Title of Invention

"A HETEROCYCLIC PHENYL OR PYRIDYL AMINO ACID COMPOUND"

Abstract A heterocyclic phenyl or pyridyl amino acid compound of the structure wherein x is 1,2, 3 or 4; m is 1 or 2; n is 1 or 2; and R1, R2, R- and R4 are as herein described, which compounds are useful as antidiabetic, hypolipidemic, and antiobesity agents.
Full Text This application takes priority from U.S. provisional application No. 60/155,400 filed September 22, 1999.
Field of the Invention The present invention relates to novel substituted acid derivatives which modulate blood glucose levels, triglyceride levels, insulin levels and non-esterified fatty acid (NEFA) levels, and thus are particularly useful in the treatment of diabetes and obesity, and to a method for treating diabetes, especially Type 2 diabetes, as well as hyperglycemia, hyperinsulinemia, hyperlipidemia, obesity, atherosclerosis and related diseases employing such substituted acid derivatives alone or in combination with another antidiabetic agent and/or a hypolipidemic agent.
Description of the Invention In accordance with the present invention, substituted acid derivatives are provided which have the structure I

(Structure Removed)
wherein x is 1, 2, 3 or 4; m is 1 or 2; n is 1 or 2;
Q is C or N;
A is O or S;
Z is O or a bond;
R1 is H or alkyl;
X is CH or N;
R2 is H, alkyl, alkoxy, halogen, amino or substituted amino;

LA29 NP
R2a, R2b and R2c may be the same or different and
are selected from H, alkyl, alkoxy, halogen, amino or
substituted amino;
R3 is H, alkyl, arylalkyl, aryloxycarbonyl,
alkyloxycarbonyl, alkynyloxycarbonyl, alkenyloxycarbonyl,
arylcarbonyl, alkylcarbonyl, aryl, heteroaryl,
alkyl(halo)aryloxycarbonyl, alkyloxy(halo)aryloxycarbonyl
cycloalkylaryloxycarbonyl,
cycloalkyloxyaryloxycarbonyl, cycloheteroalkyl,
heteroarylcarbonyl, heteroaryl-heteroarylalkyl,
alkylcarbonylamino, arylcarbonylamino,
heteroarylcarbonylamino, alkoxycarbonylamino,
aryloxycarbonylamino, neteroaryloxycarbonylaird.no,
heteroaryl-heteroarylcarbonyl, alkylsulfonyl,
alkenylsulfonyl, heteroaryloxycarbonyl,
cycloheteroalkyloxycarbonyl, heteroarylalkyl,
aminocarbonyl, substituted aminocarbonyl,
alkylaminocarbonyl, arylaminocarbonyl, heteroarylalkenyl,
cycloheteroalkyl-heteroarylalkyl; hydroxyalkyl, alkoxy,
alkoxyaryloxycarbonyl, arylalkyloxycarbonyl,
alkylaryloxycarbonyl, arylheteroarylalkyl,
arylalkylarylalkyl, aryloxyarylalkyl,
haloalkoxyaryloxycarbonyl, alkoxycarbonylaryloxycarbonyl,
aryloxyaryloxycarbonyl, arylsulfinylarylcarbonyl,
arylthioarylcarbonyl, alkoxycarbonylaryloxycarbonyl,
arylalkenyloxycarbonyl, heteroaryloxyarylalkyl,
aryloxyarylcarbonyl, aryloxyarylalkyloxycarbonyl,
arylalkenyloxycarbonyl, arylalkylcarbonyl,
aryloxyalkyloxycarbonyl, arylalkylsulfonyl,
arylthiocarbonyl, arylalkenylsulfonyl,
heteroarylsulfonyl, arylsulfonyl, alkoxyarylalkyl,
heteroarylalkoxycarbonyl, arylheteroarylalkyl,
alkoxyarylcarbonyl, aryloxyheteroarylalkyl,
heteroarylalkyloxyarylalkyl, arylarylalkyl,
arylalkenylarylalkyl, arylalkoxyarylalkyl,
arylcarbonylarylalkyl, alkylaryloxyarylalkyl,
arylcarbonylheteroarylalkyl, heteroaryloxyarylalkyl, arylalkenylheteroarylalkyl, arylaminoarylalkyl-, aminocarbonylarylarylalkyl;
Y is CO2R4 (where R4 is H or alkyl, or a prodrug ester)
(CH2)X, (CH2)n and (CH2)B, may be optionally substituted with 1, 2 or 3 substituents;
including all stereoisomers thereof, prodrug esters thereof, and pharmaceutically acceptable salts thereof, with the proviso that
where X is CH, A is O, Q is C, Z is O, and Y is CO2R4, then R3 is other than H or alkyl containing 1 to 5 carbons in the normal chain.
Preferred are compounds of formula I of the invention having the structure

(Figure Removed)
More preferred are compounds of formula I of the
invention'having the structures
(Figure Removed)
In the above compounds, it is most preferred that
R2a is alkoxy, but more preferably H, Z is a bond, but
more preferably 0, (CH2)X is CH2, (CR2)2, (CH2)3, or
— *c - , (CH2)m is CH2, or — c« - (where Ra is alkyl such
as methyl, or alkenyl such as CH2~~ CH==CH2 Or
CH2 —C=
^ ), (CH2)n is CH2, R1 is lower alkyl,
preferably -CH3, R2 is H, R2a is H, R4 is H, X is CH, and
R3 is arylalkyloxycarbonyl, arylheteroarylalkyl,
aryloxyarylalkyl, arylalkyl, aryloxycarbonyl, haloaryloxycarbonyl,
alkoxyaryloxycarbonyl, alkylaryloxycarbonyl,
aryloxyaryloxycarbonyl, heteroaryloxyarylalkyl,
heteroaryloxycarbonyl, aryloxyarylcarbonyl,
arylalkenyloxycarbonyl, cycloalkylaryloxycarbonyl,
arylalkylarylcarbonyl, heteroaryl-heteroarylalkyl,
cycloalkyloxyaryloxycarbonyl, heteroarylheteroarylcarbonyl,
alkyloxyaryloxycarbonyl,
arylalkylsulfonyl, arylalkenylsulfonyl, alkoxyarylalkyl,
arylthiocarbonyl, cycloheteroalkylalkyloxycarbonyl,
cycloheteroalkyloxycarboliyl, or polyhaloalkylaryloxycarbonyl,
wherein the above preferred groups may be
optionally substituted.
Preferred compounds of the invention include the
following:
(Figure Removed)

In addition, in accordance with the present
invention, a method is provided for treating diabetes,
especially Type 2 diabetes, and related diseases such as
insulin resistance, hyperglycemia, hyperinsulinemia,
elevated blood levels of fatty acids or glycerol,
hyperlipidemia, obesity, hypertriglyceridemia and
atherosclerosis wherein a therapeutically effective
amount of a compound of structure I is administered to a
human patient in need of treatment.
In addition, in accordance with the present
invention, a method is provided for treating early
malignant lesions (such as ductal carcinoma in situ of
the breast and lobular carcinoma in situ of the breast) ,
premalignant lesions (such as fibroadenoma of the breast
and prostatic intraepithelial neoplasia (PIN),
liposarcomas and various other epithelial tumors
(including breast, prostate, colon, ovarian, gastric and
lung), irritable bowel syndrome, Crohn's disease, gastric
ulceritis, and osteoporosis and proliferative diseases
such as psoriasis, wherein a therapeutically effective
amount of a compound of structure I is administered to a
human patient in need of treatment.
In addition, in accordance with the present
invention, a method is provided for treating diabetes and
related diseases as defined above and hereinafter,
wherein a therapeutically effective amount of a
combination of a compound of structure I and another type
antidiabetic agent and/or a hypolipidemic agent, is
administered to a human patient in need of treatment.
In the above method of the invention, the compound
of structure I will be employed in a weight ratio to the
antidiabetic agent (depending upon its mode of operation)
within the range from about 0.01:1 to about 100:1,
preferably from about 0.5:1 to about 10:1.
Detailed Description of the Invention
The compounds of the formula I of the present
invention may be prepared according to the following
general synthetic schemes, as well as relevant published
literature procedures that are used by one skilled in the
art. Exemplary reagents and procedures for these
reactions appear hereinafter and in the working Examples.
Protection and deprotection in the Schemes below may be

carried out by procedures generally known in the art
(see, for example, Greene, T. W. and Wuts, P. G. M.,
Protecting Groups in Organic Synthesis, 3rd Edition, 1999
[Wiley] ) .
Scheme 1 describes a general synthesis of the amino
acids described in this invention. An alcohol II
(R5(CH2)XOH) (of which the most favored is 2-phenyl-5-
methyl-oxazole-4-ethanol) is coupled with a hydroxy arylor
heteroaryl- aldehyde III (preferably 3- or 4-
hydroxybenzaldehyde) under standard Mitsunobu reaction
conditions (e.g. Mitsunobu, 0., Synthesis , 1981, 1).
The resulting aldehyde IV is then subjected to reductive
amination using procedures known in the literature (e.g.
Abdel-Magid et al, J. Org. Chem. 1996, '61, 3849) with an
a-amino ester hydrochloride V. PG in Scheme 1 denotes a
preferred carboxylic acid protecting group, such as a
methyl or tert-butyl ester. The resulting secondary
amino-ester VI is then subjected to a second reductive
amination using methods known in the literature (e.g.
Abdel-Magid et al, J. Org. Chem. 1996, 61, 3849) with an
R3a aldehyde VII. Final deprotection of the carboxylic
acid ester under standard conditions known in the
literature (Greene) utilizing basic conditions (for
methyl esters) or acidic conditions (for tert-butyl
esters) then furnishes the desired amino acid products
ID.
An alternative route to the aldehyde IV is shown in
Scheme 1A. The alcohol II (R5(CH2)XOH) (of which the most
favored is 2-[2-phenyl-5-methyl-oxazole-4-yl]-ethanol) is
treated with methanesulfonyl chloride to give the
corresponding mesylate VIII. The mesylate is then
alkylated under standard basic conditions with a
hydroxyaryl or hydroxyheteroaryl aldehyde III to furnish
the aldehyde IV.
An alternative route to the amino acids IF is shown
in Scheme 2. The secondary amino-ester VI is deprotected
under standard conditions (basic conditions if the
protecting group (PG) is methyl; acidic conditions if PG
is tert-butyl) to furnish the corresponding amino acid
IE. Reductive amination with an R3a aldehyde under
analogous conditions as described in Scheme 1 furnishes
the desired tertiary amino acid products IF.
Alternatively, as shown in Scheme 3, the tertiary
amino acids IF may also be obtained by alkylation of the
secondary amino-ester VI with an alkylating agent IX
(with an appropriate leaving group (LG) such as halide,
mesylate, or tosylate) under standard conditions known in
the art followed again by standard deprotection of the
carboxylic acid ester X to provide the amino acids IF.
As shown in Scheme 4, the tertiary amino acid IF
may also be assembled through reductive amination first
of the R3a aldehyde XI with an appropriate amine ester
hydrochloride V. The resulting secondary amine-ester XII
then is subjected to reductive amination with the
appropriate alkyl, aryl or heteroaryl aldehyde IV (as in
Scheme 1) followed by deprotection of the carboxylic acid
ester to give the desired amino acid analogs IF.
For further substituted amino acids, a general
synthetic scheme is shown in Scheme 5. Reductive
amination of an appropriate amine XIII with an aryl or
heteroaryl aldehyde XIV under standard conditions
furnishes the corresponding secondary amine XV, which is
then reacted with a halide-ester XVI (e.g. tert-butyl
bromoacetate) to furnish the corresponding a-amino ester
XVII. This amine-ester XVII is then deprotected under
standard conditions to provide the desired amino acid
analogs IF.
The synthetic route in Scheme 5 also provides a
general scheme for the synthesis of the corresponding
aminophosphonic acids IFA, as illustrated in Scheme 5a.
The secondary amine XV is reacted with an appropriately
protected halide-phosphonate XVIA to provide the
corresponding aminophosphonate ester XVIIA, which is then
deprotected under standard conditions (Greene & Wuts) to
furnish the amino phosphohic acid IFA. Scheme 5b
illustrates the synthesis of the aminophosphinic acids
IFB, which again involves the reaction of an
appropriately protected halide-phosphinate ester XVIB
with the secondary amine XV. Deprotection of the
resulting aminophosphinate ester then provides the
phosphinic acid IFB.
An alternative to the sequence in Scheme 5 is shown
in Scheme 6. A hydroxyaryl or heteroaryl amine XVIII is
selectively protected on nitrogen to provide protected
amine XIX. A preferred R5(CH2 )nOH (II) is then reacted
with XIX under Mitsunobu conditions to provide the
corresponding ether, followed by deprotection of the
amine, to form the free amine XX. The free amine XX is
then activated with a standard activating group (2,4-
dinit robenzenesulf onamide; T. Fukuyama et al, Tetrahedron
Lett. 1997, 38, 5831) and is then treated with an a-halo
ester XVI as in Scheme 5. The 2,4 dinitrobenzenesulfonamide
XXI is deprotected under literature
conditions (T. Fukuyama et al, Tetrahedron Lett., 1997,
38, 5831) to furnish a secondary a-amino-ester XXII which
is then subjected to a reductive amination with an R3a
aldehyde XI followed by deprotection of the ester X to
furnish the desired analogs IF.
Scheme 7 describes an alternative general route to
the amino acid analogs IG. A hydroxyaryl or heteroaryl
aldehyde III is subjected to the usual reductive
amination conditions with an appropriate amine—ester
hydrochloride V. The resulting secondary amine-ester
XXIII is functionalized, in this case by a second
reductive amination with an R3a aldehyde VII to furnish
the corresponding hydroxy tertiary amine-ester XXIV.
This can now undergo a Mitsunobu reaction with a
preferred alcohol II (R5(CH2 ) nOH) which followed by
deprotection of the ester XXV furnishes the desired
analogs IG.
Scheme 8 describes a general synthesis of diaryl
and aryl-heteroaryl-substituted amino acid analogs IH.
The secondary amine-ester XXII undergoes reductive
amination with an appropriately substituted formyl phenyl
boronic acid XXVI under standard conditions to give the
corresponding tertiary amine-ester boronic acid XXVII.
The aryl boronic acid XXVII can then undergo a Suzuki
coupling (e.g. conditions as described in Gibson, S. E.,
Transition Metals in Organic Synthesis, A Practical
Approach, pp. 47-50, 1997) with aryl or heteroaryl
halides XXVIII (especially bromides) to furnish the
appropriate cross-coupling diaryl products XXIX.
Deprotection of the amine-ester XXIX generates the
desired amino acid analogs IH.
Scheme 9 describes a general synthesis of diaryl
and aryl-heteroaryl ether-substituted amino acid analogs
IJ. The tertiary amine-ester boronic acid XXVII which is
described in Scheme 8 can be coupled with appropriately
substituted phenols XXX under literature conditions (D.
A. Evans et al, Tetrahedron Lett.,. 1998, 39, 2937) to
furnish the appropriate diaryl or aryl-heteroaryl ethers
XXXI, which after deprotection afford the desired amino
acid analogs IJ.
Alternatively, as shown in Scheme 10, reductive
amination of the secondary amine-ester XXII with an
appropriately substituted hydroxyaryl or
hydroxyheteroaryl aldehyde XXXII furnishes the
corresponding phenol-tertiary amine-ester XXXIII. The
phenol XXXIII can then undergo coupling with appropriate
aryl or heteroaryl boronic acids XXXIV under literature
conditions (D. A. Evans et al, Tetrahedron Lett., 1998,
39, 2937) to furnish the corresponding diaryl or
arylheteroaryl ether-amino esters XXXI. The desired
analogs IJ are then obtained after deprotection of the
amine-ester XXXI.
Scheme 11 illustrates the synthesis of the
carbamate-acid analogs IK. The secondary amine-ester
XXII can be reacted with appropriate chloroformates XXXV
under standard literature conditions (optimally in CHzCla
or CHC13 in the presence of a base such as Et3N) to
furnish the corresponding carbamate-esters. The
requisite analogs IK are then obtained after deprotection
of the carbaraate-ester. Alternatively, the secondary
amine-ester XXII can be reacted with phosgene to generate
the corresponding carbamyl chloride XXXVI. This carbamyl
chloride intermediate XXXVI can be reacted with R3a-OH
(XXXVII)(optimally substituted phenols) to afford the
corresponding carbamate-acids IK after deprotection.
Scheme 12 illustrates the further functionalization
of aryl carbamate-acid analogs IK. The secondary amineester
XXII is reacted with an aryl chloroformate XXXVIII
(containing a protected hydroxyl group) to form XXXIX.
The hydroxyl group is then selectively deprotected in the
presence of the ester functionality to provide XL, then
alkylated with an appropriate R6-LG (XLI) (where LG is
halide, mesylate or tosylate, and R6 is most preferably
CHF2-, or CH3CH2-) in the presence of base. Deprotection
of the ester then furnishes the desired carbamate-acid
analogs IL.
The secondary amine-ester XXIIA can be
functionalized with substituted aryl or aliphatic
carboxylic acids XLII, under standard peptide coupling
conditions, as illustrated in Scheme 13. The amide bondforming
reactions are conducted under standard peptide
coupling procedures known in the art. Optimally, the
reaction is conducted in a solvent such as DMF at 0°C to
RT using l-ethyl-3-(3-dimethylaminopropyl) carbodiimide
(EDAC or EDCI or WSC), 1-hydroxybenzotriazole (HOBT) or
l-hydroxy-7-azabenzotriazole (HOAT) and a base, for
example Hunig's base (diisopropylethylamine), N-methyl
morpholine or triethylamine. Deprotection of the amideester
then furnishes the desired amide-acid analogs IM.
The secondary amine-ester XXIIA can also be reacted
with aliphatic or aryl isocyanates XLIII to provide the
corresponding urea-esters. Deprotection of the ureaester
provides the desired urea-acid analogs IN, as shown
in Scheme 14. Alternatively, as shown in Scheme 15, the
carbamyl chloride intermediate XXXVI described in Scheme
11 can be reacted with appropriate aliphatic or aryl
amines XLIV in the presence of a tertiary amine (e.g.
Et3N) to furnish tri- or tetrasubstituted urea-acid
analogs 10 or IP after deprotection of the ester.
The secondary amine-ester XXIIA can also be reacted
with appropriate sulfonyl chlorides XLVI under standard
literature conditions (optimally in the presence of a
base such as pyridine, either neat or using chloroform as
a co-solvent), followed by deprotection, to provide the
corresponding sulfonamide-acids IQ, as shown in Scheme
16.
Replacement of the carboxylic acid functionality in
these analogs with tetrazole can be achieved as shown in
Scheme 17. An acid analog IK is coupled with an amine
(containing an appropriate tetrazole protecting group)
XLVII (preferably 3-amino propionitrile) under standard
peptide coupling conditions. The resulting secondary
amide XLVIII is then subjected to a Mitsunobu reaction
under standard conditions with trimethylsilyl azide
(TMSN3) to form the protected tetrazole XLIX.
Deprotection of the cyanoethyl group, is achieved
preferentially in the presence of base to generate the
desired free tetrazole analog IR.
Scheme 18 describes a general synthesis of the
hydrazide-acid analogs IS. A substituted aryl carboxylic
acid 1 is treated with methanesulfonyl chloride in the
presence of base; the intermediate is then reacted with a
protected hydrazine-ester VA to give the corresponding
acylated hydrazine la (ref: Synthesis, 1989, 745-747).
The acylhydrazine la is coupled with an appropriately
substituted aryl aldehyde IV under reductive amination
conditions to give the corresponding protected hydrazide
ester 3 (ref: Can. J. Cham., 1998, 76, 1180-1187).
Deprotection of the ester 3 then furnishes the hydrazideacid
analogs IS.
An alternative synthetic approach to hydrazideacids
IS is shown in Scheme 19. An aryl aldehyde IV can
be reduced to the corresponding alcohol under standard
conditions (e.g NaBH4) . This alcohol is then converted to
the corresponding bromide 4 using standard conditions
(e.g. Ph3P/CBr4 or PBr3) . The bromide 4 is then reacted
with the hydrazine -ester la (ref: Tetrahedron Lett.,
1993, 34, 207-210) to furnish the protected hydrazideester
3, which is then deprotected to give the hydrazideacid
analogs IS.
The different approaches to the preparation of the
a-alkylbenzyl amino acid and carbamate-acid analogs IT
and IU are exemplified in the following synthetic
schemes. In Scheme 20 an appropriately substituted aryl
aldehyde IV is treated with a suitable organometallic
reagent (e.g. a Grignard reagent R10MgBr) under standard
conditions to give the corresponding secondary alcohol,
which is then oxidized under standard conditions (e.g.
Swern oxidation with (COCl)2/DMSO/Et3N or using pyridinium
chlorochromate) to give the corresponding ketone 5.
Reductive amination of the ketone 5 with an appropriately
substituted amino-ester 6 provides the corresponding aalkylbenzyl
amino-ester 7. It will be understood that in
the amino ester 6, the moiety x 'n does not necessarily
represent two repeating units .
Acylation of amino-ester 7 with an appropriately
substituted aryl or heteroaryl chloroformate XXXV
followed by deprotection provides the racemic carbamateacid
analogs IT. Reductive amination of alkylbenzyl
amino-ester 7 with aryl aldehyde VII followed by
deprotection provides the racemic amino-acid analogs IU.
Alternatively, as shown in Scheme 21, asymmetric
reduction (e.g. using the Corey oxazaborolidine reduction
protocol; review: E. J. Corey & C. Helal, Angew. Chem.
Jut. Ed. Engl., 1998, 37, 1986-2012.) of the aryl-ketone
5 provides each of the desired enantiomeric alcohols 8
(although only one enantiomer is represented in the
scheme) . Treatment of the chiral alcohol 8 with azide in
a Mitsunobu-like reaction (ref: A. S. Thompson et. al.,
J. Org. Chem. 1993, 58, 5886-5888) gives the
corresponding chiral azide (with inverted stereochemistry
from the starting alcohol) . The azide is then converted
to the amine 9 by standard reduction methods (e.g.
hydrogenation or Ph3P/THF/H2O) . Treatment of the chiral
amine 9 with an ester XVIA (containing an appropriate
leaving group) provides the secondary amino-ester 10.
Acylation of amino-ester 10 with an aryl or heteroaryl
chloroformate XXXV followed by deprotection provides the
chiral carbamate-acid analogs ITa (which may be either
enantiomer depending upon the stereochemistry of 8) .
Reductive amination of alkyl amino-ester 10 with aryl
aldehydes VII followed by deprotection provides the
chiral amino-acid analogs lUa (which may be either
enantiomer depending upon the stereochemistry of 8) .
An alternative to Scheme 21 is shown in Scheme 22 ,
An appropriately protected oxyaryl ketone 11 undergoes
asymmetric reduction to give the chiral alcohol 12. This
is converted to the chiral amine 13 via the identical
sequence as in Scheme 21 (via the chiral azide) .
Treatment of the chiral amine 13 with an ester XVIA (LG =
halogen or mesylate) gives the corresponding secondary
amino-ester 14. Acylation of 14 with an aryl or
heteroaryl chloroformate XXXV provides the corresponding
carbamate-ester. Selective deprotection furnishes the
free phenol carbamate-ester 15. Alkylation of the phenol
15 with a halide or mesylate VIII followed by
deprotection provides the carbamate-acid analogs ITa. An
analogous sequence (involving reductive amination of the
secondary amino-ester 14 with an aryl or heteroaryl
aldehyde VII, then selective deprotection, alkylation
with VIII and a final deprotection) provides the amino
acid analogs lUa.
It will be appreciated that either the (R) - or (S) -
enantiomer of ITa or lUa may be synthesized in Schemes 21
and 22, depending upon the chirality of the reducing
agent employed.
A fourth synthetic sequence is shown in Scheme 23 .
The substituted aldehyde IV is condensed with an aminoester
hydrochloride 6 to give the corresponding imine 16,
which is then treated in situ with an appropriately
substituted allylic halide 17 in the presence of indium
metal (reference: Loh, T . - P . , et al., Tetrahedron Lett.,
1997, 38, 865-868) to give the a-allyl benzyl amino-ester
18. Acylation of amine 18 with an aryl or heteroaryl
chloroformate XXXV followed by deprotection provides the
carbamate-acid analogs Iv. Reductive amination of alkyl
amino-ester 18 with an aryl or heteroaryl aldehyde VII
followed by deprotection provides the amino-acid analogs
IW.
Scheme 24 shows the preparation of the required
intermediate 2-aryl-5-methyl-oxazol-4-yl methyl chloride
21 (following the general procedure described in Malamas,
M. S., et al, J. Med. Chsm., 1996, 39, 237-245) . A
substituted aryl aldehyde 19 is condensed with butane-
2,3-dione mono-oxime under acidic conditions to give the
corresponding oxazole N-oxide 20. Deoxygenation of the
oxazole N-oxide 20 with concomitant chlorination
furnishes the desired chloromethyl aryl-oxazoles 21.
Hydrolysis of chloromethyl oxazole 21 under basic
conditions furnishes the corresponding oxazole-methanol
22. Oxidation of alcohol 22 to the corresponding
aldehyde is followed by conversion to the corresponding
dibromoalkene 23 (e.g. Ph3P/CBr4) . The dibromide 23 is
converted to the corresponding alkynyl-lithium species
(using an organolithium reagent such as n-BuLi) , which
can be reacted in situ with an appropriate electrophile
such as formaldehyde to give the corresponding acetylenic
alcohol (ref: Corey, E. J. , et al., Tetrahedron Lett.
1972, 3769, or Gangakhedkar, K. K., Synth. Common. 1996,
26, 1887-1896) . This alcohol can then be converted to
the corresponding mesylate 24 and alkylated with an
appropriate phenol 25 to provide analogs Ix. Further
stereoselective reduction (e.g. H2/Lindlar's catalyst)
provides the E- or Z- alkenyl analogs IY.
Scheme 25 describes a general synthesis of the
amino-benzoxazole analogs IZ (general ref: Sato, Y., et
al, J". Med. Chem. 1998, 41, 3015-3021) . An appropriately
substituted ortho-aminophenol 26 is treated with CS2 in
the presence of base to furnish the corresponding
mercapto-benzoxazole 27. Treatment of this thiol 27 with
an appropriate chlorinating agent (e.g. PCls) provides the
key intermediate chlorobenzoxazole 28, which is reacted
with the secondary amino-ester VI to furnish, after
deprotection, the amino benzoxazole-acid analogs IZ.
The thiazole analogs IZa were synthesized according
to the general synthetic route outlined in Scheme 26
(ref. Collins, J. L. , et al., J. Med. Chem. 1998, 41,
5037) . The secondary amino-ester XXIII is reacted with
an aryl or heteroaryl chloroformate XXXV in the presence
of an appropriate base (e.g. pyridine or triethylamine)
to furnish the corresponding hydroxyaryl carbamate-ester
29. The hydroxyaryl ester 29 is then reacted with an
appropriately substituted a-bromo vinyl ketone 29a (for S3
= CH3, e.g. Weyerstahl, P., et. al., Flavour Fra.gr. J.,
1998, 13, 177 or Sokolov, N. A., et al., Zh. Org. Khim. ,
1980, 16, 281-283) in the presence of an appropriate base
(e.g. K2C03) to give the corresponding Michael reaction
adduct, the a-bromoketone carbamate-ester 30. The abromoketone
30 is then subjected to a condensation
reaction with an appropriately substituted aryl amide 31
(A = O) or aryl thioamide 31 (A = S) to furnish either
the corresponding oxazole (from the amide) or the
thiazole (from the thioamide) (ref: Malamas, M. S., et
al, J. Med.'Chem., 1996, 39, 237-245). Finally,
deprotection of esters 31 then provides the substituted
oxazole and thiazole carbamate acid analogs IZa.
It will be appreciated that in the following
schemes where the carbamate-acid analogs are prepared,
the corresponding amino acid analogs may also be prepared
by replacing the chloroformate reaction with an aldehyde
in a reductive amination reaction (as in Scheme 20 with
intermediate amine 7) .
Scheme 27 describes a general synthesis of the
acids IZb and IZc. A halo-substituted aryl aldehyde 32
(preferably iodide or bromide) is subjected to reductive
amination using procedures known in the literature (e.g.
Abdel-Magid et al, J. Org. Chem. 1996, 61, 3849) with an
a-amino acid ester hydrochloride V. The resulting
secondary amino-ester 33 is then reacted with an aryl or
heteroaryl chloroformate XXXV in the presence of an
appropriate base (e.g. pyridine or triethylatnine) to
furnish the corresponding halo-aryl carbamate-ester 34.
Aryl halide 34 is then reacted with an appropriate arylor
he teroaryl-substituted acetylene 35 (the preferred
acetylene being 5-phenyl-2-methyl-oxazol-4-ylmethylacetylene)
in the presence of an appropriate
palladium catalyst (e.g. (Ph3P)2PdCl2) and a copper (I)
salt (e.g. Cul) in a Sonogashira coupling reaction (ref:
Organocopper Reagents, a Practical Approach, R. J. K.
Taylor, Ed., Chapter 10, pp 217-236, Campbell, I. B.,
Oxford University Press, 1994) to furnish the key
intermediate, arylacetylene carbamate ester 36.
The arylacetylene ester 36 is deprotected to
provide the corresponding arylacetylene acid analogs IZb.
The acetylene moiety of 36 can be reduced by standard
methods (e.g. hydrogenation, ref: M. Hudlicky,
Reductions in Organic Chemistry, 2nd Edition, ACS, 1996,
Chapter 1) to furnish the corresponding fully saturated
alkyl aryl carbamate ester, which is then deprotected to
give the alkyl aryl carbamate acid analogs IZc.
Stereoselective reduction of the acetylene ester 36
by standard methods (e.g. Lindlar's catalyst; ref:
Preparation of Alkenes, A Practical Approach, J. J.
Williams, Ed., Chapter 6, pp 117-136, Oxford University
Press, 1996) can be achieved to provide the corresponding
cis-alkenyl aryl carbamate-ester, which is then
deprotected to furnish the Z-alkenyl aryl carbamate acid
analogs IZd (Scheme 28) . Alternatively, this sequence
can be reversed, i.e. the initial step being the
deprotection of acetylenic ester 36 to the acetylenic
acid, followed by Stereoselective reduction of the
acetylene moiety to provide the Z-alkene-acid analogs
IZd.
The corresponding trans-alkenyl aryl carbamate
acids IZe can be synthesized according to the general
route in Scheme 29. An aryl- or heteroaryl-acetylene 35
(the preferred moiety again being 5-phenyl-2-methyloxazol-
4-yl-methylacetylene) is halogenated under
standard conditions (ref: Boden, C. D. J. et al., J.
Chem. Soc. Parkin Trans. I, 1996, 2417; or Lu, W. et.
al., Tetrahedron Lett. 1998, 39, 9521) to give the
corresponding halo-acetylene, which is then converted to
the corresponding trans-alkenyl stannane 37 (ref: Boden,
C. D. J. , J. Chem. Soc., Parkin Trans. I, 1996, 2417).
This aryl- or heteroaryl-substituted trans-alkenyl
stannane 37 is then coupled with the halo-aryl carbamate
ester 34 under standard Stille coupling conditions (ref:
Farina, V. et. al., "The Stille Reaction", Organic
Reactions, 1997, 50, 1) to furnish the corresponding
trans-alkenyl aryl carbamate ester 38. This carbamateester
is then deprotected under standard conditions to
give the desired trans-alkenyl aryl carbamate acid
analogs IZe.
The corresponding cyclopropyl analogs IZf and IZg
are synthesized according to Scheme 30. For the cis- or
(Z-) cyclopropyl analogs, Stereoselective reduction (H2/
Lindlar's catalyst) of the alkynyl moiety of intermediate
alknyl ester 36 (as for analogs IZd), followed by
cyclopropanation under standard conditions (Zhao, Y . , et
al, deprotection provides the cis-cyclopropyl carbamate-acid
analogs IZf. For the trans-cyclopropyl analogs IF,
analogous cyclopropanation of the E-alkene moiety of
intermediate 38 followed by deprotection provides the
trans-cyclopropyl carbamate-acid analogs IZg.
(Table Removed)

