 2-carbamoylethoxy group, a
2-methylcarbamoylethoxy group, a 2-methanesulfonyl-ethoxy group, a 2-acetylamino-ethoxy
group, a 2-hydroxyethoxyamino group, a 3-hydroxypropionyl amino group, a
2-hydroxyethanesulfonamide group, a 1-hydroxymethyl-cyclopropylmethoxy group, a
2,3-dihydroxy-propoxy group, a lH-imidazol-2-ylmethoxy group, a
2-methylcarbamoyl-ethoxyamino group, a 2-acetylamino-ethoxyamino group, a
2-methanesulfonyl-ethoxyamino group, a lH-imidazol-2-ylmethoxyamino group, a
3-hydroxypropoxyamino group, a 2-(2-hydroxyethoxy)-ethoxy group, a 2-methylaminoethoxy
group, a 2-(2-hydroxyethylamino)-ethoxy group, a 2-morpholin-4-yl-ethoxy group, a
2-(4-hydroxy-piperidin-l-yl)-ethoxy group, a 2-methylamino-ethoxyamino group, a
2,3-dihydroxy-propoxyamino group, a formyl-methoxyamino group, an acetyl-methoxyamino
group, a methoxy-propionylamino group, an isobutyryl-methoxy-amino group, a
(2-hydroxy-acetyl)-methoxyamino group, a methoxy-(2-methoxy-acetyl)-amino group, an
acetyl-ethoxy-amino group, an ethoxy-propionyl-amino group, an acetyl-isopropoxy-amino
group, an acetylhydroxyamino group, an acetoxy-acetyl-amino group, an
acetyl-(2-hydroxy-ethoxy)-amino group, an acetyl-(3-hydroxy-propoxy)-amino group, an
acetyl-(2-hydroxy-2-methyl-propoxy)-amino group, an acetyl-(2-acetylamino-ethoxy)-amino
group, an acetyl-(2-propionylamino-ethoxy)-amino group, an
acetyl-(2-isobutyrylamino-ethoxy)-amino group, an acetyl-(2-methylsulfanyl-ethoxy)-amino
group, an acetyl-(3-methylsulfanyl-propoxy)-amino group, a 2-hydroxy-l,l-dimethyl-ethoxy
group, a methylcarbamoylmethoxyamino group, an ethylcarbamoylmethoxyamino group, a
propylcarbamoylmethoxyamino group, an isopropylcarbamoyl-methoxyamino group, a
dimethylcarbamoylmethoxyamino group, a 2-ethylcarbamoyl-ethoxyamino group, a
2-propylcarbamoyl-ethoxyamino group, a 2-isopropylcarbamoyl-ethoxyamino group, a
3-methylcarbamoyl-propoxyatnino group, a 2-methoxycarbonyl-ethoxyamino group, a
methoxyamino group, a methoxy-methyl-amino group, an ethoxyamino group, an
isopropoxyamino group, a 2-hydroxy-2-methyl-propoxyamino group, a
2-methylsulfanyl-ethoxyamino group, a 2-methanesulfinyl-ethoxyamino group, a
3-methylsulfanyl-propoxyamino group, a 3-methanesulfinyl-propoxyamino group, a
2-propionylamino-ethoxyamino group, a 2-isobutyrylamino-ethoxyamino group, a
2-hydroxy-acetylamino group, and an acetyl-(2-hydroxy-ethyl)-amino group;
[13] the compound according to [1], or a pharmaceutically acceptable salt thereof,
wherein X represents a group selected from the group consisting of a 3-oxo-[l,2]oxazinan-2-yl
group, a 3-oxo-isoxazolidin-2-yl group, a4,4-dimethyl-3-oxo-isoxazolidin-2-yl group, a
4-hydroxy-3-oxo-[l,2]oxazinan-2-yl group, a 3-oxo-[l,4,2]dioxazinan-2-yl group, a
2-oxo-pyrrolidin-l-yl group, a 2-oxo-piperidin-l-yl group, a 2-oxo-oxazolidin-3-yl group, a
2-oxo-tetrahydro-pyrirnidin-l-yl group, and a 2,3-dioxo-morpholin-4-yl group;
[14] the compound according to any one of [1] to [13], or a pharmaceutically
acceptable salt thereof, wherein RI represents an iodine atom, a bromine atom, a vinyl group, or
an ethynyl group;
[15] the compound according to any one of [1] to [14], or a pharmaceutically
acceptable salt thereof, wherein RI represents an iodine atom or an ethynyl group;
[16] the compound according to any one of [1] to [15], or a pharmaceutically
acceptable salt thereof, wherein Ra represents a chlorine atom, a fluorine atom, a methyl group,
or a hydroxymethyl group;
[17] the compound according to any one of [1] to [16], or a pharmaceutically
acceptable salt thereof, wherein R.2 represents a fluorine atom;
12
[18] the compound according to any one of [1] to [17], or a pharmaceutically
acceptable salt thereof, wherein RI represents a fluorine atom;
[19] the compound according to any one of [1] to [18], or a pharmaceutically
acceptable salt thereof, wherein R4 represents a Ci-s alkyl group substituted by one to three
hydroxyl groups;
[20] the compound according to any one of [1] to [19], or a pharmaceutically
acceptable salt thereof, wherein R4 represents a group selected from the group consisting of the
groups represented by the following formulae:
OH
[21] the compound according to [1], or a pharmaceutically acceptable salt thereof,
wherein Ra and Rb, which may be the same or different, each represent a group selected from
the group consisting of a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an
i-propyl group, an n-butyl group, an i-butyl group, a t-butyl group, a sec-butyl group, a
1,1-dimethylpropyl group, a 2,2-dimethylpropyl group, a 1,2-dimethylpropyl group, a pentyl
group, a hydroxymethyl group, a 1- hydroxyethyl group, a 1-hydroxy-l-methylethyl group, a
2-hydroxy-l-methylethyl group, a 2-hydroxy-l,l-dimethylethyl group, a 2-hydroxyethyl group,
a 1-hydroxypropyl group, a 2-hydroxypropyl group, and a 3-hydroxypropyl group;
[22] the compound according to [1] to [6], or a pharmaceutically acceptable salt
thereof, wherein X represents -Y-Z-W of the formula (i), wherein W and W, which may be the
same or different, each represent a group selected from the group consisting of -OH, -OMe, -OEt,
-OCH2OH, -O(CH2)2OH, -O(i-Pr), -O(n-Pr), -COOH, -COOMe, -COOEt, -COOCOMe, -COC1,
-CONH2, -CONHMe, -CONHEt, -CONH(n-Pr), -CONH(i-Pr), -CONMe2, -CON(Et)Me,
-S02Me, -SOMe, -SMe, -NH2, -NHMe, -NHCH2OH, -NH(CH2)2OH, -N(Me)CH2CH2OH,
-NHEt, -NMe2, -N(Et)Me, -NHCOMe, -NMeCOMe, -NHCOEt, -NHCO(n-Pr), and
NHCO(i-Pr); and
W may be a hydrogen atom when Y is not -O-;
[23] the compound according to [1], or a pharmaceutically acceptable salt thereof,
wherein the compound represented by the above formula (1) is any one selected from the group
consisting of:
(l)B-l
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-hydroxy-ethoxymethy
l)-benzamide,
(2) B-2
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-(2-hydroxy-ethoxyme
thyl)-benzamide,
(3) B-3
N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-(2-hydroxy-ethoxy
methyl)-benzamide,
(4) B-4
2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-(2-hydroxy-ethoxymeth
yl)-benzamide,
(5) B-5
3,4-difluoro-2-(2-fluoro-4-vmyl-phenylanimo)-N-(2-hydroxy-ethoxy)-5-(2-hydroxy-ethoxymeth
yl)-benzamide,
(6) B-6
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(3-hydroxypropoxymeth
yl)-benzamide,
(7) B-7
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-(3-hydroxy-2,2-dimethyl-propoxymethyl)-N-(2-
hydroxy-ethoxy)-benzamide,
(8) B-8
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(l-hydroxymethyl-cyclo
propylmethoxymethyl)-benzamide,
(9) B-9
5-(2,3-dihydroxy-propoxymethyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxyethoxy)-
benzamide,
(10)B-10
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-methylcarbamoyl-eth
oxymethyl)-benzamide,
14(ll)B-ll
5-(2-acetylamino-ethoxymethyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-et
hoxy)-benzamide,
(12)B-12
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-methanesiilfonyl-etho
xymethyl)-benzamide,
(13)B-13
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(lH-imidazol-2-yl
methoxymethyl)-benzamide,
(14)8-14
3,4-difluoro-2-(2-fluoro-4-iodo-phenylatnino)-N-(2-hydroxy-ethoxy)-5 - [2-(2-hydroxy-ethoxy)-et
hoxymethy 1] -benzamide,
(15)B-15
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-methylamino-ethoxy
methyl)-benzamide,
(16)B-16
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[2-(2-hydroxy-ethylamin
o)-ethoxymethyl] -benzamide,
(17)B-17
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-morpholin-4-yl-ethox
ymethyl)-benzamide,
(18)B-18
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[2-(4-hydroxy-piperidinl-
yl)-ethoxymethyl]-benzainide, and
(19)B-19
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-(2-hydroxy-l,l-dimethyl-ethoxymethyl)-N-(2-h
ydroxy-ethoxy)-benzamide;
[24] the compound according to [1], or a pharmaceutically acceptable salt thereof,
wherein the compound represented by the above formula (1) is any one selected from the group
consisting of:
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyamin
o)-methyl] -benzamide,
(2) C-2
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxya
mino)-methyl] -benzamide,
(3) C-3
N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-[(2-hydroxy-ethoxy
amino)-methyl]-benzamide,
(4) C-4
2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyamin
o)-methyl] -benzamide,
(5) C-5
3,4-difluoro-2-(2-fluoro-4-vinyl-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyami
no) -methyl] -benzamide,
(6) C-6
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5 - [(2-methylcarbamoyl-eth
oxyamino)-methyl] -benzamide,
(7) C-7
5-[(2-acetylamino-ethoxyamino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hy
droxy-ethoxy)-benzamide,
(8) C-8
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methanesulfonyl-eth
oxyamino)-methy 1] -benzamide,
(9) C-9
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(lH-imidazol-2-ylmeth
oxyamino)-methyl]-benzamide,
(10)C-10
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-hydroxy-propoxyami
no)-methyl] -benzamide,
(ll)C-ll
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methylamino-ethoxy
amino)-methyl] -benzamide,
(12) C-12
5-[(2,3-dihydroxy-propoxyamino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-h
ydroxy-ethoxy)-benzamide,
(13)C-13
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(methylcarbamoylmetho
xyamino-methyl)-benzamide,
(14) C-14
5-(ethylcarbamoylmethoxyamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-h
ydroxy-ethoxy)-benzamide,
(15)C-15
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(propylcarbamoylmetho
xyamino-methyl)-benzamide,
(16)C-16
3,4-difluoro-2-(2-fluoro-4-iodo-phenylatnino)-N-(2-hydroxy-ethoxy)-5 - [(isopropylcarbamoyl-m
ethoxyamino)-methyl]-benzamide,
(17) C-17
5-(dimethylcarbamoylmethoxyamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylaniino)-N-(
2-hydroxy-ethoxy)-benzamide,
(18)C-18
5-[(2-ethylcarbamoyl-ethoxyamino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2
-hydroxy-ethoxy)-benzamide,
(19) C-19
5-[(2-propylcarbamoyl-ethoxyamino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylainino)-N-(
2-hydroxy-ethoxy)-benzamide,
(20) C-20
5-[(2-isopropylcarbamoyl-ethoxyamino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylatnino)-
N-(2-hydroxy-ethoxy)-benzamide,
(21) C-21
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-inethylcarbamoyl-pr
opoxyamino) -methyl] -benzamide,
(22) C-22
3-^-[2,3-difluoro-4-(2-fluoro-4-iodo-phenylamino)-5-(2-hydroxyethoxycarbamoyl)benzyl]ainin
ooxy]propionic acid methyl ester,
(24) C-24
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(methoxyamino-methyl)-
benzamide,
(25) C-25
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(methoxy-methyl-amino
)-methyl] -benzamide,
(26) C-26
5-(ethoxyamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-b
enzamide,
(27) C-27
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(isopropoxyamino-meth
17yl)-benzamide,(28) C-283,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)5 - [(2-hydroxy-2-methyl-pro
poxyamiBo)-methyl] -benzamide,
(29) C-29
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)5-[(2-hydroxy-2-methylpropoxyamino)-
methyl]-benzamide,
(30) C-30
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methylsulfanyl-ethox
yamino)-methyl] -benzamide,
(31)C-31
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5 - [(2-methanesulfinyl-etho
xyamino)-methyl] -benzamide,
(32) C-32
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylsufanyl-propo
xyamino)-methyl] -benzamide,
(33) C-33
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methanesulfmyl-prop
oxyamino)-methyl] -benzamide,
(34) C-34
3,4-difluoro-2-(2-fluoro-4-iodo-phenylaniino)-N-(2-hydroxy-ethoxy)-5-[(2-propoionylamino-eth
oxyamino)-methyl]-benzamide, and
(35) C-35
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-isobutyrylamino-etho
xyamino)-methyl] -benzamide;
[25] the compound according to [1], or a pharmaceutically acceptable salt thereof,
wherein the compound represented by the above formula (1) is any one selected from the group
consisting of:
(l)E-l
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-hydroxy-propionyla
mino)-methyl] -benzamide
(2) E-2
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-[(3-hydroxy-propiony
lamino)-methyl] -benzamide
(3) E-3
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-[(2-hydroxy-ethanesulfonylamino)-inethyl]-N-(
2-hydroxy-ethoxy)-benzamide,
(4) E-4
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-5-[(2-hydroxy-ethanesulfonylamino)-methyl]-
N-(2-hydroxy-ethoxy)-benzamide,
(5) E-5
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-[(2-hydroxy-acetylainino)-methyl]-N-(2-hydrox
y-ethoxy)-benzamide, and
(6) E-6
5-{[acetyl-(2-hydroxy-ethyl)-amino]-methyl}-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(
2-hydroxy-ethoxy)-benzamide;
[26] the compound according to [1], or a pharmaceutically acceptable salt thereof,
wherein the compound represented by the above formula (1) is any one selected from the group
consisting of:
(1) F-l
354-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-[(formyl-methoxy-amino)-methyl]-N-(2-hydrox
y-ethoxy)-benzamide,
(2) F-2
5-[acetyl-methoxy-amino-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylammo)-N-(2-hydroxyethoxy)-
benzamide,
(3) F-3
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(methoxy-propionyl-am
ino)-methyl]-benzamide,
(4) F-4
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(isobutyryl-methoxy-am
ino)-methy 1] -benzamide,
(5) F-5
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-{[(2-hydroxy-acetyl)-memoxy-aniino]-rnethyl}-
N-(2-hydroxy-ethoxy)-benzamide,
(6) F-6
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-{[methoxy-(2-methoxy-a
cetyl)-amino]-methyl} -benzamide,
(7) F-7
5-[(acetyl-methoxy-amino)-methyl]-2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-benzamide,
(8) F-8
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-[(methoxy-propionylamino)-
methyl]-benzamide,
(9) F-9
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-[(isobutyryl-methoxyamino)-
methy 1] -benzamide,
(10)F-10
5-[(acetyl-ethoxy-amino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-e
thoxy)-benzamide,
(ll)F-ll
5-[(ethoxy-propionyl-amino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydro
xy-ethoxy)-benzamide,
(12)F-12
5-[(acetyl-isopropoxy-amino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydro
xy-ethoxy)-benzamide,
(13)F-13
5-[(acetyl-hydroxy-amino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy
-ethoxy)-benzamide,
(14)F-14
5-[(acetoxy-acetyl-amino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxyethoxy)-
benzamide,
(15)F-15
5- {[acetyl-(2-hydroxy-ethoxy)-amino] -methyl} -3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N
-(2-hydroxy-ethoxy)-benzamide,
(16)F-16
5-{[acetyl-(3-hydroxy-propoxy)-amino]-methyl}-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
N-(2-hydroxy-ethoxy)-benzamide,
(17)F-17
5-{[acetyl-(2-hydroxy-2-methyl-propoxy)-amino]-methyl}-3,4-difluoro-2-(2-fluoro-4-iodo-phen
ylamino)-N-(2-hydroxy-ethoxy)-benzamide,
(18)F-18
5-{[acetyl-(2-acetylamino-ethoxy)-amino]-methyl}-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide,
(19)F-19
5-{[acetyl-(2-propionylamino-ethoxy)-amino]-methyl}-3,4-difluoro-2-(2-fluoro-4-iodo-phenyla
mino)-N-(2-hydroxy-ethoxy)-benzamide,
20
(20) F-20
5-{[acetyl-(2-isobutyrylamino-ethoxy)-amino]-methyl}-3,4-difluoro-2-(2-fluoro-4-iodo-phenyla
mino)-N-(2-hydroxy-ethoxy)-benzamide,
(21)F-21
5-{[acetyl-(2-methylsulfanyl-ethoxy)-amino]-methyl}-3,4-difluoro-2-(2-fluoro-4-iodo-phenylam
ino)-N-(2-hydroxy-ethoxy)-benzamide,
(22) F-22
5-{[acetyl-(3-methylsulfanyl-propoxy)-amino]-methyl}-3,4-difluoro-2-(2-fluoro-4-iodo-phenyla
mino)-N-(2-hydroxy-ethoxy)-benzamide,
(23) F-23
5-[(acetyl-ethoxy-amino)-methyl]-2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydrox
y-ethoxy)-benzamide,
(24) F-24
5-[(ethoxy-propionyl-amino)-methyl]-2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hy
droxy-ethoxy)-benzamide,
(25) F-25
5-{[acetyl-(2-hydroxy-ethoxy)-amino]-methyl}-2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluor
o-N-(2-hydroxy-ethoxy)-benzamide, and
(26) F-26
5-{[acetyl-(2-hydroxy-2-methyl-propoxy)-amino]-methyl}-2-(4-ethynyl-2-fluoro-phenylamino)-
3,4-difluoro-N-(2-hydroxy-ethoxy)-benzamide;
[27] the compound according to [1], or a pharmaceutically acceptable salt thereof,
wherein the compound represented by the above formula (1) is any one selected from the group
consisting of:
(l)G-l
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(3-oxo-[l,2]oxazinan-2-
ylmethyl)-benzamide,
(2) G-23,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(3-oxo-isoxazolidin-2-yl
methyl)-benzamide,
(3) G-3
5-(4,4-dimethyl-3-oxo-isoxazolidin-2-ylmethyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
N-(2-hydroxy-ethoxy)-benzamide,
(4) G-4
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-(3-oxo-[l,2]oxazinan21
2-ylmethyl)-benzamide,
(5) G-5
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-(3-oxo-isoxazolidin-2
-ylmethyl)-benzamide,
(6) G-6
N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-(3-oxo-[l,2]oxazin
an-2-ylmethyl)-benzamide,
(7) G-7
N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-(3-oxo-isoxazolidin
-2-ylmethyl)-benzamide, and
(8) G-8
3 54-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(4-hydroxy-3 -oxo- [ 1,2] o
xazinan-2-ylmethyl)-benzamide;
[28] the compound according to [1], or a pharmaceutically acceptable salt thereof,
wherein the compound represented by the above formula (1) is any one selected from the group
consisting of:
(l)H-l
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(3-oxo-[l,4,2]dioxazinan
-2-ylmethyl)-benzaniide,
(2) H-2
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-(3-oxo-[l,4,2]dioxazi
nan-2-ylmethyl)-benzamide,
(3) H-3
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-oxo-pyrrolidin-1 -ylm
ethyl)-benzamide,
(4) H-43,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-oxo-piperidin-l-ylmet
hyl)-benzamide,
(5) H-5
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-oxo-oxazolidin-3-ylm
ethyl)-benzamide,
(6) H-6
3,4-difluoro-2-(2-fluoro-4-iodo-phenylaniino)-N-(2-hydroxy-ethoxy)-5-(2-oxo-tetrahydro-pyrimi
din-l-ylmethyl)-benzaniide, and
(7) H-7
22
5-(2,3-dioxo-morpholin-4-ylmethyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydrox
y-ethoxy)-benzamide;
[29] a synthetic intermediate (E) of the compound represented by the formula (1)
according to [1], wherein the intermediate is represented by the following formula (6):
wherein
RI represents a halogen atom, an alkenyl group, or an alkynyl group;
R2 represents a halogen atom or an alkyl group; the alkyl group may be substituted by a hydroxyl
group;
RI represents a hydrogen atom or a halogen atom;
the above formula (6), the group represented by the following formula in (a):
lirepresents
a 3- to 10-membered heterocyclic group that may have one to three substituents
selected from the group consisting of a Ci-s alkyl group, a halogen atom, -ORa, -NRaRb, and an
oxo group;
the above substituents except the oxo group and the halogen atom may be linked to each other to
form a cycloalkyl group or a heterocyclic group; the cycloalkyl group or the heterocyclic group
may have a substituent selected from the group consisting of-ORa, -NRaRb, and a d.s alkyl
group that may be substituted with -ORa;
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a C 1.5 alkyl
group; the alkyl group may be substituted by a hydroxyl group, a Ci-s alkoxy group, or an
amino group;
U represents -O-, -CONRd-, -S-, -SO-, -SO2-, -NRd-, -NRdCO-, -NRdSO2-, -SO2NRd-, a
divalent heterocyclic group, or a divalent heteroaryl group; Rd represents a hydrogen atom or a
Ci-s alkyl group; the alkyl group may be substituted by a hydroxyl group, a Ci-s alkoxy group, or
an ammo group;
RI, R2, RS, and U may have protecting group(s) required for the synthesis;
[30] the synthetic intermediate (E) according to [29], wherein RI represents an iodine
atom, a bromine atom, an ethynyl group, or a vinyl group;
RI represents a chlorine atom or a fluorine atom;
RS represents a fluorine atom; and
U represents -O-;
[31] the synthetic intermediate (E) according to [29], wherein the heterocyclic group
represented by the formula (a) is a [l,3]dioxoran-2-yl group or a [l,3]dioxan-2-yl group, which
may be substituted by a hydroxyl group or a CM alkyl group;
[32] a synthetic intermediate (F) of the compound represented by the formula (1)
according to [1], wherein the intermediate is represented by the following formula
wherein
RI represents a halogen atom, an alkenyl group, or an alkynyl group;
RI represents a halogen atom or an alkyl group; the alkyl group may be substituted by a hydroxyl
group;
RS represents a hydrogen atom or a halogen atom;
Rt represents a hydrogen atom, an alkyl group, an alkenyl group, or an alkynyl group; the alkyl
group, the alkenyl group, and the alkynyl group may have one to three substituents selected from
the group consisting of-ORa, -NRaRb, -NRaCORb, a heterocyclic group, and a heteroaryl
group; the heterocyclic group and the heteroaryl group may have one to three substituents
selected from the group consisting of a CM alkyl group, -ORa, and -NRaRb; Ra and Rb, which
may be the same or different, each represent a hydrogen atom or a CM alkyl group; the alkyl
group may be substituted by a hydroxyl group, a CM alkoxy group, or an amino group;
24
in the above formula (7), the group represented by the following formula (a):
U-
6
(a)
represents a 3- to 10-membered heterocyclic group that may have one to three substituents
selected from the group consisting of a Ci-s alkyl group, a halogen atom, -ORa, -NRaRb, and an
oxo group;
the above substituents except the oxo group and the halogen atom may be linked to each other to
form a cycloalkyl group or a heterocyclic group; the cycloalkyl group or the heterocyclic group
may have a substituent selected from the group consisting of-ORa, -NRaRb, and a Ci-s alkyl
group that may be substituted with -ORa;
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a Ci-s alkyl
group; and the alkyl group may be substituted by a hydroxyl group, a Ci_5 alkoxy group, or an
amino group;
U represents -O-, -CONRd-, -S-, -SO-, -SO2-, -NRd-, -NRdCO-, -NRdSO2-, -SO2NRd-, a
divalent heterocyclic group, or a divalent heteroaryl group; Rd represents a hydrogen atom or a
Ci-s alkyl group; the alkyl group may be substituted by a hydroxyl group, a CM alkoxy group, or
an amino group;
RI, R2, RS, and U may have protecting group(s) required for the synthesis;
[33] the synthetic intermediate (F) according to [32], wherein RI represents an iodine
atom, a bromine atom, an ethynyl group, or a vinyl group;
R2 represents a chlorine atom or a fluorine atom;
RS represents a fluorine atom;
R4 represents a hydroxy alkyl group, in whichthe hydroxy moiety may be protected; and
U represents -0-;
[34] the synthetic intermediate (F) according to [32], wherein the heterocyclic group
represented by the formula (a) is a [l,3]dioxolan-2-yl group or a [l,3]dioxan-2-yl group, which
may be substituted by a hydroxyl group or a Ci-s alkyl group;
[35] a synthetic intermediate (I) of the compound represented by the formula (1)
according to [1], wherein the intermediate is represented by the following formula
RI represents a halogen atom, an alkenyl group, or an alkynyl group;
R2 represents a halogen atom or an alkyl group; the alkyl group may be substituted by a hydroxyl
group;
RS represents a hydrogen atom or a halogen atom;
Z represents a Ci-g alkylene chain which may be substituted by one to three groups represented
byW;
W or W, which may be the same or different, each represent a hydrogen atom, a Ci-s alkyl group,
a halogen atom, an oxo group, -ORa, -COORa, -COOCORa, -CO-[halogen atom], -OCORa,
-CONRaRb, -SRa, -SORa, -S02Ra, -NRaRb, -NRaCORb, -NRaSO2Rb, -SO2NRaRb, a
heterocyclic group, or a heteroaryl group;
the heterocyclic group and the heteroaryl group may have a substituent selected from the group
consisting of a Ci-s alkyl group, -ORa, and -NRaRb; the alkyl group may be substituited by a
hydroxyl group, a Ci-s alkoxy group, or an amino group;
the above substituents except the oxo group and the halogen atom may be linked to each other to
form a cycloalkyl group or a heterocyclic group; the cycloalkyl group or the heterocyclic group
may have a substituent selected from the group consisting of-ORa, -NRaRb, and a Ci-s alkyl
group that may be substituted with -ORa;
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a C 1.5 alkyl
group; and the alkyl group may be substituted a hydroxyl group, a Ci-s alkoxy group, or an
amino group; and
RI, R2, Ra, Z, W and W may have protecting group(s) required for the synthesis;
[36] the synthetic intermediate according to [35], which is a synthetic intermediate (K)
represented by the following formula (12):
wherein
RI represents a halogen atom, an alkenyl group, or an alkynyl group;
R2 represents a halogen atom or an alkyi group; the alkyl group may be substituted by a hydroxyl
group;
RS represents a hydrogen atom or a halogen atom;
Z' represents a Ci-s alkylene chain that may be substituted by one to three groups represented by
W;
W represents any one of the groups represented by the formulae:
-OH, -OMe, -OEt, -OCH2OH, -O(CH2)2OH, -O(i-Pr), -O(n-Pr), -CONH2, -CONHMe, -CONHEt,
-CONH(n-Pr), -CONH(i-Pr), -CONMe2, -CON(Et)Me, -SO2Me, -SOMe, -SMe, -NH2, -NHMe,
-NHCH2OH, -NH(CH2)2OH, -N(Me)CH2CH2OHs -NHEt, -NMe2, -N(Et)Me, -NHCOMe,
-NMeCOMe, -NHCOEt, -NHCO(n-Pr), and -NHCO(i-Pr);
Q represents -ORc, -OCORc, -NRcRd, or a halogen atom; Re and Rd, which may be the same or
different, each represent a hydrogen atom or a C1-5 alkyl group;
RI, R2, and RS are defined herein above; and RI, R2, RS, Z', Q and W may have protecting
group(s) required for the synthesis;
[37] the synthetic intermediate according to [35] or [36], wherein RI represents an
iodine atom, a bromine atom, an ethynyl group, or a vinyl group;
R2 represents a chlorine atom or a fluorine atom; and
RS represents a fluorine atom;
[38] a synthetic intermediate (L) of the compound represented by the formula (1) the
according to [1], wherein the intermediate is represented the following formula (13):
wherein
RI represents a halogen atom, an alkenyl group, or an alkynyl group;
R.2 represents a halogen atom or an alkyl group; the alkyl group may be substituted by a hydroxyl
group;
RS represents a hydrogen atom or a halogen atom;
R4 represents a hydrogen atom, an alkyl group, an alkenyl group, or an alkynyl group; the alkyl
group, the alkenyl group, and the alkynyl group may have one to three substituents selected from
the group consisting of -ORa, -NRaRb, -NRaCORb, a heterocyclic group, and a heteroaryl
group; the heterocyclic group and the heteroaryl group may have one to three substituents
selected from the group consisting of a C 1.5 alkyl group, -ORa, and -NRaRb; Ra and Rb, which
may be the same or different, each represent a hydrogen atom or a C 1.5 alkyl group; the alkyl
group may be substituted by a hydroxyl group, a Ci-s alkoxy group, or an amino group;
Z' represents a Ci-s alkylene chain that may have one to three groups represented by W;
W represents the group represented by any one of the groups represented by the following
formulae:
-OH, -OMe, -OEt, -OCH2OH, -O(CH2)2OH, -O(i-Pr), -O(n-Pr), -CONH2, -CONHMe, -CONHEt,
-CONH(n-Pr), -CONH(i-Pr), -CONMe2, -CON(Et)Me, -SO2Me, -SOMe, -SMe, -NH2, -NHMe,
-NHCH2OH, -NH(CH2)2OH, -N(Me)CH2CH2OH, -NHEt, -NMe2, -N(Et)Me, -NHCOMe,
-NMeCOMe, -NHCOEt, -NHCO(n-Pr), and -NHCO(i-Pr);
Q represents -ORc, -OCORc, -NRcRd, or a halogen atom; Re and Rd, which may be the same or
different, each represent a hydrogen atom or a Ci-s alkyl group; and
RI, R2, R3, R4, Z', Q, and W may have protecting group(s) required for the synthesis];
[39] the synthetic intermediate (L) according to [38], wherein RI represents an iodine
atom, a bromine atom, an ethynyl group, or a vinyl group;
R2 represents a chlorine atom or a fluorine atom;
RS represents a fluorine atom; and
R* represents a hydroxy alkyl group, in which the hydroxy alkyl moiety may be protected;
[40] a method for producing any one of the compounds (M), (N), (M'), and (N'),
wherein the method comprises reacting a reducing agent, in a solvent at neutral pH or in the
presence of an acid, with a synthetic intermediate (E) represented by the following formula (6) or
a synthetic intermediate (F) represented by the following formula (7):
wherein
RI represents a halogen atom, an alkenyl group, or an alkynyl group;
R2 represents a halogen atom or an alkyl group; the alkyl group may be substituted by a
hydroxyl group;
RS represents a hydrogen atom or a halogen atom;
R4 represents a hydrogen atom, an alkyl group, an alkenyl group, or an alkynyl group;
the alkyl group, the alkenyl group, and the alkynyl group may have one to three
substituents selected from the group consisting of -ORa, -NRaRb, -NRaCORb, a
heterocyclic group, and a heteroaryl group; the heterocyclic group and the heteroaryl
group may have one to three substituents selected from the group consisting of a C 1.5
alkyl group, -ORa, and -NRaRb;
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a
Ci-5 alkyl group; and the alkyl group may be substituted by a hydroxyl group, a CM
alkoxy group, or an amino group;
in the formulae (6) and (7), the group represented by the following formula (a):
represents a 3- to 10-membered heterocyclic group that may have one to three
substituents selected from the group consisting of a Ci-s alkyl group, a halogen atom,
-ORa, -NRaRb, and an oxo group;
the above substituents except the oxo group and the halogen atom may be linked to each
other to form a cycloalkyl group or a heterocyclic group; the cycloalkyl group or the
heterocyclic group may have a substituent selected from the group consisting of -ORa,
-NRaRb, and a Ci-s alkyl group that may be substituted with -ORa;
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a
Ci-s alkyl group; and the alkyl group may be substituted by a hydroxyl group, a Ci-s
alkoxy group, or an amino group;
U represents -O-, -CONRd-, -S-, -SO-, -SO2-, -NRd-, -NRdCO-, -NRdSO2-, -SO2NRd-,
a divalent heterocyclic group, or a divalent heteroaryl group; Rd represents a hydrogen
atom or a Ci-s alkyl group; the alkyl group may be substituted by a hydroxyl group, a
Ci-5 alkoxy group, or an amino group; and
RI, R2, RS, and U may have protecting group(s) required for the synthesis
to thereby obtain the compounds (M), (N), (M'), and (N') represented by the formulae (14), (15),
(14'), and (15'), respectively:
RI, R2, RS, Rt, and U are defined herein above in formulae (6) and (7);
Z corresponds to the alkylene chain constituting the ring in the above formula (a); Z represents a
Ci-g alkylene chain, which may be substituted by one to three groups represented by W; W
represents any one of substituents selected from the group consisting of a Ci-s alkyl group, a
30
halogen atom, -ORa, -NRaRb, and an oxo group; the above substituents except the oxo group
and the halogen atom may be linked to each other to form a cycloalkyl group or a heterocyclic
group;
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a Q.s alkyl
group; the alkyl group may be substituted by a hydroxyl group, a Ci-s alkoxy group, or an amino
group;
[41] a method for producing compound (I) or compound (J), wherein the method
comprises reacting a reducing agent, in a solvent at neutral pH or in the presence of an acid, with
a synthetic intermediate (G) of the compound represented by the formula (1) according to [1],
wherein (G) is represented by the following formula (8):
wherein
RI represents a halogen atom, an alkenyl group, or an alkynyl group;
R2 represents a halogen atom or an alkyl group; the alkyl group may be substituted by a
hydroxyl group;
RS represents a hydrogen atom or a halogen atom;
Z represents a Ci_g alkylene chain that may have one to three groups represented by W ;
W or W, which may be the same or different, each represent a hydrogen atom, a Ci-s
alkyl group, a halogen atom, an oxo group, -ORa, -COORa, -COOCORa, -CO-[halogen
atom], -OCORa, -CONRaRb, -SRa, -SORa, -SO2Ra, -NRaRb, -NRaCORb, -NRaSO2Rb,
-SOaNRaRb, a heterocyclic group, or a heteroaryl group;
the heterocyclic group and the heteroaryl group may have a substituent selected from
the group consisting of a €1.5 alkyl group, -ORa, and -NRaRb; the alkyl group may be
substituted by a hydroxyl group, a Ci-s alkoxy group, or an amino group;
the above substituents except the oxo group and the halogen may be linked to each other
to form a cycloalkyl group or a heterocyclic group; the cycloalkyl group or the
heterocyclic group may have a substituent selected from the group consisting of -
-NRaRb, and a €4.5 alkyl group that may be substituted with -ORa;
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a
Ci-s alkyl group; the alkyl group may be substituted by a hydroxyl group, a Ci.5 alkoxy
group, or an amino group; and
Ri, R2, RS, Z, W, and W may have protecting group(s) required for the synthesis,
or a synthetic intermediate (H) of the compound represented by the formula (1) according to [1],
wherein (H) is represented by the following formula (9):
wherein
RI represents a halogen atom, an alkenyl group, or an alkynyl group;
R2 represents a halogen atom or an alkyl group; the alkyl group may be substituted by a
hydroxyl group;
RS represents a hydrogen atom or a halogen atom;
Rt represents a hydrogen atom, an alkyl group, an alkenyl group, or an alkynyl group;
the alkyl group, the alkenyl group, and the alkynyl group may have one to three
substituents selected from the group consisting of -ORa, -NRaRb, -NRaCORb, a
heterocyclic group, and a heteroaryl group; the heterocyclic group and the heteroaryl
group may have one to three substituents selected from the group consisting of a C\.$
alkyl group, -ORa, and -NRaRb;
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a
Ci-s alkyl group; and the alkyl group may be substituted by a hydroxyl group, a Ci-s
alkoxy group, or an amino group;
Z represents a Ci.g alkylene chain that may be substituted by one to three groups
represented by W;
W or W, which may be the same or different, each represent a hydrogen atom, a Ci.j
alkyl group, a halogen atom, an oxo group, -ORa, -COORa, -COOCORa, -CO-[halogen
atom], -OCORa, -CONRaRb, -SRa, -SORa, -SO2Ra, -NRaRb, -NRaCORb, -NRaSO2Rb,
-SO2NRaRb, a heterocyclic group, or a heteroaryl group;
the heterocyclic group and the heteroaryl group may have a substituent selected from
32
the group consisting of a Ci-s alkyl group, -ORa, and -NRaRb; the alkyl group may be
substituted by a hydroxyl group, a CM alkoxy group, or an amino group;
the above substituents except the oxo group and the halogen atom may be linked to each
other to form a cycloalkyl group or a heterocyclic group; the cycloalkyl group or the
heterocyclic group may have a substituent selected from the group consisting of -ORa,
-NRaRb, and a Ci.5 alkyl group that may be substituted with -ORa;
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a
Ci-s alkyl group; and the alkyl group may be substituted by a hydroxyl group, a €1.5
alkoxy group, or an amino group;
RI, RZ, RS, Z, W, and W may have protecting group(s) required for the synthesis,
to thereby obtain compound (I) represented by the following formula (10):
or compound (J) represented by the following formula (11):
(11)
in the formulae (10) and (11), RI, RI, RS, RA, Z, W, and W are defined herein above in formulae
(8) and (9);
[42] a method for producing compound (O) or compound (P), wherein the method
comprises allowing a synthetic intermediate (K) or (L) represented by the following formula (13)
to intramolecularly cyclize at neutral pH or in the presence of an acid or a base in a solvent that
optionally contains a peptide condensing agent,
wherein the synthetic intermediates (K) and (L) are represented by the following
n the above formulae (12) and (13),
RI represents a halogen atom, an alkenyl group, or an alkynyl group;
R2 represents a halogen atom or an alkyl group; the alkyl group may be substituted by a
hydroxyl group;
RS represents a hydrogen atom or a halogen atom;
Rt represents a hydrogen atom, an alkyl group, an alkenyl group, or an alkynyl group;
the alkyl group, the alkenyl group, and the alkynyl group may have one to three
substituents selected from the group consisting of -ORa, -NRaRb, -NRaCORb, a
heterocyclic group, and a heteroaryl group; the heterocyclic group and the heteroaryl
group may have one to three substituents selected from the group consisting of a Ci-j
alkyl group, -ORa, and -NRaRb;
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a
Ci-s alkyl group; and the alkyl group may be substituted by a hydroxyl group, a Ci-s
alkoxy group, or an amino group;
Z' represents a Ci-salkylene chain that may be substituted by one to three groups
represented by W;
W represents any one of the groups of-OH, -OMe, -OEt, -OCH2OH, -O(CH2)2OH,
-O(i-Pr), -O(n-Pr), -CONH2, -CONHMe, -CONHEt, -CONH(n-Pr), -CONH(i-Pr),
-CONMe2, -CON(Et)Me, -SO2Me, -SOMe, -SMe, -NH2, -NHMe, -NHCH2OH,
-NH(CH2)2OH, -N(Me)CH2CH2OH, -NHEt, -NMe2, -N(Et)Me, -NHCOMe,
34
-NMeCOMe, -NHCOEt, -NHCO(n-Pr), and -NHCO(i-Pr);
Q represents -ORc, -OCORc, -NRcRd, or a halogen atom; Re and Rd, which may be the
same or different, each represent a hydrogen atom or a €1.5 alkyl group;
RI, Rz, RS, R4, Z', W, and Q may have protecting group(s) required for the synthesis,
to thereby obtain compound (O) represented by the following formula (16):
R2
or compound (P) represented by the following formula (17):
in the formula (16) and (17), RI, Rz, RS, R*, and Z' are defined herein above in formulae (12) and
(13);
[43] a method for producing compound (S) or compound (T), wherein the method
comprises reacting, in the presence of a base or an acid, or at neutral pH, in a solvent that
optionally contains a condensing agent,
the synthetic intermediate (I) of the compound represented by the formula (1) according to [1],
the intermediate being represented by the following formula (10):
or the synthetic intermediate .(J) of the compound represented by the formula (1) according to [1],
the intermediate being represented by the following formula (11):
in the formulae (10) and (11),
RI represents a halogen atom, an alkenyl group, or an alkynyl group;
R2 represents a halogen atom or an alkyl group; the alkyl group may be substituted by a
hydroxyl group;
Ra represents a hydrogen atom or a halogen atom;
Rt represents a hydrogen atom, an alkyl group, an alkenyl group, or an alkynyl group;
the alkyl group, the alkenyl group, and the alkynyl group may have one to three
substituents selected from the group consisting of -ORa, -NRaRb, -NRaCORb, a
heterocyclic group, and a heteroaryl group; the heterocyclic group and the heteroaryl
group may have one to three substituents selected from the group consisting of a Ci-s
alkyl group, -ORa, and -NRaRb; Ra and Rb, which may be the same or different, each
represent a hydrogen atom or a C\.s alkyl group; the alkyl group may be substituted by a
hydroxyl group, a CM alkoxy group, or an amino group;
Z represents a Ci-g alkylene chain that may be substituted by one to three groups
represented by W;
W or W, which may be the same or different, each represent a hydrogen atom, a Ci-s
alkyl group, a halogen atom, an oxo group, -ORa, -COORa, -COOCORa, -CO-[halogen
atom], -OCORa, -CONRaRb, -SRa, -SORa, -SO2Ra, -NRaRb, -NRaCORb, -NRaSO2Rb,
-SO2NRaRb, a heterocyclic group, or a heteroaryl group;
the heterocyclic group and the heteroaryl group may have a substituent selected from
the group consisting of a C 1.5 alkyl group, -ORa, and -NRaRb; the alkyl group may be
substituted by a hydroxyl group, a Ci-s alkoxy group, or an amino group;
the above substituents except the oxo group and the halogen may be linked to each other
to form a cycloalkyl group or a heterocyclic group; the cycloalkyl group or the
heterocyclic group may have a substituent selected from the group consisting of -ORa,
-NRaRb, and a Ci_s alkyl group that may be substituted with -ORa;
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a
Ci-s alkyl group; the alkyl group may be substituted by a hydroxyl group, a Q.s alkoxy
group, or an amino group;
RI, R.2, R.3, R4, Z, W, and W may have protecting group(s) required for the synthesis
with a carboxylic acid derivative represented by the following formula:
wherein
Rg represents a hydrogen atom, an alkyl group, or -ORa; the alkyl group may be
substituted by a halogen atom, -ORa, or -NRaRb;
Q represents -ORc, -OCORc, -NRcRd, or a halogen atom; Re and Rd, which may be the
same or different, each represent a hydrogen atom or a Ci-s alkyl group;
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a
Ci-s alkyl group; and the alkyl group may be substituted by a hydroxyl group, a Ci-s
alkoxy group, or an amino group;
Rg and Q may have protecting group(s) required for the synthesis,
to thereby obtain compound (S) represented by the following formula (18):
or compound (T) represented by the following formula (19):
)
hi the formulae (18) and (19), RI, R2, RS, R4, Z, and W are defined herein above hi formulae (10)
and (11); and Rg is the carboxylic acid derivative defined herein above;
[44] a pharmaceutical composition comprising as an active ingredient the compound
according to any one of [1] to [28] or a pharmaceutically acceptable salt thereof;
[45] an MEK inhibitor comprising as an active ingredient the compound according to
any one of [1] to [28] or a pharmaceutically acceptable salt thereof;
[46] a preventive or therapeutic agent for a proliferative disease, which comprises as
an active ingredient the compound according to any one of [1] to [28] or a pharmaceutically
acceptable salt thereof;
[47] the preventive or therapeutic agent for a proliferative disease according to [46],
wherein the proliferative disease is a cancer;
[48] the preventive or therapeutic agent for a proliferative disease according to [47],
wherein the cancer is a cancer depending on the Ras-MAPK signaling pathway;
[49] the preventive or therapeutic agent for a proliferative disease according to [47] or
[48], wherein the cancer is breast, lung, colorectal, prostate, liver, ovarian, uterine, or pancreatic
cancer;
[50] a method for preventing or treating a proliferative disease, wherein the
methodcomprises administering a pharmaceutically effective dose of a composition that
comprises as an active ingredient the compound according to any one of [1] to [28] or a
pharmaceutically acceptable salt thereof to a patient who needs prevention or treatment for the
proliferative disease;
38
[51] the method according to [50], wherein the proliferative disease is a cancer;
[52] the method according to [50], wherein the cancer is a cancer depending on the
Ras-MAPK signaling pathway;
[53] the method according to [51] or [52], wherein the cancer is breast, lung,
colorectal, prostate, liver, ovarian, uterine, or pancreatic cancer;
[54] the method according to any one of [50] to [53], wherein the method further
comprises radiotherapy, another chemotherapy, or administration of an angiogenesis inhibitor;
[55] use of the compound according to any one of [1] to [28] or a pharmaceutically
acceptable salt thereof hi the production of a preventive or therapeutic agent for a disease to
which MEK inhibition is effective;
[56] a preventive or therapeutic agent for a joint disorder with inflammation, wherein
the agent comprises as an active ingredient the compound according to any one of [1] to [28] or a
pharmaceutically acceptable salt thereof;
[57] the preventive or therapeutic agent for a joint disorder with inflammation
according to [56], wherein the joint disorder with inflammation is osteoarthritis or rheumatoid
arthritis;
[58] a method for preventing or treating osteoarthritis or rheumatoid arthritis, wherein
the method comprises administering a pharmaceutically effective dose of a composition that
comprises as an active ingredient the compound according to any one of [1] to [28] or a
pharmaceutically acceptable salt thereof to a patient who needs prevention or treatment for
osteoarthritis or rheumatoid arthritis.
The present inventors synthesized the above-described
N-alkoxy-2-phenylaminobenzamide derivatives for the first time. The inventors found that the
compounds have an unexpectedly strong MEK inhibitory effect regardless of the substituent in
position 5. In addition, the inventors found that the compounds of the present invention have a
superior effect with respect to tumor growth suppression activity, as well as a superior effect
towards inflammation-related joint disorders.
Interestingly, the compounds of the present invention were found to have superior
effects in addition to the MEK inhibitory activity. Specifically, the compounds of the present
invention were found to be highly stable in hepatic micro somes, as compared with other
N-alkoxy-2-phenylamino-benzamide derivatives. Furthermore, the compounds were found to
be more soluble in water in comparison with conventional compounds.
The Cmax and AUC values, and the half-life for the above-described compounds of the
present invention are expected to be higher than those of conventional compounds.
Furthermore, the compounds of the present invention are expected to have good in vivo
absorption, and low interpatient variability in the PK parameters. The active forms can exist at
high concentrations in blood for a long period of time. Thus compared with the conventional
compounds, sufficient levels of the active forms of the compounds of the present invention are
exposed to the target molecule (i.e., MEK) as. The increased efficacy and the less frequent
administration as resulted are expected to reduce the burden of patient.
Herein, the "alkyl group" refers to a monovalent group derived from an aliphatic
hydrocarbon by removal of an arbitrary hydrogen atom, and comprises the subgroup structure of
a hydrocarbyl group or a hydrocarbon containing hydrogen and carbon atoms, but has no hetero
atoms or unsaturated carbon-carbon bonds in the backbone. The alkyl group includes groups
comprising a linear or branched structure. The alkyl group is preferably an alkyl group
comprising one to eight carbon atoms (hereinafter "Ci-g" indicates that the number of carbon
atoms in the range of one to eight), and more preferably a C\.s alkyl group.
Specifically, the alkyl group includes a methyl group, an ethyl group, an isopropyl
group, a butyl group, an n-butyl group, a sec-butyl group, an isobutyl group, a t-butyl group, a
pentyl group, an isopentyl group, a 2,3-dimethylpropyl group, a hexyl group, a
2,3-dimethylhexyl group, a 1,1-dimethylpentyl group, a heptyl group, and an octyl group.
Herein, the "alkenyl group" refers to a monovalent group having at least one double
bond (two adjacent S?2 carbon atoms). Depending on the configurations of the double bond
and the substituent (if exists), the geometry around the double bond can be of the entgegen (E) or
zusammen (Z) (trans or cis) configuration. The alkenyl group may be linear or branched, and
preferably includes Ci-g alkenyl groups, more preferably €2.5 alkenyl groups.
Specifically, such alkenyl groups include, for example, a vinyl group, an ally group, a
1-propenyl group, a 2-propenyl group, a 1-butenyl group, a 2-butenyl group (including cis and
trans forms), a 3-butenyl group, a pentenyl group, and a hexenyl group.
Herein, the "alkynyl group" refers to a monovalent group having at least one triple bond
(two adjacent SP carbon atoms). The alkynyl group may be linear or branched, and preferably
includes €2-8 alkynyl groups, more preferably Ci-s alkynyl groups.
Specifically, the alkynyl group includes, for example, an ethynyl group, a 1-propynyl
group, a propargyl group, a 3-butynyl group, a pentynyl group, a hexynyl group, a
3-phenyl-2-propynyl group, a 3-(2'-fluorophenyl)-2-propynyl group, a 2-hydroxy-2-propynyl
group, a 3-(3-fluorophenyl)-2-propynyl group, and a 3-methyl-(5-phenyl)-4-pentynyl group.
The alkenyl group and the alkynyl group may each have one or more double bonds or
triple bonds. They may also have double bonds and triple bonds at the same time.
Herein, the "cycloalkyl group" refers to a cyclic aliphatic hydrocarbon group
comprising a ring. The cycloalkyl group preferably includes Cs-g cycloalkyl groups.
Specifically, the cycloalkyl group includes, for example, a cyclopropyl group, a cyclobutyl group,
a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.
Herein, the "alkylene chain" or "alkylene group" refer to a divalent group represented
by -(CH2)n-. The alkylene chain preferably includes Ci-g alkylene chains (n = 1-8), more
preferably C\.s alkylene chains (n = 1-5), preferably Ci-s alkylene chains (n = 1-3), in particular.
Herein, the "aryl group" refers to a monovalent aromatic hydrocarbon ring. The aryl
group preferably includes Ce-io aryl groups. Specifically, the aryl group includes, for example,
a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.
Herein, the "hetero atom" refers to a sulfur atom, an oxygen atom, or a nitrogen atom.
Herein, the "heteroaryl group" refers to an aromatic ring group containing one or more
of the hetero atoms that constitute the ring. The heteroaryl group may be partially saturated.
The heteroaryl group may be a heteroaryl group in which the ring may be a monocyclic or
bicyclic group obtained through condensation with a benzene ring or a monocyclic heteroaryl
ring. The number of atoms constituting the ring preferably ranges from 5 to 10 (Cs-io heteroaryl
groups).
Specifically, the heteroaryl group includes, for example, a furyl group, a thienyl group, a
pyrrolyl group, an imidazolyl group, a pyrazolyl group, a thiazolyl group, an isothiazolyl group,
an oxazolyl group, an isooxazolyl group, an oxadiazolyl group, a thiadiazolyl group, a triazolyl
group, a tetrazolyl group, a pyridyl group, a pyrimidyl group, a pyridazinyl group, a pyrazinyl
group, a triazinyl group, a benzofuranyl group, a benzothienyl group, a benzothiadiazolyl group,a benzothiazolyl group, a benzooxazolyl group, a benzooxadiazolyl group, a benzoimidazolyl
group, an indolyl group, an isoindolyl group, an indazolyl group, a quinolyl group, an
isoquinolyl group, a cinnolinyl group, a quinazolinyl group, a quinoxalinyl group, a
benzodioxolyl group, an indolidinyl group, and an imidazopyridyl group.
Herein, the "heterocyclic group" refers to a non-aromatic monovalent ring, in which the
number of atoms constituting the ring preferably ranges from 3 to 8 (Ca-g heterocyclic group),
and wherein the ring contains one to three hetero atoms and may have double bonds.
Specifically, the heterocyclic group includes, for example, a morpholino group, a
thiomorpholino group, a piperidin-1-yl group, a 4-substituted piperidin-1-yl group, a
41
piperazin-1-yl group, a 4-substituted piperazin-1-yl group, a pyrrolidin-1-yl group, a pyrrolinyl
group, an imidazolidinyl group, an imidazolinyl group, a pyrazolidinyl group, a pyrazolinyl
group, a [l,3]dioxolan-2-yl group, and a [1,3]dioxan-2-yl group. Among these, groups that can
be used preferably are: a morpholino group, a thiomorpholino group, a piperidin-1-yl group, a
4-substituted piperidin-1-yl group, a piperazin-1-yl group, a 4-substituted piperazin-1-yl group, a
[l,3]dioxolan-2-yl group, and a [l,3]dioxan-2-yl group.
Herein, the "halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom,
or an iodine atom.
Herein, the "alkoxy group" refers to an oxy group to which the above-defined "alkyl
group" has been linked. The alkoxy group preferably includes Ci.g alkoxy groups, and more
preferably C\-s alkoxy groups. Specifically, the alkoxy group includes, for example, a methoxy
group, an ethoxy group, a 1-propoxy group, a 2-propoxy group, an n-butoxy group, an i-butoxy
group, a sec-butoxy group, at-butoxy group, a 1-pentyloxy group, a 2-pentyloxy group, a
3-pentyloxy group, a 2-methyl-l-butyloxy group, a 3-methy-l-butyloxy group, a
2-methyl-2-butyloxy group, a 3-methy-2-butyloxy group, a 2,2-dimethyl-l-propyloxy group, a
1-hexyloxy group, a 2-hexyloxy group, a 3-hexyloxy group, a 2-methyl-1-pentyloxy group, a
3-methyl-1-pentyloxy group, a 4-methyl-1-pentyloxy group, a 2-methyl-2-pentyloxy group, a
3-methyl-2-pentyloxy group, a 4-methyl-2-pentyloxy group, a 2-methyl-3-pentyloxy group, a
3-methyl-3-pentyloxy group, a 2,3-dimethyl-1-butyloxy group, a 3,3-dimethyl-1-butyloxy group,
a 2,2-dimethyl-1-butyloxy group, a 2-ethyl-1-butyloxy group, a 3,3-dimethyl-2-butyloxy group,
a 2,3-dimethyl-2-butyloxy group, and a 1-methyl cyclopropyl methoxy group.
Herein, the "amino group" refers to a monovalent group that has a nitrogen atom with
two hydrogen atoms (represented by -NH2).
Herein, the "cycloalkylalkyl group" refers to a group derived from the above-defined
"alkyl group" by substitution of the above-defined "cycloalkyl group" at an arbitrary position of
the alkyl group. The cycloalkylalkyl group preferably includes Cs_g cycloalkyl CM alkyl
groups. Specifically, the cycloalkylalkyl group includes, for example, a cyclopropylmethyl
group, a cyclopropylethyl group, a cyclopentylmethyl group, a cyclopentylethyl group, a
cyclohexylmethyl group, and a cyclohexylethyl group.
Herein, the "cycloalkylalkenyl group" refers to a group derived from the above-defined
"alkenyl group" by substitution of the above-defined "cycloalkyl group" at an arbitrary position
of the alkenyl group. The cycloalkylalkenyl group preferably includes €3.3 cycloalkyl
alkenyl groups.
Herein, the "cycloalkylalkynyl group" refers to a group derived from the above-defined
"alkynyl group" by substitution of the above-defined "cycloalkyl group" at an arbitrary position
of the alkynyl group. The cycloalkylalkynyl group preferably includes Cs-g cycloalkyl €2-4
alkynyl groups.
Herein, the "arylalkyl group" refers to a group derived from the above-defined "alkyl
group" by substitution of the above-defined "aryl group" at an arbitrary position of the aryl
group. The arylalkyl group preferably includes Ce-io aryl CM alkyl groups.
Specifically, the arylalkyl group includes, for example, a benzyl group, a phenethyl
group, and a 3-phenyl-l-propyl group.
Herein, the "arylalkenyl group" refers to a group derived from the above-defined
"alkenyl group" by substitution of the above-defined "aryl group" at an arbitrary position of the
alkenyl group. The arylalkenyl group preferably includes Ce-io aryl CIA alkenyl groups.
Herein, the "arylalkynyl group" refers to a group derived from the above-defined
"alkynyl group" by substitution of the above-defined "aryl group" at an arbitrary position of the
alkynyl group. The arylalkynyl group preferably includes Ce-io aryl €2-4 alkynyl groups.
Herein, the "heteroarylalkyl group" refers to a group derived from the above-defined
"alkyl group" by substitution of the above-defined "heteroaryl group" at an arbitrary position of
the alkyl group. The heteroarylalkyl group preferably includes CS-IQ heteroaryl d-4 alkyl
groups.
Specifically, the heteroarylalkyl group includes, for example, a pyridyl-4-ylmethyl
group, an oxazolyl-2-ylmethyl group, a 2-(pyridyl-4-yl)ethyl group, and a 2-(oxazolyl-2-yl)ethyl
group.
Herein, the "heteroarylalkenyl group" refers to a group derived from the above-defined
"alkenyl group" by substitution of the above-defined "heteroaryl group" at an arbitrary position
of the alkenyl group. The heteroarylalkenyl group preferably includes Cs-io heteroaryl Ci-4
alkenyl groups.
Herein, the "heteroarylalkynyl group" refers to a group derived from the above-defined
"alkynyl group" by substitution of the above-defined "heteroaryl group" at an arbitrary position
of the alkynyl group. The heteroarylalkynyl group preferably includes Cs-io heteroaryl €2-4
alkynyl groups.
Herein, the "heterocyclic alkyl group" refers to a group derived from the above-defined
"alkyl group" by substitution of the above-defined "heterocyclic group" at an arbitrary position
of the alkyl group. The heterocyclic alkyl group preferably includes Cs.g heterocyclic C1-C4
alkyl groups. Specifically, the heterocyclic alkyl group includes, for example, a
morpholin-4-yl-methyl group, a 2-(morpholin-4-yl)ethyl group, a
4-hydroxy-piperidin-l-yl-methyl group, a2-(4-hydroxy-piperidin-l-yl)ethyl group, a
4-methyl-piperazin-l-yl-methyl group, and a 2-(4-methyl-piperazin-l-yl)ethyl group.
Herein, the "heterocyclic alkenyl group" refers to a group derived from the
above-defined "alkenyl group" by substitution of the above-defined "heterocyclic group" at an
43
arbitrary position of the alkenyl group. The heterocyclic alkenyl group preferably includes Cs-g
heterocyclic Cz-4 alkenyl groups.
Herein, the "heterocyclic alkynyl group" refers to a group derived from the
above-defined "alkynyl group" by substitution of the above-defined "heterocyclic group" at an
arbitrary position of the alkynyl group. The heterocyclic alkynyl group preferably includes €3.8
heterocyclic €2-4 alkynyl groups.
Herein, the "hydroxyalkyl group" refers to a group derived from the above-defined
"alkyl group" by substitution of a hydroxyl group at an arbitrary position of the alkyl group.
The hydroxyalkyl group preferably includes hydroxy CM alkyl groups.
Herein, the "dihydroxyalkyl group" refers to a group derived from the above-defined
"alkyl group" by substitution of hydroxyl groups at two arbitrary positions of the alkyl group.
The dihydroxyalkyl group preferably includes dihydoroxy CM alkyl groups.
Herein, the "alkyloxyalkyl group" refers to a group derived from the above-defined
"hydroxyalkyl group" by substitution of a hydroxyl group in the above-defined "alkyl group".
The alkyloxyalkyl group preferably includes Ci-g alkyloxy CM alkyl groups.
Herein, the "hydroxyalkyloxyalkyl group" refers to a group derived from the
above-defined "alkyloxyalkyl group" by substitution of a hydroxyl group at an arbitrary position
in the terminal alkyl group. The hydroxyalkyloxyalkyl group preferably includes hydroxy Ci-g
alkyloxy CM alkyl groups.
Herein, the "aminoalkyl group" refers to a group derived from the above-defined "alkyl
group" by substitution of an amino group (HjN-) at an arbitrary position of the alkyl group.
The aminoalkyl group preferably includes amino CM alkyl groups.
Herein, the "alkylaminoalkyl group" refers to a group derived from the above-defined
"aminoalkyl group" by substitution of the above-defined "alkyl group" at one or two arbitrary
positions in the amino group. The alkylaminoalkyl group preferably includes Ci.g alkylamino
CM alkyl groups. When two hydrogen atoms are replaced with alkyl groups, the alkyl groups
may be the same or different.
Herein, the "hydroxyalkylaminoalkyl group" refers to a group derived from the
above-defined "alkylaminoalkyl group" by substitution of a hydroxyl group at an arbitrary
position in the terminal alkyl group. The hydroxyalkylaminoalkyl group preferably includes
hydroxy Ci.g alkylamino CM alkyl groups.
Herein, the "iminoalkyl group" refers to a group derived from the above-defined "alkyl
group" obtained by substitution of an imino group (=NH) at an arbitrary position of the alkyl
group. The iminoalkyl group preferably includes imino CM alkyl groups.
Herein, the "hydroxyiminoalkyl group" refers to a group derived from the
above-defined "iminoalkyl group" by substituting the hydrogen atom in the imino group with a
44
hydroxyl group. The hydroxyiminoalkyl group preferably includes hydroxyimino CM alkyl
groups.
Herein, the "alkoxyiminoalkyl group" refers to a group derived from the above-defined
"hydroxyiminoalkyl group" by substituting a hydrogen atom of the hydroxyl group with the
above-defined "alkyl group". The alkoxyiminoalkyl group preferably includes Ci-g
alkyloxyimino CM alkyl groups.
The compounds of the present invention include the free forms and the
pharmaceutically acceptable salts of the compounds. Such "salts" are not limited to any
particular salts, as long as they are pharmaceutically acceptable salts derived from the compound
represented by formula (1) of the present invention (herein sometimes also referred to as
"compound I"). The salts include, for example, acid salts formed by reacting compound I of
the present invention with an acid, and base salts formed by reacting compound I of the present
invention with a base.
Preferred acids for use in preparing the pharmaceutically acceptable acid salts of
compound I of the present invention are acids that form non-toxic acid salts of compound I of the
present invention. The acid salts include, for example, hydrochloride, hydrobromate,
hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid
citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate,
methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and
l,l'-methylene-bis-(2-hydroxy-3-naphtoic acid) salt.
Preferred bases for use in preparing pharmaceutically acceptable base salts of compound
I of the present invention are bases that form non-toxic base salts of compound I of the present
invention. The base salts include, for example, alkali metal salts such as sodium salt and
potassium salt, alkali earth metal salts such as calcium salt and magnesium salt, ammonium salts,
water-soluble amine addition salts such as the N-methyl glucamine salt, lower-alkanol
ammonium salts, and pharmaceutically acceptable salts derived from other organic amines bases.
Compound I of the present invention may contain absorbed water or forms hydrates
when it is allowed to stand in the atmosphere and to absorb moisture. Such salts are also
included in the salts of compound I of the present invention.
Furthermore, compound I of the present invention may absorb solvents to form solvates.
Such salts are also included in the salts of compound I of the present invention.
Herein, "MEK" (MAPK/ERK/Kinase; MAPK is the abbreviation for mitogen-activated
protein kinase, and ERK is the abbreviation for extracellular signal-regulated kinase) refers to
the dual-specificity kinase that is associated with the MAP kinase and the ERK kinase. "MEK
inhibition" refers to the MEK-mediated competition, inhibition, or cancellation of a cascade or of
the activities of proteins produced in the cascade. Accordingly, the inhibition includes the
45
competition, inhibition, or cancellation of the activities of the MAP/ERK kinase or of the
activities of the genes encoding the MAP/ERK kinase. Herein, the "Ras-MAPK signaling
pathway" is defined as the sequential pathway of Ras -> Raf -> MEK -> ERK, and is one of the
pathways that transmit growth signals from various growth factor receptors on the cell
membrane to the nucleus through the cytoplasm. The phrase "cancer depending on the
Ras-MAPK signaling pathway" refers to a cancer that proliferates mainly depending on the
Ras-MAPK signaling pathway. In other words, the phrase means a cancer whose growth or
survival is reduced by blocking or inhibiting the Ras-MAPK signaling pathway.
Herein, the "proliferative disease" refers to a disorder caused by deficiencies in the
cellular signal transduction system or the signal transduction mechanism of a certain protein.
The proliferative disease includes, for example, cancers, psoriasis, restenosis, autoimmune
diseases, and atherosclerosis.
Herein, the "inflammation-related joint disorders" specifically refers to diseases such as
osteoarthritis, rheumatoid arthritis, reactive arthritis, viral arthritis, purulent arthritis, and
tuberculous arthritis. The inflammation-related joint disorders also include arthralgia caused by
these diseases (for example, knee joint pain caused by rheumatoid arthritis). Herein, the
"preventive or therapeutic agent for an inflammation-related joint disorder" includes not only
therapeutic agents for the above-described joint diseases, but also preventive agents for the
diseases, agents for use in suppressing the advancement of the diseases (to prevent aggravation
or to maintain current conditions), and such.
In the present invention, there is no limitation on the type of "protecting group", as long
as it is a group commonly used to protect an ethynyl group, a hydroxyl group, or an amino
group.
An ethynyl protecting group includes, for example, silyl groups such as a trimethylsilyl
group, a triethylsilyl group, an isopropyldimethylsilyl group, a t-butyldimethylsilyl group, a
methyldiisopropylsilyl group, a methyl-t-butylsilyl group, a triisopropylsilyl group, a
diphenylmethylsilyl group, a diphenylbutylsilyl group, a diphenylisopropylsilyl group, and a
phenyldiisopropylsilyl group. Among them, a trimethylsilyl group or such is preferred.
A hydroxyl protecting group includes, for example, alkylsilyl groups such as a
trimethylsilyl group, a triethylsilyl group, an isopropyldimethylsilyl group, a t-butyldimethylsilyl
group, a methyldiisopropylsilyl group, a methyldi-t-butylsilyl group, a triisopropylsilyl group, a
diphenylmethylsilyl group, a diphenylbutylsilyl group, a diphenylisopropylsilyl group, and a
phenyldiisopropylsilyl group; Ci-e alkylcarbonyl groups such as an acetyl group and a propionyl
group; phenylcarbonyl group; Ci-e alkyloxycarbonyl groups such as a methoxycarbonyl group,
an ethoxycarbonyl group, and a t-butoxycarbonyl group; a vinyl group; a tetrahydrofuranyl
group; alkoxymethyl groups such as a methoxymethyl group and an ethoxymethyl group;
46
alkoxylated alkoxymethyl groups such as a 2-methoxyethoxymethyl group; alkoxyethyl groups
such as a 1-ethoxyethyl group; a benzyloxymethyl group; substituted benzyl groups such as a
benzyl group, a 4-methylbenzyl group, a 4-methoxybenzyl group, and an o-nitrobenzyl group;
and formyl groups. Among these, an alkylsilyl group is preferred, and a t-butyldimethylsilyl
group or such is more preferred.
Protecting groups that are used to protect an amino group include, for example, a
methoxycarbonyl group; substituted C1-C6 alkyl-oxycarbonyl groups such as a cyclopropyl
methoxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, a 2-iodoethoxycarbonyl group, a
2-trimethylsilylethoxycarbonyl group, a 2-methylthioethoxycarbonyl group, a
2-methylsulfonylethoxycarbonyl group, an isobutyloxy carbonyl group, a t-butoxycarbonyl
group (BOC group); C1-C6 alkenyl-oxycarbonyl groups such as a vinyloxycarbonyl group and
an allyloxycarbonyl group; a benzyloxycarbonyl group (CBZ group); substituted
benzyl-oxycarbonyl groups such as a p-methoxybenzyloxy carbonyl group, a
2,4-dichlorobenzyloxy carbonyl group, and a p-cyanobenzyloxy carbonyl group; formyl groups;
acetyl groups; substituted C1-C6 alkyl-carbonyl groups such as a dichloroacetyl group, a
trichloroacetyl group, and a trifluoroacetyl group; phthalimide groups (name provided as the
protected functional group); benzyl groups; and substituted benzyl groups such as a
3,4-dimethoxybenzyl group. Among these, an alkyl-oxycarbonyl group is preferred, and the
t-butoxycarbonyl (BOC) group and such are more preferred.
Compound I of the present invention represented by the above formula (1) preferably
includes compounds comprising the following:
(1) RI is preferably an iodine atom, a bromine atom, a vinyl group, or an ethynyl group,
and more preferably an iodine atom or an ethynyl group.
(2) R.2 is preferably a chlorine atom, a fluorine atom, a methyl group, or a
hydroxymethyl group, more preferably a fluorine atom or a chlorine atom, and particularly
preferably a fluorine atom.
(3) RS is preferably a hydrogen atom or a fluorine atom, and more preferably a fluorine
atom.
(4) RI is preferably an alkyl group that has one to three substituents selected from the
group consisting of -ORa, -NRaRb, -NRaCORb, a heterocyclic group, and a heteroaryl group.
Ra and Rb can each represent a hydrogen atom or an alkyl group. The alkyl group
may have preferably a hydroxyl group, an alkoxy group, or an amino group as a substituent.
The heterocyclic group and the heteroaryl group may have one to three substituents
selected from the group consisting of an alkyl group, -ORa, and -NRaRb. The alkyl group may
have a hydroxyl group, an alkoxy group, or an amino group as a substituent. The substituent is
preferably an alkyl group or -ORa, more preferably a methyl group, a hydroxyethyl group, or
47
-OH (hydroxyl group).
More preferably, R4 is an alkyl group that has one to three substituents selected from the
group consisting of -ORa, -NRaRb, and -NRaCORb.
Still more preferably, R4 is an alkyl group that has one to three -ORa, and particularly
preferably an alkyl group that has one to three -OH (hydroxyl group). The alkyl group is
preferably a C1-C8 alkyl group, more preferably a C1-C5 alkyl group, and particularly
preferably a C1-C3 alkyl group.
Preferably, Ra and Rb can each represent a hydrogen atom or a C1-C5 alkyl group, and
more preferably a hydrogen atom.
The Rt includes, for example, a hydroxyalkyl group, a dihydroxyalkyl group, a
hydroxyalkyloxyalkyl group, a hydroxyalkylaminoalkyl group, an acylaminoalkyl group, a
heteroarylalkyl group, a heterocyclic alkyl group, and a heterocyclic alkyl group containing
hydroxy groups.
More preferably, R4 represents a 2-hydroxyethyl group, a 3-hydroxypropyl group, a
2,3-dihydroxypropyl group, a2-hydroxy-l-(hydroxymethyl)ethyl group, a 2-hydroxypropyl
group, a 2-methyl-2-hydroxypropyl group, a l-methyl-2-hydroxyethyl group, a
2-(2-hydroxyethoxy)ethyl group, a 2-(2-hydroxyethylamino)ethyl group, a
2-(morpholin-4-yl)ethyl group, a 2-(4-methylpiperazin-l-yl)ethyl group, a
2-(4-hydroxypiperidin-l-yl)ethyl group, a pyridylmethyl group, an imidazol-2-ylmethyl group,
and a 2-acetylaminoethyl group.
Still more preferably, Rt represents a 2-hydroxyethyl group, a 3-hydroxypropyl group, a
2,3-dihydroxypropyl group, a 2-hydroxy-l-(hydroxymethyl)ethyl group, a 2-hydroxypropyl
group, a 2-methyl-2-hydroxypropyl group, a l-methyl-2-hydroxyethyl group, and a
2-(2-hydroxyethoxy)ethyl group. Among these, the 2-hydroxyethyl group, 3-hydroxypropyl
group, 2,3-dihydroxypropyl group, and 2-hydroxy-l-(hydroxymethyl)ethyl group shown below
are preferred.
Among these, the particularly preferred R* includes a 2-hydroxyethyl group and a
48
2,3-dihydroxypropyl group.
In the embodiments of the present invention, the above-defined RI, RI, RS, and R* can
be combined appropriately. For example, the specific combinations that are preferred are as
follows:
RI represents an iodine atom, a bromine atom, a vinyl group, or an ethynyl group;
Ra represents a chlorine atom, a fluorine atom, a methyl group, or a hydroxymethyl group;
RS represents a fluorine atom; and
Rt represents an alkyl group that is substituted by one to three hydroxyl groups; or alternatively
RI represents an iodine atom or an ethynyl group;
R2 represents a fluorine atom;
RS represents a fluorine atom; and
Rt represents a group selected from the following groups:
OH
(5) the above-defined X represents the group represented by formula (i) or formula (ii)
below:
In formula (i), Y represents -O-, -NRgO-, -ONRs-, -NRgCO-, or -NRgSO2- (unless
otherwise indicated, these substituents have Z bonded to their right-hand side);
Z represents a Ci-g alkylene chain which may be substituted by one to three groups represented
byW;
Rg represents a hydrogen atom, an alkyl group, -ORa, or -CORg; and the alkyl group may have a
halogen atom, -ORa, or -NRaRb as a substituent;
Rg represents a hydrogen atom, an alkyl group, or -ORa; and the alkyl group may have a halogen
atom, -ORa, or -NRaRb as a substituent;
49
Rg and Rg may be linked to the alkylene chain of Z, or form a heterocyclic group through a
linkage to the substituent represented by Ra or Rb in W.
In formula (ii), YI and Y2, which may be the same or different, each represent a single
bond, -CO-, -COO-, -O-, -OCO-, -NRa-, or -SO2-;
Z' represents a Ci-g alkylene chain which may be substituted by one to three groups represented
byW.
In formulae (i) and (ii) above, W and W, which may be the same or different, each
represent a Ci-s alkyl group, a halogen atom, an oxo group, -ORa, -COORa, -COOCORa,
-CO-[halogen atom], -OCORa, -CONRaRb, -SRa, -SORa, -SO2Ra, -NRaRb, -NRaCORb,
-NRaSOiRb, -SO2NRaRb, a heterocyclic group, or a heteroaryl group. The heterocyclic group
and the heteroaryl group may have a substituent selected from the group consisting of a Ci-s
alkyl group, -ORa, and -NRaRb; and the alkyl group may have a hydroxyl group, a Ci-s alkoxy
group, or an amino group as a substituent.
The above-mentioned substituents, except the oxo group and the halogen atom, may be
linked to each other to form a cycloalkyl group or a heterocyclic group. The cycloalkyl group
or heterocyclic group may have a substituent selected from the group consisting of a €1.5 alkyl
group which may be substituted with -ORa, -ORa, and -NRaRb.
When X is the group represented by the above formula (i) and Y is not -O-, W may be a
hydrogen atom.
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a
CM alkyl group; and the alkyl group may have one to three substituents selected from hydroxyl
groups, Ci-s alkoxy groups, and amino groups.
Herein, the above-defined Ra and Rb, which may be the same or different, preferably
each represent a group selected from the group consisting of: a hydrogen atom, a methyl group,
an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a t-butyl
group, a sec-butyl group, a 1,1-dimethylpropyl group, a 2,2-dimethylpropyl group, a
1,2-dimethylpropyl group, a pentyl group, a hydroxymethyl group, a 1 -hydroxyethyl group, a
1-hydroxy-l-methylethyl group, a 2-hydroxy-l-methylethyl group, a
2-hydroxy-l,l-dimethylethyl group, a 2-hydroxyethyl group, a 1-hydroxypropyl group, a
2-hydroxypropyl group, and a 3-hydroxypropyl group.
A preferred embodiment of the group represented by formula (i) above is as follows:
(i-1) In the above-defined X, the Rg in Y preferably represents a hydrogen atom, a
hydroxyl group, a Ci-s alkyl group, or -CORg, and more preferably, a hydrogen atom, a hydroxyl
group, a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, a
sec-butyl group, an i-butyl group, a t-butyl group, a 1,1-dimethylpropyl group, a
2,2-dimethylpropyl group, a 1,2-dimethylpropyl group, a pentyl group, or -
50
In this case, Rg preferably represents a hydrogen atom, a hydroxyl group, a Ci-s alkyl group, or a
Ci-5 alkoxy group, and more preferably, a hydrogen atom, a methyl group, an ethyl group, an
n-propyl group, an i-propyl group, an n-butyl group, a sec-butyl group, a t-butyl group, a
2,2-dimethylpropyl group, a 1,2-dimethylpropyl group, a pentyl group, a methoxy group, an
ethoxy group, an n-propoxy group, an i-propoxy group, an n-butoxy group, an i-butoxy group, a
sec-butoxy group, an i-butyl group, at-butoxy group, a 1,1-dimethylpropyl group, a
2,2-dimethylpropoxy group, a 1,2-dimethylpropoxy group, or a pentyloxy group.
The alkyl group and the alkoxy group represented by Rg and Rg may contain substitutions of one
to three hydroxyl groups at arbitrary positions of the hydrocarbon moiety.
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a Ci-s alkyl
group; and the alkyl group may have a hydroxyl group, a Ci_5 alkoxy group, or an amino group
as a substituent.
(i-2) More preferably, the Rg hi Y represents a hydrogen atom, a hydroxyl group, a
methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl
group, a t-butyl group, a sec-butyl group, a 1,1-dimethylpropyl group, a 2,2-dimethylpropyl
group, a 1,2-dimethylpropyl group, a pentyl group, a formyl group, an acetyl group, a
2-methoxyacetyl group, a 2-ethoxyacetyl group, a 2-hydroxyacetyl group, a propionyl group, a
2-methylpropionyl group, a 2-methoxypropionyl group, a 2-ethoxypropionyl group, a
2-hydroxypropionyl group, a 3-methoxypropionyl group, a 3-ethoxypropionyl group, a
3-hydroxypropionyl group, a methoxy group, an ethoxy group, an n-propyloxy group, an
i-propyloxy group, a hydroxymethyl group, or a 2-hydroxyethyl group.
(i-3) More preferably, the Y in the above-defined X represents -O-, -NHO-,
-N(COCH3)0-, -N(COCH2OH)0-, -N(COCH2CH3)O-, -N(COCH(OH)CH3)O-,
-N(COCH2CH2OH)O-, -N(COCH(OH)CH2OH)O-, -N(COCH2CH2CH3)O-,
-N(COCH2CH2CH2OH)O-, -N(COCH(OH)CH2CH3)O-, -N(COCH2CH(OH)CH3)Q-, -NHCO-,
or -NHSO2-.
(i-4) More preferably, the above-defined W and W, which may be the same or different,
each represent -OH, -OMe, -OEt, -OCH2OH, -O(CH2)2OH, -O(i-Pr), -O(n-Pr), -COOH,
-COOMe, -COOEt, -COOCOMe, -COC1, -CONH2, -CONHMe, -CONHEt, -CONH(n-Pr),
-CONH(i-Pr), -CONMe2, -CON(Et)Me, -SO2Me, -SOMe, -SMe, -NH2, -NHMe, -NHCH2OH,
-NH(CH2)2OH, -N(Me)CH2CH2OH, -NH Et, -NMe2, -N(Et)Me, -NHCOMe, -NMeCOMe,
-NHCOEt, -NHCO(n-Pr), or -NHCO(i-Pr); and when Y is not -O-, W may be a hydrogen atom.
(i-5) In formula (i) above, the alkylene chain of Z in the above X preferably represents
an alkylene chain having one to five carbon atoms.
The alkylene chain may have one to three substituents selected from the group consisting of: a
Ci-s alkyl group, a halogen atom, -ORa, -NRaRb, and an oxo group, and the above substituents
51
except the oxo group and the halogen atom may be linked to each other to form a cycloalkyl
group or a heterocyclic group. The cycloalkyl group and the heterocyclic group may have a
substituent selected from the group consisting of a Ci-s alkyl group, which may be substituted
with -ORa, -ORa, and -NRaRb.
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a d-s alkyl
group; and the alkyl group may have a hydroxyl group, a Ci-s alkoxy group, or an amino group
as a substituent.
(i-6) In the above-defined W or W, Ra and Rb may be the same or different, preferably
each representing a hydrogen atom or a Ci-s alkyl group; and the alkyl group may have a
hydroxyl group or a Ci-s alkoxy group.
(i-7) More preferably, in the X of formula (i) above, the alkylene chain of Z is any one
of the groups represented by the following formulae:
-CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -CH2CH(Me)-, -CH2C(Me)2-, -C(Me)2CH2-,
-(CH2)2CH(Me)-, -(CH2)2C(Me)2-, -CH(Me)(CH2)2-, -C(Me)2(CH2)2-, -CH2CH(Me)CH2-,
-CH2C(Me)2CH2-, -CH2C(CH2CH2)CH2- (where C(CH2CH2) represents a divalent cyclopropane
ring), -CO-, -CH2CO-, -COCH2-, -(CH2)2CO-, -CO(CH2)2-, -CHOH-, -CH2CH(OH)-,
-CH(OH)CH2-, -CH2CH(OH)CH2-, -CH(OH)CH2CH2-, and -CH2CH2CH(OH)-.
A preferred embodiment of the group represented by the above formula (ii) is as
follows:
(ii-1) The above-defined X is preferably any one of the groups represented by the
following formulae:
[wherein, Z' preferably represents a Ci-s alkylene chain which may be substituted by one to three
groups represented by W;
W represents a C\.s alkyl group, a halogen atom, an oxo group, -ORa, -CONRaRb, -SRa, -SORa,
-SO2Ra, -NRaRb, -NRaCORb, -NRaSO2Rb, -SO2NRaRb, a heterocyclic group, or a heteroaryl
group; the heterocyclic group and the heteroaryl group may have a substituent selected from the
group consisting of a CM alkyl group, -ORa, and -NRaRb; the alkyl group may have a hydroxyl
group, a Ci-s alkoxy group, or an amino group as a substituent;
52
the above substituents except the oxo group and the halogen atom may be linked to each other to
form a cycloalkyl group or a heterocyclic group; the cycloalkyl group or the heterocyclic group
may have a substituent selected from the group consisting of: a C\.s alkyl group which may be
substituted with -ORa, -ORa, and -NRaRb;
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a €1.5 alkyl
group; and the alkyl group may have a hydroxyl group, a Ci-s alkoxy group, or an amino group
as a substituent].
(ii-2) More preferably, the above-defined Z' represents a Ci-3 alkylene chain which may
be substituted by one to three groups represented by W.
W represents a Ci-3 alkyl group, an oxo group, -ORa, -CONRaRb, -SRa, -SORa, -SO2Ra,
-NRaRb, -NRaCORb, -NRaSO2Rb, -SO2NRaRb, a heterocyclic group, or a heteroaryl group; the
heterocyclic group and the heteroaryl group may have a substituent selected from the group
consisting of: a Ci-s alkyl group, -ORa, and -NRaRb; and the alkyl group may have a hydroxyl
group, a Ci-s alkoxy group, or an amino group as a substituent.
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a €1.5 alkyl
group; and the alkyl group may have a hydroxyl group, a Ci-s alkoxy group, or an ammo group
as a substituent.
(ii-3) Furthermore, W which may substitute for the arbitrary positions in the alkylene
chain of the above-defined Z' represents any one of the groups represented by the following
formulae:
-Me, -Et, -n-Pr, -i-Pr, -CH2OH, -CH2CH2OH, -CH(OH)CH3, -OH, -OMe, -OEt, -OCH2OH,
-0(CH2)2OH, -O(i-Pr), -O(n-Pr), -COOH, -COOMe, -COOEt, -CONH2, -CONHMe, -CONHEt,
-CONH(n-Pr), -CONH(i-Pr), -CONMe2, -CON(Et)Me, -S02Me, -SOMe, -SMe, -NH2, -NHMe,
-NHCH2OH, -NH(CH2)2OH, -N(Me)CH2CH2OH, -NHEt, -NMe2, -N(Et)Me, -NHCOMe,
-NMeCOMe, -NHCOEt, -NHCO(n-Pr), and -NHCO(i-Pr).
(ii-4) Furthermore, W which may substitute for the arbitrary positions in the alkylene
chain of the above-defined Z' represents any one of the groups represented by the following
formulae:
-Me, -Et, -n-Pr, -i-Pr, -CH2OH, -CH2CH2OH, -CH(OH)CH3, -OH, -OMe, -OEt, -OCH2OH,
-O(CH2)2OH, -O(i-Pr), -O(n-Pr), -CONH2, -CONHMe, -CONHEt, -CONH(n-Pr), -CONH(i-Pr),
-CONMe2, -CON(Et)Me, -SO2Me, -SOMe, -SMe, -NH2, -NHMe, -NHCH2OH, -NH(CH2)2OH,
-N(Me)CH2CH2OH, -NHEt, -NMe2, -N(Et)Me, -NHCOMe, -NMeCOMe, -NHCOEt,
-NHCO(n-Pr), and -NHCO(i-Pr).
(ii-5) In W of the above-defined Z', Ra and Rb, which may be the same or different,
preferably each represent a hydrogen atom or an alkyl group having one to five carbon atoms;
and the alkyl group may have a hydroxyl group or an alkoxy group having one to five carbon
53
atoms.
(ii-6) The alkylene chain of Z' in the above-defined X preferably represents any one of
the groups represented by the following formulae:
-CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -CH2CH(Me)-, -CH2C(Me)2-,
-C(Me)2CH2-, -(CH2)2CH(Me)-, -(CH2)2C(Me)2-; -CH(Me)(CH2)2-,
-C(Me)2(CH2)2-, -CH2CH(Me)CH2-, -CH2C(Me)2CH2-, -CHOH-, -CH2CH(OH)-, -CH(OH)CH2-,
-CH2CH(OH)CH2-, -CH(OH)CH2CH2-, -CH2CH2CH(OH)-, -CO-, -CH2CO-, -COCH2-,
-(CH2)2CO-, -CO(CH2)2-, and -CH2CH(OH)CH2-.
X represented by the above formula (i) or (ii) is more preferably groups represented by
formula (iv) or (iii) below:
[wherein, n represents an integer of 1 to 5, and n' represents an integer of 0 to 5; the repeating
units represented by -(CH2)n- or -(CH2)n'- may be substituted at arbitrary positions by one to
three substituents selected from the group consisting of: a Ci-s alkyl group, a halogen atom, -ORa,
-NRaRb, and an oxo group; Ra and Rb, which may be the same or different, each represent a
hydrogen atom or a Ci_s alkyl group; and the alkyl group may have a hydroxyl group, a Ci-s
alkoxy group, or an amino group as a substituent].
In another preferred embodiment, X-CH2-* in the compound of the present invention
represented by formula (1) includes compounds comprising the structure shown below as a
substructure. In the formula, * represents linkage at position 5 of the parent benzamide ring.
More specifically, X represented by the above formula (i) or (iv) includes the following
groups:
a 2-hydroxyethoxy group, a 3-hydroxy-2-dimethylpropoxy group, a 3-hydroxypropoxy group, a
2-carbamoylethoxy group, a 2-methylcarbamoylethoxy group, a 2-methanesulfonyl-ethoxy
54
group, a 2-acetylamino-ethoxy group, a 2-hydroxyethoxy-amino group, a
3-hydroxypropionylamino group, a 2-hydroxyethanesulfonamide group, a
1-hydroxymethyl-cyclopropylmethoxy group, a 2,3-dihydroxy-propoxy group, a
lH-imidazol-2-ylmethoxy group, a 2-methylcarbamoyl-ethoxyamino group, a
2-acetylamino-ethoxyamino group, a 2-methanesulfonyl-ethoxyamino group, a
lH-imidazol-2-ylmethoxyamino group, a 3-hydroxypropoxyamino group, a
2-(2-hydroxy-ethoxy)-ethoxy group, a 2-methylamino-ethoxy group, a
2-(2-hydroxy-ethylamino)-ethoxy group, a 2-morpholin-4-yl-ethoxy group, a
2-(4-hydroxy-piperidin-l-yl)-ethoxy group, a 2-methylamino-ethoxyamino group, a
2,3-dihydroxy-propoxyamino group;
a formyl-methoxyamino group, an acetyl-methoxyamino group, a methoxy-propionylamino
group, an isobutyryl-methoxy-amino group, a (2-hydroxy-acetyl)-methoxyamino group, a
methoxy-(2-methoxy-acetyl)-amino group, an acetyl-ethoxy-amino group, an
ethoxy-propionyl-amino group, an acetyl-isopropoxy-amino group, an acetyl-hydroxy-amino
group, an acetoxy-acetyl-amino group, an acetyl-(2-hydroxy-ethoxy)-amino group, an
acetyl-(3-hydroxy-propoxy)-amino group, an acetyl-(2-hydroxy-2-methyl-propoxy)-amino group,
an aceryl-(2-acetylamino-ethoxy)-arnino group, an acetyl-(2-propionyl-amino-ethoxy)-amino
group, an acetyl-(2-isobutyrylamino-ethoxy)-amino group, an
acetyl-(2-methylsulfanyl-ethoxy)-amino group, an acetyl-(3-methylsulfanyl-propoxy)-amino
group;
a 2-hydroxy-l,l-dimethyl-ethoxy group;
a methylcarbamoylmethoxyamino group, an ethylcarbamoylmethoxyamino group, a
propylcarbamoylmethoxyamino group, an isopropylcarbamoyl-methoxyamino group, a
dimethylcarbamoylmethoxyamino group, a 2-ethylcarbamoyl-ethoxyamino group, a
2-propylcarbamoyl-ethoxyamino group, a 2^isopropylcarbamoyl-ethoxyarnino group, a
3-methylcarbamoyl-propoxyamino group, a 2-methoxycarbonyl-ethoxyamino group, a
methoxyamino group, a methoxy-methyl-amino group, an ethoxyamino group, an
isopropoxyamino group, a 2-hydroxy-2-methyl-propoxyamino group, a
2-methylsulfanyl-ethoxyamino group, a 2-methanesulfinyl-ethoxyamino group, a
3-methylsulfanyl-propoxyamino group, a 3-methanesulfinyl-propoxyamino group, a
2-propionylamino-ethoxyamino group, a 2-isobutyrylammo-ethoxyamino group;
a 2-hydroxy-acetylamino group, and an acetyl-(2-hydroxy-ethyl)-amino group.
More specifically, X represented by the above formula (ii) or (iii) preferably includes
the following groups:
55
[wherein, the alkylene chain may be substituted at arbitrary positions by one to three substituents
selected from the group consisting of: a Ci-s alkyl group, a halogen atom, -ORa, -NRaRb, and an
oxo group; Ra and Rb, which may be the same or different, each represent a hydrogen atom or a
Ci-s alkyl group; and the alkyl group may have a hydroxyl group, a Ci-s alkoxy group, or an
amino group as a substituent; Ra represents a hydrogen atom or a CM alkyl group; and the alkyl
group may have a hydroxyl group, a CM alkoxy group, or an amino group as a substituent.
More specifically, X represented by the above formula (ii) or (iii) includes the following
groups:
a 3-oxo-[l,2]oxazinan-2-yl group, a 3-oxo-isoxazolidin-2-yl group, a
4,4-dimethyl-3-oxo-isoxazolidin-2-yl group, a4-hydroxy-3-oxo-[l,2]oxazinan-2-yl group, a
3-oxo-[l,4,2]dioxazinan-2-yl group, a2-oxo-pyrrolidin-l-yl group, a2-oxo-piperidin-l-yl group,
a 2-oxo-oxazolidin-3-ylmethyl group, a 2-oxo-tetrahydro-pyrimidin-l-yl group, and a
2,3-dioxo-morpholin-4-yl group.
From the preferred embodiments (l)-(5) described above, the preferred embodiments of
RI to R4, and X can be selected at one's discretion, and combined into compounds of the present
invention.
More specifically, compound I of the present invention represented by formula (1)
In the Table, compound names are also shown together with their compound numbers.
[Table 1]
Compound
No. Structure Compound name
B-1
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-
hydroxy-ethoxy)-5-(2-hydroxy-ethoxymetriyl)-benzamide
B-2
HO -''
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-
hydroxy-ethoxy)-5-(2-hydroxy-ethoxymethyl)-benzamide
B-3
N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)~
5-(2-hydroxy-ethoxymethyl)-benzamide
B-4
2-(2-chloro-4-iodo-phenylamino)-3.4-difluoro-N-{2-
hydroxy-ethoxy)-5-(2-hydroxy-ethoxymethyl)-benzamide
B-5
3,4-difluoro-2-(2-fluoro-4-viny|-phenylamino)-N-(2-
hydroxy-ethoxy)-5-(2-hydroxy-ethoxymethyl)-benzamide
B-6
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-
hydroxy-ethoxy)-5-(3-hydroxypropoxymethyl)-benzamide
B-7
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-(3-hydroxy-
2,2-dimethyl-propoxymethyl)-N-(2-hydroxy-ethoxy)-
benzamide
B-8
3,4-drfluoro-2-(2-fluoro-4-iodo-phenylamino}-N-{2-
hydroxy-ethoxy)-5-(1 -hydroxymethylcyclopropylmethoxymethyl)-
benzamide
d,|-5-(2,3-dihydroxy-propoxymethyl)-3,4-difluoro-2-(2-
fluoro~4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-
benzamide
57
B-10
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-
hydroxy-ethoxy)-5-(2-methylcarbamoyl-ethoxymethyl)-
benzamide
B-11
5-(2-acetylamino-ethoxymethyl)-3,4-difluoro-2-(2-fluoro-4-
iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide
B-12
3,4-d'rfIuoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-
hydroxy-ethoxy)-5-(2-methanesulfonyl-ethoxymethyl)-
benzamide
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-
hydroxy-ethoxy)-5-(1 H-imidazol-2-yl methoxymethyl)-
benzamide
B-14
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-
hydroxy-ethoxy)-5-[2-(2-hydroxy-ethoxy)-ethoxymethyl]-
benzamide
B-15
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-
hydroxy-ethoxy)-5-(2-methylamino-ethoxymethyl)-
benzamide
B-16
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-
hydroxy~ethoxy)-5-[2-(2-hydroxy-ethylamino)-
ethoxymethyQ-benzamide
B-17
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-
hydroxy-ethoxy)-5-(2-morpholin-4-y|-ethoxymethyl)-
benzamide
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-
hydroxy-ethoxy)-5-[2-(4-hydroxy-piperidin-1-yl)-
ethoxymethyQ-benzamide
3,4-difIuoro-2-(2-fluoro-4-iodo-phenylamino)-5-(2-hydroxy-
1,1 -dimethyl-ethoxymethyl)-N-(2-hydroxy-ethoxy)-
benzamide
Compound
No. Structure Compound name
C-1
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-
hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyamino)-methyl]-
benzamide
C-2
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-
hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyamino)-methyl]-
benzamide
C-3
N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2Hluoro-4-iodophenylamino)-
5-[(2-hydroxy-ethoxyamino)-methyl]-
benzamide
C-4
2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N-(2-
hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyamino)-methyl]-
benzamide
C-5
3,4-difluoro-2-(2-fluoro-4-vinyl-phenylarnino)-N-(2-
hydroxy-ethoxy)-5-t(2-hydroxy-ethoxyamino)-methyl]-
benzamide
C-6
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-
hydroxy-ethoxy)-5-[(2-methylcarbamoyl-ethoxyamino)-
methyl]-benzamide
C-7
5-[(2-acetylamino-ethoxyamino)-methyi]-3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-
benzamide
C-8
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-
hydroxy-ethoxy)-5-[(2-methanesulfonyl-ethoxyamino)-
methyQ-benzamide
C-9
3,4-drfluoro-2-(2muoro-4-iodo-phenylamino)-N-{2-
hydroxy-ethoxy)-5-[(1H-imidazol-2-ylmethoxyamino)-
methyl]-benzamide
-10
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-
hydroxy-ethoxy)-5-[(3-hydroxy-propoxyamino)-methyl]-
benzamide
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-
hydroxy-ethoxy)-5-[(2-methylamino-ethoxyamino)-methyl]-
benzamide
C-12
5-[(2,3-dihydroxy-propoxyamino)-methyl]-314-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-
benzamide
C-13
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-
hydroxy-ethoxy)-5-(methylcarbamoylmethoxyaminomethyl)-
benzamide
C-14
5-(ethylcarbamoylmethoxyamino-methyl)-3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-
benzamide
C-15
"VH F
-9 /Ws
o HN^AfAp t^A.,
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-
hydroxy-ethoxy)-5-(propylcarbamoylmethoxyamino-methyl)-
benzamide
C-16
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-{2-
hydroxy-ethoxy)-5-[(isopropylcarbamoy|-methoxyamino)-
methyQ-benzamide
C-17
5-(dimethylcarbamoylmethoxyamino-methyl)-3,4-difluoro-2-
(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-
benzamide
C-18
5-[(2-ethylcarbamoyl-ethoxyamino)-methyl]-3,4-difluoro-2-
(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-
benzamide
C-19
5-[(2-propylcarbamoyl-ethoxyamino)-methyl]-3,4-difluoro-
2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-
benzamide
C-20
5-[(2-isopropylcarbamoyl-ethoxyamino)-methyl]-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-{2-hydroxyethoxy)-
benzamide
' T"^"1
0 H
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-
hydroxy-ethoxy)-5-[(3-methylcarbamoyl-propoxyamino)-
methyQ-benzamide
3-[N-[2,3-difluoro-4-(2-fluoro-4-iodo-phenylamino)-5-(2-
hydroxyethoxycarbamoyl)benzyl]aminooxy]propionic acid
methyl ester
C-23
3,4-difluoro-2-(2--fluoro-4-iodo-phenylamino)-5-
hydroxyaminomethyl-N-(2-hydroxy-ethoxy)-benzaniide
C-24
HO .„
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-
hydroxy-ethoxy)-5-(methoxyamino-methyl)-benzamide
C-25
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-
hydroxy-ethoxy)-5-[(methoxy-methyl-amino)-methyl]-
benzamide
C-26
5-(ethoxyamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-
N-(2-hydroxy-ethoxy)-benzamide
C-27
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-
hydroxy-ethoxy)-5-(isopropoxyamino-methyl)-benzamide
C-28
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-
hydroxy-ethoxy)5-[(2-hydroxy-2-methyl-propoxyamino)-
methyQ-benzamide
C-29
2-{4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro~N-{2-
hydroxy-ethoxy)5-[(2-hydroxy-2-methy|-propoxyamino)-
methyl]-benzamide
3,4~difluoro-2-(2-fiuoro-4-iodo-phenylamino)-N-(2-
hydroxy-ethoxy)-5-[(2-methylsulfanyl-ethoxyamino)-
methyl]-benzamide
HN^O 3,4~difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-
hydroxy-ethoxy)-5-[(2-methanesulfinyl-ethoxyamino)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-
hydroxy-ethoxy)-5-[(3-methylsufanyl-propoxyamino)-
methyl]-benzamide
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-
hydroxy-ethoxy)-5-[(3-methanesulfmyl-propoxyamino)-
methyl]-benzamide
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-
hydroxy~ethoxy)-5-[(2-propoionylamino-ethoxyamino)-
methyl]-benzamide
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-
hydroxy-ethoxy)-5-[(2-isobutyrylamino-ethoxyamino)-
methyQ-benzamide
62
Compound
No. Structure Compound name
E-1
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-{2-
hydroxy-ethoxy)-5-[(3-hydroxy-propionylamino)-methyl]-
benzamide
E-2
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-
hydroxy-ethoxy)-5-[(3-hydroxy-propionylamino)-methyl]-
benzamide
E-3
3,4-drfluoro-2-(2—fluoro-4-iodo-phenylamino)-5-[(2-
hydroxy-ethanesulfonylamino)-methyl]-N-(2-hydroxyethoxy)-
benzamide
E-4
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-5-[(2-
hydroxy-ethanesulfonylamino)-methyl]-N-(2-hydroxyethoxy)-
benzamide
E-5
3,4-difIuoro-2-(2-fluoro-4-iodo-phenylamino)-5-[(2-
hydroxy-acetylamino)-methyl]-N-(2-hydroxy-ethoxy)-
benzamide
E-6
54[acetyl-(2-hydroxy-ethyl)-amino]-methyl}-3,4-difluoro-2-
(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-
benzamide
Compound
No. Structure Compound name
F-1
3,4-difluoro-2-(2-fluoro-4-iodo~phenylamino)-5-[(formylmethoxy-
amino)-methyl]-N-(2-hydroxy-ethoxy)-benzamide
O F
F-2
5-[acety|-methoxy-amino-methyl]-3,4-difluoro-2-(2-fluoro-
4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide
F-3
3,4-drfluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-
hydroxy-ethoxy)-5-[(methoxy-propionyl-amino)-methyl]-
benzamide
F-4 O F
3,4-d'rfluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-
hydroxy-ethoxy)-5-[(isobutyry|-methoxy-amino)-methyl]-
benzamide
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-{[(2-
hydroxy-acetyl)-methoxy-amino]-methyl}-N-(2-hydroxyethoxy)-
benzamide
F-6
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-
hydroxy-ethoxy)-5^[methoxy-(2-methoxy-acetyl)-amino]-
methylj-benzamide
F-7
5-[(acetyl-methoxy-amino)-methyl]-2-(4-ethynyl-2-fluorophenylamino)-
3,4-difluoro-N-(2-hydroxy-ethoxy)-benzamide
F-8
2-(4-ethynyl-2-fluoro-phenyIamino)-3,4-difluoro-N-(2-
hydroxy-ethoxy)-5-[(methoxy-propionyl-amino)-methyl]-
benzamide
F-9
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-
hydroxy-ethoxy)-5-[(isobutyryl~rnethoxy-amino)-methyl]-
benzamide
F-10
5-[(acety|-ethoxy-amino)-methyl]-3,4-difluoro-2-(2-fIuoro-
4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide
5-[(ethoxy-propionyl-amino)-methyl]-3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-
benzamide
F-12
5-[(acetyHsopropoxy-arnino)-rnethyl]-3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-
benzamide
F-13
5-[(acetyl-hydroxy-amino)-methyl]-3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-
benzamide
F-14 o f
5-[(acetoxy-acety|-amino)-methyl]-3.4-difluoro-2-(2-
fluoro-4-iodo~phenylamino)-N-(2-hydroxy-ethoxy)-
benzamide
F-15
2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)
benzamide
F-16
5^[acetyl-(3-hydroxy-propoxy)-amino]-methyll-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy
ethoxy)-benzamide
F-17
54[acetyl-(2-hydroxy-2-methy|-propoxy)-amino]-methyl}-
3,4-difluoro-2-(2muoro-4-iodo-phenylamino}-N-(2-
hydroxy-ethoxy)-benzamide
F-18
5^[acetyl-(2-acetylamino-ethoxy)-amino]-methyl}-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxyethoxy)-
benzamide
F-19
54[acetyl-(2-propionylamino-ethoxy)-amino]-methyl}-3I4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxyethoxy)-
benzamide
O F
F-20
5^[acetyl-(2-isobutyrylamino-ethoxy)-amino]-methyll-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylannino)-N-{2-hydroxyethoxy)-
benzamide
5^acetyl-(2-methylsulfanyl-ethoxy)-amino]-methyl}-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylannino)-N-(2-hydroxyethoxy)-
benzamide
5-{[acetyl-(3-methylsulfanyl-propoxy)-amino]-methyl}-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxyethoxy)-
benzamide
5-[(acetyl-ethoxy-amino)-methyl]-2-(4-ethynyl-2-fluorophenylamino)-
3,4-difluoro-N-(2-hydroxy-ethoxy)-benzamide
5-[(ethoxy-propiony|-amino)-methyl]-2-(4-ethynyl-2-
fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-
benzamide
F-25
5-{[acetyl-(2-hydroxy-ethoxy)-amino]-methyl}-2-(4-
ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxyethoxy)-
benzamide
F-26
54[acetyK2-hydroxy-2-methyl-propoxy)-amino]-methyl}-
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-
hydroxy-ethoxy)Haenzamide
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-
hydroxy-ethoxy)-5-(3-oxo-isoxazolidin-2-ylmethyl)-
benzamide
G-6
N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-
5-(3-oxo-[1,2]oxazinan-2-ylmethyl)-
benzamide
G-7
O-VOHt
N-(2,3-dihydroxy-propoxy)-3,4-d'rfIuoro-2-(2-fIuoro-4-iodophenylamino)-
5-(3-oxo-isoxazolidin-2-ylmethyl)-benzamide
G-8