Unless otherwise indicated, the term "lower
alkyl", "alkyl" or "alk" as employed herein alone or as
part of another group includes both straight and branched
chain hydrocarbons, containing 1 to 20 carbons,
preferably 1 to 10 carbons, more preferably 1 to 8
carbons, in the normal chain, and may optionally include
an oxygen or nitrogen in the normal chain, such as
methyl, ethyl, propyl, isopropyl, butyl, t-butyl,
isobutyl, pentyl, hexyl, isohexyl, heptyl, 4 , 4 —
dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl,
decyl, undecyl, dodecyl, the various branched chain
isomers thereof, and the like as well as such groups
including 1 to 4 substituents such as halo, for example
F, Br, Cl or I or CFa, alkoxy, aryl, aryloxy, aryl(aryl)
or diaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl,
cycloalkylalkyl, cycloalkylalkyloxy, amino, hydroxy,
hydroxyalkyl, acyl, heteroaryl, heteroaryloxy,
cycloheteroalkyl, arylheteroaryl, arylalkoxycarbonyl,
heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl/
aryloxyaryl, alkylamido, alkanoylamino,
arylcarbonylamino, nitro, cyano, thiol, haloalkyl,
trihaloalkyl and/or alkylthio and/or any of the R3
groups.
Unless otherwise indicated, the term "cycloalkyl"
as employed herein alone or as part of another group
includes saturated or partially unsaturated (containing 1
or 2 double bonds) cyclic hydrocarbon groups containing 1
to 3 rings, including monocyclicalkyl, bicyclicalkyl and
tricyclicalkyl, containing a total of 3 to 20 carbons
forming the rings, preferably 3 to 10 carbons, forming
the ring and which may be fused to 1 or 2 aromatic rings
as described for aryl, which include cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl,
(Figure Removed)
any of which groups may be optionally substituted with 1
to 4 substituents such as halogen, alkyl, alkoxy,
hydroxy, aryl, aryloxy, arylalkyl, cycloalkyl,
alkylamido, alkanoylamino, oxb, acyl, arylcarbonylamino,
amino, nitro, cyano, thiol and/or alkylthio and/or any of
the substituents for alkyl.
The term "cycloalkenyl" as employed herein alone
or as part of another group refers to cyclic hydrocarbons
containing 3 to 12 carbons, preferably 5 to 10 carbons
and 1 or 2 double bonds. Exemplary cycloalkenyl groups
include cyclopentenyl, cyclohexenyl, cycloheptenyl,
cyclooctenyl, cyclohexadienyl, and cycloheptadienyl,
which may be optionally substituted as defined for
cycloalkyl.
The term "cycloalkylene" as employed herein refers
to a "cycloalkyl" group which includes free bonds and
thus is a linking group such as
and the like, and may optionally be
substituted as defined above for "cycloalkyl".
The term "alkanoyl" as used herein alone or as x
part of another group refers to alkyl linked to a
carbonyl group.
Unless otherwise indicated, the term "lower
alkenyl" or "alkenyl" as used herein by itself or as part
of another group refers to straight or branched chain
radicals of 2 to 20 carbons, preferably 2 to 12 carbons,
and more preferably 1 to 8 carbons in the normal chain,
which include one to six double bonds in the normal
chain, and may optionally include an oxygen or nitrogen
in the normal chain, such as vinyl, 2-propenyl, 3-
butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-
hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl,
3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-
tetradecatrienyl, and the like, and which may be
optionally substituted with 1 to 4 substituents, namely,
halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl,
aryl, arylalkyl, cycloalkyl, amino, hydroxy, heteroaryl,
cycloheteroalkyl, alkanoylamino, alkylamido,
arylcarbonylamino, nitro, cyano, thiol, alkylthio and/or
any of the substituents for alkyl set out herein.
Unless otherwise indicated, the term "lower
alkynyl" or "alkynyl" as used herein by itself or as part
of another group refers to straight or branched chain
radicals of 2 to 20 carbons, preferably 2 to 12 carbons
and more preferably 2 to 8 carbons in the normal chain,
which include one triple bond in the normal chain, and
may optionally include an oxygen or nitrogen in the
normal chain, such as 2-propynyl, 3-butynyl, 2—butynyl,
4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl,
3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-
decynyl,3-undecynyl, 4-dodecynyl and the like, and which
may be optionally substituted with 1 to 4 substituents,
namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl,
alkynyl, aryl, arylalkyl, cycloalkyl, amino, heteroaryl,
cycloheteroalkyl, hydroxy, alkanoylamino, alkylamido,
arylcarbonylamino, nitro, cyano, thiol, and/or alkylthio,
and/or any of the substituents for alkyl set out herein.
The terms "arylalkenyl" and "arylalkynyl" as used
alone or as part of another group refer to alkenyl and
alkynyl groups as described above having an aryl
substituent.
Where alkyl groups as defined above have single
bonds for attachment to other groups at two different
carbon atoms, they are termed "alkylene" groups and may
optionally be substituted as defined above for "alkyl".
Where alkenyl groups as defined above and alkynyl
groups as defined above, respectively, have single bonds
for attachment at two different carbon atoms, they are
termed "alkenylene groups" and "alkynylene groups",
respectively, and may optionally be substituted as
defined above for "alkenyl" and "alkynyl".
(CH2)X, (CH2)m, (CH2)n or (CH2)y includes alkylene,
allenyl, alkenylene or alkynylene groups, as defined
herein, each of which may optionally include an oxygen or
nitrogen in the normal chain, which may optionally
include 1, 2, or 3 substituents which include alkyl,
alkenyl, halogen, cyano, hydroxy, alkoxy, amino,
thioalkyl, keto, C3-Ce cycloalkyl, alkylcarbonylamino or
alkylcarbonyloxy; the alkyl substituent may be an
alkylene moiety of 1 to 4 carbons which may be attached
to one or two carbons in the (CHa)x or (CH2)m or (CH2)n
group to form a cycloalkyl group therewith.
Examples of (CH2)x, (CH2)m, (CH2)n, (CH2) y,
alkylene, alkenylene and alkynylene include
—CH=CH—CH2 , —CH2CH=CH— f —C=C-CH2 f —CH2~"ff ,
O
—CH2—CH2—CH2—C— f -CH2CECCH2— f —C=CR-Cil2
CH3 CH3
—(CH2)2 —(CH2)3— ,—(CH2)4 , — I ' '
CH3
C2H5 n~C3H7 CH2-CH=CH2 CH C=CH2 CHg
—CH— , —CH , —CH— —CH— CH3 —C
CH2-CH2 H3C CH3 ^
_\c/_ , ->C-CH2— , -CH=C=CH—, -CH2-CSC-, -CH2-CH-CH
CH2CH , CH2CHCH2— , CHCH2— , CHCH2CH2 ,
CH3 C2HS CH3 C2H5
CH3 F
—CHCHCH2—, —CH2-C:-CH2— , —(CH2)5- , —(CH2) 2-C-CH2— ^
| CH3 CH3 F
CH3
Cl CH3 CH3
—CH2—CH-CH2— f —(CH2)2—CH— , _CH2_CH_C_
CH3 in,
CH3
CH2—CH—CH-CH2— j —CH2-CH-CH2—CH— ^ —CH-CH2CH2
CH3 CH3 ' CH3 CH3
OCH3
^ —CH2OCH2 f —OCH2CH2 f —C^NHCH.,
CH3
-HHCH2CH2—, _(CH2)3-CF2— , —ci^-N-OL,— or ~N-CH2CH2—
CH3
The term "halogen" or "halo" as used herein alone
or as part of another group refers to chlorine, bromine,
fluorine, and iodine as well as CFs, with chlorine or
fluorine being preferred.
The term "metal ion" refers to alkali metal ions
such as sodium, potassium or lithium and alkaline earth
metal ions such as magnesium and calcium, as well as zinc
and aluminum.
Unless otherwise indicated, the term "aryl" as
employed herein alone or as part of another group refers
to monocyclic and bicyclic aromatic groups containing 6
to 10 carbons in the ring portion (such as phenyl or
naphthyl including 1-naphthyl and 2-naphthyl) and may
optionally include one to three additional rings fused to
a carbocyclic ring or a heterocyclic ring (such as aryl,
cycloalkyl, heteroaryl or cycloheteroalkyl rings
for example
(Figure Removed)
and may be optionally substituted through available
carbon atoms with 1, 2, or 3 groups selected from
hydrogen, halo, haloalkyl, alkyl, haloalkyl, alkoxy,
haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy,
alkynyl, cycloalkyl-alkyl, cycloheteroalkyl,
cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl,
aryloxy, aryloxyalkyl, arylalkoxy, alkoxycarbonyl,
arylcarbonyl, arylalkenyl, aminocarbonylaryl, arylthio,
arylsulfinyl, arylazo, heteroarylalkyl,
heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy,
hydroxy, nitro, cyano, amino, substituted amino wherein
the amino includes 1 or 2 substituents (which are alkyl,
aryl or any of the other aryl compounds mentioned in the
definitions), thiol, alkylthio, arylthio, heteroarylthio,
arylthioalkyl, alkoxyarylthio, alkylcarbonyl,
arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl,
alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy,
arylcarbonyloxy, alkylcarbonylamino, arylcarbonylanu.no,
arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino or
arylsulfonaminocarbonyl and/or any of the substituents
for alkyl set out herein.
Unless otherwise indicated, the term "lower
alkoxy", "alkoxy", "aryloxy" or "aralkoxy" as employed
herein alone or as part of another group includes any of
the above alkyl, aralkyl or aryl groups linked to an
oxygen atom.
Unless otherwise indicated, the term "substituted
amino" as employed herein alone or as part of another
group refers to amino substituted with one or two
substituents, which may be the same or different, such as
alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl,
cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl or
thioalkyl. These substituents may be further substituted
with a carboxylic acid and/or any of the substituents for
alkyl as set out above. In addition, the amino
substituents may be taken together with the nitrogen atom
to which they are attached to form 1-pyrrolidinyl, 1-
piperidinyl, 1-azepinyl, 4-morpholinyl, 4-
thiamorpholinyl, 1-piperazinyl, 4-alkyl-l-piperazinyl, 4-
arylalkyl-1-piperazinyl, 4-diarylalkyl-l-piperazinyl, 1-
pyrrolidinyl, 1-piperidinyl, or 1-azepinyl, optionally
substituted with alkyl, alkoxy, alkylthio, halo,
trifluoromethyl or hydroxy.
Unless otherwise indicated, the term "lower
alkylthio", alkylthio", "arylthio" or "aralkylthio" as
employed herein alone or as part of another group
includes any of the above alkyl, aralkyl or aryl groups
linked to a sulfur atom.
Unless otherwise indicated, the term "lower
alkylamino", "alkylamino", "arylamino", or
"arylalkylamino" as employed herein alone or as part of
another group includes any of the above alkyl, aryl or
arylalkyl groups linked to a nitrogen atom.
Unless otherwise indicated, the term "acyl" as
employed herein by itself or part of another group, as
defined herein, refers to an organic radical linked to a
carbonyl x c ' group; examples of acyl groups include any
of the R3 groups attached to a carbonyl, such as
alkanoyl, alkenoyl, aroyl, aralkanoyl, heteroaroyl,
cycloalkanoyl, cycloheteroalkanoyl and the like.
Unless otherwise indicated, the term
"cycloheteroalkyl" as used herein alone or as part of
another group refers to a 5-, 6- or 7-membered saturated
or partially unsaturated ring which includes 1 to 2
hetero atoms such as nitrogen, oxygen and/or sulfur,
linked through a carbon atom or a heteroatom, where
possible, optionally via the linker (CH2)P (where p is 1,
2 or 3) , such as
(Figure Removed)
and the like. The above groups may include 1 to 4
substituents such as alkyl, halo, oxo and/or any of of
the substituents for alkyl or aryl set out herein. In
addition, any of the cycloheteroalkyl rings can be fused
to a cycloalkyl, aryl, heteroaryl or cycloheteroalkyl
ring.
Unless otherwise indicated, the term "heteroaryl"
as used herein alone or as part of another group refers
to a 5- or 6- membered aromatic ring which includes 1, 2,
3 or 4 hetero atoms such as nitrogen, oxygen or
sulfur, and such rings fused to an aryl, cycloalkyl,
heteroaryl or cycloheteroalkyl ring (e.g.
benzothiophenyl, indolyl), and includes possible Noxides.
The heteroaryl group may optionally include 1 to
4 substituents such as any of the the substituents for
alkyl or aryl set out above. Examples of heteroaryl
groups include the following:
(Figure Removed)
and the like.
The term "cycloheteroalkylalkyl" as used herein
alone or as part of another group refers to
cycloheteroalkyl groups as defined above linked through a
C atom or heteroatom to a (CH2)P chain.
The term "heteroarylalkyl" or "heteroarylalkenyl"
as used herein alone or as part of another group refers
to a heteroaryl group as defined above linked through a C
atom or heteroatom to a -(CH2)p- chain, alkylene or
alkenylene as defined above.
The term "polyhaloalkyl" as used herein refers to
an "alkyl" group as defined above which includes from 2
to 9, preferably from 2 to 5, halo substituents, such as
F or Cl, preferably F, such as CF3CH2, CF3 or CF3CF2CH2-
The term "polyhaloalkyloxy" as used herein refers
to an "alkoxy" or "alkyloxy" group as defined above which
includes from 2 to 9, preferably from 2 to 5, halo
substituents, such as F or Cl, preferably F, such as
CF3CH20, CF30 or CF3CF2CH20.
The term "prodrug esters" as employed herein
includes prodrug esters which are known in the art for
carboxylic and phosphorus acid esters such as methyl,
ethyl, benzyl and the like. Other prodrug ester examples
of R4 include the following groups:
(1-alkanoyloxy) alkyl such as,
(Figure Removed)
wherein Ra, Rb and Rc are H, alkyl, aryl or aryl-alkyl;
however, RaO cannot be HO.
Examples of such prodrug esters R4 include
(Figure Removed)
Other examples of suitable prodrug esters R4 include
(Figure Removed)
wherein Ra can be H, alkyl (such as methyl or t-butyl),
arylalkyl (such as benzyl) or aryl (such as phenyl); Rd
is H, alkyl, halogen or alkoxy, Re is alkyl, aryl,
arylalkyl or alkoxyl, and ni is 0, 1 or 2.
Where the compounds of structure I are in acid
form they may form a pharmaceutically acceptable salt
such as alkali metal salts such as lithium, sodium or
potassium, alkaline earth metal salts such as calcium or
magnesium as well as zinc or aluminum and other cations
such as ammonium, choline, diethanolamine, lysine (D or
L) , ethylenediamine, t-butylamine, t-octylamine, tris-
(hydroxymethyl)aminomethane (TRIS), N-methyl glucosamine
(NMG) , triethanolamine and dehydroabietylamine.
All stereoisomers of the compounds of the instant
invention are contemplated, either in admixture or in
pure or substantially pure form. The compounds of the
present invention can have asymmetric centers at any of
the carbon atoms including any one or the R substituents.
Consequently, compounds of formula I can exist in
enantiomeric or diastereomeric forms or in mixtures
thereof. The processes for preparation can utilize
racemates, enantiomers or diastereomers as starting
materials. When diastereomeric or enantiomeric products
are prepared, they can be separated by conventional
methods for example, chromatographic or fractional
crystallization.
Where desired, the compounds of structure I may be
used in combination with one or more hypolipidemic agents
or lipid-lowering agents and/or one or more other types
of therapeutic agents including antidiabetic agents,
anti-obesity agents, antihypertensive agents, platelet
aggregation inhibitors, and/or anti-osteoporosis agents,
which may be administered orally in the same dosage form,
in a separate oral dosage form or by injection.
The hypolipidemic agent or lipid-lowering agent
which may be optionally employed in combination with the
compounds of formula I of the invention may include 1,2,3
or more MTP inhibitors, HMG CoA reductase inhibitors,
squalene synthetase inhibitors, fibric acid derivatives,
ACAT inhibitors, lipoxygenase inhibitors, cholesterol
absorption inhibitors, ileal Na+/bile acid cotransporter
inhibitors, upregulators of LDL receptor activity, bile
acid sequestrants, and/or nicotinic acid and derivatives
thereof.
MTP inhibitors employed herein include MTP
inhibitors disclosed in U.S. Patent No. 5,595,872, U.S.
Patent No. 5,739,135, U.S. Patent No. 5,712,279, U.S.
Patent No. 5,760,246, U.S. Patent No. 5,827,875, U.S.
Patent No. 5,885,983 and U.S. Application Serial No.
09/175,180 filed October 20, 1998, now U.S. Patent No.
5,962,440. Preferred are each of the preferred MTP
inhibitors disclosed in each of the above patents and
applications.
All of the above U.S. Patents and applications are
incorporated herein by reference.
Most preferred MTP inhibitors to be employed in
accordance with the present invention include preferred
MTP inhibitors as set out in U.S. Patent Nos. 5,739,135
and 5,712,279, and U.S. Patent No. 5,760,246.
The most preferred MTP inhibitor is 9-[4- [4-[[2-
(2,2,2-Trif luoroethoxy) benzoyl] amino] -1-piperidinyl]
butyl] -N- (2,2,2-trifluoroethyl) -9H-fluorene-9-carboxamide
The hypolipidemic agent may be an HMG CoA
reductase inhibitor which includes, but is not limited
to, mevastatin and related compounds as disclosed in U.S.
Patent No. 3,983,140, lovastatin (mevinolin) and related
compounds as disclosed in U.S. Patent No. 4,231,938,
pravastatin and related compounds such as disclosed in
U.S. Patent No. 4,346,227, simvastatin and related
compounds as disclosed in U.S. Patent Nos. 4,448,784 and
4,450,171. Other HMG CoA reductase inhibitors which may
be employed herein include, but are not limited to,
fluvastatin, disclosed in U.S. Patent No. 5,354,772,
cerivastatin disclosed in U.S. Patent Nos. 5,006,530 and
5,177,080, atorvastatin disclosed in U.S. Patent Nos.
4,681,893, 5,273,995, 5,385,929 and 5,686,104,
itavastatin (Nissan/Sankyo1s nisvastatin (NK-104))
disclosed in U.S. Patent No. 5,011,930, Shionogi-
Astra/Zeneca visastatin (ZD-4522) disclosed in U.S.
Patent No. 5,260,440, and related statin compounds
disclosed in U.S. Patent No. 5,753,675, pyrazole analogs
of mevalonolactone derivatives as disclosed in U.S.
Patent No. 4,613,610, indene analogs of mevalonolactone
derivatives as disclosed in PCT application WO 86/03488,
6- [2- (substituted-pyrrol-1-yl) -alkyl)pyran-2-ones and
derivatives thereof as disclosed in U.S. Patent No.
4,647,576, Searle's SC-45355 (a 3-substituted
pentanedioic acid derivative) dichloroacetate, imidazole
analogs of mevalonolactone as disclosed in PCT
application WO 86/07054, 3-carboxy-2-hydroxy-propanephosphonic
acid derivatives as disclosed in French Patent
No. 2,596,393, 2,3-disubstituted pyrrole, furan and
thiophene derivatives as disclosed in European Patent
Application No. 0221025, naphthyl analogs of
mevalonolactone as disclosed in U.S. Patent No.
4,686,237, octahydronaphthalenes such as disclosed in
U.S. Patent No. 4,499,289, keto analogs of mevinolin
(lovastatin) as disclosed in European Patent Application
No. 0,142,146 A2, and quinoline and pyridine derivatives
disclosed in U.S. Patent No. 5,506,219 and 5,691,322.
In addition, phosphinic acid compounds useful in
inhibiting HMG CoA reductase suitable for use herein are
disclosed in GB 2205837.
The squalene synthetase inhibitors suitable for
use herein include, but are not limited to, a-phosphonosulfonates
disclosed in U.S. Patent No. 5,712,396, those
disclosed by Biller et al, J. Med. Chem., 1988, Vol. 31,
No. 10, pp 1869-1871, including isoprenoid (phosphinylmethyDphosphonates
as well as other known squalene
synthetase inhibitors, for example, as disclosed in U.S.
Patent No. 4,871,721 and 4,924,024 and in Biller, S.A.,
Neuenschwander, K., Ponpipom, M.M., and Poulter, C.D.,
Current Pharmaceutical Design, 2, 1-40 (1996).
In addition, other squalene synthetase inhibitors
suitable for use herein include the terpenoid
pyrophosphates disclosed by P. Ortiz de Montellano et al,
J. Med. Chem., 1977, 2H, 243-249, the farnesyl
diphosphate analog A and presqualene pyrophosphate
(PSQ-PP) analogs as disclosed by Corey and Volante, J.
Am. Chem. Soc., 1976, 98, 1291-1293,
phosphinylphosphonates reported by McClard, R.W. et al,
J.A.C.S., 1987, UL9_, 5544 and cyclopropanes reported by
Capson, T.L., PhD dissertation, June, 1987, Dept. Med.
Chem. U of Utah, Abstract, Table of Contents, pp 16, 17,
40-43, 48-51, Summary.
Other hypolipidemic agents suitable for use herein
include, but are not limited to, fibric acid derivatives,
such as fenofibrate, gemfibrozil, clofibrate,
bezafibrate, ciprofibrate, clinofibrate and the like,
probucol, and related compounds as disclosed in U.S.
Patent No. 3,674,836, probucol and gemfibrozil being
preferred, bile acid sequestrants such as cholestyramine,
colestipol and DEAE-Sephadex (Secholex®, Policexide®) and
cholestagel (Sankyo/Geltex), as well as lipostabil
(Rhone-Poulenc), Eisai E-5050 (an N-substituted
ethanolamine derivative), imanixil (HOE-402),
tetrahydrolipstatin (THL), istigmastanylphosphorylcholine
(SPC, Roche) , aminocyclodextrin (Tanabe
Seiyoku), Ajinomoto AJ-814 (azulene derivative),
melinamide (Sumitomo) , Sandoz 58-035, American Cyanamid
CL-277,082 and CL-283,546 (disubstituted urea
derivatives) , nicotinic acid (niacin), acipimox, acifran,
neomycin, p-aminosalicylic acid, aspirin,
poly (diallylmethylamine) derivatives such as disclosed in
U.S. Patent No. 4,759,923, quaternary amine
poly(diallyldimethylammonium chloride) and ionenes such
as disclosed in U.S. Patent No. 4,027,009, and other
known serum cholesterol lowering agents.
The hypolipidemic agent may be an ACAT inhibitor
such as disclosed in, Drugs of the Future 24, 9-15
(1999) , (Avasimibe) ; "The ACAT inhibitor, Cl-1011 is
effective in the prevention and regression of aortic
fatty streak area in hamsters", Nicolosi et al,
Atherosclerosis (Shannon, Irel). (1998), 137(1), 77-85;
"The pharmacological profile of FCE 27677: a novel ACAT
inhibitor with potent hypolipidemic activity mediated by
selective suppression of the hepatic secretion of
ApoBlOO-containing lipoprotein" , Ghiselli, Giancarlo,
Cardiovasc. Drug Rev. (1998), 16(1), 16-30; "RP 73163: a
bioavailable alkylsulfinyl-diphenylimidazole ACAT
inhibitor", Smith, C., et al, Bioorg. Med. Chem. Lett.
(1996), 6(1), 47-50; "ACAT inhibitors: physiologic
mechanisms for hypolipidemic and anti-atherosclerotic
activities in experimental animals", Krause et al,
Editor(s): Ruffolo, Robert R., Jr.; Hollinger, Mannfred
A., Inflammation: Mediators Pathways (1995), 173-98,
Publisher: CRC, Boca Raton, Fla.; "ACAT inhibitors:
potential anti-atherosclerotic agents", Sliskovic et al,
Curr. Med. Chem. (1994), 1(3), 204-25; "Inhibitors of
acyl-CoA:cholesterol 0-acyl transferase (ACAT) as
hypocholesterolemic agents. 6. The first water-soluble
ACAT inhibitor with lipid-regulating activity. Inhibitors
of acyl-CoA:cholesterol acyltransferase (ACAT). 7.
Development of a series of substituted N-phenyl-N1 - [ (1-
phenylcyclopentyl) methyl] ureas with enhanced
hypocholesterolemic activity", Stout et al, Chemtracts:
Org. Chem. (1995), 8(6), 359-62, or TS-962 (Taisho
Pharmaceutical Co. Ltd) .
The hypolipidemic agent may be an upregulator of
LD2 receptor activity such as MD-700 (Taisho
Pharmaceutical Co. Ltd) and LY295427 (Eli Lilly) .
The hypolipidemic agent may be a cholesterol
absorption inhibitor preferably Schering-Plough1 s
SCH48461 as well as those disclosed in Atherosclerosis
115, 45-63 (1995) and J. Med. Chem. 41, 973 (1998) .
The hypolipidemic agent may be an ileal Na*/bile
acid cotransporter inhibitor such as disclosed in Drugs
of the Future, 24, 425-430 (1999) .
Preferred hypolipidemic agents are pravastatin,
lovastatin, simvastatin, atorvastatin, fluvastatin,
cerivastatin, itavastatin and visastatin.
The above-mentioned U.S. patents are incorporated
herein by reference. The amounts and dosages employed
will be as indicated in the Physician's Desk Reference
and/or in the patents set out above.
The compounds of formula I of the invention will
be employed in a weight ratio to the hypolipidemic agent
(were present), within the range from about 500:1 to
about 1:500, preferably from about 100:1 to about 1:100.
The dose administered must be carefully adjusted
according to age, weight and condition of the patient, as
well as the route of administration, dosage form and
regimen and the desired result.
The dosages and formulations for the hypolipidemic
agent will be as disclosed in the various patents and
applications discussed above.
The dosages and formulations for the other
hypolipidemic agent to be employed, where applicable,
will be as set out in the latest edition of the
Physicians' Desk Reference.
For oral administration, a satisfactory result may
be obtained employing the MTP inhibitor in an amount
within the range of from about 0.01 mg to about 500 mg
and preferably from about 0.1 mg to about 100 mg, one to
four times daily.
A preferred oral dosage form, such as tablets or
capsules, will contain the MTP inhibitor in an amount of
from about 1 to about 500 mg, preferably from about 2 to
about 400 mg, and more preferably from about 5 to about
250 mg, one to four times daily.
For oral administration, a satisfactory result may
be obtained employing an HMG CoA reductase inhibitor, for
example, pravastatin, lovastatin, simvastatin,
atorvastatin, fluvastatin or cerivastatin in dosages
employed as indicated in the Physician's Desk Reference,
such as in an amount within the range of from about 1 to
2000 mg, and preferably from about 4 to about 200 mg.
The squalene synthetase inhibitor may be employed
in dosages in an amount within the range of from about 10
mg to about 2000 mg and preferably from about 25 mg to
about 200 mg.
A preferred oral dosage form, such as tablets or
capsules, will contain the HMG CoA reductase inhibitor in
an amount from about 0.1 to about 100 mg, preferably from
about 0. 5 to about 80 mg, and more preferably from about
1 to about 40 mg.
A preferred oral dosage form, such as tablets or
capsules will contain the squalene synthetase inhibitor
in an amount of from about 10 to about 500 mg, preferably
from about 25 to about 200 mg.
The hypolipidemic agent may also be a lipoxygenase
inhibitor including a 15-lipoxygenase (15-LO) inhibitor
such as benzimidazole derivatives as disclosed in WO
97/12615, 15-LO inhibitors as disclosed in WO 97/12613,
isothiazolones as disclosed in WO 96/38144, and 15-LO
inhibitors as disclosed by Sendobry et al "Attenuation of
diet-induced atherosclerosis in rabbits with a highly
selective 15-lipoxygenase inhibitor lacking significant
antioxidant properties", Brit. J. Pharmacology (1997)
120, 1199-1206, and Cornicelli et al, "15-Lipoxygenase
and its Inhibition: A Novel Therapeutic Target for
Vascular Disease", Current Pharmaceutical Design, 1999,
5, 11-20.
The compounds of formula I and the hypolipidemic
agent may be employed together in the same oral dosage
form or in separate oral dosage forms taken at the same
t ime.
The compositions described above may be
administered in the dosage forms as described above in
single or divided doses of one to four times daily. It
may be advisable to start a patient on a low dose
combination and work up gradually to a high dose
combination.
The preferred hypolipidetnic agent is pravastatin,
simvastatin, lovastatin, atorvastatin, fluvastatin or
cerivastatin as well as niacin and/or cholestagel.
The antidiabetic agent which may be optionally
employed in combination with the compound of formula I
may be 1,2,3 or more antidiabetic agents or
antihyperglycemic agents including insulin secretagogues
or insulin sensitizers, which may include biguanides,
sulfonyl ureas, glucosidase inhibitors, PPAR y agonists,
such as thiazolidinediones, aP2 inhibitors, PPAR oc/y dual
agonists, dipeptidyl peptidase IV (DP4) inhibitors, SGLT2
inhibitors, and/or meglitinides, as well as insulin,
and/or glucagon-like peptide-1 (GLP-1).
The antidiabetic agent may be an oral
antihyperglycemic agent preferably a biguanide such as
metformin or phenformin or salts thereof, preferably
metformin HC1.
Where the antidiabetic agent is a biguanide, the
compounds .of structure I will be employed in a weight
ratio to biguanide within the range from about 0.001:1 to
about 10:1, preferably from about 0.01:1 to about 5:1.
The antidiabetic agent may also preferably be a
sulfonyl urea such as glyburide (also known as
glibenclamide) , glimepiride (disclosed in U.S. Patent No.
4,379,785), glipizide, gliclazide or chlorprop amide,
other known sulfonylureas or other antihyperglycemic
agents which act on the ATP-dependent channel of the (3-
cells, with glyburide and glipizide being preferred,
which may be administered in the same or in separate oral
dosage forms.
The compounds of structure I will be employed in a
weight ratio to the sulfonyl urea in the range from about
0.01:1 to about 100:1, preferably from about O.O2:1 to
about 5:1.
The oral antidiabetic agent may also be a
glucosidase inhibitor such as acarbose (disclosed in U.S.
Patent No. 4,904,769) or miglitol (disclosed in U.S.
Patent No. 4,639,436), which may be administered in the
same or in a separate oral dosage forms.
The compounds of structure I will be employed in a
weight ratio to the glucosidase inhibitor within the
range from about 0.01:1 to about 100:1, preferably from
about 0.05:1 to about 10:1.
The compounds of structure I may be employed in
combination with a PPAR y agonist such as a
thiazolidinedione oral anti-diabetic agent or other
insulin sensitizers (which has an insulin sensitivity
effect in NIDDM patients) such as troglitazone (Warner-
Lambert' s Rezulin®, disclosed in U.S. Patent No.
4,572,912), rosiglitazone (SKB), pioglitazone (Takeda) ,
Mitsubishi's MCC-555 (disclosed in U.S. Patent No.
5,594,016), Glaxo-Welcome's GL-262570, englitazone (CP-
68722, Pfizer) or darglitazone (CP-86325, Pfizer,
isaglitazone (MIT/J&J) , JTT-501 (JPNT/P&U) , L-895645
(Merck), R-119702 (Sankyo/WL) , NN-2344 (Dr. Reddy/NN) , or
YM-440 (Yamanouchi) , preferably rosiglitazone and
pioglitazone.
The compounds of structure I will be employed in a
weight ratio to the thiazolidinedione in an amount within
the range from about 0.01:1 to about 100:1, preferably
from about 0.05 to about 10:1.
The sulfonyl urea and thiazolidinedione in amounts
of less than about 150 mg oral antidiabetic agent may be
incorporated in a single tablet with the compounds of
structure I.
The compounds of structure I may also be employed
in combination with a ant ihype rglycemic agent such as
insulin or with glucagon-like peptide-1 (GLP-1) such as
GLP-K1-36) amide, GLP-1 (7-36) amide, GLP-1 (7-37) (as
disclosed in U.S. Patent No. 5,614,492 to Habener, the
disclosure of which is incorporated herein by reference) ,
as well as AC2993 (Amylin) and LY-315902 (Lilly) / which
may be administered via injection, intranasal, inhalation
or by transdermal or buccal devices.
Where present, metformin, the sulfonyl ur-eas, such
as glyburide, glimepiride, glipyride, glipizide,
chlorpropamide and gliclazide and the glucosidase
inhibitors acarbose or miglitol or insulin (injectable,
pulmonary, buccal, or oral) may be employed in
formulations as described above and in amounts and dosing
as indicated in the Physician's Desk Reference (PDR) .
Where present, metformin or salt thereof may be
employed in amounts within the range from about 500 to
about 2000 mg per day which may be administered in single
or divided doses one to four times daily.
Where present, the thiazolidinedione anti-diabetic
agent may be employed in amounts within the range from
about 0.01 to about 2000 mg/day which may be administered
in single or divided doses one to four times per day.
Where present insulin may be employed in
formulations/ amounts and dosing as indicated by the
Physician's Desk Reference.
Where present GLP-1 peptides may be administered in
oral buccal formulations, by nasal administration or
parenterally as described in U.S. Patent Nos. 5,346,701
(TheraTech) , 5,614,492 and 5,631,224 which are
incorporated herein by reference.
The antidiabetic agent may also be a PPAR agonist such as AR-H039242 (Astra/Zeneca) , GW-409544
(Glaxo-Wellcome) , KRP297 (Kyorin Merck) as well as those
disclosed by Murakami et al, "A Novel Insulin Sensitizer
Acts As a Coligand for Peroxisome Proliferation -
Activated Receptor Alpha (PPAR alpha) and PPAR gamma.
Effect on PPAR alpha Activation on Abnormal Lipid
Metabolism in Liver of Zucker Fatty Rats", Diabetes 47,
1841-1847 (1998) .
The antidiabetic agent may be an SGLT2 inhibitor
such as disclosed in U.S. provisional application No.
60/158,773, filed October 12, 1999 (attorney file LA49) ,
employing dosages as set out therein. Preferred are the
compounds designated as preferred in the above
application.
The antidiabetic agent may be an aP2 inhibitor
such as disclosed in U.S. application Serial No.
09/391,053, filed September 7, 1999, and in U.S.
provisional application No. 60/127,745, filed April 5,
1999 (attorney file LA27*), employing dosages as set out
herein. Preferred are the compounds designated as
preferred in the above application.
The antidiabetic agent may be a DP4 inhibitor such
as disclosed in Provisional Application 60/188,555 filed
March 10, 2000 (attorney file LA50), W099/38501,
W099/46272, WO99/67279 (PROBIODRUG), W099/67278
(PROBIODRUG), W099/61431 (PROBIODRUG), NVP-DPP728A (1-
[ [ [2- [ (5-cyanopyridin-2-yl)amino] ethyl] amino] acetyl] -2-
cyano-(S)-pyrrolidine) (Novartis) (preferred) as
disclosed by Hughes et al, Biochemistry, 38(36) , 11597-
11603, 1999, TSL-225 (tryptophyl-1,2,3,4-tetrahydroisoquinoline-
3-carboxylic acid (disclosed by Yamada et
al, Bioorg. & Med. Chetn. Lett. 8 (1998) 1537-1540, 2-
cyanopyrrolidides and 4-cyanopyrrolidides as disclosed by
Ashworth et al, Bioorg. & Med. Chem. Lett., Vol. 6, No.
22, pp 1163-1166 and 2745-2748 (1996) employing dosages
as set out in the above references.
The meglitinide which may optionally be employed
in combination with the compound of formula I of the
invention may be repaglinide, nateglinide (Novartis) or
KAD1229 (PF/Kissei) , with repaglinide being preferred.
The compound of formula I will be employed in a
weight ratio to the meglitinide, PPAR y agonist, PPAR a/y
dual agonist, aP2 inhibitor, DP4 inhibitor or SGLT2
inhibitor within the range from about 0.01:1 to about
100:1, preferably from about 0.05 to about 10:1-
The other type of therapeutic agent which may be
optionally employed with a compound of formula I may be
1, 2, 3 or more of an anti-obesity agent including a beta
3 adrenergic agonist, a lipase inhibitor, a serotonin
(and dopamine) reuptake inhibitor, an aP2 inhibitor, a
thyroid receptor agonist and/or an anorectic agent.
The beta 3 adrenergic agonist which may t>e
optionally employed in combination with a compound of
formula I may be AJ9677 (Takeda/Dainippon), L750355
(Merck), or CP331648 (Pfizer) or other known beta 3
agonists as disclosed in U.S. Patent Nos. 5,541,204,
5,770,615, 5,491,134, 5,776,983 and 5,488,064, with
AJ9677, L750,355 and CP331648 being preferred.
The lipase inhibitor which may be optionally
employed in combination with a compound of formula I may
be orlistat or ATL-962 (Alizyme), with orlistat being
preferred.
The serotonin (and dopoamine) reuptake inhibitor
which may be optionally employed in combination with a
compound of formula I may be sibutramine, topiramate
(Johnson & Johnson) or axokine (Regeneron) , with
sibutramine and topiramate being preferred.
The thyroid receptor agonist which may be
optionally employed in combination with a compound of
formula I may be a thyroid receptor ligand as disclosed
in W097/21993 (U. Cal SF) , WO99/00353 (KaroBio) ,
GB98/284425 (KaroBio), and U.S. Provisional Application
60/183,223 filed February 17, 2000, with compounds of the
KaroBio applications and the above U.S. provisional
application being preferred.
The anorectic agent which may be optionally
employed in combination with a. compound of formula I may
be dexamphet amine, phentermine, phenylpropanolamine or
mazindol, with dexamphetamine being preferred.
The various anti-obesity agents described above may
be employed in the same dosage form with the compound of
formula I or in different dosage forms, in dosages and
regimens as generally known in the art or in the PDR.
The antihypertensive agents which may be employed
in combination with the compound of formula I of the
invention include ACE inhibitors, angiotensin II receptor
antagonists, NEP/ACE inhibitors, as well as calcium
channel blockers, 0-adrenergic blockers and other types
of antihypertensive agents including diuretics.
The angiotensin converting enzyme inhibitor which
may be employed herein includes those containing a
mercapto (-S-) moiety such as substituted proline
derivatives, such as any of those disclosed in U.S. Pat.
No. 4,046,889 to Ondetti et al mentioned above, with
captopril, that is, 1-[(2S)-3-mercapto-2-
methylpropionyl] -L-proline, being preferred, and
mercaptoacyl derivatives of substituted prolines such as
any of those disclosed in U.S. Pat. No. 4,316,906 with
zofenopril being preferred.
Other examples of mercapto containing ACE
inhibitors that may be employed herein include rentiapril
(fentiapril, Santen) disclosed in Clin. Exp. Phartnacol.
Physiol. 10:131 (1983); as well as pivopril and YS980.
Other examples of angiotensin converting enzyme
inhibitors which may be employed herein include any of
those disclosed in U.S. Pat. No. 4,374,829 mentioned
above, with N- (l-ethoxycarbonyl-3-phenylpropyl) -L-alanyl-
L-proline, that is, enalapril, being preferred, any of
the phosphonate substituted amino or imino acids or salts
disclosed in U.S. Pat. No. 4,452,790 with (S) -1- [6-amino-
2- [ thydroxy- (4-phenylbutyl)phosphinyl] oxy] -1-oxohexyl] -Lproline
or (ceronapril) being preferred,
phosphinylalkanoyl prolines disclosed in U.S. Pat. No.
4,168,267 mentioned above with fosinopril being
preferred, any of the phosphinylalkanoyl substituted
prolines disclosed in U.S. Pat. No. 4,337,201, and the
phosphonamidates disclosed in U.S. Pat. No. 4,432,971
discussed above.
Other examples of ACE inhibitors that may be
employed herein include Beecham's BRL 36,378 as disclosed
in European Patent Application Nos. 80822 and 60668;
Chugai's MC-838 disclosed in C.A. 102:72588v and Jap. J.
Pharmacol. 40:373 (1986); Ciba-Geigy's CGS 14824 (3-([1-
ethoxycarbonyl-3-phenyl-(IS)-propyl]amino) -2,3,4,5-
tetrahydro-2-oxo-l-(3S)-benzazepine-1 acetic acid HCl)
disclosed in U.K. Patent No. 2103614 and CGS 16,617
(3(S)-[[(is)-5-amino-1-carboxypentyl]amino]-2,3,4,5-
tetrahydro-2-oxo-lH-l-benzazepine-l-ethanoic acid)
disclosed in U.S. Pat. No. 4,473,575; cetapril
(alacepril, Dainippon) disclosed in Eur. Therap. Res.
39:671 (1986); 40:543 (1986); ramipril (Hoechsst)
disclosed in Euro. Patent No. 79-022 and Curr. Ther. Res.
40:74 (1986); Ru 44570 (Hoechst) disclosed in
Arzneimittelforschung 34:1254 (1985), cilazapril
(Hoffman-LaRoche) disclosed in J. Cardiovasc. Pharmacol.
9:39 (1987); R 31-2201 (Hoffman-LaRoche) disclosed in
FEES Lett. 165:201 (1984); lisinopril (Merck), indalapril
(delapril) disclosed in U.S. Pat. No. 4,385,051;
indolapril (Schering) disclosed in J. Cardiovasc.
Pharmacol. 5:643, 655 (1983), spirapril (Schering)
disclosed in Acta. Pharmacol. Toxicol. 59 (Supp. 5):173
(1986); perindopril (Servier) disclosed in Eur. J. clin.
Pharmacol. 31:519 (1987); quinapril (Warner-Lambert)
disclosed in U.S. Pat. No. 4,344,949 and CI925 (Warner-
Lambert) ( [3S- [2[R(*)R(*)]]3R(*)3 -2- [2- [[1- (ethoxycarbonyl)
-3-phenylpropyl] amino] -1-oxopropyl] -1, 2,3,4-
tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid
HCDdisclosed in Pharmacologist 26:243, 266 (1984), WY-
44221 (Wyeth) disclosed in J. Med. Chem. 26:394 (1983).
Preferred ACE inhibitors are captopril, fosinopril,
enalapril, lisinopril, quinapril, benazepril, fentiapril,
ramipril and moexipril.
NEP/ACE inhibitors may also be employed herein in
that they possess neutral endopeptidase (NEP) inhibitory
activity and angiotensin converting enzyme (ACE)
inhibitory activity. Examples of NEP/ACE inhibitors
suitable for use herein include those disclosed in U.S.
Pat. No.S. 5,362,727, 5,366,973, 5,225,401, 4,722,810,
5,223,516, 4,749,688, U.S. Patent. No. 5,552,397, U.S.
Pat. No. 5,504,080, U.S. Patent No. 5,612,359 ,U. S. Pat.
No. 5,525,723, European Patent Application 0599,444,
0481,522, 0599,444, 0595,610, European Patent Application
0534363A2, 534,396 and 534,492, and European Patent
Application 0629627A2.
Preferred are those NEP/ACE inhibitors and dosages
thereof which are designated as preferred in the above
patents/applications which U.S. patents are incorporated
herein by reference; most preferred are omapatrilat, BMS
189,921 ([s-(R*,R*) ] -hexahydro-6-[(2-mercapto-l-oxo-3-
phenylpropyl)amino] -2,2-dimethyl-7-oxo-lH-azepine-lacetic
acid (gemopatrilat)) and CGS 30440.
The angiotensin II receptor antagonist (also
referred to herein as angiotensin II antagonist or All
antagonist) suitable for use herein includes, but is not
limited to, irbesartan, losartan, valsartan, candesartan,
telmisartan, tasosartan or eprosartan, with irbesartan,
losartan or valsartan being preferred.
A preferred oral dosage form, such as tablets or
capsules, will contain the ACE inhibitor or All
antagonist in an amount within the range from abut 0.1 to
about 500 ing, preferably from about 5 to about 200 mg and
more preferably from about 10 to about 150 mg.
For parenteral administration, the ACE inhibitor,
angiotensin II antagonist or NEP/ACE inhibitor will be
employed in an amount within the range from about 0.005
mg/kg to about 10 mg/kg and preferably from about 0.01
mg/kg to about 1 mg/kg.
Where a drug is to be administered intravenously,
it will be formulated in conventional vehicles, such as
distilled water, saline, Ringer's solution or other
conventional carriers.
It will be appreciated that preferred dosages of
ACE inhibitor and All antagonist as well as other
antihypertensives disclosed herein will be as set out in
the latest edition of the Physician's Desk Reference
(PDR).
Other examples of preferred antihypertensive agents
suitable for use herein include omapatrilat (Vanlev®)
amlodipine besylate (Norvasc®) , prazosin HC1
(Minipress®), verapamil, nifedipine, nadolol, diltiazem,
felodipine, nisoldipine, isradipine, nicardipine,
atenolol, carvedilol, sotalol, terazosin, doxazosin,
propranolol, and clonidine HC1 (Catapres®) .
Diuretics which may be employed in combination with
compounds of formula I include hydrochlorothiaz ide,
torasemide, furosemide, spironolactono, and indapamide.
Antiplatelet agents which may be employed in
combination with compounds of formula I of the invention
include aspirin, clopidogrel, ticlopidine, dipyridamole,
abciximab, tirofiban, eptifibatide, anagrelide, and
ifetroban, with clopidogrel and aspirin being preferred.
The antiplatelet drugs may be employed in amounts
as indicated in the PDR. Ifetroban may be employed in
amounts as set out in U.S. Patent No. 5,100,889.
Antiosteoporosis agents suitable for use herein in
combination with the compounds of formula I of the
invention include parathyroid hormone or bisphosphonates,
such as MK-217 (alendronate) (Fosamax®).' Dosages
employed will be as set out in the PDR.
In carrying our the method of the invention, a
pharmaceutical composition will be employed containing
the compounds of structure I, with or without another
therapeutic agent, in association with a pharmaceutical
vehicle or diluent. The pharmaceutical composition can
be formulated employing conventional solid or liquid
vehicles or diluents and pharmaceutical additives of a
type appropriate to the mode of desired administration.
The compounds can be administered to mammalian species
including humans, monkeys, dogs, etc. by an oral route,
for example, in the form of tablets, capsules, granules
or powders, or they can be administered by a parenteral
route in the form of injectable preparations. The dose
for adults is preferably between 50 and 2,000 mg per day,
which can be administered in a single dose or in the form
of individual doses from 1-4 times per day.
A typical capsule for oral administration contains
compounds of structure I (250 mg), lactose (75 mg) and
magnesium stearate (15 mg). The mixture is passed
through a 60 mesh sieve and packed into a No. 1 gelatin
capsule.
A typical injactable preparation is produced by
aseptically placing 250 mg of compounds of structure I
into a vial, aseptically freeze-drying and sealing. For
use, the contents of the vial are mixed with 2 mL of
physiological saline, to produce an injectable
preparation.
The following Examples represent preferred
embodiments of the invention.
The following abbreviations are employed in the
Examples:
Ph = phenyl
Bn = benzyl
t-Bu = tertiary butyl
Me = methyl
Et = ethyl
TMS = trimethylsilyl
TMSN3 = trimethylsilyl azide
TBS = tert-butyldimethylsilyl
FMOC '= f luorenylmethoxycarbonyl
Boc = tert-butoxycarbonyl
Cbz = carbobenzyloxy or carbobenzoxy or benzyloxycarbonyl
THF = tetrahydrofuran
Et20 = diethyl ether
hex = hexanes
EtOAc = ethyl acetate
DMF = dimethyl formamide
MeOH = methanol
EtOH = ethanol
i-PrOH = isopropanol
DMSO = dimethyl sulfoxide
DME = 1,2 dimethoxyethane
DCE =1,2 dichloroethane
HMPA = hexamethyl phosphoric triamide
HOAc or AcOH = acetic acid
TFA = trifluoroacetic acid
= diisopropylethylamine

Et3N = triethylamine
NMM = N-methyl morpholine
DMAP = 4-dimethylaminopyridine
NaBH4 = sodium borohydride
NaBH(OAc)3 = sodium triacetoxyborohydride
DIBALH = diisobutyl aluminum hydride
LiAlH4 = lithium aluminum hydride
n-BuLi = n-butyllithium
Pd/C = palladium on carbon
PtC-2 = platinum oxide
KOH = potassium hydroxide
NaOH = sodium hydroxide
LiOH - lithium hydroxide
K2C03 = potassium carbonate
NaHCOa = sodium bicarbonate
DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene
EDC (or EDC.HC1) or EDCI (or EDCI.HC1) or EDAC = 3-ethyl-
3'- (dimethylamino)propyl- carbodiimide hydrochloride (or
1- (3-dimethylaminopropyl) -3-ethylcarbodiimide
hydrochloride)
HOBT or HOBT.H20 = 1-hydroxybenzotriazole hydrate
HOAT = l-Hydroxy-7-azabenzotriazole
BOP reagent = benzotriazol-1-yloxy-tris (dimethylamino)
phosphonium hexafluorophosphate
NaN(TMS)2 = sodium hexamethyldisilazide or sodium
bis(trimethylsilyl) amide
Ph3P = triphenylphosphine
Pd(OAc)2 = Palladium acetate
(Ph3P)4Pd° = tetrakis triphenylphosphine palladium
DEAD = diethyl azodicarboxylate
DIAD = diisopropyl azodicarboxylate
Cbz-Cl = benzyl chloroformate
CAN = eerie ammonium nitrate
SAX = Strong Anion Exchanger
SCX = Strong Cation Exchanger
Ar = argon
N2 = nitrogen
min = minute(s)
h or hr = hour(s)
L = liter
mL = milliliter
fiL = microliter
g = gram(s)
mg = milligram(s)
mol = moles
mmol = millimole (s)
meq = milliequivalent
RT = room temperature
sat or sat'd = saturated
aq. = aqueous
TLC = thin layer chromatography
HPLC = high performance liquid chromatography
LC/MS = high performance liquid chromatography/mass
spectrometry
MS or Mass Spec = mass spectrometry
NMR = nuclear magnetic resonance
NMR spectral data: s = singlet; d = doublet; m =
multiplet; br = broad; t = triplet
mp = melting point
Example 1
(Figure Removed)
To a 0°C solution of 4-hydroxybenzaldehyde (1.70 g,
12.3 mmol), 5-phenyl-2-methyl-oxazole-4-ethanol
(Maybricige; 2.50 g, 14.0 mmol) and Ph3P (4.20 g, 16.0
mmol) in dry THF (30 mL) was added dropwise DEAD (3.20 g,
15.0 mmol). The solution was stirred at 0°C for 0.5 h,
then was allowed to warm to RT and stirred overnight.
The orange-red solution was concentrated in vacua and the
residue was chromatographed (stepwise gradient from 5:1
to 5:2 hexrEtOAc) to give Part A compound (2.47 g, 65%)
as a clear, slightly yellow viscous oil.
Al. Alternative Procedure for Preparing Part A
Aldehyde
(Figure Removed)
To a -5°C solution of 5-phenyl-2-methyl-oxazole-4-
ethanol (20,00 g, 0.098 mol) in CH2C12 (100 mL) was added
methanesulfonyl chloride (12.40 g, 0.108 mol) in one
portion (exothermic reaction). After recooling to -5°C,
Et3N (ll.l g, 0.110 mol) was added slowly over 30 min
(internal temperature warm to RT and stirred for 1 h (reaction monitored by
analytical HPLC) , at which point starting material had
been consumed. The reaction was washed with aqueous HC1
(2 x 50 mL of a 3N solution) . The combined aqueous
layers were extracted with CH2C12 (50 mL) . The combined
organic extracts were successively washed with satd.
aqueous NaHCO3 and brine (50 mL each) , dried (Na2S04) , and
concentrated to ~30 mL volume. Methyl tert-butyl ether
(120 mL) was added and the mixture was stirred; a white
solid was formed. The mixture was cooled to -20°C for
complete crystallization. The product was filtered and
vacuum-dried to give the product mesylate (23.3 g, 85%)
as a white solid. The mother liquor was concentrated in
vacuo and recrystallized from methyl tert butyl
ether/heptane to give a second crop of product mesylate
(3.3 g, 12%; total yield = 97%).
(Figure Removed)
A mixture of the above mesylate (13.6 g, 0.048 mol) ,
4-hydroxybenzaldehyde (7.09 g, 0.058 mol) and K2CO3 (9.95
g, 0.072 mol) in DMF (110 mL) was heated at 10O°C for 2 h
(reaction complete by analytical HPLC) . The mixture was
allowed to cool to RT and then poured into ice-water (400
mL) and stirred for 30 min. The solid product was
filtered and washed with cold water (3 x 25 mL) and dried
in vacuo at 50°-60°C overnight. The crude product was
crystallized from MTBE-Hexane to give (12.2 g, 82%; 2
crops) the aldehyde (Part Al compound) as a white solid,
(Figure Removed)
To a solution of N-benzyl glycine ethyl ester (43
mg; 0.22 mmol) and Part Al compound (52 mg; 0.17 mmol) in
DCE (10 mL) was added NaBH(OAc)3 (56 mg; 0.26 mmol). The
reaction mixture was stirred vigorously overnight for 12
hours. Saturated agueous NaHCOs (10 mL) was added, and
the mixture was extracted with EtOAc (3x 10 mL) . The
combined organic extracts were washed with brine, dried
(Na2SO4) , concentrated in vacua and chromatographed
(hex:EtOAc 4:1) to give Part B compound (45 mg; 55%) as a
pale yellow oil in addition to recovered starting
material (14 mg; 27%) .
C.
To a solution of Part B compound (45 mg) in MeOH (2
mL) was added aqueous NaOH (3 mL of a 1M solution). The
solution was stirred overnight for 14 h and then
acidified to pH 5 with excess aqueous HC1 (1M solution) .
The mixture was extracted with EtOAc (2 x 10 mL) ; the
combined organic extracts were washed with brine, dried
(Na2SO4) , and concentrated in vacua to give the desired
acid which was still contaminated with starting material.
This mixture was dissolved in MeOH (2 mL) and aqueous
- 86 -
NaOH (3.0 mL of a 1M solution) and the resulting solution
was refluxed for 1.5 h. Acidic extractive workup as
above gave the desired title compound as a colorless
solid (28 mg; 71%). [M + H]+ = 457.2
Example 2
N CO2H
A.
To a solution of Example 1 Part A compound (147 mg;
0.479 mmol) and glycine ethyl ester hydrochloride (73 mg;
0.52 mmol) in DCE (2 mL) was added Et3N and NaBH(OAc)3
(156 mg; 0.74 mmol) and the reaction was stirred
overnight at RT. Flash chromatography (stepwise gradient
from 7:3 to 2:3 hex: EtOAc) gave 35 mg (21%) of the
dibenzyl glycine ester (Example 2 Part A compound) . In
addition, 127 mg (67%) of the monobenzyl glycine ester
(Example 3 Part A compound) was obtained.
(Figure Removed)
A solution of Example 1 Part A compound (35 mg;
0.051 mmol) in MeOH (2 mL) and aqueous NaOH (3 mL of a 1M
solution) was heated under reflux for 12 h. The solution
was adjusted to pH 5 with aqueous 1M HC1 and aqueous 1 M
NaOH, then extracted with EtOAc (3x). The combined
organic extracts were washed with brine, dried (NaaSO^ ,
and concentrated in vacuo to give title compound (13 mg)
as a colorless solid. [M + H]+ = 658.2
Example 3
(Figure Removed)
To a solution of Example 1 Part A compound (147 mg;
0.479 mmol) and glycine ethyl ester hydrochloride (73 mg;
mmol) in DCE was added Et3N and NaBH(OAc)3 (156 mg; 0.74
mmol). Flash chromatography (stepwise gradient from 7:3
to 2:3 hex: EtOAc) gave 127 mg (67%) of the title
compound. In addition, 35 mg (21%) of the bis—benzyl
glycine ester (Example 2 Part A compound) was obtained as
a byproduct.
(Figure Removed)
A solution of Part A compound (72 mg; 0.18 iranol) in
aqueous NaOH (2 mL of a 1M solution) and MeOH (2 mL) was
refluxed for 3 h. The reaction was adjusted to pH 5 with
aqueous 1M HC1, and solids were filtered off. The
filtrate was extracted with EtOAc (3x) . The combined
organic extracts were washed with brine, dried (NaaSCU)
and concentrated in vacuo to give a colorless solid,
which was purified by preparative HPLC (utilizing a YMC
S5 ODS 20 mm x 100 mm column with a continuous gradient
from 70% A:30 %B to 100% B for 10 min at a flow rate of
20 mL/min, where A = 90:10:0.1 H20:MeOH:TFA and where B =
90:10:0.1 MeOH:H20:TFA) to give title compound (10 mg;
15%) as a colorless solid. [M + H]+ = 367.2
Example 4 *
A solution of the amino t-butyl ester (0.040 g,
0.095 mmol), (prepared as described for Example 7 Part C,
except that the aldehyde used in the reductive amination
was Example 1 Part A instead of Example 7 Part A)
CH3
and propargyl bromide (0.014 g, 0.120 mmol) and DBU (0.5
mL; 2.96 mmol) in DCE (1 mL) was stirred at 0°C for 5 h.
TLC showed that the reaction was complete at this point.
EtOAc (10 mL) was added and the organic phase was washed
with fyO and concentrated in vacua. The residual oil was
dissolved in CH2C12/TFA (1:1, 1 mL) and stirred at RT for
5 h, then concentrated in vacuo. The residue was
purified by preparative HPLC (YMC S5 ODS 30 mm x 250 mm.
reverse phase column; flow rate = 25 mL/min; 30 min
continuous gradient from 70:30 A:B to 100% B; where A =
90:10:0.1 H20:MeOH:TFA and where B = 90:10:0.1
MeOH:H20:TFA) to give the title compound (34 mg, 92%) as
an oil. LC/MS (electrospray) gave the correct [M +H]+ =
405.2 for the title compound.
A solution of 2-chlorobenzoxazole (20 mg; 0.131
mmol), the secondary amine-methyl ester (52 mg; 0.146
mmol)
(prepared as described in Example 3 Part A except glycine
ethyl ester HC1 was replaced by glycine methyl ester HC1
and the Example 7 Part A aldehyde was employed) , and
excess Et3N (0.5 mL) in THF (2.0 mL) was heated to 100°C
in a sealed tube and the reaction was monitored by LC/MS.
After 4 days, starting amine had been consumed. The
reaction was cooled to RT and aqueous LiOH (0.50 mL of a
1 M solution) was added to the solution. The solution
was stirred at RT for' 5 h, after which the hydrolysis was
complete. The mixture was concentrated in vacuo to give
the crude acid as an oil, which was purified by
preparative HPLC (30 min continuous gradient from 70:30
A:B to 100% B, where A = 90:10:0.1 H20:MeOH:TFA and B =
90:10:0.1 MeOH:H20:TFA; flow rate = 25 mL/min; YMC S5 CDS
30 x 250 mm reverse-phase column) to give the title
compound (52 mg; 82%) as a solid after lyophilization
from (MeOH/H20) . [M + H]+ = 484.2
(Figure Removed)
The title compound (13 mg; 21%) was prepared in an
analogous fashion to Example 5 using the corresponding
secondary amine-methyl ester.
(Figure Removed)
(This compound was prepared as described in Example 3
Part A except glycine ethyl ester HC1 was replaced by
glycine methyl ester HC1). Example 6: [M+H]+ = 484.2
Example 7
(Figure Removed)
To a 0°C solution of 3-hydroxybenzaldehyde (3.00 g;
24.6 mmol), 2-phenyl-5-methyl-oxazole-4-ethanol (5.00 g;
24.6 mmol) and Ph3P (7.10 g; 27.1 mmol) in dry THF (75
mL) was added dropwise DEAD (4.27 mL; 27.1 mmol) over 10
min. The brown-orange solution was allowed to warm to RT
and stirred at RT for 24 h. The solution was
concentrated in vacua and chromatographed (SiO2; stepwise
gradient: 100% hex to hex:EtOAc 3:1) to give Part A
compound as a pale yellow viscous oil (4.01 g; 53%).
A.I. Alternative Procedure for Preparing Part A
Aldehyde
(Figure Removed)