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-
hydroxy-ethoxy)-5-(4-hydroxy-3-oxo-[1,2]oxazinan-2-
ylmethyl)-benzamide
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-
hydroxy-ethoxy)-5-(3-oxo-[1,4,2]dioxazinan-2-ylmethyl)-
benzamide
2-(4-ethynyl-2-fluoro-phenylamino)-3.4-difluoro-N-(2-
hydroxy-ethoxy)-5-(3-oxo-[1,4,2]dioxazinan-2-ylmethyl)-
benzamide
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-
hydroxy-ethoxy)-5-(2-oxo-pyrrolidin-1^ylmethyl)-benzamide
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-{2-
hydroxy-ethoxy)-5-(2-oxo-piperidin-1-ylmethyl)-benzamide
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-{2-
hydroxy-ethoxy)-5-(2-oxo-oxazolidin-3-ylmethyl)-
benzamide
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-{2-
hydroxy-ethoxy)-5-(2-oxo-tetrahydro-pyrimidin~1-
ylmethyl)-benzamide
5-{2,3-dioxo-morpholin-4-ylmethyl}-3,4-difluoro-2-{2-
fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-
benzamide
Compound I of the present invention preferably includes, Exemplary Compound NOs.
B-1, B-2, B-6, B-9, B-12, C-1, C-2, C-6, C-7, C-8, C-10, C-13, C-24, C-28, C-29, C-31, C-34,
C-35, F-1, F-2, F-3, F-4, F-5, F-6, F-7, F-8, F-9, G-1, G-2, G-3, G-4, and G-5, more preferably
Exemplary Compound NOs. B-1, B-2, B-9, B-12, C-1, C-6, C-7, C-8, C-10, C-13, C-24, C-28,
C-31, C-35, F-1, F-2, F-3, F-4, F-5, F-6, F-7, F-8, F-9, G-1, G-2, G-3, G-4, and G-5, particularly
preferably Exemplary Compound NOs. B-1, C-1, C-10, C-13, F-1, F-2, F-5, G-1, G-2, G-3, G-4,
and G-5.
Synthetic intermediates are used to produce compound I. For example, synthetic
68
intermediates A, B, C, D, E, F, G, H, I, J, K, and L represented by the following formulae (2) to
(13) can be preferably used, but they are not limited thereto.
Synthetic intermediate (A)
Synthetic intermediate (A) represented by formula (2):
wherein, RI, R2, and RS are the same as RI, R.2, and Rs in the above formula (1). Preferred
embodiments thereof are the same. These may comprise protecting group(s) required for the
synthesis.
For example, as preferred embodiments, RI is an iodine atom, a bromine atom, an
ethynyl group, a vinyl group, or a carbamoyl group, R2 is a chlorine atom or a fluorine atom, and
RS is a fluorine atom.
The compounds represented by the formula (2) include, for example,
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-vinyl-benzoic acid (Ri=I, R2=F, R3=F).
Synthetic intermediate (B)
Synthetic intermediate (B) represented by formula (3):
wherein, RI, RI, RS, and R4 are the same as RI, R2, RS, and R4 in the above formula (1).
Preferred embodiments thereof are the same. These may comprise protecting group(s) required
for the synthesis.
For example, as preferred embodiments of intermediate (B), RI is an iodine atom, a
bromine atom, an ethynyl group, or a vinyl group, Rz is a chlorine atom or a fluorine atom, RS is
a fluorine atom, and R4 is a hydroxyalkyl group.
The compounds represented by the formula (3) include, for example,
N-[2-tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-vi
nyl-benzamide (Ri=I, R2=F, R3=F, R4=2-t-butyl-dimethyl-silanyloxyethyl).
Synthetic intermediate (C)
Synthetic intermediate (C) represented by formula (4):
wherein, RI, R2, and R3 are the same as RI, R2, and R3 in the above formula (1). Preferred
embodiments thereof are the same. These may comprise protecting group(s) required for the
synthesis.
For example, as preferred embodiments, RI is an iodine atom, a bromine atom, an
ethynyl group, or a vinyl group, R2 is a chlorine atom or a fluorine atom, and R3 is a fluorine
atom.
The compounds represented by the formula (4) include, for example,
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-benzoic acid (Ri=I, R2=F, R3=F).
Synthetic intermediate (D)
Synthetic intermediate (D) represented by formula (5):
wherein, RI, R2, R3, and R» are the same as RI, R2, R3, and R4 in the above formula (1).
Preferred embodiments thereof are the same. These may comprise protecting group(s) required
for the synthesis.
For example, as preferred embodiments, RI is an iodine atom, a bromine atom, an
ethynyl group, or a vinyl group, R2 is a chlorine atom or a fluorine atom, R3 is a fluorine atom,
and R4 is a hydroxyalkyl group.
The compounds represented by the formula (5) include, for example,
70
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide(Ri=I,
R2=F, R3=F, R4=2-hydroxyethyl).
Synthetic intermediate (E)
Synthetic intermediate (E) represented by formula (6):
wherein, RI, R2, and RS are the same as RI, R2, and RS in the above formula (1). Preferred
embodiments thereof are the same. RI, R2, RS, and U may comprise protecting group(s)
required for the synthesis.
For example, RI is preferably an iodine atom, a bromine atom, an ethynyl group, or a
vinyl group; R2 is preferably a chlorine atom or a fluorine atom; and RS is preferably a fluorine
atom.
In the above formula (6), a group represented by formula (a):
indicates a 3 to 10-membered heterocyclic group which may have one to three substituents
selected from the group consisting of a C 1.5 alkyl group, a halogen atom, an oxo group, -ORa,
-COORa, -COOCORa, -CO-[halogen atom], -OCORa, -CONRaRb, -SRa, -SORa, -S02Ra,
-NRaRb, -NRaCORb, -NRaS02Rb, -SO2NRaRb, a heterocyclic group, and a heteroaryl group.
The heterocyclic group and the heteroaryl group in the (a) may have a substituent
selected from the group consisting of a C 1.5 alkyl group, -ORa, and -NRaRb The alkyl group
may be substituted by a hydroxyl group, a CM alkoxy group, or an amino group. The above
substituents except the oxo group and the halogen atom may be linked to each other to form a
cycloalkyl group or a heterocyclic group; the cycloalkyl group or the heterocyclic group may
have a substituent selected from the group consisting of -ORa, -NRaRb, and a Ci-s alkyl group
which may be substituted with -ORa.
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a
Ci-s alkyl group; the alkyl group may be substituted by one to three groups selected from a
hydroxyl group, a Ci-s alkoxy group, and an amino group.
The group represented by the above (a) more preferably indicates a 3 to 10-membered
heterocyclic group which may have one to three substituents selected from the group consisting
of a CM alkyl group, a halogen atom, -ORa, -NRaRb, and an oxo group, and still more
preferably indicates a 3 to 10-membered heterocyclic group which may be substituted by one to
three hydroxyl groups or CM alkyl groups. The above substituents except the above oxo group
and halogen atom may be linked to each other to form a cycloalkyl group or a heterocyclic
group; the cycloalkyl group or the heterocyclic group may have a substituent selected from the
group consisting of-ORa, -NRaRb, and a CM alkyl group which may be substituted with -ORa.
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a CM alkyl
group; the alkyl group may be substituted by a hydroxyl group, a CM alkoxy group, or an amino
group.
U represents -O-, -CONRd-, -S-, -SO-, -SO2-, -NRd-, -NRdCO-, -NRdSO2-, -SO2NRd-,
a bivalent heterocyclic group, or a bivalent heteroaryl group. Rd represents a hydrogen atom or
a CM alkyl group; the alkyl group may be substituted by a hydroxyl group, a CM alkoxy group,
or an amino group.
The above U is preferably -O-, -CONRd-, -SO2-, -NRdCO-, a heterocyclic group, or a
heteroaryl group, and more preferably -0-, -CONRd-, -SO2-, -NRdCO-, or a heteroaryl group.
Rb is preferably a hydrogen atom, a methyl group or an ethyl group.
The above U is more preferably -O-, -CONH-, -SO2-, -NHCO-, a bivalent imidazolyl
group, and particularly preferably -O-.
Alternatively, the (a) is preferably a 5- or 6-membered heterocyclic group which may be
substituted by one to three hydroxyl groups or C 1.5 alkyl groups, and more preferably a
[l,3]dioxolan-2-yl group or a [l,3]dioxan-2-yl group which may be substituted by one to three
hydroxyl groups or CM alkyl groups.
More specifically, preferred embodiments include the case where the RI is an iodine
atom, a bromine atom, an ethynyl group, or a vinyl group; the R2 is a chlorine atom or a fluorine
atom; the RS is a fluorine atom; and the U is -O-.
The compounds represented by the formula (6) include, for example,
5-[l,3]dioxolan-2-yl-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid (Ri-I, R2=F,
R3=F, T>-0- ((a) is a [l,3]dioxolan-2-yl group)).
Synthetic intermediate (F)
Synthetic intermediate (F) represented by formula (7):
, RI, R2, Ra, and Rt are the same as RI, R2, RS, and Rt in the above formula (1).
Preferred embodiments thereof are the same. These may comprise protecting group(s) required
for the synthesis.
For example, as preferred embodiments, RI is preferably an iodine atom, a bromine
atom, an ethynyl group, or a vinyl group, R2 is preferably a chlorine atom or a fluorine atom, RS
is preferably a fluorine atom, and Rt is preferably a hydroxyalkyl group.
In the above formula (7), a group represented by formula (a):
indicates a 3 to 10-membered heterocyclic group which may have one to three substituentsselected from the group consisting of a Ci-s alkyl group, a halogen atom, an oxo group, -ORa,
-COORa, -COOCORa, -CO-[halogen atom], -OCORa, -CONRaRb, -SRa, -SORa, -SO2Ra,
-NRaRb, -NRaCORb, -NRaSO2Rb, -SO2NRaRb, a heterocyclic group, and a heteroaryl group.
The heterocyclic group and the heteroaryl group in the (a) may have a substituent
selected from the group consisting of a C 1.5 alkyl group, -ORa, and -NRaRb. The alkyl group
may be substituted by a hydroxyl group, a Ci-s alkoxy group, or an amino group. The above
substituents except the oxo group and the halogen atom may be linked to each other to form a
cycloalkyl group or a heterocyclic group; the cycloalkyl group or the heterocyclic group may
have a substituent selected from the group consisting of -ORa, -NRaRb, and a €1.5 alkyl group
which may be substituted with -ORa.
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a
CM alkyl group; the alkyl group may be substituted by one to three groups selected from a
hydroxyl group, a Ci-s alkoxy group, and an amino group.
The group represented by the above (a) more preferably indicates a 3 to 10-membered
heterocyclic group which may have one to three substituents selected from the group consisting
of a C 1.5 alkyl group, a halogen atom, -ORa, -NRaRb, and an oxo group, and still more
preferably indicates a 3 to 10-membered heterocyclic group which may be substituted by one to
73
three hydroxyl groups or C1-5 alkyl groups. The above substituents except the above oxo group
and halogen atom may be linked to each other to form a cycloalkyl group or a heterocyclic
group; the cycloalkyl group or the heterocyclic group may have a substituent selected from the
group consisting of-ORa, -NRaRb, and a Ci-s alkyl group which may be substituted with -ORa.
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a Ci-s alkyl
group; the alkyl group may be substituted by a hydroxyl group, a Ci-s alkoxy group, and an
amino group.
U represents -O-, -CONRd-, -S-, -SO-, -SO2-, -NRd-, -NRdCO-, -NRdSO2-, -SO2NRd-,
a bivalent heterocyclic group or a bivalent heteroaryl group. Rd and Re which may be the same
or different, each represent a hydrogen atom or a €1.5 alkyl group; the alkyl group may be
substituted a hydroxyl group, a C\.s alkoxy group, or an amino group. U may comprise
protecting group(s) required for the synthesis.
The above U is preferably -O-, -CONRd-, -SO2-, -NRdCO-, the heterocyclic group or
the heteroaryl group, and more preferably -O-, -CONRd-, -SO2-, -NRdCO-, or the heteroaryl
group. Rd is preferably a hydrogen atom, a methyl group or an ethyl group.
The above U is still more preferably -O-, -CONH-, -SO2-, -NHCO-, a bivalent
imidazolyl group, and particularly preferably -O-.
Alternatively, the (a) is preferably a 5- or 6-membered heterocyclic group which may be
substituted by one to three hydroxyl groups or Ci-s alkyl groups.
The (a) is more preferably a 5- or 6-membered ring which may be substituted by one to
three hydroxyl groups or CM alkyl groups, and U is -O-. Still more preferably, the (a) is a
[l,3]dioxolan-2-yl group or a [l,3]dioxan-2-yl group which may be substituted by one to three
hydroxyl groups or Ci-s alkyl groups.
More specifically, preferred embodiments include the case where the RI is an iodine
atom, a bromine atom, an ethynyl group, or a vinyl group; the R2 is a chlorine atom or a fluorine
atom; the RS is a fluorine atom; R» is a hydroxyalkyl group; and the U is -O-.
The compounds represented by the formula (7) include, for example,
5-[l,3]dioxolane-2-yl-3,4-difluoro-2-(2-fluoro-4-iodo-phenylarnino)-N-(2-hydroxy-ethoxy)-benz
amide (Ri=I, R2=F, R3=F, F4=2-hydroxyethyl, U=-O- ((a) is a [l,3]dioxolan-2-yl group)).
Synthetic intermediate (G)
Synthetic intermediate (G) represented by formula (8):
74
wherein
RI represents a halogen atom, an alkenyl group, or an alkynyl group;
R2 represents a halogen atom or an alkyl group; the alkyl group may be substituted by a hydroxyl
group; and
RS represents a hydrogen atom or a halogen atom.
Z represents an alkylene chain having one to eight carbon atoms, which may be
substituted by one to three groups represented by W'];
W and W, which may be the same or different, each represent a Ci-s alkyl group, a
halogen atom, an oxo group, -ORa, -COORa, -COOCORa, -CO-[halogen atom], -OCORa,
-CONRaRb, -SRa, -SORa, -SO2Ra, -NRaRb, -NRaCORb, -NRaSO2Rb, -SO2NRaRb, a
heterocyclic group, or a heteroaryl group. The heterocyclic group and the heteroaryl group may
have a substituent selected from the group consisting of a Ci-s alkyl group, -ORa, and -NRaRb.
The alkyl group may be substituted by a hydroxyl group, a Ci-s alkoxy group or an amino group.
The above substituents except the oxo group and the halogen atom may be linked to
each other to form a cycloalkyl group or a heterocyclic group; the cycloalkyl group or the
heterocyclic group may have a substituent selected from the group consisting of-ORa, -NRaRb,
and a €1.5 alkyl group which may be substituted with -ORa;
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a
Ci-s alkyl group; the alkyl group may be substituted by one to three groups selected from a
hydroxyl group, a Ci-s alkoxy group, and an amino group.
Furthermore, the preferred embodiments of W or W are the same as the above.
The above RI, R2, RS, Z, W, and W may comprise protecting group(s) required for the
synthesis.
The RI is preferably an iodine atom, a bromine atom, an ethynyl group, or a vinyl group,
the R2 is preferably a chlorine atom or a fluorine atom, and the RS is preferably a fluorine atom.
Synthetic intermediate (H)
Synthetic intermediate (H) represented by formula (9):
wherein
RI represents a halogen atom, an alkenyl group, or an alkynyl group;
R2 represents a halogen atom or an alkyl group; the alkyl group may be substituted by a hydroxyl
group;
RS represents a hydrogen atom or a halogen atom; and
Rt represents a hydrogen atom, an alkyl group, an alkenyl group, or an alkynyl group. The
alkyl group, the alkenyl group, and the alkynyl group may have one to three substituents selected
from the group consisting of -ORa, -NRaRb, -NRaCORb, a heterocyclic group, and a heteroaryl
group. The heterocyclic group and the heteroaryl group may have one to three substituents
selected from the group consisting Ci-s alkyl groups, -ORa, and -NRaRb.
Ra and Rb, which may be the same or different, each represent a hydrogen atoms or a
CM alkyl group; the alkyl group may be substituted by a hydroxyl group, a Ci-s alkoxy group, or
an amino group.
Z represents an alkylene chain having one to eight carbon atoms, which may be
substituted by one to three groups reprenseted by W.
W and W, which may be the same or different, each represent a Ci-s alkyl group, a
halogen atom, an oxo group, -ORa, -COORa, -COOCORa, -CO-[halogen atom], -OCORa,
-CONRaRb, -SRa, -SORa, -SO2Ra, -NRaRb, -NRaCORb, -NRaSO2Rb, -SO2NRaRb, a
heterocyclic group, or a heteroaryl group. The heterocyclic group and the heteroaryl group may
have substituents selected from the group consisting of a C 1.5 alkyl group, -ORa, and -NRaRb.
The alkyl group may be susbstituted by a hydroxyl group, a €1.5 alkoxy group, or an amino
group.
The above substituents except the oxo group and the halogen atom may be linked to
each other to form a cycloalkyl group or a heterocyclic group; the cycloalkyl group or the
heterocyclic group may have a substituent selected from the group consisting of -ORa, -NRaRb,
and a Ci-s alkyl group which may be substituted with -ORa.
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a
Ci-s alkyl group; the alkyl group may be substituted by one to three groups selected from a
hydroxyl group, a CM alkoxy group, and an amino group.
76
Furthermore, the preferred embodiments of W or W are the same as the above.
The above RI, R2, RS, Z, W, and W may comprise protecting group(s) required for the
synthesis.
The RI is preferably an iodine atom, a bromine atom, an ethynyl group, or a vinyl group,
the R2 is preferably a chlorine atom or a fluorine atom, the RS is preferably a fluorine atom, and
the Rt is preferably a hydroxyalkyl group. The hydroxyalkyl group may be protected.
Synthetic intermediate (I)
Synthetic intermediate (I) represented by formula (10):
wherein
RI represents a halogen atom, an alkenyl group, or an alkynyl group;
R2 represents a halogen atom or an alkyl group; the alkyl group may have a hydroxyl group as a
substituent; and
RS represents a hydrogen atom or a halogen atom.
Z represents an alkylene chain having one to eight carbon atoms, which may be
substituted by one to three groups represented by W.
W and W, which may be the same or different, each represent a Ci-s alkyl group, a
halogen atom, an oxo group, -ORa, -COORa, -COOCORa, -CO-[halogen atom], -OCORa,
-CONRaRb, -SRa, -SORa, -SO2Ra, -NRaRb, -NRaCORb, -NRaSO2Rb, -SO2NRaRb,
heterocyclic group, or a heteroaryl group. The heterocyclic group and the heteroaryl group may
have substituents selected from the group consisting of a Ci-s alkyl group, -ORa, and -NRaRb.
The alkyl group may be substituted by a hydroxyl group, a d.s alkoxy group, or an amino group.
The above substituents except the oxo group and the halogen atom may be linked to
each other to form a cycloalkyl group or a heterocyclic group; the cycloalkyl group or the
heterocyclic group may have a substituent selected from the group consisting of -ORa, -NRaRb,
and a Ci-s alkyl group which may be substituted with -ORa.
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a
Ci-s alkyl group; the alkyl group may be substituted by one to three groups selected from a
hydroxyl group, a Ci-s alkoxy group, and an amino group.
Furthermore, the preferred embodiments of W or W are the same as the above.
The above RI, R2, RS, Z, W, and W may comprise protecting group(s) required for the
synthesis.
The RI is preferably an iodine atom, a bromine atom, an ethynyl group, or a vinyl group,
the R2 is preferably a chlorine atom or a fluorine atom, and the RS is preferably a fluorine atom.
Synthetic intermediate (J)
Synthetic intermediate (J) represented by formula (11).
wherein
RI represents a halogen atom, an alkenyl group, or an alkynyl group;
R2 represents a halogen atom or an alkyl group; the alkyl group may have a hydroxyl group as a
substituent;
RS represents a hydrogen atom or a halogen atom; and
R4 represents a hydrogen atom, an alkyl group, an alkenyl group, or an alkynyl group. The
alkyl group, the alkenyl group, and the alkynyl group may have one to three substituents selected
from the group consisting of -ORa, -NRaRb, -NRaCORb, a heterocyclic group, and a heteroaryl
group. The heterocyclic group and the heteroaryl group may have one to three substituents
selected from the group consisting of a Ci.5 alkyl group, -ORa, and -NRaRb. Ra and Rb, which
may be the same or different, each represent a hydrogen atom or a Ci-s alkyl group; the alkyl
group may be substituted by a hydroxyl group, a Ci-s alkoxy group, or an amino group.
Z represents an alkylene chain having one to eight carbon atoms, which may be
substituted by one to three groups represented by W.
W and W, which may be the same or different, each represent a Ci-s alkyl group, a
halogen atom, an oxo group, -ORa, -COORa, -COOCORa, -CO-[halogen atom], -OCORa,
-CONRaRb, -SRa, -SORa, -SO2Ra, -NRaRb, -NRaCORb, -NRaSO2Rb, -SO2NRaRb, a
heterocyclic group, or a heteroaryl group. The heterocyclic group and the heteroaryl group may
have substituents selected from the group consisting of a CM alkyl group, -ORa, and -NRaRb.
The alkyl group may be substituted by a hydroxyl group, a Ci-s alkoxy group, or an amino group
as substituents.
78
The above substituents except the oxo group and the halogen atom may be linked to
each other to form a cycloalkyl group or a heterocyclic group. The cycloalkyl group or the
heterocyclic group may have a substituent selected from the group consisting of -ORa, -NRaRb,
and a CM alkyl group which may be substituted with -ORa.
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a
Ci-s alkyl group; the alkyl group may be substituted by one to three groups selected from a
hydroxyl group, a CM alkoxy group, and an amino group.
Furthermore, the preferred embodiments of W or W are the same as the above.
The above RI, R2, RS, R*, Z, W, and W may comprise protecting group(s) required for
the synthesis.
The RI is preferably an iodine atom, a bromine atom, an ethynyl group, or a vinyl group,
the R2 is preferably a chlorine atom or a fluorine atom, the RS is preferably a fluorine atom, and
the Rt is preferably a hydroxyalkyl group. The hydroxyalkyl group may be protected.
Synthetic intermediate (K)
Synthetic intermediate (K) represented by formula (12):
.
wherein
RI represents a halogen atom, an alkenyl group, or an alkynyl group;
R2 represents a halogen atom or an alkyl group; the alkyl group may have a hydroxyl group as a
substituent;
Ra represents a hydrogen atom or a halogen atom; and
Q is -ORc, -OCORc, -NRcRd, or a halogen atom, Re and Rd are the same or different, and each
represent a hydrogen atom or an alkyl group.
Z' represents an alkylene chain having one to five carbon atoms, which may be
substituted by one to three groups represented by W.
W preferably represents a CM alkyl group, a halogen atom, an oxo group, -ORa,
-COORa, -COOCORa, -CO-[halogen atom], -OCORa, -CONRaRb, -SRa, -SORa, -SO2Ra,
-NRaRb, -NRaCORb, -NRaSO2Rb, -SO2NRaRb, a heterocyclic group, or a heteroaryl group.
The heterocyclic group and the heteroaryl group may have substituents selected from the group
consisting of a CM alkyl group, -ORa, and -NRaRb. The alkyl group may have a hydroxyl
79
group, a CM alkoxy group, or an amino group as substituents. The above substituents except
the oxo group and the halogen atom may be linked to each other to form a cycloalkyl group or a
heterocyclic group. The cycloalkyl group or the heterocyclic group may have a substituent
selected from the group consisting of-ORa, -NRaRb, and a Ci-s alkyl group which may be
substituted with -ORa.
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a
Ci-s alkyl group; the alkyl group may be substituted by one to three groups selected from a
hydroxyl group, a Ci-s alkoxy group, and an amino group.
W is more preferably a group represented by the following formulae, -OH, -OMe, -OEt,
-OCH2OH, -0(CH2)2OH, -O(i-Pr), -O(n-Pr), -CONH2, -CONHMe, -CONHEt, -CONH(n-Pr),
-CONH(i-Pr), -CONMe2, -CON(Et)Me, -SO2Me, -SOMe, -SMe, -NH2, -NHMe, -NH CH2OH,
-NH (CH2)2OH, -N(Me)CH2CH2OH, -NH Et, -NMe2, -N(Et)Me, -NHCOMe, -NMeCOMe,
-NHCOEt, -NHCO(n-Pr), or -NHCO(i-Pr).
Furthermore, the preferred embodiments of W are the same as the above.
The above RI, R2, Ra, Z1, Q, and W may comprise protecting group(s) required for the
synthesis.
The RI is preferably an iodine atom, a bromine atom, an ethynyl group, or a vinyl group,
the R2 is preferably a chlorine atom or a fluorine atom, and the RS is preferably a fluorine atom.
Synthetic intermediate (L)
Synthetic intermediate (L) represented by formula (13):
wherein
RI represents a halogen atom, an alkenyl group, or an alkynyl group;
R2 represents a halogen atom or an alkyl group; the alkyl group may have a hydroxyl group as a
substituent;
RS represents a hydrogen atom or a halogen atom; and
R4 represents a hydrogen atom, an alkyl group, an alkenyl group, or an alkynyl group. The
alkyl group, the alkenyl group; and the alkynyl group may have one to three substituents selected
from the group consisting of -ORa, -NRaRb, -NRaCORb, a heterocyclic group, and a heteroaryl
80
group. The heterocyclic group and the heteroaryl group may have one to three substituents
selected from the group consisting of a Ci-s alkyl group, -ORa, and -NRaRb. Ra and Rb, which
may be the same or different, each represent a hydrogen atom or a Ci.5 alkyl group; the alkyl
group may be substituted by a hydroxyl group, a Ci-5 alkoxy group, and an amino group.
Z1 represents an alkylene chain having one to five carbon atoms, which may be
substituted by one to three groups represented by W.
W preferably represents a Ci_s alkyl group, a halogen atom, an oxo group, -ORa,
-COORa, -COOCORa, -CO-[halogen atom], -OCORa, -CONRaRb, -SRa, -SORa, -SO2Ra,
-NRaRb, -NRaCORb, -NRaSO2Rb, -SO2NRaRb, a heterocyclic group, or a heteroaryl group.
The heterocyclic group and the heteroaryl group may have substituents selected from the group
consisting of a Ci-s alkyl group, -ORa, and -NRaRb. The alkyl group may be substituted by a
hydroxyl group, a CM alkoxy group, or an amino group. The above substituents except the oxo
group and the halogen atom may be linked to each other to form a cycloalkyl group or a
heterocyclic group; the cycloalkyl group or the heterocyclic group may have a substituent
selected from the group consisting of-ORa, -NRaRb, and a C\.$ alkyl group which may be
substituted with -ORa.
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a
Ci-s alkyl group; the alkyl group may be substituted by one to three groups selected from a
hydroxyl group, a Ci-s alkoxy group, and an amino group.
W is more preferably a group represented by the following formulae, -OH, -OMe, -OEt,
-OCH2OH, -O(CH2)2OH, -O(i-Pr), -0(n-Pr), -CONH2, -CONHMe, -CONHEt, -CONH(n-Pr),
-CONH(i-Pr), -CONMe2, -CON(Et)Me, -SO2Me, -SOMe, -SMe, -NH2, -NHMe, -NH CH2OH,
-NH (CH2)2OH, -N(Me)CH2CH2OH, -NH Et, -NMe2, -N(Et)Me, -NHCOMe, -NMeCOMe,
-NHCOEt, -NHCO(n-Pr), or -NHCO(i-Pr).
Furthermore, the preferred embodiments of W are the same as the above.
Q is -ORc, -OCORc, -NRcRd, or a halogen atom, Re and Rd are the same or different,
and represent a hydrogen atom or a Ci-s alkyl group.
The above RI, R2, RS, R4, Z', W, and Q may comprise protecting group(s) required for
the synthesis.
The RI is preferably an iodine atom, a bromine atom, an ethynyl group, or a vinyl group,
the R2 is preferably a chlorine atom or a fluorine atom, the RS is preferably a fluorine atom, the
R4 is preferably a hydroxyalkyl group, and the hydroxyalkyl group may be protected.
Methods for producing compound (1) according to the present invention using these
synthetic intermediates of compound (1) include the following methods (1) to (4).
(1) Production method when Z is-Y-Z-W
81
This method comprises reacting synthetic intermediate (E) represented by the above
formula (6) with a reducing agent in a solvent at a neutral pH or in the presence of an acid, to
thereby obtain compound (M) or (M1) represented by formula (14) or (14') respectively.
Alternatively, this method comprises reacting the synthetic intermediate (F) represented
by the above formula (7) with a reducing agent in a solvent at a neutral pH or in the presence of
an acid, to thereby obtain compound (N) or (N1) represented by formula (15) or (15')
respectively.
HO R2
(14')
In the formulae (14), (14'), (15), and (15'), RI, R2, Ra, R4, and U each are the same as
those in the formulae (6) and (7). In the formulae (14), (14'), (15), and (15'), Z corresponds to
the cyclized alkylene chain in the above (a), and the Z represents an alkylene chain having one to
eight carbon atoms, which may be substituted by one to three groups represented by W.
W preferably includes a group selected from the group consisting of a C 1.5 alkyl group,
a halogen atom, an oxo group, -ORa, -COORa, -COOCORa, -CO-[halogen atom], -OCORa,
-CONRaRb, -SRa, -SORa, -S02Ra, -NRaRb, -NRaCORb, -NRaSO2Rb, -SO2NRaRb, a
heterocyclic group, and a heteroaryl group.
The heterocyclic group and the heteroaryl group in the (a) may have substituents
selected from the group consisting of a Ci-s alkyl group, -ORa, and -NRaRb. The alkyl group
may have a hydroxyl group, a CM alkoxy group, or an amino group as a substituent. The above
substituents except the oxo group and the halogen atom may be linked to each other to form a
cycloalkyl group or a heterocyclic group; the cycloalkyl group or the heterocyclic group may
have a substituent selected from the group consisting of -ORa, -NRaRb, and a Ci_s alkyl group
which may be substituted with -ORa.
The above W includes more preferably a group selected from the group consisting of a
82
Ci-s alkyl group, a halogen atom, -ORa, -NRaRb, and an oxo group, and still more preferably a
hydroxyl group or a Ci-s alkyl group. The above substituents except the oxo group and the
halogen atom may be linked to each other to form a cycloalkyl group or a heterocyclic group; the
cycloalkyl group or the heterocyclic group may have a substituent selected from the group
5 consisting of -ORa, -NRaRb, and a C\.s alkyl group which may be substituted with -ORa.
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a
Ci-s alkyl group; the alkyl group may be substituted by one to three groups selected from a
hydroxyl group, a CM alkoxy group, and an amino group.
The above solvent includes methanol, ethanol, diethyl ether, tetrahydrofuran, toluene,
10 methylene chloride, and acetonitrile.
The above reducing agent includes sodium boron hydride, sodium borocyanohydride,
triethylsilane, trimethylsilane, lithium aluminum hydride, diisopropyl aluminum hydride,
borane-pyridine complex, decaborane, diborane, borane-dimethylsulfide complex, borane-THF
complex, hydrogen, zinc boron hydride, samarium (II) iodide, and tributyltin hydride.
15 Preferable examples include, diisopropyl aluminum hydride, sodium boron hydride, and
triethylsilane.
The above acid includes acetic acid, hydrochloric acid, trifluoroacetic acid,
trifiuoroboron-diethyl ether complex, trimethylsilyl triflate, Bids, AlCls, titanium tetrachloride,
and trimethylsilyl chloride.
20 The above reaction can be performed typically at about -78°C to about 120°C for about
one hour to about 2 days.
(2) Production method when Z is -Y-Z-W (2)
Compound (I) represented by the above formula (10) can be obtained by reacting
25 synthetic intermediate (G) represented by the above formula (8) with a reducing agent in a
solvent at a neutral pH or hi the presence of an acid. Alternatively, compound (J) represented
by the above formula (11) can be obtained by reacting synthetic intermediate (H) represented by
the above formula (9) with a reducing agent in a solvent at a neutral pH or in the presence of an
acid.
30 The above solvent include methanol, ethanol, diethyl ether, tetrahydrofuran, toluene,
methylene chloride, and acetonitrile.
The above reducing agent includes sodium boron hydride, sodium boron
cyanohydride, triethylsilane, trimethylsilane, lithium aluminum hydride, diisopropyl aluminum
hydride, borane-pyridine complex, decaborane, diborane, borane-dimethylsulfide complex,
35 borane-THF complex, zinc boron hydride, and tributyltin hydride. Preferably, sodium boron
cyanohydride, sodium boron hydride, triethylsilane, and borane-pyridine complex can be
83
included.
The above acid includes acetic acid, hydrochloric acid, trifluoroacetic acid,
dichloroacetic acid, trifluoroboron-diethyl ether complex, trimethylsilyl triflate, Aids, titanium
tetrachloride, and trimethylsilyl chloride. Preferable examples include dichloroacetic acid,
hydrochloric acid, and trifluoroacetic acid.
The above reaction can be performed typically at about -78°C to about 120°C for about
one hour to about 2 days.
(3) Production method when Z is a heterocyclic group
Compound (O) represented by the following formula (16) can be obtained by
intramolecularly cyclizing synthetic intermediate (K) represented by the above formula (12) in a
solvent at a neutral pH, in the presence of an acid or in the presence of a base, and further in the
presence of a peptide condensing agent if necessary, for example, in the case of Q=OH.
Alternatively, compound (P) represented by the following formula (17) can be obtained by
intramolecularly cyclizing synthetic intermediate (L) represented by the above formula (13) in a
solvent at a neutral pH, in the presence of an acid or in the presence of a base, and further in the
presence of a peptide condensing agent if necessary, for example, in the case of
In the above formulae (16) and (17), RI, RI, RS, R4, and Z' each are the same as those in
the above formulae (12) and (13).
Preparation of compound (XXV)
The above solvent includes methanol, ethanol, diethyl ether, tetrahydrofuran, toluene,
methylene chloride, and acetonitrile.
84
The above acid includes AlMe3, acetic acid, hydrochloric acid, trifluoroacetic acid,
dichloroacetic acid, trifluoroboron-diethyl ether complex, trimethylsilyl triflate, AlCb, titanium
tetrachloride, and trimethylsilyl chloride.
The above base includes triethylamine, Hunig's base, DBU, sodium methylate, and
potassium carbonate.
The above reaction can be performed typically at room temperature to about 80°C for
about one hour to about one day.
In the case of Q=OH, compound (16) or (17) can be obtained by treating compound (12)
or (13) with a condensing agent for peptide synthesis and a base in an appropriate solvent. In
this case, the above solvent may be dichloromethane, THF, and dimethylformamide, and
preferably dichloromethane.
The above base includes triethylamine, Hunig's base, or DBU, and preferably Hunig's
base.
The above peptide condensing agent includes 1,3-dicyclohexylcarbodiimide (DCC),
2-ethoxy-l-ethoxycarbonyl-l, 2-dihydroquinoline (EEDQ),
bromo-tris(pyrrolidmo)-phosphonium hexafluorophosphate (PyBrOP),
1 -ethyl-3 -(3 '-dunethylaminopropyl)carbodiimide (EDC),
(benzotriazolyloxy)tripyrrolidino-phosphonium hexafluorophosphate (PyBOP),
3-hydroxy-4-oxo-3,4-dihydro-l,2,3-benzotriazine (HODhBt), and hydroxybenzotriazole (HOBt).
The above reaction can be performed typically at about 10°C to about 30°C, preferably
about 22°C (room temperature) for about one hour to about 2 days, preferably about 10 hours.
(4) Production method when Z is a chain substituent having a partial structure -N(OR)CO-R'
This method comprises reacting synthetic intermediate (I) represented by the above
formula (10) with a carboxylate derivative (including carboxylic acid) represented by RgCO-Q in
a solvent in the presence of a base or an acid or at a neutral pH, in the presence of a condensing
agent if necessary to thereby obtain compound (S) represented by the following formula (18).
Alternatively, this method comprises reacting synthetic intermediate (J) represented by the above
formula (11) with a carboxylate derivative (including carboxylic acid) represented by R9CO-Q in
a solvent hi the presence of a base or an acid or at a neutral pH, in the presence of a condensing
agent if necessary, to thereby obtain compound (T) represented by the following formula (19).
Rg represents a hydrogen atom, an alkyl group, or -ORa; the alkyl group may be
substituted by a halogen atom, -ORa, or -NRaRb.
Q is -ORc, -OCORc, -NRcRd, or a halogen atom, and Re and Rd are the same or
different and represent a hydrogen atom or a C\.$ alkyl group.
Ra and Rb are the same or different, and represent a hydrogen atom or a Ci-s alkyl
85
group; the alkyl group may have a hydroxyl group, a CM alkoxy group, or an amino group as
substituents.
Rg and Q may comprise protecting group(s) required for the synthesis.
In the formulae (18) and (19), RI, RI, RS, R*, Z, and W each are the same as those hi the
formulae (10) and (11), and Rg is the same as that defined for the above carboxylate derivative.
The above solvent includes dichloromethane, THF, and dimethylforrnamide. The
above base includes triethylamine, Hunig's base, or DBU, and preferably Hunig's base.
The above peptide condensing agent includes 1,3-dicyclohexylcarbodiimide (DCC),
2-ethoxy- 1 -ethoxycarbonyl- 1 ,2-dihydroquinoline (EEDQ),
bromo-tris(pyrrolidino)-phosphonium hexafluorophosphate (PyBrOP),
l-ethyl-3-(3'-dimethylaminopropyl) carbodiimide (EDC), (benzotriazolyloxy) tripyrrolidino
-phosphonium hexafluorophosphate (PyBOP), 3-hydroxy-4-oxo-3,4-dihydro-l,2,3-benzotriazine
(HODhBt), and hydroxybenzotriazole (HOBt). Preferable examples include the combination of
1 -ethy 1-3 -(3 '-dimethylaminopropyl)carbodiimide (EDC) with N-hydroxybenzotriazole (HOBt),
and the combination of l-emyl-3-(3'-dimethylaminopropyl)carbodiimide (EDC) with
3-hydroxy-4-oxo-3,4-dihydro-l,2,3-benzotriazine (HODhBt).
The above reaction can be performed typically at about 0°C to about 30°C, preferably
about 22°C (room temperature) for about one hour to about 2 days, preferably about 10 hours.
Compound I represented by the formula (1) according to the present invention can be
produced, for example in accordance with the following methods. In the following reaction
processes 1 to 4 and descriptions thereof, RI to R4, Rg, Rg, X, Y, Z, Z1, W, Ra, Rb, and compound I
86
are the same as those described in the above formula (1).
Reaction process 1
Reaction process 1 indicates a method for producing compound I represented by the
formula (1). In this process, L means a leaving group, for example, fluorine, chlorine, bromine,
or iodine, or an activated hydroxyl group, for example, phosphate ester and sulfonate ester.
The compound (5-iodinated or 5-brominated benzoic acid derivative) represented by the
formula (II) can be easily obtained by, for example, using methods described in publicly known
literature (F. Mongin, E. Marzi, and M. Schlosser, European Journal of Organic Chemistry,
2771-2777 (2001) or A. Groweiss, Organic Process Research & Development, 4, 30-33 (2000))
or similar methods thereto.
Preparation of 5-vinylbenzoic acid derivative (III)
5-Vinylbenzoic acid derivative (III) can be obtained by, for example, reacting
5-iodinated or 5-brominated benzoic acid derivative (II) with a vinylated organic metal reagent
in an appropriate solvent in the presence of a transition metal catalyst.
The above solvent includes, for example, dimethylformamide, THF (tetrahydrofuran),
DMSO (dimethyl sulfoxide), isopropanol, methanol, and ethanol, and preferably, THF or
isopropanol is used.
As the above transition metal catalyst, for example, palladium complex can be
preferably used. As the palladium complex, for example, Pd(PPli3)4, (PhCN)2PdCl2,
(MeCN)2PdCl2, and (PPh3)2PdCl2 can be used.
The above vinylated organic metal reagent includes, for example, vinylated organic
magnesium, vinylated organic aluminum, vinylated organic silicon, vinylated organic boron,
vinylated organic zinc, and vinylated organic tin. Among them, vinyl organic tin (Stille's
method) or vinyl borate (Suzuki's method) can be preferably used. If necessary, it is possible to
add an appropriate base such as t-butylamine, triethylamine, or Hunig's base in the reaction
system.
The reaction can be performed typically at about 15°C to about 130°C, preferably about
60°C for about four hours to about four days, preferably about 10 hours.
The reaction can be easily performed with reference to the following literature.
a) J. K. StiUe, Angew. Chem., Int. Ed. Engl. 1986,25, 508-524.
b) N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457-2483
c) A. Suzuki, J. Organomet. Chem., 1999, 576, 147-168.
d) Suzuki, A, In Metal-Catalyzed Cross Coupling Reactions; Diederich, F., Stang, P. J., Eds.;
VCH: Weinheim, 1998; pp49-97.
90
Preparation of 2-(phenylamino)-5-vinylbenzoic acid derivative (V)
2-(Phenylamino)-5-vinylbenzoic acid derivative (V) can be synthesized by reacting
aniline derivative (IV) with 5-vinylbenzoic acid derivative (III). This reaction can be
performed using, for example, methods described in a patent document (WO 00/64856) and
literature (M. H. Chen, V. G. Beylin, E. lakovleva, S. J. Kesten, J. Magano, D. Drieze, Synthetic
Communications, 32(3), 411-417 (2002)) or similar methods thereto.
Specifically, the reaction can be performed by reacting 5-vinylbenzoic acid derivative
(III) with an equal or excessive amount of aniline derivative (IV) in a solvent in the presence of a
base.
The above solvent includes, for example, THF and toluene, and preferably THE
The above base includes, for example, lithium diisopropylamide, lithium
hexamethyldisilazide, lithium n-butyl, sodium hydride, and sodium amide, and preferably
lithium isopropylamide or lithium hexamethyldisilazide.
The above reaction can be performed typically at about -78°C to about 25°C for about
four hours to about four days, preferably about one day.
Preparation of hydroxamic acid derivative (VII)
A 2-phenylamino-5-vinylbenzoic acid derivative (V) can converted into a hydroxamic
acid derivative (VII) by reacting (V) with a hydroxylamine derivative (VI) represented by
NHiOIL} in an appropriate solvent in the presence of a condensing agent for peptide synthesis
and in the presence or the absence of a base.
The above solvent includes dichloromethane, THF, and dimethylformamide, and
preferably dichloromethane.
The above base includes triethylamine, Hunig's base, or DBU
(l,8-diazabicyclo[5.4.0]-undecene), or DMAP (4-dimethylaminopyridine), and preferably
Hunig's base.
The above peptide condensing agent include 1,3-dicyclohexylcarbodiimide (DCC),
2-ethoxy-1 -ethoxycarbonyl-1,2-dihydroquinoline (EEDQ),
bromo-tris(pyrrolidino)-phosphonium hexafluorophosphate (PyBrOP),
1 -ethyl-3-(3l-dimethylaminopropyl)carbodiimide (EDC),
(benzotriazolyloxy)tripyrrolidino-phosphonium hexafluorophosphate (PyBOP),
3-hydroxy-4-oxo-3,4-dihydro-l,2,3-benzotriazine (HODhBt), and hydroxybenzotriazole (HOBt).
Preferable examples include the combination of
l-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (EDC) with N-hydroxybenzotriazole (HOBt),
and the combination of l-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (EDC) with
3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HODhBt).
The above reaction can be performed typically at about 10°C to about 30°C, preferably
about 22°C (room temperature) for about one hour to about two days, preferably about 10 hours.
Preparation of aldehyde (VHP
A hydroxamic acid derivative (VII) can be converted into an aldehyde (VIII) by
reacting (VIII) with an appropriate oxidizing agent in an appropriate solvent.
The above solvent includes THE, diethyl ether, dichloromethane, dimethylformamide,
DMSO, chloroform, carbon tetrachloride, or acetonitrile, and preferably THF and
dichloromethane.
The above oxidizing agent includes ozone, osmium tetroxide-sodium metaperiodate,
and ruthenium chloride-sodium metaperiodate.
The above reaction can be performed typically at about 10°C to about 30°C, preferably
about 22°C (room temperature) for about two hours to about two days, preferably about 10
hours.
Preparation of compound (I)
An aldehyde (VIII) can be converted into compound (I) by reacting (VIII) with
compound (DC) hi an appropriate solvent in the presence of an appropriate reducing agent and if
necessary an appropriate acid.
The above solvent includes methanol, ethanol, diethyl ether, tetrahydrofuran, toluene,
and methylene chloride.
The above reducing agent includes sodium boron hydride, sodium boron cyanohydride,
triethylsilane, lithium aluminum hydride, diisopropyl aluminum hydride, borane-pyridine
complex, and decaborane.
The above acid includes acetic acid, hydrochloric acid, trifluoroacetic acid,
trifluoroboron-diethyl ether complex, trimethylsilyl triflate, BiCla, trifluoromethanesulfonic acid,
p-toluenesulfonic acid, and pyridinium-p-toluenesulfonic acid.
The above reaction can be performed typically at about -78°C to about 120°C for about
one hour to about two days.
The reaction can be easily performed by, for example, using methods described in the
following literature or similar methods thereto.
a) Daniel Dube and Adrew A. Scholte, Tetrahedron Letters, 1999,40, 2295-2298
b) Koich Fukase, Yoshiyuki Fukase, Masato Oikawa, Wen-Chi Liu, Yasuo, Suda, and Shoichi
Kusumoto, Tetrahedron, 1998, 54, 4033-4050
c) Seung Hwan Lee, Yong Lune Park, and Cheol Min Yoon, Tetrahedron Letters, 1999,40,
6049-6050
d) Makoto Wada, Sonoe Nagayama, Kaori Mizurtani, Ryoichi Hiroi, and Norikazu Miyoshi,
Chemistry Letters, 2002, 248-249
e) Kikkugawa, Y, Ogawa, Y, Chem. Pharm. Bull., 1979,27,2405-2410
Reaction process 2
Reaction process 2 is an example process for preparing compound I from
2-(phenylamino)-5-vinylbenzoic acid derivative (V) shown in reaction process 1 by a process
other than reaction process 1.
Preparation of carbonyl (XI)
2-(Phenylamino)-5-vinylbenzoic acid derivative (V) can be converted into a carbonyl
(X) in accordance with the method for converting a hydroxamic acid derivative (VII) into a
carbonyl (VIII) described above.
More specifically, the conversion can be accomplished by reacting a
2-(4-iodophenylamino)-5-vinylbenzoic acid derivative (V) with an appropriate oxidizing agent in
an appropriate solvent.
The appropriate solvent includes THF, diethyl ether, dichloromethane,
dimethylformamide, DMSO, chloroform, carbon tetrachloride, or acetonitrile, and preferably
THF and dichloromethane. The above oxidizing agent includes ozone, osmium
tetroxide-sodium metaperiodate, and ruthenium chloride-sodium metaperiodate. The above
reaction can be performed typically at about 10°C to about 30°C, preferably about 22°C (room
temperature) for about two hours to about two days, preferably about 10 hours.
Preparation of compound (XT)
A carbonyl (X) can be converted into compound (XI) in accordance with the method for
converting an aldehyde (VIII) into compound I described above.
More specifically, the conversion can be accomplished by reacting a carbonyl (X) with
compound (IX) in an appropriate solvent in the presence of an appropriate reducing agent and if
necessary an appropriate acid.
The above solvent includes methanol, ethanol, diethyl ether, tetrahydrofuran, toluene,
and methylene chloride.
The above reducing agent includes sodium boron hydride, sodium boron cyanohydride,
triethylsilane, lithium aluminum hydride, diisopropyl aluminum hydride, borane-pyridine
complex, and decaborane.
The above acid includes acetic acid, hydrochloric acid, trifluoroacetic acid,
trifluoroboron-diethyl ether complex, trimethylsilyl triflate, Bids, trifluoromethanesulfonic acid,
p-toluenesulfonic acid, and pyridinium-p-toluenesulfonic acid.
The above reaction can be performed typically at about -78°C to about 120°C for about
one hour to about two days.
The reaction can be easily performed by, for example, using methods described in the
following literature or similar methods thereto.
a) Daniel Dube and Adrew A. Scholte, Tetrahedron Letters, 1999,40, 2295-2298
b) Koich Fukase, Yoshiyuki Fukase, Masato Oikawa, Wen-Chi Liu, Yasuo, Suda, and Shoichi
Kusumoto, Tetrahedron, 1998, 54,4033-4050
c) Seung Hwan Lee, Yong Lune Park, and Cheol Min Yoon, Tetrahedron Letters, 1999, 40,
6049-6050
d) Makoto Wada, Sonoe Nagayama, Kaori Mizurtani, Ryoichi Hiroi, and Norikazu Miyoshi,
Chemistry Letters, 2002, 248-249
e) Kikkugawa, Y, Ogawa, Y, Chem. Pharm. Bull., 1979,27,2405-2410
Preparation of compound I (1)
Compound (XI) can be converted into compound I in accordance with the method for
converting a 2-(phenylamino)-5-vinylbenzoic acid derivative (V) into a hydroxamic acid
derivative (VII) described above.
More specifically, compound I can be obtained by reacting compound (XI) with a
hydroxylamine derivative (VI) represented by NHiOR* in an appropriate solvent in the presence
of a peptide condensing agent and in the presence or the absence of a base.
The above solvent include dichloromethane, THF, and dimethylformamide, and
preferably dichloromethane.
The above base include triethylamine, Hunig's base, or DBU, and preferably Hunig's
base.
The above peptide condensing agent include 1,3-dicyclohexylcarbodiimide (DCC),
2-ethoxy-1 -ethoxycarbonyl-1,2-dihydroquinoline (EEDQ),
bromo-tris(pyrrolidmo)-phosphonium hexafluorophosphate (PyBrOP),
l-ethyl-3-(3'-dimethylaminopropyl)carbodiimide(EDC),
(benzotriazolyloxy)tripyrrolidino-phosphonium hexafluorophosphate (PyBOP),
3-hydroxy-4-oxo-3,4-dihydro-l,2,3-benzotriazine (HODhBt), and hydroxybenzotriazole (HOBt).
Preferable examples include the combination of
l-ethyl-3-(3'-dmiethylaminopropyl)carbodiimide (EDC) with N-hydroxybenzotriazole (HOBt),
and the combination of l-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (EDC) with
3-hydroxy-4-oxo-3,4-dihydro-l,2,3-benzotriazine (HODhBt).
The above reaction can be performed typically at about 10°C to about 30°C, preferably
about 22°C (room temperature) for about one hour to about two days, preferably about 10 hours.
Reaction process 3
Reaction process 3 is an example process for preparing, from compound (XII),
compounds (I-a) and (I-b), in particular among compounds I represented by the formula (1).
Compound (XII) is one of compound I where RI is a halogen atom such as iodine atom,
bromine atom, or chlorine atom, and preferably iodine atom.
In compounds (I-a) and (I-b), RI is an alkynyl group or an alkenyl group; an
unsaturated bond is present between a carbon directly bound to a benzene ring containing R2 and
an adjacent carbon thereto. Rh to Rk represent substituents on the carbon atoms that are
connected by an unsaturated bond. Rh, Ri, Rj, Rk independently represent a hydrogen atom or
a Ci-e alkyl group.
Preparation of compound (I-a)
Compound (XII) can be converted into compound (I-a) using, for example, Sonogashira
method described in literature (K. Sonogashira, Y. Tohda and N. Hagihara, Tetrahedron Lett. 1 6,
4467-4470 (1 975)). Specifically, compound (I-a) can be obtained by reacting compound (XII)
with alkyne in an appropriate solvent, e.g., THF, in the presence of a catalytic amount of
palladium complex, e.g., (PPh3)2PdCl2, as well as a catalytic amount of a copper reagent, e.g.,
copper iodide, and an appropriate base, e.g., triethylamine or Hunig's base. The above reaction
can be performed typically at about 10°C to about 100°C, preferably about 40°C to 60°C for
about two hours to about two days.
Preparation of compound (I-b) (1)
Compound (XII) can be converted into compound (I-b) in accordance with the method
for converting a 5-iodinated, 5-brominated benzoic acid derivative (II) into a 5-vinylbenzoic acid
derivative (III) shown hi reaction process 1 .
More specifically, compound (I-b) can be obtained by reacting compound (XII) with a
vinylated organic metal reagent in an appropriate solvent in the presence of a transition metal
catalyst. The above solvent includes dimethylformamide, THF, DMSO, isopropanol, methanol,
and ethanol, and preferably THF or isopropanol. The above transition metal catalyst includes,
for example palladium complex, and specifically Pd(PPh3)4, (PhCN)2PdCl2, (MeCN)2PdCl2, or
(PPhs)2PdCl2. The above vinylated organic metal reagent includes, for example, vinylated
organic magnesium, vinylated organic aluminum, vinylated organic silicon, vinylated organic
boron, vinylated organic zinc, and vinylated organic tin. Preferable examples include vinyl
organic tin (Stille's method) or vinyl borate (Suzuki's method). If necessary, it is possible to add
95
an appropriate base such as triethylamine, t-butylamine, or Hunig's base in the reaction system.
The above reaction can be performed typically at about 15°C to about 130°C, preferably
about 60°C for about four hours to about four days, preferably about 10 hours.
The reaction can be easily performed with reference to the following literature:
a) J. K. Stille, Angew. Chem., Int. Ed. Engl. 1986,25, 508-524.
b) N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457-2483
c) A. Suzuki, J. Organomet. Chem., 1999, 576,147-168.
d) Suzuki, A, In Metal-Catalyzed Cross Coupling Reactions; Diederich, R, Stang, P. J.,
VCH: Weinheim, 1998; pp49-97.
Preparation of compound (I-b) (2)
Compound (I-b) can also be obtained by reducing compound (I-a). A reducing method
includes, for example, a method of hydrogenating in a solvent in the presence of Lindler catalyst.
The above solvent includes ethanol, methanol, and hexane. The reaction can be performed
typically at about 10°C to about 30°C, preferably about 22°C (room temperature) for about 10
minutes to about two days.
Reaction process 4
Reaction process 4 is an example process for preparing compound I represented by the
formula (1), particularly compound (I-c) having Y=O (oxygen atom) and W=OH, from
compound (X) or (VIII).
Preparation of compound (XIV)
An acetal compound (XIV) can be prepared by reacting carbonyl compound (X) with a
diol (XIII) in an appropriate solvent in the presence of an acid in a catalytic amount.
The above solvent includes THF, DMF, and dichloromethane.
The above acid includes p-toluene sulfonic acid, camphor sulfonic acid, hydrochloric
acid, and pyridinium-p-toluenesulfonic acid.
The reaction can be performed typically at about 10°C to about 30°C, preferably about
22°C (room temperature) for about one hour to about two days.
Preparation of compound (XV)
Carboxylic acid (XIV) can be converted into hydroxamate ester (XV) in accordance
with the method for converting a 2-(phenylamino)-5-vinylbenzoic acid derivative (V) into a
hydroxamic acid derivative (VII) described above.
More specifically, compound (XV) can be obtained by reacting compound (XIV) with a
96
hydroxylamine derivative (VI) represented by Nt^ORi in an appropriate solvent in the presence
of a peptide condensing agent and in the presence or the absence of a base.
The above solvent includes dichloromethane, THF, and dimethylformamide, and
preferably dichloromethane.
The above base includes triethylamine, Hunig's base, or DBU, and preferably Hunig's
base.
The above peptide condensing agent includes 1,3-dicyclohexylcarbodiimide (DCC),
2-ethoxy-1 -ethoxycarbonyl-1,2-dihydroquinoline (EEDQ),
bromo-tris(pyrrolidino)-phosphonium hexafluorophosphate (PyBrOP),
1 -ethyl-3 -(3 '-dimethylamrnopropyl)carbodiunide (EDC),
(benzotriazolyloxy)tripyrrolidino-phosphonium hexafluorophosphate (PyBOP),
3-hydroxy-4-oxo-3,4-dihydro-l,2,3-benzotriazine (HODhBt), and hydroxybenzotriazole (HOBt).
Preferably, the combination of l-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (EDC) with
N-hydroxybenzotriazole (HOBt), and the combination of
l-ethyl-3-(3'-dunethylaminopropyl)carbodiimide (EDC) with
3-hydroxy-4-oxo-3,4-dihydro-l,2,3-benzotriazine (HODhBt) can be included.
The above reaction can be performed typically at about 10°C to about 30°C, preferably
about 22°C (room temperature) for about one hour to about two days, preferably about 10 hours.
An aldehyde (VIII) can be converted into a cyclic acetal (XV) by the same method as
the above method for conversion of an aldehyde (X) into a cyclic acetal (XIV). More
specifically, the conversion can be accomplished by reacting acarbonyl compound (VIII) with a
diol (XIII) hi an appropriate solvent in the presence of an acid in a catalytic amount.
The above solvent includes THF, DMF, and dichloromethane.
The above acid includes p-toluenesulfonic acid, camphor sulfonic acid, hydrochloric
acid, and pyridinium-p-toluenesulfonic acid.
The reaction can be performed typically at about 10°C to about 30°C, preferably about
22°C (room temperature) for about one hour to about two days.
Preparation of compound (I-c)
A cyclic acetal (XV) can be converted into compound (I-c) by reacting a cyclic acetal
(XV) with an appropriate reducing agent in an appropriate solvent and if necessary in the
presence of an appropriate acid.
The above solvent includes methanol, ethanol, diethyl ether, tetrahydrofuran, toluene,
methylene chloride, and acetonitrile.
The above reducing agent includes sodium boron hydride, sodium boron cyanohydride,
triethylsilane, trimethylsilane, lithium aluminum hydride, diisopropyl aluminum hydride,
borane-pyridine complex, decaborane, diborane, borane-dimethylsulfide complex, borane-THF
complex, hydrogen, zinc boron hydride, samarium (II) iodide, and tributyltin hydride.
Preferable examples include, diisopropyl aluminum hydride, sodium boron hydride, and
triethylsilane.
The above acid includes acetic acid, hydrochloric acid, trifluoroacetic acid,
trifluoroboron-diethyl ether complex, trimethylsilyl triflate, BiCla, AlCla, titanium tetrachloride,
trimethylsilyl chloride, trifluoromethanesulfonic acid, p-toluenesulfonic acid, and
pyridinium-p-toluenesulfonic acid.
The above reaction can be performed typically at about -78°C to about 120°C for about
one hour to about two days.
The above reaction can be performed by using methods described hi the following
literature or similar methods thereto.
a) E. L. Eliel, V. G. Badding, and M. N. Rerick, J. Am. Chem. Soc., 1962, 84, 2371.
b) A. R. Abdum-Nur, and C. H. Issidorides, J. Org. Chem., 1962, 27, 67.
c) L. I. Zakharkin and I. M. Khorlina, Izvest. Akad. Nauk S.S.S.R., Otd. Khim. Nauk. 1959,
2255; Chem. Abs. 1960, 54,10837h.
d) W. L. Howard, and J. H. Jr. Brown, J. Org. Chem., 1961,26, 1026.
e) B. Fleming, and H. I. Bolker, Can. J. Chem. 1974, 52, 888.
f) L. I. Zakharkin, V. I. Stanko, Y. A. Chapovskii, Izvest. Akad. Nauk S.S.S.R., Otd. Khim. Nauk.
1962,1118; Chem. Abs. 1962, 981b.
g) D. A. Hove, and A. Jordan, Tetrahedron Lett., 1978,19,1357.
h) T. Tsunoda, M. Suzuki, and R. Noyori, Tetrahedron Lett., 1979,20,4679.
i) D. N. Kursanov, Z. N. Parnes, N. M. Loim, Synthesis, 1974, 633.
j) H. Kotsuki, Y. Ushio, N. Yoshimura, and M. Ochi, J. Org. Chem., 1987, 52, 2594-2596.
k) B. Bartels, and R. Hunter, J. Org. Chem., 1993, 58, 6756-6765.
1) G. Adam, and D. Seebach, Synthesis, 1988, 5, 373-375.
m) B-Z. Zheng, M. Yamauchi, H. Dei, S-I. Kusaka, K. Matusui, and O. Yonemitsu, Tetrahedron
Lett., 2000,41,6441-6446.
n) T. Ohta, T. Michibata, K. Yamada, R. Omori, I. Furukawa, Chem. Commun., 2003,10,
1192-1193.
o) Org. Prep. Proc. Int. 1985,17,11.
Reaction process 5
Reaction process 5 is an example process for preparingcompound I represented by the
formula (1), particularly compound (I-d) having Y=-NHO-, from compound (X) or compound
Preparation of compound (XVID
An aldehyde (X) can be converted into oxime ether (XVII) by stirring an aldehyde (X)
with an o-alkyl-hydroxylamine derivative (XVI) in an appropriate solvent.
The above solvent includes dichloromethane, ethanol, chloroform, THF,
dimethylformamide, and diethyl ether, and preferably dichloromethane or ethanol.
Preparation of compound (XVIII)
Compound (XVII) can be converted into hydroxamate ester (XVIII) in accordance with
the method for converting a 2-(phenylamino)-5-vinylbenzoic acid derivative (V) into a
hydroxamic acid derivative (VII) described above.
More specifically, hydroxamate ester (XVIII) can be obtained by reacting compound
(XVII) with a hydroxylamine derivative (VI) represented by NH2OR4 in an appropriate solvent
in the presence of a peptide condensing agent and in the presence or the absence of a base.
The above solvent includes dichloromethane, THF, and dimethylformamide, and
preferably dichloromethane.
The above base includes triethylamine, Hunig's base, or DBU, and preferably Hunig's
base.
The above peptide condensing agent includes 1,3-dicyclohexylcarbodiimide (DCC),
2-ethoxy-1 -ethoxycarbonyl-1,2-dihydroquinoline (EEDQ),
bromo-tris(pyrrolidino)-phosphonium hexafluorophosphate (PyBrOP),
l-ethyl-3-(3'-dimemylaminopropyl)carbodiimide(EDC),
(benzotriazolyloxy)tripyrrolidino-phosphonium hexafluorophosphate (PyBOP),
3-hydroxy-4-oxo-3,4-dihydro-l,2,3-benzotriazine (HODhBt), and hydroxybenzotriazole (HOBt).
Preferable examples include the combination of
l-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (EDC) with N-hydroxybenzotriazole (HOBt),
and the combination of l-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (EDC) with
3 -hydroxy-4-oxo-3,4-dihydro-1,2,3 -benzotriazine (HODhBt).
The above reaction can be performed typically at about 10°C to about 30°C, preferably
about 22°C (room temperature) for about one hour to about two days, preferably about 10 hours.
Compound (XVIII) can also be prepared from the aldehyde (VIII). Specifically,
compound (XVIII) can be obtained by stirring an aldehyde (VIII) with an o-alkyl-hydroxylamine
derivative (XVI) in an appropriate solvent.
The above solvent includes dichloromethane, ethanol, chloroform, THF,
dimethylformamide, and diethyl ether, and preferably dichloromethane or ethanol.
Preparation of compound (I-d)
Oxime ether (XVIII) can be converted into compound (I-d) by reacting oxime ether
(XVIII) with an appropriate reducing agent in an appropriate solvent and if necessary in the
presence of an appropriate acid.
The above solvent includes methanol, ethanol, diethyl ether, tetrahydrofuran, toluene,
methylene chloride, and acetonitrile.
The above reducing agent includes sodium boron hydride, sodium boron cyanohydride,
triethylsilane, trimethylsilane, lithium aluminum hydride, diisopropyl aluminum hydride,
borane-pyridine complex, decaborane, diborane, borane-dimethylsulfide complex, borane-THF
complex, zinc boron hydride, and tributyltin hydride. Preferable examples include sodium
boron cyanohydride, sodium boron hydride, triethylsilane, and borane-pyridine complex.
The above acid includes acetic acid, hydrochloric acid, trifluoroacetic acid,
dichloroacetic acid, trifluoroboron-diethyl ether complex, trimethylsilyl triflate, AlCb, titanium
tetrachloride, and trimethylsilyl chloride. Preferable examples include dichloroacetic acid,
hydrochloric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, and
pyridinium-p-toluenesulfonic acid.
The above reaction can be performed typically at about -78°C to about 120°C for about
one hour to about two days.
The reaction can be performed by using methods described in the following literature or
similar methods thereto.
a) M. Kawase, and Y. Kikugawa, J. Chem. Soc. Perkin Trans. 1,1979, 643-645.
b) B. Hegedues, and A. F. Krasso, Helv. Chim. Acta, 1970, 53,959-963.
c) R. F. Borch, et al, J. Am. Chem. Soc., 1971, 93, 2897-2904.
d) D D. Sternbach, W. C. L. Jamison, Tetrahedron Lett., 1981,22, 3331-3334.
e) M. Ueda, H. Miyabe, M. Namba, T. Nakabayashi, and T. Naito, Tetrahedron Lett.,
f) M. Gustafsson, R. Olsson, C-M. Andersson, Tetrahedron Lett., 2001,42,133-136.
g) M. Fujita, H. Oishi, T. Hiyama, Chem. Lett., 1986, 837-838.
h) R. Camehn, K. Rehse, Arch. Pharma. (Weinheim Ger.), 2000, 333,130-134.
Reaction process 6
Reaction process 6 is an example process for preparing compound I represented by the
formula (1), particularly compound (I-e) having Y—NRgO- and R=C(=O)R9> from compound
(I-d) or compound (XVII).
Preparation of compound (I-e) from compound (I-d)
100
Compound (I-e) can be prepared from compound (I-d)by making carboxylic acid (XXI)
represented by Rg-COOH into an active ester with an appropriate peptide condensing agent in an
appropriate solvent, and reacting the ester with compound (I-d) in the presence or the absence of
an appropriate base.
The above solvent includes dichloromethane, THF, and dimethylformamide.
The above base includes triethylamine, Hunig's base, or DBU, and preferably Hunig's
base.
The above peptide condensing agent includes 1,3-dicyclohexylcarbodiimide (DCC),
2-ethoxy-1 -ethoxycarbonyl-1,2-dihydroquinoline (EEDQ),
bromo-tris(pyrrolidino)-phosphonium hexafluorophosphate (PyBrOP),
1 -ethyl-3-(3'-dimethylaminopropyl)carbodiimide (EDC),
(benzotriazolyloxy)tripyrrolidino-phosphonium hexafluorophosphate (PyBOP),
3-hydroxy-4-oxo-3,4-dihydro-l,2,3-benzotriazine (HODhBt), and hydroxybenzotriazole (HOBt).
Preferable examples include the combination of
l-ethyl-3-(3l-dimethylaminopropyl)carbodiimide (EDC) with N-hydroxybenzotriazole (HOBt),
and the combination of l-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (EDC) with
3 -hydroxy-4-oxo-3,4-dihydro-1,2,3 -benzotriazine (HODhBt).
The above reaction can be performed typically at about 0°C to about 30°C, preferably
about 22°C (room temperature) for about one hour to about two days, preferably about 10 hours.
Compound (I-e) can be prepared from compound (XVII).
Preparation of compound (XIX)
Oxime ether (XVII) can be converted into a reduced compound (XIX) thereof in
accordance with the method for converting a oxime (XVIII) into compound (I-d) described
above.
Specifically, the conversion can be accomplished by reacting oxime ether (XVII) with
an appropriate reducing agent in an appropriate solvent and if necessary in the presence of an
appropriate acid.
The above solvent includes methanol, ethanol, diethyl ether, tetrahydrofuran, toluene,
methylene chloride, and acetonitrile.
The above reducing agent includes sodium boron hydride, sodium boron cyanohydride,
triethylsilane, trimethylsilane, lithium aluminum hydride, diisopropyl aluminum hydride,
borane-pyridine complex, decaborane, diborane, borane-dimethylsulfide complex, borane-THF
complex, zinc boron hydride, and tributyltin hydride. Preferable examples include sodium
boron cyanohydride, sodium boron hydride, triethylsilane, and borane-pyridine complex.
The above acid includes acetic acid, hydrochloric acid, trifluoroacetic acid,
dichloroacetic acid, trifluoroboron-diethyl ether complex, trimethylsilyl triflate, AlCla, titanium
tetrachloride, and trimethylsilyl chloride. Preferable examples include dichloroacetic acid,
hydrochloric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, and
pyridinium-p-toluenesulfonic acid.
The above reaction can be performed typically at about -78°C to about 120°C for about
one hour to about five days.
Preparation of compound (XX)
An alkoxyamine (XIX) can be converted into an amide (XX) in accordance with the
method for converting compound (I-d) into compound (I-e) described above.
More specifically, the preparation can be performed by making carboxylic acid (XXI)
represented by Rg-COOH into an active ester with an appropriate peptide condensing agent in an
appropriate solvent, and reacting the ester with the amine (XIX) in the presence or the absence of
an appropriate base.
The above solvent includes dichloromethane, THF, and dimethylformamide.
The above base includes triethylamine, Hunig's base, or DBU, and preferably Hunig's
base.
The above peptide condensing agent includes 1,3-dicyclohexylcarbodiimide (DCC),
2-ethoxy-1 -ethoxycarbonyl-1,2-dihydroquinoline (EEDQ),
bromo-tris(pyrrolidino)-phosphonium hexafluorophosphate (PyBrOP),
1 -ethyl-3-(3'-dimethylaminopropyl)carbodiimide (EDC),
(benzotriazolyloxy)tripyrrolidino-phosphonium hexafluorophosphate (PyBOP),
3-hydroxy-4-oxo-3,4-dihydro-l,2,3-benzotriazine (HODhBt), and hydroxybenzotriazole (HOBt).
Preferable examples include the combination of
l-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (EDC) with N-hydroxybenzotriazole (HOBt),
and the combination of l-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (EDC) with
3-hydroxy-4-oxo-3,4-dihydro-l,2,3-benzotriazine (HODhBt).
The above reaction can be performed typically at about 0°C to about 30°C, preferably
about 22°C (room temperature) for about one hour to about two days, preferably about 10 hours.
Preparation of compound (I-e)
A carboxylic acid (XX) can be converted into a desired compound (I-e) in accordance
with the method for converting a 2-(phenylamino)-5-vinylbenzoic acid derivative (V) into a
hydroxamic acid derivative (VII) described above.
More specifically, compound (I-e) can be obtained by reacting compound (XX) with a
hydroxylamine derivative (VI) represented by NH2OR4 in an appropriate solvent in the presence
102
of a peptide condensing agent and in the presence or the absence of a base.
The above solvent includes dichloromethane, THF, and dimethylformamide, and
preferably dichloromethane.
The above base includes triethylamine, Hunig's base, or DBU, and preferably Hunig's
base.
The above peptide condensing agent includes 1,3-dicyclohexylcarbodiimide (DCC),
2-ethoxy-l-ethoxycarbonyl-l, 2-dihydroquinoline (EEDQ),
bromo-tris(pyrrolidino)-phosphonium hexafluorophosphate (PyBrOP),
1 -ethyl-3-(3'-dimethylammopropyl)carbodiimide (EDC),
(benzotriazolyloxy)tripyrrolidino-phosphonium hexafluorophosphate (PyBOP),
3-hydroxy-4-oxo-3,4-dihydro-l,2,3-benzotriazine (HODhBt), and hydroxybenzotriazole (HOBt).
Preferable examples include the combination of
l-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (EDC) with N-hydroxybenzotriazole (HOBt),
and the combination of l-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (EDC) with
3-hydroxy-4-oxo-3,4-dihydro-l ,2,3-benzotriazine (HODhBt).
The above reaction can be performed typically at about 10°C to about 30°C, preferably
about 22°C (room temperature) for about one hour to about two days, preferably about 10 hours.
Reaction process 7
Reaction process 7 shows a method of synthesizing compound I represented by the
formula (1), particularly compound (I-g) where X is particularly represented by the folio whig
formula.
The preparation can be performed by using compounds (XXII) and (XXIII) where W is
represented by C(=O)Q in an oxime ether represented by (XVII) or (XVIII) in reaction process 5.
Here, Q represents -ORc, -OCORc, -NRcRd, or a halogen atom; Re and Rd, which may be the
same or different, each represent a hydrogen atom or a Ci_5 alkyl group.
Preparation of compound fXXIVl
A carboxylic acid-oxime (XXII) can be converted into carboxylic acid-alkoxyamine
(XXIV) in accordance with the method for converting an oxime (XVIII) into compound (I-d)
described above.
More specifically, the conversion can be accomplished by reacting oxime ether (XVII)
ith an appropriate reducing agent in an appropriate solvent and if necessary in the presence of
an appropriate acid.
The above solvent includes methanol, ethanol, diethyl ether, tetrahydrofuran, toluene,
methylene chloride, and acetonitrile.
The above reducing agent includes sodium boron hydride, sodium boron cyanohydride,
triethylsilane, trirnethylsilane, lithium aluminum hydride, diisopropyl aluminum hydride,
borane-pyridine complex, decaborane, diborane, borane-dimethylsulfide complex, borane-THF
complex, zinc boron hydride, and tributyltin hydride. Preferable examples include sodium
boron cyanohydride, sodium boron hydride, triethylsilane, and borane-pyridine complex.
The above acid includes acetic acid, hydrochloric acid, trifluoroacetic acid,
dichloroacetic acid, trifiuoroboron-diethyl ether complex, trimethylsilyl triflate, AlCls, titanium
tetrachloride, trimethylsilyl chloride, trifiuoromethanesulfonic acid, p-toluenesulfonic acid, and
pyridinium-p-toluenesulfonic acid. Preferable examples include dichloroacetic acid,
hydrochloric acid, and trifluoroacetic acid.
The above reaction can be performed typically at about -78°C to about 120°C for about
one hour to about five days.
Preparation of compound (XXV)
Alkoxyamine (XXIV) can be converted into a cyclized compound (XXV) by stirring in
I an appropriate solvent at a neutral pH or in the presence of an appropriate acid or an appropriate
base at an appropriate temperature.
In some cases, during the preparation of alkoxyamine (XXIV), cyclization can be
accomplished only by heating the reaction system .
The above solvent includes methanol, ethanol, diethyl ether, tetrahydrofuran, toluene,
i methylene chloride, and acetonitrile.
The above acid includes AlMes, acetic acid, hydrochloric acid, trifluoroacetic acid,
dichloroacetic acid, trifiuoroboron-diethyl ether complex, trimethylsilyl triflate, AlCb, titanium
tetrachloride, trimethylsilyl chloride, trifiuoromethanesulfonic acid, p-toluenesulfonic acid, and
pyridinium-p-toluenesulfonic acid.
) The above base includes triethylamine, Hunig's base, DBU, sodium methylate, and
potassium carbonate.
The above reaction can be performed typically at room temperature to about 80°C for
about one hour to about one day.
> Preparation of compound (I-g)
Compound (XXV) can be converted into compound (I-g) in accordance with the method
for converting a 2-(phenylamino)-5-vinylbenzoic acid derivative (V) into a hydroxamic acid
derivative (VII) described above.
More specifically, compound (I-g) can be obtained by reacting compound (XXV) with a
hydroxylamine derivative (VI) represented by NH2OR4 in an appropriate solvent in the presence
of a peptide condensing agent and in the presence or the absence of a base.
The above solvent includes dichloromethane, THF, and dimethylformamide, and
preferably dichloromethane.
The above base includes triethylamine, Hunig's base, or DBU, and preferably Hunig's
base.
The above peptide condensing agent includes 1,3-dicyclohexylcarbodiimide (DCC),
2-ethoxy-1 -ethoxycarbonyl-1,2-dihydroquinoline (EEDQ),
bromo-tris(pyrrolidino)-phosphonium hexafluorophosphate (PyBrOP),
1 -ethyl-3-(3'-dimethylaminopropyl)carbodiimide (EDC),
(benzotriazolyloxy)tripyrrolidino-phosphonium hexafluorophosphate (PyBOP),
3-hydroxy-4-oxo-3,4-dmydro-l,2,3-benzotriazine (HODhBt), and hydroxybenzotriazole (HOBt).
Preferable examples include the combination of
l-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (EDC) with N-hydroxybenzotriazole (HOBt),
and the combination of l-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (EDC) with
3-hydroxy-4-oxo-3,4-dihydro-l ,2,3-benzotriazine (HODhBt).
The above reaction can be performed typically at about 10°C to about 30°C, preferably
about 22°C (room temperature) for about one hour to about two days, preferably about 10 hours.
Compound (I-g) can also be obtained, by the same conversion method, from oxime
(XXIII) to which hydroxamic acid ester has been already introduced.
Reduction of oxime (XXIII) can be performed in accordance with the method for
converting oxime (XVIII) into compound (I-d) described above.
More specifically, the conversion can be accomplished by reacting oxime ether (XVII)
with an appropriate reducing agent in an appropriate solvent and if necessary an appropriate acid.
The above solvent includes methanol, ethanol, diethyl ether, tetrahydrofuran, toluene,
methylene chloride, and acetonitrile.
The above reducing agent includes sodium boron hydride, sodium boron cyanohydride,
triethylsilane, trimethylsilane, lithium aluminum hydride, diisopropyl aluminum hydride,
borane-pyridine complex, decaborane, diborane, borane-dimethylsulfide complex, borane-THF
complex, hydrogenated zinc boron, and tributyltin hydride. Preferable examples include
sodium boron cyanohydride, sodium boron hydride, triethylsilane, and borane-pyridine
complex.
The above acid includes acetic acid, hydrochloric acid, trifluoroacetic acid,
dichloroacetic acid, trifluoroboron-diethyl ether complex, trimethylsilyl triflate, Aids, titanium
tetrachloride, trimethylsilyl chloride, trifluoromethanesulfonic acid, p-toluenesulfonic acid, and
pyridinium-p-toluenesulfonic acid. Preferable examples include dichloroacetic acid,
hydrochloric acid, and trifluoroacetic acid.
The above reaction can be performed typically at about -78°C to about 120°C for about
one hour to about five days.
Preparation of compound (I-g)
A cyclized compound (XXVI) can be converted into compound (I-g) in accordance
with the method for converting alkoxyamine (XXIV) into a cyclized compound (XXV)
described above.
More specifically, the conversion can be accomplished by stirring in an appropriate
solvent at a neutral pH or in the presence of an appropriate acid or an appropriate base at an
appropriate temperature.
In some cases, during the preparation of alkoxyamine (XXIV), cyclization can be
accomplished only by heating the reaction system. The cyclization can also be accomplished in
the presence of an acid catalyst without the addition of a condensing agent when Q is OH in the
above alkoxyamine (XXVI).
The above solvent includes methanol, ethanol, diethyl ether, tetrahydrofuran, toluene,
methylene chloride, and acetonitrile.
The above acid includes AlMes, acetic acid, hydrochloric acid, trifluoroacetic acid,
dichloroacetic acid, trifluoroboron-diethyl ether complex, trimethylsilyl triflate, Aids, titanium
tetrachloride, trimethylsilyl chloride, trifluoromethanesulfonic acid, p-toluenesulfonic acid, and
pyridinium-p-toluenesulfonic acid.
The above base includes triethylamine, Hunig's base, DBU, sodium methylate, and
potassium carbonate.
The above reaction can be performed typically at room temperature to about 80°C for
about one hour to about one day.
In particular, when Q is OH, compound (I-g) can be obtained by treating compound
(XXVI) with a peptide condensing agent in the presence or the absence of a base and in an
appropriate solvent.
The above solvent includes dichloromethane, THF, and dimethylformamide, and
preferably dichloromethane.
The above base includes triethylamine, Hunig's base, or DBU, and preferably Hunig's
base.
The above peptide condensing agent includes 1,3-dicyclohexylcarbodiimide (DCC),
2-ethoxy-1 -ethoxycarbonyl-1,2-dihydroquinoline (EEDQ),
bromo-tris(pyrrolidino)-phosphonium hexafluorophosphate (PyBrOP),
1 -ethyl-3-(3'-dimethylaminopropyl)carbodiimide (EDC),
(benzotriazolyloxy)tripyrrolidino-phosphoniurn hexafluorophosphate (PyBOP),
3-hydroxy-4-oxo-3,4-dihydro-l,2,3-benzotriazine (HODhBt), and hydroxybenzotriazole (HOBt).
Preferable examples include the combination of
l-emyl-3-(3'-dimethylaminopropyl)carbodiimide (EDC) with N-hydroxybenzotriazole (HOBt),
and the combination of l-ethyl-3-(3'-dimethylaminopropyl)carbodiunide (EDC) with
3 -hydroxy-4-oxo-3,4-dihydro-1,2,3 -benzotriazine (HODhBt).
The above reaction can be performed typically at about 10°C to about 30°C, preferably
about 22°C (room temperature) for about one hour to about two days, preferably about 10 hours.
As in the above, examples of methods for producing compound I according to the
present invention have been described. Isolation and purification of desired compounds shown
in reaction processes 1 to 7 above can be performed by applying standard chemical
manipulations such as extraction, concentration, evaporation, crystallization, filtration,
recrystallization, and various chromatographic operations.
The compounds of the present invention and pharmaceutically acceptable salts thereof
include all stereoisomers of compound I represented by the formula (1) (e.g., enantiomers,
diastereomers (including cis and trans geometric isomers)), racemic bodies of the above isomers
and mixtures thereof. Particularly, hi the present invention, compound I includes stereoisomers.
The compounds of the present invention and pharmaceutically acceptable salts thereof
can be in some tautomer forms, e.g., enol and imine forms, keto and enamine forms, and mixture
thereof. The tautomers are present as a mixture of a tautomer set in a solution. In a solid form,
typically one tautomer is dominant. One tautomer is sometimes described, but all tautomers of
the compounds of the present invention are included in the present invention.
Furthermore, the present invention includes atropisomers. The atropisomer means
compound I represented by the formula (1), which can be divided into isomers whose rotation is
limited.
These isomers can be isolated by standard methods utilizing physicochemical difference
between the isomers. For example, a racemic compound can be made into a sterically purified
isomer by a general optical resolution, e.g., the optical resolution method by leading to a
diastereomer salt with an optically active acid such as tartaric acid. A mixture of diastereomers
can be separated using fractional crystallization or various chromatographic operations (e.g., thin
layer chromatography, column chromatography, gas chromatography and such).
107
When compound I according to the present invention is obtained as a free compound, it
is possible to convert it into a salt which the above compound I may form, or a hydrate or a
solvate thereof in accordance with standard methods.
When compound I according to the present invention is obtained as a salt, a hydrate or a
solvate of compound I, it is possible to convert it into compound I in a free form in accordance
with standard methods.
Compound I of the present invention or pharmaceutically acceptable salts thereof have a
strong MEK inhibitory effect, are excellent in stability in vivo and solubility in water, and are
useful as preventing agents or therapeutic agents for proliferative diseases.
Compound I of the present invention or pharmaceutically acceptable salts thereof are
particularly useful as preventing agents or therapeutic agents for cancers and joint disorders with
inflammation.
The cancers include, for example, breast cancer, lung cancer, colorectal cancer, prostate
cancer, liver cancer, ovarian cancer, uterine cancer, and pancreatic cancer. The joint disorders
with inflammation include, for example, osteoarthritis, rheumatoid arthritis, reactive arthritis,
viral arthritis, purulent arthritis, and tuberculous arthritis.
Furthermore, they are useful as preventing agents or therapeutic agents (especially,
therapeutic agents) for other various cancers such as brain cancer acute leukemia, stomach
cancer and non-small cell lung cancer, and diseases such as psoriasis, restenosis, autoimmune
diseases, and atherosclerosis, as well as sequelae of heart failure, heterograft rejection,
osteoarthritis, chronic rheumatoid arthritis, asthma, cystic fibrosis, hepatomegalia, cardiac
hypertrophy, Alzheimer disease, diabetes, septic shock, and HIV infection.
They are particularly useful as preventing agents or therapeutic agents (especially,
therapeutic agents) for cancers depending on the Ras-MAPK signaling pathway.
Furthermore, the present invention relates to methods for preventing or treating
proliferative diseases, e.g., cancers or joint diseases with inflammation. Another embodiment
of the present invention includes methods for preventing or treating solid or hematopoietic
MEK-related (including Ras-related) cancers or joint diseases with inflammation. Examples of
the cancers are the same as the above. Examples of the other cancer and disease are the same
as the above.
These methods include a step of administering a pharmaceutically effective dose of a
pharmaceutical composition comprising compound I disclosed herein or apharmaceutically
acceptable salt thereof to a patient in need of such a treatment or with such a disease or
condition.
When the pharmaceutical compositions of the present invention are used as an MEK
inhibitor, therapeutic agents or preventing agents for the proliferative diseases, administration
108
methods thereof include oral, rectal, parenteral (intravenous, intramuscular, subcutaneous),
intracisternal, intravaginal, intraperitoneal, intrabladder, topical (infusion, powder medicine,
ointment, gel or cream) administrations and inhalation (oral or nasal spray). Dosage forms
thereof include, for example, tablets, capsules, granules, powder, pills, aqueous and non-aqueous
oral solutions and suspensions, and parenteral solutions filled in containers which adapt for
dispensing an individual dosage. The dosage form can also be adapted to various
administration methods which comprise controlled release formulations such as subcutaneous
implant.
The above formulations are produced by well-known methods using additives such as
an excipient, a lubricant (coating agent), a binder, a disintegrating agent, a stabilizer, a taste
masking/flavoring agent, and a diluting agent.
For example, the excipient includes lactose, crystalline cellulose, calcium
hydrogenphosphate, and starches such as starch, potato starch, and corn starch.
The coating agent includes, for example, ethylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose, shellac, talc, carnauba wax, and paraffin.
The binder includes, for example, polyvinyl pyrrolidone, macrogol, and the same
compounds as in the above excipients.
The disintegrating agent includes, for example, the same compounds as in the above
excipients, and chemically modified starches and celluloses such as cross carmellose sodium,
sodium carboxymethylstarch, and crosslinked polyvinyl pyrrolidone.
The stabilizer includes, for example, paraoxybenzoic acid esters such as methylparaben
and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol;
benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and
sorbic acid.
The taste masking/flavoring agent includes, for example, sweeteners, acidifiers and
flavors usually used.
As solvents for producing liquid formulations, it is possible to use ethanol, phenol,
chlorocresol, purified water, distilled water and such.
A surfactant or an emulsifier includes, for example, polysorbate 80, polyoxyl stearate 40,
and lauromacrogol.
When the pharmaceutical compositions of the present invention are used as a MEK
inhibitor, or therapeutic agents or preventing agents for proliferative diseases, amounts of the
compounds of the present invention and pharmaceutically acceptable salts thereof to be used
vary depending on condition, age, body weight, relative health state, presence of other
medicaments, administration method and such. For example, for a patient (warm-blooded
animal, especially human), in the case of an oral agent, an effective amount is preferably 0.1 to
109
1000 mg, more preferably 1 to 300 mg per kg of body weight per day, and an amount to be used
per day is preferably in the range of 10 to 800 mg for an adult patient with usual body weight as
an active ingredient (compound I). In the case of a parenteral agent, an effective amount is
preferably 0.1 to 1000 mg, and more preferably 10 to 800 mg per kg of body weight per day. It
is desirable to administer this once a day or by dividing into several times a day depending on
the condition.
The above pharmaceutical compositions of the present invention can be used in
combination with the other radiation therapy, chemotherapy and administration of an
angiogenesis inhibitor.
The compounds according to the present invention and the pharmaceutically acceptable
salts thereof have a MEK inhibitory effect, a cell growth inhibitory effect, are excellent in
stability in vivo and solubility in water, and are useful as preventing agents or therapeutic agents
for proliferative diseases, e.g., cancers and joint diseases with inflammation.
Any patents, published patent applications, and publications cited herein are
incorporated by reference.
Brief Description of the Drawing
Figure 1 is a graph showing the inhibitory effect on the development of arthritis in terms
of the relation between arthritis score (Y axis) and days after LPS administration (X axis). (Test
Example 6).
Best Mode for Carrying Out the Invention
The present invention is illustrated in more detail below with reference to Examples.
However, the present invention is not to be construed as being limited thereto.
NMR analyses were performed on JNM-EX270 (270 MHz, JEOL) or JNM-GSX400
(400 MHz, JEOL), and the NMR data are expressed as ppm (parts per million, 8) referencing the
deuterium lock signal from the sample solvent.
Mass spectral data were obtained using JMS-DX303 (JEOL) or JMS-SX/SX102A
(JEOL), or a micromass spectrometer (Navigator, Finnigan) equipped with a gradient high
performance liquid chromatography (Agilent 1100, Agilent Technologies).
Specific rotation was measured using sodium D line (589 nm) at room temperature.
Commercially available reagents were used without further purification. Room
temperature represents a range from about 20 to about 25°C. All the non-aqueous reactions
were carried out under a nitrogen atmosphere. Concentration or evaporation of the solvent
under reduced pressure was done using a rotary evaporator.
In the preparation of a compound, functional groups were protected with protecting
110
groups as needed, and after having prepared the target molecule, the protecting groups were
removed. The selection of the protecting groups and the procedures for protection and
deprotection were done according to the methods described in, for example, Greene and Wuts,
"Protective Groups in Organic Synthesis" (2nd Ed., John Wiley & Sons, 1991).
[Example 1]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-hydroxy-ethoxymeth
yl)-benzamide (Compound B-l)
Step A
Preparation of 2,3,4-trifluoro-5-iodo-benzoic acid
2,3,4-Trifluoro-5-iodo-benzoic acid was prepared according to the method described hi
literature (F. Mongin, E. Marzi, and M. Schlosser, European Journal of Organic Chemistry,
2771-2777 (2001)).
StepB
Preparation of 2,3,4-trifluoro-5-vinyl-benzoic acid
To a solution of 2,3,4-trifluoro-5-iodo-benzoic acid (447 mg, 1.48 mmol) prepared in
Step A in tetrahydrofuran (10 mL) were added tris(dibenzylideneacetone)dipalladium (45 mg,
0.05 mmol, product No. 32877-4, Aldrich), tri-2-furylphosphine (23 mg, 0.01 mmol), and
vinyltributyltin (865 |aL, 3.0 mmol) under an argon atmosphere, and the mixture was stirred at
40°C for 3 hours.
After completion of the reaction, insoluble matter was removed through a celite column.
One mol/L sodium hydroxide solution (30 mL), and then methylene chloride were added to the
reaction solution, and the layers were separated. Another 1 mol/L sodium hydroxide solution
(30 mL) was added to the organic layer, and the layers were separated. One mol/L hydrochloric
acid solution (60 mL) was added to acidify the resultant aqueous layer, and the aqueous layer
was extracted twice with methylene chloride (50 mL). The resultant organic layer was dried
over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced
pressure, and the residue was washed with hexane, filtered, and dried to give
2,3,4-trifluoro-5-vinyl-benzoic acid (248.9 mg, 83% yield) as a pale yellow solid.
^-NMRCCDCU, 270MHz) 5(PPM): 5.54(1H, d, J=11.2Hz), 5.92(1H, d, J=17.8Hz), 6.78(1H, dd,
J= 17.8,11.2Hz), 7.95(1H, td, J=7.6,2.6Hz)
EIMSm/z202(M+H)
StepC
Preparation of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamrno)-5-vinyl-benzoic acid
To a solution of 2-fluoro-4-iodoaniline (5.056 g, 21.336 mmol) in tetrahydrofuran
(anhydrous, 30 mL) was added dropwise 2.0 M lithium diisopropylamide (a solution in
heptane/tetrahydrofuran/ethylbenzene, 13 mL, 26 mmol) with stirring at -78°C under an argon
atmosphere.
After 5 minutes, a solution of 2,3,4-trifluoro-5-vinyl-benzoic acid (1.724 g, 8.534
mmol) prepared in Step B in tetrahydrofuran (anhydrous, 20 mL) was added dropwise to the
reaction mixture. The reaction mixture was warmed gradually to room temperature, and stirred
for 3 days.
One mol/L hydrochloric acid solution was added to the reaction mixture to bring pH
3. Then, the solution was extracted with ethyl acetate. The extract was washed sequentially
with water and saturated brine, and the organic layer was dried over anhydrous sodium sulfate
and filtered. The solvent was evaporated under reduced pressure, and the resultant dark brown
solid was triturated with methylene chloride to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-vinyl-benzoic acid (2.352 g, 66% yield) as a
pale yellow solid.
'H-NMRXCDaOD, 270MHz) 8(PPM): 5.41(1H, d, J=11.5Hz), 5.86(1H, d, J=17.2Hz), 6.76(1H,
td, J=8.6, 5.6Hz), 6.79(1H, dd, J=17.2, ll.SHz), 7.41(1H, m), 7.48(1H, dd, J=10.6,2.0Hz),
8.05(1H, dd, 7.9, 2.0Hz)
ESI(LC/MS positive mode) m/z 420 (M+H)
StepD
Preparation of
N-[2-(tert-butyldimethylsilanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-5-vin
yl-benzamide
To a solution of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-vinyl-benzoic acid (6.2
g, 14.8 mmol) prepared in Step C in methylene chloride (100 ml) were added
O-[2-(tert-butyldimethylsilanyloxy)-ethyl]-hydroxylamine (3.40 g, 17.8 mmol),
l-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (3.40 g, 17.8 mmol),
1-hydroxybenzotriazole monohydrate (3.0 g, 22.1 mmol), and N5N-diisopropylethylamine (5.1
ml, 29.6 mmol), and the mixture was stirred at room temperature for 20 hours.
The reaction mixture was concentrated under reduced pressure, and water (300 ml) was
added thereto. The mixture was extracted with ethyl acetate (500 ml), and the organic layer
was washed with saturated brine (200 ml), dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The residue was purified by silica gel column
chromatography (500 g, n-hexane/ethyl acetate (20:1)) to give
N- [2-(tert-butyldimethylsilanyloxy)ethoxy] -3,4-difiuoro-2-(2-fluoro-4-iodophenylamino)-5-viny
113
Ibenzamide (6.36 g, 73%) as a pale yellow solid.
'H-NMRtCDsOD, 270MHz) 5(PPM) 0.07 (6H, s), 0.86 (9H, s), 3.91 (2H, dd, J = 5.0,4.0 Hz),
4.07 (2H, dd, J = 5.0, 4.0 Hz), 5.44 (IH, d, J = 11.2 Hz), 5.81 (IH, d, J = 17.5 Hz), 6.57 (IH, td, J
= 8.9, 5.0 Hz), 6.74 (IH, dd, J = 17.8,10.9 Hz), 7.32 (IH, br. d, J = 7.9 Hz), 7.37 - 7.42 (2H, m),
8.20 (IH, br. s), 9.38 (IH, br. s)
ESI(LC/MS positive mode) m/z 593 (M+H)
StepE
Preparation of
N-[2-(tert-butyldimethylsilanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-5-for
myl-benzamide
N-[2-(Teit-butyldimethylsilanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylami
no)-5-vinyl-benzamide (27.4 g, 46.27 mmol) prepared in Step D was dissolved in a mixed
solvent of tetrahydrofuran (300 ml) and water (90 ml). To this solution, an aqueous solution of
osmium tetroxide (0.1 mM, 9.25 ml, 0.95 mmol) and sodium metaperiodate (38.6 g, 0.180 mol)
were added at 0°C, and the mixture was stirred at room temperature for 3 hours.
Insoluble matter was removed by celite filtration, and washed with ethyl acetate. The
combined filtrate and washing were washed with an aqueous solution of 0.2 M sodium
thiosulfate and saturated brine, dried over magnesium sulfate, and evaporated under reduced
pressure to give a mixture (37.1 g) of
N-[2-(tert-butyldimethylsilanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylammo)-5-for
myl-benzamide and a desilylated product,
3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide(the
same compound as the product in the next step). (Pure
N-[2-(tert-butyldimethylsilanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-5-for
myl-benzamide can be obtained by purification with silica gel chromatography (300 g,
n-hexane/ethyl acetate (5:1)).
'H-NMRtCDsOD, 270MHz) 6(PPM) 0.11 (6H, s), 0.78 (9H, s), 3.97 (2H, dd, J = 5.1,4.3 Hz),
4.13 (2H, dd, J = 4.6,4.3 Hz), 6.82 (1H, td, J = 8.6,4.1 Hz), 7.30 - 7.38 (2H, m), 7.78 (1H, dd, J
= 6.8,2.2 Hz), 9.64 (2H, br s), 10.15 (1H, s)
ESI(LC/MS positive mode) m/z 595 (M+H)
StepF
Preparation of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylarnino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide
N- [2-(Tert-butyldimethylsilanyloxy)-ethoxy] -3,4-difluoro-2-(2-fluoro-4-iodophenylami
no)-5-formyl-benzamide (37.1 g as a crude product containing the desilylated product) prepared
in Step E was dissolved in a mixed solvent of tetrahydrofuran (200 ml) and water (16 ml). To
this solution, p-toluenesulfonic acid monohydrate (1.76 g, 9.25 mmol) was added, and the
mixture was stirred at room temperature for 12 hours. The reaction mixture was extracted with
ethyl acetate, and the organic layer was washed with saturated brine, dried over magnesium
sulfate, and evaporated under reduced pressure. The resultant residue was triturated with ethyl
acetate to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide(16.0
g, 72% yield in two steps) as a yellow solid.
!H-NMR(DMSO-d6 270MHz) 6(PPM) 3.17(1H, d, J=4.6Hz), 3.59(2H, t, J=4.6Hz), 3.85(2H, t,
J=4.6Hz), 6.99(1H, td, J=8.9, 3.0), 7.48(1H5 d=8.3Hz), 7.67(1H, d, J=10.9Hz), 7.86(1H, d,
J=6.9Hz), 9.64(1H, br.s), 10.02(1H, s)
ESI(LC/MS positive mode) m/z 481 (M+H)
StepG
Preparation of
5-[l,3]dioxolan-2-yl-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benza
115
To a solution of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide
(15.99 g, 33.3 mmol) prepared in Step F in anhydrous THF (150 ml) were added ethylene glycol
(70 ml) and p-toluenesulfonic acid monohydrate (316.6 mg, 1.66 mmol) at room temperature,
and the mixture was stirred for 14 hours. Then ethylene glycol (100 ml) was added, and the
reaction mixture was stirred for additional 8 hours. The reaction mixture was poured into
saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer was
washed with saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium
sulfate, and concentrated under reduced pressure to give
5-[l,3]dioxolan-2-yl-3,4-difluoro-2-(2-fluoro-4-iodo-phenylammo)-N-(2-hydroxy-ethoxy)-benza
mide (21.69 g) as a crude product.
!H-NMR(CDCl3,270MHz) 6(PPM) 3.76 (IH, br. s, OH), 4.04-4.23 (8H, m), 6.00 (IH, s), 6.60
(IH, td, J = 8.6,4.3 Hz), 7.33 (IH, dt, J = 6.9, 1.3 Hz), 7.42 (IH, dd, J = 9.9,1.7 Hz), 7.52 (IH,
br. d, J = 6.9 Hz), 8.32 (IH, br. s), 9.09 (IH, br. s)
ESI(LC/MS positive mode) m/z 525 (M+H)
StepH
Preparation of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylaniino)-N-(2-hydroxy-ethoxy)-5-(2-hydroxy-ethoxymethy
l)-benzamide
To a solution of
5-[l,3]dioxolan-2-yl-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benza
mide (21 .69 g) obtained in Step G in anhydrous THF (100 ml) were added sodium borohydride
(4.21 g, 111.4 mmol) and trifluoroacetic acid (5.08 ml, 66.8 mmol) with ice-cooling, and the
mixture was stirred at room temperature overnight. The reaction mixture was poured into
saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer was
washed with saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium
sulfate, and concentrated under reduced pressure. The residue was purified by silica gel
column chromatography (SiO2 600 g, 100% AcOEt to AcOEt/MeOH (50:1 to 20:1)) to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-hydroxy-ethoxymethy
l)-benzamide (13.9 g, 80%) as a white powder.
, 270MHz) S(PPM) 3.51 (2H, dd, J = 3.9, 3.3 Hz), 3.60-3.63 (4H, m), 3.86
(2H, dd, J = 4.9, 4.3 Hz), 4.52 (2H, s), 6.50 (IH, td, J = 8.6, 4.6 Hz), 7.23 (IH, ddd, J = 8.6, 2.0,
1.0 Hz), 7.33 (IH, dd, J = 10.9, 2.0 Hz), 7.43 (IH, dd, J = 6.9, 2.0 Hz)
ESI(LC/MS positive mode) m/z 527(M+H)
[Example 2]
2-(4-Emynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-(2-hydroxy-ethoxym
ethyl)-benzamide (Compound B-2)

To a solution of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-hydroxy-ethoxymethy
l)-benzamide (46.1 mg, 87.6 μmol) obtained in Step H of Example 1 in tetrahydrofuran
(anhydrous, 2.0 ml) were added trimethylsilylacetylene (48.5 μL, 0.350 mmol), copper iodide
(3.3 mg, 17.5 μmol), (PPh3)2PdCl2 (3.7 mg, 5.3 umol), and Hunig's base (diisopropylethylamine,
149 μL, 0.876 mmol), and the mixture was stirred at 50°C for 2 hours.
The reaction mixture was concentrated under reduced pressure. 0.1 N Hydrochloric
acid was added to the resultant residue, and the mixture was extracted with ethyl acetate. The
organic layer was washed with 0.1 N hydrochloric acid and brine, dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure. The resultant residue was
purified by silica gel column chromatography (Presep Silica Gel Type S (Wako Pure Chemical
Industries), 10 g, CH2Cl2/MeOH (10:1)) to give
3,4-difluoro-2-(2-fluoro-4-trimethylsilanylethynyl-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-hy
droxy-ethoxymethyl)-benzamide (37.6 mg, 86%).
To a solution of the resultant
3,4-difluoro-2-(2-fluoro-4-trimethylsilanylethynyl-phenylammo)-N-(2-hydroxy-ethoxy)-5-(2-hy
droxy-ethoxymethyl)-benzamide (37.6 mg) in tetrahydrofuran (anhydrous, 1.0 ml) was added
tetra-n-butylammonium fluoride (1 M solution in THF, 113 |aL, 113 umol) at room temperature,
and the mixture was stirred for 3 hours. The reaction mixture was concentrated under reduced
pressure. 0.1 N Hydrochloric acid was added to the resultant residue, and the mixture was
extracted with ethyl acetate. The combined organic layers were washed with 0.1 N
hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure. The resultant residue was purified by silica gel column
chromatography (Presep Silica Gel Type S (Wako Pure Chemical Industries), 10 g,
CH2Cl2/MeOH (10:1 to 5:1)) to give
2-(4-emynyl-2-fluoro-phenylarnino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-(2-hydroxy-ethoxyrne
thyl)-benzamide (21.9 mg, 68%) as a yellow powder.
JH-NMR(CD3OD, 270MHz) 8(PPM) 3.03 (IH, s), 3.66 (2H, dd, J = 4.6, 3.6 Hz), 3.75 (2H, t, J =
4.3 Hz), 3.83 (2H, t, J = 4.3 Hz), 4.04 (2H, dd, J = 4.6, 3.6 Hz), 4.58 (2H, s), 6.68 (IH, td, J = 8.3,
5.6 Hz), 7.14 (d, J = 8.6 Hz), 7.18 (dd, J = 11.2,1.6 Hz), 7.54 (d, J = 5.3 Hz), 8.50 (IH, br. s)
ESI(LC/MS positive mode) m/z 425 (M+H)
The compounds of Examples 3 and 4 below were synthesized by preparing cyclic
acetal compounds using an aldehyde,
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide
obtained in Step F of Example 1 as a starting material, and 1,3-propanediol or
2,2-dimethyl-l,3-propanediol, respectively, instead of ethylene glycol used as a reagent in Step G
of Example 1, and subjecting the acetal compounds to reducing conditions similar to those in
Step H of Example 1.
[Example 3]
3,4-Difluoro-2-(2-fluoro-4-iodophenylamino)-N-(2-hydroxy-ethoxy)-5-(3-hydroxy-propoxymeth
yl)-benzamide (Compound B-6)
HO,
, 270MHz) 8(PPM) 1.83(2H, quin., J=6.3Hz), 3.64(4H, m), 3.68(2H, m),
3.95(2H, m), 4.57(2H, br.s), 6.59(1H, td, J=8.9,4.6Hz), 7.34(1H, dd, J=8.6,1.3Hz), 7.43(1H, dd,
J=10.9,2.0Hz),7.50(lH,m)
ESI(LC/MS positive mode) m/z 541(M+H)
[Example 4]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-(3-hydroxy-2,2-dimethyl-propoxymethyl)-N-(2
-hydroxy-ethoxy)-benzamide (Compound B-7)
270MHz) 6(PPM) 0.90(6H, s), 3.37(2H, s), 3.70(2H, dd, J=4.9,4.3Hz),
3.93(2H, dd, J=4.9,4.3Hz), 4.57(2H, s), 6.60(1H, td, J=8.9, 4.6Hz), 7.34(1H, d, J=8.6Hz),
7.44(1H, dd, J=10.6, 2.0Hz), 7.47(1H, m)
ESI(LC/MS positive mode) m/z 569(M+H)
119
[Example 5]
5-(2,3-Dihydroxy-propoxvmethyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxyethoxy)
benzamide
Step A
Preparation of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-benzoic acid
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-vinylbenzoic acid (200 mg, 0.477
mmol) prepared in Step C of Example 1 was dissolved in tetrahydrofuran (20 ml) and water (1
mL). To this reaction mixture, an aqueous solution of 0.1 M osmium tetroxide (1.0 mL) and
sodium metaperiodate (510 mg, 2.39 mmol) were added at room temperature, and the mixture
was stirred for 2 hours. Insoluble matter was removed through a celite column, and ethyl
acetate extraction was performed.
The extract was washed sequentially with water and saturated brine, and the organic
layer was dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under
reduced pressure, and the resultant dark brown solid was triturated with methanol to give
3,4-difluoro-2-(2-fluoro-4-iodophenylammo)-5-formyl-benzoic acid (133.6 mg, 66% yield) as a
pale yellow solid.
'H-NMR(DMSO-d6,270MHz) 5(PPM) 7.11(1H, td, J=8.6, 3.6), 7.53(1H, m), 7.71(1H, dd,
J=10.2,1.7Hz), 8.27(1H, dd, J=7.3,1.3Hz), 10.00(lH,s), 10.08(lH,br.s)
ESI(LC/MS positive mode) m/z 422 (M+H)
120
StepB
Preparation of 5-allyloxymethyl-3,4-difluoro-2-(2-fluoro-4-iodo-phenylaniino)-benzoic acid
To bismuth (III) chloride (37 mg, 0.188 mmol) that was dried by heating under reduced
pressure, methylene chloride (anhydrous, 3 ml suspension) was added under argon flow, and the
mixture was stirred thoroughly. To this suspension, allyl alcohol (40 uL, 0.57 mmol),
triethylsilane (107 uL, 0.671 mmol), and
3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-5-formyl-benzoic acid (200 mg, 0.475 mmol)
prepared in Step A were added at room temperature, and the mixture was stirred for a whole day
and night. After completion of the reaction, the reaction mixture was extracted with ethyl
acetate.
The extract was washed sequentially with water and saturated brine, and the organic
layer was dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under
reduced pressure, and the resultant dark brown solid was purified with Presep (Wako Pure
Chemical Industries, 10 g).
5-Allyloxymethyl-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzoic acid (140.7 mg, 64%
yield) was obtained as a light brown solid from fractions eluted with 100% ethyl acetate.
, 270MHz) 6(PPM) 4.08(2H, m), 4.56(2H, s), 5.25(1H, d, J=10.2Hz), 5.32(1H,
d, J=17.1Hz), 5.92(1H, m), 6.80(1H, m), 7.41(1H, d, J=10.2Hz), 7.48(1H, d, J=10.6Hz), 7.96(1H,
ESI(LC/MS positive mode) m/z 464 (M+H)
StepC
Preparation of
5-allyloxymethyl-N-[2-(tert-butyldimethylsilanyloxy)ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodophe
nylamino)-benzamide
121
To a solution of 5-allyloxymethyl-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzoic
acid (140 mg, 0.302 mmol) prepared in Step B in N,N-dimethylformamide (anhydrous, 4 mL)
were added N-hydroxysuccinimide (41 mg, 0.363 mmol) and
l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (70 mg, 0.363 mmol) at room
temperature under argon flow, and the mixture was stirred thoroughly. Subsequently,
0-[2-(t-butyldimethylsilanyloxy)ethyl]-hydroxyamine (86 mg, 0.453 mmol) was added thereto,
and the mixture was stirred for 2 hours. After completion of the reaction, the reaction mixture
was extracted with ethyl acetate.
The extract was washed sequentially with water and saturated brine, and the organic
layer was dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under
reduced pressure, and the resultant brown oil was purified with Mega Bond Elut silica gel
(Varian, 5 g).
5-Allyloxymethyl-N-[2-(tert-butyldimethylsilanyloxy)ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodoph
enylamino)benzamide (35.5 mg, 18% yield) was obtained as a pale yellow oil from fractions
eluted with 10% ethyl acetate/hexane.
, 270MHz) 8(ppm) 0.04(6H, s), 0.79(9H, s), 3.83(2H, m), 4.03(2H, m), 4.44(2H,
s), 5.18(1H, d, J=11.5Hz), 5.26(1H, m), 5.87(1H, m), 6.48(1H, td, J=8.6, 4.9Hz), 7.23(1H, d,
J=8.9Hz), 7.31(1H, m), 7.32(1H, m), 8.30(1H, br.s), 9.25(1H, br.s)
ESI(LC/MS positive mode) m/z 637 (M+H)
StepD
Preparation of
5-allyloxymemyl-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzarni
To a solution of
5-allyloxymethyl-N-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodop
henylamino)-benzamide (35.5 mg, 0.056 mmol) prepared in Step C in tetrahydrofuran
(anhydrous, 4 mL) was added dropwise tetra-n-butylammonium fluoride (1 mol/L solution in
tetrahydrofuran, 0.5 mL, 0.5 mmol) at room temperature, and the mixture was stirred for 4 hours.
After completion of the reaction, the solvent was evaporated under reduced pressure,
and the yellow oil was extracted with ethyl acetate. The extract was washed sequentially with
water and saturated brine, and the organic layer was dried over anhydrous sodium sulfate, and
filtered. The solvent was evaporated under reduced pressure, and the resultant brown oil was
purified by preparative TLC (60% ethyl acetate/hexane as a developing solvent) to give
5-allyloxymethyl-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzami
de (11 mg, 38% yield) as a white solid.
, 270MHz) 5(PPM) 3.70(2H, dd, J=4.9, 4.3Hz), 3.93(2H, dd, J=4.9, 4.3Hz),
4.09(2H, dt, J=5.6, 1.3Hz), 4.57(2H, s), 5.21(1H, ddd, J=10.2, 3.0, 1.3Hz), 5.33(1H, ddd, J=17.1,
4.9, 1.6Hz), 5.96(1H, m), 6.61(1H, td, J=8.6, 4.3Hz), 7.34(1H, dt, J=8.6, l.OHz), 7.45(1H, dd,
J=8.6, 2.0Hz), 7.46(1H, dd, J=6.9, 2.0Hz)
ESI(LC/MS positive mode) m/z523 (M+H)
StepE
Preparation of
d,l-5-(2,3-dihydroxy-propoxymethyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydro
xyethoxy)-benzamide
To a solution of
5-allyloxymethyl-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzami
de (11 mg, 0.021 mmol) prepared in Step D in tetrahydrofuran (anhydrous, 4 mL) and water (1
mL) were added 4% osmium tetroxide solution (100 uL) and 30% hydrogen peroxide solution
(0.5 mL) at room temperature, and the mixture was stirred for 3 hours. After completion of the
reaction, the reaction mixture was extracted with ethyl acetate.
The extract was washed sequentially with water and saturated brine, and the organic
layer was dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under
reduced pressure, and the resultant brown oil was purified with Mega Bond Elut silica gel
(Varian, 5 g).
d,l-5-(2,3-Dihydroxy-propoxymethyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2 -hydro
xy-ethoxy)-benzamide (6.8 mg, 58%) was obtained as a white solid from fractions eluted with
10% methanol/methylene chloride.
, 270MHz) 5(PPM) 3.51-3.64(4H, m), 3.70(2H, dd, J=5.3, 4.6Hz), 3.81(1H,
quin. J=5.3Hz), 3.94(2H, t, J=4.9), 4.63(2H, s), 6.61(1H, td, J=8.6, 4.6Hz), 7.35(1H, m), 7.50(1H,
br.d, J=5.9Hz)
ESI(LC/MS positive mode) m/z557 (M+H)
[Example 6]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyamin
Step A
Preparation of
(E)-N-[2-(t-butyl-dimethyl-silanyloxy)-ethoxy]-5-{[2-(t-butyl-dimethyl-silanyloxy)-ethoxyimino
]-methyl} -3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
To a solution of 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-5-formyl-benzoic acid
(130 mg, 0.309 mmol) prepared in Step A of Example 5 in methylene chloride (anhydrous, 5
mL) were added 1-hydroxybenzotriazole (42 mg, 0.309 mmol),
l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (177 mg, 0.926 mmol), and
N,N-diisopropylethylamine (161 uL, 0.926 mmol) at room temperature under argon flow, and
the mixture was stirred thoroughly. Subsequently,
O-[2-(t-butyl-dimethyl-silanyloxy)-ethyl]-hydroxyamine (177 mg, 0.926 mmol) was added
thereto, and the mixture was stirred for 17 hours. After completion of the reaction, the reaction
mixture was extracted with ethyl acetate.
The extract was washed sequentially with water and saturated brine, and the organic
layer was dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under
reduced pressure, and the resultant brown oil was purified with Mega Bond Elut silica gel
(Varian, 10 g).
(E)-N-[2-(t-Butyl-dimethyl-silanyloxy)-ethoxy]-5-{[2-(t-butyl-dimethyl-silanyloxy)-ethoxyimin
o]-methyl}-3,4-difluoro-2-(2-fluoro-4-iodo-phenylarnino)-benzamide (137.1 mg, 58% yield) was
obtained as a pale yellow solid from fractions eluted with 10% ethyl acetate/hexane.
'H-NMR(CDCl3, 270MHz) 8(PPM): 0.08(6H,s), 0.09(6H, s), 0.87(9H,s), 0.91(9H,s),
3.92(4H,m), 4.12(2H,m), 4.26(2H,m), 6.64(1H, td, J=8.6, 5.3Hz), 7.35(lH,m), 7.41(1H, dd,
J=10.3,1.7Hz), 7.73(1H, br.s), 8.22(lH,s), 8.78(lH,br.s), 9.43(1H, br.s)
EIMS m/z 767(M+H)
StepB
Preparation of
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyi
mino)-methyl]-benzarnide
To a solution of
(E)-N-[2-(t-butyl-dirnethyl-silanyloxy)-ethoxy]-5-{[2-(t-butyl-dimethyl-silanyloxy)-ethoxyimino
]-methyl}-3,4-difluoro-2-(2-fluoro-4-iodo-phenylammo)-benzamide (410 mg, 0.534 mmol)
prepared in Step A in tetrahydrofuran (anhydrous, 20 mL) was added dropwise
tetra-n-butylammonium fluoride (1 mol/L solution in tetrahydrofuran, 1.4 mL, 1.4 mmol) at
room temperature, and the mixture was stirred for 4 hours.
After completion of the reaction, the solvent was evaporated under reduced pressure,
and the yellow oil was extracted with ethyl acetate. The extract was washed sequentially with
water and saturated brine, and the organic layer was dried over anhydrous sodium sulfate, and
filtered. The solvent was evaporated under reduced pressure, and the resultant brown oil was
purified with Mega Bond Elut silica gel (Varian, 5 g). The pale yellow solid obtained from
fractions eluted with 100% ethyl acetate was triturated with ethyl acetate to give
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylarnino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyi
mino)-methyl]-benzamide (134 mg, 47% yield) as a white solid.
1H-NMR(CD3OD, 270MHz) 8(PPM): 3.72(2H, t, J=4.9Hz), 3.82(2H, t, J=4.9Hz), 3.95(2H, dd,
J=4.9,4.3Hz), 4.26(2H, dd, J=4.9, 4.6), 6.72(1H, td, J=8.6, 4.3Hz), 7.39(1H, m), 7.47(1H, dd,
J=10.6,1.6Hz), 7.81(1H, dd, J=4.9,1.6Hz), 8.29(1H, s)
126
ESI(LC/MS positive mode) m/z 540 (M+H)
StepC
Preparation of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyamin
o)-methyl] -benzamide
To a solution of
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyi
mino)-methyl] -benzamide (3.62 g, 6.70 mmol) obtained in Step B in methanol (100 ml) were
added portionwise trifluoroacetic acid (6.5 ml) and sodium cyanoborohydride (3.78 g, 60.2
mmol) over 2 days while monitoring the progression of the reaction by TLC. The reaction
mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed
with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and concentrated
under reduced pressure. The residue was purified by silica gel column chromatography
(CHiCb/MeOH (15:1)), and the resultant crude compound was crystallized from methyl ene
chloride to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyamin
o)-methyl] -benzamide (1.66 g, 46%, as a total of first and second crystals).
, 270MHz) 5(PPM): 3.63 - 3.70 (6H, m), 3.94 (2H, dd, J = 4.9, 4.3 Hz), 4.08
(2H, s), 6.59 (1H, td, J=8.6, 4.3 Hz), 7.34(1H5 d, J = 8.2 Hz), 7.44 (1H, dd, J = 10.9, 2.0 Hz),
7.50 (1H, dd, J = 6.9, 2.0Hz).
ESI(LC/MS positive mode) m/z 542 (M+H)
Step B'
The oxime compound,
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyi
mino)-methyl]-benzamide obtained in Step B of Example 6 may be easily prepared from
127
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide
obtained in Step F of Example 1 by a reaction with 2-aminooxyethanol in THF at room
temperature.
Namely,
3,4-difluoro-2-(2-fluoro-44odo-phenylamino)-5-forrnyl-N-(2-hydroxy-ethoxy)-benzarnide(1.37
g) and aminooxy ethanol (262 mg) were mixed in THF at room temperature for 12 hours, and
then the solvent was evaporated to give
3 ,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5 - [(2-hydroxy-ethoxyimin
o)-methyl] -benzamide.
NH
Step C'
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-eth
oxyamino)-methyl] -benzamide obtained in Step C of Example 6 may be prepared hi another
condition. Namely,
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyrmin
o)-methyl] -benzamide (1.76 g, 3.27 mmol) obtained hi Step B (or Step B') of Example 6 was
suspended in methyl ene chloride, and borane-pyridine complex (1.21 g, 13.1 mmol) and
dichloroacetic acid (1.69 g, 13.1 mmol) were added thereto at room temperature. The mixture
was stirred for 3 hours. The solvent was evaporated, and the residue was purified by silica gel
chromatography using CHiCb/MeOH as a developing solvent to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyamin
o)-methyl] -benzamide (1.40 g).
[Example 7]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)5-[(3-hydroxy-propoxyami
no)-methyl] -benzamide (Compound C-10)
Step A
Synthesis of
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-hydroxy-propoxy
imino)-methyl]-benzamide
The title compound was obtained by a procedure similar to that in Step B' of Example 6
using 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide
obtained in Step F of Example 1 as a starting material and 3-aminooxy n-propanol as a reagent.
'H-NMRCDMSO-de, 400MHz) 8(PPM) 1.58(2H, m), 3.37(2H, t, J=6.4Hz), 3.55(4H, m),
3.81(2H, t, J=4.6Hz), 3.93(2H, d, J=5.9Hz), 4.38(1H, br), 4.71(1H, br), 6.59(1H, m), 6.77(1H, t,
J=5.9Hz), 7.34(1H, d, J=8.8Hz), 7.48(1H, d, J=6.9Hz), 7.55(1H, dd, J=10.7Hz, 2.0Hz), 8.63(1H,
br), 11.72(lH,br)
ESI(LC/MS positive mode) m/z 556 (M+H)
StepB
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)5-[(3-hydroxy-propoxyami
no)-methyl]-benzamide (Compound C-10)
The title compound was obtained by a procedure similar to that in Step C' of Example 6
129
from
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-hydroxy-propoxy
imino)-methyl]-benzamide obtained in Step A.
'H-NMRflDMSO-de, 400MHz) 8(PPM) 1.58(2H, m), 3.37(2H, t, J=6.4Hz), 3.55(4H, m),
3.81(2H, t, J=4.6Hz), 3.93(2H, d, J=5.9Hz), 4.38(1H, br), 4.71(1H, br), 6.59(1H, m), 6.77(1H, t,
J=5.9Hz), 7.34(1H, d, J=8.8Hz), 7.48(1H, d, J=6.9Hz), 7.55(1H, dd, J=10.7Hz, 2.0Hz), 8.63(1H,
br), 11.72(lH,br)
ESI(LC/MS positive mode) m/z 556 (M+H)
[Example 8]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-2-methyl-p
ropoxyamino)-methyl]-benzamide (Compound C-28)
Step A
Preparation of l-aminooxy-2-methyl-propan-2-ol hydrochloride
Preparation of l-aminooxy-2-methyl-propan-2-ol hydrochloride was performed as
described in the following literature:
Monatsh Chem Verw Teile Andere Wiss (1961) 92 p 725-739.
StepB
(E)-3,4-Difluoro-2-(2-fluoro-4-iodophenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-2-methy
l-propoxyimino)-methyl] -benzamide
The title compound was obtained by a procedure similar to that in Step B' of Example 6
130
using 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide
obtained in Step F of Example 1 as a starting material and l-aminooxy-2-methyl-propan-hydrochloride obtained in Step A.
'H-NMRtCDaOD, 270MHz) 5(PPM) 3.30(6H, s), 3.72(2H, m), 3.94(2H, m), 4.08(2H, s),
6.72(1H, m), 7.38(1H, d=8.6Hz), 7.47(1H, d, J=10.9Hz), 7.80(1H, br.d, J=5.3Hz), 8.30(1H, s)
ESI(LC/MS positive mode) m/z 568 (M+H)
StepC
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-2-methyl-p
ropoxyamino)-methyl]-benzarnide (Compound C-28)
The title compound was obtained by a procedure similar to that in Step C' of Example 6
from
(E)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-2-methyl
-propoxyimino)-methyl]-benzamide obtained in Step A.
-de, 400MHz) 5(PPM) 1.01(6H, s), 3.55(2H, t, J=4.4Hz), 3.82(2H, t, J=4.4Hz),
3.95(2H, d, J=4.9Hz), 4.40(1H, br), 4.70(1H, br), 6.58(1H, m), 6.96(1H, t, J=4.9Hz), 7.34(1H, d,
J=8.3Hz), 7.49(1H, d, J=6.8Hz), 7.55(1H, d, J=10.8Hz), 8.56(1H, br), 11.72(1H, br). The peak of
a methylene group is overlapping with that of t^O peak.
ESI(LC/MS positive mode) m/z 570 (M+H)
[Example 9]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-rnethylsulfanyl-etho
xyamino)-methyl]-benzamide (Compound C-30)
Synthesis of O-(2-methylsulfanyl-ethyl)-hydroxylamine
O-(2-Methylsulfanyl-ethyl)-hydroxylamme (CAS No. 101512-32-7) was prepared
according to the method described in the following literature:
Bull. Acad. Sci. USSRDiv. Chem. Sci. (Engl. Transl.); 1967; 1743-1745.
StepB
Synthesis of
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methylsulfanyl-e
thyoxyimino)-methyl]-benzamide
The title compound was obtained by a procedure similar to that in Step B' of Example 6
using 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide
obtained in Step F of Example 1 as a starting material and
0-(2-methylsulfanyl-ethyl)-hydroxylamine obtained in Step A as a reagent. Namely,
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide
(2.6 g, 5.415 mmol) was dissolved in a mixed solvent of methylene chloride (50 mL), THF (20
mL), and methanol (10 mL).
O-(2-Methylsulfanyl-ethyl)-hydroxylamine (924 mg, 8.621 mmol) was added thereto,
and the mixture was stirred at room temperature for 3 hours.
After completion of the reaction, the solvent was evaporated under reduced pressure to
give a pale yellow crude product. The residue was triturated with a proper amount of ethyl
acetate :hexane (7:3) to give
(E)-3 ,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5 - [(2-methylsulfanyl-e
thoxyimino)-methyl]-benzamide (1.1 g) as a white solid.
'H-NMRtCDaOD, 270MHz) 8(PPM) 2.15(3H, s), 2.82(2H, dd, 3=6.9, 6.6Hz), 3.72(2H, dd, J=
4.9, 4.3Hz), 3.95(2H, dd, J= 4.9, 4.3Hz), 4.34(2H, dd, J=6.9, 6.6Hz), 6.72(1H, td, JM8.6, 4.3Hz),
7.39(1H, m), 7.47(1H, dd, J=10.6, 2.0Hz), 7.81(1H, dd, J=7.3, 2.0Hz), 8.25(1H, s)
ESI(LC/MS positive mode) m/z 570(M+H)
StepC
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methylsulfanyl-etho
xyamino)-methyl]-benzamide (Compound C-30)
The title compound was obtained by a procedure similar to that in Step C' of Example 6
using
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methylsulfanyl-e
thy oxyimino) -methyl] -benzamide obtained in Step B as a starting material.
Namely,
(E)-3 ,4-difluoro-2-(2-fluoro-4-iodo-phenylamuio)-N-(2-hydroxy-ethoxy)-5 - [(2-methylsulfanyl-e
thyoxyimino)-methyl] -benzamide (104.8 mg, 0.184 mmol) was dissolved in methylene chloride
(anhydrous, 10 mL). Borane-pyridine complex (140 uL, 1.38 mmol) and then dichloroacetic
acid (115 uL, 1 .38 mmol) were added thereto with cooling the reaction vessel in an ice-bath
under a nitrogen atmosphere. The ice-bath was removed, and the mixture was stirred at room
temperature for 1 7 hours. After completion of the reaction, the reaction mixture was extracted
with ethyl acetate, and the organic layer was washed sequentially with water and saturated brine,
dried over anhydrous NaiSO,}, and concentrated under reduced pressure. The resultant yellow
residue was purified by silica gel column chromatography (Mega Bond Elut, Varian, 5%
methanol/methylene chloride as an eluent). The resultant fraction was concentrated under
reduced pressure and the oily residue was triturated with 5% ethyl acetate/hexane to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methylsulfanyl-ethox
yamino)-methyl] -benzamide (110 mg) as a white solid.
, 270MHz) 5(PPM) 2.06(3H, s), 2.62(2H, t, J=6.6Hz), 3.70(2H, m), 3.77(2H, t,
J=6.6Hz), 3.94(2H, m), 4.07(2H, s), 6.56(1H, td, J=8.7, 4.8Hz), 7.32(1H, m), 7.43(1H, dd,
J=10.7, 2.0Hz), 7.53(1H, dd, J=7.3, 2.0Hz)
ESI(LC/MS positive mode) m/z 572(M+H)
[Example 10]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methanesulfmyl-eth
oxyamino)-methyl]-benzamide (Compound C-31)
To a solution of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methylsulfanyl-ethox
yamino)-methyl]-benzamide (10 mg, 0.017 mmol) obtained in Step C of Example 9 in a mixed
solvent of acetone (1.8 mL) and water (0.2 mL) was added 30% aqueous hydrogen peroxide (3
uL, 0.026 mmol), and the mixture was stirred for 17 hours.
After completion of the reaction, the reaction mixture was extracted with ethyl acetate,
and the organic layer was washed sequentially with water and saturated brine, dried over
anhydrous sodium sulfate, and concentrated under reduced pressure. The resultant residue was
purified by preparative TLC (No. 5744, Merck, 5% methanol/methylene chloride as a developing
solvent) to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methanesulfinyl-etho
xyamino)-methyl]-benzaniide (4.0 mg, 39%) as an off-white solid.
'H-NMRXCDaOD, 270MHz) 6(PPM) 2.62(3H, s), 2.88(1H, m), 2.92(1H, m), 3.70(2H, m),
3.93(2H, m), 4.00(2H, m), 4.08(2H, s), 6.60(1H, td, J=8.7,4.6Hz), 7.34(1H, m), 7.44(1H, dd,
J=10.6,2.0Hz),7.48(lH,m)
ESI(LC/MS positive mode) m/z 588(M+H)
[Example 11]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methanesulfonyl-eth
oxyamino)-methyl]-benzamide (Compound C-8)
134
To a solution of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methanesulfinyl-etho
xyamino)-methyl]-benzamide (10 mg, 0.017 mmol) obtained in Example 10 in a mixed solvent
of methanol (1.8 mL) and water (0.2 mL) was added sodium metaperiodate (6 mg, 0.026 mmol)
at room temperature, and the mixture was stirred for 17 hours. After completion of the reaction,
the reaction mixture was extracted with ethyl acetate, and the organic layer was washed
sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The resultant residue was purified by preparative TLC
(No. 5744, Merck, 5% methanol/methylene chloride as a developing solvent) to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methanesulfonyl-eth
oxyamino)-methyl]-benzamide (1.3 mg, 13%) as an off-white solid.
, 270MHz) S(PPM) 2.94(3H, s), 3.26(2H, partial hidden), 3.71(2H, dd, J=4.9,
4.3Hz), 3.93(2H, dd, J=4.9, 4.3Hz), 4.04(2H, dd, J=5.7, 5.4Hz), 4.10(2H, s), 6.61(1H, td, J=8.7,
4.6Hz), 7.33(1HS m), 7.43(1H, dd, J=10.7, l.SHz), 7.50(1H, m)
ESI(LC/MS positive mode) m/z 604(M+H)
[Example 12]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylsulfanyl-prop
oxyamino)-methyl]-benzaniide (Compound C-32)
Step A
Preparation of 2-(3-methylsulfanyl-propoxy)-isoindole-l ,3-dione
3-Methylsulfanyl-propan-l-ol (4.133 g, 38.92 mmol) was dissolved in THF (anhydrous,
100 mL). To this solution, triphenylphosphine (10.2 g, 38.92 mmol) and
N-hydroxyphthalirnide (6.4 mg, 38.92 mmol) were added and dissolved with stirring.
Diisopropyl azodicarboxylate (8.5 mL, 42.812 mmol) was added dropwise thereto with cooling
the reaction vessel in an ice-bath under nitrogen atmosphere. The reaction mixture was warmed
to room temperature, and stirred for 5 hours. After completion of the reaction, the reaction
mixture was concentrated under reduced pressure, and triturated with diethyl ethenhexane (1:1,
about 100 ml) to precipitate triphenylphosphine oxide as a white solid, which was filtered off.
The filtrate was concentrated under reduced pressure to give a yellow oily residue. The
resultant yellow oil was purified by silica gel flash chromatography (BW300, Fuji Silysia
Chemical, 20% ethyl acetate/hexane as an eluent) to give
2-(3-methylsulfanyl-propoxy)-isoindole-l,3-dione (6.4 g, 65%).
!H-NMR(CDCl3, 270MHz) 8(PPM) 2.04(2H, m), 2.15(3H, s), 2.78(2H, m), 4.33(2H, dd, J=6.3,
6.1Hz),7.72-7.88(4H,m)
ESI(LC/MS positive mode) m/z 252(M+H)
StepB
Synthesis of O-(3-methylsulfanyl-propyl)-hydroxylamine
2-(3-Methylsulfanyl-propoxy)-isoindole-l,3-dione (6.4 g, 25.5 mmol) obtained in Step
A was dissolved in methylene chloride (anhydrous, 50 mL). To this solution, methylhydrazine
(1.5 mL, 28 mmol) was added dropwise, and the mixture was stirred for 1 hour. The
precipitated white solid was filtered off, and the filtrate was concentrated under reduced pressure.
The yellow oily residue was extracted with ethyl acetate, and the organic layer was washed
sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The resultant yellow oily residue was purified by vacuum
distillation (1 mmHg, 57°C) to give O-(3-methylsulfanyl-propyl)-hydroxylamine (3.15 g, 68%)
as a colorless oil.
, 270MHz) 6(PPM) 1.88(2H, m), 2.11(3H, s), 2.55(2H, dd, J=7.6, 7.1Hz),
3.75(2H, dd, J=6.3, 6.1Hz), 5.37(2H, br.s)
ESI(LC/MS positive mode) m/z 122(M+H)
StepC
Synthesis of
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylsulfanyl-p
ropoxyimino)-methyl]-benzamide
The title compound was obtained by a procedure similar to that in Step B of Example 9
using 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide
obtained in Step F of Example 1 as a starting material and
O-(3-rnethylsulfanyl-propyl)-hydroxylamine obtained in Step B as a reagent. Namely,
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide(76
mg, 0. 158 mmol) was dissolved hi a mixed solvent of methylene chloride (5 mL) and methanol
(1 mL). O-(3-Methylsulfanyl-propyl)-hydroxylamine (100 uL) was added thereto, and the
mixture was stirred at room temperature for 3 hours. After completion of the reaction, the
solvent was evaporated under reduced pressure to give a pale yellow crude product. The
residue was triturated with a proper amount of ethyl acetate:hexane (1:9) to give
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylsulfanyl-p
ropoxyimino)-methyl]-benzamide (88.8 mg, 96%) as a white solid.
, 270MHz) 8(PPM) 2.03(2H, m), 2.13(3H, s), 2.63(2H, dd, J=7.3, 7.1Hz),
3.79(2H, m), 4.30(2H, t, J=6.3Hz), 6.66(1 H, td, J=8.6, 4.5Hz), 7.35(1H, m), 7.42(1H, dd, J=10.2,
l.SHz), 7.77(1H, dd, J=6.8, 2.0Hz), 8.21(1H, s), 8.60(1H, br.s), 9.15(1H, br.s)
ESI(LC/MS positive mode) m/z584(M+H)
StepD
Synthesis of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-rnethylsulfanyl-prop
oxyamino)-rnethyl]-benzamide (Compound C-32)
The title compound was obtained by a procedure similar to that in Step C of Example 9.
Namely,
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylsulfanyl-p
ropoxyimino)-methyl]-benzamide was reduced with borane-pyridine complex in the presence of
dichloroacetic acid to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylsulfanyl-prop
oxyamino)-methyl]-benzamide (26.54 mg, 79%).
JH-NMR(CD3OD, 270MHz) 8(PPM) 1.78(2H, m), 2.03(3H, s), 2.47(2H, dd, J=7.4, 7.1Hz),
3.70(2H, t, J=6.1Hz), 3.71(2H, m), 3.92(2H, m), 4.06(2H, s), 6.59(1H, td, J=8.7,4.3Hz),
7.34(1H, dd, J=8.4, l.lHz), 7.44(1H, dd, J=10.7,l.SHz), 7.49(1H, m)
ESI(LC/MS positive mode) m/z586(M+H)
[Example 13]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methanesulfinyl-pro
poxyamino)-methyl]-benzamide (Compound C-33)
The title compound was obtained by a procedure similar to that in Example 10 using
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylsulfanyl-prop
oxyamino)-methyl]-benzamide obtamed in Example 12 as a starting material. Namely,
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylsulfanyl-prop
oxyamino)-methyl]-benzamide was treated with 30% aqueous hydrogen peroxide in aqueous
acetone to synthesize
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methanesulfinyl-prop
oxyamino)-methyl]-benzamide (6.34 mg, 62%).
'H-NMRtCDsOD, 270MHz) 8(PPM) 1.96(2H, m), 2.64(3H, s), 2.83(2H, m), 3.71(2H, m),
3.75(2H, dd, J=6.1, 5.9Hz), 3.92(2H, dd, J=4.9,4.3Hz), 6.59(1H, td J=8.7, 4.3Hz), 7.34(1H, br,d,
J=8.6Hz), 7.44(1H, dd, J=10.7,2.0 Hz), 7.49(1H, dd, J=7.3, l.SHz)
ESI(LC/MS positive mode) m/z602(M+H)
[Example 14]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-hydroxyaminomethyl-N-(2-hydroxy-ethoxy)-be
nzamide (Compound C-23)
Step A
Synthesis of
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(hydroxyimino-meth
yl)-benzamide
The title compound was obtained by a procedure similar to that in Step B of Example 9
using 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide
obtained in Step F of Example 1 as a starting material and N-hydroxyamine hydrochloride
(commercially available) as a reagent. 111.7 mg (1 00%).
, 270MHz) 6(PPM) 3.71 (2H, dd, J = 4.9, 4.3 Hz), 3.93 (2H, dd, J = 4.6, 4.3
Hz), 6.70 (1H, td, J = 8.6, 4.3 Hz), 7.38 (1H, dt, J = 8.3, 1.3 Hz), 7.46 (1H, dd, J = 10.9, 2.0 Hz),
7.80 (1H, br. d, J = 5.9 Hz), 8.21 (1H, s)
ESI(LC/MS positive mode) m/z 496 (M+H)
StepB
Synthesis of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-hydroxyaminomethyl-N-(2-hydroxy-ethoxy)-be
nzamide (Compound C-23)
The title compound was obtained by a procedure similar to that in Step C of Example 9.
Namely,
(E)O,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(hydroxyiniino-meth
yl)-benzamide was reduced with borane-pyridine complex hi the presence of dichloroacetic acid
to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-hydroxyaminomethyl-N-(2-hydroxy-ethoxy)-be
nzamide (28.14 mg, 81%).
, 270MHz) 6(PPM) 3.71 (2H, dd, J=4.8, 4.4Hz), 3.94(2H, dd, J=4.8, 4.1Hz),
4.08(2H, s), 6.60(1H, td, J=8.7, 4.5Hz), 7.35(1H, br.d, J=8.6Hz), 7.44(1H, dd, J=10.6, l.SHz),
7.52(1 H, br.d, J=7.4Hz)
ESI(LC/MS positive mode) m/z 498 (M+H)
[Example 15]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylammo)-N-(2-hydroxy-ethoxy)-5-(methoxyaniino-methyl)
-benzamide (Compound C-24)
Step A
Synthesis of
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(methoxyimino-meth
yl)-benzamide
The title compound was obtained by a procedure similar to that in Step B of Example 9
using 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide
obtained in Step F of Example 1 as a starting material and N-methoxyamine hydrochloride
(commercially available) as a reagent. 128 mg (99%).
'H-NMRtCDsOD, 270MHz) 6(PPM) 3.72(2H, dd, J=4.8,4.6Hz), 3.95(2H, dd, J=4.8, 4.6Hz),
3.98(3H, s), 6.71(1H, td, J=8.7, 4.5Hz), 7.41(1H, m), 7.47(1H, dd, J=10.6, 2.0Hz), 7.81(1H, dd,
1=7.4,2.1 Hz), 8.22(1 H,s)
ESI(LC/MS positive mode) m/z 510(M+H)
StepB
Synthesis of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(methoxyamino-methyl)-
benzamide (Compound C-24)
The title compound was obtained by a procedure similar to that in Step C of Example
Namely,
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylarnino)-N-(2-hydroxy-ethoxy)-5-(methoxyimino-meth
yl)-benzamide was reduced with borane-pyridine complex in the presence of dichloroacetic acid
to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(methoxyamrno-methyl)-
benzamide (28.14 mg, 81%).
, 270MHz) 5(PPM) 3.50(3H, s), 3.70(2H, m), 3.93(2H, m), 4.08(2H, s),
6.59(1H, td, J=8.9, 4.2Hz), 7.34(1H, m), 7.44(1H, dd, J=10.6, l.SHz), 7.48(1H, br.s)
ESI(LC/MS positive mode) m/z 512(M+H)
[Example 16]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-emoxy)-5-[(methoxy-methyl-amrn
o)-methyl] -benzamide (Compound C-25)
To a solution of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide(56.2
mg, 0.117 mmol) in tetrahydrofuran (anhydrous) were added O,N-dimethyl-hydroxylamine
hydrochloride (commercially available, 34 mg, 0.351 mmol) and sodium cyanoborohydride (34
mg, 0.541 mmol) under nitrogen atmosphere, and the mixture was stirred at room temperature
for 3 hours. After completion of the reaction, the reaction mixture was extracted with ethyl
acetate, and the organic layer was washed sequentially with water and saturated brine, dried over
anhydrous sodium sulfate, and concentrated under reduced pressure. The resultant residue was
purified by silica gel flash chromatography (Mega Bond Elut, Varian, 5% methanol/methylene
chloride as an eluent) to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(methoxy-memyl-amino
)-methyl]-benzamide (9.72 mg, 17%) as a white solid.
, 270MHz) 8(PPM) 2.63(3H, s), 3.37(3H, s), 3.71(2H, dd, J=4.9, 4.3Hz),
3.85(2H, s), 3.94(2H, dd, J=4.8, 4.5Hz), 6.59(1H, td, J=8.9, 4.6Hz), 7.34(1H, m), 7.44(1H, dd,
J=10.6, 1.8Hz), 7.47(1H, dd, J=8.7, 2.0Hz)
ESI(LC/MS positive mode) m/z 526(M+H)
[Example 17]
5-(Ethoxyamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-b
enzamide (Compound C-26)
Step A
Synthesis of
(E)-5-(ethoxyimino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy
)-benzamide
The title compound was obtained by a procedure similar to that in Step B of Example 9
using 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide
obtained in Step F of Example 1 as a starting material and N-ethoxyamine hydrochloride
(commercially available) as a reagent.
, 270MHz) 8(PPM) 1.31(3H, t, J=7.0Hz), 3.72(2H, m), 3.94(2H, m), 4.23(2H,
q, J=7.0Hz), 6.70(1H, m), 7.39(1H, br.d, J=8.4Hz), 7.47(1H, dd, J=10.7, 2.0Hz), 7.80(1H, m),
8.22(1H, s)
ESI(LC/MS positive mode) m/z 524(M+H)
StepB
Synthesis of
5-(emoxyamino-methyl)-3s4-difluoro-2-(2-fluoro-4-iodo-phenylarnino)-N-(2-hydroxy-ethoxy)-b
enzamide (Compound C-26)
The title compound was obtained by a procedure similar to that in Step C of Example 9.
Namely,
(E)-5-(ethoxyimmo-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy
)-benzamide was reduced with borane-pyridine complex in the presence of dichloroacetic acid to
give
5-(ethoxyamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-b
enzamide (97.7 mg, 80% in 2 steps).
-de, 270MHz) 5(PPM) 1.03(3H, t, J=6.9Hz), 3.55(2H, m), 3.57(2H, q, J=6.9Hz),
143
3.83(2H, m), 3.99(2H, m), 4.71(1H, br.s), 6.60(1H, m), 7.39(1H, d, J=8.7Hz), 7.47(1H, d,
J=6.6Hz), 7.57(1H, dd, J=10.9,1.8Hz), 8.50(1H, br.s), 11.80(1H, br.s)
ESI(LC/MS positive mode) m/z 526(M+H)
[Example 18]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(isopropoxyamino-meth
yl)-benzamide (Compound C-27)
Step A
Synthesis of
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(isopropoxyimino-m
ethyl)-benzamide
The title compound was obtained by a procedure similar to that in Step B of Example 9
using 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide
obtained in Step F of Example 1 as a starting material and O-isopropylhydroxylamine
hydrochloride (commercially available) as a reagent.
'H-NMRODMSO-de, 270MHz) 5(PPM) 1.27 (6H, d, J = 6.3 Hz), 3.57 (2H, br. q, J = 4.3 Hz),
3.84 (2H, t, J = 4.6 Hz), 4.44 (IH, qui, J = 6.3 Hz) 4.73 (IH, br. t, J = 5.6 Hz), 6.80 (IH, td, J =
9.2,4.3 Hz), 7.40 (IH, br. d, J = 7.9 Hz), 7.61 (IH, dd, J = 10.9, 2.0 Hz), 7.69 (IH, br. d, J = 6.9
Hz), 8.22 (IH, s), 8.84 (IH, br. s, NH), 11.98 (IH, br. s, NH).
ESI(LC/MS positive mode) m/z 538 (M+H)
StepB
Synthesis of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylarnino)-N-(2-hydroxy-ethoxy)-5-(isopropoxyamino-meth
yl)-benzamide (Compound C-27)
The title compound was obtained by a procedure similar to that in Step C of Example 9.
Namely,
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(isopropoxyimino-m
ethyl)-benzamide was reduced with borane-pyridine complex in the presence of dichloroacetic
acid to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(isopropoxyamino-meth
yl)-benzamide (65.0 mg, 89% in 2 steps).
!H-NMR(DMSO-d6, 270MHz) S(PPM) 1.02 (6H, d, J = 6.2 Hz), 3.56 (2H, br. t, J = 4.9 Hz), 3.67
(1H, qui, J = 6.2 Hz), 3.83 (2H, br. t, J = 4.9 Hz), 3.92 (2H, br. d, J = ca 5 Hz), 4.72 (1H, br. s),
6.59 (1H, td, J = 8.9, 4.1 Hz), 7.36 (1H, br. d, J = 8.1 Hz), 7.48 (1H, br. d, J - 7.0 Hz), 7.57 (1H,
dd, J = 10.8,1.9 Hz), 8.57 (1H, br. s).
ESI(LC/MS positive mode) m/z 540(M+H)
[Example 19]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(methylcarbamoyhnetho
xyamino-methyl)-benzamide (Compound C-13)
Step A
Synthesis of (l,3-dioxo-l,3-dihydro-isoindol-2-yloxy)-acetic acid methyl ester
The title compound was prepared according to the method described in the following
literature:
Sheppard, andrew et al.; J. Chem. Soc. Perkin Trans 1; 1990; 2519-2525.
145
StepB
Synthesis of 2-aminooxy-N-methyl-acetamide
To a solution of (l,3-dioxo-l,3-dihydro-isoindol-2-yloxy)-acetic acid methyl ester
(120.9 g, 0.51 mol) obtained in Step A in methanol (300 ml) was added methylamine (40%
solution in methanol, 1.0 L) at room temperature, and stirred at 60°C over night. The reaction
mixture was concentrated under reduced pressure, and methylene chloride was added to the
resultant residue to precipitate a solid, which was filtered and washed with methylene chloride.
The combined filtrate and washing were concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (1.4 kg, CHbCh/MeOH (30:1 to 10:1)) to give
2-aminooxy-N-methyl-acetamide (50.3 g, 94%) as a colorless syrup.
1H-NMR(CDC13,270MHz) 5(PPM) 2.88 (3H, d, J = 5.0 Hz), 4.17 (2H, s), 5.69 (2H, br. s).
StepC
Synthesis of
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[methylcarbamoyhn
ethoxyimino-methyl] -benzamide
To a solution of 2-aminooxy-N-methyl-acetamide (1.71 g, 16.4 mmol) obtained in Step
B in a mixed solvent of methylene chloride (50 ml) and THF (25 ml) was added
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide (3.94
g, 8.20 mmol) obtained in Step F of Example 1 at room temperature, and the mixture was stirred
for 15 hours. The reaction mixture was concentrated under reduced pressure, and methylene
chloride (40 ml) was added to the resultant residue to precipitate a solid, which was filtered and
washed with methylene chloride. The resultant solid was dried under reduced pressure to give
(E)-3 ,4-difluoro-2-(2-fluoro-4-iodo-phenylainino)-N-(2-hydroxy-ethoxy)-5 - [methylcarbamoylm
ethoxyimino-methyl]-benzainide (3.57 g, 77%) as a white solid.
-de, 270MHz) 8(PPM) 2.63 (3H, d, J = 4.6 Hz), 3.56 (2H, t, J = 4.6 Hz), 3.83
(2H, t, J = 4.3 Hz), 4.57 (2H, s), 4.73 (1H, br. s), 6.82 (1H, td, J = 8.9, 4.0 Hz), 7.41 (1H, br. d, J
= 8.6 Hz), 7.61 (1H, dd, J = 10.9, 2.0 Hz), 7.69 (1H, br. d, J = 6.3 Hz), 7.87 (1H, br q, J = 4.6 Hz),
8.40 (1H, s), 8.92 (1H, br. s), 12.01 (1H, br. s).
ESI(LC/MS positive mode) m/z 567 (M+H)
StepD
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylam.ino)-N-(2-hydroxy-ethoxy)-5-(methylcarbarnoylraetho
xyamino-methyl)-benzamide (Compound C-13)
HO,
To a solution of
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[methylcarbamoylm
ethoxyimino-methylj-benzamide (69.8 nig, 0.12 mmol) obtained in Step C in methylene chloride
(15 ml) were added borane-pyridine complex (199 ul, 1.92 mmol) and dichloroacetic acid
ul, 1 .92 mmol) at room temperature, and the mixture was stirred for 3.5 days. Additional
borane-pyridine complex (199 ul, 1.92 mmol) and dichloroacetic acid (162 ul, 1.92 mmol) were
added, and the mixture was stirred for 1 day. The reaction mixture was diluted with methylene
chloride (20 ml), and washed with saturated brine (2x 20 ml). The organic layer was dried over
anhydrous magnesium sulfate, and concentrated under reduced pressure. The resultant residue
was purified by preparative TLC (EtOAc/MeOH (9:1)) to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylarnino)-N-(2-hydroxy-ethoxy)-5-(rnethylcarbamoylmetho
xyamino-methyl)-benzamide (36.9 mg, 53%) as a colorless oil.
, 270MHz) 5(PPM) 2.77 (3H, s), 3.68-3.76 (2H, m), 3.92-3.98 (2H, m), 4.09
(2H, s), 4.13 (2H, s), 6.61 (1H, dt, J = 4.3, 8.6 Hz), 7.34 (1H, ddd, J = 1.2, 1.9, 8.6 Hz), 7.45 (1H,
dd, J= 1.9, 10.8 Hz), 7.50 (1H, dd, J- 1.9, 7.3 Hz).
ESI(LC/MS positive mode) m/z 569 (M+H)
[Example 20]
5-(Ethylcarbamoylmethoxyamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylammo)-N-(2-h
ydroxy-ethoxy)-benzamide (Compound C-14)
Step A
Synthesis of 2-aminooxy-N-ethyl-acetamide
To a suspension of (l,3-dioxo-l,3-dihydro-isoindol-2-yloxy)-acetic acid methyl ester
(996 mg, 4.23 mmol) obtained in Step A of Example 19 in THF (5 mL) was added ethylamine
(2.0 M solution in THF, 25 ml) at room temperature, and the mixture was stirred at 60°C for 18
hours. The reaction mixture was concentrated under reduced pressure, and methylene chloride
was added to the resultant residue to precipitate a solid, which was filtered and washed with
methylene chloride. The combined filtrate and washing were concentrated under reduced
pressure. The residue was purified by silica gel column chromatography (40 g, C^Ch/MeOH
(30:1 to 20:1)) to give 2-aminooxy-N-ethyl-acetamide (160 mg, 32%) as a colorless syrup.
1H-NMR(CD3OD, 270MHz) 5(PPM) 1.14 (3H, t, J = 7.3 Hz), 3.27 (2H, q, J = 7.3 Hz), 4.07 (2H,
s).
StepB
Synthesis of
(E)-5-(ethylcarbamoylmethoxyimino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(
2-hydroxy-ethoxy)-benzamide
Using 2-aminooxy-N-ethyl-acetamide obtained in Step A, synthesis was performed
according to the procedure described in Step C of Example 19 to give
(E)-5-(ethylcarbamoylmethoxyimino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(
148
2-hydroxy-ethoxy)-benzamide.
1H-NMR(DMSO-d6,270MHz) 8(PPM) 1.03 (3H, t, J = 7.3 Hz), 3.14 (2H, quint., J = 7.3 Hz),
3.56 (2H, br), 3.83 (2H, br), 4.55 (2H, s), 4.72 (IH, br), 6.82 (IH, dt, J = 3.8, 8.9 Hz), 7.40 (IH,
br. d, J = 8.9 Hz), 7.61 (IH, dd, J = 1.6,10.8 Hz), 7.67 (IH, br. d, J = 5.1 Hz), 7.92 (IH, t, J = 5.7
Hz), 8.40 (IH, s), 8.92 (IH, br), 11.98 (IH, br).
ESI(LC/MS positive mode) m/z 581 (M+H)
StepC
Synthesis of
5-(ethylcarbamoymiemoxyamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-h
ydroxy-ethoxy)-benzamide (Compound C-14)
(E)-5-(ethylcarbamoylmethoxyimino-niethyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(
2-hydroxy-ethoxy)-benzamide obtained in Step B, synthesis was performed according to the
procedure described in Step D of Example 19 to give
5-(ethylcarbamoylmethoxyamino-niethyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylaniino)-N-(2-h
ydroxy-ethoxy)-benzamide.
'H-NMRCCDaOD, 270MHz) 8(PPM) 1.14 (3H, t, J = 7.3 Hz), 3.26 (2H, q, J = 7.3 Hz), 3.68-3.76
(2H, m), 3.91-3.99 (2H, m), 4.09 (2H, s), 4.13 (2H, s), 6.61 (IH, dt, J = 4.6, 8.6 Hz), 7.35 (IH,
ddd, J = 1.1,1.9, 8.6 Hz), 7.45 (IH, dd, J = 1.9,10.8 Hz), 7.50 (IH, dd, J = 1.9,7.2 Hz).
ESI(LC/MS positive mode) m/z 583 (M+H)
[Example 21]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(propylcarbamoylmetho
xyamino-methyl)-benzamide (Compound C-15)
Synthesis of 2-aminooxy-N-propyl-acetamide
Using (l,3-dioxo-l,3-dihydro-isoindol-2-yloxy)-acetic acid methyl ester obtained in
Step A of Example 19 and n-propylamine as an amine, synthesis was performed according to the
procedure described in Step A of Example 20 to give 2-aminooxy-N-propyl-acetamide.
, 270MHz) 8(PPM) 0.93 (3H, t, J = 7.3 Hz), 1.54 (2H, hextet, J = 7.3 Hz),3.21
(2H, t, J = 7.3 Hz), 4.07 (2H, s).
StepB
Synthesis of
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(propylcarbamoylme
thoxyimino-methyl)-benzamide
Using 2-aminooxy-N-propyl-acetamide obtained in Step A, synthesis was performed
according to the procedure described in Step C of Example 19 to give
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(propylcarbamoylme
thoxyimino-methyl)-benzamide .
-de, 270MHz) 6(PPM) 0.82 (3H, t, J = 7.3 Hz), 1.43 (2H, hextet, J = 7.3 Hz),
3.07 (2H, q, J = 7.3 Hz), 3.51-3.62 (2H, m), 3.76-3.90 (2H, m), 4.56(2H, s), 4.72 (IH, br), 6.82
(IH, dt, J = 4.1, 8.6 Hz), 7.40 (IH, dd, J = 0.8, 8.6 Hz), 7.61 (IH, dd, J = 1.6, 10.8 Hz), 7.62-7.71
(IH, m), 7.90 (IH, br. t, J = 5.7 Hz), 8.40 (IH, s), 8.92 (IH, br), 11.98 (IH, br).
ESI(LC/MS positive mode) m/z 595 (M+H)
StepC
Synthesis of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(propylcarbamoyhnetho
xyamino-methyl)-benzamide (Compound C-15)
Using
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(propylcarbamoylme
thoxyimino-methyl)-benzamide obtained in Step B, synthesis was performed according to the
procedure described in Step D of Example 19 to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(propylcarbamoylmetho
xyamino-methyl)-benzamide.
'H-NMRCCDsOD, 270MHz) 5(PPM) 0.93 (3H, t, J = 7.3 Hz), 1.54 (2H, hextet, J = 7.3 Hz), 3.19
(2H, q, J = 7.3 Hz), 3.68-3.76 (2H, m), 3.91-3.99 (2H, m), 4.09 (2H, s), 4.14 (2H, s), 6.61 (IH, dt,
J - 4.3, 8.6 Hz), 7.35 (IH, ddd, J = 1.1,1.9, 8.6 Hz), 7.46 (IH, dd, J = 1.9, 10.8 Hz), 7.50 (IH,
dd,J=1.9, 7.2 Hz).
ESI(LC/MS positive mode) m/z 597 (M+H)
[Example 22]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(isopropylcarbamoyl-m
ethoxyamino)-methyl]-benzamide (Compound C-16)
Step A
Synthesis of 2-aminooxy-N-isopropyl-acetamide
Using (l,3-dioxo-l,3-dihydro-isoindol-2-yloxy)-acetic acid methyl ester obtained hi
Step A of Example 19 and isopropylamine as an amine, synthesis was performed according to the
procedure described in Step A of Example 20 to give 2-aminooxy-N-isopropyl-acetamide.
, 270MHz) 5(PPM) 1.17 (6H, d, J = 6.5 Hz), 3.98-4.12 (IH, m), 4.05 (2H, s).
StepB
Synthesis of
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(isopropylcarbamoy
l-methoxyimino)-methyl] -benzamide
Using 2-aminooxy-N-isopropyl-acetamide obtained in Step A, synthesis was performed
according to the procedure described in Step C of Example 19 to give
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(isopropylcarbamoy
l~methoxyimino)-methyl] -benzamide.
'H-NMRODMSO-de, 270MHz) 5(PPM) 1.08 (3H x 2, d, J = 6.8 Hz), 3.57 (2H, br), 3.83 (2H, br),
3.85-4.02 (IH, m), 4.54(2H, s), 4.72 (IH, br), 6.82 (IH, dt, J = 4.1, 8.6 Hz), 7.41 (IH, br. d, J =
8.6 Hz), 7.61 (IH, dd, J = 1.6,10.8 Hz), 7.62-7.76 (IH, m), 7.90 (IH, br. t, J = 5.7 Hz), 8.40 (IH,
s), 8.88 (lH,br), 11.98 (lH,br).
ESI(LC/MS positive mode) m/z 595 (M+H)
StepC
Synthesis of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(isopropylcarbamoyl-m
ethoxyamino)-methyl] -benzamide (Compound C-16)
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(isopropylcarbamoy
l-methoxyimino)-methyl]-benzamide obtained in Step B, synthesis was performed according to
the procedure described in Step D of Example 19 to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(isopropylcarbamoyl-m
ethoxyamino)-methyl]-benzamide.
1H-NMR(CD3OD, 270MHz) S(PPM) 1.16 (3H x 2, d, J = 6.8 Hz), 3.72 (2H, t, J = 4.6 Hz), 3.95
(2H, t, J = 4.6 Hz), 3.96-4.12 (1H, m), 4.07 (2H, s), 4.13 (2H, s), 6.61 (1H, dt, J = 4.6, 8.6 Hz),
7.32-7.38 (1H, m), 7.46 (1H, dd, J = 1.9, 10.8 Hz), 7.51 (1H, dd, J = 1.9, 7.0 Hz).
ESI(LC/MS positive mode) m/z 597 (M+H)
[Example 23]
5-(Dimetiiylcarbarnoylrnethoxyarnino-rnethyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylarnino)-N-
(2-hydroxy-ethoxy)-benzamide (Compound C-17)
Step A
Synthesis of 2-aminooxy-N,N-diniethyl-acetamide
To a solution of (l,3-dioxo-l,3-dihydro-isoindol-2-yloxy)-acetic acid methyl ester (992
mg, 4.22 mmol) obtained in Step A of Example 19 in methanol (4 ml) was added dimethylamine
(2.0 M solution in methanol, 1 0 ml), and the mixture was stirred at 60°C for 1 6 hours. After
cooling down to room temperature, the reaction mixture was concentrated under reduced
pressure. The resultant residue was dissolved in methanol (7 ml), and methylhydrazine (0.27
ml, 6.74 mmol) was added thereto. The mixture was stirred at 60°C for 1 5 hours. After
cooling down to room temperature, the reaction mixture was concentrated under reduced
pressure. The residue was purified by silica gel column chromatography (40 g, CHaCb/MeOH
(40:1 to 30:1)) to give 2-aminooxy-N,N-dimethyl-acetamide (125 mg, 25%) as a colorless syrup.
'H-NMRtCDsOD, 270MHz) 5(PPM) 2.94 (3H, s), 2.97 (3H, s),4.37 (2H, s).
StepB
(E)-5-(Dime1iiylcarbamoylrnethoxyimino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylarnmo)
-N-(2-hydroxy-ethoxy)-benzamide
153
Using 2-aminooxy-N,N-dimethyl-acetaniide obtained in Step A, synthesis was
performed according to the procedure described in Step C of Example 19 to give
(E)-5-(dimethylcarbamoylmethoxyimino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
N-(2-hydroxy-ethoxy)-benzamide.
1H-NMR(DMSO-d6, 270MHz) 8(PPM) 1.08 (6H, d, J = 6.8 Hz), 3.57 (2H, br), 3.83 (2H, br),
3.85-4.02 (1H, m), 4.54 (2H, s), 4.72 (1H, br), 6.81 (1H, dt, J = 4.1, 8.6 Hz), 7.40 (1H, dd, J =
1.1, 8.6 Hz), 7.61 (1H, dd, J = 1.9,10.8 Hz), 7.63-7.76 (1H, m), 8.36 (1H, s), 8.88 (1H, br), 11.96
(lH.br).
ESI(LC/MS positive mode) m/z 581 (M+H)
StepC
Synthesis of
5-(dimethylcarbamoylmethoxyamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(
2-hydroxy-ethoxy)-benzamide (Compound C-17)
(E)-5-(dimethylcarbamoylmethoxyimino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
N-(2-hydroxy-ethoxy)-benzamide obtained in Step B, synthesis was performed according to the
procedure described in Step D of Example 19 to give
5-(dimethylcarbamoylmethoxyamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(
2-hydroxy-ethoxy)-benzamide.
154
'H-NMRXCDsOD, 270MHz) 8(PPM) 2.93 (3H, s), 2.96 (3H, s), 3.73 (2H, t, J = 4.6 Hz), 3.97
(2H, t, J = 4.6 Hz), 4.13 (2H, s), 4.38 (2H, s), 6.61 (1H, dt, J = 4.6, 8.6 Hz), 7.31-7.38 (1H, m),
7.44 (1H, dd, J = 1.9,10.5 Hz), 7.54 (1H, dd, J = 1.9, 7.3 Hz).
ESI(LC/MS positive mode) m/z 583 (M+H)
[Example 24]
5-[(2-ethylcarbamoyl-ethoxyamino)-rnethyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2
-hydroxy-ethoxy)-benzamide (Compound C-18)
Step A
Synthesis of N-(2-ethylcarbamoyl-ethoxy)-acetimidic acid ethyl ester
To a known compound, 3-(l-ethoxyethylideneaminooxy)-propanoic acid methyl ester
(CAS No. 97164-30-2, 300 mg, 1.585 mmol) was added a 2 M solution of methylamine in
methanol (7 ml), and the mixture was stirred at 60°C for 13 hours. The reaction mixture was
concentrated under reduced pressure, and the residue was purified by silica gel column
chromatography to give N-(2-ethylcarbamoyl-ethoxy)-acetimidic acid ethyl ester (182 mg, 57%
yield).
'H-NMRXCDCb, 400MHz) 5(PPM) 1.13(3H, t, J=7.1Hz), 1.27(3H, t, J=7.3Hz), 1.92(3H, s),
2.53(2H, t, J=5.9Hz), 3.26-3.33(2H, m), 4.00(2H, q, J=7.3Hz), 4.15(2H, t, J=5.9Hz), 5.93(1H,
br.s)
StepB
Synthesis of
(E)-5-[(2-ethylcarbamoyl-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
N-(2-hydroxy-ethoxy)-benzamide
155
To N-(2-ethylcarbamoyl-ethoxy)-acetimidic acid ethyl ester (180 mg, 0.890 mmol)
obtained in Step A was added 2 M hydrochloric acid (2 ml), and the mixture was stirred at room
temperature for 30 minutes. The reaction mixture was concentrated to give a crude product of
3-aminooxy-N-ethyl-propionamide hydrochloride as a residue. To this residue, a mixed solvent
of tetrahydrofuran/methanol (3:1,20 ml) and
3,4-difluoro-2-(2-fluoro-4-iodophenylamino-5-forniyl-N-(2-hydroxy-ethoxy)-benzamide(500
mg, 1.078 mmol) obtained in Step F of Example 1 were added, and the mixture was stirred for 1
hour. The reaction mixture was poured into purified water, and the resultant mixture was
extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium
sulfate, and concentrated under reduced pressure. The residue was purified by silica gel
column chromatography to give
(E)-5-[(2-ethylcarbarnoyl-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
N-(2-hydroxy-ethoxy)-benzamide (200 mg, 31% yield).
ESI(LC/MS positive mode) m/z 595 (M+H)
StepC
Synthesis of
5-[(2-ethylcarbamoyl-ethoxyamino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2
-hydroxy-ethoxy)-benzamide
H
To
(E)-5-[(2-ethylcarbamoyl-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
N-(2-hydroxy-ethoxy)-benzamide (40 mg, 0.067 mmol) obtained in Step B was added
dichloromethane (2 ml). The mixture was stirred at room temperature, and borane-pyridine
complex (40 ul) and dichloroacetic acid (40 ul) were added thereto. After stirring for 1 hour,
the reaction mixture was poured into purified water, and the resultant mixture was extracted with
dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The residue was purified by silica gel column
156
chromatography to give
5-[(2-ethylcarbamoyl-e1iioxyamino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2
-hydroxy-ethoxy)-benzamide (C-18, 29 mg, 75% yield).
, 400MHz) 8(PPM) 1.07(3H, t, J=7.2Hz), 2.37(2H, t, J=6.2Hz), 3.16(2H, q,
J=7.2Hz), 3.71(2H, t, J=4.4Hz), 3.86(2H, t, J=6.2Hz), 3.95(2H, t, J=4.4Hz), 4.04(2H, s), 6.60(1H,
ddd, J=8.8, 8.8, 4.4Hz), 7.33(1H, br.d, J=8.3Hz), 7.42-7.45(2H, m)
ESI(LC/MS positive mode) m/z 597 (M+H)
[Example 25]
5-[(2-Propylcarbamoyl-ethoxyamino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-
(2-hydroxy-ethoxy)-benzamide (Compound C-19)
Step A
Synthesis of N-(2-propylcarbamoyl-ethoxy)-acetimidic acid ethyl ester
To a known compound, 3-(l-ethoxy-ethylideneaminooxy)-propanoic acid methyl ester
(CAS No. 97164-30-2, 300 mg, 1.585 mmol) were added methanol (3 ml) and n-propylamine
(1 .3 ml), and the mixture was stirred at 55°C for 1 5 hours. The reaction mixture was
concentrated under reduced pressure, and the residue was purified by silica gel column
chromatography to give N-(2-propylcarbamoyl-ethoxy)-acetimidic acid ethyl ester (296 mg,
86% yield).
, 400MHz) 6(PPM) 0.92(3H, t, J=7.4Hz), 1.26(3H, t, J=6.8Hz), 1.47-1.56(2H,
m), 1.93(3H, s), 2.55(2H, t, J=6.0Hz), 3.22(2H, dt, J=6.8, 6.8Hz), 4.01(2H, q, J=6.8Hz), 4.16(2H,
t, J=6.0Hz), 5.83(1H, br.s)
ESI(LC/MS positive mode) m/z 217 (M+H)
StepB
Synthesis of
(E)-5-[(2-propylcarbamoyl-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)
-N-(2-hydroxy-ethoxy)-benzamide
157
Using N-(2-propylcarbamoyl-ethoxy)-acetimidic acid ethyl ester obtained in Step A,
synthesis was performed according to the procedure described in Step B of Example 24 to give
(E)-5-[(2-propylcarbamoyl-emoxymiino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylarnino)
-N-(2-hydroxy-ethoxy)-benzamide.
^-NMRCCDsOD, 400MHz) 8(PPM) 0.89(3H, t, J=7.3Hz), 1.46-1.52(2H, m), 2.59(2H, t,
J=6.4Hz), 3.13(2H, t, J=7.1Hz), 3.72(2H, t, J=4.6Hz), 3.95(2H, t, J=4.6Hz), 4.43(2H, t, J=6.4Hz),
6.71(1H, ddd, J=8.8, 8.8,4.4Hz), 7.37-7.39(lH, m), 7.46(1H, dd, J=10.7, 2.0Hz), 7.81(1H, br.d,
J=5.9Hz), 8.22(1H, s)
ESI(LC/MS positive mode) m/z 609 (M+H)
StepC
Synthesis of
5-[(2-propylcarbamoyl-ethoxyamino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(
2-hydroxy-ethoxy)-benzamide (Compound C-19)
Using
(E)-5-[(2-propylcarbamoyl-ethoxyimino)-methyl]-354-difluoro-2-(2-fluoro-4-iodo-phenylamino)
-N-(2-hydroxy-ethoxy)-benzamide obtained in Step B, synthesis was performed according to the
procedure described in Step C of Example 24 to give
5-[(2-propylcarbamoyl-ethoxyamino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(
2-hydroxy-ethoxy)-benzamide (Compound C-19).
, 400MHz) 6(PPM) 0.87(3H, t, J=7.6Hz), 1.39-1.50(2H, m), 2.38(2H, t,
, 3.09(2H, t, J=7.0Hz), 3.71(2H, t, J=4.6Hz), 3.86(2H, t, J=6.1Hz), 3.95(2H, t, J=4.6Hz),
158
4.04(2H, s), 6.59(1H, ddd, J=8.8, 8.8,4.4Hz), 7.32-7.35(lH, m), 7.42-7.45(2H, m)
ESI(LC/MS positive mode) m/z 611 (M+H)
[Example 26]
5-[(2-Isopropylcarbamoyl-ethoxyamino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
N-(2-hydroxy-ethoxy)-benzamide (Compound C-20)
Step A
Synthesis of N-(2-isopropylcarbamoyl-ethoxy)-acetimidic acid ethyl ester
To a known compound, 3-(l-ethoxy-ethylideneaminooxy)-propanoic acid methyl ester
(CAS No. 97164-30-2, 300 mg, 1.585 mmol) were added methanol (3 ml) and isopropylamine
(1 .4 ml), and the mixture was stirred at 55°C for 14 hours. Additional isopropylamine (1 .0 ml)
was added, and the mixture was stirred for 3 hours using a focused microwave synthesis system
(Discover ™, CEM) at 100 W. The reaction mixture was concentrated under reduced pressure,
and the residue was purified by silica gel column chromatography to give
N-(2-isopropylcarbamoyl-ethoxy)-acetimidic acid ethyl ester (46 mg, 13% yield).
s, 400MHz) 8(PPM) 1.12(6H, d, J=7.3Hz), 1.28(3H, t, J=7.1Hz), 1.91(3H, s),
2.50(2H, t, J=5.9), 4.00(2H, q, J=7.1Hz), 4.06-4.11(1H, m), 4.15(2H, t, J=5.9Hz), 5.72(1H, br.s)
StepB
Synthesis of
(E)-5-[(2-isopropylcarbamoyl-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylami
no)-N-(2-hydroxy-ethoxy)-benzamide
Using N-(2-isopropylcarbamoyl-ethoxy)-acetimidic acid ethyl ester obtained in Step A,
synthesis was performed according to the procedure described in Step B of Example 24 to give
159
(E)-5-[(2-isopropylcarbamoyl-ethoxyimino)-methyl]-354-difluoro-2-(2-fluoro-4-iodo-phenylami
no)-N-(2-hydroxy-ethoxy)-benzamide.
, 400MHz) 6(PPM) 1.02(6H, d, J=6.4Hz), 2.47(2H, t, J=6.4Hz), 3.63(2H, t,
J=4.6Hz), 3.84-3.89(3H, m), 4.34(2H, t, J=6.4Hz), 6.62(1H, ddd, J=8.8, 8.8, 4.4Hz), 7.29(1H,
br.d, J=8.8Hz), 7.37(1H, dd, J=10.3, 2.0Hz), 7.72(1H, br.d, J=6.8Hz) , 8.13(1H, s)
ESI(LC/MS positive mode) m/z 609 (M+H)
Step C
Synthesis of
5-[(2-isopropylcarbamoyl-ethoxyamino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
N-(2-hydroxy-ethoxy)-benzamide (Compound C-20)
Using
(E)-5-[(2-isopropylcarbamoyl-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylami
no)-N-(2-hydroxy-ethoxy)-benzamide obtained in Step B, synthesis was performed according to
the procedure described in Step C of Example 24 to give
5 - [(2-isopropylcarbamoy l-ethoxyamino)-methyl] -3 ,4-difluoro-2-(2 -fluoro-4-iodo-phenylamino)-
N-(2-hydroxy-ethoxy)-benzamide (Compound C-20).
, 400MHz) 5(PPM) 0.99(6H, d, J=6.4Hz), 2.27(2H, t, J=6.1Hz), 3.62(2H, t,
J=4.6Hz), 3.76(2H, t, J=6.1Hz), 3.80-3.87(3H, m), 3.95(2H, s), 6.50(1H, ddd, J=8.8, 8.8, 4.4Hz),
7.24(lH,br.d, J=8.8Hz), 7.33-7.36(2H, m)
ESI(LC/MS positive mode) m/z 611 (M+H)
[Example 27]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methylcarbamoyl-et
hoxyamino)-methyl]-benzamide (Compound C-6)
Step A
Synthesis of N-(2-methylcarbamoyl-ethoxy)-acetimidic acid ethyl ester
160
0
To a solution of a known compound, 3-(l-ethoxyethylideneaminooxy)-propanoic acid
methyl ester (CAS No. 97164-30-2, 41 .3 g, 0.21 8 mol) in methanol (150 ml) was added
methylamine (40% solution in methanol, 200 ml) at room temperature, and the mixture was
stirred at 60°C for 12 hours. The reaction mixture was concentrated under reduced pressure to
giveN-(2-methylcarbamoyl-ethoxy)-acetimidic acid ethyl ester (41.0 g, 100%).
, 400MHz) 8(PPM) 1.28(3H, t, J=7.1Hz), 1.92(3H, s), 2.56(2H, t, J=5.9Hz),
2.81(3H, d, J=4.9Hz), 4.00(2H, q, J=7.1Hz), 4.15(2H, t, J=5.9Hz), 6.00(1H, br.s)
StepB
Synthesis of 3-aminooxy-N-methyl-propionamide
N-(2-Methylcarbamoyl-ethoxy)-acetimidic acid ethyl ester (41.0 g, 0.218 mol) obtained
in Step A was dissolved in methanol (210 mL), and the solution was cooled to 0°C. To this
solution, cone, hydrochloric acid (28 mL) was added dropwise over 30 minutes, and the mixture
was stirred at room temperature for 30 minutes. The reaction mixture was cooled again, to
which 28% aqueous ammonia (42 mL) was added portionwise, and then concentrated under
reduced pressure. To the resultant residue, acetonirrile was added, and insoluble matter was
filtered off. The filtrate was concentrated under reduced pressure to give
3-aminooxy-N-methyl-propionamide (25.8 g, 99%).
^-NMRtCDCls, 400MHz) 5(PPM) 2.43(2H, t, J=6.4Hz), 2.70(3H, s), 3.85(2H, t, J=6.4Hz)
StepC
Synthesis of
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methylcarbamoyl
161
-ethoxyimino)-methyl]-benzamide
Using 3-aminooxy-N-methyl-propionamide obtained in Step B, synthesis was
performed according to the procedure described in Step C of Example 19 to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylammo)-N-(2-hydroxy-ethoxy)-5-[(2-methylcarbamoyl-eth
oxyimino)-methyl]-benzamide as a white solid.
, 270MHz) 5(PPM) 2.59(2H, t, J=5.9Hz), 2.72(3H, s), 3.72(2H, m), 3.95(2H,
m), 4.43(2H, t, J=5.9Hz), 6.72(1H, dt, J=8.9, 4.3Hz), 7.39(1H, m), 7.47(1H, dd, J=10.9, 2.0Hz),
7.80(1H, dd, J=6.9, 2.0Hz), 8.23(1H, s)
ESI(LC/MS positive mode) m/z 581 (M+H)
StepD
Synthesis of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methylcarbamoyl-eth
oxyamino)-methyl]-benzamide (Compound C-6)
HOV
Using
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methylcarbamoyl-eth
oxyimino)-methyl]-benzamide obtained in Step C, synthesis was performed according to the
procedure described in Step C of Example 24 to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methylcarbamoyl-eth
oxyamino)-methyl]-benzamide (Compound C-6).
, 270MHz) S(PPM) 2.32-2.41(2H, m), 2.69(3H, s), 3.71(2H, t, J=4.6Hz),
162
3.85(2H, t, J=5.9Hz), 3.89-3.96(2H, m), 4.04(2H, s), 6.54-6.64(lH, m), 7.34(1H, br.d, J=9.9Hz),
7.43(2H,dd,J=10.6,1.9Hz)
ESI(LC/MS positive mode) m/z 583 (M+H)
[Example 28]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylcarbamoyl-pr
opoxyamino)-methyl]-benzamide (Compound C-21)
Step A
Synthesis of 4-(l,3-dioxo-l,3-dihydro-isoindol-2-yloxy)-butyric acid ethyl ester
To a solution of 4-bromo-n-butyric acid ethyl ester (1.2 g, 6.13 mmol) in
dimethylformamide (9 ml) were added N-hydroxyphthalimide (1.5 g, 9.19 mmol) and Hunig
base (N,N-diisopropylethylamine, 2.13 mL) at room temperature, and the mixture was stirred at
80°C over night. The reaction mixture was poured into saturated aqueous ammonium chloride,
and the resultant mixture was extracted with ethyl acetate (3x 40 ml). The combined organic
layers were washed with saturated brine (2x 30 ml), dried over NaaSO^ and concentrated under
reduced pressure. The resultant residue was purified by silica gel column chromatography (100
g, n-hexane/ethyl acetate (2:1)) to give 4-(l,3-dioxo-l,3-dihydro-isoindol-2-yloxy)-butyric acid
ethyl ester (1.47 g, 100%).
270MHz) 8(PPM) 1.28 (3H, t, J = 6.9 Hz), 2.11 (2H, q, J = 6.9 Hz), 2.64 (2H, t,
J = 7.3 Hz), 4.17 (2H, q, J = 7.3 Hz), 4.27 (2H, t, J = 6.3 Hz), 7.72-7.79 (2H, m), 7.81-7.89 (2H,
m).
StepB
Synthesis of 4-aminooxy-N-methyl-butylamide
163
To a solution of 4-(l,3-dioxo-l,3-dihydro-isoindol-2-yloxy)-butyric acid ethyl ester
(997.5 mg, 4.59 mmol) obtained in Step A in methanol (4 mL) was added methylamine (40%
solution in methanol, 10 ml, 98.0 mmol), and the mixture was stirred at 60°C overnight. The
reaction mixture was concentrated under reduced pressure, and methylene chloride was added to
the resultant residue to precipitate a solid, which was filtered and washed with methylene
chloride. The combined filtrate and washing were concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (30 g, CHiCk/MeOH (8:1)) to give
4-aminooxy-N-methyl-butylamide (467.3 mg, 77%) as a colorless syrup.
, 270MHz) 6(PPM) 1.94 (2H, q, J = 6.3 Hz), 2.25 (2H, t, J = 6.9 Hz), 2.81 (3H,
d, J = 4.6 Hz), 3.70 (t, J = 5.9 Hz).
StepC
Synthesis of
(E)-3 ,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5 - [(3 -methylcarbamoyl
-propoxyimino)-methyl] -benzamide
To 4-aminooxy-N-methyl-butylamide (1.79 g, 13.54 mmol) obtained in Step B were
added a mixed solvent of tetrahydrofuran/methanol (3:1,100 ml) and
3,4-difluoro-2-(2-fluoro-4-iodophenylamino-5-formyl-N-(2-hydroxy-ethoxy)-benzamide(5.00 g,
10.41 mmol) obtained in Step F of Example 1, and the mixture was stirred for 13 hours. The
reaction mixture was concentrated under reduced pressure to an extent where a little solvent
remained, and acetonitrile was added thereto to precipitate the product. This precipitate was
filtered, washed with acetonitrile, and dried under reduced pressure to give
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylcarbamoyl
-propoxyimino)-methyl]-benzamide (4.93 g, 79% yield).
1H-NMR(DMSO-d6, 270MHz) 8(PPM) 1.88 (2H, qui, J = 7.6 Hz), 2.17 (2H, t, J = 6.9 Hz), 2.56
(3H, d, J = 4.6 Hz), 3.57 (2H, br. q, J = 4.6 Hz), 3.83 (2H, t, J = 4.6 Hz), 4.14 (2H, t, J = 6.3 Hz),
4.73 (IH, t, J = 5.6 Hz, OH), 6.80 (IH, td, J = 8.9,4.0 Hz), 7.40 (IH, br. d, J = 8.6 Hz), 7.61 (IH,
164
dd, J = 10.9,2.0 Hz), 7.68 (1H, br. d, J = 5.6 Hz), 7.77 (1H, br q, J = 4.6 Hz, NH), 8.26 (1H, s),
8.87 (1H, br. s, NH), 11.99 (1H, br. s, NH).
ESI(LC/MS positive mode) m/z 595 (M+H)
StepD
Synthesis of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylcarbamoyl-pr
opoxyamino)-methyl]-benzamide (Compound C-21)
To
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylcarbamoyl
-propoxyimino)-methyl]-benzamide (50 mg, 0.084 mmol) obtained in Step C was added
dichloromethane (6 ml). The mixture was stirred at room temperature, and borane-pyridine
complex (67 ul, 0.673 mmol) and dichloroacetic acid (55 ul, 0.673 mmol) were added thereto.
After stirring for 14 hours, the reaction mixture was diluted with ethyl acetate, and washed with
purified water and saturated aqueous sodium chloride. The organic layer was dried over
anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylcarbamoyl-pr
opoxyamino)-methyl]-benzamide (Compound C-21, 32 mg, 65% yield).
, 400MHz) S(PPM) 1.72-1.84(2H, m), 2.18(2H, t, J=7.3Hz), 2.67(3H, s),
3.63(2H, t, J=6.4Hz), 3.70(2H, t, J=4.4Hz), 3.94(2H, t, J=4.4Hz), 4.05(2H, s), 6.58(1H, ddd,
J=8.8, 8.8, 4.4Hz), 7.32-7.35(lH, m), 7.43(1H, dd, J=10.5, 1.7Hz), 6.84(1H, br.d, J=6.8Hz)
ESI(LC/MS positive mode) m/z 597 (M+H)
[Example 29]
5-[(2-Acetylamino-ethoxyamino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-h
ydroxy-ethoxy)-benzamide (Compound C-7)
Step A
165
Synthesis of 2-aminooxy-ethyl-carbamic acid t-butyl ester
The title compound was synthesized according to the methods described in J. Med.
Chem., 1999, 42, 2007 and WO02/06213.
StepB
(E)-{2-[2,3-difluoro-4-(2-fluoro-4-iodo-phenylamino)-5-(2-hydroxy-ethoxycarbamoyl)-benzylid
eneaminooxy] -ethyl }-carbamic acid tert-butyl ester
Using 2-ammooxy-ethyl-carbarnic acid t-butyl ester obtained in Step A, synthesis was
performed according to the procedure described in Step C of Example 19 to give
(E)-{2-[2,3-difluoro-4-(2-fluoro-4-iodo-phenylamino)-5-(2-hydroxy-ethoxycarbamoyl)-benzylid
eneaminooxy]-ethyl}-carbamic acid tert-butyl ester.
'H-NMRpMSO-de, 270MHz) 8(PPM) 1.38 (9H, s), 3.26 (2H, t, J = 5.9 Hz), 3.56 (2H, t, J = 4.3
Hz), 3.83 (2H, t, J = 4.3 Hz), 4.36 (2H, t, J = 5.9 Hz), 4.72 (IH, s), 6.79 (IH, m), 6.95 (IH, m),
7.38 (IH, d, J = 8.9 Hz), 7.60 (IH, d, J = 10.6 Hz), 7.69 (IH, d, J = 6.3 Hz), 8.27(1H, s), 8.86
(0.5H,br.s), 11.98 (0.5H,br.s)
ESI(LC/MS positive mode) m/z 639 (M+H)
StepC
Synthesis of
(E)-5-[(2-amino-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydr
oxy-ethoxy)-benzamide
To a solution of
{2-[2,3-difluoro-4-(2-fluoro-4-iodo-phenylamino)-5-(2-hydroxy-ethoxycarbamoyl)-ben2ylidenea
minooxy]-ethyl}-carbamic acid tert-butyl ester (55 mg, 0.31 mmol) prepared in Step B in ethyl
acetate (5 ml) was added 1 N HCI solution in ethyl acetate (1 ml), and the mixture was stirred at
room temperature for 1.5 hours. After completion of the reaction, the reaction mixture was
neutralized with saturated solution of sodium bicarbonate (50 ml), and extracted with ethyl
acetate (3x 100 ml). The extract was washed with saturated brine, and the organic layer was
dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced
pressure, and after washing with diethyl ether (10 ml), the residue was recrystallized from
methanol to give
(E)-5-[(2-amino-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydr
oxy-ethoxy)-benzamide (17.31 mg, 37% yield) as a pale yellow solid.
'H-NMRCDMSO-cU, 270MHz) 8(PPM) 3.05 (2H, t, J - 5.6), 3.56(2H, t, J = 4.6), 3.80 (2H, t, J =
4.6), 4.28 (2H, t, J = 5.3 Hz), 6.79 (1H, m), 7.38 (1H, d, J = 9.0 Hz), 7.61 (1H, d, J = 10.9 Hz),
8.08 (1H, d, J = 7.3 Hz), 8.26 (1H, s)
ESI(LC/MS positive mode) m/z 539 (M+H)
StepD
Preparation of
(E)-5-[(2-acetylamino-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2
-hydroxy-ethoxy)-benzamide
167
To a solution of
(E)-5-[(2-amino-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylainino)-N-(2-hydr
oxy-ethoxy)-benzamide (8.14 mg, 0.02 mmol) described in Step C in a mixed solvent of
dimethylformamide (1 ml) and methanol (5 ml) was added N-methoxydiacetamide (100 mg,
0.76 mmol), and the mixture was stirred at room temperature for 14 hours. After completion of
the reaction, the solvent was evaporated under reduced pressure, and the resultant residue was
purified with Mega Bond Elut silica gel (Varian, 5 g).
(E)-5-[(2-Acetylamino-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(
2-hydroxy-ethoxy)-benzamide (8.10 mg, 92% yield) was obtained as a pale yellow solid from
fractions eluted with 6% methanol/methylene chloride.
'H-NMRCDMSO-de, 400MHz) 5(PPM) 1.82 (3H, s), 3.36 (2H, t, J = 5.6), 3.57(2H, br.s), 3.84
(2H, br.s), 4.15 (2H, t, J = 5.6 Hz), 4.73 (1H, s), 6.81 (1H, m), 7.40 (1H, d, J = 7.6 Hz), 7.61 (1H,
d, J = 10.8 Hz), 7.71 (1H, br.s), 8.00 (1H, s), 8.28 (1H, s), 8.90 (0.5H, br.s), 11.98 (0.5H, br.s)
ESI(LC/MS positive mode) m/z 581 (M+H)
Synthesis of
5-[(2-acetylamino-ethoxyamino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hy
droxy-ethoxy)-benzamide (Compound C-7)
To
(E)-5-[(2-acetylamino-emoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2
-hydroxy-ethoxy)-benzamide (57.6 mg, 99.3 umol) obtained in Step D was added
dichloromemane (2.5 ml). The mixture was stirred at room temperature, and borane-pyridine
complex (80 ul, 0.79 mmol) and dichloroacetic acid (67 ul, 0.80 mmol) were added thereto.
After stirring for 3 hours, water (10 ml) and saturated aqueous sodium bicarbonate (2 ml) were
added to the reaction mixture, which was then extracted with methylene chloride (15 ml and 2x 8
ml). The combined organic layers were washed with aqueous sodium bicarbonate (8 ml) and
168
saturated aqueous sodium chloride(8 ml), dried over anhydrous sodium sulfate, and concentrated
under reduced pressure. The residue was purified by silica gel column chromatography
(methylene chloride/methanol (10:1)) to give
5-[(2-acetylamino-ethoxyamino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hy
droxy-ethoxy)-benzamide (Compound C-7,44.0 mg, 76%).
'H-NMRtCDaOD, 270MHz) 8(PPM) 1.92 (3H, s), 3.36 (2H, t, J = 5.6), 3.67 (2H, t, J = 5.4 Hz),
3.70 (2H, t, J = 4.8 Hz), 3.93 (2H, t, J = 4.3 Hz), 4.07 (2H, s), 6.59 (1H, td, J = 8.7,4.5 Hz), 7.34
(1H, br. d, J = 8.4 Hz), 7.44 (1H, dd, J = 10.7, 2.0 Hz), 1H is overlapped with the dd peak at 7.44
ppm. 2H is overlapped with the peak of HiO around 3.3ppm.
ESI(LC/MS positive mode) m/z 583 (M+H)
[Example 30]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-propionylamino-eth
oxyamino)-methyl]-benzamide (Compound C-34)
Step A
Synthesis of
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-propionylaminoethoxyimino)-
methyl]-benzamide
To a solution of propionic acid (84 ul, 1.13 mmol) in methylene chloride (2 ml) were
added l-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (212.0 mg, 1.10 mmol)
and N-hydroxybenzotriazole (156.5 mg, 1.17 mmol) at room temperature, and the mixture was
stirred at room temperature for 30 minutes to give a solution of an active ester of propionic acid
in methylene chloride (0.55 M). To a solution of
5-[(2-amino-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxyethoxy)-
benzamide (101.9 mg, 0.189 mmol) obtained in Step C of Example 29 in DMF (2.5 ml)
were added dimethylaminopyridine (54.0 mg, 0.442 mmol) and the solution of the active ester in
methylene chloride (0.55 M, 0.35 ml, 0.193 mmol) obtained above, and the mixture was stirred
at room temperature. With monitoring the reaction, 0.18 ml (0.10 mmol) and 0.20 ml (0.11
169
mmol) of the active ester solution were added after 40 minutes and 13 hours, respectively, and
the mixture was stirred for another 8 hours. Water (10 ml) was added to the reaction mixture,
which was then extracted with ethyl acetate (20 ml + 3x 10 ml). The combined organic layers
were washed with aqueous sodium bicarbonate (2x 15 ml), 0.2 N hydrochloric acid (15 ml), and
saturated brine (15 ml), dried over sodium sulfate, and concentrated under reduced pressure.
The resultant residue was triturated with n-hexane/ethyl acetate (3:1) to give an oxime,
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-propionylaminoethoxyimino)-
methyl]-benzamide (94.6 mg, 84%) as a pale yellow solid.
ESI(LC/MS positive mode) m/z 595 (M+H)
StepB
Synthesis of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-propionylaniino-etho
xyamino)-methyl]-benzamide (Compound C-34)
The oxime,
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-propionylaniinoethoxyunino)-
methyl]-benzamide (33.0 mg, 51.0 umol) obtained in Step A was suspended in
methylene chloride (1 ml), and dichloroacetic acid (60 ml) and borane-pyridine complex (70 ul)
were added thereto at room temperature. The mixture was stirred at room temperature for 2
hours. Water (6 ml) and aqueous sodium bicarbonate (2 ml) were added to the reaction mixture,
which was then extracted with methylene chloride (2x 10 ml). The combined organic layers
were washed with aqueous sodium bicarbonate (5-fold dilution of saturated solution, 8 ml) and
saturated brine (8 ml), dried over sodium sulfate, and concentrated under reduced pressure. The
resultant residue was purified by silica gel column chromatography (methylene
chloride/methanol (40:3)) to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-propionylamino-etho
xyamino)-methyl]-benzamide (Compound C-34, 21.6 mg, 71%) as a colorless syrup.
170
'H-NMRXCDsOD, 270MHz) 6(PPM) 1.09 (3H, t, J = 7.8 Hz), 2.17 (2H, q, J = 7.8 Hz), 3.33 (2H,
t, J = 5.7 Hz), 3.67 (2H, dd (like t), J = 5.1, 5.7 Hz), 3.70( 2H, br. t, J = 5.1 Hz), 3.93 (2H, br. t, J
= 4.1 Hz), 4.07 (2H, s), 6.58 (1H, td, J = 8.9,4.3 Hz), 7.34 (1H, ddd, J - 8.4,1.6,1.4 Hz), 7.44
(1H, dd, J = 10.5, 1.9 Hz), 1H is overlapped with the dd peak at 7.44 ppm.
ESI(LC/MS positive mode) m/z 597 (M+H)
[Example 31]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-isobutyrylamino-eth
oxyamino)-methyl]-benzamide (Compound C-35)
Step A
Synthesis of
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-isobutyrylaminoethoxyimino)-
methyl]-benzamide
To a solution of isobutyric acid (172 ul, 1.85 mmol) in a mixed solvent of methylene
chloride and DMF (3 ml and 1 ml) were added l-ethyl-3-(3'-dimethylaminopropyl)carbodiimide
hydrochloride (352.1 mg, 1.84 mmol) and N-hydroxybenzotriazole (250.0 mg, 1.87 mmol) at
room temperature, and the mixture was stirred at room temperature for 30 minutes to give a
solution of an active ester of isobutyric acid in methylene chloride - DMF (0.46 M). To a
suspension of
5-[(2-amino-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxyethoxy)-
benzamide (106.7 mg, 0.198 mmol) obtained in Step C of Example 29 in DMF (2 ml)
were added dimethylaminopyridine (51.2 mg, 0.419 mmol) and the solution of the active ester in
methylene chloride (0.46 M, 0.50 ml, 0.23 mmol) obtained above, and the mixture was stirred at
room temperature. With monitoring the reaction, 0.20 ml (0.09 mmol) and 0.20 ml (0.09
mmol) of the active ester solution were added after 20 minutes and 13 hours, respectively, and
the mixture was stirred for another 8 hours. Water (10 ml) was added to the reaction mixture,
which was then extracted with ethyl acetate (20 ml + 3x 10 ml). The combined organic layers
were washed with aqueous sodium bicarbonate (2x 10 ml), 0.2 N hydrochloric acid (15 ml), and
171
saturated brine (10 ml), dried over sodium sulfate, and concentrated under reduced pressure.
The resultant residue was triturated with n-hexane/ethyl acetate (3:1) to give an oxime,
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-isobutyrylaminoethoxyimino)-
methyl]-benzamide (98.5 mg, 82%) as a pale yellow solid.
ESI(LC/MS positive mode) m/z 609 (M+H)
StepB
Synthesis of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-isobutyrylamino-etho
xyamino)-methyl]-benzamide (Compound C-35)
The oxime,
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-isobutyrylaminoethoxyimino)-
methyl]-benzamide (28.8 mg, 47.3 umol) obtained in Step A was suspended in
methylene chloride (1 ml), and dichloroacetic acid (60 ml) and borane-pyridine complex (70 ul)
were added thereto at room temperature. The mixture was stirred at room temperature for 2
hours. Water (6 ml) and aqueous sodium bicarbonate (2 ml) were added to the reaction mixture,
which was then extracted with methylene chloride (2x 10 ml). The combined organic layers
were washed with aqueous sodium bicarbonate (5-fold dilution of saturated solution, 8 ml) and
saturated brine (8 ml), dried over sodium sulfate, and concentrated under reduced pressure. The
resultant residue was purified by silica gel column chromatography (methylene
chloride/methanol (40:3)) to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-isobutyrylamino-etho
xyamino)-methyl]-benzamide (Compound C-35, 20.5 mg, 71%) as a colorless syrup.
'H-NMRCCDaOD, 270MHz) 6(PPM) 1.07 (6H, d, J = 6.8 Hz), 2.40 (IH, quinted, J = 6.8 Hz),
3.34 (2H, t, J = 5.4 Hz), 3.67 (2H, t, J - 5.4 Hz), 3.70 (2H, br. t, J = 4.9 Hz), 3.93 (2H, br. t, J =
4.3 Hz), 4.07 (2H, s), 6.58 (IH, td, J = 8.6,4.1 Hz), 7.34 (IH, ddd, J = 8.6,1.9,1.1 Hz), 7.44 (IH,
172
dd, J = 10.8,1.9 Hz), 1H is overlapped with the dd peak at 7.44 ppm.
ESI(LC/MS positive mode) m/z 611 (M+H)
[Example 32]
2-(4-Ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)5 - [(2-hydroxy-2-methyl
-propoxyamino)-methyl]-benzamide (Compound C-29)
Step A
(E)-2-(4-Ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-2-m
ethyl-propoxyimino)-methyl]-benzamide
(E)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-
2-methyl-propoxyimino)-methyl]-benzamide (200 mg, 0.35 mmol), Pd(CHsCN)2Cl2 (4.5 mg,
0.0176 mmol), triphenylphosphine-3,3',3"-trisulfonic acid tnsodium salt (25.0 mg, 0.037 mmol),
N('Pr)2Et (48.0 mg, 0.37 mmol), trimethylsilyl acetylene (172 mg, 1.76 mmol), and Cul (3.4 mg,
0.0176 mmol) were stirred in MeOH at room temperature for 1 hour, and the solvent was
evaporated. The resultant residue was added to THF/HbO containing tetrabutylammonium
fluoride (0.35 mmol), and the mixture was stirred for 1 hour. EtOAc was added thereto, and the
organic layer was washed with 0.4 N aqueous HC1, dried over Na2SO4, and evaporated. The
resultant residue was purified by silica gel chromatography (CHiCk/MeOH as a developing
solvent) to give a title compound (99 mg).
'H-NMI^CDsOD, 270MHz) 5(PPM) 1.26(6H, s), 3.46(1H, s), 3.71(2H, m), 3.95(2H, m),
4.08(2H, s), 6.85(1H, m), 7.16(d, J=8.9Hz), 7.21(1H, dd, J=13.9,1.6Hz), 7.82(1H, br.d,
J=5.3Hz), 8.31(1H, s)
ESI(LC/MS positive mode) m/z 466 (M+H)
StepB
2-(4-Ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)5-[(2-hydroxy-2-methyl
-propoxyamino)-methyl]-benzamide (Compound C-29)
173
Using
(E)-2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-2-me
thyl-propoxyimino)-methyl]-benzamide obtained in Step A as a starting material, synthesis was
performed according to the procedure described in Step C of Example 24 to give