To a solution of 3-hydroxybenzaldehyde (9.1 g;
0.074 mmol) in CH3CN (206 mL) was added K2CO3 (10.3 g) .
The mixture was heated to 90°C in an oil bath and stirred
for 18 h at 90°C (the reaction was complete at this point
by analytical HPLC) . The reaction was cooled to RT, then
diluted with EtOAc (500 mL) , washed with H20, aqueous NaOH
( 2 x l O O m L o f a l M solution) and brine. The organic
phase was dried (MgSOj and concentrated in vacuo. The
residual oil was chromatographed (SiO2; hex:EtOAc from 9:1
to 4:1) to give the Part A aldehyde (12.7 g; 67%) as a
viscous, clear, pale yellow oil.
(Figure Removed)
A solution of the Part Al compound (4.00 g; 13.0
nunol) , glycine tert-butyl ester hydrochloride (2.40 g;
14.3 mmol) and Et3N (2.18 mL; 15.7 nunol) in MeOH (30 mL)
was stirred at RT for 6 h and then cooled to 0°C. A
solution of NaBH4 (594 mg; 15.7 mmol) in MeOH (10 mL) was
added portionwise at 0°C to the solution of crude inline
over -15 min. The solution was stirred at 0°C for 3 h,
then at RT for 3 h, then concentrated in vacua without
heating to removed MeOH. The residue was partitioned
between saturated aqueous NaCl and EtOAc (50 mL each).
The aqueous layer was extracted with EtOAc (2 x 50 mL) .
The combined organic extracts were dried (Na2SO4) and
concentrated in vacua to give a yellow oil, which was
chromatographed on Si02 (stepwise gradient; hex:EtOAc
from 4:1 to 2:3) to give Part B compound as a pale
viscous yellow oil (4.82 g; 88%).
C.
To a solution of Part B compound (0.400 g; 0.95
mmol) and 4-phenoxybenzaldehyde (0.216 g; 1.09 mmol) in
DCE (5 mL) was added NaBH(OAc)3 (0.300 g; 1.42 mmol),
followed by HOAc (25 jiL) . The reaction was stirred at RT
for 24 h. 10% unreacted starting amine was still present
by analytical HPLC. Additional aldehyde (30 mg) and
NaBH(OAc)3 (60 mg) were added and the reacton was stirred
at RT for a further 18 h, after which reaction was
complete. The solution was partitioned between aqueous
NaHC03 (50 mL of a 10% solution) and EtOAc (50 mL) . The
aqueous layer was extracted with EtOAc (2 x 25 mL) . The
combined organic extracts were washed with aqueous NaHCOa
(2 x 15 mL of a 10% solution) , dried (Na2SO4) and
concentrated in vacua to give Part C compound (521 mg
crude material) as a clear, colorless oil.
D.
Part C compound was dissolved in CHCls (2 mL) and
TFA (1.5 mL) and the solution was stirred at RT for 24 h.
The solution was concentrated in vacuo and the residue
was purified by preparative HPLC (YMC S5 ODS 2O x 250 mm
column; continuous gradient from 40:60 solvent A:B to
100% solvent B; where solvent A = 90:10:0.1 H2O :MeOH:TFA;
solvent B = 90:10:0.1 MeOH:H20:TFA ). The purified
product was lyophilized from MeOH/H20 to give the title
amino acid (312 mg; 48% over 2 steps) as its TFA salt
(off-white lyophilate). [M+H]+ (electrospray) = 549.3
A mixture of the amino-ester (39 mg; 0.092 mmol) ,
(Figure Removed)
(prepared as described in Example 4),
2-naphthaldehyde (29 mg; 0.185 mmol), and NaBH(OAc)3 (100
mg; 0.472 mmol) in DCE (1.5 mL) was stirred at RT for 16
h. TFA (1.0 mL) was then added to the mixture, which was
stirred at RT for a further 12 h. Volatiles were removed
in vacuo. The resulting residue was diluted with MeOH
(1.5 mL) , filtered, and purified by preparative HPLC (YMC
S5 ODS 30mm x 250 mm column; continuous 30 min gradient @
25 mL/min from 100% A to 100% B; solvent A = 90:10:0.1
H20:MeOH:TFA; B = 90:10:0.1 MeOH:H20: TFA) to give the
desired title product (39 mg; 68%) as a clear, viscous
oil. [M + H]+ = 507.3
A.
A solution of the amino acid tert-butyl ester (1.8
g, 4.27 mmol) CH3
(prepared as described in Example 7 Part B) ,
and TFA (20 mL) in CH2C12 (40 mL) was stirred at RT
overnight. The solution was concentrated in vacuo, and
- 95 -
the residue was dissolved' in CH2C12 and eluted through
solid NaHC03 (to remove excess TFA) with excess CH2C12.
The combined filtrates were concentrated in vacua to
provide the desired amino acid Part A compound (1.48 g;
95%). [M + H]+ = 457.2
B.
The title compound was prepared as part of a
solution phase library run using the following exemplary
procedure:
To a solution of the Part A amino acid compound (27
mg, 0.074 mmol; in 2 mL CH2C12) was added (4-chlorophenoxy)-
3-benzaldehyde (86 mg; 0.37 mmol), NaBH(OAc)3
(79 mg, 0.37 mmol) and HOAc (0.1 mL) . The reaction was
stirred at RT for 15 h.
The product was purified via solid-phase extraction
using a Varian SAX cartridge (3 g of sorbent in a 6 mL
column, 0.3 meq/g) by the procedure outlined below:
1) The column was conditioned with MeOH (10 mL) and CHaCl2
(20 mL)
2) The reaction mixture was loaded onto the SAX column
3) The column was rinsed with CH2C12 (10 mL)
4) The column was rinsed with 1% TFA in MeOH (3 mL)
5) The product was eluted with 1% TFA in MeOH (20 mL)
The product solution (combined fractions from step 5)
was concentrated using a Speed Vac for 16 h to afford the
crude product (25 mg; 49%) as a solid. Reverse-phase
HPLC analysis (YMC S5 ODS 4.6 x 33 mm column, continuous
gradient from 100% A to 100% B for 2 min at a flow rate
of 5 mL/min [Solvent A = 10% MeOH/90% H20/0.2% H3P04;
Solvent B = 90% MeOH/10% H20/0.2% H3P04] ) indicated that
the product purity was 92%. In addition, LC/MS
(electrospray) gave the correct molecular ion [(M+H)+ =
583] for the title compound.
Example 10
(procedure used with heterocyclic aldehydes)
The title compound was prepared as part of a
solution phase library run using the following exemplary
procedure.
A mixture of the amino acid (14 mg; 0.038 mmol) ,
(Figure Removed)
(prepared as described in Example 9 Part A),
5-(4-chlorophenyl)-2-furfural (16 mg; 0.076 mmol), and
NaBH(OAc)3 (72 mg; 0.34 mmol) in DCE (1.5 ml) was stirred
at RT for 16 h. TFA (1.0 ml) was then added to the
mixture, which was stirred at RT for a further 12 h.
Volatiles were removed in vacuo. The resulting residue
was diluted with MeOH' (1.5 mL), filtered, and purified by
preparative HPLC (YMC S5 ODS 30mm x 250 mm column;
continuous 30 minute gradient @ 25 mL/min from 100% A to
100% B; solvent A = 90:10:0.1 H20:MeOH:TFA; B = 90:10:0.1
MeOH:H2O:TFA) to give the desired title product (39 ing;
68%) as a clear, viscous oil.
Example IDA
An alternative purification procedure to
preparative HPLC was used as follows:
The crude reductive amination product was purified
by solid-phase extraction using an SAX cartridge (United
Chemicals; 3 g of sorbent in a 6 mL column, 0.3 meq/g) by
the procedure outlined below:
1) The column was conditioned with MeOH (5 mL) and CH2C12
(5 mL)
2) The reaction mixture (diluted with 2 mL CH2Cl-2) was
loaded onto the SAX column
3) The column was rinsed with CH2Cl2 (8 mL)
4) The product was eluted with 1% TFA in MeOH (20 mL)
The product-containing fractions were concentrated
in vacuo using a Speed Vac for 16 h to afford the crude
product. This was dissolved in CH2Cl2:MeOH (95:5) and
loaded onto a silica gel cartridge (1.5 g Si02) and the
product was eluted with CH2Cl2:MeOH (95:5; 8 mL.) . The
product-containing fractions were concentrated in vacuo
using a Speed Vac to give the desired title product.
Reverse Phase HPLC analysis (YMC S5 ODS 4.6 x 33
mm column, continuous gradient from 100% A to 100%B for 2
min at a flow rate of 5 mL/min [Solvent A=10% MeOH/90%
H20/0.2% H3P04; Solvent B = 90% MeOH/10% H2O/0.2% H3P04] )
indicated that the product purity was 92%. In addition,
LC/MS (electrospray) gave the correct molecular ion
[(M+H)+= 583] for title compound.
Example 11
A.
To a mixture of the amino-tert-butyl ester (0.339 g,
0.80 mmol) ,
(Figure Removed)
(prepared as described in Example 7, Part B),
4-hydroxybenzaldehyde (0.127 g, 1.0.3 mmol) and NaBH(OAc)3
(0.510 g, 2.4 mmol) was added 7 drops of HOAc. The
reaction was stirred at RT for 16 h. The mixture was
diluted with EtOAc, then washed with aqueous NaHC03. The
organic phase was dried (MgS04) and concentrated in
vacuo. The crude product was chromatographed (SiOa;
hexanes/EtOAc 3:1 to 1:4) to provide the 4-hydroxybenzyl
amino ester title compound compound (0.381 g, 90%).
B.
The title compound was prepared as part of a
solution phase library run using the following exemplary
procedure.
To a solution of Part A phenol compound (30 mg,
0.057 mmol) in CH2C12 (1 mL) was added 3-fluorophenyl
boronic acid (12 mg; 0.086 mmol) and 4A molecular sieves
(pre-dried at 400°C overnight) at RT. After stirring for
5 min, Cu(OAc)2 (\ eq) , Et3N (5 eq) and pyridine (5 eq)
were added to the mixture. The vial was capped and air
was allowed to pass into the reaction. The reaction was
stirred at RT for 60 h and was complete by analytical
HPLC and LC/MS. (For other reactions which were
incomplete after this time, additional boronic acid (1.5
equivalent) was added in order to form additional desired
product) . The reaction mixture was filtered and
concentrated in vacuo.
The product was purified via solid-phase extraction
using a United Technology SCX column (2 g of sorbent in a
6 mL column) by the procedure outlined below.
1) The column was conditioned with MeOH (10 mL) and CH2C12
(10 mL)
2) The residue was dissolved in a minimal volume of CH2C12
and loaded onto the SCX column.
3) The cartridge was successively washed with CH2C12 (20
mL), CH2Cl2/MeOH (20% MeOH, 20 mL) and MeOH (20 mL)