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)5-[(2-hydroxy-2-methylpropoxyamino)-
methyl]-benzamide (Compound C-29).
-de, 400MHz) 5(PPM) 1.00(6H, s)s 3.53(2H,br), 3.81(2H, br), 3.96(2H, d,
J=5.9Hz), 4.08(1H, s), 4.40(1H, br), 4.71(1H, br), 6.69(1H, m), 6.97(1H, t, J=5.9Hz), 7.13(1H, d,
J=8.8Hz)5 7.30(1H, d, J=11.6Hz), 7.49(1H, d, J=6.8Hz), 8.66(1H, br), 11.73(1H, br). The peak of
a methyl ene group is overlapping with that of HiO peak.
ESI(LC/MS positive mode) m/z 468 (M+H)
[Example 33]
2-(4-Ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxya
mino)-methyl]-benzamide (Compound C-2)
Step A
Synthesis of
(E)-2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-etho
xyimino)-methyl] -benzamide
174
Starting from
(E)3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyi
mino)-methyl]-benzamide obtained in Step B of Example 6, synthesis was performed according
to the procedure described in Step A of Example 32 to give
(E)-2-(4-ethynyl-2-fluoro-phenylamino)-354-difluoro-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-etho
xyimino)-methyl]-benzamide.
'H-NMRtCDsOD, 270MHz) 6(PPM): 3.45(1H, s), 3.72( 2H, dd, J=4.9,4.3Hz), 3.82(2H, dd,
J=5.3, 4.6Hz), 3.96(2H, dd, 4.9,4.3Hz), 4.27(2H, t, J=4.9Hz), 6.85(1H, td, J=8.6, 4.6Hz),
7.18(2H, m), 7.83(1H, dd, J=7.0,2.0Hz), 8.39(lH,s)
ESI(LC/MS positive mode) m/z 438 (M+H)
StepB
Synthesis of
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5 - [(2-hydroxy-ethoxya
mino)-methyl]-benzamide (Compound C-2)
Using
(E)-2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-etho
xyimino)-methyl]-benzamide obtained in Step A, synthesis was performed according to the
procedure described in Step C of Example 24 to give
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxya
mino)-methyl]-benzamide (Compound C-2).
-de, 400MHz) 8(PPM) 3.46(2H, t, J=4.7Hz), 3.55(4H,m), 3.82(2H, t, J=4.7Hz),
3.96(2H, d, J=5.8Hz), 4.08(1H, s), 4.53(1H, br), 4.71(1H, br), 6.70(1H, m), 6.85(1H, t, J=5.8Hz),
7.13(1H, d, J=8.3Hz), 7.30(1H, dd, J=12.0Hz, 2.0Hz), 7.49(1H, d, J=6.3Hz), 8.66(1H, br),
11.72(lH,br).
175
ESI(LC/MS positive mode) m/z 440 (M+H)
[Example 34]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-(2-hydroxy-l,l-dimethyl-ethoxymethyl)-N-(2-
hydroxy-ethoxy)-benzamide (Compound B-19)
Step A
Synthesis of 2-methyl-propane- 1 ,2-diol
2-Methyl-propane-l,2-diol is a known compound (CAS No. 558-43-0), and may be
prepared by one of the method described in the following literatures:
Zh. Obshch. Khim. 7,1319 (1937),
Chem. Zentralbl. 109, 561 (1938),
Meml. Poudres, 28,263 (1938), and
Chem. Zentralbl. 110,2398 (1939).
Practically, the title compound was prepared by the following procedure.
To a suspension of lithium aluminum hydride (321.3 mg, 8.47 mmol) in THF (5 ml) was
added dropwise a solution of 2-hydroxy-2-methyl-propionic acid methyl ester (commercially
available, 1.0 g, 8.47 mmol) in THF (3 ml), and the mixture was stirred at room temperature for
4 hours. Water (0.70 ml) was added to the reaction mixture, which was stirred for additional 10
minutes. The resultant mixture was filtered through a mixed bed of celite powder and sodium
sulfate powder. The filtrate was concentrated under reduced pressure, and the residue was
diluted with THF, dried over sodium sulfate, and concentrated under reduced pressure to give
2-methyl-propane-1,2-diol (659.7 mg, 86%) as an oily crude product.
'H-NMRflDMSO-de, 270MHz) 5(PPM) 1.03 (6H, s), 3.13 (2H, d, J = 5.6 Hz), 4.10 (1H, s), 4.50
(1H, t, J = 5.9 Hz).
Step B
Synthesis of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5 -(2-hydroxy-1,1 -dimethyl-ethoxymethyl)-N-(2-h
ydroxy-ethoxy)-benzamide (Compound B-19)
Using
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide
obtained in Step F of Example 1 as a starting material, and 2-methyl-propane-l,2-diol obtained
in Step A instead of ethylene glycol used as a reagent in Step G of Example 1, synthesis similar
to that in Step G of Example 1 was performed. The resultant cyclic acetal was subjected to
reduction condition similar to that in Step H of Example 1 to give the title compound.
'H-NMRtDMSO-de, 270MHz) 8(PPM) 1.18 (6H, s), 3.35 (2H, overlapped with H2O peak in
DMSO, singlet after addition of D2O), 3.37(2H, s), 3.56(2H, dd, J = 4.9, 4.6 Hz), 3.83 (2H, dd, J
= 4.9,4.6 Hz), 4.50 (2H, s), 4.69 (IH, t, J = 5.6 Hz, disappeared after addition of D2O), 4.70 (IH,
br. s, disappeared after addition of D2O), 6.60(1H, td, J = 8.7,4.1 Hz), 7.36 (IH, br. d, J = 8.4
Hz),7.46 (IH, br. d, J = 6.6 Hz), 7.57 (IH, dd, J = 10.9,1.8 Hz), 8.61 (IH, br. s, disappeared after
addition of D2O), 11.80 (IH, br. s, disappeared after addition of D2O).
ESI(LC/MS positive mode) m/z 569(M+H)
[Example 35]
Synthesis of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-methanesulfonyl-etho
xymethyl)-benzamide (Compound B-12)
To a suspension of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide(52
mg, 0.108 mmol) obtained in Step F of Example 1 in methylene chloride (anhydrous, 5 mL)
were added copper trifluoromethanesulfonate (20 mg, 0.005 mmol), methanesulfonylethanol
(200 uL), and triethylsilane (500 uL, 3.13 mmol) under a nitrogen atmosphere, and the mixture
was stirred thoroughly for a whole day and night. After completion of the reaction, the reaction
mixture was extracted with ethyl acetate, and the organic layer was washed sequentially with 2%
aqueous EDTA, water, and saturated brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The resultant residue was purified by preparative TLC
(No. 5744, Merck, 5% methanol/methylene chloride as a developing solvent) to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-methanesulfonyl-etho
xymethyl)-benzamide (13.3 mg, 21%) as a white solid.
'H-NMRtCDsOD, 270MHz) 8(PPM) 3.02(3H, s), 3.41(2H, dd, J=5.4, S.lHz), 3.71(2H, dd,
J=4.8, 4.5Hz), 3.95(4H, m), 4.60(2H, s), 6.63(1H, td, J=8.9, 4.3Hz), 7.35(1H, br.d, J=8.4Hz),
7.45(1H, dd, J=10.9, l.SHz), 7.50(1H, m)
ESI(LC/MS positive mode) m/z 589(M+H)
[Example 36]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(3-oxo-[l,2]oxazinan-2-
ylmethyl)-benzamide (Compound G-l)
(E)-3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylc
arbamoyl-propoxyimino)-methyl]-benzamide (8.0 g, 13.5 mmol) obtained in Step C of Example
28 was suspended in methylene chloride (240 ml), and borane-pyridine complex (5.45 ml, 53.8
mmol) and dichloroacetic acid (6.65 ml, 80.8 mmol) were added thereto at room temperature.
The reaction mixture was stirred at room temperature for 15 hours, and dichloromethane was
removed under reduced pressure with a rotary evaporator. The residue was diluted with
1,2-dichloroethane (240 ml), and the mixture was stirred at 60°C for 8 hours, and filtered. The
residue obtained by concentrating the filtrate was diluted with ethyl acetate (800 ml), and washed
sequentially with water (400 ml), saturated aqueous sodium bicarbonate (400 ml), and saturated
brine (400 ml). The organic layer was dried over anhydrous sodium sulfate, and concentrated
178
under reduced pressure. The residue was purified by silica gel column chromatography
(CH2Cl2/MeOH (25:1)) to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(3-oxo-[l,2]oxazinan-2-
ylmethyl)-benzamide (Compound G-l, 6.93 g, 91% yield).
This compound may also be obtained as a by-product (18 mg, 35% yield) in a synthesis
of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylcarbamoyl-pr
opoxyamino)-methyl]-benzamide (Compound C-21) in Example 28.
, 400MHz) 5(PPM) 2.10(2H, quinted, J=6.8Hz), 2.53(2H, t, J=6.8Hz), 3.72(2H,
t, J=4.4Hz), 3.92(2H, t, J=4.4Hz), 4.04(2H, t, J=6.8Hz), 4.86(2H, s), 6.61 (1H, ddd, J=8.8, 8.8,
3.9Hz), 7.33-7.36(lH, m), 7.41(1H, dd, J=7.0, 1.7Hz), 7.45(1H, dd, J=10.3, 2.0Hz)
ESI(LC/MS positive mode) m/z 566 (M+H)
[Example 37]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(3-oxo-isoxazolidin-2-yl
methyl)-benzamide (Compound G-2)
To
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5 - [(2-methylcarbamoyl
-ethoxyimino)-methyl]-benzamide (9.60 g, 15.54 mmol) were added sequentially
dichloromethane (300 ml) and borane-pyridine complex (11.70 ml, 115.80 mmol) to give a
suspension. This mixture was stirred at room temperature, and dichloroacetic acid (9.51 ml,
115.80 mmol) was added dropwise thereto over 10 minutes. After the mixture was stirred at
room temperature for 13 hours, dichloromethane was removed under reduced pressure with a
rotary evaporator, and the resultant residue was diluted with 1,2-dichloroethane (300 ml). This
mixture was stirred at 60°C for 6 hours, diluted with ethyl acetate, and washed sequentially with
0.1 M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated aqueous
sodium chloride. The organic layer was dried over anhydrous sodium sulfate, and concentrated
under reduced pressure. The residue was purified by silica gel column chromatography to give
the title compound (8.28 g, 90% yield).
This compound may also be obtained as a by-product in a synthesis of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methylcarbamoyl-eth
oxyamino)-methyl]-benzamide (Compound C-6) in Example 27.
'H-NMRXCDaOD, 400MHz) 5(PPM) 2.84(2H, t, J=8.3Hz), 3.70(2H, t, J=4.7Hz), 3.93(2H, t,
J=4.7Hz), 4.36(2H, t, J=8.3Hz), 4.76(2H, s), 6.62(lH,ddd, J=8.8, 8.8, 3.9Hz), 7.34-7.36(lH, m),
7.39(1H, br.d, J=5.4Hz), 7.45(1H, dd, J=10.5,1.7Hz)
ESI(LC/MS positive mode) m/z 552 (M+H)
[Example 38]
2-(4-Ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-(3-oxo-isoxazolidin-2
-ylmethyl)-benzamide (Compound G-5)
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamrno)-N-(2-hydroxy-ethoxy)-5-(3-oxo-isoxazol
idin-2-ylmethyl)-benzamide (36.9 mg, 66.9 umol) obtained in Example 37,
bis(acetonitrile)dichloropalladium (II) (3.5 mg, 13.5 umol),
3,3',3"-phosphinidine-tris(benzenesulfonic acid) trisodium salt (19.0 mg, 33.4 umol), and
copper iodide (I) (2.6 mg, 13.6 umol) were suspended in methanol (2.5 ml) under a nitrogen
atmosphere. To this suspension, N,N-diisopropylethylamine (14.0 ul, 80.4 umol) and
trimethylsilylacetylene (47.3 ul, 334.7 umol) were added at room temperature, and the mixture
was stirred for 1 hour. The reaction mixture was diluted with methylene chloride (30 ml), and
washed with saturated brine (2x 15 ml). The organic layer was dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure. The resultant residue was
dissolved in THF (2 ml). To this solution, tetrabutylammonium fluoride (1.0 M solution in THF,
0.10 ml, 0.10 mmol) was added, and the mixture was stirred for 1 hour, and then concentrated
under reduced pressure. The resultant residue was purified by preparative TLC (EtOAc/MeOH
(8:1)) to give
180
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-(3-oxo-isoxazolidin-2
-ylmethyl)-benzamide (Compound G-5, 11.1 mg, 37%) as a brown oil.
, 270MHz) 6(PPM) 2.85 (2H, t, J = 8.1 Hz), 3,43 (1H, s), 3.70 (2H, t, J = 4.6
Hz), 3.93 (2H, t, J = 4.6 Hz), 4.36 (2H, t, J = 8.1 Hz), 4.78 (2H, s), 6.75 (1H, dt, J = 4.6, 8.6 Hz),
7.11-7.17 (1H, m), 7.20 (1H, dd, J - 1.8, 11.9 Hz), 7.41 (1H, dd, J = 1.8, 7.3 Hz).
ESI(LC/MS positive mode) m/z 450 (M+H)
[Example 39]
2-(4-Ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-(3-oxo-[l,2]oxadinan
-2-ylmethyl)-benzamide (Compound G-4)
Using
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(3-oxo-[l,2]oxazinan-2-
ylmethyl)-benzamide obtained in Example 36, synthesis was performed according to the
procedure described in Example 38 to give
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-(3-oxo-[l,2]oxadinan
-2-ylrnethyl)-benzamide (Compound G-4).
'H-NMRCCDaOD, 270MHz) 8(PPM) 2.11 (2H, quint., J = 6.9 Hz), 2.54 (2H, t, J = 6.9 Hz), 3,43
(1H, s), 3.70 (2H, t, J = 4.5 Hz), 3.93 (2H, t, J = 4.5 Hz), 4.05 (2H, t, J = 6.9 Hz), 4.87 (2H, s),
6.75 (1H, dt, J = 4.6, 8.6 Hz), 7.10-7.17 (1H, m), 7.19 (1H, dd, J = 1.9,11.9 Hz), 7.43 (1H, dd, J
= 1.9, 7.0 Hz).
ESI(LC/MS positive mode) m/z 464 (M+H)
[Example 40]
5-(4,4-Drmethyl-3-oxo-isoxazolidm-2-ylmethyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
N-(2-hydroxy-ethoxy)-benzamide (Compound G-3)
Step A
181
Synthesis of 3-(l,3-dioxo-l,3-dihydro-isoindol-2-yloxy)-2,2-dimemyl-propionic acid methyl
ester
To methyl hydroxypivalate (1.31 g, 9.89 mmol) were added tetrahydrofuran (40 ml),
hydroxyphthalimide (3.23 g, 19.78 mmol) and triphenylphosphine (6.48 g, 24.73 mmol). After
this solution was cooled to 0°C, diisopropyl azodicarboxylate (4.87 ml, 24.73 mmol) was added
dropwise to the solution. While being allowed to warm gradually, the reaction mixture was
stirred for 12 hours, and concentrated under reduced pressure. The residue was roughly
purified by silica gel column chromatography to give the title compound (922 mg).
, 400MHz) 8(PPM) 1.35(6H, s), 3.74(3H, s), 4.26(2H, s), 7.27-7.76(2H, m),
7.81-7.85(2H,m)
StepB
Synthesis of 3-aminooxy-2,2,N-trimethyl-propionamide
To 3-(l,3-dioxo-l,3-dihydro-isoindol-2-yloxy)-2,2-dimethyl-propionic acid methyl ester
(800 mg) obtained in Step A was added a 40% solution of methylamine in methanol (6 ml), and
the mixture was stirred at 60°C for 13 hours. After the reaction mixture was concentrated under
reduced pressure, dichloromethane was added to the residue, and insoluble matter was filtered.
The filtrate was concentrated, and the residue was purified by silica gel column chromatography
to give the title compound (202 mg).
'H-NMR^CDsOD, 400MHz) 5(PPM) 1.14(6H, s), 2.71(3H, s), 3.64(2H, s)
StepC
Synthesis of
182
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-[(2-methyl-2-methylcarba
moyl-propoxyimino)-methyl]-benzamide
The title compound was synthesized as a mixture of E/Z geometric isomers, using the
procedure described in Step C of Example 19, from 3-aminooxy-2,2,N-trimethyl-propionamide
obtained in Step B and
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-fomiyl-N-(2-hydroxy-ethoxy-benzamide
obtained in Step F of Example 1.
ESI(LC/MS positive mode) m/z 609 (M+H)
5-(4,4-Dimethyl-3-oxo-isoxazolidin-2-ylmethyl)-354-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
N-(2-hydroxy-ethoxy)-benzamide (Compound G-3)
The title compound was synthesized by a similar procedure to that in Example 36 from
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-[(2-methyl-2-methylcarba
moyl-propoxyimino)-methyl]-benzamide obtained in Step C.
, 400MHz) 8(PPM) 1.20(6H, s), 3.70(2H, t, J=3.7Hz), 3.92(2H, t, J=3.7Hz),
4.07-4.12(5H, m), 4.77(2H, s), 6.61-6.65(1H, m), 7.35(1H, d, J=8.3Hz), 7.39(1H, d, J=7.3Hz),
7.44(1 H,br.d,J=10.7Hz)
ESI(LC/MS positive mode) m/z 580 (M+H)
[Example 41]
183
5-{[Acetyl N-(2-hydroxy-ethoxy)-benzamide (Compound F-15)
CH3CO2H (300 mg), EDC -HC1 (958 mg), and HODhbt (816 mg) were mixed in
CHjCh (5 mL) for 2 hours to give an active ester solution. A portion of this solution (0.2 mL)
was added to a solution of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyamin
o)-methyl]-benzamide (80 mg) obtained in Example 6 and NEta (29 uL) in THF, and the mixture
was stirred for 12 hours. The reaction mixture was washed with 0.3 N aqueous HC1 and
aqueous NaHCOs, and subjected to silica gel chromatography (CFkCk/MeOH as a developing
solvent) to give the title compound (12.0 mg).
, 400MHz) 8(PPM) 2.21 (3H, s), 3.69(2H, t, J=4.5Hz), 3.73(2H, t, J=4.5Hz),
3.92(2H, t, J=4.5Hz), 4.03(2H, t, J=4.5Hz), 4.91(2H, s), 6.60(1H, m), 7.34(1H, d, J=8.3Hz),
7.43(2H, m)
ESI(LC/MS positive mode) m/z 584 (M+H)
In Examples 42 to 53 below, an alkoxyamine as a starting material was acetylated by a
similar procedure to that in Example 41 to give the target compound.
[Example 42]
5-{[Acetyl-(2-hydroxy-ethoxy)-amino]-methyl}-2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluor
o-N-(2-hydroxy-ethoxy)-benzamide (Compound F-25)
184
1H-NMR(CD3OD, 400MHz) 8(PPM) 2.23(3H, s), 3.42(1H, s), 3.69(2H, t, J=4.4Hz), 3.74(2H, t,
J=4.4Hz), 3.93(2H51, J=4.4Hz), 4.03(2H, t, J=4.4Hz), 4.93(2H, s), 6.74(1H, m), 7.13(1H, d,
J=8.3Hz), 7.18(1H, dd, J=8.3Hz, 2.0Hz), 7.35(1H, d, J=7.4)
ESI(LC/MS positive mode) m/z 482 (M+H)
[Example 43]
5-{[Acetyl-(3-hydroxy-propoxy)-amino]-methyl}-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)
-N-(2-hydroxy-ethoxy)-benzamide (Compound F-16)
, 400MHz) 8(PPM) 1.83(2H, m), 2.21(3H, s), 3.61(2H, t, J=6.3Hz), 3.70(2H, t,
J=4.4), 3.92(2H, br), 4.05(2H, t, J=6.3Hz), 4.90(2H, s), 6.61(1H, m), 7.35(1H, d, J=8.8Hz),
7.40(1H, d, J=5.4Hz), 7.44(1H, dd, J=10.7Hz, 1.9Hz)
ESI(LC/MS positive mode) m/z 598 (M+H)
[Example 44]
5-{[Acetyl-(2-hydroxy-2-methyl-propoxy)-amino]-methyl}-3,4-difluoro-2-(2-fluoro-4-iodo-phe
nylamino)-N-(2-hydroxy-ethoxy)-benzamide (Compound F-17)
H0>
, 400MHz) 8(PPM) 1.22(6H, s), 2.20(3H, s), 3.70(2H, t, J=4.4Hz), 3.78(2H, s),
3.92(2H, br), 4.91(2H, s), 6.61(1H, m), 7.34(1H, d, J=7.4Hz), 7.43(2H, m)
ESI(LC/MS positive mode) m/z 612 (M+H)
85 [Example 45]
5-{[Acetyl-(2-hydroxy-2-methyl-propoxy)-amino]-methyl}-2-(4-ethynyl-2-fluoro-phenylamino)
-3,4-difluoro-N-(2-hydroxy-ethoxy)-benzamide (Compound F-26)
'H-NMRtCDsOD, 400MHz) 6(PPM) 1.22(6H, s), 2.21 (3H, s), 3.42(1H, s), 3.69(2H, t, J=4.6Hz),
3.79(2H, s), 3.92(2H, t, J=4.6Hz), 4.92(2H, s), 6.74(1H, m), 7.13(1H, d, J=8.8Hz), 7.19(1H, dd,
J=11.7Hz, 2.0Hz), 7.44(2H, d, J=6.8Hz)
ESI(LC/MS positive mode) m/z 510 (M+H)
[Example 46]
5-[Acetyl-methoxy-amino-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxyethoxy)-
benzamide (Compound F-2)
JH-NMR(DMSO-d6,400MHz) 6(PPM) 2.10(3H, s), 3.55(2H, t, J=4.4Hz), 3.81(2H,br), 4.81(2H,
s), 6.63(1H, m), 7.32(1H, br), 7.34(1H, m), 7.56(1H, dd, J=10.7Hz, 2.0Hz), 8.53(1H, br),
11.85(1H, br), The peak of CHs(methoxy) was overlapping with that of HiO in solvent.
ESI(LC/MS positive mode) m/z554 (M+H)
[Example 47]
5-[(Acetyl-hydroxy-amino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydrox
y-ethoxy)-benzamide (Compound F-13)
186
-de, 400MHz) 6(PPM) 2.01(3H, s), 3.77(2H, br), 3.98(2H,br), 4.71(2H, s),
6.58(1H, m), 7.31(2H, m), 7.53(1H, d, J=10.8Hz), 8.50(1H, br), 9.96(1H, br), 11.81(1H, br), 117
To a solution of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-hydroxy-ethoxymethy
l)-benzamide (46.1 mg, 87.6 μmol) obtained in Step H of Example 1 in tetrahydrofuran
(anhydrous, 2.0 ml) were added trimethylsilylacetylene (48.5 μL, 0.350 mmol), copper iodide
(3.3 mg, 17.5 μmol), (PPh3)2PdCl2 (3.7 mg, 5.3 umol), and Hunig's base (diisopropylethylamine,
149 μL, 0.876 mmol), and the mixture was stirred at 50°C for 2 hours.
The reaction mixture was concentrated under reduced pressure. 0.1 N Hydrochloric
acid was added to the resultant residue, and the mixture was extracted with ethyl acetate. The
organic layer was washed with 0.1 N hydrochloric acid and brine, dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure. The resultant residue was
purified by silica gel column chromatography (Presep Silica Gel Type S (Wako Pure Chemical
Industries), 10 g, CH2Cl2/MeOH (10:1)) to give
3,4-difluoro-2-(2-fluoro-4-trimethylsilanylethynyl-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-hy
droxy-ethoxymethyl)-benzamide (37.6 mg, 86%).
To a solution of the resultant
3,4-difluoro-2-(2-fluoro-4-trimethylsilanylethynyl-phenylammo)-N-(2-hydroxy-ethoxy)-5-(2-hy
droxy-ethoxymethyl)-benzamide (37.6 mg) in tetrahydrofuran (anhydrous, 1.0 ml) was added
tetra-n-butylammonium fluoride (1 M solution in THF, 113 |aL, 113 umol) at room temperature,
and the mixture was stirred for 3 hours. The reaction mixture was concentrated under reduced
pressure. 0.1 N Hydrochloric acid was added to the resultant residue, and the mixture was
extracted with ethyl acetate. The combined organic layers were washed with 0.1 N
hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure. The resultant residue was purified by silica gel column
chromatography (Presep Silica Gel Type S (Wako Pure Chemical Industries), 10 g,
CH2Cl2/MeOH (10:1 to 5:1)) to give
2-(4-emynyl-2-fluoro-phenylarnino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-(2-hydroxy-ethoxyrne
thyl)-benzamide (21.9 mg, 68%) as a yellow powder.
JH-NMR(CD3OD, 270MHz) 8(PPM) 3.03 (IH, s), 3.66 (2H, dd, J = 4.6, 3.6 Hz), 3.75 (2H, t, J =
4.3 Hz), 3.83 (2H, t, J = 4.3 Hz), 4.04 (2H, dd, J = 4.6, 3.6 Hz), 4.58 (2H, s), 6.68 (IH, td, J = 8.3,
5.6 Hz), 7.14 (d, J = 8.6 Hz), 7.18 (dd, J = 11.2,1.6 Hz), 7.54 (d, J = 5.3 Hz), 8.50 (IH, br. s)
ESI(LC/MS positive mode) m/z 425 (M+H)
The compounds of Examples 3 and 4 below were synthesized by preparing cyclic
acetal compounds using an aldehyde,
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide
118
obtained in Step F of Example 1 as a starting material, and 1,3-propanediol or
2,2-dimethyl-l,3-propanediol, respectively, instead of ethylene glycol used as a reagent in Step G
of Example 1, and subjecting the acetal compounds to reducing conditions similar to those in
Step H of Example 1.
[Example 3]
3,4-Difluoro-2-(2-fluoro-4-iodophenylamino)-N-(2-hydroxy-ethoxy)-5-(3-hydroxy-propoxymeth
yl)-benzamide (Compound B-6)
HO,
, 270MHz) 8(PPM) 1.83(2H, quin., J=6.3Hz), 3.64(4H, m), 3.68(2H, m),
3.95(2H, m), 4.57(2H, br.s), 6.59(1H, td, J=8.9,4.6Hz), 7.34(1H, dd, J=8.6,1.3Hz), 7.43(1H, dd,
J=10.9,2.0Hz),7.50(lH,m)
ESI(LC/MS positive mode) m/z 541(M+H)
[Example 4]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-(3-hydroxy-2,2-dimethyl-propoxymethyl)-N-(2
-hydroxy-ethoxy)-benzamide (Compound B-7)
270MHz) 6(PPM) 0.90(6H, s), 3.37(2H, s), 3.70(2H, dd, J=4.9,4.3Hz),
3.93(2H, dd, J=4.9,4.3Hz), 4.57(2H, s), 6.60(1H, td, J=8.9, 4.6Hz), 7.34(1H, d, J=8.6Hz),
7.44(1H, dd, J=10.6, 2.0Hz), 7.47(1H, m)
ESI(LC/MS positive mode) m/z 569(M+H)
119
[Example 5]
5-(2,3-Dihydroxy-propoxvmethyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxyethoxy)
benzamide
Step A
Preparation of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-benzoic acid
HO>
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-vinylbenzoic acid (200 mg, 0.477
mmol) prepared in Step C of Example 1 was dissolved in tetrahydrofuran (20 ml) and water (1
mL). To this reaction mixture, an aqueous solution of 0.1 M osmium tetroxide (1.0 mL) and
sodium metaperiodate (510 mg, 2.39 mmol) were added at room temperature, and the mixture
was stirred for 2 hours. Insoluble matter was removed through a celite column, and ethyl
acetate extraction was performed.
The extract was washed sequentially with water and saturated brine, and the organic
layer was dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under
reduced pressure, and the resultant dark brown solid was triturated with methanol to give
3,4-difluoro-2-(2-fluoro-4-iodophenylammo)-5-formyl-benzoic acid (133.6 mg, 66% yield) as a
pale yellow solid.
'H-NMR(DMSO-d6,270MHz) 5(PPM) 7.11(1H, td, J=8.6, 3.6), 7.53(1H, m), 7.71(1H, dd,
J=10.2,1.7Hz), 8.27(1H, dd, J=7.3,1.3Hz), 10.00(lH,s), 10.08(lH,br.s)
ESI(LC/MS positive mode) m/z 422 (M+H)
120
StepB
Preparation of 5-allyloxymethyl-3,4-difluoro-2-(2-fluoro-4-iodo-phenylaniino)-benzoic acid
To bismuth (III) chloride (37 mg, 0.188 mmol) that was dried by heating under reduced
pressure, methylene chloride (anhydrous, 3 ml suspension) was added under argon flow, and the
mixture was stirred thoroughly. To this suspension, allyl alcohol (40 uL, 0.57 mmol),
triethylsilane (107 uL, 0.671 mmol), and
3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-5-formyl-benzoic acid (200 mg, 0.475 mmol)
prepared in Step A were added at room temperature, and the mixture was stirred for a whole day
and night. After completion of the reaction, the reaction mixture was extracted with ethyl
acetate.
The extract was washed sequentially with water and saturated brine, and the organic
layer was dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under
reduced pressure, and the resultant dark brown solid was purified with Presep (Wako Pure
Chemical Industries, 10 g).
5-Allyloxymethyl-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzoic acid (140.7 mg, 64%
yield) was obtained as a light brown solid from fractions eluted with 100% ethyl acetate.
, 270MHz) 6(PPM) 4.08(2H, m), 4.56(2H, s), 5.25(1H, d, J=10.2Hz), 5.32(1H,
d, J=17.1Hz), 5.92(1H, m), 6.80(1H, m), 7.41(1H, d, J=10.2Hz), 7.48(1H, d, J=10.6Hz), 7.96(1H,
m)
ESI(LC/MS positive mode) m/z 464 (M+H)
StepC
Preparation of
5-allyloxymethyl-N-[2-(tert-butyldimethylsilanyloxy)ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodophe
nylamino)-benzamide
121
To a solution of 5-allyloxymethyl-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzoic
acid (140 mg, 0.302 mmol) prepared in Step B in N,N-dimethylformamide (anhydrous, 4 mL)
were added N-hydroxysuccinimide (41 mg, 0.363 mmol) and
l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (70 mg, 0.363 mmol) at room
temperature under argon flow, and the mixture was stirred thoroughly. Subsequently,
0-[2-(t-butyldimethylsilanyloxy)ethyl]-hydroxyamine (86 mg, 0.453 mmol) was added thereto,
and the mixture was stirred for 2 hours. After completion of the reaction, the reaction mixture
was extracted with ethyl acetate.
The extract was washed sequentially with water and saturated brine, and the organic
layer was dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under
reduced pressure, and the resultant brown oil was purified with Mega Bond Elut silica gel
(Varian, 5 g).
5-Allyloxymethyl-N-[2-(tert-butyldimethylsilanyloxy)ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodoph
enylamino)benzamide (35.5 mg, 18% yield) was obtained as a pale yellow oil from fractions
eluted with 10% ethyl acetate/hexane.
, 270MHz) 8(ppm) 0.04(6H, s), 0.79(9H, s), 3.83(2H, m), 4.03(2H, m), 4.44(2H,
s), 5.18(1H, d, J=11.5Hz), 5.26(1H, m), 5.87(1H, m), 6.48(1H, td, J=8.6, 4.9Hz), 7.23(1H, d,
J=8.9Hz), 7.31(1H, m), 7.32(1H, m), 8.30(1H, br.s), 9.25(1H, br.s)
ESI(LC/MS positive mode) m/z 637 (M+H)
StepD
Preparation of
5-allyloxymemyl-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzarni
de
122
To a solution of
5-allyloxymethyl-N-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodop
henylamino)-benzamide (35.5 mg, 0.056 mmol) prepared in Step C in tetrahydrofuran
(anhydrous, 4 mL) was added dropwise tetra-n-butylammonium fluoride (1 mol/L solution in
tetrahydrofuran, 0.5 mL, 0.5 mmol) at room temperature, and the mixture was stirred for 4 hours.
After completion of the reaction, the solvent was evaporated under reduced pressure,
and the yellow oil was extracted with ethyl acetate. The extract was washed sequentially with
water and saturated brine, and the organic layer was dried over anhydrous sodium sulfate, and
filtered. The solvent was evaporated under reduced pressure, and the resultant brown oil was
purified by preparative TLC (60% ethyl acetate/hexane as a developing solvent) to give
5-allyloxymethyl-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzami
de (11 mg, 38% yield) as a white solid.
, 270MHz) 5(PPM) 3.70(2H, dd, J=4.9, 4.3Hz), 3.93(2H, dd, J=4.9, 4.3Hz),
4.09(2H, dt, J=5.6, 1.3Hz), 4.57(2H, s), 5.21(1H, ddd, J=10.2, 3.0, 1.3Hz), 5.33(1H, ddd, J=17.1,
4.9, 1.6Hz), 5.96(1H, m), 6.61(1H, td, J=8.6, 4.3Hz), 7.34(1H, dt, J=8.6, l.OHz), 7.45(1H, dd,
J=8.6, 2.0Hz), 7.46(1H, dd, J=6.9, 2.0Hz)
ESI(LC/MS positive mode) m/z523 (M+H)
StepE
Preparation of
d,l-5-(2,3-dihydroxy-propoxymethyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydro
xyethoxy)-benzamide
123
To a solution of
5-allyloxymethyl-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzami
de (11 mg, 0.021 mmol) prepared in Step D in tetrahydrofuran (anhydrous, 4 mL) and water (1
mL) were added 4% osmium tetroxide solution (100 uL) and 30% hydrogen peroxide solution
(0.5 mL) at room temperature, and the mixture was stirred for 3 hours. After completion of the
reaction, the reaction mixture was extracted with ethyl acetate.
The extract was washed sequentially with water and saturated brine, and the organic
layer was dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under
reduced pressure, and the resultant brown oil was purified with Mega Bond Elut silica gel
(Varian, 5 g).
d,l-5-(2,3-Dihydroxy-propoxymethyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2 -hydro
xy-ethoxy)-benzamide (6.8 mg, 58%) was obtained as a white solid from fractions eluted with
10% methanol/methylene chloride.
, 270MHz) 5(PPM) 3.51-3.64(4H, m), 3.70(2H, dd, J=5.3, 4.6Hz), 3.81(1H,
quin. J=5.3Hz), 3.94(2H, t, J=4.9), 4.63(2H, s), 6.61(1H, td, J=8.6, 4.6Hz), 7.35(1H, m), 7.50(1H,
br.d, J=5.9Hz)
ESI(LC/MS positive mode) m/z557 (M+H)
[Example 6]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyamin
o)-methyl]-benzamide (Compound C-l)
124
Step A
Preparation of
(E)-N-[2-(t-butyl-dimethyl-silanyloxy)-ethoxy]-5-{[2-(t-butyl-dimethyl-silanyloxy)-ethoxyimino
]-methyl} -3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
To a solution of 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-5-formyl-benzoic acid
(130 mg, 0.309 mmol) prepared in Step A of Example 5 in methylene chloride (anhydrous, 5
mL) were added 1-hydroxybenzotriazole (42 mg, 0.309 mmol),
l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (177 mg, 0.926 mmol), and
N,N-diisopropylethylamine (161 uL, 0.926 mmol) at room temperature under argon flow, and
the mixture was stirred thoroughly. Subsequently,
O-[2-(t-butyl-dimethyl-silanyloxy)-ethyl]-hydroxyamine (177 mg, 0.926 mmol) was added
thereto, and the mixture was stirred for 17 hours. After completion of the reaction, the reaction
mixture was extracted with ethyl acetate.
The extract was washed sequentially with water and saturated brine, and the organic
layer was dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under
reduced pressure, and the resultant brown oil was purified with Mega Bond Elut silica gel
(Varian, 10 g).
(E)-N-[2-(t-Butyl-dimethyl-silanyloxy)-ethoxy]-5-{[2-(t-butyl-dimethyl-silanyloxy)-ethoxyimin
o]-methyl}-3,4-difluoro-2-(2-fluoro-4-iodo-phenylarnino)-benzamide (137.1 mg, 58% yield) was
obtained as a pale yellow solid from fractions eluted with 10% ethyl acetate/hexane.
125
'H-NMR(CDCl3, 270MHz) 8(PPM): 0.08(6H,s), 0.09(6H, s), 0.87(9H,s), 0.91(9H,s),
3.92(4H,m), 4.12(2H,m), 4.26(2H,m), 6.64(1H, td, J=8.6, 5.3Hz), 7.35(lH,m), 7.41(1H, dd,
J=10.3,1.7Hz), 7.73(1H, br.s), 8.22(lH,s), 8.78(lH,br.s), 9.43(1H, br.s)
EIMS m/z 767(M+H)
StepB
Preparation of
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyi
mino)-methyl]-benzarnide
To a solution of
(E)-N-[2-(t-butyl-dirnethyl-silanyloxy)-ethoxy]-5-{[2-(t-butyl-dimethyl-silanyloxy)-ethoxyimino
]-methyl}-3,4-difluoro-2-(2-fluoro-4-iodo-phenylammo)-benzamide (410 mg, 0.534 mmol)
prepared in Step A in tetrahydrofuran (anhydrous, 20 mL) was added dropwise
tetra-n-butylammonium fluoride (1 mol/L solution in tetrahydrofuran, 1.4 mL, 1.4 mmol) at
room temperature, and the mixture was stirred for 4 hours.
After completion of the reaction, the solvent was evaporated under reduced pressure,
and the yellow oil was extracted with ethyl acetate. The extract was washed sequentially with
water and saturated brine, and the organic layer was dried over anhydrous sodium sulfate, and
filtered. The solvent was evaporated under reduced pressure, and the resultant brown oil was
purified with Mega Bond Elut silica gel (Varian, 5 g). The pale yellow solid obtained from
fractions eluted with 100% ethyl acetate was triturated with ethyl acetate to give
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylarnino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyi
mino)-methyl]-benzamide (134 mg, 47% yield) as a white solid.
1H-NMR(CD3OD, 270MHz) 8(PPM): 3.72(2H, t, J=4.9Hz), 3.82(2H, t, J=4.9Hz), 3.95(2H, dd,
J=4.9,4.3Hz), 4.26(2H, dd, J=4.9, 4.6), 6.72(1H, td, J=8.6, 4.3Hz), 7.39(1H, m), 7.47(1H, dd,
J=10.6,1.6Hz), 7.81(1H, dd, J=4.9,1.6Hz), 8.29(1H, s)
126
ESI(LC/MS positive mode) m/z 540 (M+H)
StepC
Preparation of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyamin
o)-methyl] -benzamide
HO,
To a solution of
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyi
mino)-methyl] -benzamide (3.62 g, 6.70 mmol) obtained in Step B in methanol (100 ml) were
added portionwise trifluoroacetic acid (6.5 ml) and sodium cyanoborohydride (3.78 g, 60.2
mmol) over 2 days while monitoring the progression of the reaction by TLC. The reaction
mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed
with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and concentrated
under reduced pressure. The residue was purified by silica gel column chromatography
(CHiCb/MeOH (15:1)), and the resultant crude compound was crystallized from methyl ene
chloride to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyamin
o)-methyl] -benzamide (1.66 g, 46%, as a total of first and second crystals).
, 270MHz) 5(PPM): 3.63 - 3.70 (6H, m), 3.94 (2H, dd, J = 4.9, 4.3 Hz), 4.08
(2H, s), 6.59 (1H, td, J=8.6, 4.3 Hz), 7.34(1H5 d, J = 8.2 Hz), 7.44 (1H, dd, J = 10.9, 2.0 Hz),
7.50 (1H, dd, J = 6.9, 2.0Hz).
ESI(LC/MS positive mode) m/z 542 (M+H)
Step B'
The oxime compound,
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyi
mino)-methyl]-benzamide obtained in Step B of Example 6 may be easily prepared from
127
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide
obtained in Step F of Example 1 by a reaction with 2-aminooxyethanol in THF at room
temperature.
Namely,
3,4-difluoro-2-(2-fluoro-44odo-phenylamino)-5-forrnyl-N-(2-hydroxy-ethoxy)-benzarnide(1.37
g) and aminooxy ethanol (262 mg) were mixed in THF at room temperature for 12 hours, and
then the solvent was evaporated to give
3 ,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5 - [(2-hydroxy-ethoxyimin
o)-methyl] -benzamide.
NH
Step C'
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-eth
oxyamino)-methyl] -benzamide obtained in Step C of Example 6 may be prepared hi another
condition. Namely,
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyrmin
o)-methyl] -benzamide (1.76 g, 3.27 mmol) obtained hi Step B (or Step B') of Example 6 was
suspended in methyl ene chloride, and borane-pyridine complex (1.21 g, 13.1 mmol) and
dichloroacetic acid (1.69 g, 13.1 mmol) were added thereto at room temperature. The mixture
was stirred for 3 hours. The solvent was evaporated, and the residue was purified by silica gel
chromatography using CHiCb/MeOH as a developing solvent to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyamin
o)-methyl] -benzamide (1.40 g).
[Example 7]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)5-[(3-hydroxy-propoxyami
no)-methyl] -benzamide (Compound C-10)
128
Step A
Synthesis of
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-hydroxy-propoxy
imino)-methyl]-benzamide
The title compound was obtained by a procedure similar to that in Step B' of Example 6
using 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide
obtained in Step F of Example 1 as a starting material and 3-aminooxy n-propanol as a reagent.
'H-NMRCDMSO-de, 400MHz) 8(PPM) 1.58(2H, m), 3.37(2H, t, J=6.4Hz), 3.55(4H, m),
3.81(2H, t, J=4.6Hz), 3.93(2H, d, J=5.9Hz), 4.38(1H, br), 4.71(1H, br), 6.59(1H, m), 6.77(1H, t,
J=5.9Hz), 7.34(1H, d, J=8.8Hz), 7.48(1H, d, J=6.9Hz), 7.55(1H, dd, J=10.7Hz, 2.0Hz), 8.63(1H,
br), 11.72(lH,br)
ESI(LC/MS positive mode) m/z 556 (M+H)
StepB
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)5-[(3-hydroxy-propoxyami
no)-methyl]-benzamide (Compound C-10)
The title compound was obtained by a procedure similar to that in Step C' of Example 6
129
from
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-hydroxy-propoxy
imino)-methyl]-benzamide obtained in Step A.
'H-NMRflDMSO-de, 400MHz) 8(PPM) 1.58(2H, m), 3.37(2H, t, J=6.4Hz), 3.55(4H, m),
3.81(2H, t, J=4.6Hz), 3.93(2H, d, J=5.9Hz), 4.38(1H, br), 4.71(1H, br), 6.59(1H, m), 6.77(1H, t,
J=5.9Hz), 7.34(1H, d, J=8.8Hz), 7.48(1H, d, J=6.9Hz), 7.55(1H, dd, J=10.7Hz, 2.0Hz), 8.63(1H,
br), 11.72(lH,br)
ESI(LC/MS positive mode) m/z 556 (M+H)
[Example 8]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-2-methyl-p
ropoxyamino)-methyl]-benzamide (Compound C-28)
Step A
Preparation of l-aminooxy-2-methyl-propan-2-ol hydrochloride
o,NH2
HC I
Preparation of l-aminooxy-2-methyl-propan-2-ol hydrochloride was performed as
described in the following literature:
Monatsh Chem Verw Teile Andere Wiss (1961) 92 p 725-739.
StepB
(E)-3,4-Difluoro-2-(2-fluoro-4-iodophenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-2-methy
l-propoxyimino)-methyl] -benzamide
The title compound was obtained by a procedure similar to that in Step B' of Example 6
130
using 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide
obtained in Step F of Example 1 as a starting material and l-aminooxy-2-methyl-propan-2-ol
hydrochloride obtained in Step A.
'H-NMRtCDaOD, 270MHz) 5(PPM) 3.30(6H, s), 3.72(2H, m), 3.94(2H, m), 4.08(2H, s),
6.72(1H, m), 7.38(1H, d=8.6Hz), 7.47(1H, d, J=10.9Hz), 7.80(1H, br.d, J=5.3Hz), 8.30(1H, s)
ESI(LC/MS positive mode) m/z 568 (M+H)
StepC
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-2-methyl-p
ropoxyamino)-methyl]-benzarnide (Compound C-28)
The title compound was obtained by a procedure similar to that in Step C' of Example 6
from
(E)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-2-methyl
-propoxyimino)-methyl]-benzamide obtained in Step A.
-de, 400MHz) 5(PPM) 1.01(6H, s), 3.55(2H, t, J=4.4Hz), 3.82(2H, t, J=4.4Hz),
3.95(2H, d, J=4.9Hz), 4.40(1H, br), 4.70(1H, br), 6.58(1H, m), 6.96(1H, t, J=4.9Hz), 7.34(1H, d,
J=8.3Hz), 7.49(1H, d, J=6.8Hz), 7.55(1H, d, J=10.8Hz), 8.56(1H, br), 11.72(1H, br). The peak of
a methylene group is overlapping with that of t^O peak.
ESI(LC/MS positive mode) m/z 570 (M+H)
[Example 9]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-rnethylsulfanyl-etho
xyamino)-methyl]-benzamide (Compound C-30)
131
Step A
Synthesis of O-(2-methylsulfanyl-ethyl)-hydroxylamine
O-(2-Methylsulfanyl-ethyl)-hydroxylamme (CAS No. 101512-32-7) was prepared
according to the method described in the following literature:
Bull. Acad. Sci. USSRDiv. Chem. Sci. (Engl. Transl.); 1967; 1743-1745.
StepB
Synthesis of
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methylsulfanyl-e
thyoxyimino)-methyl]-benzamide
The title compound was obtained by a procedure similar to that in Step B' of Example 6
using 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide
obtained in Step F of Example 1 as a starting material and
0-(2-methylsulfanyl-ethyl)-hydroxylamine obtained in Step A as a reagent. Namely,
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide
(2.6 g, 5.415 mmol) was dissolved in a mixed solvent of methylene chloride (50 mL), THF (20
mL), and methanol (10 mL).
O-(2-Methylsulfanyl-ethyl)-hydroxylamine (924 mg, 8.621 mmol) was added thereto,
and the mixture was stirred at room temperature for 3 hours.
132
After completion of the reaction, the solvent was evaporated under reduced pressure to
give a pale yellow crude product. The residue was triturated with a proper amount of ethyl
acetate :hexane (7:3) to give
(E)-3 ,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5 - [(2-methylsulfanyl-e
thoxyimino)-methyl]-benzamide (1.1 g) as a white solid.
'H-NMRtCDaOD, 270MHz) 8(PPM) 2.15(3H, s), 2.82(2H, dd, 3=6.9, 6.6Hz), 3.72(2H, dd, J=
4.9, 4.3Hz), 3.95(2H, dd, J= 4.9, 4.3Hz), 4.34(2H, dd, J=6.9, 6.6Hz), 6.72(1H, td, JM8.6, 4.3Hz),
7.39(1H, m), 7.47(1H, dd, J=10.6, 2.0Hz), 7.81(1H, dd, J=7.3, 2.0Hz), 8.25(1H, s)
ESI(LC/MS positive mode) m/z 570(M+H)
StepC
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methylsulfanyl-etho
xyamino)-methyl]-benzamide (Compound C-30)
The title compound was obtained by a procedure similar to that in Step C' of Example 6
using
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methylsulfanyl-e
thy oxyimino) -methyl] -benzamide obtained in Step B as a starting material.
Namely,
(E)-3 ,4-difluoro-2-(2-fluoro-4-iodo-phenylamuio)-N-(2-hydroxy-ethoxy)-5 - [(2-methylsulfanyl-e
thyoxyimino)-methyl] -benzamide (104.8 mg, 0.184 mmol) was dissolved in methylene chloride
(anhydrous, 10 mL). Borane-pyridine complex (140 uL, 1.38 mmol) and then dichloroacetic
acid (115 uL, 1 .38 mmol) were added thereto with cooling the reaction vessel in an ice-bath
under a nitrogen atmosphere. The ice-bath was removed, and the mixture was stirred at room
temperature for 1 7 hours. After completion of the reaction, the reaction mixture was extracted
with ethyl acetate, and the organic layer was washed sequentially with water and saturated brine,
dried over anhydrous NaiSO,}, and concentrated under reduced pressure. The resultant yellow
residue was purified by silica gel column chromatography (Mega Bond Elut, Varian, 5%
methanol/methylene chloride as an eluent). The resultant fraction was concentrated under
reduced pressure and the oily residue was triturated with 5% ethyl acetate/hexane to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methylsulfanyl-ethox
yamino)-methyl] -benzamide (110 mg) as a white solid.
, 270MHz) 5(PPM) 2.06(3H, s), 2.62(2H, t, J=6.6Hz), 3.70(2H, m), 3.77(2H, t,
J=6.6Hz), 3.94(2H, m), 4.07(2H, s), 6.56(1H, td, J=8.7, 4.8Hz), 7.32(1H, m), 7.43(1H, dd,
J=10.7, 2.0Hz), 7.53(1H, dd, J=7.3, 2.0Hz)
133
ESI(LC/MS positive mode) m/z 572(M+H)
[Example 10]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methanesulfmyl-eth
oxyamino)-methyl]-benzamide (Compound C-31)
To a solution of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methylsulfanyl-ethox
yamino)-methyl]-benzamide (10 mg, 0.017 mmol) obtained in Step C of Example 9 in a mixed
solvent of acetone (1.8 mL) and water (0.2 mL) was added 30% aqueous hydrogen peroxide (3
uL, 0.026 mmol), and the mixture was stirred for 17 hours.
After completion of the reaction, the reaction mixture was extracted with ethyl acetate,
and the organic layer was washed sequentially with water and saturated brine, dried over
anhydrous sodium sulfate, and concentrated under reduced pressure. The resultant residue was
purified by preparative TLC (No. 5744, Merck, 5% methanol/methylene chloride as a developing
solvent) to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methanesulfinyl-etho
xyamino)-methyl]-benzaniide (4.0 mg, 39%) as an off-white solid.
'H-NMRXCDaOD, 270MHz) 6(PPM) 2.62(3H, s), 2.88(1H, m), 2.92(1H, m), 3.70(2H, m),
3.93(2H, m), 4.00(2H, m), 4.08(2H, s), 6.60(1H, td, J=8.7,4.6Hz), 7.34(1H, m), 7.44(1H, dd,
J=10.6,2.0Hz),7.48(lH,m)
ESI(LC/MS positive mode) m/z 588(M+H)
[Example 11]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methanesulfonyl-eth
oxyamino)-methyl]-benzamide (Compound C-8)
134
To a solution of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methanesulfinyl-etho
xyamino)-methyl]-benzamide (10 mg, 0.017 mmol) obtained in Example 10 in a mixed solvent
of methanol (1.8 mL) and water (0.2 mL) was added sodium metaperiodate (6 mg, 0.026 mmol)
at room temperature, and the mixture was stirred for 17 hours. After completion of the reaction,
the reaction mixture was extracted with ethyl acetate, and the organic layer was washed
sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The resultant residue was purified by preparative TLC
(No. 5744, Merck, 5% methanol/methylene chloride as a developing solvent) to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methanesulfonyl-eth
oxyamino)-methyl]-benzamide (1.3 mg, 13%) as an off-white solid.
, 270MHz) S(PPM) 2.94(3H, s), 3.26(2H, partial hidden), 3.71(2H, dd, J=4.9,
4.3Hz), 3.93(2H, dd, J=4.9, 4.3Hz), 4.04(2H, dd, J=5.7, 5.4Hz), 4.10(2H, s), 6.61(1H, td, J=8.7,
4.6Hz), 7.33(1HS m), 7.43(1H, dd, J=10.7, l.SHz), 7.50(1H, m)
ESI(LC/MS positive mode) m/z 604(M+H)
[Example 12]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylsulfanyl-prop
oxyamino)-methyl]-benzaniide (Compound C-32)
Step A
Preparation of 2-(3-methylsulfanyl-propoxy)-isoindole-l ,3-dione
3-Methylsulfanyl-propan-l-ol (4.133 g, 38.92 mmol) was dissolved in THF (anhydrous,
135
100 mL). To this solution, triphenylphosphine (10.2 g, 38.92 mmol) and
N-hydroxyphthalirnide (6.4 mg, 38.92 mmol) were added and dissolved with stirring.
Diisopropyl azodicarboxylate (8.5 mL, 42.812 mmol) was added dropwise thereto with cooling
the reaction vessel in an ice-bath under nitrogen atmosphere. The reaction mixture was warmed
to room temperature, and stirred for 5 hours. After completion of the reaction, the reaction
mixture was concentrated under reduced pressure, and triturated with diethyl ethenhexane (1:1,
about 100 ml) to precipitate triphenylphosphine oxide as a white solid, which was filtered off.
The filtrate was concentrated under reduced pressure to give a yellow oily residue. The
resultant yellow oil was purified by silica gel flash chromatography (BW300, Fuji Silysia
Chemical, 20% ethyl acetate/hexane as an eluent) to give
2-(3-methylsulfanyl-propoxy)-isoindole-l,3-dione (6.4 g, 65%).
!H-NMR(CDCl3, 270MHz) 8(PPM) 2.04(2H, m), 2.15(3H, s), 2.78(2H, m), 4.33(2H, dd, J=6.3,
6.1Hz),7.72-7.88(4H,m)
ESI(LC/MS positive mode) m/z 252(M+H)
StepB
Synthesis of O-(3-methylsulfanyl-propyl)-hydroxylamine
2-(3-Methylsulfanyl-propoxy)-isoindole-l,3-dione (6.4 g, 25.5 mmol) obtained in Step
A was dissolved in methylene chloride (anhydrous, 50 mL). To this solution, methylhydrazine
(1.5 mL, 28 mmol) was added dropwise, and the mixture was stirred for 1 hour. The
precipitated white solid was filtered off, and the filtrate was concentrated under reduced pressure.
The yellow oily residue was extracted with ethyl acetate, and the organic layer was washed
sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The resultant yellow oily residue was purified by vacuum
distillation (1 mmHg, 57°C) to give O-(3-methylsulfanyl-propyl)-hydroxylamine (3.15 g, 68%)
as a colorless oil.
, 270MHz) 6(PPM) 1.88(2H, m), 2.11(3H, s), 2.55(2H, dd, J=7.6, 7.1Hz),
3.75(2H, dd, J=6.3, 6.1Hz), 5.37(2H, br.s)
ESI(LC/MS positive mode) m/z 122(M+H)
StepC
136
Synthesis of
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylsulfanyl-p
ropoxyimino)-methyl]-benzamide
The title compound was obtained by a procedure similar to that in Step B of Example 9
using 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide
obtained in Step F of Example 1 as a starting material and
O-(3-rnethylsulfanyl-propyl)-hydroxylamine obtained in Step B as a reagent. Namely,
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide(76
mg, 0. 158 mmol) was dissolved hi a mixed solvent of methylene chloride (5 mL) and methanol
(1 mL). O-(3-Methylsulfanyl-propyl)-hydroxylamine (100 uL) was added thereto, and the
mixture was stirred at room temperature for 3 hours. After completion of the reaction, the
solvent was evaporated under reduced pressure to give a pale yellow crude product. The
residue was triturated with a proper amount of ethyl acetate:hexane (1:9) to give
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylsulfanyl-p
ropoxyimino)-methyl]-benzamide (88.8 mg, 96%) as a white solid.
, 270MHz) 8(PPM) 2.03(2H, m), 2.13(3H, s), 2.63(2H, dd, J=7.3, 7.1Hz),
3.79(2H, m), 4.30(2H, t, J=6.3Hz), 6.66(1 H, td, J=8.6, 4.5Hz), 7.35(1H, m), 7.42(1H, dd, J=10.2,
l.SHz), 7.77(1H, dd, J=6.8, 2.0Hz), 8.21(1H, s), 8.60(1H, br.s), 9.15(1H, br.s)
ESI(LC/MS positive mode) m/z584(M+H)
StepD
Synthesis of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-rnethylsulfanyl-prop
oxyamino)-rnethyl]-benzamide (Compound C-32)
137
The title compound was obtained by a procedure similar to that in Step C of Example 9.
Namely,
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylsulfanyl-p
ropoxyimino)-methyl]-benzamide was reduced with borane-pyridine complex in the presence of
dichloroacetic acid to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylsulfanyl-prop
oxyamino)-methyl]-benzamide (26.54 mg, 79%).
JH-NMR(CD3OD, 270MHz) 8(PPM) 1.78(2H, m), 2.03(3H, s), 2.47(2H, dd, J=7.4, 7.1Hz),
3.70(2H, t, J=6.1Hz), 3.71(2H, m), 3.92(2H, m), 4.06(2H, s), 6.59(1H, td, J=8.7,4.3Hz),
7.34(1H, dd, J=8.4, l.lHz), 7.44(1H, dd, J=10.7,l.SHz), 7.49(1H, m)
ESI(LC/MS positive mode) m/z586(M+H)
[Example 13]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methanesulfinyl-pro
poxyamino)-methyl]-benzamide (Compound C-33)
The title compound was obtained by a procedure similar to that in Example 10 using
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylsulfanyl-prop
oxyamino)-methyl]-benzamide obtamed in Example 12 as a starting material. Namely,
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylsulfanyl-prop
oxyamino)-methyl]-benzamide was treated with 30% aqueous hydrogen peroxide in aqueous
acetone to synthesize
138
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methanesulfinyl-prop
oxyamino)-methyl]-benzamide (6.34 mg, 62%).
'H-NMRtCDsOD, 270MHz) 8(PPM) 1.96(2H, m), 2.64(3H, s), 2.83(2H, m), 3.71(2H, m),
3.75(2H, dd, J=6.1, 5.9Hz), 3.92(2H, dd, J=4.9,4.3Hz), 6.59(1H, td J=8.7, 4.3Hz), 7.34(1H, br,d,
J=8.6Hz), 7.44(1H, dd, J=10.7,2.0 Hz), 7.49(1H, dd, J=7.3, l.SHz)
ESI(LC/MS positive mode) m/z602(M+H)
[Example 14]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-hydroxyaminomethyl-N-(2-hydroxy-ethoxy)-be
nzamide (Compound C-23)
Step A
Synthesis of
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(hydroxyimino-meth
yl)-benzamide
HO,
The title compound was obtained by a procedure similar to that in Step B of Example 9
using 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide
obtained in Step F of Example 1 as a starting material and N-hydroxyamine hydrochloride
(commercially available) as a reagent. 111.7 mg (1 00%).
, 270MHz) 6(PPM) 3.71 (2H, dd, J = 4.9, 4.3 Hz), 3.93 (2H, dd, J = 4.6, 4.3
Hz), 6.70 (1H, td, J = 8.6, 4.3 Hz), 7.38 (1H, dt, J = 8.3, 1.3 Hz), 7.46 (1H, dd, J = 10.9, 2.0 Hz),
7.80 (1H, br. d, J = 5.9 Hz), 8.21 (1H, s)
ESI(LC/MS positive mode) m/z 496 (M+H)
StepB
Synthesis of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-hydroxyaminomethyl-N-(2-hydroxy-ethoxy)-be
nzamide (Compound C-23)
139
HO
The title compound was obtained by a procedure similar to that in Step C of Example 9.
Namely,
(E)O,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(hydroxyiniino-meth
yl)-benzamide was reduced with borane-pyridine complex hi the presence of dichloroacetic acid
to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-hydroxyaminomethyl-N-(2-hydroxy-ethoxy)-be
nzamide (28.14 mg, 81%).
, 270MHz) 6(PPM) 3.71 (2H, dd, J=4.8, 4.4Hz), 3.94(2H, dd, J=4.8, 4.1Hz),
4.08(2H, s), 6.60(1H, td, J=8.7, 4.5Hz), 7.35(1H, br.d, J=8.6Hz), 7.44(1H, dd, J=10.6, l.SHz),
7.52(1 H, br.d, J=7.4Hz)
ESI(LC/MS positive mode) m/z 498 (M+H)
[Example 15]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylammo)-N-(2-hydroxy-ethoxy)-5-(methoxyaniino-methyl)
-benzamide (Compound C-24)
Step A
Synthesis of
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(methoxyimino-meth
yl)-benzamide
The title compound was obtained by a procedure similar to that in Step B of Example 9
using 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide
140
obtained in Step F of Example 1 as a starting material and N-methoxyamine hydrochloride
(commercially available) as a reagent. 128 mg (99%).
'H-NMRtCDsOD, 270MHz) 6(PPM) 3.72(2H, dd, J=4.8,4.6Hz), 3.95(2H, dd, J=4.8, 4.6Hz),
3.98(3H, s), 6.71(1H, td, J=8.7, 4.5Hz), 7.41(1H, m), 7.47(1H, dd, J=10.6, 2.0Hz), 7.81(1H, dd,
1=7.4,2.1 Hz), 8.22(1 H,s)
ESI(LC/MS positive mode) m/z 510(M+H)
StepB
Synthesis of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(methoxyamino-methyl)-
benzamide (Compound C-24)
The title compound was obtained by a procedure similar to that in Step C of Example 9.
Namely,
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylarnino)-N-(2-hydroxy-ethoxy)-5-(methoxyimino-meth
yl)-benzamide was reduced with borane-pyridine complex in the presence of dichloroacetic acid
to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(methoxyamrno-methyl)-
benzamide (28.14 mg, 81%).
, 270MHz) 5(PPM) 3.50(3H, s), 3.70(2H, m), 3.93(2H, m), 4.08(2H, s),
6.59(1H, td, J=8.9, 4.2Hz), 7.34(1H, m), 7.44(1H, dd, J=10.6, l.SHz), 7.48(1H, br.s)
ESI(LC/MS positive mode) m/z 512(M+H)
[Example 16]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-emoxy)-5-[(methoxy-methyl-amrn
o)-methyl] -benzamide (Compound C-25)
141
To a solution of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide(56.2
mg, 0.117 mmol) in tetrahydrofuran (anhydrous) were added O,N-dimethyl-hydroxylamine
hydrochloride (commercially available, 34 mg, 0.351 mmol) and sodium cyanoborohydride (34
mg, 0.541 mmol) under nitrogen atmosphere, and the mixture was stirred at room temperature
for 3 hours. After completion of the reaction, the reaction mixture was extracted with ethyl
acetate, and the organic layer was washed sequentially with water and saturated brine, dried over
anhydrous sodium sulfate, and concentrated under reduced pressure. The resultant residue was
purified by silica gel flash chromatography (Mega Bond Elut, Varian, 5% methanol/methylene
chloride as an eluent) to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(methoxy-memyl-amino
)-methyl]-benzamide (9.72 mg, 17%) as a white solid.
, 270MHz) 8(PPM) 2.63(3H, s), 3.37(3H, s), 3.71(2H, dd, J=4.9, 4.3Hz),
3.85(2H, s), 3.94(2H, dd, J=4.8, 4.5Hz), 6.59(1H, td, J=8.9, 4.6Hz), 7.34(1H, m), 7.44(1H, dd,
J=10.6, 1.8Hz), 7.47(1H, dd, J=8.7, 2.0Hz)
ESI(LC/MS positive mode) m/z 526(M+H)
[Example 17]
5-(Ethoxyamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-b
enzamide (Compound C-26)
Step A
Synthesis of
(E)-5-(ethoxyimino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy
)-benzamide
142
The title compound was obtained by a procedure similar to that in Step B of Example 9
using 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide
obtained in Step F of Example 1 as a starting material and N-ethoxyamine hydrochloride
(commercially available) as a reagent.
, 270MHz) 8(PPM) 1.31(3H, t, J=7.0Hz), 3.72(2H, m), 3.94(2H, m), 4.23(2H,
q, J=7.0Hz), 6.70(1H, m), 7.39(1H, br.d, J=8.4Hz), 7.47(1H, dd, J=10.7, 2.0Hz), 7.80(1H, m),
8.22(1H, s)
ESI(LC/MS positive mode) m/z 524(M+H)
StepB
Synthesis of
5-(emoxyamino-methyl)-3s4-difluoro-2-(2-fluoro-4-iodo-phenylarnino)-N-(2-hydroxy-ethoxy)-b
enzamide (Compound C-26)
The title compound was obtained by a procedure similar to that in Step C of Example 9.
Namely,
(E)-5-(ethoxyimmo-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy
)-benzamide was reduced with borane-pyridine complex in the presence of dichloroacetic acid to
give
5-(ethoxyamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-b
enzamide (97.7 mg, 80% in 2 steps).
-de, 270MHz) 5(PPM) 1.03(3H, t, J=6.9Hz), 3.55(2H, m), 3.57(2H, q, J=6.9Hz),
143
3.83(2H, m), 3.99(2H, m), 4.71(1H, br.s), 6.60(1H, m), 7.39(1H, d, J=8.7Hz), 7.47(1H, d,
J=6.6Hz), 7.57(1H, dd, J=10.9,1.8Hz), 8.50(1H, br.s), 11.80(1H, br.s)
ESI(LC/MS positive mode) m/z 526(M+H)
[Example 18]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(isopropoxyamino-meth
yl)-benzamide (Compound C-27)
Step A
Synthesis of
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(isopropoxyimino-m
ethyl)-benzamide
The title compound was obtained by a procedure similar to that in Step B of Example 9
using 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide
obtained in Step F of Example 1 as a starting material and O-isopropylhydroxylamine
hydrochloride (commercially available) as a reagent.
'H-NMRODMSO-de, 270MHz) 5(PPM) 1.27 (6H, d, J = 6.3 Hz), 3.57 (2H, br. q, J = 4.3 Hz),
3.84 (2H, t, J = 4.6 Hz), 4.44 (IH, qui, J = 6.3 Hz) 4.73 (IH, br. t, J = 5.6 Hz), 6.80 (IH, td, J =
9.2,4.3 Hz), 7.40 (IH, br. d, J = 7.9 Hz), 7.61 (IH, dd, J = 10.9, 2.0 Hz), 7.69 (IH, br. d, J = 6.9
Hz), 8.22 (IH, s), 8.84 (IH, br. s, NH), 11.98 (IH, br. s, NH).
ESI(LC/MS positive mode) m/z 538 (M+H)
StepB
Synthesis of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylarnino)-N-(2-hydroxy-ethoxy)-5-(isopropoxyamino-meth
yl)-benzamide (Compound C-27)
144
The title compound was obtained by a procedure similar to that in Step C of Example 9.
Namely,
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(isopropoxyimino-m
ethyl)-benzamide was reduced with borane-pyridine complex in the presence of dichloroacetic
acid to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(isopropoxyamino-meth
yl)-benzamide (65.0 mg, 89% in 2 steps).
!H-NMR(DMSO-d6, 270MHz) S(PPM) 1.02 (6H, d, J = 6.2 Hz), 3.56 (2H, br. t, J = 4.9 Hz), 3.67
(1H, qui, J = 6.2 Hz), 3.83 (2H, br. t, J = 4.9 Hz), 3.92 (2H, br. d, J = ca 5 Hz), 4.72 (1H, br. s),
6.59 (1H, td, J = 8.9, 4.1 Hz), 7.36 (1H, br. d, J = 8.1 Hz), 7.48 (1H, br. d, J - 7.0 Hz), 7.57 (1H,
dd, J = 10.8,1.9 Hz), 8.57 (1H, br. s).
ESI(LC/MS positive mode) m/z 540(M+H)
[Example 19]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(methylcarbamoyhnetho
xyamino-methyl)-benzamide (Compound C-13)
Step A
Synthesis of (l,3-dioxo-l,3-dihydro-isoindol-2-yloxy)-acetic acid methyl ester
The title compound was prepared according to the method described in the following
literature:
Sheppard, andrew et al.; J. Chem. Soc. Perkin Trans 1; 1990; 2519-2525.
145
StepB
Synthesis of 2-aminooxy-N-methyl-acetamide
To a solution of (l,3-dioxo-l,3-dihydro-isoindol-2-yloxy)-acetic acid methyl ester
(120.9 g, 0.51 mol) obtained in Step A in methanol (300 ml) was added methylamine (40%
solution in methanol, 1.0 L) at room temperature, and stirred at 60°C over night. The reaction
mixture was concentrated under reduced pressure, and methylene chloride was added to the
resultant residue to precipitate a solid, which was filtered and washed with methylene chloride.
The combined filtrate and washing were concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (1.4 kg, CHbCh/MeOH (30:1 to 10:1)) to give
2-aminooxy-N-methyl-acetamide (50.3 g, 94%) as a colorless syrup.
1H-NMR(CDC13,270MHz) 5(PPM) 2.88 (3H, d, J = 5.0 Hz), 4.17 (2H, s), 5.69 (2H, br. s).
StepC
Synthesis of
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[methylcarbamoyhn
ethoxyimino-methyl] -benzamide
To a solution of 2-aminooxy-N-methyl-acetamide (1.71 g, 16.4 mmol) obtained in Step
B in a mixed solvent of methylene chloride (50 ml) and THF (25 ml) was added
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide (3.94
g, 8.20 mmol) obtained in Step F of Example 1 at room temperature, and the mixture was stirred
for 15 hours. The reaction mixture was concentrated under reduced pressure, and methylene
chloride (40 ml) was added to the resultant residue to precipitate a solid, which was filtered and
washed with methylene chloride. The resultant solid was dried under reduced pressure to give
146
(E)-3 ,4-difluoro-2-(2-fluoro-4-iodo-phenylainino)-N-(2-hydroxy-ethoxy)-5 - [methylcarbamoylm
ethoxyimino-methyl]-benzainide (3.57 g, 77%) as a white solid.
-de, 270MHz) 8(PPM) 2.63 (3H, d, J = 4.6 Hz), 3.56 (2H, t, J = 4.6 Hz), 3.83
(2H, t, J = 4.3 Hz), 4.57 (2H, s), 4.73 (1H, br. s), 6.82 (1H, td, J = 8.9, 4.0 Hz), 7.41 (1H, br. d, J
= 8.6 Hz), 7.61 (1H, dd, J = 10.9, 2.0 Hz), 7.69 (1H, br. d, J = 6.3 Hz), 7.87 (1H, br q, J = 4.6 Hz),
8.40 (1H, s), 8.92 (1H, br. s), 12.01 (1H, br. s).
ESI(LC/MS positive mode) m/z 567 (M+H)
StepD
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylam.ino)-N-(2-hydroxy-ethoxy)-5-(methylcarbarnoylraetho
xyamino-methyl)-benzamide (Compound C-13)
HO,
To a solution of
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[methylcarbamoylm
ethoxyimino-methylj-benzamide (69.8 nig, 0.12 mmol) obtained in Step C in methylene chloride
(15 ml) were added borane-pyridine complex (199 ul, 1.92 mmol) and dichloroacetic acid (162
ul, 1 .92 mmol) at room temperature, and the mixture was stirred for 3.5 days. Additional
borane-pyridine complex (199 ul, 1.92 mmol) and dichloroacetic acid (162 ul, 1.92 mmol) were
added, and the mixture was stirred for 1 day. The reaction mixture was diluted with methylene
chloride (20 ml), and washed with saturated brine (2x 20 ml). The organic layer was dried over
anhydrous magnesium sulfate, and concentrated under reduced pressure. The resultant residue
was purified by preparative TLC (EtOAc/MeOH (9:1)) to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylarnino)-N-(2-hydroxy-ethoxy)-5-(rnethylcarbamoylmetho
xyamino-methyl)-benzamide (36.9 mg, 53%) as a colorless oil.
, 270MHz) 5(PPM) 2.77 (3H, s), 3.68-3.76 (2H, m), 3.92-3.98 (2H, m), 4.09
(2H, s), 4.13 (2H, s), 6.61 (1H, dt, J = 4.3, 8.6 Hz), 7.34 (1H, ddd, J = 1.2, 1.9, 8.6 Hz), 7.45 (1H,
dd, J= 1.9, 10.8 Hz), 7.50 (1H, dd, J- 1.9, 7.3 Hz).
ESI(LC/MS positive mode) m/z 569 (M+H)
147
[Example 20]
5-(Ethylcarbamoylmethoxyamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylammo)-N-(2-h
ydroxy-ethoxy)-benzamide (Compound C-14)
Step A
Synthesis of 2-aminooxy-N-ethyl-acetamide
To a suspension of (l,3-dioxo-l,3-dihydro-isoindol-2-yloxy)-acetic acid methyl ester
(996 mg, 4.23 mmol) obtained in Step A of Example 19 in THF (5 mL) was added ethylamine
(2.0 M solution in THF, 25 ml) at room temperature, and the mixture was stirred at 60°C for 18
hours. The reaction mixture was concentrated under reduced pressure, and methylene chloride
was added to the resultant residue to precipitate a solid, which was filtered and washed with
methylene chloride. The combined filtrate and washing were concentrated under reduced
pressure. The residue was purified by silica gel column chromatography (40 g, C^Ch/MeOH
(30:1 to 20:1)) to give 2-aminooxy-N-ethyl-acetamide (160 mg, 32%) as a colorless syrup.
1H-NMR(CD3OD, 270MHz) 5(PPM) 1.14 (3H, t, J = 7.3 Hz), 3.27 (2H, q, J = 7.3 Hz), 4.07 (2H,
s).
StepB
Synthesis of
(E)-5-(ethylcarbamoylmethoxyimino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(
2-hydroxy-ethoxy)-benzamide
Using 2-aminooxy-N-ethyl-acetamide obtained in Step A, synthesis was performed
according to the procedure described in Step C of Example 19 to give
(E)-5-(ethylcarbamoylmethoxyimino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(
148
2-hydroxy-ethoxy)-benzamide.
1H-NMR(DMSO-d6,270MHz) 8(PPM) 1.03 (3H, t, J = 7.3 Hz), 3.14 (2H, quint., J = 7.3 Hz),
3.56 (2H, br), 3.83 (2H, br), 4.55 (2H, s), 4.72 (IH, br), 6.82 (IH, dt, J = 3.8, 8.9 Hz), 7.40 (IH,
br. d, J = 8.9 Hz), 7.61 (IH, dd, J = 1.6,10.8 Hz), 7.67 (IH, br. d, J = 5.1 Hz), 7.92 (IH, t, J = 5.7
Hz), 8.40 (IH, s), 8.92 (IH, br), 11.98 (IH, br).
ESI(LC/MS positive mode) m/z 581 (M+H)
StepC
Synthesis of
5-(ethylcarbamoymiemoxyamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-h
ydroxy-ethoxy)-benzamide (Compound C-14)
HO,
Using
(E)-5-(ethylcarbamoylmethoxyimino-niethyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(
2-hydroxy-ethoxy)-benzamide obtained in Step B, synthesis was performed according to the
procedure described in Step D of Example 19 to give
5-(ethylcarbamoylmethoxyamino-niethyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylaniino)-N-(2-h
ydroxy-ethoxy)-benzamide.
'H-NMRCCDaOD, 270MHz) 8(PPM) 1.14 (3H, t, J = 7.3 Hz), 3.26 (2H, q, J = 7.3 Hz), 3.68-3.76
(2H, m), 3.91-3.99 (2H, m), 4.09 (2H, s), 4.13 (2H, s), 6.61 (IH, dt, J = 4.6, 8.6 Hz), 7.35 (IH,
ddd, J = 1.1,1.9, 8.6 Hz), 7.45 (IH, dd, J = 1.9,10.8 Hz), 7.50 (IH, dd, J = 1.9,7.2 Hz).
ESI(LC/MS positive mode) m/z 583 (M+H)
[Example 21]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(propylcarbamoylmetho
xyamino-methyl)-benzamide (Compound C-15)
Step A
149
Synthesis of 2-aminooxy-N-propyl-acetamide
Using (l,3-dioxo-l,3-dihydro-isoindol-2-yloxy)-acetic acid methyl ester obtained in
Step A of Example 19 and n-propylamine as an amine, synthesis was performed according to the
procedure described in Step A of Example 20 to give 2-aminooxy-N-propyl-acetamide.
, 270MHz) 8(PPM) 0.93 (3H, t, J = 7.3 Hz), 1.54 (2H, hextet, J = 7.3 Hz),3.21
(2H, t, J = 7.3 Hz), 4.07 (2H, s).
StepB
Synthesis of
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(propylcarbamoylme
thoxyimino-methyl)-benzamide
Using 2-aminooxy-N-propyl-acetamide obtained in Step A, synthesis was performed
according to the procedure described in Step C of Example 19 to give
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(propylcarbamoylme
thoxyimino-methyl)-benzamide .
-de, 270MHz) 6(PPM) 0.82 (3H, t, J = 7.3 Hz), 1.43 (2H, hextet, J = 7.3 Hz),
3.07 (2H, q, J = 7.3 Hz), 3.51-3.62 (2H, m), 3.76-3.90 (2H, m), 4.56(2H, s), 4.72 (IH, br), 6.82
(IH, dt, J = 4.1, 8.6 Hz), 7.40 (IH, dd, J = 0.8, 8.6 Hz), 7.61 (IH, dd, J = 1.6, 10.8 Hz), 7.62-7.71
(IH, m), 7.90 (IH, br. t, J = 5.7 Hz), 8.40 (IH, s), 8.92 (IH, br), 11.98 (IH, br).
ESI(LC/MS positive mode) m/z 595 (M+H)
StepC
Synthesis of
150
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(propylcarbamoyhnetho
xyamino-methyl)-benzamide (Compound C-15)
Using
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(propylcarbamoylme
thoxyimino-methyl)-benzamide obtained in Step B, synthesis was performed according to the
procedure described in Step D of Example 19 to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(propylcarbamoylmetho
xyamino-methyl)-benzamide.
'H-NMRCCDsOD, 270MHz) 5(PPM) 0.93 (3H, t, J = 7.3 Hz), 1.54 (2H, hextet, J = 7.3 Hz), 3.19
(2H, q, J = 7.3 Hz), 3.68-3.76 (2H, m), 3.91-3.99 (2H, m), 4.09 (2H, s), 4.14 (2H, s), 6.61 (IH, dt,
J - 4.3, 8.6 Hz), 7.35 (IH, ddd, J = 1.1,1.9, 8.6 Hz), 7.46 (IH, dd, J = 1.9, 10.8 Hz), 7.50 (IH,
dd,J=1.9, 7.2 Hz).
ESI(LC/MS positive mode) m/z 597 (M+H)
[Example 22]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(isopropylcarbamoyl-m
ethoxyamino)-methyl]-benzamide (Compound C-16)
Step A
Synthesis of 2-aminooxy-N-isopropyl-acetamide
Using (l,3-dioxo-l,3-dihydro-isoindol-2-yloxy)-acetic acid methyl ester obtained hi
Step A of Example 19 and isopropylamine as an amine, synthesis was performed according to the
procedure described in Step A of Example 20 to give 2-aminooxy-N-isopropyl-acetamide.
151
, 270MHz) 5(PPM) 1.17 (6H, d, J = 6.5 Hz), 3.98-4.12 (IH, m), 4.05 (2H, s).
StepB
Synthesis of
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(isopropylcarbamoy
l-methoxyimino)-methyl] -benzamide
Using 2-aminooxy-N-isopropyl-acetamide obtained in Step A, synthesis was performed
according to the procedure described in Step C of Example 19 to give
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(isopropylcarbamoy
l~methoxyimino)-methyl] -benzamide.
'H-NMRODMSO-de, 270MHz) 5(PPM) 1.08 (3H x 2, d, J = 6.8 Hz), 3.57 (2H, br), 3.83 (2H, br),
3.85-4.02 (IH, m), 4.54(2H, s), 4.72 (IH, br), 6.82 (IH, dt, J = 4.1, 8.6 Hz), 7.41 (IH, br. d, J =
8.6 Hz), 7.61 (IH, dd, J = 1.6,10.8 Hz), 7.62-7.76 (IH, m), 7.90 (IH, br. t, J = 5.7 Hz), 8.40 (IH,
s), 8.88 (lH,br), 11.98 (lH,br).
ESI(LC/MS positive mode) m/z 595 (M+H)
StepC
Synthesis of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(isopropylcarbamoyl-m
ethoxyamino)-methyl] -benzamide (Compound C-16)
H°—?
HN. ...
Using
152
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(isopropylcarbamoy
l-methoxyimino)-methyl]-benzamide obtained in Step B, synthesis was performed according to
the procedure described in Step D of Example 19 to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(isopropylcarbamoyl-m
ethoxyamino)-methyl]-benzamide.
1H-NMR(CD3OD, 270MHz) S(PPM) 1.16 (3H x 2, d, J = 6.8 Hz), 3.72 (2H, t, J = 4.6 Hz), 3.95
(2H, t, J = 4.6 Hz), 3.96-4.12 (1H, m), 4.07 (2H, s), 4.13 (2H, s), 6.61 (1H, dt, J = 4.6, 8.6 Hz),
7.32-7.38 (1H, m), 7.46 (1H, dd, J = 1.9, 10.8 Hz), 7.51 (1H, dd, J = 1.9, 7.0 Hz).
ESI(LC/MS positive mode) m/z 597 (M+H)
[Example 23]
5-(Dimetiiylcarbarnoylrnethoxyarnino-rnethyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylarnino)-N-
(2-hydroxy-ethoxy)-benzamide (Compound C-17)
Step A
Synthesis of 2-aminooxy-N,N-diniethyl-acetamide
To a solution of (l,3-dioxo-l,3-dihydro-isoindol-2-yloxy)-acetic acid methyl ester (992
mg, 4.22 mmol) obtained in Step A of Example 19 in methanol (4 ml) was added dimethylamine
(2.0 M solution in methanol, 1 0 ml), and the mixture was stirred at 60°C for 1 6 hours. After
cooling down to room temperature, the reaction mixture was concentrated under reduced
pressure. The resultant residue was dissolved in methanol (7 ml), and methylhydrazine (0.27
ml, 6.74 mmol) was added thereto. The mixture was stirred at 60°C for 1 5 hours. After
cooling down to room temperature, the reaction mixture was concentrated under reduced
pressure. The residue was purified by silica gel column chromatography (40 g, CHaCb/MeOH
(40:1 to 30:1)) to give 2-aminooxy-N,N-dimethyl-acetamide (125 mg, 25%) as a colorless syrup.
'H-NMRtCDsOD, 270MHz) 5(PPM) 2.94 (3H, s), 2.97 (3H, s),4.37 (2H, s).
StepB
(E)-5-(Dime1iiylcarbamoylrnethoxyimino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylarnmo)
-N-(2-hydroxy-ethoxy)-benzamide
153
Using 2-aminooxy-N,N-dimethyl-acetaniide obtained in Step A, synthesis was
performed according to the procedure described in Step C of Example 19 to give
(E)-5-(dimethylcarbamoylmethoxyimino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
N-(2-hydroxy-ethoxy)-benzamide.
1H-NMR(DMSO-d6, 270MHz) 8(PPM) 1.08 (6H, d, J = 6.8 Hz), 3.57 (2H, br), 3.83 (2H, br),
3.85-4.02 (1H, m), 4.54 (2H, s), 4.72 (1H, br), 6.81 (1H, dt, J = 4.1, 8.6 Hz), 7.40 (1H, dd, J =
1.1, 8.6 Hz), 7.61 (1H, dd, J = 1.9,10.8 Hz), 7.63-7.76 (1H, m), 8.36 (1H, s), 8.88 (1H, br), 11.96
(lH.br).
ESI(LC/MS positive mode) m/z 581 (M+H)
StepC
Synthesis of
5-(dimethylcarbamoylmethoxyamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(
2-hydroxy-ethoxy)-benzamide (Compound C-17)
HO, ^
r^" VJ^t '
Jl
HN
Using
(E)-5-(dimethylcarbamoylmethoxyimino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
N-(2-hydroxy-ethoxy)-benzamide obtained in Step B, synthesis was performed according to the
procedure described in Step D of Example 19 to give
5-(dimethylcarbamoylmethoxyamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(
2-hydroxy-ethoxy)-benzamide.
154
'H-NMRXCDsOD, 270MHz) 8(PPM) 2.93 (3H, s), 2.96 (3H, s), 3.73 (2H, t, J = 4.6 Hz), 3.97
(2H, t, J = 4.6 Hz), 4.13 (2H, s), 4.38 (2H, s), 6.61 (1H, dt, J = 4.6, 8.6 Hz), 7.31-7.38 (1H, m),
7.44 (1H, dd, J = 1.9,10.5 Hz), 7.54 (1H, dd, J = 1.9, 7.3 Hz).
ESI(LC/MS positive mode) m/z 583 (M+H)
[Example 24]
5-[(2-ethylcarbamoyl-ethoxyamino)-rnethyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2
-hydroxy-ethoxy)-benzamide (Compound C-18)
Step A
Synthesis of N-(2-ethylcarbamoyl-ethoxy)-acetimidic acid ethyl ester
Q
o-
•0—N=^
To a known compound, 3-(l-ethoxyethylideneaminooxy)-propanoic acid methyl ester
(CAS No. 97164-30-2, 300 mg, 1.585 mmol) was added a 2 M solution of methylamine in
methanol (7 ml), and the mixture was stirred at 60°C for 13 hours. The reaction mixture was
concentrated under reduced pressure, and the residue was purified by silica gel column
chromatography to give N-(2-ethylcarbamoyl-ethoxy)-acetimidic acid ethyl ester (182 mg, 57%
yield).
'H-NMRXCDCb, 400MHz) 5(PPM) 1.13(3H, t, J=7.1Hz), 1.27(3H, t, J=7.3Hz), 1.92(3H, s),
2.53(2H, t, J=5.9Hz), 3.26-3.33(2H, m), 4.00(2H, q, J=7.3Hz), 4.15(2H, t, J=5.9Hz), 5.93(1H,
br.s)
StepB
Synthesis of
(E)-5-[(2-ethylcarbamoyl-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
N-(2-hydroxy-ethoxy)-benzamide
155
To N-(2-ethylcarbamoyl-ethoxy)-acetimidic acid ethyl ester (180 mg, 0.890 mmol)
obtained in Step A was added 2 M hydrochloric acid (2 ml), and the mixture was stirred at room
temperature for 30 minutes. The reaction mixture was concentrated to give a crude product of
3-aminooxy-N-ethyl-propionamide hydrochloride as a residue. To this residue, a mixed solvent
of tetrahydrofuran/methanol (3:1,20 ml) and
3,4-difluoro-2-(2-fluoro-4-iodophenylamino-5-forniyl-N-(2-hydroxy-ethoxy)-benzamide(500
mg, 1.078 mmol) obtained in Step F of Example 1 were added, and the mixture was stirred for 1
hour. The reaction mixture was poured into purified water, and the resultant mixture was
extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium
sulfate, and concentrated under reduced pressure. The residue was purified by silica gel
column chromatography to give
(E)-5-[(2-ethylcarbarnoyl-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
N-(2-hydroxy-ethoxy)-benzamide (200 mg, 31% yield).
ESI(LC/MS positive mode) m/z 595 (M+H)
StepC
Synthesis of
5-[(2-ethylcarbamoyl-ethoxyamino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2
-hydroxy-ethoxy)-benzamide
H
To
(E)-5-[(2-ethylcarbamoyl-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
N-(2-hydroxy-ethoxy)-benzamide (40 mg, 0.067 mmol) obtained in Step B was added
dichloromethane (2 ml). The mixture was stirred at room temperature, and borane-pyridine
complex (40 ul) and dichloroacetic acid (40 ul) were added thereto. After stirring for 1 hour,
the reaction mixture was poured into purified water, and the resultant mixture was extracted with
dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The residue was purified by silica gel column
156
chromatography to give
5-[(2-ethylcarbamoyl-e1iioxyamino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2
-hydroxy-ethoxy)-benzamide (C-18, 29 mg, 75% yield).
, 400MHz) 8(PPM) 1.07(3H, t, J=7.2Hz), 2.37(2H, t, J=6.2Hz), 3.16(2H, q,
J=7.2Hz), 3.71(2H, t, J=4.4Hz), 3.86(2H, t, J=6.2Hz), 3.95(2H, t, J=4.4Hz), 4.04(2H, s), 6.60(1H,
ddd, J=8.8, 8.8, 4.4Hz), 7.33(1H, br.d, J=8.3Hz), 7.42-7.45(2H, m)
ESI(LC/MS positive mode) m/z 597 (M+H)
[Example 25]
5-[(2-Propylcarbamoyl-ethoxyamino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-
(2-hydroxy-ethoxy)-benzamide (Compound C-19)
Step A
Synthesis of N-(2-propylcarbamoyl-ethoxy)-acetimidic acid ethyl ester
To a known compound, 3-(l-ethoxy-ethylideneaminooxy)-propanoic acid methyl ester
(CAS No. 97164-30-2, 300 mg, 1.585 mmol) were added methanol (3 ml) and n-propylamine
(1 .3 ml), and the mixture was stirred at 55°C for 1 5 hours. The reaction mixture was
concentrated under reduced pressure, and the residue was purified by silica gel column
chromatography to give N-(2-propylcarbamoyl-ethoxy)-acetimidic acid ethyl ester (296 mg,
86% yield).
, 400MHz) 6(PPM) 0.92(3H, t, J=7.4Hz), 1.26(3H, t, J=6.8Hz), 1.47-1.56(2H,
m), 1.93(3H, s), 2.55(2H, t, J=6.0Hz), 3.22(2H, dt, J=6.8, 6.8Hz), 4.01(2H, q, J=6.8Hz), 4.16(2H,
t, J=6.0Hz), 5.83(1H, br.s)
ESI(LC/MS positive mode) m/z 217 (M+H)
StepB
Synthesis of
(E)-5-[(2-propylcarbamoyl-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)
-N-(2-hydroxy-ethoxy)-benzamide
157
Using N-(2-propylcarbamoyl-ethoxy)-acetimidic acid ethyl ester obtained in Step A,
synthesis was performed according to the procedure described in Step B of Example 24 to give
(E)-5-[(2-propylcarbamoyl-emoxymiino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylarnino)
-N-(2-hydroxy-ethoxy)-benzamide.
^-NMRCCDsOD, 400MHz) 8(PPM) 0.89(3H, t, J=7.3Hz), 1.46-1.52(2H, m), 2.59(2H, t,
J=6.4Hz), 3.13(2H, t, J=7.1Hz), 3.72(2H, t, J=4.6Hz), 3.95(2H, t, J=4.6Hz), 4.43(2H, t, J=6.4Hz),
6.71(1H, ddd, J=8.8, 8.8,4.4Hz), 7.37-7.39(lH, m), 7.46(1H, dd, J=10.7, 2.0Hz), 7.81(1H, br.d,
J=5.9Hz), 8.22(1H, s)
ESI(LC/MS positive mode) m/z 609 (M+H)
StepC
Synthesis of
5-[(2-propylcarbamoyl-ethoxyamino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(
2-hydroxy-ethoxy)-benzamide (Compound C-19)
Using
(E)-5-[(2-propylcarbamoyl-ethoxyimino)-methyl]-354-difluoro-2-(2-fluoro-4-iodo-phenylamino)
-N-(2-hydroxy-ethoxy)-benzamide obtained in Step B, synthesis was performed according to the
procedure described in Step C of Example 24 to give
5-[(2-propylcarbamoyl-ethoxyamino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(
2-hydroxy-ethoxy)-benzamide (Compound C-19).
, 400MHz) 6(PPM) 0.87(3H, t, J=7.6Hz), 1.39-1.50(2H, m), 2.38(2H, t,
, 3.09(2H, t, J=7.0Hz), 3.71(2H, t, J=4.6Hz), 3.86(2H, t, J=6.1Hz), 3.95(2H, t, J=4.6Hz),
158
4.04(2H, s), 6.59(1H, ddd, J=8.8, 8.8,4.4Hz), 7.32-7.35(lH, m), 7.42-7.45(2H, m)
ESI(LC/MS positive mode) m/z 611 (M+H)
[Example 26]
5-[(2-Isopropylcarbamoyl-ethoxyamino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
N-(2-hydroxy-ethoxy)-benzamide (Compound C-20)
Step A
Synthesis of N-(2-isopropylcarbamoyl-ethoxy)-acetimidic acid ethyl ester
0
o-
0 —N=H
H
To a known compound, 3-(l-ethoxy-ethylideneaminooxy)-propanoic acid methyl ester
(CAS No. 97164-30-2, 300 mg, 1.585 mmol) were added methanol (3 ml) and isopropylamine
(1 .4 ml), and the mixture was stirred at 55°C for 14 hours. Additional isopropylamine (1 .0 ml)
was added, and the mixture was stirred for 3 hours using a focused microwave synthesis system
(Discover ™, CEM) at 100 W. The reaction mixture was concentrated under reduced pressure,
and the residue was purified by silica gel column chromatography to give
N-(2-isopropylcarbamoyl-ethoxy)-acetimidic acid ethyl ester (46 mg, 13% yield).
s, 400MHz) 8(PPM) 1.12(6H, d, J=7.3Hz), 1.28(3H, t, J=7.1Hz), 1.91(3H, s),
2.50(2H, t, J=5.9), 4.00(2H, q, J=7.1Hz), 4.06-4.11(1H, m), 4.15(2H, t, J=5.9Hz), 5.72(1H, br.s)
StepB
Synthesis of
(E)-5-[(2-isopropylcarbamoyl-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylami
no)-N-(2-hydroxy-ethoxy)-benzamide
Using N-(2-isopropylcarbamoyl-ethoxy)-acetimidic acid ethyl ester obtained in Step A,
synthesis was performed according to the procedure described in Step B of Example 24 to give
159
(E)-5-[(2-isopropylcarbamoyl-ethoxyimino)-methyl]-354-difluoro-2-(2-fluoro-4-iodo-phenylami
no)-N-(2-hydroxy-ethoxy)-benzamide.
, 400MHz) 6(PPM) 1.02(6H, d, J=6.4Hz), 2.47(2H, t, J=6.4Hz), 3.63(2H, t,
J=4.6Hz), 3.84-3.89(3H, m), 4.34(2H, t, J=6.4Hz), 6.62(1H, ddd, J=8.8, 8.8, 4.4Hz), 7.29(1H,
br.d, J=8.8Hz), 7.37(1H, dd, J=10.3, 2.0Hz), 7.72(1H, br.d, J=6.8Hz) , 8.13(1H, s)
ESI(LC/MS positive mode) m/z 609 (M+H)
Step C
Synthesis of
5-[(2-isopropylcarbamoyl-ethoxyamino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
N-(2-hydroxy-ethoxy)-benzamide (Compound C-20)
Using
(E)-5-[(2-isopropylcarbamoyl-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylami
no)-N-(2-hydroxy-ethoxy)-benzamide obtained in Step B, synthesis was performed according to
the procedure described in Step C of Example 24 to give
5 - [(2-isopropylcarbamoy l-ethoxyamino)-methyl] -3 ,4-difluoro-2-(2 -fluoro-4-iodo-phenylamino)-
N-(2-hydroxy-ethoxy)-benzamide (Compound C-20).
, 400MHz) 5(PPM) 0.99(6H, d, J=6.4Hz), 2.27(2H, t, J=6.1Hz), 3.62(2H, t,
J=4.6Hz), 3.76(2H, t, J=6.1Hz), 3.80-3.87(3H, m), 3.95(2H, s), 6.50(1H, ddd, J=8.8, 8.8, 4.4Hz),
7.24(lH,br.d, J=8.8Hz), 7.33-7.36(2H, m)
ESI(LC/MS positive mode) m/z 611 (M+H)
[Example 27]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methylcarbamoyl-et
hoxyamino)-methyl]-benzamide (Compound C-6)
Step A
Synthesis of N-(2-methylcarbamoyl-ethoxy)-acetimidic acid ethyl ester
160
0
To a solution of a known compound, 3-(l-ethoxyethylideneaminooxy)-propanoic acid
methyl ester (CAS No. 97164-30-2, 41 .3 g, 0.21 8 mol) in methanol (150 ml) was added
methylamine (40% solution in methanol, 200 ml) at room temperature, and the mixture was
stirred at 60°C for 12 hours. The reaction mixture was concentrated under reduced pressure to
giveN-(2-methylcarbamoyl-ethoxy)-acetimidic acid ethyl ester (41.0 g, 100%).
, 400MHz) 8(PPM) 1.28(3H, t, J=7.1Hz), 1.92(3H, s), 2.56(2H, t, J=5.9Hz),
2.81(3H, d, J=4.9Hz), 4.00(2H, q, J=7.1Hz), 4.15(2H, t, J=5.9Hz), 6.00(1H, br.s)
StepB
Synthesis of 3-aminooxy-N-methyl-propionamide
o
N
H
N-(2-Methylcarbamoyl-ethoxy)-acetimidic acid ethyl ester (41.0 g, 0.218 mol) obtained
in Step A was dissolved in methanol (210 mL), and the solution was cooled to 0°C. To this
solution, cone, hydrochloric acid (28 mL) was added dropwise over 30 minutes, and the mixture
was stirred at room temperature for 30 minutes. The reaction mixture was cooled again, to
which 28% aqueous ammonia (42 mL) was added portionwise, and then concentrated under
reduced pressure. To the resultant residue, acetonirrile was added, and insoluble matter was
filtered off. The filtrate was concentrated under reduced pressure to give
3-aminooxy-N-methyl-propionamide (25.8 g, 99%).
^-NMRtCDCls, 400MHz) 5(PPM) 2.43(2H, t, J=6.4Hz), 2.70(3H, s), 3.85(2H, t, J=6.4Hz)
StepC
Synthesis of
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methylcarbamoyl
161
-ethoxyimino)-methyl]-benzamide
Using 3-aminooxy-N-methyl-propionamide obtained in Step B, synthesis was
performed according to the procedure described in Step C of Example 19 to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylammo)-N-(2-hydroxy-ethoxy)-5-[(2-methylcarbamoyl-eth
oxyimino)-methyl]-benzamide as a white solid.
, 270MHz) 5(PPM) 2.59(2H, t, J=5.9Hz), 2.72(3H, s), 3.72(2H, m), 3.95(2H,
m), 4.43(2H, t, J=5.9Hz), 6.72(1H, dt, J=8.9, 4.3Hz), 7.39(1H, m), 7.47(1H, dd, J=10.9, 2.0Hz),
7.80(1H, dd, J=6.9, 2.0Hz), 8.23(1H, s)
ESI(LC/MS positive mode) m/z 581 (M+H)
StepD
Synthesis of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methylcarbamoyl-eth
oxyamino)-methyl]-benzamide (Compound C-6)
HOV
Using
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methylcarbamoyl-eth
oxyimino)-methyl]-benzamide obtained in Step C, synthesis was performed according to the
procedure described in Step C of Example 24 to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methylcarbamoyl-eth
oxyamino)-methyl]-benzamide (Compound C-6).
, 270MHz) S(PPM) 2.32-2.41(2H, m), 2.69(3H, s), 3.71(2H, t, J=4.6Hz),
162
3.85(2H, t, J=5.9Hz), 3.89-3.96(2H, m), 4.04(2H, s), 6.54-6.64(lH, m), 7.34(1H, br.d, J=9.9Hz),
7.43(2H,dd,J=10.6,1.9Hz)
ESI(LC/MS positive mode) m/z 583 (M+H)
[Example 28]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylcarbamoyl-pr
opoxyamino)-methyl]-benzamide (Compound C-21)
Step A
Synthesis of 4-(l,3-dioxo-l,3-dihydro-isoindol-2-yloxy)-butyric acid ethyl ester
To a solution of 4-bromo-n-butyric acid ethyl ester (1.2 g, 6.13 mmol) in
dimethylformamide (9 ml) were added N-hydroxyphthalimide (1.5 g, 9.19 mmol) and Hunig
base (N,N-diisopropylethylamine, 2.13 mL) at room temperature, and the mixture was stirred at
80°C over night. The reaction mixture was poured into saturated aqueous ammonium chloride,
and the resultant mixture was extracted with ethyl acetate (3x 40 ml). The combined organic
layers were washed with saturated brine (2x 30 ml), dried over NaaSO^ and concentrated under
reduced pressure. The resultant residue was purified by silica gel column chromatography (100
g, n-hexane/ethyl acetate (2:1)) to give 4-(l,3-dioxo-l,3-dihydro-isoindol-2-yloxy)-butyric acid
ethyl ester (1.47 g, 100%).
270MHz) 8(PPM) 1.28 (3H, t, J = 6.9 Hz), 2.11 (2H, q, J = 6.9 Hz), 2.64 (2H, t,
J = 7.3 Hz), 4.17 (2H, q, J = 7.3 Hz), 4.27 (2H, t, J = 6.3 Hz), 7.72-7.79 (2H, m), 7.81-7.89 (2H,
m).
StepB
Synthesis of 4-aminooxy-N-methyl-butylamide
163
To a solution of 4-(l,3-dioxo-l,3-dihydro-isoindol-2-yloxy)-butyric acid ethyl ester
(997.5 mg, 4.59 mmol) obtained in Step A in methanol (4 mL) was added methylamine (40%
solution in methanol, 10 ml, 98.0 mmol), and the mixture was stirred at 60°C overnight. The
reaction mixture was concentrated under reduced pressure, and methylene chloride was added to
the resultant residue to precipitate a solid, which was filtered and washed with methylene
chloride. The combined filtrate and washing were concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (30 g, CHiCk/MeOH (8:1)) to give
4-aminooxy-N-methyl-butylamide (467.3 mg, 77%) as a colorless syrup.
, 270MHz) 6(PPM) 1.94 (2H, q, J = 6.3 Hz), 2.25 (2H, t, J = 6.9 Hz), 2.81 (3H,
d, J = 4.6 Hz), 3.70 (t, J = 5.9 Hz).
StepC
Synthesis of
(E)-3 ,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5 - [(3 -methylcarbamoyl
-propoxyimino)-methyl] -benzamide
To 4-aminooxy-N-methyl-butylamide (1.79 g, 13.54 mmol) obtained in Step B were
added a mixed solvent of tetrahydrofuran/methanol (3:1,100 ml) and
3,4-difluoro-2-(2-fluoro-4-iodophenylamino-5-formyl-N-(2-hydroxy-ethoxy)-benzamide(5.00 g,
10.41 mmol) obtained in Step F of Example 1, and the mixture was stirred for 13 hours. The
reaction mixture was concentrated under reduced pressure to an extent where a little solvent
remained, and acetonitrile was added thereto to precipitate the product. This precipitate was
filtered, washed with acetonitrile, and dried under reduced pressure to give
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylcarbamoyl
-propoxyimino)-methyl]-benzamide (4.93 g, 79% yield).
1H-NMR(DMSO-d6, 270MHz) 8(PPM) 1.88 (2H, qui, J = 7.6 Hz), 2.17 (2H, t, J = 6.9 Hz), 2.56
(3H, d, J = 4.6 Hz), 3.57 (2H, br. q, J = 4.6 Hz), 3.83 (2H, t, J = 4.6 Hz), 4.14 (2H, t, J = 6.3 Hz),
4.73 (IH, t, J = 5.6 Hz, OH), 6.80 (IH, td, J = 8.9,4.0 Hz), 7.40 (IH, br. d, J = 8.6 Hz), 7.61 (IH,
164
dd, J = 10.9,2.0 Hz), 7.68 (1H, br. d, J = 5.6 Hz), 7.77 (1H, br q, J = 4.6 Hz, NH), 8.26 (1H, s),
8.87 (1H, br. s, NH), 11.99 (1H, br. s, NH).
ESI(LC/MS positive mode) m/z 595 (M+H)
StepD
Synthesis of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylcarbamoyl-pr
opoxyamino)-methyl]-benzamide (Compound C-21)
To
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylcarbamoyl
-propoxyimino)-methyl]-benzamide (50 mg, 0.084 mmol) obtained in Step C was added
dichloromethane (6 ml). The mixture was stirred at room temperature, and borane-pyridine
complex (67 ul, 0.673 mmol) and dichloroacetic acid (55 ul, 0.673 mmol) were added thereto.
After stirring for 14 hours, the reaction mixture was diluted with ethyl acetate, and washed with
purified water and saturated aqueous sodium chloride. The organic layer was dried over
anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylcarbamoyl-pr
opoxyamino)-methyl]-benzamide (Compound C-21, 32 mg, 65% yield).
, 400MHz) S(PPM) 1.72-1.84(2H, m), 2.18(2H, t, J=7.3Hz), 2.67(3H, s),
3.63(2H, t, J=6.4Hz), 3.70(2H, t, J=4.4Hz), 3.94(2H, t, J=4.4Hz), 4.05(2H, s), 6.58(1H, ddd,
J=8.8, 8.8, 4.4Hz), 7.32-7.35(lH, m), 7.43(1H, dd, J=10.5, 1.7Hz), 6.84(1H, br.d, J=6.8Hz)
ESI(LC/MS positive mode) m/z 597 (M+H)
[Example 29]
5-[(2-Acetylamino-ethoxyamino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-h
ydroxy-ethoxy)-benzamide (Compound C-7)
Step A
165
Synthesis of 2-aminooxy-ethyl-carbamic acid t-butyl ester
The title compound was synthesized according to the methods described in J. Med.
Chem., 1999, 42, 2007 and WO02/06213.
StepB
(E)-{2-[2,3-difluoro-4-(2-fluoro-4-iodo-phenylamino)-5-(2-hydroxy-ethoxycarbamoyl)-benzylid
eneaminooxy] -ethyl }-carbamic acid tert-butyl ester
Using 2-ammooxy-ethyl-carbarnic acid t-butyl ester obtained in Step A, synthesis was
performed according to the procedure described in Step C of Example 19 to give
(E)-{2-[2,3-difluoro-4-(2-fluoro-4-iodo-phenylamino)-5-(2-hydroxy-ethoxycarbamoyl)-benzylid
eneaminooxy]-ethyl}-carbamic acid tert-butyl ester.
'H-NMRpMSO-de, 270MHz) 8(PPM) 1.38 (9H, s), 3.26 (2H, t, J = 5.9 Hz), 3.56 (2H, t, J = 4.3
Hz), 3.83 (2H, t, J = 4.3 Hz), 4.36 (2H, t, J = 5.9 Hz), 4.72 (IH, s), 6.79 (IH, m), 6.95 (IH, m),
7.38 (IH, d, J = 8.9 Hz), 7.60 (IH, d, J = 10.6 Hz), 7.69 (IH, d, J = 6.3 Hz), 8.27(1H, s), 8.86
(0.5H,br.s), 11.98 (0.5H,br.s)
ESI(LC/MS positive mode) m/z 639 (M+H)
StepC
Synthesis of
(E)-5-[(2-amino-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydr
oxy-ethoxy)-benzamide
166
To a solution of
{2-[2,3-difluoro-4-(2-fluoro-4-iodo-phenylamino)-5-(2-hydroxy-ethoxycarbamoyl)-ben2ylidenea
minooxy]-ethyl}-carbamic acid tert-butyl ester (55 mg, 0.31 mmol) prepared in Step B in ethyl
acetate (5 ml) was added 1 N HCI solution in ethyl acetate (1 ml), and the mixture was stirred at
room temperature for 1.5 hours. After completion of the reaction, the reaction mixture was
neutralized with saturated solution of sodium bicarbonate (50 ml), and extracted with ethyl
acetate (3x 100 ml). The extract was washed with saturated brine, and the organic layer was
dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced
pressure, and after washing with diethyl ether (10 ml), the residue was recrystallized from
methanol to give
(E)-5-[(2-amino-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydr
oxy-ethoxy)-benzamide (17.31 mg, 37% yield) as a pale yellow solid.
'H-NMRCDMSO-cU, 270MHz) 8(PPM) 3.05 (2H, t, J - 5.6), 3.56(2H, t, J = 4.6), 3.80 (2H, t, J =
4.6), 4.28 (2H, t, J = 5.3 Hz), 6.79 (1H, m), 7.38 (1H, d, J = 9.0 Hz), 7.61 (1H, d, J = 10.9 Hz),
8.08 (1H, d, J = 7.3 Hz), 8.26 (1H, s)
ESI(LC/MS positive mode) m/z 539 (M+H)
StepD
Preparation of
(E)-5-[(2-acetylamino-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2
-hydroxy-ethoxy)-benzamide
167
To a solution of
(E)-5-[(2-amino-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylainino)-N-(2-hydr
oxy-ethoxy)-benzamide (8.14 mg, 0.02 mmol) described in Step C in a mixed solvent of
dimethylformamide (1 ml) and methanol (5 ml) was added N-methoxydiacetamide (100 mg,
0.76 mmol), and the mixture was stirred at room temperature for 14 hours. After completion of
the reaction, the solvent was evaporated under reduced pressure, and the resultant residue was
purified with Mega Bond Elut silica gel (Varian, 5 g).
(E)-5-[(2-Acetylamino-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(
2-hydroxy-ethoxy)-benzamide (8.10 mg, 92% yield) was obtained as a pale yellow solid from
fractions eluted with 6% methanol/methylene chloride.
'H-NMRCDMSO-de, 400MHz) 5(PPM) 1.82 (3H, s), 3.36 (2H, t, J = 5.6), 3.57(2H, br.s), 3.84
(2H, br.s), 4.15 (2H, t, J = 5.6 Hz), 4.73 (1H, s), 6.81 (1H, m), 7.40 (1H, d, J = 7.6 Hz), 7.61 (1H,
d, J = 10.8 Hz), 7.71 (1H, br.s), 8.00 (1H, s), 8.28 (1H, s), 8.90 (0.5H, br.s), 11.98 (0.5H, br.s)
ESI(LC/MS positive mode) m/z 581 (M+H)
StepE
Synthesis of
5-[(2-acetylamino-ethoxyamino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hy
droxy-ethoxy)-benzamide (Compound C-7)
To
(E)-5-[(2-acetylamino-emoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2
-hydroxy-ethoxy)-benzamide (57.6 mg, 99.3 umol) obtained in Step D was added
dichloromemane (2.5 ml). The mixture was stirred at room temperature, and borane-pyridine
complex (80 ul, 0.79 mmol) and dichloroacetic acid (67 ul, 0.80 mmol) were added thereto.
After stirring for 3 hours, water (10 ml) and saturated aqueous sodium bicarbonate (2 ml) were
added to the reaction mixture, which was then extracted with methylene chloride (15 ml and 2x 8
ml). The combined organic layers were washed with aqueous sodium bicarbonate (8 ml) and
168
saturated aqueous sodium chloride(8 ml), dried over anhydrous sodium sulfate, and concentrated
under reduced pressure. The residue was purified by silica gel column chromatography
(methylene chloride/methanol (10:1)) to give
5-[(2-acetylamino-ethoxyamino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hy
droxy-ethoxy)-benzamide (Compound C-7,44.0 mg, 76%).
'H-NMRtCDaOD, 270MHz) 8(PPM) 1.92 (3H, s), 3.36 (2H, t, J = 5.6), 3.67 (2H, t, J = 5.4 Hz),
3.70 (2H, t, J = 4.8 Hz), 3.93 (2H, t, J = 4.3 Hz), 4.07 (2H, s), 6.59 (1H, td, J = 8.7,4.5 Hz), 7.34
(1H, br. d, J = 8.4 Hz), 7.44 (1H, dd, J = 10.7, 2.0 Hz), 1H is overlapped with the dd peak at 7.44
ppm. 2H is overlapped with the peak of HiO around 3.3ppm.
ESI(LC/MS positive mode) m/z 583 (M+H)
[Example 30]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-propionylamino-eth
oxyamino)-methyl]-benzamide (Compound C-34)
Step A
Synthesis of
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-propionylaminoethoxyimino)-
methyl]-benzamide
To a solution of propionic acid (84 ul, 1.13 mmol) in methylene chloride (2 ml) were
added l-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (212.0 mg, 1.10 mmol)
and N-hydroxybenzotriazole (156.5 mg, 1.17 mmol) at room temperature, and the mixture was
stirred at room temperature for 30 minutes to give a solution of an active ester of propionic acid
in methylene chloride (0.55 M). To a solution of
5-[(2-amino-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxyethoxy)-
benzamide (101.9 mg, 0.189 mmol) obtained in Step C of Example 29 in DMF (2.5 ml)
were added dimethylaminopyridine (54.0 mg, 0.442 mmol) and the solution of the active ester in
methylene chloride (0.55 M, 0.35 ml, 0.193 mmol) obtained above, and the mixture was stirred
at room temperature. With monitoring the reaction, 0.18 ml (0.10 mmol) and 0.20 ml (0.11
169
mmol) of the active ester solution were added after 40 minutes and 13 hours, respectively, and
the mixture was stirred for another 8 hours. Water (10 ml) was added to the reaction mixture,
which was then extracted with ethyl acetate (20 ml + 3x 10 ml). The combined organic layers
were washed with aqueous sodium bicarbonate (2x 15 ml), 0.2 N hydrochloric acid (15 ml), and
saturated brine (15 ml), dried over sodium sulfate, and concentrated under reduced pressure.
The resultant residue was triturated with n-hexane/ethyl acetate (3:1) to give an oxime,
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-propionylaminoethoxyimino)-
methyl]-benzamide (94.6 mg, 84%) as a pale yellow solid.
ESI(LC/MS positive mode) m/z 595 (M+H)
StepB
Synthesis of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-propionylaniino-etho
xyamino)-methyl]-benzamide (Compound C-34)
The oxime,
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-propionylaniinoethoxyunino)-
methyl]-benzamide (33.0 mg, 51.0 umol) obtained in Step A was suspended in
methylene chloride (1 ml), and dichloroacetic acid (60 ml) and borane-pyridine complex (70 ul)
were added thereto at room temperature. The mixture was stirred at room temperature for 2
hours. Water (6 ml) and aqueous sodium bicarbonate (2 ml) were added to the reaction mixture,
which was then extracted with methylene chloride (2x 10 ml). The combined organic layers
were washed with aqueous sodium bicarbonate (5-fold dilution of saturated solution, 8 ml) and
saturated brine (8 ml), dried over sodium sulfate, and concentrated under reduced pressure. The
resultant residue was purified by silica gel column chromatography (methylene
chloride/methanol (40:3)) to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-propionylamino-etho
xyamino)-methyl]-benzamide (Compound C-34, 21.6 mg, 71%) as a colorless syrup.
170
'H-NMRXCDsOD, 270MHz) 6(PPM) 1.09 (3H, t, J = 7.8 Hz), 2.17 (2H, q, J = 7.8 Hz), 3.33 (2H,
t, J = 5.7 Hz), 3.67 (2H, dd (like t), J = 5.1, 5.7 Hz), 3.70( 2H, br. t, J = 5.1 Hz), 3.93 (2H, br. t, J
= 4.1 Hz), 4.07 (2H, s), 6.58 (1H, td, J = 8.9,4.3 Hz), 7.34 (1H, ddd, J - 8.4,1.6,1.4 Hz), 7.44
(1H, dd, J = 10.5, 1.9 Hz), 1H is overlapped with the dd peak at 7.44 ppm.
ESI(LC/MS positive mode) m/z 597 (M+H)
[Example 31]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-isobutyrylamino-eth
oxyamino)-methyl]-benzamide (Compound C-35)
Step A
Synthesis of
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-isobutyrylaminoethoxyimino)-
methyl]-benzamide
To a solution of isobutyric acid (172 ul, 1.85 mmol) in a mixed solvent of methylene
chloride and DMF (3 ml and 1 ml) were added l-ethyl-3-(3'-dimethylaminopropyl)carbodiimide
hydrochloride (352.1 mg, 1.84 mmol) and N-hydroxybenzotriazole (250.0 mg, 1.87 mmol) at
room temperature, and the mixture was stirred at room temperature for 30 minutes to give a
solution of an active ester of isobutyric acid in methylene chloride - DMF (0.46 M). To a
suspension of
5-[(2-amino-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxyethoxy)-
benzamide (106.7 mg, 0.198 mmol) obtained in Step C of Example 29 in DMF (2 ml)
were added dimethylaminopyridine (51.2 mg, 0.419 mmol) and the solution of the active ester in
methylene chloride (0.46 M, 0.50 ml, 0.23 mmol) obtained above, and the mixture was stirred at
room temperature. With monitoring the reaction, 0.20 ml (0.09 mmol) and 0.20 ml (0.09
mmol) of the active ester solution were added after 20 minutes and 13 hours, respectively, and
the mixture was stirred for another 8 hours. Water (10 ml) was added to the reaction mixture,
which was then extracted with ethyl acetate (20 ml + 3x 10 ml). The combined organic layers
were washed with aqueous sodium bicarbonate (2x 10 ml), 0.2 N hydrochloric acid (15 ml), and
171
saturated brine (10 ml), dried over sodium sulfate, and concentrated under reduced pressure.
The resultant residue was triturated with n-hexane/ethyl acetate (3:1) to give an oxime,
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-isobutyrylaminoethoxyimino)-
methyl]-benzamide (98.5 mg, 82%) as a pale yellow solid.
ESI(LC/MS positive mode) m/z 609 (M+H)
StepB
Synthesis of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-isobutyrylamino-etho
xyamino)-methyl]-benzamide (Compound C-35)
The oxime,
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-isobutyrylaminoethoxyimino)-
methyl]-benzamide (28.8 mg, 47.3 umol) obtained in Step A was suspended in
methylene chloride (1 ml), and dichloroacetic acid (60 ml) and borane-pyridine complex (70 ul)
were added thereto at room temperature. The mixture was stirred at room temperature for 2
hours. Water (6 ml) and aqueous sodium bicarbonate (2 ml) were added to the reaction mixture,
which was then extracted with methylene chloride (2x 10 ml). The combined organic layers
were washed with aqueous sodium bicarbonate (5-fold dilution of saturated solution, 8 ml) and
saturated brine (8 ml), dried over sodium sulfate, and concentrated under reduced pressure. The
resultant residue was purified by silica gel column chromatography (methylene
chloride/methanol (40:3)) to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-isobutyrylamino-etho
xyamino)-methyl]-benzamide (Compound C-35, 20.5 mg, 71%) as a colorless syrup.
'H-NMRCCDaOD, 270MHz) 6(PPM) 1.07 (6H, d, J = 6.8 Hz), 2.40 (IH, quinted, J = 6.8 Hz),
3.34 (2H, t, J = 5.4 Hz), 3.67 (2H, t, J - 5.4 Hz), 3.70 (2H, br. t, J = 4.9 Hz), 3.93 (2H, br. t, J =
4.3 Hz), 4.07 (2H, s), 6.58 (IH, td, J = 8.6,4.1 Hz), 7.34 (IH, ddd, J = 8.6,1.9,1.1 Hz), 7.44 (IH,
172
dd, J = 10.8,1.9 Hz), 1H is overlapped with the dd peak at 7.44 ppm.
ESI(LC/MS positive mode) m/z 611 (M+H)
[Example 32]
2-(4-Ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)5 - [(2-hydroxy-2-methyl
-propoxyamino)-methyl]-benzamide (Compound C-29)
Step A
(E)-2-(4-Ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-2-m
ethyl-propoxyimino)-methyl]-benzamide
(E)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-
2-methyl-propoxyimino)-methyl]-benzamide (200 mg, 0.35 mmol), Pd(CHsCN)2Cl2 (4.5 mg,
0.0176 mmol), triphenylphosphine-3,3',3"-trisulfonic acid tnsodium salt (25.0 mg, 0.037 mmol),
N('Pr)2Et (48.0 mg, 0.37 mmol), trimethylsilyl acetylene (172 mg, 1.76 mmol), and Cul (3.4 mg,
0.0176 mmol) were stirred in MeOH at room temperature for 1 hour, and the solvent was
evaporated. The resultant residue was added to THF/HbO containing tetrabutylammonium
fluoride (0.35 mmol), and the mixture was stirred for 1 hour. EtOAc was added thereto, and the
organic layer was washed with 0.4 N aqueous HC1, dried over Na2SO4, and evaporated. The
resultant residue was purified by silica gel chromatography (CHiCk/MeOH as a developing
solvent) to give a title compound (99 mg).
'H-NMI^CDsOD, 270MHz) 5(PPM) 1.26(6H, s), 3.46(1H, s), 3.71(2H, m), 3.95(2H, m),
4.08(2H, s), 6.85(1H, m), 7.16(d, J=8.9Hz), 7.21(1H, dd, J=13.9,1.6Hz), 7.82(1H, br.d,
J=5.3Hz), 8.31(1H, s)
ESI(LC/MS positive mode) m/z 466 (M+H)
StepB
2-(4-Ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)5-[(2-hydroxy-2-methyl
-propoxyamino)-methyl]-benzamide (Compound C-29)
173
Using
(E)-2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-2-me
thyl-propoxyimino)-methyl]-benzamide obtained in Step A as a starting material, synthesis was
performed according to the procedure described in Step C of Example 24 to give
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)5-[(2-hydroxy-2-methylpropoxyamino)-
methyl]-benzamide (Compound C-29).
-de, 400MHz) 5(PPM) 1.00(6H, s)s 3.53(2H,br), 3.81(2H, br), 3.96(2H, d,
J=5.9Hz), 4.08(1H, s), 4.40(1H, br), 4.71(1H, br), 6.69(1H, m), 6.97(1H, t, J=5.9Hz), 7.13(1H, d,
J=8.8Hz)5 7.30(1H, d, J=11.6Hz), 7.49(1H, d, J=6.8Hz), 8.66(1H, br), 11.73(1H, br). The peak of
a methyl ene group is overlapping with that of HiO peak.
ESI(LC/MS positive mode) m/z 468 (M+H)
[Example 33]
2-(4-Ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxya
mino)-methyl]-benzamide (Compound C-2)
Step A
Synthesis of
(E)-2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-etho
xyimino)-methyl] -benzamide
174
Starting from
(E)3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyi
mino)-methyl]-benzamide obtained in Step B of Example 6, synthesis was performed according
to the procedure described in Step A of Example 32 to give
(E)-2-(4-ethynyl-2-fluoro-phenylamino)-354-difluoro-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-etho
xyimino)-methyl]-benzamide.
'H-NMRtCDsOD, 270MHz) 6(PPM): 3.45(1H, s), 3.72( 2H, dd, J=4.9,4.3Hz), 3.82(2H, dd,
J=5.3, 4.6Hz), 3.96(2H, dd, 4.9,4.3Hz), 4.27(2H, t, J=4.9Hz), 6.85(1H, td, J=8.6, 4.6Hz),
7.18(2H, m), 7.83(1H, dd, J=7.0,2.0Hz), 8.39(lH,s)
ESI(LC/MS positive mode) m/z 438 (M+H)
StepB
Synthesis of
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5 - [(2-hydroxy-ethoxya
mino)-methyl]-benzamide (Compound C-2)
Using
(E)-2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-etho
xyimino)-methyl]-benzamide obtained in Step A, synthesis was performed according to the
procedure described in Step C of Example 24 to give
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxya
mino)-methyl]-benzamide (Compound C-2).
-de, 400MHz) 8(PPM) 3.46(2H, t, J=4.7Hz), 3.55(4H,m), 3.82(2H, t, J=4.7Hz),
3.96(2H, d, J=5.8Hz), 4.08(1H, s), 4.53(1H, br), 4.71(1H, br), 6.70(1H, m), 6.85(1H, t, J=5.8Hz),
7.13(1H, d, J=8.3Hz), 7.30(1H, dd, J=12.0Hz, 2.0Hz), 7.49(1H, d, J=6.3Hz), 8.66(1H, br),
11.72(lH,br).
175
ESI(LC/MS positive mode) m/z 440 (M+H)
[Example 34]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-(2-hydroxy-l,l-dimethyl-ethoxymethyl)-N-(2-
hydroxy-ethoxy)-benzamide (Compound B-19)
Step A
Synthesis of 2-methyl-propane- 1 ,2-diol
HO
2-Methyl-propane-l,2-diol is a known compound (CAS No. 558-43-0), and may be
prepared by one of the method described in the following literatures:
Zh. Obshch. Khim. 7,1319 (1937),
Chem. Zentralbl. 109, 561 (1938),
Meml. Poudres, 28,263 (1938), and
Chem. Zentralbl. 110,2398 (1939).
Practically, the title compound was prepared by the following procedure.
To a suspension of lithium aluminum hydride (321.3 mg, 8.47 mmol) in THF (5 ml) was
added dropwise a solution of 2-hydroxy-2-methyl-propionic acid methyl ester (commercially
available, 1.0 g, 8.47 mmol) in THF (3 ml), and the mixture was stirred at room temperature for
4 hours. Water (0.70 ml) was added to the reaction mixture, which was stirred for additional 10
minutes. The resultant mixture was filtered through a mixed bed of celite powder and sodium
sulfate powder. The filtrate was concentrated under reduced pressure, and the residue was
diluted with THF, dried over sodium sulfate, and concentrated under reduced pressure to give
2-methyl-propane-1,2-diol (659.7 mg, 86%) as an oily crude product.
'H-NMRflDMSO-de, 270MHz) 5(PPM) 1.03 (6H, s), 3.13 (2H, d, J = 5.6 Hz), 4.10 (1H, s), 4.50
(1H, t, J = 5.9 Hz).
Step B
Synthesis of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5 -(2-hydroxy-1,1 -dimethyl-ethoxymethyl)-N-(2-h
ydroxy-ethoxy)-benzamide (Compound B-19)
176
Using
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide
obtained in Step F of Example 1 as a starting material, and 2-methyl-propane-l,2-diol obtained
in Step A instead of ethylene glycol used as a reagent in Step G of Example 1, synthesis similar
to that in Step G of Example 1 was performed. The resultant cyclic acetal was subjected to
reduction condition similar to that in Step H of Example 1 to give the title compound.
'H-NMRtDMSO-de, 270MHz) 8(PPM) 1.18 (6H, s), 3.35 (2H, overlapped with H2O peak in
DMSO, singlet after addition of D2O), 3.37(2H, s), 3.56(2H, dd, J = 4.9, 4.6 Hz), 3.83 (2H, dd, J
= 4.9,4.6 Hz), 4.50 (2H, s), 4.69 (IH, t, J = 5.6 Hz, disappeared after addition of D2O), 4.70 (IH,
br. s, disappeared after addition of D2O), 6.60(1H, td, J = 8.7,4.1 Hz), 7.36 (IH, br. d, J = 8.4
Hz),7.46 (IH, br. d, J = 6.6 Hz), 7.57 (IH, dd, J = 10.9,1.8 Hz), 8.61 (IH, br. s, disappeared after
addition of D2O), 11.80 (IH, br. s, disappeared after addition of D2O).
ESI(LC/MS positive mode) m/z 569(M+H)
[Example 35]
Synthesis of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-methanesulfonyl-etho
xymethyl)-benzamide (Compound B-12)
To a suspension of
177
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide(52
mg, 0.108 mmol) obtained in Step F of Example 1 in methylene chloride (anhydrous, 5 mL)
were added copper trifluoromethanesulfonate (20 mg, 0.005 mmol), methanesulfonylethanol
(200 uL), and triethylsilane (500 uL, 3.13 mmol) under a nitrogen atmosphere, and the mixture
was stirred thoroughly for a whole day and night. After completion of the reaction, the reaction
mixture was extracted with ethyl acetate, and the organic layer was washed sequentially with 2%
aqueous EDTA, water, and saturated brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The resultant residue was purified by preparative TLC
(No. 5744, Merck, 5% methanol/methylene chloride as a developing solvent) to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-methanesulfonyl-etho
xymethyl)-benzamide (13.3 mg, 21%) as a white solid.
'H-NMRtCDsOD, 270MHz) 8(PPM) 3.02(3H, s), 3.41(2H, dd, J=5.4, S.lHz), 3.71(2H, dd,
J=4.8, 4.5Hz), 3.95(4H, m), 4.60(2H, s), 6.63(1H, td, J=8.9, 4.3Hz), 7.35(1H, br.d, J=8.4Hz),
7.45(1H, dd, J=10.9, l.SHz), 7.50(1H, m)
ESI(LC/MS positive mode) m/z 589(M+H)
[Example 36]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(3-oxo-[l,2]oxazinan-2-
ylmethyl)-benzamide (Compound G-l)
(E)-3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylc
arbamoyl-propoxyimino)-methyl]-benzamide (8.0 g, 13.5 mmol) obtained in Step C of Example
28 was suspended in methylene chloride (240 ml), and borane-pyridine complex (5.45 ml, 53.8
mmol) and dichloroacetic acid (6.65 ml, 80.8 mmol) were added thereto at room temperature.
The reaction mixture was stirred at room temperature for 15 hours, and dichloromethane was
removed under reduced pressure with a rotary evaporator. The residue was diluted with
1,2-dichloroethane (240 ml), and the mixture was stirred at 60°C for 8 hours, and filtered. The
residue obtained by concentrating the filtrate was diluted with ethyl acetate (800 ml), and washed
sequentially with water (400 ml), saturated aqueous sodium bicarbonate (400 ml), and saturated
brine (400 ml). The organic layer was dried over anhydrous sodium sulfate, and concentrated
178
under reduced pressure. The residue was purified by silica gel column chromatography
(CH2Cl2/MeOH (25:1)) to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(3-oxo-[l,2]oxazinan-2-
ylmethyl)-benzamide (Compound G-l, 6.93 g, 91% yield).
This compound may also be obtained as a by-product (18 mg, 35% yield) in a synthesis
of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylcarbamoyl-pr
opoxyamino)-methyl]-benzamide (Compound C-21) in Example 28.
, 400MHz) 5(PPM) 2.10(2H, quinted, J=6.8Hz), 2.53(2H, t, J=6.8Hz), 3.72(2H,
t, J=4.4Hz), 3.92(2H, t, J=4.4Hz), 4.04(2H, t, J=6.8Hz), 4.86(2H, s), 6.61 (1H, ddd, J=8.8, 8.8,
3.9Hz), 7.33-7.36(lH, m), 7.41(1H, dd, J=7.0, 1.7Hz), 7.45(1H, dd, J=10.3, 2.0Hz)
ESI(LC/MS positive mode) m/z 566 (M+H)
[Example 37]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(3-oxo-isoxazolidin-2-yl
methyl)-benzamide (Compound G-2)
To
(E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5 - [(2-methylcarbamoyl
-ethoxyimino)-methyl]-benzamide (9.60 g, 15.54 mmol) were added sequentially
dichloromethane (300 ml) and borane-pyridine complex (11.70 ml, 115.80 mmol) to give a
suspension. This mixture was stirred at room temperature, and dichloroacetic acid (9.51 ml,
115.80 mmol) was added dropwise thereto over 10 minutes. After the mixture was stirred at
room temperature for 13 hours, dichloromethane was removed under reduced pressure with a
rotary evaporator, and the resultant residue was diluted with 1,2-dichloroethane (300 ml). This
mixture was stirred at 60°C for 6 hours, diluted with ethyl acetate, and washed sequentially with
0.1 M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated aqueous
sodium chloride. The organic layer was dried over anhydrous sodium sulfate, and concentrated
under reduced pressure. The residue was purified by silica gel column chromatography to give
179
the title compound (8.28 g, 90% yield).
This compound may also be obtained as a by-product in a synthesis of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methylcarbamoyl-eth
oxyamino)-methyl]-benzamide (Compound C-6) in Example 27.
'H-NMRXCDaOD, 400MHz) 5(PPM) 2.84(2H, t, J=8.3Hz), 3.70(2H, t, J=4.7Hz), 3.93(2H, t,
J=4.7Hz), 4.36(2H, t, J=8.3Hz), 4.76(2H, s), 6.62(lH,ddd, J=8.8, 8.8, 3.9Hz), 7.34-7.36(lH, m),
7.39(1H, br.d, J=5.4Hz), 7.45(1H, dd, J=10.5,1.7Hz)
ESI(LC/MS positive mode) m/z 552 (M+H)
[Example 38]
2-(4-Ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-(3-oxo-isoxazolidin-2
-ylmethyl)-benzamide (Compound G-5)
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamrno)-N-(2-hydroxy-ethoxy)-5-(3-oxo-isoxazol
idin-2-ylmethyl)-benzamide (36.9 mg, 66.9 umol) obtained in Example 37,
bis(acetonitrile)dichloropalladium (II) (3.5 mg, 13.5 umol),
3,3',3"-phosphinidine-tris(benzenesulfonic acid) trisodium salt (19.0 mg, 33.4 umol), and
copper iodide (I) (2.6 mg, 13.6 umol) were suspended in methanol (2.5 ml) under a nitrogen
atmosphere. To this suspension, N,N-diisopropylethylamine (14.0 ul, 80.4 umol) and
trimethylsilylacetylene (47.3 ul, 334.7 umol) were added at room temperature, and the mixture
was stirred for 1 hour. The reaction mixture was diluted with methylene chloride (30 ml), and
washed with saturated brine (2x 15 ml). The organic layer was dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure. The resultant residue was
dissolved in THF (2 ml). To this solution, tetrabutylammonium fluoride (1.0 M solution in THF,
0.10 ml, 0.10 mmol) was added, and the mixture was stirred for 1 hour, and then concentrated
under reduced pressure. The resultant residue was purified by preparative TLC (EtOAc/MeOH
(8:1)) to give
180
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-(3-oxo-isoxazolidin-2
-ylmethyl)-benzamide (Compound G-5, 11.1 mg, 37%) as a brown oil.
, 270MHz) 6(PPM) 2.85 (2H, t, J = 8.1 Hz), 3,43 (1H, s), 3.70 (2H, t, J = 4.6
Hz), 3.93 (2H, t, J = 4.6 Hz), 4.36 (2H, t, J = 8.1 Hz), 4.78 (2H, s), 6.75 (1H, dt, J = 4.6, 8.6 Hz),
7.11-7.17 (1H, m), 7.20 (1H, dd, J - 1.8, 11.9 Hz), 7.41 (1H, dd, J = 1.8, 7.3 Hz).
ESI(LC/MS positive mode) m/z 450 (M+H)
[Example 39]
2-(4-Ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-(3-oxo-[l,2]oxadinan
-2-ylmethyl)-benzamide (Compound G-4)
Using
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(3-oxo-[l,2]oxazinan-2-
ylmethyl)-benzamide obtained in Example 36, synthesis was performed according to the
procedure described in Example 38 to give
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-(3-oxo-[l,2]oxadinan
-2-ylrnethyl)-benzamide (Compound G-4).
'H-NMRCCDaOD, 270MHz) 8(PPM) 2.11 (2H, quint., J = 6.9 Hz), 2.54 (2H, t, J = 6.9 Hz), 3,43
(1H, s), 3.70 (2H, t, J = 4.5 Hz), 3.93 (2H, t, J = 4.5 Hz), 4.05 (2H, t, J = 6.9 Hz), 4.87 (2H, s),
6.75 (1H, dt, J = 4.6, 8.6 Hz), 7.10-7.17 (1H, m), 7.19 (1H, dd, J = 1.9,11.9 Hz), 7.43 (1H, dd, J
= 1.9, 7.0 Hz).
ESI(LC/MS positive mode) m/z 464 (M+H)
[Example 40]
5-(4,4-Drmethyl-3-oxo-isoxazolidm-2-ylmethyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
N-(2-hydroxy-ethoxy)-benzamide (Compound G-3)
Step A
181
Synthesis of 3-(l,3-dioxo-l,3-dihydro-isoindol-2-yloxy)-2,2-dimemyl-propionic acid methyl
ester
0.
0—N
To methyl hydroxypivalate (1.31 g, 9.89 mmol) were added tetrahydrofuran (40 ml),
hydroxyphthalimide (3.23 g, 19.78 mmol) and triphenylphosphine (6.48 g, 24.73 mmol). After
this solution was cooled to 0°C, diisopropyl azodicarboxylate (4.87 ml, 24.73 mmol) was added
dropwise to the solution. While being allowed to warm gradually, the reaction mixture was
stirred for 12 hours, and concentrated under reduced pressure. The residue was roughly
purified by silica gel column chromatography to give the title compound (922 mg).
, 400MHz) 8(PPM) 1.35(6H, s), 3.74(3H, s), 4.26(2H, s), 7.27-7.76(2H, m),
7.81-7.85(2H,m)
StepB
Synthesis of 3-aminooxy-2,2,N-trimethyl-propionamide
Q
/MR,
0
To 3-(l,3-dioxo-l,3-dihydro-isoindol-2-yloxy)-2,2-dimethyl-propionic acid methyl ester
(800 mg) obtained in Step A was added a 40% solution of methylamine in methanol (6 ml), and
the mixture was stirred at 60°C for 13 hours. After the reaction mixture was concentrated under
reduced pressure, dichloromethane was added to the residue, and insoluble matter was filtered.
The filtrate was concentrated, and the residue was purified by silica gel column chromatography
to give the title compound (202 mg).
'H-NMR^CDsOD, 400MHz) 5(PPM) 1.14(6H, s), 2.71(3H, s), 3.64(2H, s)
StepC
Synthesis of
182
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-[(2-methyl-2-methylcarba
moyl-propoxyimino)-methyl]-benzamide
The title compound was synthesized as a mixture of E/Z geometric isomers, using the
procedure described in Step C of Example 19, from 3-aminooxy-2,2,N-trimethyl-propionamide
obtained in Step B and
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-fomiyl-N-(2-hydroxy-ethoxy-benzamide
obtained in Step F of Example 1.
ESI(LC/MS positive mode) m/z 609 (M+H)
StepD
5-(4,4-Dimethyl-3-oxo-isoxazolidin-2-ylmethyl)-354-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
N-(2-hydroxy-ethoxy)-benzamide (Compound G-3)
The title compound was synthesized by a similar procedure to that in Example 36 from
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-[(2-methyl-2-methylcarba
moyl-propoxyimino)-methyl]-benzamide obtained in Step C.
, 400MHz) 8(PPM) 1.20(6H, s), 3.70(2H, t, J=3.7Hz), 3.92(2H, t, J=3.7Hz),
4.07-4.12(5H, m), 4.77(2H, s), 6.61-6.65(1H, m), 7.35(1H, d, J=8.3Hz), 7.39(1H, d, J=7.3Hz),
7.44(1 H,br.d,J=10.7Hz)
ESI(LC/MS positive mode) m/z 580 (M+H)
[Example 41]
183
5-{[Acetyl N-(2-hydroxy-ethoxy)-benzamide (Compound F-15)
CH3CO2H (300 mg), EDC -HC1 (958 mg), and HODhbt (816 mg) were mixed in
CHjCh (5 mL) for 2 hours to give an active ester solution. A portion of this solution (0.2 mL)
was added to a solution of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyamin
o)-methyl]-benzamide (80 mg) obtained in Example 6 and NEta (29 uL) in THF, and the mixture
was stirred for 12 hours. The reaction mixture was washed with 0.3 N aqueous HC1 and
aqueous NaHCOs, and subjected to silica gel chromatography (CFkCk/MeOH as a developing
solvent) to give the title compound (12.0 mg).
, 400MHz) 8(PPM) 2.21 (3H, s), 3.69(2H, t, J=4.5Hz), 3.73(2H, t, J=4.5Hz),
3.92(2H, t, J=4.5Hz), 4.03(2H, t, J=4.5Hz), 4.91(2H, s), 6.60(1H, m), 7.34(1H, d, J=8.3Hz),
7.43(2H, m)
ESI(LC/MS positive mode) m/z 584 (M+H)
In Examples 42 to 53 below, an alkoxyamine as a starting material was acetylated by a
similar procedure to that in Example 41 to give the target compound.
[Example 42]
5-{[Acetyl-(2-hydroxy-ethoxy)-amino]-methyl}-2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluor
o-N-(2-hydroxy-ethoxy)-benzamide (Compound F-25)
184
1H-NMR(CD3OD, 400MHz) 8(PPM) 2.23(3H, s), 3.42(1H, s), 3.69(2H, t, J=4.4Hz), 3.74(2H, t,
J=4.4Hz), 3.93(2H51, J=4.4Hz), 4.03(2H, t, J=4.4Hz), 4.93(2H, s), 6.74(1H, m), 7.13(1H, d,
J=8.3Hz), 7.18(1H, dd, J=8.3Hz, 2.0Hz), 7.35(1H, d, J=7.4)
ESI(LC/MS positive mode) m/z 482 (M+H)
[Example 43]
5-{[Acetyl-(3-hydroxy-propoxy)-amino]-methyl}-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)
-N-(2-hydroxy-ethoxy)-benzamide (Compound F-16)
, 400MHz) 8(PPM) 1.83(2H, m), 2.21(3H, s), 3.61(2H, t, J=6.3Hz), 3.70(2H, t,
J=4.4), 3.92(2H, br), 4.05(2H, t, J=6.3Hz), 4.90(2H, s), 6.61(1H, m), 7.35(1H, d, J=8.8Hz),
7.40(1H, d, J=5.4Hz), 7.44(1H, dd, J=10.7Hz, 1.9Hz)
ESI(LC/MS positive mode) m/z 598 (M+H)
[Example 44]
5-{[Acetyl-(2-hydroxy-2-methyl-propoxy)-amino]-methyl}-3,4-difluoro-2-(2-fluoro-4-iodo-phe
nylamino)-N-(2-hydroxy-ethoxy)-benzamide (Compound F-17)
H0>
, 400MHz) 8(PPM) 1.22(6H, s), 2.20(3H, s), 3.70(2H, t, J=4.4Hz), 3.78(2H, s),
3.92(2H, br), 4.91(2H, s), 6.61(1H, m), 7.34(1H, d, J=7.4Hz), 7.43(2H, m)
ESI(LC/MS positive mode) m/z 612 (M+H)
185
[Example 45]
5-{[Acetyl-(2-hydroxy-2-methyl-propoxy)-amino]-methyl}-2-(4-ethynyl-2-fluoro-phenylamino)
-3,4-difluoro-N-(2-hydroxy-ethoxy)-benzamide (Compound F-26)
'H-NMRtCDsOD, 400MHz) 6(PPM) 1.22(6H, s), 2.21 (3H, s), 3.42(1H, s), 3.69(2H, t, J=4.6Hz),
3.79(2H, s), 3.92(2H, t, J=4.6Hz), 4.92(2H, s), 6.74(1H, m), 7.13(1H, d, J=8.8Hz), 7.19(1H, dd,
J=11.7Hz, 2.0Hz), 7.44(2H, d, J=6.8Hz)
ESI(LC/MS positive mode) m/z 510 (M+H)
[Example 46]
5-[Acetyl-methoxy-amino-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxyethoxy)-
benzamide (Compound F-2)
JH-NMR(DMSO-d6,400MHz) 6(PPM) 2.10(3H, s), 3.55(2H, t, J=4.4Hz), 3.81(2H,br), 4.81(2H,
s), 6.63(1H, m), 7.32(1H, br), 7.34(1H, m), 7.56(1H, dd, J=10.7Hz, 2.0Hz), 8.53(1H, br),
11.85(1H, br), The peak of CHs(methoxy) was overlapping with that of HiO in solvent.
ESI(LC/MS positive mode) m/z554 (M+H)
[Example 47]
5-[(Acetyl-hydroxy-amino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydrox
y-ethoxy)-benzamide (Compound F-13)
186
-de, 400MHz) 6(PPM) 2.01(3H, s), 3.77(2H, br), 3.98(2H,br), 4.71(2H, s),
6.58(1H, m), 7.31(2H, m), 7.53(1H, d, J=10.8Hz), 8.50(1H, br), 9.96(1H, br), 11.81(1H, br),
ESI(LC/MS positive mode) m/z540 (M+H)
[Example 48]
5-[(Acetoxy-acetyl-amino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy
-ethoxy)-benzamide (Compound F-14)
The title compound was obtained as a by-product in the preparation of
5-[(Acetyl-hydroxy-amino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydrox
y-ethoxy)-benzamide in Example 47.
-de, 400MHz) 5(PPM) 1.22(3H, s), 2.17(3H, s), 3.54(2H, br), 3.80(2H,br),
4.85(2H, s), 6.62(1H, m), 7.37(2H, m), 7.56(1H, d, J=6.8Hz), 8.64(1H, br), 11.85(1H, br),
ESI(LC/MS positive mode) m/z582 (M+H)
[Example 49]
5- {[Acetyl-(2-methylsulfanyl-ethoxy)-amino]-methyl} -3,4-difluoro-2-(2-fluoro-4-iodo-phenyla
mino)-N-(2-hydroxy-ethoxy)-benzamide (Compound F-21)
187
-de, 400MHz) 8(PPM) 2.04(3H, s), 2.12(3H, s), 2.66(2H, t, J=6.3Hz), 3.80(1H,
br), 4.02(2H, m), 4.82(2H, s), 6.62(1H, m), 7.34(2H, d,br, J=8.3Hz), 7.55(1H, dd, J=10.7Hz,
1.7Hz), 8.52(1H, s), 11.8(1H, s). The peaks of two methylene groups are overlapping with that of
HbO peak.
ESI(LC/MS positive mode) m/z 614 (M+H)
[Example 50]
5-{[Acetyl-(3-methylsulfanyl-propoxy)-amino]-methyl}-3,4-difluoro-2-(2-fluoro-4-iodo-phenyla
mino)-N-(2-hydroxy-ethoxy)-benzamide
HO>
'H-NMRCDMSO-de, 400MHz) 8(PPM) 1.75(2H, m), 2.04(3H, s), 2.12(3H, s), 2.66(2H, t,
J-6.3Hz), 3.80(2H, br), 4.02(2H, m), 4.82(2H, s), 6.62(1H, m), 7.34(2H, d,br, J=8.3Hz), 7.55(1H,
dd, J=10.7Hz, 1.7Hz), 8.52(1H, s), 11.8(1H, s). Apeak of methylene group is overlapping with
that of H2O peak.
ESI(LC/MS positive mode) m/z 628 (M+H)
[Example 51]
5 - {[ Acetyl-(2-acetylammo-ethoxy)-amino] -methyl} -3,4-difluoro-2-(2-fluoro-4-iodo-phenylamin
o)-N-(2-hydroxy-ethoxy)-benzamide (Compound F-18)
188
'H-NMRCDMSO-de, 400MHz) 8(PPM) 1.76(3H, s), 2.07(3H, s), 3.23(2H, m), 3.80(2H, br),
3.89(2H, t, J=5.0Hz), 4.79(2H, s), 6.64(1H, m), 7.33(2H, m), 7.56(1H, dd, J=10.7Hz, 2.0Hz),
8.00(1H, t, J=5.6Hz), 8.53(1H, br), 11.8(1H, br). Apeak of methylene group is overlapping with
that of H2O peak.
ESI(LC/MS positive mode) m/z 625 (M+H)
[Example 52]
5- {[Acetyl-(2-propionylamino-ethoxy)-amino]-methyl} -3,4-difluoro-2-(2-fluoro-4-iodo-phenyla
mino)-N-(2-hydroxy-ethoxy)-benzamide (Compound F-19)
-de, 400MHz) 6(PPM) 0.94(3H, t, J=7.7Hz), 2.04(2H, d, J=7.7Hz), 2.07(3H, s),
3.24(2H, m), 3.80(2H, br), 3.89(2H, t, J=5.0Hz), 4.79(2H, s), 6.64(1H, m), 7.33(2H, m), 7.55(1H,
dd, J=10.7Hz, 2.0Hz), 7.94(1H, t, J=5.1Hz), 8.53(1H, br), 11.85(1H, br). Apeak of methylene
group is overlapping with that of HiO peak.
ESI(LC/MS positive mode) m/z 639 (M+H)
[Example 53]
5- {[ Acetyl-(2-isobutyrylamino-ethoxy)-amino] -methyl} -3,4-difluoro-2-(2-fluoro-4-iodo-phenyla
mino)-N-(2-hydroxy-ethoxy)-benzamide (Compound F-20)
189
-de, 400MHz) 5(PPM) 0.92(6H, d, J=6.8Hz), 2.07(3H, s), 2.30(1H, hepta,
J=6.8Hz), 3.24(2H, m), 3.80(2H, br), 3.90(2H51, J=5.0Hz), 4.79(2H, s), 6.63(1H, m), 7.33(2H,
m), 7.55(1H, dd, J=10.7Hz, 1.5Hz), 7.91(1H, t, J=5.6Hz), 8.53(1H, br), 11.84(1H, br). The peak
of a methylene group is overlapping with that of H2O peak.
ESI(LC/MS positive mode) m/z 639 (M+H)
[Example 54]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(3-oxo-tl,4,2]dioxazina
n-2-ylmethyl)-benzamide (Compound H-l)
H0_
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-eth
oxyamino)-methyl]-benzamide (100 mg, 0.185 mmol) obtained in Example 6,
N,N'-disuccinimidyl carbonate (59 mg, 0.231 mmol) andNEt3 (113 mg, 1.12 mmol) were stirred
in a mixed solvent of CHiC^/THF (1 mL/1 mL) at room temperature for 10 hours. The
reaction mixture was purified by silica gel column chromatography (CtbCk/MeOH as a
developing solvent) to give the title compound (12.5 mg).
'H-NMR^MSO-de, 400MHz) 8(PPM) 3.54(2H, br), 3.82(2H, br), 4.16(2H, t, J=4.4), 4.42(2H, t,
J=4.4Hz), 4.76(2H+1H, s+br), 6.65(1H, m), 7.35(1H, d, J=8.3Hz), 7.40(1H, d, J=6.3Hz),
7.56(1H, d, J=10.8Hz), 8.68(1H, br), 11.88(1H, br)
ESI(LC/MS positive mode) m/z 568 (M+H)
[Example 55]
190
2-(4-Ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-(3-oxo-[l,4,2]dioxazi
nan-2-ylmethyl)-benzamide (Compound H-2)
H0>
The title compound was synthesized by a similar procedure to that in Example 3 8 from
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(3-oxo-[l,4,2]dioxazinan
-2-ylmethyl)-benzamide obtained in Example 54.
'H-NMRXDMSO-de, 400MHz) 8(PPM) 3.54(2H, br), 3.83(2H, br), 4.09(1H, br), 4.17(2H, br),
4.42(2H, br), 4.72(1H, br), 4.78(2H, br), 6.77(1H, br), 7.14(1H, d, J=6.8Hz), 7.31(1H, d,
J=11.8Hz), 7.42(1H, d, J=6.4Hz), 8.78(1H, br), 11.87(1H, br)
ESI(LC/MS positive mode) m/z 466 (M+H)
[Example 56]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5- {[methoxy-(2-methoxyacetyl)-
amino]-methyl}-benzamide (Compound F-6)
To a solution of methoxyacetic acid (9.0 pi, 0.12 mmol) in methylene chloride (1 ml)
were added 3-hydroxy-4-oxo-354-dihydro-l,2,3-benzotriazine (18.9 mg, 0.12 mmol) and
l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (22.5 mg, 0.12 mmol), and the
mixture was stirred for 3 hours. This solution was added dropwise to a solution of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(methoxyamino-methyl)-
benzamide (50.0 mg, 0.10 mmol) obtained in Example 15 in THF (3 ml), and triethylamine (40.9
ul, 0.29 mmol) was added thereto. The mixture was stirred for 15 hours. The reaction
191
mixture was diluted with ethyl acetate (45 ml), and washed with saturated aqueous ammonium
chloride (20 ml), and then with saturated brine (2x 20 ml). The organic layer was dried over
anhydrous magnesium sulfate, and concentrated under reduced pressure. The resultant residue
was purified by preparative TLC (CH2Cl2/MeOH (10:1)) to give
3 ,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5 - { [methoxy-(2-methoxy-a
cetyl)-amino] -methyl} -benzamide (Compound F-6, 19.1 mg, 34%) as a colorless oil.
, 270MHz) 8(PPM) 3.44 (3H, s), 3.67-3.73 (2H, m), 3.76 (3H, s), 3.89-3.95
(2H, m), 4.30 (2H, s), 4.90 (2H, s), 6.61 (1H, dt, J = 4.3, 8.6 Hz), 7.34 (1H, ddd, J = 1.1, 1.9, 8.6
Hz), 7.37-7.43 (1H, m),7.44 (1H, dd, J = 1.9, 10.8 Hz).
ESI(LC/MS positive mode) m/z 584 (M+H)
[Example 57]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-{[(2-hydroxy-acetyl)-methoxy-amino]-methyl}
-N-(2-hydroxy-ethoxy)-benzamide (Compound F-5)
To a solution of acetoxyacetic acid (13.9 mg, 0.12 mmol) in methylene chloride (1 ml)
were added 3-hydroxy-4-oxo-3,4-dihydro-l,2,3-benzotriazine (18.9 mg, 0.12 mmol) and
l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (22.5 mg, 0.12 mmol), and the
mixture was stirred for 3 hours. This solution was added dropwise to a solution of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(methoxyamino-methyl)-
benzamide (50.0 mg, 0.10 mmol) obtained in Example 15 in THF (2 ml), and triethylamine (40.9
ul, 0.29 mmol) was added thereto. The mixture was stirred for 24 hours. The reaction
mixture was diluted with ethyl acetate (45 ml), and washed with saturated aqueous ammonium
chloride (20 ml), and then with saturated brine (2x 20 ml). The organic layer was dried over
anhydrous magnesium sulfate, and concentrated under reduced pressure. The resultant residue
was roughly purified by preparative TLC (CH2Cl2/MeOH (10:1)) to give
{[2,3-difluoro-4-(2-fluoro-4-iodo-phenylamino)-5-(2-hydroxy-ethoxycarbamoyl)-benzyl]-metho
192
xy-carbamoyl}acetic acid methyl ester (14.0 mg, containing impurities) as a colorless oil. To a
solution of the resultant
{[2,3-difluoro-4-(2-fluoro-4-iodo-phenylamino)-5-(2-hydroxy-ethoxycarbamoyl)-ben2yl]-metho
xy-carbamoyl}acetic acid methyl ester (14.0 mg, containing impurities) in methanol (1 ml) was
added sodium methoxide (3.0 mg, 0.06 mmol), and the mixture was stirred for 2 hours. The
reaction mixture was diluted with saturated ammoniuni chloride, and extracted with methylene
chloride (30 ml and 15 ml). The organic layer was dried over anhydrous magnesium sulfate,
and concentrated under reduced pressure. The resultant residue was purified by preparative
TLC (CH2Cl2/MeOH (10:1)) to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-{[(2-hydroxy-acetyl)-methoxy-amino]-niethyl}-
N-(2-hydroxy-ethoxy)-benzamide (F-5, 5.8 mg, 12% for 2 steps) as a colorless oil.
1H-NMR(CD30D> 270MHz) 8(PPM) 3.70 (2H, t, J - 4.6 Hz), 3.75 (3H, s), 3.92 (2H, t, J = 4.6
Hz), 4.36 (2H, s), 4.90 (2H, s), 6.61 (1H, dt, J = 4.3, 8.9 Hz), 7.31-7.37 (1H, m),7.37-7.43 (1H,
m),7.44 (1H, dd, J = 1.9,10.8 Hz).
ESI(LC/MS positive mode) m/z 570 (M+H)
[Example 58]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(isobutvryl-methoxy-a
mino)-methyl]-benzamide (Compound F-4)
HO,
The title compound was prepared by a procedure similar to that in Example 41.
Namely,
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(methoxyamino-methyl)-
benzamide obtained in Example 15 was reacted with 4-oxo-4H-benzo[d][l,2,3]triazin-3-yl
isobutyrate prepared from isobutyric acid to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylarnino)-N-(2-hydroxy-ethoxy)-5-[(isobutyryl-methoxy-am
ino)-methyl]-benzamide (88.9 mg, 77%).
-de, 270MHz) 8(PPM) 1.04(6H, d, J=6.8Hz), 2.95(1H, m), 3.00(3H, s), 3.54(2H,
193
m), 3.80(2H, m), 4.75(1H, br.s), 4.85(2H, s), 6.63(1H, td, J=8.6, 3.8Hz), 7.30(1H, br.d, J=6.8Hz),
7.36(1H, d, J=8.4Hz), 7.58(1H, dd, J=10.9,1.8Hz), 8.53(1H, br.s)
ESI(LC/MS positive mode) m/z 582(M+H)
[Example 59]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(methoxy-propionyl-a
mino)-methyl]-benzamide (Compound F-3)
The title compound was prepared by a procedure similar to that in Example 41.
Namely,
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(methoxyamino-methyl)-
benzamide obtained in Example 15 was reacted with 4-oxo-4H-benzo[d][l,2,3]triazin-3-yl
propionate prepared from propionic acid to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(methoxy-propionyl-am
ino)-methyl] -benzamide (35.0 mg, 31%).
-de, 270MHz) 6(PPM) 1.02(3H, t, J=7.5Hz), 2.45(2H, q, J=7.5Hz), 3.31(3H, s),
3.54(2H, t, J=4.8Hz), 3.81(2H, t, J=4.8Hz), 4.83(2H, s), 6.64(1H, td, J=8.7, 4.3Hz), 7.32(1H,
br.s), 7.36(1H, br.d, J=8.4Hz), 7.57(1H, dd, J=10.9, l.SHz), 8.62(1H, br.s)
ESI(LC/MS positive mode) m/z 568(M+H)
[Example 60]
5-[(Acetyl-ethoxy-amino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxyethoxy)-
benzamide (Compound F-10)
194
The title compound was prepared by a procedure similar to that in Example 41.
Namely,
5-(ethoxyamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylammo)-N-(2-hydroxy-ethoxy)-b
enzamide obtained in Example 17 was reacted with 4-oxo-4H-benzo[d][l,2,3]triazin-3-yl acetate
prepared from acetic acid to give
5-[(acetyl-ethoxy-amino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-e
thoxy)-benzarnide (19.3 mg, 71%).
16, 270MHz) 8(PPM) 1.15(3H, t, J=6.9Hz), 2.10(3H, s), 3.31(3H, s), 3.55(2H,
m), 3.82(2H, m), 3.94(2H, q, J=6.9Hz), 4.71(1H, br.s), 4.81(2H, s), 6.64(1H, m), 7.34(1H, m),
7.36(1H, m), 7.58(1H, d, J=9.7Hz), 8.53(1H, br.s), 11.84(1H, br.s)
ESI(LC/MS positive mode) m/z 568(M+H)
[Example 61]
5-[(Ethoxy-propionyl-amino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydro
xy-ethoxy)-benzamide (Compound F-ll)
HO,
The title compound was prepared by a procedure similar to that in Example 41 .
Namely,
5-(ethoxyamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-b
enzamide obtained in Example 17 was reacted with 4-oxo-4H-benzo[d][l,2,3]triazin-3-yl
propionate prepared from propionic acid to give
5-[(ethoxy-propionyl-amino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydro
xy-ethoxy)-benzamide (17.0 mg, 61%).
, 270MHz) 5(PPM) 1.12(3H, t, JM7.4Hz), 1.24(3H, t, J=7.1Hz), 2.53(2H, q,
J=7.4Hz), 3.67(2H, m), 3.92(2H, m), 3.99(2H, q, J=7.1Hz), 4.89(2H, s), 6.61(1H, td, J=8.7,
4.3Hz), 7.34(1H, m), 7.38(1H, m), 7.44(1H, dd, J=10.7, 2.0 Hz)
ESI(LC/MS positive mode) m/z 582(M+H)
195
[Example 62]
2-(4-Ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5 - [(isobutyryl-methoxy
-amino)-methyl]-benzamide (Compound F-9)
Dichlorobis(triphenylphosphine)-palladium (Aldrich, 4 mg, 0.006 mmol), copper iodide
(2.2 mg, 0.012 mmol), and N,N-diisopropylethylamine (30 |^L, 0.175 mmol) were added to a
solution of
5-[(acetyl-methoxy-amino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy
-ethoxy)-benzamide (67.78 mg, 0.117 mmol) obtained in Example 58 in tetrahydrofuran
(anhydrous, 2.0 mL) under a nitrogen atmosphere. The mixture was stirred thoroughly. After
a homogenous solution was obtained, trimethylsilylacetylene (65 uL, 0.466 mmol) was added to
the solution, which was stirred at room temperature for a whole day and night.
After completion of the reaction, the solvent was evaporated under reduced pressure,
and the yellowish brown oily residue was extracted with ethyl acetate. The organic layer was
washed sequentially with 2% aqueous EDTA, water, and saturated brine, dried over anhydrous
sodium sulfate, and concentrated under reduced pressure. The resultant residue was purified by
silica gel flash chromatography (Mega Bond Elut, Varian, 5% methanol/methylene chloride as an
eluent). The resultant
5-[(acetyl-memoxy-amino)-memyl]-3,4-difluoro-2-(2-fluoro-4-trimethylsilanylethynyl-phenyla
mino)-N-(2-hydroxy-ethoxy)-benzamide was dissolved in tetrahydrofuran (anhydrous, 2.0 mL),
and tetra-n-butylammonium fluoride (1 mol/L solution in tetrahydrofuran, 150 uL, 0.150 mmol)
was added thereto. The mixture was stirred for 1 day. After completion of the reaction, the
solvent was evaporated under reduced pressure, and the yellowish brown oily residue was
extracted with ethyl acetate. The organic layer was washed sequentially with diluted (1%)
hydrochloric acid, water, and saturated brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The resultant residue was purified by silica gel flash
chromatography (Mega Bond Elut, Varian, ethyl acetate as an eluent) to give a yellow solid,
which was triturated with 10% ethyl acetate/hexane to give a pale yellow solid (23.6 mg, 42% in
2 steps).
196
, 270MHz) 6(PPM) 1.12(6H, d, J=6.8Hz), 3.06(1H, quin., J=6.8Hz), 3.42(1H,
s), 3.68(2H, m), 3.78(3H, s), 3.91(2H, m), 4.91(2H, s), 6.73(1H, td, J=8.7,4.5Hz), 7.14(1H, br.d,
J=9.2Hz), 7.19(1H, dd, J=11.9, l.SHz), 7.39(1H, m)
ESI(LC/MS positive mode) m/z 480(M+H)
[Example 63]
2-(4-Ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5 - [(methoxy-propionylamino)-
methyl]-benzamide (Compound F-8)
The title compound was synthesized in 2 steps by a procedure similar to that in Example
62 from
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(methoxy-propionyl-am
ino)-methyl]-benzamide obtained in Example 59. 6.9 mg (35% in 2 steps).
, 270MHz) 5(PPM) 1.12(3H, t, J=7.4Hz), 2.54(1H, q, J=7.4Hz), 3.42(1H, s),
3.70(2H, m), 3.76(3H, s), 3.91(2H, m), 4.90(2H, s), 6.73(1H, td, J=8.6, 4.6Hz), 7.14(1H, br.d,
J=9.1Hz), 7.19(1H, dd, J=11.9, l.SHz), 7.39(1H, br.d, J=5.4Hz)
ESI(LC/MS positive mode) m/z 466(M+H)
[Example 64]
5-[(Acetyl-methoxy-amino)-methyl]-2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydr
oxy-ethoxy)-benzamide (Compound F-7)
197
The title compound was synthesized in 2 steps by a procedure similar to that in Example
62 from
5-[(acetyl-methoxy-amino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy
-ethoxy)-benzamide obtained in Example 46. 191.67 mg (79% in 2 steps).
'H-NMR^OD, 270MHz) S(PPM) 2.18(3H, s), 3.42(1H, s), 3.68(2H, m), 3.77(3H, s),
3.92(2H, m), 4.90(2H, s), 6.74(1H5 td, J=8.6,4.3Hz), 7.13(1H, br.d, J=9.1Hz), 7.19(1H, dd,
J=11.9, l.SHz), 7.40(1H, br.d, J=6.4Hz)
ESI(LC/MS positive mode) m/z 452(M+H)
[Example 65]
5-[(Ethoxy-propionyl-amino)-methyl]-2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hy
droxy-ethoxy)-benzamide (Compound F-24)
The title compound was synthesized in 2 steps by a procedure similar to that in Example
62 from
5-[(ethoxy-propionyl-amino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2 -hydro
xy-ethoxy)-benzamide obtained in Example 61 . 3.5 mg (45% in 2 steps).
, 270MHz) 8(PPM) 1.11(3H, t, J=7.4Hz), 1.22(3H, t, J=7.1Hz), 2.53(2H, q,
J=7.4Hz), 3.39(1H, s), 3.69(2H, m), 3.94(2H, m), 3.97(2H, q, J=7.4Hz), 4.90(2H, s), 6.69(1H, td,
J=8.6, 5.4Hz), 7.12(1H, br.d, J=8.7Hz), 7.17(1H, dd, J=12.0, l.SHz) , 7.50(1H, br.d, J=5.8 Hz)
ESI(LC/MS positive mode) m/z 480(M+H)
[Example 66]
5-[(Acetyl-ethoxy-amino)-methyl]-2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydro
xy-ethoxy)-benzamide (Compound F-23)
198
The title compound was synthesized in 2 steps by a procedure similar to that hi Example
62 from
5-[(acetyl-ethoxy-amino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-e
thoxy)-benzamide obtained in Example 60. 1.8 mg (22%).
, 270MHz) 8(PPM) 1.25(3H, t, J=7.1Hz), 2.18(3H, s), 3.43(1H, s), 3.63(2H, m),
3.68(2H, m), 4.01(2H, q, J=7.1Hz), 4.90(2H, s), 6.74(1H, td, J=8.6, 4.5Hz), 7.14(1H, br.d,
J=8.2Hz), 7.20(1H, dd, J=11.9, l.SHz) , 7.40(1H, m)
ESI(LC/MS positive mode) m/z 466(M+H)
[Example 67]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylammo)-5-[(foraiyl-methoxy-amino)-methyl]-N-(2 -hydro
xy-ethoxy)-benzamide (Compound F-l)
Ethyl formate (0.2 mL) was added to
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(methoxyammo-methyl)-
benzamide (Compound C-24, 50 mg, 0.0978 mmol) obtained in Example 15, and the mixture
was heated to reflux at 80°C for 1 hour.
After completion of the reaction, the reaction mixture was concentrated under reduced
pressure. The resultant white solid was fractionated by TLC (No. 5715, Merck, 5%
methanol/methylene chloride as a developing solvent), and the resultant white solid was further
triturated with 10% methylene chloride/hexane to give
199
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-[(formyl-methoxy-amino)-methyl]-N-(2-hydrox
y-ethoxy)-benzamide (Compound F-l, 18.2 mg, 35%) as a white solid.
-de, 400MHz, at 80°C) 5(PPM) 3.55(2H, dd, J=5.4, 4.9Hz), 3.69(3H, s),
3.84(2H, dd, J=5.4, 4.9Hz), 4.77(2H, s), 6.65(1H, td, J=8.9, 3.9Hz), 7.35(1H, d, J=8.3Hz),
7.45(1H, d, J=7.3Hz), 7.51(1H, dd, J=11.0, 2.0Hz), 8.35(1H, br.s)
ESI(LC/MS positive mode) m/z 540(M+H)
[Example 68]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylammo)-N-(2-hydroxy-ethoxy)-5-(2-oxo-pyrrolidin-l-ylm
ethyl)-benzamide (Compound H-3)
Methyl 4-amino-butyrate hydrochloride (commercially available, 48 mg, 0.312 mmol)
and sodium cyanoborohydride (20 mg, 0.312 mmol) were added to a solution of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide(50
mg, 0.104 mmol) obtained in Step F of Example 1 in methanol (2.0 mL). The mixture was
stirred at room temperature for 18 hours. Then, the reaction vessel was equipped with a reflux
condenser, and the mixture was heated at 80°C for 2 hours. After completion of the reaction,
the reaction mixture was extracted with ethyl acetate, and the organic layer was washed
sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The resultant residue was purified by silica gel flash
chromatography (Mega Bond Elut, Varian, 5% methanol/methylene chloride as an eluent) to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-oxo-pyrrolidin-l-yhn
ethyl)-benzamide (Compound H-3,26.8 mg, 47%) as a white solid.
), 270MHz) 8(PPM) 2.06(2H, m), 2.43(2H, dd, J=8.4, 7.7Hz), 3.44(2H, dd,
J=7.1, 6.9Hz), 3.70(2H, dd, J=4.8, 4.5Hz), 3.93(2H, dd, J=4.9, 4.0Hz), 4.53(2H, s), 6.62(1H, td,
J=8.7,4.3Hz), 7.32(1H, m), 7.35(1H, m), 7.45(1 H, dd, J=10.7, 2.0Hz)
ESI(LC/MS positive mode) m/z 550(M+H)
200
[Example 69]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-oxo-piperidin-l-ylme
thyl)-benzamide (Compound H-4)
Methyl 5-amino-pentanoate hydrochloride {see J. Org. Chem. (1968) 1581} (128 mg,
0.178 mmol) and sodium cyanoborohydride (45 mg, 0.718 mmol) were added to a solution of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide (115
mg, 0.239 mmol) obtained in Step F of Example 1 in tetrahydrofuran (anhydrous, 4.0 mL). The
mixture was stirred at room temperature for 1 .5 hours. Then, the reaction vessel was equipped
with a reflux condenser, and the mixture was heated at 60°C for 2 days. After completion of
the reaction, the reaction mixture was extracted with ethyl acetate, and the organic layer was
washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The resultant residue was purified by silica gel flash
chromatography (Mega Bond Elut, Varian, 4% methanol/methylene chloride as an eluent) to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-oxo-piperidin-l-ylmet
hyl)-benzamide (Compound H-4, 42.7 mg, 37%) as a white solid.
, 270MHz) 8(PPM) 1.85(4H, m), 2.42(2H, m), 3.40(2H, m) 3.70(2H, dd, J=4.9,
4.3Hz), 3.92(2H, dd, J=4.9, 4.3Hz), 4.65(2H, s), 6.56(1H, td, J=8.9, 4.3Hz), 7.34(1H, m),
7.35(1H, m) , 7.45(1H, dd, J=10.7, 2.0Hz)
ESI(LC/MS positive mode) m/z 564(M+H)
[Example 70]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-[(2-hydroxy-acetylamino)-methyl]-N-(2-hydro
xy-ethoxy)-benzamide (Compound E-5)
Step A
Synthesis of 5-aminomethyl-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid
trifluoroacetate
201
TFA H2N
tert-Butyl carbamate (commercially available, 187 mg, 1.602 mmol), trifluoroacetic acid
(123 uL, 1.602 mmol), and triethylsilane (255 uL, 1.602 mmol) were added sequentially to a
suspension of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-benzoic acid (225 mg,
0.534 mmol) obtained in Step A of Example 5 in acetonitrile (anhydrous, 20 mL). The mixture
was stirred at room temperature for 5 days. After completion of the reaction, the reaction
mixture was evaporated under reduced pressure, and the resultant residue was extracted with
ethyl acetate. The organic layer was washed sequentially with water and saturated brine, dried
over anhydrous sodium sulfate, and evaporated under reduced pressure. The resultant crude
product was purified by silica gel flash chromatography (Mega Bond Elut, Varian, 5%
methanol/methylene chloride as an eluent) to give
5-(tert-butoxycarbonylamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic
acid. [LC/MS m/z 523(M+1)]. Then, trifluoroacetic acid (0.5 mL) was added to a solution of
the resultant product in methylene chloride (20 mL), and the mixture was stirred at room
temperature for 14 hours. After completion of the reaction, the reaction mixture was
evaporated under reduced pressure, and the resultant residue was recrystallized from a mixed
solvent of diethyl ether:hexane (1:1) to give
5-aminomethyl-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid trifluoroacetate (285
mg, 99% in 2 steps) as white crystals.
1H-NMRCCD3OP, 270MHz) 5(PPM) 4.19(2H, s), 6.84(1H, td, J=8.6,4.8Hz), 7.44(1H, br.d,
J=10.1Hz), 7.51(1H, dd, J=10.4,2.0Hz), 8.06(1H, dd, J=7.8, l.SHz)
ESI(LC/MS positive mode) m/z 423(M+H)
StepB
Synthesis of
5-(acryloylamino-methyl)-N-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluor
o-4-iodo-phenylamino)-benzamide
202
Acryloyl chloride (100 uL, 0.986 mmol) and triethylamine (689 uL, 4.93 mmol) were
added to a solution of hydroxy-pyrrolidine-2,5-dione (commercially available, 227 mg, 1.973
mmol) in methylene chloride (anhydrous, 2 mL), and the mixture was stirred at room
temperature for 30 minutes.
5-aminomethyl-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid (150 mg, 0.355
mmol) obtained in Step A was added to this solution, and the mixture was stirred for 1 hour.
After completion of the reaction, the reaction mixture was evaporated under reduced pressure,
and the resultant residue was extracted with ethyl acetate. The organic layer was washed
sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure to give
5-(acryloylamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid as a white
solid. This product was confirmed for the structure by LC/MS. LC/MS (positive mode) m/z
477(M+1). This compound was dissolved in methylene chloride (anhydrous, 10 mL) under
argon flow. N,N-diisopropylethylamine (250 uL, 1.42 mmol),
O-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-hydroxylamine (135 mg, 0.71 mmol),
1-hydroxy-lH-benzotriazole (71mg, 0.533 mmol), and
(3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (102 mg, 0.533 mmol) were added
sequentially to the solution. The mixture was stirred at room temperature for 20 hours.
After completion of the reaction, the reaction mixture was evaporated under reduced
pressure, and the resultant residue was extracted with ethyl acetate. The organic layer was
washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and
evaporated under reduced pressure. The resultant crude product was purified by silica gel flash
chromatography (Mega Bond Elut, Varian, 40% ethyl acetate/hexane as an eluent) and
preparative TLC (No. 5744, Merck, 40% ethyl acetate/hexane as a developing solvent) to give
5-(acryloylamino-methyl)-N-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluor
o-4-iodo-phenylamino)-benzamide (7.4 mg, 3%) as a waxy solid.
!H-NMR(CDCl3, 270MHz) 8(PPM) 0.07(6H, s), 0.09(9H, s), 3.89(2H, m), 4.07(2H, m), 4.51(2H,
d, J=6.1Hz), 5.71(2H, dd, J=10.1, 1.5Hz), 6.12(1H, dd, J=17.0Hz, 10.2Hz), 6.20(1H, br.s),
6.33(1H, dd, J=17.0,1.5Hz), 6.56(1H, td, J=8.7, 5.3Hz), 7.30(1H, dt, J=8.6, 3.0Hz), 7.38(1H, dd,
203
J=10.2,2.0Hz), 7.40(1H, m), 8.57(1H, br.s)
ESI(LC/MS positive mode) m/z 650(M+H)
StepC
Synthesis of
N-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-[(
2-hydroxy-acetylamino)-methyl]-benzamide
Aqueous osmium tetroxide (4%, 0.1 mL) and sodium metaperiodate (12 mg, 0.056
mmol) were added to a solution of
5-(aciyloylamino-methyl)-N-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluor
o-4-iodo-phenylamino)-benzamide (7.3 mg, 0.011 mmol) obtained in Step B in tetrahydrofuran
(4 mL) and water (1 mL). The mixture was stirred for 3 hours. After the disappearance of the
starting material was confirmed by LC/MS, the reaction mixture was extracted with ethyl acetate.
The organic layer was washed sequentially with water and saturated brine, dried over anhydrous
sodium sulfate, and concentrated under reduced pressure to give
N-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-[(
2-oxo-acetylamino)-methyl]-benzamide. Subsequently, this was dissolved in methanol (2.0
mL). Sodium borohydride (3 mg, 0.079 mmol) was added to this solution at room temperature,
and the mixture was stirred for 1 hour. After completion of the reaction, the reaction mixture
was extracted with ethyl acetate, and the organic layer was washed sequentially with water and
saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure.
The resultant crude product was purified by silica gel flash chromatography (Mega Bond Elut,
Varian, 60% ethyl acetate/hexane as an eluent) to give
N-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-[(
2-hydroxy-acetylamino)-methyl]-benzamide (4.34 mg, 60% in 2 steps) as a pale yellow solid.
ESI(LC/MS positive mode) m/z 654(M+H)
StepD
Synthesis of
204
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-[(2-hydroxy-acetylainino)-methyl]-N-(2-hydrox
y-ethoxy)-benzamide (Compound E-5)
Tetra-n-butylammonium fluoride (1 mol/L solution in tetrahydrofuran, 0.5 mL, 0.500
mmol) was added to a solution of
N-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3s4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-[(
2-hydroxy-acetylamino)-methyl]-benzamide (4.34 mg, 0.00665 mmol) obtained in Step C in
tetrahydrofuran (anhydrous, 1 mL) at room temperature. The mixture was stirred for 1 .5 hours.
After completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the
organic layer was washed sequentially with water and saturated brine, dried over anhydrous
sodium sulfate, and evaporated under reduced pressure. The resultant crude product was
purified sequentially with silica gel flash chromatography (Mega Bond Elut, Varian, 5%
methanol/methylene chloride as an eluent) and preparative TLC (No. 5715, Merck, 7%
methanol/methylene chloride as a developing solvent) to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-[(2-hydroxy-acetylamino)-methyl]-N-(2-hydrox
y-ethoxy)-benzamide (Compound E-5, 1.4 mg, 39%) as a white solid.
, 270MHz) 8(PPM) 3.71(2H, dd, J=7.4, 4.7Hz), 3.94(2H, dd, J=7.4, 4.7Hz),
4.03(2H, s), 4.50(2H, s), 6.55(1H, td, J=8.6, 5.3Hz), 7.32(1H, m), 7.42(1H, dd, J=10.7, l.SHz),
7.45(lH,dd,J=5.8,2.1Hz)
ESI(LC/MS positive mode) m/z 540(M+H)
[Example 71]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-oxo-tetrahyo^o-pyrim
idin-l-ylmethyl)-benzamide (Compound H-6)
Step A
Synthesis of
5-[(3-amino-propylamino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy
-ethoxy)-benzamide
205
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzam
ide obtained in Step F of Example 1 was reacted with propane-1,3 -diamine in THF. The
thus-obtained imine was reduced with sodium borohydride in methanol to give the title
compound.
ESI(LC/MS positive mode) m/z 539 (M+H)
StepB
Synthesis of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-oxo-tetrahydro-pyrimi
din-l-ylmethyl)-benzamide (Compound H-6)
HO,
The amine synthesized in Step A (66.4 mg, 0.1233 mmol) was dissolved in THF:CH3CN
(1:1 v/v, 3.0 ml). N,N-disuccinimidyl carbonate (47.4 mg, 1.5 eq., 0.1849 mmol) and
triethylamine (103.1 ul, 6.0 eq., 0.7398 mmol) were added sequentially to this solution, and the
mixture was stirred at room temperature for 20 hours. The solvent was removed under reduced
pressure, and the residue was purified by LC/MS to give white crystals (42.6 mg).
-de, 400MHz) 6(PPM) 1.83(2H, t, J=5.2Hz), 3.14(2H, t, J=5.6Hz), 3.23(2H, t,
J=5.6Hz), 3.51-3.58(2H, m), 3.82(2H, brt), 4.49(2H, s), 6.41(1H, brs), 6.6K1H, dt, J=3.9, 8.3Hz),
7.28(1H, d, J=6.4Hz), 7.34(1H, d, J=7.9Hz), 7.56(1H, d, J=10.8Hz) , 8.48(1H, s), 12.0(1H, s)
206
ESI(LC/MS positive mode) m/z 565 (M+H)
[Example 72]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-oxo-oxazolidin-3-yl
methyl)-benzamide (Compound H-5)
Step A
Synthesis of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-{[(E)-2-hydroxy-ethylim
ino] -methyl} -benzamide
The title compound was synthesized by reacting
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide
obtained in Step F of Example 1 with ethanolamine in THF.
, 400MHz) 5(PPM) 3.72-3.74(4H, m), 3.81-3.84(2H, m), 3.96-3.99(2H, m),
6.64-6.68(lH, m), 7.36(1H, d, J=8.79Hz), 7.43(1H, d, J=9.99Hz), 8.13(1H, d, J=5.6Hz), 8.50(1H,
s)
ESI(LC/MS positive mode) m/z 524 (M+H)
StepB
Synthesis of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethylamino)
-methyl] -benzamide
207
Sodium borohydride was added to a solution of the imine,
3 ,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5 - { [(E)-2-hydroxy-ethylim
ino]-methyl}-benzamide obtained in Step A in MeOH at 0°C. While being allowed to warm
gradually, the mixture was stirred overnight. The solvent was removed under reduced pressure,
and the residue was purified with a silica gel column (CFbCk'.MeOH (4:1 to 2:1)) to give the
title compound as a white solid.
, 400MHz) 6(PPM) 2.80(2H, t, J=5.38Hz), 3.69-3.72(4H, m), 3.92-3.95(4H,
m), 6.59(1H, dt, J=3.9, 8.3Hz), 7.34(1H, d, J=10.3Hz), 7.44(1H, dd, J=1.95, 10.3Hz), 7.49(1H, d,
J=7.3Hz)
ESI(LC/MS positive mode) m/z 526 (M+H)
Step B' (an alternative to Step B)
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-eth
ylamino)-methyl]-benzamide obtained in Step B can be prepared in 1 step by reductive
amination of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide
obtained in Step F of Example 1. Namely, 2-aminoethanol (0.070 ml), acetic acid (0.080 ml),
and sodium cyanoborohydride (44 mg) were added to a solution of an aldehyde,
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide (65.7
mg, 0.136 mmol) in methanol (2 ml) at room temperature. The mixture was stirred overnight.
Water (6 ml), saturated brine (3 ml), and aqueous sodium bicarbonate (2 ml) were added, and the
reaction mixture was extracted with ethyl acetate (2x 10 ml). The combined organic layers
were washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The residue was triturated with ethyl acetate/n-hexane
(2:1) to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethylamino)
-methylj-benzamide (60.4 mg, 84%) as a colorless solid.
StepC
208
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-oxo-oxazolidin-3-yl
methyl)-benzamide (Compound H-5)
Using
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethylamino)
-methyl]-benzamide obtained in Step B (or Step B') as a starting material, synthesis was
performed according to the procedure described in Step B of Example 27 to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-oxo-oxazolidin-3-yhn
ethyl)-benzamide (Compound H-5).
JH-NMR(DMSO-d6, 400MHz) 8(PPM) 3.49-3.59(4H, m), 3.83-3.85(2H, m), 4.28-4.32(2H, m),
4.42(2H, s), 6.87(1H, td, J=8.8, 3.9Hz), 7.36(1H, d,J=7.9Hz), 7.46(1H, d, J=8.4Hz), 7.57(1H, dd,
J=1.9,10.8Hz), 8.76(1H, s), 12.3(1H, s)
ESI(LC/MS positive mode) m/z 552 (M+H)
[Example 73]
5-(2,3-Dioxo-morpholin-4-ylmethyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydrox
y-ethoxy)-benzamide (Compound H-7)
4-Dimethylaminopyridine (12.1 mg) and dibenzotriazol-1-yl oxalate (9.2 mg, 27.4
(J,mol) were added to a solution of
209
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethylamino)
-methyl]-benzamide (15.9 mg, 30.2 umol) obtained in Step B (or Step B') of Example 72 in
anhydrous N,N-dimethylforrnamide (1.5 ml) at room temperature. The mixture was stirred at
room temperature for 2 hours. Water (6 ml) and 1 N hydrochloric acid (0.5 ml) were added,
and the reaction mixture was extracted with ethyl acetate (2x 10 ml). The combined organic
layers were washed with saturated brine (8 ml), dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The residue was purified with a preparative silica gel
plate (No. 5744, Merck, CH2Cl2/MeOH (10:1) as a developing solvent) to give
5-(2,3-dioxo-morpholin-4-ylmethyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydrox
y-ethoxy)-benzamide (Compound H-7, 1.0 mg, 6% yield).
-de, 270MHz) 8(PPM) 3.57 (2H,br.s), 3.70 (2H5 t, J = 6.1 Hz), 3.86 (2H, t, J =
4.9 Hz), 4.55 (2H, t, J = 5.4 Hz), 4.66 (2H, s), 6.67 (IH, td, J = J = 8.4, 4.3 Hz), 7.32 - 7.40 (2H,
m), 7.59 (IH, dd, J = 10.8, 1.4 Hz).
ESI(LC/MS positive mode) m/z 580(M+H)
[Example 74]
5-{[Acetyl-(2-hydroxy-ethyl)-amino]-methyl}-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamuio)-N-
(2-hydroxy-ethoxy)-benzamide (Compound E-6)
Using
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethylamino)
-methyl]-benzamide obtained in Step B (or Step B') of Example 72 as a starting material,
synthesis was performed according to the procedure described in Example 41 to give
5- {[acetyl-(2-hydroxy-ethyl)-arnino] -methyl} -3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(
2-hydroxy-ethoxy)-benzamide (Compound E-6).
'H-NMRtDMSO-de, 270MHz) 6(PPM) 2.07 (3H x 1/3, s), 2.12 (3H x 2/3, s), 3.47 - 3.56 (4H, m),
210
3.83 (2H, t, J = 4.5 Hz), 4.58 (2H x 2/3, s), 4.69 (2H x 1/3, s), 6.61 (1H, td, J = 8.9,4.3 Hz), 7.24
(1H, d, J = 7.4 Hz), 7.35 (1H, d, J = 8.6 Hz), 7.57 (1H, d, J = 7.6 Hz),
ESI(LC/MS positive mode) m/z 568(M+H)
[Test Example 1]
[Measurement of MEK inhibitory activity]
MEK inhibitory activities were measured for Compounds B-l, B-2, B-6, B-9, B-12, C-l,
C-6, C-7, C-8, C-10, C-13, C-24, C-28, C-31, F-l, F-2, F-3, F-4, F-5, F-6, F-7, F-8, F-9, G-l,
G-2, G-3, G-4, and G-5 obtained in the Examples, and the following known compounds, P
(W002/06213, Example 9), Q (WO02/06213, Example 39), and R (WO99/01426,
Compound P was prepared according to the description (Example 9) of WO02/06213.
Compound Q was prepared according to the description (Example 39) of WO02/06213.
Compound R was prepared according to the description (Example 95) of WO99/01426.
For the measurement of MEK inhibitory activities, an assay system was constructed so
that phosphorylation of MBP (Myelin Basic Protein) could occur in proportion to the MEK
kinase activity, with adjusting the amount of the enzyme and the like, according to the method of
211
Raf-1 Kinase Cascade Assay Kit (cat. 17-172, Upstate Biotechnology Inc., New York, USA).
[y33?] ATP (Amersham Biosciences) was used as a radioisotope.
The amount of the 33P-labelled MBP was measured using Microbeta 1450 (PerkinElmer
Inc., Massachusetts, USA), and 50% inhibitory concentration (IC50) was calculated.
Results are shown in Table 2.
[Test Example 2]
[Measurement of growth inhibitory activity against cancer cells]
Growth inhibitory activities against cancer cells based on MEK inhibitory activities
were measured for Compounds B-1, B-2, B-6, B-9, B-12, C-1, C-6, C-7, C-8, C-10, C-13, C-24,
C-28, C-31, F-l, F-2, F-3, F-4, F-5, F-6, F-7, F-8, F-9, G-l, G-2, G-3, G-4, and G-5 obtained in
the Examples, and the known compounds, P, Q, and R shown above.
The growth inhibitory activities against cancer cells were measured using Cell Counting
Kit-8 (Dojindo Laboratories).
Human colon cancer cell line HT-29 obtained from American Type Culture Collection
(Virginia, USA) and human non-small cell lung carcinoma cell line QG56 obtained from
Immuno-Biological Laboratories Co., Ltd. were plated onto 96-well culture plate at a density of
2000 cells/well, a designated concentration of MEK inhibitor was added, and the cells were
incubated for 4 days.
On the 4th day of culture, a solution of Cell Counting Kit-8 was added, and absorbance
(measurement wavelength: 450 nm; reference wavelength: 615 nm) was measured according to
the protocol attached to the kit, and 50% inhibitory concentration (IC50) was calculated.
Results are shown in Table 2.
[Test Example 3]
[Measurement of stability against mouse liver microsome]
A variety of metabolic enzymes exist in the liver, and play a key role in the foreign
substance detoxication. Many enzymes involved in drug metabolism (e.g., cytochrome P450)
are localized in the endoplasmic reticulum in the cells, and are collected in the microsome
fraction during preparation from the cells. The stability in liver microsome is used universally
as a simple measure for evaluation of drug metabolism.
There is a correlation between in vitro intrinsic clearance calculated from the stability in
human liver microsome and human in vivo clearance (Ito K. et al. Annu. Rev. Pharmacol.
Toxicol. 1998, 38: 461-99, Naritomi Y. et al. Drug Metab. Dispos. 2001,29:1316-24, Yuichi
Sugiyama et al., Pharmacokinetics - Understanding by exercises, Nanzando).
Clearance is an important parameter that determines a blood concentration. The better
the drug stability in liver microsome is, the smaller the clearance is and the higher the blood
concentration is. A drug having a good stability in liver microsome can achieve a certain blood
212
concentration with a lower dose, compared to a drug having a poor stability.
Compounds B-l, B-2, B-6, B-9, B-12, C-l, C-2, C-6, C-7, C-10, C-24, C-28, C-29,
C-31, C-34, C-35, F-l, F-2, F-5, F-7, G-l, G-2, G-3, G-4, and G-5 obtained in the Examples, and
the known compounds, P, Q, and R shown above were incubated with mouse liver microsome (1
mg protein/mL) in 50 mM phosphate buffer (pH 7.4) containing 5 mM MgCb and 2 mM
NADPH (the reduced form of nicotinamide adenine dinucleotide phosphate) at 37°C for 1 hour.
After the enzyme reaction was terminated with the addition of a three-fold volume of acetonitrile,
the reaction mixture was centrifuged at 1500 rpm for 10 minutes, and the resultant supernatant
was used as a test sample to measure the stability in human liver microsome by quantitating the
compound in the sample using FIPLC/MS.
Table 3 shows the stability of the test compounds in mouse liver microsome. When a
test compound has a longer half-life, the compound is metabolically very stable, and can produce
a high blood concentration.
[Test Example 4]
[Measurement of water solubility]
Biopharmaceutical Classification System (BCS) is widely used to scientifically classify
oral formulations in regard to membrane permeability and solubility. Drugs having good
membrane permeability and good solubility are classified into Class 1, and guaranteed that they
are absorbed almost perfectly after oral administration, and that the variability among individuals
is small (Lenneras H. et al. J. Pharm. Pharmacol. 2005, 57: 273-85, KasimNAef al. Mol.
Pharmaceutics 2004,1: 85-96).
Excessive amount of each of Compounds B-l, B-2, B-6, B-9, B-12, C-l, C-2, C-6, C-7,
C-10, C-24, C-28, C-29, C-31, C-34, C-35, F-l, F-2, F-5, F-7, G-l, G-2, G-3, G-4, and G-5
obtained in the Examples, and the known compounds, P, Q, and R shown above was added to a
glass vessel, to which 50 mM phosphate buffer (pH 6.5) was added. The vessel was sealed,
sonicated at room temperature (20°C) for 10 minutes, and agitated on an agitator for 2 hours.
After dissolution equilibrium was achieved, the reaction mixture was filtered through a
membrane filter, and the solute concentration in the filtrate was determined by HPLC.
Results are shown in Table 3.
[Test Example 5]
[Measurement of tumor growth suppressive activity]
A mouse model carrying human cancer was used to measure tumor growth suppressive
activity of Compounds B-l, C-l, C-10, C-13, F-l, F-2, F-5, G-l, G-2, G-3, G-4, and H-
obtained in the Examples, and the known compound, Q shown above.
Human colon cancer cell line HT-29 (obtained from American Type Culture Collection)
was inoculated subcutaneously to BALB/c nu/nu mice. The test compound was dissolved in
213
the vehicle (10% Cremophor, 10% ethanol, and 80% distilled water for injection), and orally
given to the mice once a day for 14 consecutive days after the average tumor volume (0.5x long
diameter x short diameter2) reached to about 200 mm3. One day after the last administration,
the tumor volume was measured, and the tumor growth suppression rate, (1 - tumor volume
increase in the group received the test compound/tumor volume increase in the group received
the vehicle) x 100, of each of the test compounds was determined compared to the group
received the vehicle. The higher value (%) indicates the stronger tumor suppressive activity.
Results of the tumor growth suppression rate at maximum tolerance dose (MTD) are
shown in Table 4.
Table 4 shows very high tumor growth suppression rates of the compounds of this
invention, indicating that they have very strong effect of tumor regression, compared to control
compound Q, which has the tumor growth suppression rate of 66 - 82%.
[Test Example 6]
Anti-Type II collagen antibody-induced arthritis in mice]
Suppressive effects of compounds B-l and G-2 obtained in Examples on arthritis
development were determined using anti-Type II collagen antibody (anti-CII)-induced arthritis (J
Immunol. 2002 Aug 1; 169(3):1459-66).
Anti-CII (10 mg/mL of antibody cocktail for arthritis, code No. 62200, Chondrex) was
administered intravenously at 1 mg/body/100 jaL to BALB/c mice (female mice of 5 weeks old
were purchased from Charles River Japan, Inc., and used at 5 animals per group after 1 week
acclimation), and after 3 days, LPS (lipopolysaccharide) solution (0111:B4 250 p-g/mL, code No.
62200, Chondrex) was administered intraperitoneally at 25 j.ig/0.1 mL/body. The test
compounds were dissolved in the vehicle (10% Cremophor, 10% ethanol, and 80% distilled
water for injection), and orally administered 1 hour before, 1, 2,4-8, and 11 days after LPS
administration (once a day, 1 mg/kg).
Arthritis score was evaluated with the full score 4 points per limb, and 16 points per
animal. Score indicates as follows:
0.5: erythema is observed at 1 joint;
1: erythema is observed at 2 joints. Or reddening of the upper surface of the paws is observed,
but swelling is not observed;
2: Slight swelling is observed;
3: Moderate swelling is observed on the upper surface of the paws;
4: Severe swelling is observed on the upper surface of the paws and digits.
In the group received the vehicle, arthritis developed the day after LPS administration.
On the other hand, arthritis development was strongly suppressed in both groups received B-l
and G-2. Results of suppressive effect on arthritis development (arthritis score; mean +/-
214
standard deviation) are shown in Figure 1. Figure 1 shows that the present compounds
Test Examples 1-3 described above were performed according to "Development of
Pharmaceuticals, Vol. 15, "Physicochemical property of formulation", edited by Koichiro
Miyajima, Professor of Kyoto University, pages 45 to 48", and Test Example 4 described above
was performed according to "2.2 Method for measuring solubility, 2.2.1 Equilibrium method, a.
Stirring method, Hirokawa Publishing Co."
Industrial Applicability
The compounds according to the present invention and the pharmaceutically acceptable
salts thereof have a MEK inhibitory effect, a cell growth inhibitory effect, are excellent hi
stability in vivo and solubility in water, and are useful as preventing agents or therapeutic agents
for proliferative diseases, e.g., cancers and joint diseases with inflammation.