4) The product was eluted with a solution of 0. 5N NH3 in
MeOH.
The product-containing fractions were concentrated
in vacua to give the desired tert-butyl ester. (Some
incomplete reactions required chromatography (on Si02) of
the crude material to give esters of the requisite
purity). The t-butyl ester was treated with a solution
of 30% TFA in CH2C12 overnight. Volatiles were removed
and the residue was redissolved in CHsCla (1 mL) and
concentrated in vacuo on a Speed Vac to afford the
desired title product (30 mg; 77%). Reverse phase HPLC
analysis indicated that the product purity was 90%. In
addition LC/MS gave the correct molecular ion [ (M+H)"1" =
567] for the desired title compound.
A.
To a solution of the secondary amine-tert butyl
ester (110 mg; 0.26 mmol)
(Figure Removed)
(prepared as described in Example 7, Part B),
in 1,2-dichloroethane (4 mL) were successively added 4-
formyl phenylboronic acid (47 mg; 0.31 mmol} and
NaBH(OAc)3 (165 mg; 0.78 mmol). The mixture was stirred
at RT for 3 h. Analytical HPLC and LC/MS indicated that
the reaction was complete at ths point. Volatiles were
removed in vacuo and the residue was chromatographed
(Si02; stepwise gradient from 3:1 to 1:1 hexane: EtOAc) to
provide title compound (133 mg; 91%) as a white foam.
B.
(Figure Removed)
The title compound was prepared as part of a
solution phase library run using the following procedure.
To a solution of the Part A boronic acid compound
(40 mg, 0.072 mmol) in CH2C12 (1 mL) was added m-cresol
(23 mg; 0.22 mmol) and 4A molecular sieves (150 mg; predried
at 400°C overnight) . After stirring for 5 min,
Cu(OAc)2 (1 eq) , Et3N (5 eq) and pyridine (5 eq) were
added to the mixture. The vial was capped and air was
allowed to pass into the reaction, which was stirred at
RT for 24 h. The reaction mixture was filtered through a
pad of Celite and concentrated in vacuo.
The product was purified via solid-phase extraction
using a United Technology SCX column (2 g of sorbent in a
6 mL column) by the procedure outlined below.
1) The column was conditioned with MeOH (10 mL) and CH2C12
(10 mL)
2) The residue was dissolved in a minimal volume of
and loaded onto the SCX column.
3) The cartridge was successively washed with CH2C12 (20
mL) and MeOH (20 mL).
4) The product was eluted with a solution of 0.5N NHs in
MeOH.
5) The product-containing fractions were concentrated in
vacuo
6) The residue was dissolved in a minimum amount of CH2Cl2
and loaded onto a silica gel cartridge (2 mL)
7) The cartridge was eluted with hexane:EtOAc (3:1; 20 mL)
8) The product-containing fractions were collected and
concentrated in vacuo to give the purified tert-butyl
ester
The t-butyl ester was treated with a solution of 1:1
TFA in CH2C12 overnight. Volatiles were removed and the
residue was redissolved in CH2C12 (1 mL) and concentrated
in vacuo on a Speed Vac to afford the desired title
product (25 mg; 48%) as a slightly yellowish oil.
Reverse phase HPLC analysis indicated that the product
purity was 91%. In addition LC/MS gave the correct
molecular ion [(M+H)+ = 563.2] for the desired compound.
(Figure Removed)The title compound was prepared as part of a
solution phase library run using the following exemplary
procedure.
To a solution of 3-bromopyridine (32 mg; 0.2 mmol)
in DME (1 mL) were successively added (PhaP^Pd (5 mg;
0.05 mol equiv) and the Example 12 Part A boronic acid
(50 mg; 0.09 mmol)
(Figure Removed)Finally, aqueous Na2C03 (19 mg in 0.3 mL HaO) was
added and the mixture was heated in an oil bath at 85°C
for 5 h; LC/MS indicated that the reaction was complete
at this point.
The reaction mixture was filtered and the filtrate
was chromatographed on a silica gel cartridge (2 mL;
EtOAc). The product-containing fractions were
concentrated in vacuo and the residue was chromatographed
on another silica gel cartridge (2 mL; stepwise gradient
of hexanes, hex:EtOAc 3:1 and EtOAc). The productcontaining
fractions were concentrated in vacuo and the
residue was eluted through an SCX (2 g) cartridge (20 mL
each of CH2C12 and MeOH; then product eluted with 2M
ammonia in MeOH) . The product-containing fractions were
concentrated in vacuo to give the desired biaryl amine
tert-butyl ester product. This was treated with a
solution of CH2C12/TFA (7:3; 1 mL) overnight for 14 h.
Volatiles were removed to give title compound (39 mg;
67%) as an oil. [M + H]+ = 534.3
Examples 14 to 124
Following one of the above procedures, the following
compounds of the invention were prepared:
Table 1
(Table Removed)
Example 125
A.
A solution of Example 7 Part A aldehyde (60 mg; 0.20
mmol) and (S)-a-raethyl benzylamine (30 mg; 0.24 rnmol) in
MeOH (1 mL) was stirred at RT for 6 h. The solution was
cooled to 0°C and a pre-formed solution of NaBH4 (9 mg;
0.24 mmol) in MeOH (0.5 mL) was added portionwise. The
reaction was stirred at RT overnight, then concentrated
in vacuo without heating. The residue was partitioned
between aqueous NaHCOs and EtOAc (5 mL each). The
aqueous layer was extracted with EtOAc (2x5 mL) . The
combined organic extracts were dried (Na2SO4) and
concentrated in vacuo to give title compound as an orange
yellow-oil (81 mg crude).
B.
A solution of the Part A compound (70 mg; 0.17
mmol), tert-butyl bromoacetate (66 mg; 0.34 mmol), and
iPr2NEt in DMF (0.5 mL) was stirred at RT for 2 days.
LC/MS showed that the reaction was complete and clean.
The crude reaction mixture was partitioned between
(30 inL) and EtOAc (20 mL) . The aqueous layer was
extracted with Et20 (2 x 10 mL) ; the combined organic
extracts were dried (MgS04) and concentrated in vacuo to
give the crude amino-tert-butyl ester.
This crude product was stirred in a 1:1 solution of
CHC13 and TFA (2 mL) for 18 h at RT. The solution was
then concentrated in vacuo and purified by preparative
reverse-phase HPLC (as in Example 10). The purified
material was lyophilized from MeOH-H20 to give the title
compound (71 mg; 71%) as a white lyophilate. [M + H]+ =
471.2
Example 126
(Figure Removed)The title compound was synthesized following the
same procedure as described above in Example 125 except
that (S)-ct-methyl benzylamine was replaced by (R)-Dimethyl
benzylamine in the synthesis of the part A
compound. The title compound was obtained in 67% yield
(66 mg) overall. [M + H]+ = 471.2
Example 127
A mixture of Example 7 Part A compound (30 mg,
0.098 mmol), D-alanine tert-butyl ester hydrochloride (23
mg; 0.127 mmol), Et3N (5 drops) and 4A molecular sieves
in MeOH (2 mL) was stirre'd at RT for 4 h. NaBH4 (12 mg,
0.0294 mmol) was added and the reaction was stirred at RT
for 30 min. The reaction mixture was then concentrated
in vacuo, diluted with CH2C12 (2 mL) , and filtered through
cotton. TFA (1 mL) was added to the filtrate and the
reaction was stirred at RT overnight. The reaction
mixture was concentrated in vacuo, diluted with EtOAc,
washed several times with sat'd. aqueous NaHCOa/- then
with brine. The organic phase was dried (MgSC>4) and
concentrated in vacuo. The residue was purified by
preparative HPLC (YMC ODS 30mm x 250mm reverse-phase
column; flow rate = 25 mL/min; 30 min continuous gradient
from 50:50 A:B to 100% B, where A = 90:10:0.1 H20:MeOH:
TFA and B = 90:10:0.1 MeOH :H20: TFA) to provide the title
compound (7.8 mg, 21%) as a white lyophilate.
[M + H]+ = 381.1
Example 128
(Figure Removed)
Title compound (20% overall yield) was synthesized
using the same procedure as described in Example 125,
using D-phenylalanine tert-butyl ester hydrochloride
instead of D-alanine tert-butyl ester hydrochloride.
[M + H]+ = 457.2
Example 129
A mixture of Example 7 Part A (40 mg, 0.13 mmol) , Dalanine
tert-butyl ester hydrochloride (31 mg, 0.17
mmol) , Et3N (6 drops) and 4A molecular sieves in MeOH (2
mL) was stirred at RT for 4 h. NaBfU (15 mg, 3 equiv)
was added and the mixture was stirred at RT for 30 min,
then concentrated in vacuo. The residue was dissolved in
CH2C12 (2 mL) and filtered. To the filtrate in a vial
were added 4-phenoxybenzaldehyde (77 mg, 0.39 mmol) and
NaBH(OAc)3 (138 mg, 0.65 mmol). The reaction was stirred
at RT for 18 h. The reaction mixture was chromatographed
on SiO2 using hexanes/EtOAc (9:1 to 4:1) to obtain the
pure tert-butyl. ester. This material was dissolved in
CH2C12 (2 mL) and TFA (1 mL) was added slowly. The
solution was stirred at RT overnight, then was
concentrated in vacuo. The residue was redissolved in
CH2C12 and filtered through solid NaHC03 to remove
residual TFA. This solution was further diluted with
CH2C12, washed with 1 M aq NaHS04 and brine, dried
(MgS04) , filtered and concentrated in vacuo to obtain the
title compound (9.1 mg, 12%). [M + H]+ = 563.2
The title compound (13% overall yield) was
synthesized using the same procedure as described in
Example 127, using D-phenyl-alanine tert-butyl ester
hydrochloride instead of D-alanine tert-butyl ester
hydrochloride. [M + H]+ = 639.2
- 118 -
Examples 131 to 135
Other analogs in this series were prepared by
analogous procedures and are shown in the following
table:
(Table Removed)
(prepared as described in Example 3 Part A) in MeOH (2
mL) and aqueous NaOH (2 mL of a 1M solution) was heated
under reflux for 12 h. The pH of the solution was
adjusted to 5 (with aqueous 1M NaOH and 1M HCl) , upon
which a colorless solid precipitated. This was filtered
off and the filtrate was extracted with EtOAc (3x); the
combined organic extracts were dried. (NajSC^) and
concentrated in vacuo to give the crude title amino acid
as a colorless solid (97 mg).
(Figure Removed)To a solution of the Part A amino acid (15 mg; 0.04
mmol) in dioxane:H20 (1:1, 8 mL) was added K2CO3 (22 mg;
0.16 mmol) followed by benzyl chloroformate (15 mg; 0.09
mmol). The reaction was stirred overnight, then
concentrated in vacua and acidified with excess aqueous
1M HC1. This was extracted with EtOAc (3x); the combined
organic extracts were washed with brine, dried (Na2S04) ,
and concentrated in vacua to give title compound (13 mg;
63%) as a colorless solid. [M + H]+ = 501.3
Example 137
To a 0°C solution of the amino-tert-butyl ester (75
mg; 0.18 mmol)
(prepared as described in Example 7 Part B),
in CH2C12 (1 mL) was added CbzCl (28 p.L; 0.20 mmol),
followed by Et3N (54 ^iL; 0.39 mmol). The reaction was
allowed to warm to RT and then stirred at RT overnight
for 18 h. Aqueous NaHC03 (2 mL of a 10% solution) was
added and the aqueous layer was extracted with EtOAc (2 x
2 mL) . The combined organic extracts were dried (Na2SO4)
and concentrated in vacua. The crude carbamate-ester was
dissolved in CHCls (3 mL) and TFA (1 mL) ; the solution
was stirred at RT for 24 h, then concentrated in vacuo.
The crude carbamate-acid was purified by reverse-phase
preparative HPLC on a C-18 column (continuous gradient
over 14 min; 4 min hold time; flow rate = 20 mL/min from
1:1 A:B to 100% B; solvent A = 90:10:0.1 H20:MeOH:TFA;
solvent B = 90:10:0.1 MeOH:H20:TFA) . The product was

lyophilized from MeOH/H20 to give title compound as a
white lyophilate. [M + H]+ = 501.3.
A. The required aryl chloroformates (where not
commercially available) were prepared according to the
following general procedure, which is exemplified by the
synthesis of 2-methoxy phenyl chloroformate:
A solution of 2-methoxyphenol (2 g, 16.1 rnmol), N,Ndimethylaniline
(1.95 g, 16.1 mmol), phosgene (8.34 mL of
a 1.93 M solution in toluene, 16.1 mmol) and a catalytic
amount of DMF in chlorobenzene (5 ml) was stirred in a
pressure tube for 2 h at 80°C. The organic layer was
separated and concentrated in vacuo. The residue was
distilled (Buchi Kugelrohr; bp = 115°C @ 10 mm Hg) to
provide 2-methoxyphenyl chloroformate (1.5g; 50%) as a
clear oil.
B.
A solution of the amino-t-butyl ester (20 mg, 0.05
mmol),
Pf.
(Figure Removed)
(prepared as described in Example 7 Part B),
2-methoxyphenyl chloroformate (8 mg, 0.05 mmol; prepared
as above) and polyvinylpyridine (Aldrich; 16 mg, 0.3
mmol) in CH2C12 (1 inL) was stirred for 30 min at RT.
Amine resin WA21J (Supelco; 200 mg) was added and the
mixture was stirred at RT for 30 min in order to remove
unreacted chloroformate. The reaction mixture was
filtered and concentrated in vacuo to give the desired 2--
methoxyphenyl carbamate-ester.
The ester was treated with a solution of 30% TFA in
CH2Cl2 (5 mL) overnight. Volatiles were removed in vacuo
to give the crude acid. This material was purified via
solid-phase extraction using an anion exchange column
(CHQAX13M6 column; United Technologies; 3 g of sorbent in
a 6 mL column) by the exemplary procedure outlined below.
1) The column was conditioned with MeOH (10 mL) and CH2C12
(10 mL).
2) The crude acid was dissolved in a minimal volume of
CH2C12 and loaded onto the SAX column.
3) The cartridge was washed with CH2Cl2 (10 mL) ,
CH2Cl2/MeOH (10 mL of a 4:1 CH2Cl2:MeOH solution) .
4) The product was eluted with CH2Cl2/MeOH (10 mL of a 4:1
CH2Cl2:MeOH solution).
The product-containing fractions were concentrated
in vacuo on a Speed Vac to afford title compound as an
oil. Analytical reverse-phase HPLC (standard conditions)
indicated that the purity of the product was 90%. In
addition LC/MS gave the correct molecular ion [ (M+H)+ =
517.3] for the desired title compound.
Example 139
(Figure Removed)A.
Phosgene (0.21 mL of a 1.93 M solution in toluene;
0.40 immol) was added dropwise to a solution of the aminotert-
butyl ester (100 mg, 0.24 mmol)
(prepared as described in Example 7 Part B),
and Et3N (30.3 mg; 0.30 mmol) in 3 ml CH2C12 at -5°C. The
reaction mixture was stirred at RT for 2 h. The mixture
was concentrated in vacuo to give the crude product which
was chromatographed (SiOa; hexane/EtOAc 1:5) to provide
title compound (0.105 g, 91%)'.
B.
The title compound was prepared as part of a
solution phase library run using the following exemplary
procedure.

A mixture of the Part A carbamoyl chloride (20 mg;
0.045 mmol), 3,5-dichlorophenol (16 mg; 0.07 mmol), and
pyridine (0.5 ml) was stirred at 80°C for 16 h. Pyridine
was removed in vacua and the residue was purified via
solid-phase extraction using a CHQAX1 cartridge (2 g of
sorbent in a 6 ml column, 0.3 mg/g) by the procedure
outlined below:
1) The column was conditioned with MeOH (10 ml) and
CH2C12(20 mL)
2) The reaction mixture in CH2C12 was loaded onto the SAX
column
3) The product was eluted with CH2C12 (10 mL).
The product-containing fractions were concentrated
in vacuo using a Speed Vac over 16 h to afford the pure
aryl carbamate-tert-butyl ester which was treated .with a
solution of 30% TFA in CH2C12 overnight. Volatiles were
removed using a Speed Vac for 16 h to afford the crude
acid final product. The product was initially purified
via solid-phase extraction using a Varian SAX cartridge
(2 g of sorbent in a 6 mL column, 0.3 meq/g) by the
procedure outlined below:
1) The column was conditioned with MeOH (10 mL) and CH2C12
(20 mL)
2) The reaction mixture in CH2C12 was loaded onto the SAX
column
3) The column was rinsed with CH2C12 (10 mL)
4) The column was rinsed with 10% MeOH in CH2C12 (10 mL)