ESI(LC/MS positive mode) m/z540 (M+H)
[Example 48]
5-[(Acetoxy-acetyl-amino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy
-ethoxy)-benzamide (Compound F-14)
The title compound was obtained as a by-product in the preparation of
5-[(Acetyl-hydroxy-amino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydrox
y-ethoxy)-benzamide in Example 47.
-de, 400MHz) 5(PPM) 1.22(3H, s), 2.17(3H, s), 3.54(2H, br), 3.80(2H,br),
4.85(2H, s), 6.62(1H, m), 7.37(2H, m), 7.56(1H, d, J=6.8Hz), 8.64(1H, br), 11.85(1H, br),
ESI(LC/MS positive mode) m/z582 (M+H)
[Example 49]
5- {[Acetyl-(2-methylsulfanyl-ethoxy)-amino]-methyl} -3,4-difluoro-2-(2-fluoro-4-iodo-phenyla
mino)-N-(2-hydroxy-ethoxy)-benzamide (Compound F-21)
187
-de, 400MHz) 8(PPM) 2.04(3H, s), 2.12(3H, s), 2.66(2H, t, J=6.3Hz), 3.80(1H,
br), 4.02(2H, m), 4.82(2H, s), 6.62(1H, m), 7.34(2H, d,br, J=8.3Hz), 7.55(1H, dd, J=10.7Hz,
1.7Hz), 8.52(1H, s), 11.8(1H, s). The peaks of two methylene groups are overlapping with that of
HbO peak.
ESI(LC/MS positive mode) m/z 614 (M+H)
[Example 50]
5-{[Acetyl-(3-methylsulfanyl-propoxy)-amino]-methyl}-3,4-difluoro-2-(2-fluoro-4-iodo-phenyla
mino)-N-(2-hydroxy-ethoxy)-benzamide
HO>
'H-NMRCDMSO-de, 400MHz) 8(PPM) 1.75(2H, m), 2.04(3H, s), 2.12(3H, s), 2.66(2H, t,
J-6.3Hz), 3.80(2H, br), 4.02(2H, m), 4.82(2H, s), 6.62(1H, m), 7.34(2H, d,br, J=8.3Hz), 7.55(1H,
dd, J=10.7Hz, 1.7Hz), 8.52(1H, s), 11.8(1H, s). Apeak of methylene group is overlapping with
that of H2O peak.
ESI(LC/MS positive mode) m/z 628 (M+H)
[Example 51]
5 - {[ Acetyl-(2-acetylammo-ethoxy)-amino] -methyl} -3,4-difluoro-2-(2-fluoro-4-iodo-phenylamin
o)-N-(2-hydroxy-ethoxy)-benzamide (Compound F-18)
188
'H-NMRCDMSO-de, 400MHz) 8(PPM) 1.76(3H, s), 2.07(3H, s), 3.23(2H, m), 3.80(2H, br),
3.89(2H, t, J=5.0Hz), 4.79(2H, s), 6.64(1H, m), 7.33(2H, m), 7.56(1H, dd, J=10.7Hz, 2.0Hz),
8.00(1H, t, J=5.6Hz), 8.53(1H, br), 11.8(1H, br). Apeak of methylene group is overlapping with
that of H2O peak.
ESI(LC/MS positive mode) m/z 625 (M+H)
[Example 52]
5- {[Acetyl-(2-propionylamino-ethoxy)-amino]-methyl} -3,4-difluoro-2-(2-fluoro-4-iodo-phenyla
mino)-N-(2-hydroxy-ethoxy)-benzamide (Compound F-19)
-de, 400MHz) 6(PPM) 0.94(3H, t, J=7.7Hz), 2.04(2H, d, J=7.7Hz), 2.07(3H, s),
3.24(2H, m), 3.80(2H, br), 3.89(2H, t, J=5.0Hz), 4.79(2H, s), 6.64(1H, m), 7.33(2H, m), 7.55(1H,
dd, J=10.7Hz, 2.0Hz), 7.94(1H, t, J=5.1Hz), 8.53(1H, br), 11.85(1H, br). Apeak of methylene
group is overlapping with that of HiO peak.
ESI(LC/MS positive mode) m/z 639 (M+H)
[Example 53]
5- {[ Acetyl-(2-isobutyrylamino-ethoxy)-amino] -methyl} -3,4-difluoro-2-(2-fluoro-4-iodo-phenyla
mino)-N-(2-hydroxy-ethoxy)-benzamide (Compound F-20)
189
-de, 400MHz) 5(PPM) 0.92(6H, d, J=6.8Hz), 2.07(3H, s), 2.30(1H, hepta,
J=6.8Hz), 3.24(2H, m), 3.80(2H, br), 3.90(2H51, J=5.0Hz), 4.79(2H, s), 6.63(1H, m), 7.33(2H,
m), 7.55(1H, dd, J=10.7Hz, 1.5Hz), 7.91(1H, t, J=5.6Hz), 8.53(1H, br), 11.84(1H, br). The peak
of a methylene group is overlapping with that of H2O peak.
ESI(LC/MS positive mode) m/z 639 (M+H)
[Example 54]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(3-oxo-tl,4,2]dioxazina
n-2-ylmethyl)-benzamide (Compound H-l)
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-eth
oxyamino)-methyl]-benzamide (100 mg, 0.185 mmol) obtained in Example 6,
N,N'-disuccinimidyl carbonate (59 mg, 0.231 mmol) andNEt3 (113 mg, 1.12 mmol) were stirred
in a mixed solvent of CHiC^/THF (1 mL/1 mL) at room temperature for 10 hours. The
reaction mixture was purified by silica gel column chromatography (CtbCk/MeOH as a
developing solvent) to give the title compound (12.5 mg).
'H-NMR^MSO-de, 400MHz) 8(PPM) 3.54(2H, br), 3.82(2H, br), 4.16(2H, t, J=4.4), 4.42(2H, t,
J=4.4Hz), 4.76(2H+1H, s+br), 6.65(1H, m), 7.35(1H, d, J=8.3Hz), 7.40(1H, d, J=6.3Hz),
7.56(1H, d, J=10.8Hz), 8.68(1H, br), 11.88(1H, br)
ESI(LC/MS positive mode) m/z 568 (M+H)
[Example 55]
190
2-(4-Ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-(3-oxo-[l,4,2]dioxazi
nan-2-ylmethyl)-benzamide (Compound H-2)
H0>
The title compound was synthesized by a similar procedure to that in Example 3 8 from
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(3-oxo-[l,4,2]dioxazinan
-2-ylmethyl)-benzamide obtained in Example 54.
'H-NMRXDMSO-de, 400MHz) 8(PPM) 3.54(2H, br), 3.83(2H, br), 4.09(1H, br), 4.17(2H, br),
4.42(2H, br), 4.72(1H, br), 4.78(2H, br), 6.77(1H, br), 7.14(1H, d, J=6.8Hz), 7.31(1H, d,
J=11.8Hz), 7.42(1H, d, J=6.4Hz), 8.78(1H, br), 11.87(1H, br)
ESI(LC/MS positive mode) m/z 466 (M+H)
[Example 56]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5- {[methoxy-(2-methoxyacetyl)-
amino]-methyl}-benzamide (Compound F-6)
To a solution of methoxyacetic acid (9.0 pi, 0.12 mmol) in methylene chloride (1 ml)
were added 3-hydroxy-4-oxo-354-dihydro-l,2,3-benzotriazine (18.9 mg, 0.12 mmol) and
l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (22.5 mg, 0.12 mmol), and the
mixture was stirred for 3 hours. This solution was added dropwise to a solution of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(methoxyamino-methyl)-
benzamide (50.0 mg, 0.10 mmol) obtained in Example 15 in THF (3 ml), and triethylamine (40.9
ul, 0.29 mmol) was added thereto. The mixture was stirred for 15 hours. The reaction
191
mixture was diluted with ethyl acetate (45 ml), and washed with saturated aqueous ammonium
chloride (20 ml), and then with saturated brine (2x 20 ml). The organic layer was dried over
anhydrous magnesium sulfate, and concentrated under reduced pressure. The resultant residue
was purified by preparative TLC (CH2Cl2/MeOH (10:1)) to give
3 ,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5 - { [methoxy-(2-methoxy-a
cetyl)-amino] -methyl} -benzamide (Compound F-6, 19.1 mg, 34%) as a colorless oil.
, 270MHz) 8(PPM) 3.44 (3H, s), 3.67-3.73 (2H, m), 3.76 (3H, s), 3.89-3.95
(2H, m), 4.30 (2H, s), 4.90 (2H, s), 6.61 (1H, dt, J = 4.3, 8.6 Hz), 7.34 (1H, ddd, J = 1.1, 1.9, 8.6
Hz), 7.37-7.43 (1H, m),7.44 (1H, dd, J = 1.9, 10.8 Hz).
ESI(LC/MS positive mode) m/z 584 (M+H)
[Example 57]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-{[(2-hydroxy-acetyl)-methoxy-amino]-methyl}
-N-(2-hydroxy-ethoxy)-benzamide (Compound F-5)
To a solution of acetoxyacetic acid (13.9 mg, 0.12 mmol) in methylene chloride (1 ml)
were added 3-hydroxy-4-oxo-3,4-dihydro-l,2,3-benzotriazine (18.9 mg, 0.12 mmol) and
l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (22.5 mg, 0.12 mmol), and the
mixture was stirred for 3 hours. This solution was added dropwise to a solution of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(methoxyamino-methyl)-
benzamide (50.0 mg, 0.10 mmol) obtained in Example 15 in THF (2 ml), and triethylamine (40.9
ul, 0.29 mmol) was added thereto. The mixture was stirred for 24 hours. The reaction
mixture was diluted with ethyl acetate (45 ml), and washed with saturated aqueous ammonium
chloride (20 ml), and then with saturated brine (2x 20 ml). The organic layer was dried over
anhydrous magnesium sulfate, and concentrated under reduced pressure. The resultant residue
was roughly purified by preparative TLC (CH2Cl2/MeOH (10:1)) to give
{[2,3-difluoro-4-(2-fluoro-4-iodo-phenylamino)-5-(2-hydroxy-ethoxycarbamoyl)-be
nzyl]-metho
xy-carbamoyl}acetic acid methyl ester (14.0 mg, containing impurities) as a colorless oil. To asolution of the resultant
{[2,3-difluoro-4-(2-fluoro-4-iodo-phenylamino)-5-(2-hydroxy-ethoxycarbamoyl)-ben2yl]-metho
xy-carbamoyl}acetic acid methyl ester (14.0 mg, containing impurities) in methanol (1 ml) was
added sodium methoxide (3.0 mg, 0.06 mmol), and the mixture was stirred for 2 hours. The
reaction mixture was diluted with saturated ammoniuni chloride, and extracted with methylene
chloride (30 ml and 15 ml). The organic layer was dried over anhydrous magnesium sulfate,
and concentrated under reduced pressure. The resultant residue was purified by preparative
TLC (CH2Cl2/MeOH (10:1)) to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-{[(2-hydroxy-acetyl)-methoxy-amino]-niethyl}-
N-(2-hydroxy-ethoxy)-benzamide (F-5, 5.8 mg, 12% for 2 steps) as a colorless oil.
1H-NMR(CD30D> 270MHz) 8(PPM) 3.70 (2H, t, J - 4.6 Hz), 3.75 (3H, s), 3.92 (2H, t, J = 4.6
Hz), 4.36 (2H, s), 4.90 (2H, s), 6.61 (1H, dt, J = 4.3, 8.9 Hz), 7.31-7.37 (1H, m),7.37-7.43 (1H,
m),7.44 (1H, dd, J = 1.9,10.8 Hz).
ESI(LC/MS positive mode) m/z 570 (M+H)
[Example 58]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(isobutvryl-methoxy-a
mino)-methyl]-benzamide (Compound F-4)
HO,
The title compound was prepared by a procedure similar to that in Example 41.
Namely,
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(methoxyamino-methyl)-
benzamide obtained in Example 15 was reacted with 4-oxo-4H-benzo[d][l,2,3]triazin-3-yl
isobutyrate prepared from isobutyric acid to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylarnino)-N-(2-hydroxy-ethoxy)-5-[(isobutyryl-methoxy-am
ino)-methyl]-benzamide (88.9 mg, 77%).
-de, 270MHz) 8(PPM) 1.04(6H, d, J=6.8Hz), 2.95(1H, m), 3.00(3H, s), 3.54(2H,
193
m), 3.80(2H, m), 4.75(1H, br.s), 4.85(2H, s), 6.63(1H, td, J=8.6, 3.8Hz), 7.30(1H, br.d, J=6.8Hz),
7.36(1H, d, J=8.4Hz), 7.58(1H, dd, J=10.9,1.8Hz), 8.53(1H, br.s)
ESI(LC/MS positive mode) m/z 582(M+H)
[Example 59]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(methoxy-propionyl-a
mino)-methyl]-benzamide (Compound F-3)
The title compound was prepared by a procedure similar to that in Example 41.
Namely,
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(methoxyamino-methyl)-
benzamide obtained in Example 15 was reacted with 4-oxo-4H-benzo[d][l,2,3]triazin-3-yl
propionate prepared from propionic acid to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(methoxy-propionyl-am
ino)-methyl] -benzamide (35.0 mg, 31%).
-de, 270MHz) 6(PPM) 1.02(3H, t, J=7.5Hz), 2.45(2H, q, J=7.5Hz), 3.31(3H, s),
3.54(2H, t, J=4.8Hz), 3.81(2H, t, J=4.8Hz), 4.83(2H, s), 6.64(1H, td, J=8.7, 4.3Hz), 7.32(1H,
br.s), 7.36(1H, br.d, J=8.4Hz), 7.57(1H, dd, J=10.9, l.SHz), 8.62(1H, br.s)
ESI(LC/MS positive mode) m/z 568(M+H)
[Example 60]
5-[(Acetyl-ethoxy-amino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxyethoxy)-
benzamide (Compound F-10)
194
The title compound was prepared by a procedure similar to that in Example 41.
Namely,
5-(ethoxyamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylammo)-N-(2-hydroxy-ethoxy)-b
enzamide obtained in Example 17 was reacted with 4-oxo-4H-benzo[d][l,2,3]triazin-3-yl acetate
prepared from acetic acid to give
5-[(acetyl-ethoxy-amino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-e
thoxy)-benzarnide (19.3 mg, 71%).
16, 270MHz) 8(PPM) 1.15(3H, t, J=6.9Hz), 2.10(3H, s), 3.31(3H, s), 3.55(2H,
m), 3.82(2H, m), 3.94(2H, q, J=6.9Hz), 4.71(1H, br.s), 4.81(2H, s), 6.64(1H, m), 7.34(1H, m),
7.36(1H, m), 7.58(1H, d, J=9.7Hz), 8.53(1H, br.s), 11.84(1H, br.s)
ESI(LC/MS positive mode) m/z 568(M+H)
[Example 61]
5-[(Ethoxy-propionyl-amino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydro
xy-ethoxy)-benzamide (Compound F-ll)
The title compound was prepared by a procedure similar to that in Example 41 .
Namely,
5-(ethoxyamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-b
enzamide obtained in Example 17 was reacted with 4-oxo-4H-benzo[d][l,2,3]triazin-3-yl
propionate prepared from propionic acid to give
5-[(ethoxy-propionyl-amino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydro
xy-ethoxy)-benzamide (17.0 mg, 61%).
, 270MHz) 5(PPM) 1.12(3H, t, JM7.4Hz), 1.24(3H, t, J=7.1Hz), 2.53(2H, q,
J=7.4Hz), 3.67(2H, m), 3.92(2H, m), 3.99(2H, q, J=7.1Hz), 4.89(2H, s), 6.61(1H, td, J=8.7,
4.3Hz), 7.34(1H, m), 7.38(1H, m), 7.44(1H, dd, J=10.7, 2.0 Hz)
ESI(LC/MS positive mode) m/z 582(M+H)
195
[Example 62]
2-(4-Ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5 - [(isobutyryl-methoxy
-amino)-methyl]-benzamide (Compound F-9)
Dichlorobis(triphenylphosphine)-palladium (Aldrich, 4 mg, 0.006 mmol), copper iodide
(2.2 mg, 0.012 mmol), and N,N-diisopropylethylamine (30 |^L, 0.175 mmol) were added to a
solution of
5-[(acetyl-methoxy-amino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy
-ethoxy)-benzamide (67.78 mg, 0.117 mmol) obtained in Example 58 in tetrahydrofuran
(anhydrous, 2.0 mL) under a nitrogen atmosphere. The mixture was stirred thoroughly. After
a homogenous solution was obtained, trimethylsilylacetylene (65 uL, 0.466 mmol) was added to
the solution, which was stirred at room temperature for a whole day and night.
After completion of the reaction, the solvent was evaporated under reduced pressure,
and the yellowish brown oily residue was extracted with ethyl acetate. The organic layer was
washed sequentially with 2% aqueous EDTA, water, and saturated brine, dried over anhydrous
sodium sulfate, and concentrated under reduced pressure. The resultant residue was purified by
silica gel flash chromatography (Mega Bond Elut, Varian, 5% methanol/methylene chloride as an
eluent). The resultant
5-[(acetyl-memoxy-amino)-memyl]-3,4-difluoro-2-(2-fluoro-4-trimethylsilanylethynyl-phenyla
mino)-N-(2-hydroxy-ethoxy)-benzamide was dissolved in tetrahydrofuran (anhydrous, 2.0 mL),
and tetra-n-butylammonium fluoride (1 mol/L solution in tetrahydrofuran, 150 uL, 0.150 mmol)was added thereto. The mixture was stirred for 1 day. After completion of the reaction, the
solvent was evaporated under reduced pressure, and the yellowish brown oily residue was
extracted with ethyl acetate. The organic layer was washed sequentially with diluted (1%)
hydrochloric acid, water, and saturated brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The resultant residue was purified by silica gel flash
chromatography (Mega Bond Elut, Varian, ethyl acetate as an eluent) to give a yellow solid,
which was triturated with 10% ethyl acetate/hexane to give a pale yellow solid (23.6 mg, 42% in
2 steps).
196
, 270MHz) 6(PPM) 1.12(6H, d, J=6.8Hz), 3.06(1H, quin., J=6.8Hz), 3.42(1H,
s), 3.68(2H, m), 3.78(3H, s), 3.91(2H, m), 4.91(2H, s), 6.73(1H, td, J=8.7,4.5Hz), 7.14(1H, br.d,
J=9.2Hz), 7.19(1H, dd, J=11.9, l.SHz), 7.39(1H, m)
ESI(LC/MS positive mode) m/z 480(M+H)
[Example 63]
2-(4-Ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5 - [(methoxy-propionylamino)-
methyl]-benzamide (Compound F-8)
The title compound was synthesized in 2 steps by a procedure similar to that in Example
62 from
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(methoxy-propionyl-am
ino)-methyl]-benzamide obtained in Example 59. 6.9 mg (35% in 2 steps).
, 270MHz) 5(PPM) 1.12(3H, t, J=7.4Hz), 2.54(1H, q, J=7.4Hz), 3.42(1H, s),
3.70(2H, m), 3.76(3H, s), 3.91(2H, m), 4.90(2H, s), 6.73(1H, td, J=8.6, 4.6Hz), 7.14(1H, br.d,
J=9.1Hz), 7.19(1H, dd, J=11.9, l.SHz), 7.39(1H, br.d, J=5.4Hz)
ESI(LC/MS positive mode) m/z 466(M+H)
[Example 64]
5-[(Acetyl-methoxy-amino)-methyl]-2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydr
oxy-ethoxy)-benzamide (Compound F-7)
197
The title compound was synthesized in 2 steps by a procedure similar to that in Example
62 from
5-[(acetyl-methoxy-amino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy
-ethoxy)-benzamide obtained in Example 46. 191.67 mg (79% in 2 steps).
'H-NMR^OD, 270MHz) S(PPM) 2.18(3H, s), 3.42(1H, s), 3.68(2H, m), 3.77(3H, s),
3.92(2H, m), 4.90(2H, s), 6.74(1H5 td, J=8.6,4.3Hz), 7.13(1H, br.d, J=9.1Hz), 7.19(1H, dd,
J=11.9, l.SHz), 7.40(1H, br.d, J=6.4Hz)
ESI(LC/MS positive mode) m/z 452(M+H)
[Example 65]
5-[(Ethoxy-propionyl-amino)-methyl]-2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hy
droxy-ethoxy)-benzamide (Compound F-24)
The title compound was synthesized in 2 steps by a procedure similar to that in Example
62 from
5-[(ethoxy-propionyl-amino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2 -hydro
xy-ethoxy)-benzamide obtained in Example 61 . 3.5 mg (45% in 2 steps).
, 270MHz) 8(PPM) 1.11(3H, t, J=7.4Hz), 1.22(3H, t, J=7.1Hz), 2.53(2H, q,
J=7.4Hz), 3.39(1H, s), 3.69(2H, m), 3.94(2H, m), 3.97(2H, q, J=7.4Hz), 4.90(2H, s), 6.69(1H, td,
J=8.6, 5.4Hz), 7.12(1H, br.d, J=8.7Hz), 7.17(1H, dd, J=12.0, l.SHz) , 7.50(1H, br.d, J=5.8 Hz)
ESI(LC/MS positive mode) m/z 480(M+H)
[Example 66]
5-[(Acetyl-ethoxy-amino)-methyl]-2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydro
xy-ethoxy)-benzamide (Compound F-23)
198
The title compound was synthesized in 2 steps by a procedure similar to that hi Example
62 from
5-[(acetyl-ethoxy-amino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-e
thoxy)-benzamide obtained in Example 60. 1.8 mg (22%).
, 270MHz) 8(PPM) 1.25(3H, t, J=7.1Hz), 2.18(3H, s), 3.43(1H, s), 3.63(2H, m),
3.68(2H, m), 4.01(2H, q, J=7.1Hz), 4.90(2H, s), 6.74(1H, td, J=8.6, 4.5Hz), 7.14(1H, br.d,
J=8.2Hz), 7.20(1H, dd, J=11.9, l.SHz) , 7.40(1H, m)
ESI(LC/MS positive mode) m/z 466(M+H)
[Example 67]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylammo)-5-[(foraiyl-methoxy-amino)-methyl]-N-(2 -hydro
xy-ethoxy)-benzamide (Compound F-l)
Ethyl formate (0.2 mL) was added to
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(methoxyammo-methyl)-
benzamide (Compound C-24, 50 mg, 0.0978 mmol) obtained in Example 15, and the mixture
was heated to reflux at 80°C for 1 hour.After completion of the reaction, the reaction mixture was concentrated under reduced
pressure. The resultant white solid was fractionated by TLC (No. 5715, Merck, 5%
methanol/methylene chloride as a developing solvent), and the resultant white solid was further
triturated with 10% methylene chloride/hexane to give
199
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-[(formyl-methoxy-amino)-methyl]-N-(2-hydrox
y-ethoxy)-benzamide (Compound F-l, 18.2 mg, 35%) as a white solid.
-de, 400MHz, at 80°C) 5(PPM) 3.55(2H, dd, J=5.4, 4.9Hz), 3.69(3H, s),
3.84(2H, dd, J=5.4, 4.9Hz), 4.77(2H, s), 6.65(1H, td, J=8.9, 3.9Hz), 7.35(1H, d, J=8.3Hz),
7.45(1H, d, J=7.3Hz), 7.51(1H, dd, J=11.0, 2.0Hz), 8.35(1H, br.s)
ESI(LC/MS positive mode) m/z 540(M+H)
[Example 68]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylammo)-N-(2-hydroxy-ethoxy)-5-(2-oxo-pyrrolidin-l-ylm
ethyl)-benzamide (Compound H-3)
Methyl 4-amino-butyrate hydrochloride (commercially available, 48 mg, 0.312 mmol)
and sodium cyanoborohydride (20 mg, 0.312 mmol) were added to a solution of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide(50
mg, 0.104 mmol) obtained in Step F of Example 1 in methanol (2.0 mL). The mixture was
stirred at room temperature for 18 hours. Then, the reaction vessel was equipped with a reflux
condenser, and the mixture was heated at 80°C for 2 hours. After completion of the reaction,
the reaction mixture was extracted with ethyl acetate, and the organic layer was washed
sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The resultant residue was purified by silica gel flash
chromatography (Mega Bond Elut, Varian, 5% methanol/methylene chloride as an eluent) to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-oxo-pyrrolidin-l-yhn
ethyl)-benzamide (Compound H-3,26.8 mg, 47%) as a white solid.
), 270MHz) 8(PPM) 2.06(2H, m), 2.43(2H, dd, J=8.4, 7.7Hz), 3.44(2H, dd,
J=7.1, 6.9Hz), 3.70(2H, dd, J=4.8, 4.5Hz), 3.93(2H, dd, J=4.9, 4.0Hz), 4.53(2H, s), 6.62(1H, td,
J=8.7,4.3Hz), 7.32(1H, m), 7.35(1H, m), 7.45(1 H, dd, J=10.7, 2.0Hz)
ESI(LC/MS positive mode) m/z 550(M+H)
[Example 69]3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-oxo-piperidin-l-ylmethyl)-benzamide (Compound H-4)Methyl 5-amino-pentanoate hydrochloride {see J. Org. Chem. (1968) 1581} (128 mg,
0.178 mmol) and sodium cyanoborohydride (45 mg, 0.718 mmol) were added to a solution of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide (115
mg, 0.239 mmol) obtained in Step F of Example 1 in tetrahydrofuran (anhydrous, 4.0 mL). The
mixture was stirred at room temperature for 1 .5 hours. Then, the reaction vessel was equipped
with a reflux condenser, and the mixture was heated at 60°C for 2 days. After completion of
the reaction, the reaction mixture was extracted with ethyl acetate, and the organic layer was
washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The resultant residue was purified by silica gel flash
chromatography (Mega Bond Elut, Varian, 4% methanol/methylene chloride as an eluent) to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-oxo-piperidin-l-ylmet
hyl)-benzamide (Compound H-4, 42.7 mg, 37%) as a white solid.
, 270MHz) 8(PPM) 1.85(4H, m), 2.42(2H, m), 3.40(2H, m) 3.70(2H, dd, J=4.9,
4.3Hz), 3.92(2H, dd, J=4.9, 4.3Hz), 4.65(2H, s), 6.56(1H, td, J=8.9, 4.3Hz), 7.34(1H, m),
7.35(1H, m) , 7.45(1H, dd, J=10.7, 2.0Hz)
ESI(LC/MS positive mode) m/z 564(M+H)
[Example 70]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-[(2-hydroxy-acetylamino)-methyl]-N-(2-hydro
xy-ethoxy)-benzamide (Compound E-5)
Step A
Synthesis of 5-aminomethyl-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid
trifluoroacetate
tert-Butyl carbamate (commercially available, 187 mg, 1.602 mmol), trifluoroacetic acid
(123 uL, 1.602 mmol), and triethylsilane (255 uL, 1.602 mmol) were added sequentially to a
suspension of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-benzoic acid (225 mg,
0.534 mmol) obtained in Step A of Example 5 in acetonitrile (anhydrous, 20 mL). The mixture
was stirred at room temperature for 5 days. After completion of the reaction, the reaction
mixture was evaporated under reduced pressure, and the resultant residue was extracted with
ethyl acetate. The organic layer was washed sequentially with water and saturated brine, dried
over anhydrous sodium sulfate, and evaporated under reduced pressure. The resultant crude
product was purified by silica gel flash chromatography (Mega Bond Elut, Varian, 5%
methanol/methylene chloride as an eluent) to give
5-(tert-butoxycarbonylamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic
acid. [LC/MS m/z 523(M+1)]. Then, trifluoroacetic acid (0.5 mL) was added to a solution of
the resultant product in methylene chloride (20 mL), and the mixture was stirred at room
temperature for 14 hours. After completion of the reaction, the reaction mixture was
evaporated under reduced pressure, and the resultant residue was recrystallized from a mixed
solvent of diethyl ether:hexane (1:1) to give
5-aminomethyl-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid trifluoroacetate (285
mg, 99% in 2 steps) as white crystals.
1H-NMRCCD3OP, 270MHz) 5(PPM) 4.19(2H, s), 6.84(1H, td, J=8.6,4.8Hz), 7.44(1H, br.d,
J=10.1Hz), 7.51(1H, dd, J=10.4,2.0Hz), 8.06(1H, dd, J=7.8, l.SHz)
ESI(LC/MS positive mode) m/z 423(M+H)
StepB
Synthesis of
5-(acryloylamino-methyl)-N-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluor
o-4-iodo-phenylamino)-benzamide
202
Acryloyl chloride (100 uL, 0.986 mmol) and triethylamine (689 uL, 4.93 mmol) were
added to a solution of hydroxy-pyrrolidine-2,5-dione (commercially available, 227 mg, 1.973
mmol) in methylene chloride (anhydrous, 2 mL), and the mixture was stirred at room
temperature for 30 minutes.
5-aminomethyl-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid (150 mg,
mmol) obtained in Step A was added to this solution, and the mixture was stirred for 1 hour.
After completion of the reaction, the reaction mixture was evaporated under reduced pressure,
and the resultant residue was extracted with ethyl acetate. The organic layer was washed
sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure to give
5-(acryloylamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid as a white
solid. This product was confirmed for the structure by LC/MS. LC/MS (positive mode) m/z
477(M+1). This compound was dissolved in methylene chloride (anhydrous, 10 mL) under
argon flow. N,N-diisopropylethylamine (250 uL, 1.42 mmol),
O-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-hydroxylamine (135 mg, 0.71 mmol),
1-hydroxy-lH-benzotriazole (71mg, 0.533 mmol), and
(3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (102 mg, 0.533 mmol) were added
sequentially to the solution. The mixture was stirred at room temperature for 20 hours.
After completion of the reaction, the reaction mixture was evaporated under reduced
pressure, and the resultant residue was extracted with ethyl acetate. The organic layer was
washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and
evaporated under reduced pressure. The resultant crude product was purified by silica gel flash
chromatography (Mega Bond Elut, Varian, 40% ethyl acetate/hexane as an eluent) and
preparative TLC (No. 5744, Merck, 40% ethyl acetate/hexane as a developing solvent) to give
5-(acryloylamino-methyl)-N-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluor
o-4-iodo-phenylamino)-benzamide (7.4 mg, 3%) as a waxy solid.
!H-NMR(CDCl3, 270MHz) 8(PPM) 0.07(6H, s), 0.09(9H, s), 3.89(2H, m), 4.07(2H, m), 4.51(2H,
d, J=6.1Hz), 5.71(2H, dd, J=10.1, 1.5Hz), 6.12(1H, dd, J=17.0Hz, 10.2Hz), 6.20(1H, br.s),
6.33(1H, dd, J=17.0,1.5Hz), 6.56(1H, td, J=8.7, 5.3Hz), 7.30(1H, dt, J=8.6, 3.0Hz), 7.38(1H, dd,
203
J=10.2,2.0Hz), 7.40(1H, m), 8.57(1H, br.s)
ESI(LC/MS positive mode) m/z 650(M+H)
StepC
Synthesis of
N-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-[(
2-hydroxy-acetylamino)-methyl]-benzamide
Aqueous osmium tetroxide (4%, 0.1 mL) and sodium metaperiodate (12 mg, 0.056
mmol) were added to a solution of
5-(aciyloylamino-methyl)-N-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluor
o-4-iodo-phenylamino)-benzamide (7.3 mg, 0.011 mmol) obtained in Step B in tetrahydrofuran
(4 mL) and water (1 mL). The mixture was stirred for 3 hours. After the disappearance of the
starting material was confirmed by LC/MS, the reaction mixture was extracted with ethyl acetate.The organic layer was washed sequentially with water and saturated brine, dried over anhydrous
sodium sulfate, and concentrated under reduced pressure to give
N-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-[(
2-oxo-acetylamino)-methyl]-benzamide. Subsequently, this was dissolved in methanol (2.0
mL). Sodium borohydride (3 mg, 0.079 mmol) was added to this solution at room temperature,
and the mixture was stirred for 1 hour. After completion of the reaction, the reaction mixture
was extracted with ethyl acetate, and the organic layer was washed sequentially with water and
saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure.
The resultant crude product was purified by silica gel flash chromatography (Mega Bond Elut,
Varian, 60% ethyl acetate/hexane as an eluent) to give
N-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-[(
2-hydroxy-acetylamino)-methyl]-benzamide (4.34 mg, 60% in 2 steps) as a pale yellow solid.
ESI(LC/MS positive mode) m/z 654(M+H)
StepD
Synthesis of
204
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-[(2-hydroxy-acetylainino)-methyl]-N-(2-hydrox
y-ethoxy)-benzamide (Compound E-5)
Tetra-n-butylammonium fluoride (1 mol/L solution in tetrahydrofuran, 0.5 mL, 0.500
mmol) was added to a solution of
N-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3s4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-[(
2-hydroxy-acetylamino)-methyl]-benzamide (4.34 mg, 0.00665 mmol) obtained in Step C in
tetrahydrofuran (anhydrous, 1 mL) at room temperature. The mixture was stirred for 1 .5 hours.
After completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the
organic layer was washed sequentially with water and saturated brine, dried over anhydrous
sodium sulfate, and evaporated under reduced pressure. The resultant crude product was
purified sequentially with silica gel flash chromatography (Mega Bond Elut, Varian, 5%
methanol/methylene chloride as an eluent) and preparative TLC (No. 5715, Merck, 7%
methanol/methylene chloride as a developing solvent) to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-[(2-hydroxy-acetylamino)-methyl]-N-(2-hydrox
y-ethoxy)-benzamide (Compound E-5, 1.4 mg, 39%) as a white solid.
, 270MHz) 8(PPM) 3.71(2H, dd, J=7.4, 4.7Hz), 3.94(2H, dd, J=7.4, 4.7Hz),
4.03(2H, s), 4.50(2H, s), 6.55(1H, td, J=8.6, 5.3Hz), 7.32(1H, m), 7.42(1H, dd, J=10.7, l.SHz),
7.45(lH,dd,J=5.8,2.1Hz)
ESI(LC/MS positive mode) m/z 540(M+H)
[Example 71]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-oxo-tetrahyo^o-pyrim
idin-l-ylmethyl)-benzamide (Compound H-6)
Step A
Synthesis of
5-[(3-amino-propylamino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy
-ethoxy)-benzamide
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzam
ide obtained in Step F of Example 1 was reacted with propane-1,3 -diamine in THF. The
thus-obtained imine was reduced with sodium borohydride in methanol to give the title
compound.
ESI(LC/MS positive mode) m/z 539 (M+H)
StepB
Synthesis of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-oxo-tetrahydro-pyrimi
din-l-ylmethyl)-benzamide (Compound H-6)
HO,
The amine synthesized in Step A (66.4 mg, 0.1233 mmol) was dissolved in THF:CH3CN
(1:1 v/v, 3.0 ml). N,N-disuccinimidyl carbonate (47.4 mg, 1.5 eq., 0.1849 mmol) and
triethylamine (103.1 ul, 6.0 eq., 0.7398 mmol) were added sequentially to this solution, and the
mixture was stirred at room temperature for 20 hours. The solvent was removed under reduced
pressure, and the residue was purified by LC/MS to give white crystals (42.6 mg).
-de, 400MHz) 6(PPM) 1.83(2H, t, J=5.2Hz), 3.14(2H, t, J=5.6Hz), 3.23(2H, t,
J=5.6Hz), 3.51-3.58(2H, m), 3.82(2H, brt), 4.49(2H, s), 6.41(1H, brs), 6.6K1H, dt, J=3.9, 8.3Hz),
7.28(1H, d, J=6.4Hz), 7.34(1H, d, J=7.9Hz), 7.56(1H, d, J=10.8Hz) , 8.48(1H, s), 12.0(1H, s)
206
ESI(LC/MS positive mode) m/z 565 (M+H)
[Example 72]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-oxo-oxazolidin-3-yl
methyl)-benzamide (Compound H-5)
Step A
Synthesis of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-{[(E)-2-hydroxy-ethylim
ino] -methyl} -benzamide
The title compound was synthesized by reacting
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide
obtained in Step F of Example 1 with ethanolamine in THF.
, 400MHz) 5(PPM) 3.72-3.74(4H, m), 3.81-3.84(2H, m), 3.96-3.99(2H, m),
6.64-6.68(lH, m), 7.36(1H, d, J=8.79Hz), 7.43(1H, d, J=9.99Hz), 8.13(1H, d, J=5.6Hz), 8.50(1H,
s)
ESI(LC/MS positive mode) m/z 524 (M+H)
StepB
Synthesis of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethylamino)
-methyl] -benzamide
Sodium borohydride was added to a solution of the imine,
3 ,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5 - { [(E)-2-hydroxy-ethylim
ino]-methyl}-benzamide obtained in Step A in MeOH at 0°C. While being allowed to warm
gradually, the mixture was stirred overnight. The solvent was removed under reduced pressure,
and the residue was purified with a silica gel column (CFbCk'.MeOH (4:1 to 2:1)) to give the
title compound as a white solid.
, 400MHz) 6(PPM) 2.80(2H, t, J=5.38Hz), 3.69-3.72(4H, m), 3.92-3.95(4H,
m), 6.59(1H, dt, J=3.9, 8.3Hz), 7.34(1H, d, J=10.3Hz), 7.44(1H, dd, J=1.95, 10.3Hz), 7.49(1H, d,
J=7.3Hz)
ESI(LC/MS positive mode) m/z 526 (M+H)
Step B' (an alternative to Step B)
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-eth
ylamino)-methyl]-benzamide obtained in Step B can be prepared in 1 step by reductive
amination of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide
obtained in Step F of Example 1. Namely, 2-aminoethanol (0.070 ml), acetic acid (0.080 ml),
and sodium cyanoborohydride (44 mg) were added to a solution of an aldehyde,
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide (65.7
mg, 0.136 mmol) in methanol (2 ml) at room temperature. The mixture was stirred overnight.
Water (6 ml), saturated brine (3 ml), and aqueous sodium bicarbonate (2 ml) were added, and the
reaction mixture was extracted with ethyl acetate (2x 10 ml). The combined organic layers
were washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The residue was triturated with ethyl acetate/n-hexane
(2:1) to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethylamino)
-methylj-benzamide (60.4 mg, 84%) as a colorless solid.
StepC
208
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-oxo-oxazolidin-3-yl
methyl)-benzamide (Compound H-5)
Using
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethylamino)
-methyl]-benzamide obtained in Step B (or Step B') as a starting material, synthesis was
performed according to the procedure described in Step B of Example 27 to give
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-oxo-oxazolidin-3-yhn
ethyl)-benzamide (Compound H-5).
JH-NMR(DMSO-d6, 400MHz) 8(PPM) 3.49-3.59(4H, m), 3.83-3.85(2H, m), 4.28-4.32(2H, m),
4.42(2H, s), 6.87(1H, td, J=8.8, 3.9Hz), 7.36(1H, d,J=7.9Hz), 7.46(1H, d, J=8.4Hz), 7.57(1H, dd,
J=1.9,10.8Hz), 8.76(1H, s), 12.3(1H, s)
ESI(LC/MS positive mode) m/z 552 (M+H)
[Example 73]
5-(2,3-Dioxo-morpholin-4-ylmethyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydrox
y-ethoxy)-benzamide (Compound H-7)
4-Dimethylaminopyridine (12.1 mg) and dibenzotriazol-1-yl oxalate (9.2 mg, 27.4
(J,mol) were added to a solution of
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethylamino)
-methyl]-benzamide (15.9 mg, 30.2 umol) obtained in Step B (or Step B') of Example 72 in
anhydrous N,N-dimethylforrnamide (1.5 ml) at room temperature. The mixture was stirred at
room temperature for 2 hours. Water (6 ml) and 1 N hydrochloric acid (0.5 ml) were added,
and the reaction mixture was extracted with ethyl acetate (2x 10 ml). The combined organic
layers were washed with saturated brine (8 ml), dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The residue was purified with a preparative silica gel
plate (No. 5744, Merck, CH2Cl2/MeOH (10:1) as a developing solvent) to give
5-(2,3-dioxo-morpholin-4-ylmethyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydrox
y-ethoxy)-benzamide (Compound H-7, 1.0 mg, 6% yield).
-de, 270MHz) 8(PPM) 3.57 (2H,br.s), 3.70 (2H5 t, J = 6.1 Hz), 3.86 (2H, t, J =
4.9 Hz), 4.55 (2H, t, J = 5.4 Hz), 4.66 (2H, s), 6.67 (IH, td, J = J = 8.4, 4.3 Hz), 7.32 - 7.40 (2H,
m), 7.59 (IH, dd, J = 10.8, 1.4 Hz).
ESI(LC/MS positive mode) m/z 580(M+H)
[Example 74]
5-{[Acetyl-(2-hydroxy-ethyl)-amino]-methyl}-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamuio)-N-
(2-hydroxy-ethoxy)-benzamide (Compound E-6)
Using
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethylamino)
-methyl]-benzamide obtained in Step B (or Step B') of Example 72 as a starting material,
synthesis was performed according to the procedure described in Example 41 to give
5- {[acetyl-(2-hydroxy-ethyl)-arnino] -methyl} -3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(
2-hydroxy-ethoxy)-benzamide (Compound E-6).
'H-NMRtDMSO-de, 270MHz) 6(PPM) 2.07 (3H x 1/3, s), 2.12 (3H x 2/3, s), 3.47 - 3.56 (4H, m),
3.83 (2H, t, J = 4.5 Hz), 4.58 (2H x 2/3, s), 4.69 (2H x 1/3, s), 6.61 (1H, td, J = 8.9,4.3 Hz), 7.24
(1H, d, J = 7.4 Hz), 7.35 (1H, d, J = 8.6 Hz), 7.57 (1H, d, J = 7.6 Hz),
ESI(LC/MS positive mode) m/z 568(M+H)
[Test Example 1]
[Measurement of MEK inhibitory activity]
MEK inhibitory activities were measured for Compounds B-l, B-2, B-6, B-9, B-12, C-l,
C-6, C-7, C-8, C-10, C-13, C-24, C-28, C-31, F-l, F-2, F-3, F-4, F-5, F-6, F-7, F-8, F-9, G-l,
G-2, G-3, G-4, and G-5 obtained in the Examples, and the following known compounds, P
(W002/06213, Example 9), Q (WO02/06213, Example 39), and R (WO99/01426,
Compound P was prepared according to the description (Example 9) of WO02/06213.
Compound Q was prepared according to the description (Example 39) of WO02/06213.
Compound R was prepared according to the description (Example 95) of WO99/01426.
For the measurement of MEK inhibitory activities, an assay system was constructed
that phosphorylation of MBP (Myelin Basic Protein) could occur in proportion to the MEK
kinase activity, with adjusting the amount of the enzyme and the like, according to the method of
Raf-1 Kinase Cascade Assay Kit (cat. 17-172, Upstate Biotechnology Inc., New York, USA).
[y33?] ATP (Amersham Biosciences) was used as a radioisotope.
The amount of the 33P-labelled MBP was measured using Microbeta 1450 (PerkinElmer
Inc., Massachusetts, USA), and 50% inhibitory concentration (IC50) was calculated.
Results are shown in Table 2.
[Test Example 2]
[Measurement of growth inhibitory activity against cancer cells]
Growth inhibitory activities against cancer cells based on MEK inhibitory activities
were measured for Compounds B-1, B-2, B-6, B-9, B-12, C-1, C-6, C-7, C-8, C-10, C-13, C-24,
C-28, C-31, F-l, F-2, F-3, F-4, F-5, F-6, F-7, F-8, F-9, G-l, G-2, G-3, G-4, and G-5 obtained in
the Examples, and the known compounds, P, Q, and R shown above.
The growth inhibitory activities against cancer cells were measured using Cell Counting
Kit-8 (Dojindo Laboratories).
Human colon cancer cell line HT-29 obtained from American Type Culture Collection
(Virginia, USA) and human non-small cell lung carcinoma cell line QG56 obtained from
Immuno-Biological Laboratories Co., Ltd. were plated onto 96-well culture plate at a density of
2000 cells/well, a designated concentration of MEK inhibitor was added, and the cells were
incubated for 4 days.
On the 4th day of culture, a solution of Cell Counting Kit-8 was added, and absorbance
(measurement wavelength: 450 nm; reference wavelength: 615 nm) was measured according to
the protocol attached to the kit, and 50% inhibitory concentration (IC50) was calculated.
Results are shown in Table 2.
[Test Example 3]
[Measurement of stability against mouse liver microsome]
A variety of metabolic enzymes exist in the liver, and play a key role in the foreign
substance detoxication. Many enzymes involved in drug metabolism (e.g., cytochrome P450)
are localized in the endoplasmic reticulum in the cells, and are collected in the microsome
fraction during preparation from the cells. The stability in liver microsome is used universally
as a simple measure for evaluation of drug metabolism.
There is a correlation between in vitro intrinsic clearance calculated from the stability in
human liver microsome and human in vivo clearance (Ito K. et al. Annu. Rev. Pharmacol.
Toxicol. 1998, 38: 461-99, Naritomi Y. et al. Drug Metab. Dispos. 2001,29:1316-24, YuichiSugiyama et al., Pharmacokinetics - Understanding by exercises, Nanzando).
Clearance is an important parameter that determines a blood concentration. The better
the drug stability in liver microsome is, the smaller the clearance is and the higher the blood
concentration is. A drug having a good stability in liver microsome can achieve a certain blood
concentration with a lower dose, compared to a drug having a poor stability.
Compounds B-l, B-2, B-6, B-9, B-12, C-l, C-2, C-6, C-7, C-10, C-24, C-28, C-29,
C-31, C-34, C-35, F-l, F-2, F-5, F-7, G-l, G-2, G-3, G-4, and G-5 obtained in the Examples, and
the known compounds, P, Q, and R shown above were incubated with mouse liver microsome (1
mg protein/mL) in 50 mM phosphate buffer (pH 7.4) containing 5 mM MgCb and 2 mM
NADPH (the reduced form of nicotinamide adenine dinucleotide phosphate) at 37°C for 1 hour.
After the enzyme reaction was terminated with the addition of a three-fold volume of acetonitrile,
the reaction mixture was centrifuged at 1500 rpm for 10 minutes, and the resultant supernatant
was used as a test sample to measure the stability in human liver microsome by quantitating the
compound in the sample using FIPLC/MS.
Table 3 shows the stability of the test compounds in mouse liver microsome. When a
test compound has a longer half-life, the compound is metabolically very stable, and can produce
a high blood concentration.
[Test Example 4]
[Measurement of water solubility]
Biopharmaceutical Classification System (BCS) is widely used to scientifically classify
oral formulations in regard to membrane permeability and solubility. Drugs having good
membrane permeability and good solubility are classified into Class 1, and guaranteed that they
are absorbed almost perfectly after oral administration, and that the variability among individuals
is small (Lenneras H. et al. J. Pharm. Pharmacol. 2005, 57: 273-85, KasimNAef al. Mol.
Pharmaceutics 2004,1: 85-96).
Excessive amount of each of Compounds B-l, B-2, B-6, B-9, B-12, C-l, C-2, C-6, C-
C-10, C-24, C-28, C-29, C-31, C-34, C-35, F-l, F-2, F-5, F-7, G-l, G-2, G-3, G-4, and G-5
obtained in the Examples, and the known compounds, P, Q, and R shown above was added to a
glass vessel, to which 50 mM phosphate buffer (pH 6.5) was added. The vessel was sealed,
sonicated at room temperature (20°C) for 10 minutes, and agitated on an agitator for 2 hours.
After dissolution equilibrium was achieved, the reaction mixture was filtered through a
membrane filter, and the solute concentration in the filtrate was determined by HPLC.
Results are shown in Table 3.
[Test Example 5]
[Measurement of tumor growth suppressive activity]
A mouse model carrying human cancer was used to measure tumor growth suppressive
activity of Compounds B-l, C-l, C-10, C-13, F-l, F-2, F-5, G-l, G-2, G-3, G-4, and H-
obtained in the Examples, and the known compound, Q shown above.
Human colon cancer cell line HT-29 (obtained from American Type Culture Collection)
was inoculated subcutaneously to BALB/c nu/nu mice. The test compound was dissolved in
the vehicle (10% Cremophor, 10% ethanol, and 80% distilled water for injection), and orally
given to the mice once a day for 14 consecutive days after the average tumor volume (0.5x long
diameter x short diameter2) reached to about 200 mm3. One day after the last administration,
the tumor volume was measured, and the tumor growth suppression rate, (1 - tumor volume
increase in the group received the test compound/tumor volume increase in the group received
the vehicle) x 100, of each of the test compounds was determined compared to the group
received the vehicle. The higher value (%) indicates the stronger tumor suppressive activity.
Results of the tumor growth suppression rate at maximum tolerance dose (MTD) are
shown in Table 4.
Table 4 shows very high tumor growth suppression rates of the compounds of this
invention, indicating that they have very strong effect of tumor regression, compared to control
compound Q, which has the tumor growth suppression rate of 66 - 82%.
[Test Example 6]
Anti-Type II collagen antibody-induced arthritis in mice]
Suppressive effects of compounds B-l and G-2 obtained in Examples on arthritis
development were determined using anti-Type II collagen antibody (anti-CII)-induced arthritis (J
Immunol. 2002 Aug 1; 169(3):1459-66).
Anti-CII (10 mg/mL of antibody cocktail for arthritis, code No. 62200, Chondrex) was
administered intravenously at 1 mg/body/100 jaL to BALB/c mice (female mice of 5 weeks old
were purchased from Charles River Japan, Inc., and used at 5 animals per group after 1 week
acclimation), and after 3 days, LPS (lipopolysaccharide) solution (0111:B4 250 p-g/mL, code No.
62200, Chondrex) was administered intraperitoneally at 25 j.ig/0.1 mL/body. The test
compounds were dissolved in the vehicle (10% Cremophor, 10% ethanol, and 80% distilled
water for injection), and orally administered 1 hour before, 1, 2,4-8, and 11 days after LPS
administration (once a day, 1 mg/kg).
Arthritis score was evaluated with the full score 4 points per limb, and 16 points per
animal. Score indicates as follows:
0.5: erythema is observed at 1 joint;
1: erythema is observed at 2 joints. Or reddening of the upper surface of the paws is observed,
but swelling is not observed;
2: Slight swelling is observed;
3: Moderate swelling is observed on the upper surface of the paws;
4: Severe swelling is observed on the upper surface of the paws and digits.
In the group received the vehicle, arthritis developed the day after LPS administration.
On the other hand, arthritis development was strongly suppressed in both groups received B-l
and G-2. Results of suppressive effect on arthritis development (arthritis score; mean +/-
214
standard deviation) are shown in Figure 1. Figure 1 shows that the present compounds are
effective anti-arthritis drugs.
Test Examples 1-3 described above were performed according to "Development of
Pharmaceuticals, Vol. 15, "Physicochemical property of formulation", edited by Koichiro
Miyajima, Professor of Kyoto University, pages 45 to 48", and Test Example 4 described above
was performed according to "2.2 Method for measuring solubility, 2.2.1 Equilibrium method, a.
Stirring method, Hirokawa Publishing Co."
Industrial Applicability
The compounds according to the present invention and the pharmaceutically acceptable
salts thereof have a MEK inhibitory effect, a cell growth inhibitory effect, are excellent hi
stability in vivo and solubility in water, and are useful as preventing agents or therapeutic agents
for proliferative diseases, e.g., cancers and joint diseases with inflammation.