5) The product was eluted with 2% TFA in CH2C12 (10 mL)
The product-containing fractions were concentrated
in vacua using a Speed Vac for 16 h to afford the
purified product (20 mg, 80%) as a solid. Reverse phase
HPLC analysis (YMC S5 ODS 4.6 x 33 mm column, continuous
gradient from 50% A to 100% B -for 2 min at a flow rate of
5 mL/min [Solvent A = 10%MeOH/90%H20/0.2% H3P04; Solvent
B = 90%MeOH/10% H20/0.2% H3P04] ) indicated that the
product purity was 96%. In addition, LC/MS gave the
correct molecular ion [(M+H)+= 555.2] (electrospray) for
the title compound.
Example 140
Benzyl chloroformates were synthesized by the
following general procedure, as exemplified by m-methoxy
benzyl chloroformate:
To a solution of 3-methoxybenzyl alcohol (2.0 g;
7.24 nunol) , N,N-dimethylaniline (0.877 g; 7.24 iranol) in
anhydrous ether (5 mL) was added phosgene dropwise (3.8
mL of a 1.93 M solution in toluene; 7.3 mmol) at 0°C.
The reaction mixture was stirred at 0°C for 2 h, after
which solids were filtered off. The filtrate was
concentrated in vacua at RT. The crude chlorof ormate was
stripped from anhydrous Et20 (2x2 mL) and used without
further purification in the next reaction. Subsequently
other chloroformates were also prepared using this
standard procedure.
B.
The title compound was prepared as part of a
solution phase library which was run using the following
standard procedure.
To a suspension of the Example 3 amino acid
(trifluoroacetic acid salt)
(25 mg, 0.05 mmol) in CH2C12 (1 mL) was added Part A
compound (10 mg; 0.05 mmol) and iPr2NEt (19.4 mg; 0.15
mmol) . After stirring for 30 min at RT, the reaction
mixture was concentrated in vacuo.
The product was purified via solid-phase extraction
using a Varian CHQAX13M6 (anion exchange) column (3 g of
sorbent in a 6 mL column) by the procedure outlined
below:
1) The column was conditioned with MeOH (10 mL) .and CH2C12
(10 mL)
2) The residue was dissolved in a minimal volume of CH2C12
and loaded onto the SAX column.
3) The cartridge was washed successively with CH2C12 (10
mL), 20% MeOH/CH2Cl2 (10 mL).
4) The product was eluted with a solution of 20%
MeOH/CH2Cl2 (10 mL) .
The product-containing fractions were concentrated
in vacuo using a Speed Vac to afford the title compound.
Reverse Phase HPLC analysis using standard conditions
indicated that the product purity was 90%. In addition,
LC/MS (electrospray) gave the correct molecular ion
[(M+H)+ = 531.3] for the desired title compound.
Example 141
A solution of 4-(benzyloxy)phenol (2.0 g; 9.99
mmol), N,N-dimethylaniline (1.21 g; 9.99 rranol) , phosgene
(5.2 mL of a 1.95 M solution in toluene; 10 mmol) and a
catalytic amount of DMF in chlorobenzene (5 mL) was
heated at 80°C in a pressure tube for 2.5 h. The mixture
was allowed to cool to.RT. The upper clear solution was
separated and concentrated in vacuo to give the crude
title aryl chloroformate as crystals (2 g crude product)
B.
To a mixture of the Part A chloroformate (184 mg,
0.70 mmol) in CH2C12 (5 mL) and polyvinylpyridine
(Aldrich; 315 mg, 1 mmol) was added a solution of the
amino-tert-butyl ester (280 mg, 0.66 mmol)
(prepared as described in Example 7 Part B),
in CH2C12 (5 mL) . The reaction was stirred at RT for 15
min. Resin-bound amine (WA21J, Supelco; 150 mg) was
added to the mixture. The reaction mixture was stirred
for another 15 min. The resin-bound amine and
polyvinylpyridine were filtered off and the filtrate was
concentrated in vacuo to give the crude product. The
crude product was chromatographed (Si02; hexane/EtOAc
1:4) to provide title compound (0.30 g, 70%).
C.
A solution of Part B compound (75 mg; 0.42 mmol) in
20 ml MeOH was hydrogenated in the presence of 20 mg of
10% Pd/C under an atmosphere of H2 (balloon) for 24 h.
The palladium catalyst was removed by filtration and the
filtrate was concentrated in vacua to give the crude
title t-butyl ester (240 mg, 90%) which was used without
further purification in the next step.
D.
The solution of Part C phenol-tert-butyl ester (50
mg; 0.089 mmol) , catalytic Bu4NBr (1.5 mg, 0.0047 mmol)
aq NaOH (0.7 mL of a 1 M solution) and isopropanol (2 mL)
in a pressure tube was cooled to -50°C. Freon gas was
bubbled into the solution for 1 min. The tube was sealed
and heated to 80°C for 12 h. The mixture was extracted
with EtOAc (3 x 10 mL) . The combined organic extracts
were washed with brine, dried (Na2S04) and concentrated in
vacua to give an oil, which was then treated with a
solution of 30% TFA in CH2C12 overnight. Volatiles were
removed in vacua and the residue was purified using
preparative HPLC (YMC S5 ODS 30 x 250mm reverse phase
column; 30 minute continuous gradient from 70:30 A:B to
100% B, where A = 90:10:0.1 H20:MeOH:TFA, and B =
90:10:0.1 MeOH: H20:TFA) to afford the desired title
product (14 mg; 28%) . Reverse Phase HPLC analysis
indicated that the product purity was 97%. In addition
LC/MS (electrospray) gave the correct molecular ion
[(M+H)+ = 553.1] for the desired compound.
Example 142
Following the Example 141 procedure, the analogous
compound was prepared [(M+H)+ = 553.2]:
(Figure Removed)Intermediates corresponding to Example 141 Parts B
and C were deprotected using the same TFA/CHC13 procedure
as above and purified as usual to give the following
analogs:
Example 143 Example 144
CO2H
Example 143: [M + H]+ = 593.4
Example 144: [M + H]+ = 503.1
Examples 145 to 305
The following carbamate-acid analogs in Tables 4 and
5 were synthesized according to one of the above methods :
Table 4
(Table Removed)
in CH2C12 (10 mL) was added 4-methylphenyl chloroformate
(0.79 mL; 5.52 mmol) and polyvinyl pyridine (Aldrich;
1.74 g; 16.5 mmmol). The mixture was stirred at RT for
15 min; at this point TLC showed that starting material
had been consumed. The solution was filtered,
concentrated in vacua, and the residue was
chromatographed (Si02; hexiEtOAc 4:1) to provide the pure
carbamate-ester (2 g). This was dissolved in a mixture
of THF (10 mL), MeOH (1 mL) and aqueous LiOH (8 mL of a 1
M solution). The solution was stirred at RT overnight,
then acidified to pH 3 with excess aqueous 1 M HC1. The
solution was extracted with EtOAc (2 x 50 mL). The
combined organic extracts were washed with HaO (2 x 50
mL) and brine (50 mL) , dried (Na2S04) , and concentrated in
vacuo to provide title compound as a white solid (1.75 g;
63%) . [M + H]+ = 501.2
[M + H]+ = 501.2; XH NMR (400 MHz; CDC13) : 8 7.93-7.99
(m, 2H) , 7.38-7.43 (m, 3H) , 7.23 (q, 1H, J = 8 Hz), 7.02-
7.12 (m, 3H), 6.98-7.02(m, 2H), 6.82-6.89 (m, 2H), 4.71
(s, 1H), 4.64 (s, 1H), 4.25 (t, 2H, J= 7 Hz), 4.07 (s,
2H), 2.90-2.98 (m, 2H), 2.37 (s, 3H),2.29 (s, 3H)
Example 230
(Figure Removed)
To a 0°C solution of the secondary amine (3.0 g; 7.9
rranol)

in CH2C12 (45 mL) were successively added pyridine (0.8
mL; 9.9 mmol) and 4 -me thoxyphenyl chloroformate (1.3 mL;
8.7 mmol). The reaction was stirred at 0°C for 3 h, at
which point starting material had been consumed (by
analytical HPLC) . The reaction solution was washed with
aqueous HC1 (2 x 25 mL of a 1 M solution) , brine (2x) ,
dried (NasSC^), and concentrated in vacua. The crude
product was chromatographed (Si02; stepwise gradient from
4:1 to 3:7 hex:EtOAc) to provide the desired carbamateester
(4.2 g; 100%). 'The ester was dissolved in
THF:MeOH:H20 (50 mL of a 3:1:1 solution) and LiOH.H20 (0.5
g; 11.9 mmol) was added. The solution was stirred
overnight at RT. Starting material was still present by
HPLC. More LiOH.H20 (0.2 g; 4.8 mmol) was added and the
mixture was briefly heated to solubilize the LiOH, then
stirred at RT for 4 h. The reaction was complete at this
point, and the mixture was acidified to pH 3 with excess
aqueous 1 M HC1, then organic solvents were removed in
vacuo. The residual aqueous phase was extracted with
EtOAc (3 x 50 mL) . The combined organic extracts were
successively washed with H20 and brine (50 mL each),
dried (Na2S04), filtered and concentrated in vacuo to give
title compound as a colorless solid (3.07 g; 75%).
[M + H]+ = 517.2; XH NMR (400 MHz; CDC13) : 6 7.96-7.98
(m, 2H) , 7.4-7.45 (m, 3H) , 7.2-7.3 (m, 2H) , 7.0-7.1 (on,
2H) , 6.8-7.0 (m, 4 H) , 4.65 (s, 1H) , 4.55 (s, 1H) , 4.20-
4.24 (m, 2H), 4.02 (s, 2H) , 3.77 (s, 3H) , 3.00 (s, 2H) ,
2.38 (s, 3H) .
The following examples (167, 187, 216, 229, 247 and 263)
were all synthesized according to the methods described
for Examples 149 and 230.
OCH3
XH NMR (DMSO-d6; 500 MHz): 8 2.37 (s, 3H) , 2.94 (m, 2H) ,
3.73 (2s, 3H) , 4.06 (d, J = 4.8 Hz, 2H) , 4.25 (t, J = 7.2
Hz, 2H) , 4.66 (2s, 2H) , 6.71 (m, 3H) , 6.85 (m, 2H) , 7.06
(d, J = 16 Hz, 1H), 7.22 (m, 2H), 7.39 (m, 3H), 7.96 (m,
2H)
C02H
"H NMR (DMSO-ds; 500 MHz): 5 2.36 (s, 3H) , 2.93 (t, J =
6.6 Hz, 2H) , 4.02 (2s, 2H) , 4.21 (t, J = 6.6 Hz, 2H) ,
4.55 (2s, 2H) , 6.94 (tn, 3H) , 7.48 (m, 8H) , 7.90 (m, 2H)
Kxampl& 21K
(Figure Removed)
XH NMR (CDC13; 400 MHz): 6 1.3-1.4 (m, 3H) , 2.39 (s, 3H) ,
2.9-3.05 (m, 2 H), 3.9-4.05 (m, 2 H), 4.06 (br s, 2H),
4.25 (t, J = 7.0 Hz, 2 H), 6.85 (dd, J = 11.4, 8.8 Hz,
2H) , 6.99 (dd, J = 15.8, 8.8 Hz, 2H) , 7.18 (dd, J = 8.4,
2.6 Hz, 2H), 7.38-7.50 (m, 5H), 7.99 (br d, J = 7.9 Hz,
2H)
Example 229
CH3
XH NMR (CDC13; 400 MHz) : 5 2.30 (2 peaks, 3H) , 2.38 (2
peaks, 3H) , 3.03 (dd, J = 5 . 7 , 5.7 Hz; 2H) , 3.99 (s, 2H) ,
4.21 (dd, J = 6.1, 6.1 Hz; 2H), 4.63 (2 peaks, 2H) , 6.82-
6.87 (m, 2H), 6.96-7.01 (m, 2H), 7.09-7.14 (m, 2H) , 7.18-
7.20 (m, 2H), 7.43-7.45 (m, 3H), 7.96-7.98 (m, 2H)
Example 247
*H NMR (DMSO-ds; 500 MHz): 8 2.36 (s, 3H) , 2.93 (t, J =
6.6 Hz, 2H) , 3.74 (s, 3H) , 3.96 (2s, 2H) , 4.20 (t, J =
6.6 Hz, 2H) , 4.55 (2s, 2H), 6.65 (m, 2H) , 6.94 (m, 3H) ,
7.27(m, 3H) , 7.48 (m, 3H) , 7.91 (d, J = 6.1 Hz, 2H)
(Figure Removed)
Ex-amp 1
CH3
1H NMR .(CDC13; 400 MHz): 5 2.42 (2s, 3H; rotamers) ; 3.0-
3.5 (m, 2 H) , 3.99 {br s, 2 H) , 4.15-4.25 (m, 2 H) , 4.57
(AB doublet, J = 38.2 Hz, 2 H ) , 6.85 (dd, J = 11.4, 8.8
Hz, 2H), 6.99 (dd, J = 15.8, 8.8 Hz, 2H), 7.18 (dd, J =
8.4, 2.6 Hz, 2H), 7.38-7.50 (m, 5H), 7.99 (br d, J = 7.9
Hz, 2H)
Example 306

A.
A solution of resorcinol monoacetate (2g; 13.14
nunol) , N,N-dimethylaniline (1.6g; 13.14 mmol) , phosgene
(6.8 mL of a 1.95M solution in toluene; 13.1 mmol) and a
catalytic amount of DMF in chlorobenzene (5 mL) was
heated at 80°C in a pressure tube for 2.5 h and then
allowed to cool to RT. The clear supernatant solution
was separated and concentrated in vacua. The residue was
purified via distillation in vacua (140-150°C @ 1.0 mm.
Hg) to give title .compound in the form of a clear oil (2
g; 71%) .
B.
CO2t-Bu
To a mixture of Part A chloroformate (50 mg, 0.237
mmol)and polyvinylpyridine (PVP) (75 mg, 0.70 mmol) was
added a Ct^Cla solution (2 mL) of the amino-tert-butyl
ester (100 mg, 0.237 mmol),
CH3 C02t-Bu
(prepared as described in Example 7 Part B).
The reaction was stirred at RT for 15 min. Resinbound
amine (WA21J, Supelco; 150 mg) was added to the
mixture. The reaction mixture was stirred for another 15
min. The Resin-bound amine and PVP were removed via
filtration and the filtrate was concentrated in vacua to
give the crude product. The crude product was
chromatographed (SiOa; hexane/EtOAc 1:4) to provide title
compound (0.1 g, 70%).
C.
A solution of the Part B phenol-tert butyl ester
compound (60 mg; 0.10 mmol), Bu4NBr* (0.32 mg, 0.001
mmol), aqueous NaOH (0.5 mL of a 1 M solution; 0.5 mmol)
and isopropanol (1 mL) in a pressure tube was cooled to
-50°C. Freon gas was bubbled into the solution for 1
min. The tube was sealed and heated to 80°C for 12 h.
The mixture was extracted with EtOAc (3'x 10 mL) . The
combined organic extracts were washed with brine, dried
(Na2S04) and concentrated in vacua to give the crude
difluoromethoxy ether-tert butyl ester as an oil. The
crude ester was then treated with a solution of 30% TFA
in CH2C12 overnight. Volatiles were removed in vacuo and
the residue was purified using preparative reverse-phase
HPLC (as in Example 127, except that the continuous
gradient used was from A:B 70:30 to 100% B) to afford two
products, the desired title difluoromethoxy ether-acid
(13 mg; 23%) and the phenol-acid set out below (32 mg;
63%). Reverse phase HPLC analysis using standard
conditions indicated that the product purity was >92%.
In addition LC/MS (electrospray) gave the correct
molecular ion [(M+H)+ = 553.2 and 503.2 respectively] for
the two compounds.
Phenol-Acid
Examples 307 and 308
Following the above general procedure of Example
306, the following compounds were prepared:
(Figure Removed)Example 307 Example 308
Example 307: [M + H]+ = 553.2
Example 308: [M + H]+ = 503.2
Example 309
To a mixture of phenyl chlorothionoformate (11 mg,
0.063 mmol)and triethylamine (6.5 mg, 0.063 mmol) was
added a solution of the amino-tert-butyl ester (20 mg,
0.053 mmol),
(prepared as described in Example 7 Part B)
in CH2C12 (1 mL). The reaction was stirred at RT for 15
min and the mixture was concentrated in vacuo to give the
crude thionocarbamate tert-butyl ester. This material
was dissolved in aqueous LiOH (0.50 mL of a 1.0 M
solution) and THF (2 mL) and stirred at RT for 5 h. The
solution was concentrated in vacuo to give the crude acid
as an oil. The crude product was purified using
preparative HPLC to afford the desired title product (10
mg; 38%). [M + H]+ = 503.2
Example 310
The corresponding thiocarbamate in the 1,4 series
was prepared in the same manner as described for Example
309.
[M + H]+ = 503.2
Example 311
To a mixture of the amine-tert butyl ester (306 mg,
0.73 mmol)
Ph
CH3
(prepared as described in Example 7 Part B),
and p-phenoxybenzoic acid (220 mg; 1.02 mmol; 1.4 equiv)
in CH3CN (20 mL) was added BOP reagent (372 mg, ^0.84
mmol, 1.15 equiv) in a single portion followed by iPr2NEt
(0.5 mL; 2.9 mmol; 3.9 equiv) dropwise. The reaction was
stirred overnight at RT, after which volatiles were
removed in vacua. The residue was dissolved in EtOAc and
washed with aqueous IN HC1. The aqueous layer was
extracted with EtOAc (2x) and the combined organic
extracts were washed with H20, sat'd aqueous NaHCOa and
brine, dried (Na2SCU) and concentrated in vacuo to give
the desired product. The resulting crude amide-ester was
used in the next step without further purification.
A solution of the crude amide ester in 40% TFA-CH2C12
(25 mL) was stirred for 5h at RT. Volatiles were removed
in vacuo and the crude acid was purified by Prep HPLC
(YMC S5 ODS 30mm x 250 mm reverse phase column; flow rate
= 25 mL/min; 30 min continuous gradient from 70:30 A:B to
100% B; solvent A = 90:10:0.1 H20:MeOH:TFA; solvent B =
90:10:0.1 MeOH:H20:TFA) to yield title compound (238 mg;
58% yield over 2 steps) as a white solid. Analytical
Reverse-phase HPLC: Retention time =7.53 min.
(Continuous gradient solvent system: from 50% A: 50% B to
0% A: 100% B (A = 90% H20/10% MeOH/0.2% H3P04; B = 90%
MeOH/10% H20/0.2% H3P04) for 8 min; detection at 220 nm;
YMC S3 ODS 4 . 6 x 50 mm column). [M + H]+ = 563.3
Example 311A
(alternative synthetic procedure)
To a solution of the secondary amine tert-butyl
ester (35 mg, 0.083 mmol),(prepared as described in
Example 7 Part B)
CH3
4-phenoxy benzoic acid (30 mg, 0.14 mmol) and HOAT (30
mg, 0.22 mmol) in THF/DMF (I mL/0.05 mL) was added EDCI
(20 mg, 0.10 mmol) and the -mixture was stirred at RT
overnight. The reaction was diluted with EtOAc, washed
with aqueous IN HC1 , H20, sat'd. aqueous NaHCO3 and
brine, dried (Na2S04) and concentrated in vacuo. The
crude amide-tert butyl ester was dissolved in TFA/CH2Cl2
(5 mL of a 1:1 solution). The resulting pink solution
was stirred overnight and concentrated in vacuo to
provide the crude acid-amide as a dark brown oil. The
crude product was purified by preparative HPLC (YMC S5
ODS 20 x 100 mm column, 10 min continuous gradient from
60:40 A:B to 100 % B; solvent A = 90:10:0.1-H2O:MeOH:TFA;
solvent B = 90:10:0.1 MeOH:H2O:TFA; flow rate = 20
mL/min) to provide the title compound (32 mg, 69%) .
[M + H]+ = 563.3
Example 312
1) To a solution of the secondary amine-tert-butyl ester
(25 mg; 006 mmol)
Ph
CH3 C02t-Bu
(prepared as described in Example 7 Part B ) ,
in THF (0.5 mL) was added 2-naphthalene carboxylic acid
(25 mg; 0.15 mmol; 2.5 equiv).
2)HOAT (48 mg; 0.35 mmol; 5.8 equiv) was added.
3) DMF (50 uL) was added.
4) EDCI ((20 mg, 0.1 minol, 1.8 m eq) was added.
5) The reaction vessel was shaken for 24 h at RT.
6) The reaction was diluted with MeOH (2 mL) and
filtered.
7) The amide-tert butyl ester was purified by preparative
HPLC (YMC S5 ODS 20 x 100 mm column; flow rate = 25
mL/min; 10 min continuous gradient from 70:30 A:B to
100% B; solvent A = 90:10:0.1 H20:MeOH:TFA; solvent B =
90:10:0.1 MeOH: H20: TFA) .
The fractions containing the purified amide-ester were
treated with a solution of TFA in CH2C12 (0.5 mL of a
1:1 solution) overnight. The reaction was concentrated
in vacuo (Speed Vac) to give title compound (8 mg;
25%). Reverse-phase analytical HPLC showed that the
purity of the product was > 88%; LC/MS (electrospray
detection) gave the correct [M + H]"1" = 521.2 for the
title compound.
Example 313
A mixture of the amino-ester (20 ing; 0.0474 mmol) ,
CH3
(prepared as described in Example 7 Part B),
thiophene-2-carboxylic acid (9.1 mg, 0.71 mmol), EDCI (26
mg, 1.4 mmol) and DMAP (a catalytic amount) was dissolved
in CH2C12 (2 mL) and stirred at RT overnight. The
reaction solution was successively washed with aqueous IN
HC1 (2 mL) and sat'd aqueous NaHC03 (2 mL) . To the
organic phase was then added 0.5 g anhydrous Na2S04,and
0.2 g WA21J amine-bound resin (Supelco) . The mixture was
shaken for 0.5 h and the solids were filtered off. TFA
(2.0 mL) was added to the filtrate and the solution was
shaken at RT overnight. The reaction solution was
concentrated in vacuo using a Speed Vac for 16 h to
afford title compound as a yellow oil. Reverse phase
analytical HPLC (YMC S5 ODS 4.6 x 33 mm column,
continuous gradient from 100% A to 100%B for 2 min at a.
flow rate of 5 mL/min [Solvent A = 10% MeOH/90% H20/0.2%
H3P04; Solvent B = 90% MeOH/10% H20/0.2% H3P04]) indicated
that the product purity was 92.7%. In addition, LC/MS
(electrospray) gave the correct molecular ion [(M+H)+=
477.2] for the desired title compound.
Example 314
Another purification protocol using amine-bound
resin for the amide-acid product is illustrated by the
following synthesis:
To a mixture of the amino-ester (20 mg; 0.0474
mmol),
(prepared as described in Example 7 Part B), and
3,5-dimethoxybenzoic acid (13 mg, 0.071 mmol) in
anhydrous CH3CN (0.5 mL) was added a solution of BOP
reagent (31 mg, 0.071 mmol) in CH3CN (0.5 mL) , followed
by DIEA (41 jiL, 0.23 mmol) in CH3CN (0.5 mL) . The
reaction was shaken at RT overnight. Volatiles were
removed in vacuo using a Speed Vac and CH2C12 (2 mL) was
added. The solution was washed successively with aqueous
IN HC1 (2 mL) and sat'd aqueous NaHC03 (2 mL) . To the
organic phase was added 0.5 g anhydrous NajSO^and 0.2 g
WA21J'amine-bound resin (Supelco). The mixture was
shaken for 0.5 h and the solids were filtered. TFA (2
mL) was added to the filtrate and the solution was shaken
at RT overnight. The reaction solution was concentrated
in vacuo using a Speed Vac for 16 h to afford the final
product as a yellow gum. Reverse-phase analytical HPLC
(YMC S5 CDS 4.6 x 33 mm column, continuous gradient from
100% A to 100% B for 2 min at a flow rate of 5 mL/min
[Solvent A = 10% MeOH/90% H20/0.2% H3P04; Solvent B = 90%
MeOH/10% H20/0.2% H3P04] ) indicated that the product
purity was 90%. In addition, LC/MS (electrospray) gave
the correct molecular ion [(M+H)'I"= 531.3] for the title
compound.
Examples 315 to 391
Following one of the above procedures, the
following compounds in Tables 6 and 7 of the invention
were prepared.
Table 6: (Amide-Acids)
(Table Removed)
To a solution of the amine (47 mg; 0.12 mmol)
(prepared as described in Example 3 Part A),
in CH2C12 (5 mL) were added iPr2NEt (0.1 mL; 0.57 mmol)
and DMAP (14 mg; 0.12 mmol) followed by benzyl isocyanate
(24 mg; 0.18 mmol). The reaction was stirred for 14h,
then passed through an SCX cartridge [the 3g SCX
cartridge was prewashed successively with MeOH (10 mL)
and CH2C12 (5 mL) ] by eluting with CH2C12 (15 mL) . The
filtrate was concentrated in vacuo to give the crude urea
Part A compound (53 mg; 84%), which was sufficiently pure
to be used in the next step without further purification.
B.
A solution of the crude Part A urea-ethyl ester (53
rag) and LiOH.H20 (12 mg) in THF: MeOH:H20 (3:1:1; 5 mL)
was stirred at RT for 2 days. The solution was acidified
to pH3 with aqueous 1M HC1, concentrated in vacuo, and
purified by preparative HPLC (utilizing a YMC S5 ODS 20mm
x 100 mm column; with a continuous gradient from
70%A:30%B to 100% B for 10 minutes at a flow rate of 20
mL/min, where A = 90:10:0.1 H20:MeOH:TFA and where B =
90:10:0.1 MeOH:H20:TFA) to give title compound (12 mg;
24%) as an off-white solid. [M + H]+ = 500.2
Example 393
(Figure Removed)To a solution of the amine (0.25 g, 0.66 mmol)
(prepared as described in Example 6) ,
in CH2C12 (5 mL) was added 4-methoxyphenyl isocyanate
(0.20 g, 1.32 mmol) in one portion and the resulting
solution was stirred for 1 h at RT. The reaction mixture
was then concentrated in vacuo to give an oil, which was
- 168 -
chromatographed (Si02; 1.5% MeOH/CH2Cl2) to provide title
compound (0.34 g; 97%) as a colorless oil.
B.
(Figure Removed)A solution of Part A compound (0.14 g, 0.26 mmol)
and LiOH (0.1 g, 4.3 mmol) in H2O/THF (5 ml of a 40:60
solution) was stirred for 12 h at 25°C. The reaction
mixture was acidified with HOAc and extracted with EtOAc
(2x). The combined organic extracts were dried (MgS04)
and concentrated in vacuo to provide title compound (0.12
g; 90%) as a colorless oil. [M + H]+ = 516
*H NMR (CD3OD; 8): 7.94 (m, 2H) , 7.45 (m, 3H) , 7.23 (m,
3H), 6.80 (m, 2H), 6.80 (m, 3H), 4.58 (s, 2H), 4.23 (t, J
= 7.9 Hz, 2H), 3.81 (s, 2H), 3.73 (s, 3H) , 2.98 (t, J =
7.9 Hz, 2H), 2.36 (s, 3H).
Example 394
(Figure Removed)A.
OCH3
A solution of the previously described carbamoyl
chloride (Example 139 Part A compound; 0.15 g; 0.34 mmol)
N-methyl-p-anisidine (0.14 g, 1.0 mmol) and K2C03 (0.15 g,
1.1 mmol) in 5 ml of acetone was stirred at 25 °C for 12
h. The reaction mixture was concentrated in vacuo to
yield an oily residue, which was chromatographed (SiC>2;
1.5% MeOH/CH2Cl2) to provide title compound (0.12 g; 65%)
as a colorless oil.
B.