CLAIMS
1. A compound represented by the following formula (1), or a pharmaceutically
acceptable salt thereof,
(Figure Removed)wherein
RI represents a halogen atom, an alkenyl group, or an alkynyl group;
R2 represents a halogen atom or an alkyl group; the alkyl group may be substituted by a hydroxyl
group;
Rs represents a hydrogen atom or a halogen atom;
R4 represents a hydrogen atom, an alkyl group, an alkenyl group, or an alkynyl group; the alkyl
group, the alkenyl group, and the alkynyl group may have one to three substituents selected from
the group consisting of -ORa, -NRaRb, -NRaCORb, a heterocyclic group, and a heteroaryl
group; the heterocyclic group and the heteroaryl group may have one to three substituents
selected from the group consisting of a C 1.5 alkyl group, -ORa, and -NRaRb;
X represents a group represented by the following formula (i);
(Figure Removed)Y represents -O-, -NR8O, -ONR8-, -NR8CO-, or -NR8SO2-;
Z represents an C\.g alkylene chain which may be substituted by one to three
groups represented by W;
where R8 represents a hydrogen atom, an alkyl group, -ORa, or
-CORg; and the alkyl group may be substituted by a halogen atom,
-ORa, or -NRaRb;
R9 represents a hydrogen atom, an alkyl group, or -ORa; and the alkyl
group may be substituted by a halogen atom, -ORa, or -NRaRb;
Rg and Rg may be linked to the alkylene chain of Z or form a
heterocyclic group through a linkage to the substituent represented by
RaorRbofW.)
or alternatively,
X represents a group represented by the following formula (ii):
in the above formulae (i) and (ii),
W and W, which may be the same or different, each represent a CM alkyl group, a
halogen atom, an oxo group, -ORa, -COORa, -COOCORa, -CO-halogen atom, -OCORa,
-CONRaRb, -SRa, -SORa, -SO2Ra, -NRaRb, -NRaCORb, -NRaSO2Rb, -SO2NRaRb, a
heterocyclic group, or a heteroaryl group; the heterocyclic group and the heteroaryl
group may have a substituent selected from the group consisting of a €1.5 alkyl group,
-ORa, and -NRaRb; the alkyl group may be substituted by a hydroxyl group, a CM
alkoxy group, or an amino group;
the above substituents except the oxo group and the halogen may be linked to each other
to form a cycloalkyl group or a heterocyclic group; the cycloalkyl group or the
heterocyclic group may have a substituent selected from the group consisting of, -ORa,
-NRaRb, and a CM alkyl group that may be substituted with -ORa;
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a
CM alkyl group; the alkyl group may be substituted by one to three groups selected
from the group consisting of a hydroxyl group, a CM alkoxy group, and an amino
group;
provided that, when X is the group represented by the above formula (i) and Y is not -O-,
W may be a hydrogen atom.
2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof,
wherein X represents the group -Y-Z-W of the formula (i) and Z represents a d.5 alkylene
chain,
wherein the alkylene chain may have one to three substituents selected from the group
consisting of a C].5 alkyl group, a halogen atom, -ORa, -NRaRb, and an oxo group; the
above substituents except the oxo group and the halogen atom may be linked to each
other to form a cycloalkyl g group;
the cycloalkyl group orthe heterocyclic group may have a substituent selected from the
group consisting of-ORa, -NRaRb, and a Ci_5 alkyl group that may be substituted with
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a
CM alkyl group; and the alkyl group may be substituted by a hydroxyl group, a C\.s
alkoxy group, or an amino group.
3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt
thereof, wherein X represents the group -Y-Z-W of the formula (i), wherein the alkylene chain of
Z is any one of the groups represented by the following formulae:
-CH2-, -(CH2)r, -(CH2)3-, -(CH2)4-, -CH2CH(Me)-, -CH2C(Me)2-, -C(Me)2CH2-,
-(CH2)2CH(Me)-, -(CH2)2C(Me)2-, -CH(Me)(CH2) 2-, -C(Me)2(CH2)2-, -CH2CH(Me)CH2-,
-CH2C(Me)2CH2-, -CH2C(CH2CH2)CH2-, -CO-, -CH2CO-, -COCH2-, -(CH2)2CO-, -CO(CH2)2-,
-CHOH-, -CH2CH(OH)-, -CH(OH)CH2-, -CH2CH(OH)CH2-, -CH(OH)CH2CH2-, and
-CH2CH2CH(OH)-. (Figure Removed)
4. The compound according to any one of claims 1 to 3, or a pharmaceutically
acceptable salt thereof, wherein X represents -Y-Z-W of the formula (i), wherein Rg represents a
hydrogen atom, a hydroxyl group, a Ci.5 alkyl group, or -CORg;
R9 represents a hydrogen atom, a hydroxyl group, a C\.s alkyl group, or a C\.s alkoxy group;
the alkyl group and the alkoxy group represented byRg and Rg may be substituted by one to three
hydroxyl groups at arbitrary positions of the hydrocarbon moiety.
5. The compound according to any one of claims 1 to 4, or a pharmaceutically
acceptable salt thereof, wherein X represents -Y-Z-W of the formula (i), wherein Rg represents a
hydrogen atom, a hydroxyl group, a methyl group, an ethyl group, an n-propyl group, an i-propyl
group, an n-butyl group, an i-butyl group, a t-butyl group, a sec-butyl group, a
1,1-dimethylpropyl group, a 2,2-dimethylpropyl group, a 1,2-dimethylpropyl group, a pentyl
group, a formyl group, an acetyl group, a 2-methoxyacetyl group, a 2-ethoxyacetyl group, a
2-hydroxyacetyl group, a propionyl group, a 2-methylpropionyl group, a 2-methoxypropionyl
group, a 2-ethoxypropionyl group, a 2-hydroxypropionyl group, a 3-methoxypropionyl group, a
3-ethoxypropionyl group, a 3-hydroxypropionyl group, a methoxy group, an ethoxy group, an
n-propyloxy group, an i-propyloxy group, a hydroxymethyl group, or a 2-hydroxyethyl group.
6. The compound according to any one of claims 1 to 5, or a pharmaceutically
acceptable salt thereof, wherein X represents -Y-Z-W of the formula (i), wherein Y represents
-O-, -NHO-, -N(COCH3)O-, -N(COCH2OH)O-, -N(COCH2CH3)O-, -N(COCH(OH)CH3)O-,
-N(COCH2CH2OH)0-, -N(COCH(OH)CH2OH)O-, -N(COCH2CH2CH3)O-,
-N(COCH2CH2CH2OH)O-, -N(COCH(OH)CH2CH3)O-, -N(COCH2CH(OH)CH3)O-, -NHCO-,
or -NHSO2-.
7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof,
wherein X represents a group represented by the formula (ii) and X is any one of the groups
represented by the following formulae(Figure Removed)
wherein Z' represents a Cj.s alkylene chain which may be substituted by one to threegroups represented by W ;
W represents a Ci-s alkyl group, a halogen atom, an oxo group, -ORa, -CONRaRb,
-SRa, -SORa, -SO2Ra, -NRaRb, -NRaCORb, -NRaSO2Rb, -SO2NRaRb, a heterocyclic
group, or a heteroaryl group;
the heterocyclic group and the heteroaryl group may have substituents selected from the
group consisting of a Ci.5 alkyl group, -ORa, and -NRaRb; the alkyl group may be
substituted by a hydroxyl group, a Ci_5 alkoxy group, or an amino group;
the above substituents except the oxo group and the halogen may be linked to each other
to form a cycloalkyl group or a heterocyclic group; the cycloalkyl group or the
heterocyclic group may have a substituent selected from the group consisting of -ORa,
-NRaRb, and a CM alkyl group that may be substituted with -ORa;
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a
Ci-s alkyl group; and the alkyl group may be substituted by a hydroxyl group, a Ci-s
alkoxy group, or an amino group.
8. The compound according to any one of claims 1 or 7, or a pharmaceutically
acceptable salt thereof, wherein X represents the group represented by the formula (ii), wherein
W represents any one of the groups represented by the formulae:
-Me, -Et, -n-Pr, -i-Pr, -CH2OH, -CH2CH2OH, -CH(OH)CH3, -OH, -OMe, -OEt, -OCH2OH,
-O(CH2)2OH, -O(i-Pr), -O(n-Pr), -CONH2, -CONHMe, -CONHEt, -CONH(n-Pr), -CONH(i-Pr),
-CONMe2, -CON(Et)Me, -SO2Me, -SOMe, -SMe, -NH2, -NHMe, -NHCH2OH, -NH(CH2)2OH,
-N(Me)CH2CH2OH, -NHEt, -NMe2, -N(Et)Me, -NHCOMe, -NMeCOMe, -NHCOEt,
-NHCO(n-Pr), and -NHCO(i-Pr).
9. The compound according to any one of claims 1, 7, and 8, or a pharmaceutically
acceptable salt thereof, wherein X represents the group represented by the formula (ii), wherein
the alkylene chain of Z' is any one of the groups represented by the following formulae:
-CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -CH2CH(Me)-, -CH2C(Me)2-, -C(Me)2CH2-,
-(CH2)2CH(Me)-, -(CH2)2C(Me)2-, -CH(Me)(CH2)2-, -C(Me)2(CH2)2-, -CH2CH(Me)CH2-,
-CH2C(Me)2CH2-, -CHOH-, -CH2CH(OH)-, -CH(OH)CH2-, -CH2CH(OH)CH2-,
-CH(OH)CH2CH2-, -CH2CH2CH(OH)-, -CO-, -CH2CO-, -COCH2-, -(CH2)2CO-, -CO(CH2)2-,
and -CH2CH(OH)CH2-.
10. The compound according to any one of claims 1, 7, 8, and 9, or a pharmaceutically
acceptable salt thereof, wherein X represents the group represented by the formula (ii) and X is
any one of the groups represented by the following formulae:
wherein the alkylene chain may be substituted at arbitrary positions by one to three
substituents selected from the group consisting of a CM alkyl group, a halogen atom,
-ORa, -NRaRb, and an oxo group; Ra and Rb, which may be the same or different, each
represent a hydrogen atom or a CM alkyl group; the alkyl group may be substituted by a
hydroxyl group, a CM alkoxy group, or an amino group; Ra represents a hydrogen atom
or a CM alkyl group; and the alkyl group may be substituted by a hydroxyl group, a CM
alkoxy group, or an amino group.
11. The compound according to claim 1, or a pharmaceutically acceptable salt thereof,
wherein X represents the group represented by the following formula (iii) or (iv):
wherein n represents an integer ranging from 1 to 5 and n' represents an integer ranging
from 0 to 5; the repeated units represented by -(CH2)n- or ~(CH2)n'- in the formulae
may be substituted at arbitrary positions in the hydrocarbon moiety by one to three
substituents selected from the group consisting of a CM alkyl group, a halogen atom,
-ORa, -NRaRb, and an oxo group; Ra and Rb, which may be the same or different, each
represent a hydrogen atom or a C 1.5 alkyl group; and the alkyl group may be substituted
by a hydroxyl group, a CM alkoxy group, or an amino group.
12. The compound according to claim 1, or a pharmaceutically acceptable salt thereof,
wherein X represents a group selected from the group consisting of a 2-hydroxyethoxy group, a
3-hydroxy-2-dimethylpropoxy group, a 3-hydroxypropoxy group, a 2-carbamoylethoxy group, a
2-methylcarbamoylethoxy group, a 2-methanesulfonyl-ethoxy group, a 2-acetylamino-ethoxy
group, a 2-hydroxyethoxyamino group, a 3-hydroxypropionyl amino group, a
2-hydroxyethanesulfonamide group, a 1-hydroxymethyl-cyclopropylmethoxy group, a
2,3-dihydroxy-propoxy group, a lH-imidazol-2-ylmethoxy group, a
2-methylcarbamoyl-ethoxyamino group, a 2-acetylamino-ethoxyamino group, a
2-methanesulfonyl-ethoxyamino group, a lH-imidazol-2-ylmethoxyamino group, a
3-hydroxypropoxyamino group, a 2-(2-hydroxyethoxy)-ethoxy group, a 2-methylaminoethoxy
group, a 2-(2-hydroxyethylamino)-ethoxy group, a 2-morpholin-4-yl-ethoxy group, a
2-(4-hydroxy-piperidin-l-yl)-ethoxy group, a 2-methylamino-ethoxyamino group, a
2,3-dihydroxy-propoxyamino group, a formyl-methoxyamino group, an acetyl-methoxyamino
group, a methoxy-propionylamino group, an isobutyryl-methoxy-amino group, a
(2-hydroxy-acetyl)-methoxyamino group, a methoxy-(2-methoxy-acetyl)-amino group, an
acetyl-ethoxy-amino group, an ethoxy-propionyl-amino group, an acetyl-isopropoxy-amino
group, an acetylhydroxyamino group, an acetoxy-acetyl-amino group, an
acetyl-(2-hydroxy-ethoxy)-amino group, an acetyl-(3-hydroxy-propoxy)-amino group, an
acetyl-(2-hydroxy-2-methyl-propoxy)-amino group, an acetyl-(2-acetylamino-ethoxy)-amino
group, an acetyl-(2-propionylamino-ethoxy)-amino group, an
acetyl-(2-isobutyrylamino-ethoxy)-amino group, an acetyl-(2-methylsulfanyl-ethoxy)-amino
group, an acetyl-(3-methylsulfanyl-propoxy)-amino group, a 2-hydroxy-l,l-dimethyl-ethoxy
group, a methylcarbamoylmethoxyamino group, an ethylcarbamoylmethoxyamino group, a
propylcarbamoylmethoxyamino group, an isopropylcarbamoyl-methoxyamino group, a
dimethylcarbamoylmethoxyamino group, a 2-ethylcarbamoyl-ethoxyamino group, a
2-propylcarbamoyl-ethoxyamino group, a 2-isopropylcarbamoyl-ethoxyamino group, a
3-methylcarbamoyl-propoxyamino group, a 2-methoxycarbonyl-ethoxyamino group, a
methoxyamino group, a methoxy-methyl-amino group, an ethoxyamino group, an
isopropoxyamino group, a 2-hydroxy-2-methyl-propoxyamino group, a
2-methylsulfanyl-ethoxyamino group, a 2-methanesulfmyl-ethoxyamino group, a
3-methylsulfanyl-propoxyamino group, a 3-methanesulfinyl-propoxyamino group, a
2-propionylamino-ethoxyamino group, a 2-isobutyrylamino-ethoxyamino group, a
2-hydroxy-acetylamino group, and an acetyl-(2-hydroxy-ethyl)-amino group.
13. The compound according to claim 1, or a pharmaceutically acceptable salt thereof,
wherein X represents a group selected from the group consisting of a 3-oxo-[l,2]oxazinan-2-yl
group, a 3-oxo-isoxazolidin-2-yl group, a 4,4-dimethyl-3-oxo-isoxazolidin-2-yl group, a
4-hydroxy-3-oxo-[l,2]oxazinan-2-yl group, a 3-oxo-[l,4,2]dioxazinan-2-yl group, a
2-oxo-pyrrolidin-l-yl group, a 2-oxo-piperidin-l-yl group, a 2-oxo-oxazolidin-3-yl group, a
2-oxo-tetrahydro-pyrimidin-l-yl group, and a 2,3-dioxo-morpholin-4-yl group.
14. The compound according to any one of claims 1 to 13, or a pharmaceutically
acceptable salt thereof, wherein RI represents an iodine atom, a bromine atom, a vinyl group, or
an ethynyl group.
15. The compound according to any one of claims 1 to 14, or a pharmaceutically
acceptable salt thereof, wherein RI represents an iodine atom or an ethynyl group.
16. The compound according to any one of claims 1 to 15, or a pharmaceutically
acceptable salt thereof, wherein Ra represents a chlorine atom, a fluorine atom, a methyl group,
or a hydroxymethyl group.
17. The compound according to any one of claims 1 to 16, or a pharmaceutically
acceptable salt thereof, wherein R2 represents a fluorine atom.
18. The compound according to any one of claims 1 to 17, or a pharmaceutical ly
acceptable salt thereof, wherein Ra represents a fluorine atom.
19. The compound according to any one of claims 1 to 18, or a pharmaceutically
acceptable salt thereof, wherein R» represents a CM alkyl group substituted by one to three
hydroxyl groups.
20. The compound according to any one of claims 1 to 19, or a pharmaceutically
acceptable salt thereof, wherein R» represents a group selected from the group consisting of the
groups represented by the following formulae:
21. The compound according to claim 1, or a pharmaceutically acceptable salt thereof,
i wherein Ra and Rb, which may be the same or different, each represent a group selected from
the group consisting of a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an
i-propyl group, an n-butyl group, an i-butyl group, a t-butyl group, a sec-butyl group, a
1,1-dimethylpropyl group, a 2,2-dimethylpropyl group, a 1,2-dimethylpropyl group, a pentyl
group, a hydroxymethyl group, a 1- hydroxyethyl group, a 1-hydroxy-l-methylethyl group, a
: 2-hydroxy-1 -methylethyl group, a 2-hydroxy-1,1 -dimethylethyl group, a 2-hydroxyethyl group,
a 1-hydroxypropyl group, a 2-hydroxypropyl group, and a 3-hydroxypropyl group.
22. The compound according to claims 1 to 6, or a pharmaceutically acceptable salt
thereof, wherein X represents -Y-Z-W of the formula (i), wherein W and W, which may be the
> same or different, each represent a group selected from the group consisting of-OH, -OMe, -OEt,
-OCH2OH, -O(CH2)2OH, -O(i-Pr), -O(n-Pr), -COOH, -COOMe, -COOEt, -COOCOMe, -COC1,
-CONH2, -CONHMe, -CONHEt, -CONH(n-Pr), -CONH(i-Pr), -CONMe2, -CON(Et)Me,
-S02Me, -SOMe, -SMe, -NH2, -NHMe, -NHCH2OH, -NH(CH2)2OH, -N(Me)CH2CH2OH,
-NHEt, -NMe2, -N(Et)Me, -NHCOMe, -NMeCOMe, -NHCOEt, -NHCO(n-Pr), and
-NHCO(i-Pr); and
W may be a hydrogen atom when Y is not -O-.
23. The compound according to claim 1, or a pharmaceutically acceptable salt thereof,
wherein the compound represented by the above formula (1) is any one selected from the group
consisting of:
(l)B-l
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-hydroxy-ethoxymethy
l)-benzamide, (Figure Removed)
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-(2-hydroxy-ethoxyme
thyl)-benzamide,
(3)B-3
N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-(2-hydroxy-ethoxy
methyl)-benzamide,
(4) B-4
2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-(2-hydroxy-ethoxymeth
yl)-benzamide,
(5)B-5
3,4-difluoro-2-(2-fluoro-4-vinyl-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-hydroxy-ethoxymeth
yl)-benzamide,
(6) B-6
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(3-hydroxypropoxymeth
yl)-benzamide,
(7)B-7
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-(3-hydroxy-2,2-dimethyl-propoxymethyl)-N-(2-
hydroxy-ethoxy)-benzamide,
(8) B-8
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(l-hydroxymethyl-cyclo
propylmethoxymethyl)-benzamide,
(9) B-9
5-(2,3-dihydroxy-propoxymethyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxyethoxy)-
benzamide,
2-32-
(10)8-10
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-methylcarbamoyl-eth
oxymethyl)-benzamide,
(ll)B-ll
5-(2-acetylamino-ethoxymethyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-et
hoxy)-benzamide,
(12)8-12
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-methanesulfonyl-etho
xymethyl)-benzarnide,
(13)8-13
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(lH-imidazol-2-yl
methoxymethyl)-benzamide,
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[2-(2-hydroxy-ethoxy)-et
hoxymethyl]-benzamide,
(15)8-15
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-methylamino-ethoxy
methyl)-benzamide,
(16)8-16
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[2-(2-hydroxy-ethylamin
o)-ethoxymethyl] -benzamide,
(17)8-17
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-morpholin-4-yl-ethox
ymethyl)-benzamide,
(18)8-18
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[2-(4-hydroxy-piperidin-
1 -yl)-ethoxymethyl]-benzamide, and
(19)8-19
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-(2-hydroxy-l, 1 -dimethyl-ethoxymethyl)-N-(2-h
ydroxy-ethoxy)-benzamide.
24. The compound according to claim 1, or a pharmaceutically acceptable salt thereof,
wherein the compound represented by the above formula (1) is any one selected from the group
consisting of:
(l)C-l
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyamin
o)-methyl]-benzamide,
(2) C-2
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxya
mino)-methyl]-benzamide,
(3) C-3
N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-[(2-hydroxy-ethoxy
amino)-methyl]-benzamide,
(4)C-4
2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyamin
o)-methyl]-benzamide,
(5)C-5
3,4-difluoro-2-(2-fluoro-4-vinyl-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethoxyami
no)-methyl]-benzamide,
(6) C-6
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methylcarbamoyl-eth
oxyam ino)-m ethyl] -benzamide,
(7)C-7
5-[(2-acetylamino-ethoxyamino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hy
droxy-ethoxy)-benzamide,
(8) C-8
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methanesulfonyl-eth
oxyamino)-methyl] -benzamide,
(9) C-9
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(lH-imidazol-2-ylmeth
oxyamino)-methyl]-benzamide,
(10)C-10
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-hydroxy-propoxyami
no)-m ethyl] -benzamide,
(ll)C-ll
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methylamino-ethoxy
amino)-methyl]-benzamide,
(12)C-12
5-[(2,3-dihydroxy-propoxyamino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-h
ydroxy-ethoxy)-benzamide,
(13)C-13
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(methylcarbamoylmetho
xyamino-methyl)-benzamide,
(14)C-14
5-(ethylcarbamoylmethoxyamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-h
ydroxy-ethoxy)-benzamide,
(15)C-15
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(propylcarbamoylmetho
xyamino-methyl)-benzamide,
(16)C-16
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(isopropylcarbamoyl-m
ethoxyam ino)-methyl] -benzam ide,
(17)C-17
5-(dimethylcarbamoylmethoxyamino-tnethyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(
2-hydroxy-ethoxy)-benzamide,
(18)C-18
5-[(2-ethylcarbamoyl-ethoxyamino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2
-hydroxy-ethoxy)-benzamide,
(19)C-19
5-[(2-propylcarbamoyl-ethoxyamino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(
2-hydroxy-ethoxy)-benzamide,
(20) C-20
5-[(2-isopropylcarbamoyl-ethoxyamino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
N-(2-hydroxy-ethoxy)-benzamide,
(21)C-21
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylcarbamoyl-pr
opoxyamino)-methyl]-benzamide,
(22) C-22
3-[N-[2,3-difluoro-4-(2-fluoro-4-iodo-phenylamino)-5-(2-hydroxyethoxycarbamoyl)benzyl]amin
ooxyjpropionic acid methyl ester,
(24) C-24
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(methoxyamino-methyl)-
benzamide,
(25) C-25
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(methoxy-methyl-amino
)-methyl] -benzamide,
(26) C-26
5-(ethoxyamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-b
enzamide,
(27) C-27
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(isopropoxyamino-nieth
yl)-benzamide,
(28) C-28
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)5-[(2-hydroxy-2-methyl-pro
poxyamino)-methyl]-benzamide,
(29) C-29
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)5-[(2-hydroxy-2-methylpropoxyamino)-
methyl]-benzamide,
(30) C-30
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methylsulfanyl-ethox
yamino)-methyl]-benzatnide,
(31)C-31
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methanesulfinyl-etho
xyamino)-methyl]-benzamide,
(32) C-32
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylsufanyl-propo
xyamino)-methyl]-benzamide,
(33) C-33
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methanesulfinyl-prop
oxyamino)-methyl]-benzamide,
(34) C-34
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-propoionylamino-eth
oxyamino)-tnethyl]-benzamide, and
(35) C-35
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-isobutyrylamino-etho
xyamino)-methyl]-benzamide.
25. The compound according to claim 1, or a pharmaceutically acceptable salt thereof,
wherein the compound represented by the above formula (1) is any one selected from the group
consisting of:
(l)E-l
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-hydroxy-propionyla
mino)-methyl]-benzamide
(2)E-2
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-[(3-hydroxy-propiony
lamino)-methyl]-benzamide
(3)E-3
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-[(2-hydroxy-ethanesulfonylamino)-methyl]-N-(
2-hydroxy-ethoxy)-benzamide,
(4)E-4
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-5-[(2-hydroxy-ethanesulfonylamino)-methyl]-
N-(2-hydroxy-ethoxy)-benzamide,
(5)E-5
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-[(2-hydroxy-acetylamino)-methyl]-N-(2-hydrox
y-ethoxy)-benzamide, and
(6) E-6
5-{[acetyl-(2-hydroxy-ethyl)-amino]-methyl}-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(
2-hydroxy-ethoxy)-benzamide.
26. The compound according to claim 1, or a pharmaceutically acceptable salt thereof,
wherein the compound represented by the above formula (1) is any one selected from the group
consisting of:
(l)F-l
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-[(formyl-methoxy-amino)-methyl]-N-(2-hydrox
y-ethoxy)-benzamide,
(2) F-2
5-[acetyl-methoxy-amino-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxyethoxy)-
benzamide,
(3)F-3
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(methoxy-propionyl-am
ino)-methy 1] -benzamide,
(4)F-4
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(isobutyryl-methoxy-am
ino)-methy 1] -benzam ide,
(5)F-5
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-{[(2-hydroxy-acetyl)-methoxy-amino]-methyl}-
N-(2-hydroxy-ethoxy)-benzamide,
(6)F-6
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-{[methoxy-(2-methoxy-a
cetyl)-amino]-methyl}-benzamide,
(7)F-7
5-[(acetyl-methoxy-amino)-methyl]-2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydr
oxy-ethoxy)-benzamide, .
(8) F-8
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-[(methoxy-propionylamino)-
methyl]-benzamide,
(9) F-9
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-[(isobutyryl-methoxyamino)-
methy 1] -benzamide,
(10)F-10
5-[(acetyl-ethoxy-amino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-e
thoxy)-benzamide,
(ll)F-ll
5-[(ethoxy-propionyl-amino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydro
xy-ethoxy)-benzamide,
(12)F-12
5-[(acetyl-isopropoxy-amino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydro
xy-ethoxy)-benzamide,
(13)F-13
5-[(acetyl-hydroxy-amino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy
-ethoxy)-benzamide,
(14)F-14
5-[(acetoxy-acetyl-amino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxyethoxy)-
benzam ide,
(15)F-15
5-{[acetyl-(2-hydroxy-ethoxy)-amino]-methyl}-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N
-(2-hydroxy-ethoxy)-benzamide,
(16)F-16
5-{[acetyl-(3-hydroxy-propoxy)-amino]-methyl}-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
N-(2-hydroxy-ethoxy)-benzamide,
(17JF-17
5-{[acetyl-(2-hydroxy-2-methyl-propoxy)-amino]-methyl}-3,4-difluoro-2-(2-fluoro-4-iodo-phen
ylamino)-N-(2-hydroxy-ethoxy)-benzamide,
(18)F-18
5-{[acetyl-(2-acetylamino-ethoxy)-amino]-methyl}-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino
)-N-(2-hydroxy-ethoxy)-benzamide,
(19)F-19
5-{[acetyl-(2-propionylamino-ethoxy)-amino]-methyl}-3,4-difluoro-2-(2-fluoro-4-iodo-phenyla
mino)-N-(2-hydroxy-ethoxy)-benzamide,
(20) F-20
5-{[acetyl-(2-isobutyrylamino-ethoxy)-amino]-methyl}-3,4-difluoro-2-(2-fluoro-4-iodo-phenyla
mino)-N-(2-hydroxy-ethoxy)-benzamide,
(21)F-21
5-{[acetyl-(2-methylsulfanyl-ethoxy)-amino]-methyl}-3,4-difluoro-2-(2-fluoro-4-iodo-phenylam
ino)-N-(2-hydroxy-ethoxy)-benzamide,
(22) F-22
5-{[acetyl-(3-methylsulfanyl-propoxy)-amino]-methyl}-3,4-difluoro-2-(2-fluoro-4-iodo-phenyla
mino)-N-(2-hydroxy-ethoxy)-benzamide,
(23) F-23
5-[(acetyl-ethoxy-amino)-methyl]-2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydrox
y-ethoxy)-benzamide,
(24) F-24
5 - [(ethoxy-propionyl-amino)-methyl]-2-(4-ethyny l-2-fluoro-phenylamino)-3,4-difluoro-N -(2-hy
droxy-ethoxy)-benzamide,
(25) F-25
5-{[acetyl-(2-hydroxy-ethoxy)-amino]-methyl}-2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluor
o-N-(2-hydroxy-ethoxy)-benzamide, and
(26) F-26
5-{[acetyl-(2-hydroxy-2-tnethyl-propoxy)-amino]-methyl}-2-(4-ethynyl-2-fluoro-phenylamino)-
3,4-difluoro-N-(2-hydroxy-ethoxy)-benzamide.
27. The compound according to claim 1, or a pharmaceutically acceptable salt thereof,
wherein the compound represented by the above formula (1) is any one selected from the group
consisting of:
(l)G-l
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(3-oxo-[l,2]oxazinan-2-
ylmethyl)-benzamide,
(2) G-2
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(3-oxo-isoxazolidin-2-yl
methyl)-benzamide,
(3) G-3
5-(4,4-dimethyl-3-oxo-isoxazolidin-2-ylmethyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
N-(2-hydroxy-ethoxy)-benzamide,
(4) G-4
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-(3-oxo-[l,2]oxazinan-
2-ylmethyl)-benzamide,
(5)G-5
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-(3-oxo-isoxazolidin-2
-ylmethyl)-benzamide,
(6) G-6
N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-(3-oxo-[l,2]oxazin
an-2-ylmethyl)-benzamide,
(7)G-7
N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-(3-oxo-isoxazolidin
-2-ylmethyl)-benzamide, and
(8) G-8
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(4-hydroxy-3-oxo-[l,2]o
xazinan-2-ylmethyl)-benzamide.
28. The compound according to claim 1, or a pharmaceutically acceptable salt thereof,
(Figure Removed)wherein the compound represented by the above formula (1) is any one selected from the group
consisting of:
(l)H-l
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(3-oxo-[l,4,2]dioxazinan
-2-ylmethyl)-benzamide,
(2) H-2
2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-(3-oxo-[l,4,2]dioxazi
nan-2 -y lmethyl)-benzam ide,
(3) H-3
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-oxo-pyrrolidin-l-ylm
ethy l)-benzam ide,
(4) H-4
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-oxo-piperidin-l-ylmet
hyl)-benzamide,
(5)H-5
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-oxo-oxazolidin-3-ylm
ethyl)-benzamide,
(6) H-6
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-oxo-tetrahydro-pyrimi
din-l-ylmethyl)-benzamide, and
(7)H-7
5-(2,3-dioxo-morpholin-4-ylmethyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydrox
y-ethoxy)-benzamide.
29. A synthetic intermediate (E) of the compound represented by the formula (1)
according to claim 1, wherein the intermediate is represented by the following formula (6):
wherein
RI represents a halogen atom, an alkenyl group, or an alkynyl group;
Ra represents a halogen atom or an alkyl group; the alkyl group may be substituted by a hydroxyl
group;
RS represents a hydrogen atom or a halogen atom;
in the above formula (6), the group represented by the following formula (a):
Ub
(a)
represents a 3- to 10-membered heterocyclic group that may have one to three substituents
selected from the group consisting of a C 1.5 alkyl group, a halogen atom, -ORa, -NRaRb, and an
oxo group;
the above substituents except the oxo group and the halogen atom may be linked to each other to
form a cycloalkyl group or a heterocyclic group; the cycloalkyl group or the heterocyclic group
may have a substituent selected from the group consisting of-ORa, -NRaRb, and a Q.s alkyl
group that may be substituted with -ORa;
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a C 1.5 alkyl
group; the alkyl group may be substituted by a hydroxyl group, a Ci_5 alkoxy group, or an
amino group;
U represents -O-, -CONRd-, -S-, -SO-, -SO2-, -NRd-, -NRdCO-, -NRdSO2-, -SO2NRd-, a
divalent heterocyclic group, or a divalent heteroaryl group; Rd represents a hydrogen atom or a
Ci-s alkyl group; the alkyl group may be substituted by a hydroxyl group, a CM alkoxy group, or
an amino group;
RI, R2, Rs, and U may have protecting group(s) required for the synthesis.
30. The synthetic intermediate (E) according to claim 29, wherein RI represents an
iodine atom, a bromine atom, an ethynyl group, or a vinyl group;
R2 represents a chlorine atom or a fluorine atom;
Rs represents a fluorine atom; and
U represents -O-.
31. The synthetic intermediate (E) according to claim 29, wherein the heterocyclic
group represented by the formula (a) is a [l,3]dioxoran-2-yl group or a [l,3]dioxan-2-yl group,
which may be substituted by a hydroxyl group or a CM alkyl group.
32. A synthetic intermediate (F) of the compound represented by the formula (1)
according to claim 1, wherein the intermediate is represented by the following formula (7):
wherein
RI represents a halogen atom, an alkenyl group, or an alkynyl group;
R2 represents a halogen atom or an alkyl group; the alkyl group may be substituted by a hydroxyl
group;
RS represents a hydrogen atom or a halogen atom;
R4 represents a hydrogen atom, an alkyl group, an alkenyl group, or an alkynyl group; the alkyl
group, the alkenyl group, and the alkynyl group may have one to three substituents selected from
the group consisting of -ORa, -NRaRb, -NRaCORb, a heterocyclic group, and a heteroaryl
group; the heterocyclic group and the heteroaryl group may have one to three substituents
selected from the group consisting of a CM alkyl group, -ORa, and -NRaRb; Ra and Rb, which
may be the same or different, each represent a hydrogen atom or a CM alkyl group; the alkyl
group may be substituted by a hydroxyl group, a CM alkoxy group, or an amino group;
in the above formula (7), the group represented by the following formula (a):
represents a 3- to 10-membered heterocyclic group that may have one to three substituents
selected from the group consisting of a CM alkyl group, a halogen atom, -ORa, -NRaRb, and an
oxo group; (Figure Removed)
the above substituents except the oxo group and the halogen atom may be linked to each other to
form a cycloalkyl group or a heterocyclic group; the cycloalkyl group or the heterocyclic group
may have a substituent selected from the group consisting of-ORa, -NRaRb, and a CM alkyl
group that may be substituted with -ORa;
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a CM alkyl
group; and the alkyl group may be substituted by a hydroxyl group, a CM alkoxy group, or an
amino group;
U represents -O-, -CONRd-, -S-, -SO-, -SO2-, -NRd-, -NRdCO-, -NRdSO2-, -SO2NRd-, a
divalent heterocyclic group, or a divalent heteroaryl group; Rd represents a hydrogen atom or a
CM alkyl group; the alkyl group may be substituted by a hydroxyl group, a CM alkoxy group, or
an amino group;
RI, R2, RS, and U may have protecting group(s) required for the synthesis.
33. The synthetic intermediate (F) according to claim 32, wherein RI represents an
iodine atom, a bromine atom, an ethynyl group, or a vinyl group;
R2 represents a chlorine atom or a fluorine atom;
Ra represents a fluorine atom;
R4 represents a hydroxy alkyl group, in whichthe hydroxy moiety may be protected; and
U represents -O-.
34. The synthetic intermediate (F) according to claim 32, wherein the heterocyclic group
represented by the formula (a) is a [l,3]dioxolan-2-yl group or a [l,3]dioxan-2-yl group, which
may be substituted by a hydroxyl group or a C1-5 alkyl group.
35. A synthetic intermediate (I) of the compound represented by the formula (1)
according to claim 1, wherein the intermediate is represented by the following formula (10):
(Figure Removed)RI represents a halogen atom, an alkenyl group, or an alkynyl group;
R2 represents a halogen atom or an alkyl group; the alkyl group may be substituted by a hydroxyl
group;
RS represents a hydrogen atom or a halogen atom;
Z represents a C\.» alkylene chain which may be substituted by one to three groups represented
byW;
W or W, which may be the same or different, each represent a hydrogen atom, a CM alkyl group,
a halogen atom, an oxo group, -ORa, -COORa, -COOCORa, -CO-[halogen atom], -OCORa,
-CONRaRb, -SRa, -SORa, -SO2Ra, -NRaRb, -NRaCORb, -NRaSO2Rb, -SO2NRaRb, a
heterocyclic group, or a heteroaryl group;
the heterocyclic group and the heteroaryl group may have a substituent selected from the group
consisting of a C 1.5 alkyl group, -ORa, and -NRaRb; the alkyl group may be substituited by a
hydroxyl group, a C\-s alkoxy group, or an amino group;
the above substituents except the oxo group and the halogen atom may be linked to each other to
form a cycloalkyl group or a heterocyclic group; the cycloalkyl group or the heterocyclic group
may have a substituent selected from the group consisting of-ORa, -NRaRb, and a C\-s alkyl
group that may be substituted with -ORa;
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a C 1.5 alkyl
group; and the alkyl group may be substituted a hydroxyl group, a CM alkoxy group, or an
amino group; and
RI, R2, RS, Z, W and W may have protecting group(s) required for the synthesis.
36. The synthetic intermediate according to claim 35, which is a synthetic intermediate
(K) represented by the following formula (12):
(Figure Removed)wherein
RI represents a halogen atom, an alkenyl group, or an alkynyl group;
R2 represents a halogen atom or an alkyl group; the alkyl group may be substituted by a hydroxyl
group;
Rs represents a hydrogen atom or a halogen atom;
Z' represents a CM alkylene chain that may be substituted by one to three groups represented by
W;
W represents any one of the groups represented by the formulae:
-OH, -OMe, -OEt, -OCH2OH, -O(CH2)2OH, -O(i-Pr), -O(n-Pr), -CONH2, -CONHMe, -CONHEt,
-CONH(n-Pr), -CONH(i-Pr), -CONMe2, -CON(Et)Me, -SO2Me, -SOMe, -SMe, -NH2, -NHMe,
-NHCH2OH, -NH(CH2)2OH, -N(Me)CH2CH2OH, -NHEt, -NMe2, -N(Et)Me, -NHCOMe,
-NMeCOMe, -NHCOEt, -NHCO(n-Pr), and -NHCO(i-Pr);
Q represents -ORc, -OCORc, -NRcRd, or a halogen atom; Re and Rd, which may be the same or
different, each represent a hydrogen atom or a Ci_5 alkyl group;
RI, R2, and Rs are defined herein above; and RI, R2, RS, Z', Q and W may have protecting
group(s) required for the synthesis.
37. The synthetic intermediate according to claim 35 or 36, wherein RI represents an
iodine atom, a bromine atom, an ethynyl group, or a vinyl group;
R2 represents a chlorine atom or a fluorine atom; and
RS represents a fluorine atom.
38. A synthetic intermediate (L) of the compound represented by the formula (1) the
according to claim 1, wherein the intermediate is represented the following formula (13):
wherein
RI represents a halogen atom, an alkenyl group, or an alkynyl group;
Ra represents a halogen atom or an alkyl group; the alkyl group may be substituted by a hydroxyl
group;
Rs represents a hydrogen atom or a halogen atom;
R4 represents a hydrogen atom, an alkyl group, an alkenyl group, or an alkynyl group; the alkyl
group, the alkenyl group, and the alkynyl group may have one to three substituents selected from
the group consisting of -ORa, -NRaRb, -NRaCORb, a heterocyclic group, and a heteroaryl
group; the heterocyclic group and the heteroaryl group may have one to three substituents
selected from the group consisting of a C 1.5 alkyl group, -ORa, and -NRaRb; Ra and Rb, which
may be the same or different, each represent a hydrogen atom or a C\.s alkyl group; the alkyl
group may be substituted by a hydroxyl group, a C\.s alkoxy group, or an amino group;
Z' represents a Ci-s alkylene chain that may have one to three groups represented by W;
W represents the group represented by any one of the groups represented by the following
formulae:
-OH, -OMe, -OEt, -OCH2OH, -O(CH2)2OH, -O(i-Pr), -O(n-Pr), -CONH2, -CONHMe, -CONHEt,
-CONH(n-Pr), -CONH(i-Pr), -CONMe2, -CON(Et)Me, -SO2Me, -SOMe, -SMe, -NH2, -NHMe,
-NHCH2OH, -NH(CH2)2OH, -N(Me)CH2CH2OH, -NHEt, -NMe2, -N(Et)Me, -NHCOMe,
-NMeCOMe, -NHCOEt, -NHCO(n-Pr), and -NHCO(i-Pr);
Q represents -ORc, -OCORc, -NRcRd, or a halogen atom; Re and Rd, which may be the same or
different, each represent a hydrogen atom or a C\.$ alkyl group; and
RI, R2, RS, R4, Z', Q, and W may have protecting group(s) required for the synthesis].
39. The synthetic intermediate (L) according to claim 38, wherein RI represents an
iodine atom, a bromine atom, an ethynyl group, or a vinyl group;
R2 represents a chlorine atom or a fluorine atom;
RS represents a fluorine atom; and
R4 represents a hydroxy alkyl group, in which the hydroxy alkyl moiety may be protected.
40. A method for producing any one of the compounds (M), (N), (M'), and (N'),
wherein the method comprises reacting a reducing agent, in a solvent at neutral pH or in the
presence of an acid, with a synthetic intermediate (E) represented by the following formula (6) or
a synthetic intermediate (F) represented by the following formula (7):
(Figure Removed)wherein
RI represents a halogen atom, an alkenyl group, or an alkynyl group;
R2 represents a halogen atom or an alkyl group; the alkyl group may be substituted by a
hydroxyl group;
Ra represents a hydrogen atom or a halogen atom;
R4 represents a hydrogen atom, an alkyl group, an alkenyl group, or an alkynyl group;
the alkyl group, the alkenyl group, and the alkynyl group may have one to three
substituents selected from the group consisting of-ORa, -NRaRb, -NRaCORb, a
heterocyclic group, and a heteroaryl group; the heterocyclic group and the heteroaryl
group may have one to three substituents selected from the group consisting of a C 1.5
alkyl group, -ORa, and -NRaRb;
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a
Ci-s alkyl group; and the alkyl group may be substituted by a hydroxyl group, a C\.$
alkoxy group, or an amino group;
in the formulae (6) and (7), the group represented by the following formula (a):
represents a 3- to 10-membered heterocyclic group that may have one to three
substituents selected from the group consisting of a CM alkyl group, a halogen atom,
-ORa, -NRaRb, and an oxo group;
the above substituents except the oxo group and the halogen atom may be linked to each
other to form a cycloalkyl group or a heterocyclic group; the cycloalkyl group or the
heterocyclic group may have a substituent selected from the group consisting of-ORa,
-NRaRb, and a CM alkyl group that may be substituted with -ORa;
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a
CM alkyl group; and the alkyl group may be substituted by a hydroxyl group, a CM
alkoxy group, or an amino group;
U represents -O-, -CONRd-, -S-, -SO-, -SO2-, -NRd-, -NRdCO-, -NRdSO2-, -SO2NRd-,
a divalent heterocyclic group, or a divalent heteroaryl group; Rd represents a hydrogen
atom or a CM alkyl group; the alkyl group may be substituted by a hydroxyl group, a
CM alkoxy group, or an amino group; and
RI, R2, RS, and U may have protecting group(s) required for the synthesis
to thereby obtain the compounds (M), (N), (M'), and (N') represented by the formulae (14), (15),
(14'), and (15'), respectively:
(Figure Removed)wherein
RI, R2, RS, R4, and U are defined herein above in formulae (6) and (7);
Z corresponds to the alkylene chain constituting the ring in the above formula (a); Z represents a
Ci-8 alkylene chain, which may be substituted by one to three groups represented by W; W
represents any one of substituents selected from the group consisting of a CM alkyl group, a
halogen atom, -ORa, -NRaRb, and an oxo group; the above substituents except the oxo group
and the halogen atom may be linked to each other to form a cycloalkyl group or a heterocyclic
group;
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a C 1.5 alkyl
group; the alkyl group may be substituted by a hydroxyl group, a C\.5 alkoxy group, or an amino
group.
41. A method for producing compound (I) or compound (J), wherein the method
comprises reacting a reducing agent, in a solvent at neutral pH or in the presence of an acid, with
a synthetic intermediate (G) of the compound represented by the formula (1) according to claim
1, wherein (G) is represented by the following formula (8):
R2
wherein
RI represents a halogen atom, an alkenyl group, or an alkynyl group;
R2 represents a halogen atom or an alkyl group; the alkyl group may be substituted by a
hydroxyl group;
Rj represents a hydrogen atom or a halogen atom;
Z represents a C\.% alkylene chain that may have one to three groups represented by W ;
W or W, which may be the same or different, each represent a hydrogen atom, a C\.s
alkyl group, a halogen atom, an oxo group, -ORa, -COORa, -COOCORa, -CO-[halogen
atom], -OCORa, -CONRaRb, -SRa, -SORa, -SO2Ra, -NRaRb, -NRaCORb, -NRaSO2Rb,
-SOaNRaRb, a heterocyclic group, or a heteroaryl group;
the heterocyclic group and the heteroaryl group may have a substituent selected from
the group consisting of a C\.s alkyl group, -ORa, and -NRaRb; the alkyl group may be
substituted by a hydroxyl group, a C\.$ alkoxy group, or an amino group;
the above substituents except the oxo group and the halogen may be linked to each other
to form a cycloalkyl group or a heterocyclic group; the cycloalkyl group or the
heterocyclic group may have a substituent selected from the group consisting of-ORa,
-NRaRb, and a C\.$ alkyl group that may be substituted with -ORa;
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a
Ci.5 alkyl group; the alkyl group may be substituted by a hydroxyl group, a Ci.5 alkoxy
group, or an amino group; and
RO, R2, RS, Z, W, and W may have protecting group(s) required for the synthesis,
or a synthetic intermediate (H) of the compound represented by the formula (1) according to
claim 1, wherein (H) is represented by the following formula (9):
(Figure Removed)wherein
RI represents a halogen atom, an alkenyl group, or an alkynyl group;
R.2 represents a halogen atom or an alkyl group; the alkyl group may be substituted by a
hydroxyl group;
Rs represents a hydrogen atom or a halogen atom;
R4 represents a hydrogen atom, an alkyl group, an alkenyl group, or an alkynyl group;
the alkyl group, the alkenyl group, and the alkynyl group may have one to three
substituents selected from the group consisting of-ORa, -NRaRb, -NRaCORb, a
heterocyclic group, and a heteroaryl group; the heterocyclic group and the heteroaryl
group may have one to three substituents selected from the group consisting of a C 1.5
alkyl group, -ORa, and -NRaRb;
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a
Ci-s alkyl group; and the alkyl group may be substituted by a hydroxyl group, a C\.$
alkoxy group, or an amino group;
Z represents a Ci.g alkylene chain that may be substituted by one to three groups
represented by W;
W or W, which may be the same or different, each represent a hydrogen atom, a C\.s
alkyl group, a halogen atom, an oxo group, -ORa, -COORa, -COOCORa, -CO-[halogen
atom], -OCORa, -CONRaRb, -SRa, -SORa, -SO2Ra, -NRaRb, -NRaCORb, -NRaSO2Rb,
-SO2NRaRb, a heterocyclic group, or a heteroaryl group;
the heterocyclic group and the heteroaryl group may have a substituent selected from
the group consisting of a Ci.5 alkyl group, -ORa, and -NRaRb; the alkyl group may be
substituted by a hydroxyl group, a C\.$ alkoxy group, or an amino group;
the above substituents except the oxo group and the halogen atom may be linked to each
other to form a cycloalkyl group or a heterocyclic group; the cycloalkyl group or the
.38-2.ro
heterocyclic group may have a substituent selected from the group consisting of-ORa,
-NRaRb, and a C\.s alky] group that may be substituted with -ORa;
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a
Ci-s alkyl group; and the alkyl group may be substituted by a hydroxyl group, a C\-$
alkoxy group, or an amino group;
RI, R2, Ra, Z, W, and W may have protecting group(s) required for the synthesis,
to thereby obtain compound (I) represented by the following formula (10):
or compound (J) represented by the following formula (11):
in the formulae (10) and (11), RI, R2, RS, R4, Z, W, and W are defined herein above in formulae(8) and (9).42. A method for producing compound (O) or compound (P), wherein the method
comprises allowing a synthetic intermediate (K) or (L) represented by the following formula (13)
to intramolecularly cyclize at neutral pH or in the presence of an acid or a base in a solvent that
optionally contains a peptide condensing agent,
wherein the synthetic intermediates (K) and (L) are represented by the following formulae
RI represents a halogen atom, an alkenyl group, or an alkynyl group;
R2 represents a halogen atom or an alkyl group; the alkyl group may be substituted by a
hydroxyl group;
RS represents a hydrogen atom or a halogen atom;
R4 represents a hydrogen atom, an alkyl group, an alkenyl group, or an alkynyl group;
the alkyl group, the alkenyl group, and the alkynyl group may have one to three
substituents selected from the group consisting of -ORa, -NRaRb, -NRaCORb, a
heterocyclic group, and a heteroaryl group; the heterocyclic group and the heteroaryl
group may have one to three substituents selected from the group consisting of a C 1.5
alkyl group, -ORa, and -NRaRb;
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a
Cus alkyl group; and the alkyl group may be substituted by a hydroxyl group, a Ci-s
alkoxy group, or an amino group;
Z' represents a Ci-salkylene chain that may be substituted by one to three groups
represented by W;
W represents any one of the groups of-OH, -OMe, -OEt, -OCH2OH, -O(CH2)2OH,
-O(i-Pr), -O(n-Pr), -CONH2, -CONHMe, -CONHEt, -CONH(n-Pr), -CONH(i-Pr),
-CONMe2, -CON(Et)Me, -SO2Me, -SOMe, -SMe, -NH2, -NHMe, -NHCH2OH,
-NH(CH2)2OH, -N(Me)CH2CH2OH, -NHEt, -NMe2, -N(Et)Me, -NHCOMe,
-NMeCOMe, -NHCOEt, -NHCO(n-Pr), and -NHCO(i-Pr);
Q represents -ORc, -OCORc, -NRcRd, or a halogen atom; Re and Rd, which may be the
same or different, each represent a hydrogen atom or a C 1.5 alkyl group;
RI, R2, RS, R4, Z', W, and Q may have protecting group(s) required for the synthesis,
to thereby obtain compound (O) represented by the following formula (16):
or compound (P) represented by the following formula (17):
R2
in the formula (16) and (17), RI,
(13).
S, R4, and Z' are defined herein above in formulae (12) and
43. A method for producing compound (S) or compound (T), wherein the method
comprises reacting, in the presence of a base or an acid, or at neutral pH, in a solvent that
optionally contains a condensing agent,
the synthetic intermediate (I) of the compound represented by the formula (1) according to claim
1, the intermediate being represented by the following formula (10):
or the synthetic intermediate (J)of the compound represented by the formula (1) according to
claim 1, the intermediate being represented by the following formula (11):
in the formulae (10) and (11),
RI represents a halogen atom, an alkenyl group, or an alkynyl group;
(Figure Removed)R2 represents a halogen atom or an alkyl group; the alkyl group may be substituted by a
hydroxyl group;
RS represents a hydrogen atom or a halogen atom;
R4 represents a hydrogen atom, an alkyl group, an alkenyl group, or an alkynyl group;
the alkyl group, the alkenyl group, and the alkynyl group may have one to three
substituents selected from the group consisting of -ORa, -NRaRb, -NRaCORb, a
heterocyclic group, and a heteroaryl group; the heterocyclic group and the heteroaryl
group may have one to three substituents selected from the group consisting of a C 1.5
alkyl group, -ORa, and -NRaRb; Ra and Rb, which may be the same or different, each
represent a hydrogen atom or a C 1.5 alkyl group; the alkyl group may be substituted by a
hydroxyl group, a C].5 alkoxy group, or an amino group;
Z represents a Ci.g alkylene chain that may be substituted by one to three groups
represented by W;
W or W, which may be the same or different, each represent a hydrogen atom, a C\.s
alkyl group, a halogen atom, an oxo group, -ORa, -COORa, -COOCORa, -CO-[halogen
atom], -OCORa, -CONRaRb, -SRa, -SORa, -SO2Ra, -NRaRb, -NRaCORb, -NRaSO2Rb,
-SO2NRaRb, a heterocyclic group, or a heteroaryl group;
the heterocyclic group and the heteroaryl group may have a substituent selected from
the group consisting of a C 1.5 alkyl group, -ORa, and -NRaRb; the alkyl group may be
substituted by a hydroxyl group, a C\.s alkoxy group, or an amino group;
the above substituents except the oxo group and the halogen may be linked to each other
to form a cycloalkyl group or a heterocyclic group; the cycloalkyl group or the
heterocyclic group may have a substituent selected from the group consisting of-ORa,
-NRaRb, and a C\.s alkyl group that may be substituted with -ORa;
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a
CM alkyl group; the alkyl group may be substituted by a hydroxyl group, a CM alkoxy
group, or an amino group;
RI, R2, RS, R», Z, W, and W may have protecting group(s) required for the synthesis
with a carboxylic acid derivative represented by the following formula:
(Figure Removed)wherein
Rg represents a hydrogen atom, an alkyl group, or -ORa; the alkyl group may be
substituted by a halogen atom, -ORa, or -NRaRb;
Q represents -ORc, -OCORc, -NRcRd, or a halogen atom; Re and Rd, which may be the
same or different, each represent a hydrogen atom or a CM alkyl group;
Ra and Rb, which may be the same or different, each represent a hydrogen atom or a
CM alkyl group; and the alkyl group may be substituted by a hydroxyl group, a CM
alkoxy group, or an amino group;
Rg and Q may have protecting group(s) required for the synthesis,
to thereby obtain compound (S) represented by the following formula (18):
or compound (T) represented by the following formula (19):
(Figure Removed)in the formulae (18) and (19), Rl s R2, RS, Rt, Z, and W are defined herein above in formulae (10)
and (11); and Rg is the carboxylic acid derivative defined herein above.
44. A pharmaceutical composition comprising as an active ingredient the compound
according to any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof.
45. An MEK inhibitor comprising as an active ingredient the compound according to
any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof.
46. A preventive or therapeutic agent for a proliferative disease, which comprises as an
active ingredient the compound according to any one of claims 1 to 28 or a pharmaceutically
acceptable salt thereof.
47. The preventive or therapeutic agent for a proliferative disease according to claim 46,
wherein the proliferative disease is a cancer.
48. The preventive or therapeutic agent for a proliferative disease according to claim 47,
wherein the cancer is a cancer depending on the Ras-MAPK signaling pathway.
49. The preventive or therapeutic agent for a proliferative disease according to claim 47
or 48, wherein the cancer is breast, lung, colorectal, prostate, liver, ovarian, uterine, or pancreatic
cancer.
50. A method for preventing or treating a proliferative disease, wherein the
methodcomprises administering a pharmaceutically effective dose of a composition that
compri(Figure Removed)ses as an active ingredient the compound according to any one of claims 1 to 28 or a
pharmaceutically acceptable salt thereof to a patient who needs prevention or treatment for the
proliferative disease.
51. The method according to claim 50, wherein the proliferative disease is a cancer.
52. The method according to claim 50, wherein the cancer is a cancer depending on the
Ras-MAPK signaling pathway.
53. The method according to claim 51 or 52, wherein the cancer is breast, lung,
colorectal, prostate, liver, ovarian, uterine, or pancreatic cancer.
54. The method according to any one of claims 50 to 53, wherein the method further
comprises radiotherapy, another chemotherapy, or administration of an angiogenesis inhibitor.
55. Use of the compound according to any one of claims 1 to 28 or a pharmaceutically
acceptable salt thereof in the production of a preventive or therapeutic agent for a disease to
which MEK inhibition is effective.
56. A preventive or therapeutic agent for a joint disorder with inflammation, wherein the
agent comprises as an active ingredient the compound according to any one of claims 1 to 28 or
a pharmaceutically acceptable salt thereof.
57. The preventive or therapeutic agent for a joint disorder with inflammation according
to claim 56, wherein the joint disorder with inflammation is osteoarthritis or rheumatoid arthritis.
58. A method for preventing or treating osteoarthritis or rheumatoid arthritis, wherein
the method comprises administering a pharmaceutically effective dose of a composition that
comprises as an active ingredient the compound according to any one of claims 1 to 28 or a
pharmaceutically acceptable salt thereof to a patient who needs prevention or treatment for
osteoarthritis or rheumatoid arthritis.
59. A compound (O) represented by the following formula (16):
(Figure Removed)wherein
RI represents a halogen atom, an alkenyl group, or an alkynyl group;
R2 represents a halogen atom or an alkyl group; the alkyl group may be substituted by a hydroxyl
group;
Rs represents a hydrogen atom or a halogen atom;
Z' represents a C\.s alkylene chain that may be substituted by one to three groups represented (Figure Removed)by
W represents any one of the groups of-OH, -OMe, -OEt, -OCH2OH, -O(CH2)2OH, -O(i-Pr),
-O(n-Pr), -CONH2, -CONHMe, -CONHEt, -CONH(n-Pr), -CONH(i-Pr), -CONMe2,
-CON(Et)Me, -SO2Me, -SOMe, -SMe, -NH2, -NHMe, -NHCH2OH, -NH(CH2)2OH,
-N(Me)CH2CH2OH, -NHEt, -NMe2, -N(Et)Me, -NHCOMe, -NMeCOMe, -NHCOEt,
-NHCO(n-Pr), and -NHCO(i-Pr);
RI, R2, R3, Z', and W may have a protecting group(s) required for the synthesis.
60. A method for producing compound (I-g) represented by the following formula,
wherein the method comprises reacting a compound (XXV) represented by the following
formula with a hydroxylamine derivative (VI) represented by NfbOR/i, in a solvent in the
presence of a condensing agent for peptide synthesis and in the presence or absence of a base,
(Figure Removed)wherein
RI represents a halogen atom, an alkenyl group, or an alkynyl group;
R2 represents a halogen atom or an alkyl group; the alkyl group may be substituted by a hydroxyl
group;
RS represents a hydrogen atom or a halogen atom;
R4 represents a hydrogen atom, an alkyl group, an alkenyl group, or an alkynyl group; the alkyl
group, the alkenyl group, and the alkynyl group may have one to three substituents selected from
the group consisting of-ORa, -NRaRb, -NRaCORb, a heterocyclic group, and a heteroaryl
group; the heterocyclic group and the heteroaryl group may have one to three substituents
selected from the group consisting of a C\.5 alkyl group, -ORa, and -NRaRb; Ra and Rb, which
may be the same or different, each represents a hydrogen atom or a C 1.5 alkyl group; the alkyl
group may be substituted by a hydroxyl group, a C\.s alkoxy group, or an amino group;
Z' represents a CM alkylene chain that may be substituted by one to three groups represented by
W;
W represents any one of the groups of-OH, -OMe, -OEt, -OCH2OH, -O(CH2)2OH, -O(i-Pr),
-O(n-Pr), -CONH2, -CONHMe, -CONHEt, -CONH(n-Pr), -CONH(i-Pr), -CONMe2,
-CON(Et)Me, -SO2Me, -SOMe, -SMe, -NH2, -NHMe, -NHCH2OH, -NH(CH2)2OH,
-N(Me)CH2CH2OH, -NHEt, -NMe2, -N(Et)Me, -NHCOMe, -NMeCOMe, -NHCOEt,
-NHCO(n-Pr), and -NHCO(i-Pr);
R1, R2, RS, Rt, Z', and W may have a protecting group(s) required for the synthesis.

Documents:

1319-delnp-2007-1-Correspondence Others-(13-08-2014).pdf

1319-delnp-2007-1-Correspondence Others-(25-04-2013).pdf

1319-delnp-2007-1-Form-3-(25-04-2013).pdf

1319-delnp-2007-abstract.pdf

1319-delnp-2007-Claims-(18-07-2013).pdf

1319-delnp-2007-Claims-(29-08-2014).pdf

1319-Delnp-2007-Claims-(30-11-2012).pdf

1319-delnp-2007-claims.pdf

1319-delnp-2007-Correspondence Others-(15-05-2013).pdf

1319-delnp-2007-Correspondence Others-(01-01-2014).pdf

1319-delnp-2007-Correspondence Others-(03-06-2014).pdf

1319-delnp-2007-Correspondence Others-(09-11-2012).pdf

1319-delnp-2007-Correspondence Others-(12-08-2013).pdf

1319-delnp-2007-Correspondence Others-(12-11-2012).pdf

1319-delnp-2007-Correspondence Others-(13-08-2014).pdf

1319-delnp-2007-Correspondence Others-(14-08-2012).pdf

1319-delnp-2007-Correspondence Others-(15-02-2013).pdf

1319-DELNP-2007-Correspondence Others-(15-07-2011).pdf

1319-delnp-2007-Correspondence Others-(17-10-2013).pdf

1319-delnp-2007-Correspondence Others-(20-07-2012).pdf

1319-delnp-2007-Correspondence Others-(25-04-2013).pdf

1319-delnp-2007-Correspondence Others-(25-11-2013).pdf

1319-delnp-2007-Correspondence Others-(26-03-2013).pdf

1319-delnp-2007-Correspondence Others-(29-08-2014).pdf

1319-delnp-2007-Correspondence Others-(30-11-2012).pdf

1319-delnp-2007-Correspondence-others (06-06-2008).pdf

1319-delnp-2007-Correspondence-Others-(01-07-2013).pdf

1319-delnp-2007-Correspondence-Others-(03-05-2013).pdf

1319-delnp-2007-Correspondence-Others-(03-07-2013).pdf

1319-delnp-2007-Correspondence-Others-(14-08-2014).pdf

1319-delnp-2007-Correspondence-Others-(18-07-2013).pdf

1319-delnp-2007-Correspondence-Others-(21-06-2013).pdf

1319-delnp-2007-correspondence-others.pdf

1319-delnp-2007-description(complete).pdf

1319-delnp-2007-form-1.pdf

1319-DELNP-2007-Form-13 (06-06-2008).pdf

1319-delnp-2007-Form-13-(18-07-2013).pdf

1319-delnp-2007-Form-18 (06-06-2008).pdf

1319-delnp-2007-Form-2-(30-11-2012).pdf

1319-delnp-2007-form-2.pdf

1319-delnp-2007-Form-3-(01-01-2014).pdf

1319-delnp-2007-Form-3-(03-07-2013).pdf

1319-delnp-2007-Form-3-(09-11-2012).pdf

1319-delnp-2007-Form-3-(14-08-2014).pdf

1319-DELNP-2007-Form-3-(15-07-2011).pdf

1319-delnp-2007-form-3.pdf

1319-delnp-2007-form-5.pdf

1319-delnp-2007-GPA-(25-04-2013).pdf

1319-delnp-2007-gpa.pdf

1319-delnp-2007-pct-301.pdf

1319-delnp-2007-pct-304.pdf

1319-delnp-2007-pct-308.pdf

1319-delnp-2007-pct-332.pdf

1319-delnp-2007-pct-338.pdf

1319-delnp-2007-pct-409.pdf

1319-delnp-2007-Petition-137-(12-11-2012).pdf

1319-delnp-2007-Petition-137-(20-07-2012).pdf

abstract.jpg

Cover letter along with relevant documents.pdf

Cover letter with petition.pdf

Petition under Rule 137.pdf

Petition u_R 137.pdf


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Patent Number 262657
Indian Patent Application Number 1319/DELNP/2007
PG Journal Number 36/2014
Publication Date 05-Sep-2014
Grant Date 03-Sep-2014
Date of Filing 19-Feb-2007
Name of Patentee CHUGAI SEIYAKU KABUSHIKI KAISHA
Applicant Address 5-1, UKIMA 5-CHOME, KITA-KU, TOKYO 1158543 JAPAN
Inventors:
# Inventor's Name Inventor's Address
1 ISSHIKI, YOSHIAKI C/O CHUGAI SEIYAKU KABUSHIKI KAISHA, 200, KAJIWARA, KAMAKURA-SHI, KANAGAWA 2478530, JAPAN
2 KOHCHI, YASUNORI C/O CHUGAI SEIYAKU KABUSHIKI KAISHA, 200, KAJIWARA, KAMAKURA-SHI, KANAGAWA 2478530, JAPAN
3 TSUJII, SHINJI C/O CHUGAI SEIYAKU KABUSHIKI KAISHA, 200, KAJIWARA, KAMAKURA-SHI, KANAGAWA 2478530, JAPAN
4 SHIMMA, NOBUO C/O CHUGAI SEIYAKU KABUSHIKI KAISHA, 200, KAJIWARA, KAMAKURA-SHI, KANAGAWA 2478530, JAPAN
5 MIWA, MASANORI C/O CHUGAI SEIYAKU KABUSHIKI KAISHA, 200, KAJIWARA, KAMAKURA-SHI, KANAGAWA 2478530, JAPAN
6 AIDA, SATOSHI C/O CHUGAI SEIYAKU KABUSHIKI KAISHA, 200, KAJIWARA, KAMAKURA-SHI, KANAGAWA 2478530, JAPAN
7 KOHCHI, MASAMI C/O CHUGAI SEIYAKU KABUSHIKI KAISHA, 200, KAJIWARA, KAMAKURA-SHI, KANAGAWA 2478530, JAPAN
8 MIZUGUCHI, EISAKU C/O CHUGAI SEIYAKU KABUSHIKI KAISHA, 200, KAJIWARA, KAMAKURA-SHI, KANAGAWA 2478530, JAPAN
9 IIKURA, HITOSHI C/O CHUGAI SEIYAKU KABUSHIKI KAISHA, 200, KAJIWARA, KAMAKURA-SHI, KANAGAWA 2478530, JAPAN
10 MATSUBARA, YASUAKI C/O CHUGAI SEIYAKU KABUSHIKI KAISHA, 200, KAJIWARA, KAMAKURA-SHI, KANAGAWA 2478530, JAPAN
11 MURATA, TAKESHI C/O CHUGAI SEIYAKU KABUSHIKI KAISHA, 200, KAJIWARA, KAMAKURA-SHI, KANAGAWA 2478530, JAPAN
12 ASO, KOSUKE C/O CHUGAI SEIYAKU KABUSHIKI KAISHA, 200, KAJIWARA, KAMAKURA-SHI, KANAGAWA 2478530, JAPAN
PCT International Classification Number C07C 259/10
PCT International Application Number PCT/JP2005/013620
PCT International Filing date 2005-07-26
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 2005-072093 2005-03-14 Japan
2 2004-218004 2004-07-26 Japan