A solution of Part A compound (0.12 g, 0.22 mmol)
and LiOH (0.050 g, 2.1 mmol) in H20/THF (5 mL of a 40:60
solution) was stirred at RT for 12 h. The reaction
mixture was concentrated in vacuo to yield an oily
residue, which was purified by preparative HPLC (YMC S5
ODS 30 x 250 mm column; flow rate = 25 ml/min. 30 min
continuous gradient from A:B = 50:50 to 100%B; solvent A=
90:10:0.1 H20:MeOH:TFA; solvent B = 90:10:0.1
MeOH:H20:TFA) to provide title compound (59 mg, 50%) as a
colorless oil. [M + H]+ = 530.3
NMR (CDC13) : 7.99 (d, 6.2 Hz, 2H, 7.45 (m, 3H), 7.24 (m,
3H), 6.82 (d, 6.2 Hz, 2H) , 6.79 (m, 1H), 6.63 (m, 1H) ,
6.55 (s, 1H), 4.24 (s, 2H), 4.16 (t, 7.8 Hz), 2H), 3.72
(s, 3H), 3.59 (s, 2H), 3.16 (s, 2H), 3.02 (t, 7.8 Hz,
2H), 2.40 (s, 3H).
Examples 395 to 410
Utilizing one of the above procedures, the analogs in
Tables 8 and 9 were synthesized.
Table 8: (Urea-Acids)
(Figure Removed)
(prepared as described in Example 8)
(20 mg, 0.05 mmol) in pyridine (0.6 mL) . The reaction
was stirred at RT for 20 h. Resin-bound amine (WA21J,
Supelco; 5.8 mmol/g loading; 150 mg) was added to the
mixture. The reaction was stirred for a further 4 h.
The resin was filtered off and the filtrate was
concentrated in vacua to give the crude product, which
was chromatographed (CUSIL12M6 column; United technology;
2 g of sorbent in a 6 mL column) by the procedure
outlined below.
1) The column was conditioned with hexane (20 mL) .
2) The residue was dissolved in a minimal volume of EtOAc
and loaded onto the silica gel column.
3) The cartridge was eluted with Hex/EtOAc(3:1) ,
Hex/EtOAc (1:1). The desired fraction (identified by
TLC) was collected and concentrated to give title
compound as a viscous oil which was used in the next step
without any further purification.

B.
CH3
Et3N ((0.3 ml of a 1M solution in CH2C12) and TMSI
(0.3 ml of a 1M solution in CHaCla) were successively
added to a solution of Part A compound in CH2Cl2. The
reaction mixture was stirred at RT for 12h and then was
concentrated in vacua to give the crude product. The
product was purified by solid-phase extraction using a
CHQAX12M6 column (United technology; 2 g of sorbent in a
6 mL column) by the procedure outlined below.
1) The column was conditioned with CH2C12 (25 mL) .
2) The residue was dissolved in a minimal volume of CH2C12
and loaded onto the SAX column.
3) The cartridge was washed successively with CH2C12 (25
mL), CH2Cl2/MeOH (5% MeOH, 15 mL) , CH2Cl2/MeOH (50% MeOH,
15 mL), MeOH (20 mL) .
4) The product was eluted with a solution of 1% TFA in
MeOH (20 mL).
The final product-containing fraction was collected
and concentrated in vacua using a Speed Vac to afford
BMS-329075 (16 mg; 62%). Reverse-phase analytical HPLC
indicated that the product purity was 90%. In addition,
LC/MS (electrospray) gave the correct molecular ion
[(M+H)+ = 557.1] for the desired compound.
Example 411
F
A.
O 0
(X = halogen, alkyl, CF3, CF30, etc.)
The following general procedure was utilized for the
preparation of the requisite substituted benzyl sulfonyl
chlorides:
C12 gas was bubbled into a 0°C solution of 4-
fluorobenzyl mercaptan (1.0 g, Lancaster) in glacial
acetic acid (100 inL) and H20 (5.0 mL) for Ih. The
reaction mixture was then poured into ice-H20 and
immediately extracted with CH2C12 (200 mL) ; the organic
phase was cautiously washed successively with H20 (200
mL), aqueous saturated NaHCOs (2 x 100 mL) , and finally
brine (200 mL) . The organic phase was dried (MgS04) and
concentrated in vacuo to furnish 4-fluorobenzyl sulfonyl
chloride as a colorless solid (1.3 g; 89%).
B.
F
CH3
To a solution of the secondary amine methyl ester
(25 mg; 0.066 rtunol)
Ph~ (prepared as described in Example 6),
in pyridine (0.8 mL) was added 4-fluorobenzyl sulfonyl
chloride (68 mg; 0.33 mmol; 5 equiv). The mixture was
heated to 75°C, stirred overnight at 75°C, and then
concentrated in vacuo. The black residue was treated
with aqueous LiOH (1.0 mL of a 0.3 M solution) in
H20/MeOH/THF for 18 h, then concentrated in vacuo. The
residue was acidified with 1.0 M aqueous HC1 to pH = 1-2
and extracted with EtOAc (2x) , dried (Na2SO4) and
concentrated in vacuo to give the crude product.
Purification by preparative HPLC (YMC S5 ODS 20mm x 250
mm reverse-phase column; 15 min continuous gradient from
60:4C A:B to 100% B with 10 min hold time, where A =
90:10:0.1 H20:MeOH:TFA and B = 90:10:0.1 MeOH: H20:TFA;
flow rate = 25 mL/min) gave the title compound (12 mg;
34%) as a white solid. [M + H]+ (LC/MS) = 539.1
Examples 412 to 456
Utilizing one of the above procedures, the analogs
in Tables 10 and 11 were synthesized.
- 177 -
(Sulfonamide-Acids)
(Table Removed)
To a 0°C solution of methyl 2-hydroxypyridine-5-
carboxylate (0.2 g, 1.3 mmol), 2-(5-methyl-2-phenyl
oxazol-4-yl)ethanol (0.32 g, 1.56 mmol) and Ph3P (0.38 g,
1.56 mmol) in CH2C12 (10 mL) was added DEAD (0.2 mL, 1.95
mmol) dropwise and the reaction was stirred at 25°C for
12 h. The solution was concentrated in vacua, and
chromatographed on SiO2 (4:1 hex:EtOAc) to provide title
compound (0.28 g, 63%) as an oil.
B.
To a -78°C solution of Part A compound (0.28g., 0.82
mmol) in THF (10 mL) was added DIBALH (2.0 mL of a 1 M
solution in CH2C12; 1.95 mmol) and the reaction was
stirred at -78°C for 4 h. TLC of an aliquot of the
reaction showed the presence of both the corresponding
aldehyde and alcohol. The reaction was warmed to 25°C
and stirred at RT for 1 h, after which only the alcohol
was observed by TLC. The reaction was quenched with
water and diluted with EtOAc. The organic layer was
washed with brine, dried (MgS04) , and concentrated in
- 182 -
vacuo to furnish title compound as an oil. This crude
material was used in the next reaction without further
purification.
(Figure Removed)To a -78°C solution of oxalyl chloride (0.22 mL,
2.6 mmol) and DMSO (0.37 mL, 5.2 mmol) in CH2C12 (15 mL)
was added dropwise a solution of Part B compound (0.42 g
of crude material in 5 mL CH2C12) . The reaction mixture
was stirred for 2 h at -78°C and then Et3N (1 mL) was
added dropwise. The reaction mixture was stirred for an
additional 0.5 h at -78°C and then was slowly warmed to
25°C. The reaction mixture was diluted with EtOAc (200
mL) and washed successively with aqueous NaHC03 and brine.
The organic layer was dried (MgSO4) , then concentrated in
vacuo to provide title compound (0.40 g; 95%) as an oil,
which was used in the next step without further
purification.
D.
(Figure Removed)A mixture of Part C compound ( methyl ester hydrochloride (0.5g., 4.0 mmol), NaBH(OAc)3
(0.85g., 4.0 mmol) and DCE (10 mL) was stirred at 25°C
for 12 h. The reaction mixture was then diluted with
EtOAc (50 mL) and washed successively with aqueous NaHC03
and brine. The organic layer was dried (MgSO4) , then
concentrated in vacuo to give title compound (0.31 g;
82%) as an oil (>95% pure by analytical reverse-phase
HPLC) which was used in the next step without further
purification.
E.
A mixture of Part D compound (0.050 g; 0.13 mmol) ,
4-phenoxybenzaldehyde (0.048 g; 0.26 mmol), NaBH(OAc)3
(0.082 g; 0.39 mmol) in DCE (10 mL) was stirred at 25°C
for 12 h. The reaction mixture was diluted with EtOAc
(50 mL) and washed successively with aqueous NaHC03 and
brine. The organic layer was dried (MgS04) , then
concentrated in vacua to give the tertiary amino methyl
ester as an oily residue. To this residue, LiOH (0.050
g) and H20/THF (2 mL of a 60/40 solution) were added and
the reaction was stirred at RT for 12 h. Preparative
HPLC (YMC S5 ODS 30 x 250mm column - continuous gradient
over 30 min; flow rate = 25 mL/min from 30:70 A:B to
100% B; A = 90:10:0.1 H20:MeOH: CF3CO2H; B = 90:10:0.1
MeOH:H2O:CF3C02H) provided title compound (0.021 g; 30%)
as a TFA salt.
XH NMR (CDC13) 6: 8.18 (s, 1H) , 7.94 (d, 6.6 Hz, 2H) ,
7.86 (d, 8.8 Hz, 1H), 7.45 (m, 3H), 7.34 (m, 3H) , 7.14
(t, 7.4 Hz, 1H), 7.02-6.92 (m, 5H) , 6.81 (t, 8.8 Hz, 1H) ,
4.51 (m, 6H), 3.59 (s, 2H) , 3.06 (t, 6.2 Hz, 2H)
Example 458
A.
HO N C02CH3
A mixture of 2-hydroxypyridine-6-carboxylic acid
(1.30 g, 9.4 mmol), concentrated H2S04 (0.5 mL) and MeOH
(20 mL) was heated to reflux for 12 h. The reaction was
complete at this point by analytical HPLC. The reaction
mixture was concentrated in vacuo to give a light yellow
oil, which was diluted with EtOAc and washed with aqueous
NaHCOa. The organic phase was dried (MgSO^) and
concentrated in vacuo to yield title compound as a solid
(0.43 g, 30%).
B.
To a solution of Part A compound (0.43 g, 2.8 mmol),
2-(5-methyl-2-phenyloxazol-4-yl) ethanol (0.68 g, 3.3
mmol) and Ph3P (1.0 g, 4.07 mmol) in THF (10 mL) was
added DEAD (0.66 mL, 4.2 mmol) and the reaction was
stirred at RT for 12 h. The solution was concentrated in
vacuo and the residue was chromatographed (SiOa; 20%
acetone/hexanes) to provide title compound as an oil
(0.92 g; 97%).
(Figure Removed)To a solution of Part B compound (0.92 g, 2.7 mmol)
in THF (50 mL) was added LiAlH4 (5 mL of a 1.0 M solution
in THF, 5 mmol) dropwise at -78°C and the resulting
reaction was allowed to warm to 0°C over 2 h. The
reaction was then quenched by adding a few pieces of ice
into the mixture. The reaction mixture was partitioned
between EtOAc (200 mL) and brine (50 mL). The organic
phase was dried (MgS04) and concentrated in vacuo to give
an oil (0.92 g; 95%) which was used in the next reaction
without further purification.
D.
To a solution of oxalyl chloride (0.47 mL, 5.4 mmol)
and DMSO (0.36 mL, 10.8 mmol) in CH2C12 (15 mL) was added
dropwise a solution of Part C compound (0.92 g; >2.7
iranol) in CH2C12 (10 mL) at -78 °C. The reaction mixture
was stirred for 2 h and then Et3N (1 mL) was added
dropwise. The reaction mixture was allowed to stir for
an additional 0.5 h at -78°C and then slowly warmed to
25°C. The reaction mixture was then diluted with EtOAc
(200 mL) and washed successively with aqueous NaHCOa and
brine. The organic layer was dried (MgSO,j) and then
concentrated in vacuo to yield title compound (0.90 g;
>90% pure by XH NMR analysis) as an oil. This material
was used in the next step without further purification.
E.
(Figure Removed)To a solution of Part D compound (0.90g; 2.7 mmol),
glycine methyl ester hydrochloride (1.7 g, 13.5 mmol)in
1,2 dichloroethane (10 mL) was added NaBH(OAc)3 (1.7 g,
8.1 mmol) in one portion. The resulting solution was
stirred at 25°C for 12 h. The reaction mixture was
concentrated in vacua to give an oil, which was
chromatographed (SiOa; 30% acetone in hexane) to provide
title compound (0.86 g; 83%) as a colorless oil.
F.
A solution of Part E compound (0.040 g, 0.1 mmol)/
4-phenoxybenzaldehyde (0.030 g, 0.15 mmol) and NaBH(OAc)a
(0.060 g, 0.3 mmol) in DCE (10 mL) was stirred at RT for
12 h. The reaction mixture was concentrated in vacua and
the oily residue was chromatographed (SiOa; 30% acetone
in hexane) to provide the amino-ester title compound (56
mg; >95%) as a colorless oil.
G.
A solution of Part F compound (56 mg; 0.1 mmol) and
LiOH (0.050 g; 0.21 mmol) in H20/THF (2 mL of a 6:4
solution) was stirred at RT for 12 h. The reaction
mixture was concentrated in vacuo to give a white solid,
which was dissolved in MeOH and purified by preparative
HPLC (YMC S5 ODS 30 x 250mm column; continuous gradient
over 30 min; flow rate = 25 mL/min from 30:70 A:B to
100% B; A = 90:10:0.1 H20:MeOH:TFA; B = 90:10:0.1
MeOH:H2O:TFA) . Title compound (41 mg; 72%) was obtained
as a TFA salt.
1H NMR (MeOH-D4) :. 7.90 (m, 2H) , 7.71 (t, 8.4 Hz, 1H) ,
7.51 (d, 8.7 Hz, 2H), 7.44 (m, 3H), 7.36 (t, 8.7 Hz, 2H),
7.17 (t, 8.4 Hz, 1H), 6.96 (m, 5H), 6.82 (d, 8.4 Hz, 1H),
4.62 (t, 6.2 Hz, 2H), 4.56 (s, 2H), 4.50 (s, 2H), 4.17
(s, 2H), 3.00 (t, 6.2 Hz, 2H), 2.36 (s, 3H).
550.23 (M + H+) by LC/MS (electrospray).
Example 459
(Figure Removed)To a 0°C solution of 2- (5-methyl-2-phenyloxazol-4-
yDethanol (1.07 g, 5.25 mmol), Ph3P (1.38 g, 5.25 mmol)
and N-Boc-4-hydroxyphenylethylamine (1.24 g, 5.25 mmol)
in THF (36 mL) was added DEAD (0.83 mL, 5.25 mmol). The
reaction was allowed to warm to RT and stirred for 15 h.
- 188 -
The reaction mixture was concentrated in vacuo, and the
residue was chromatographed (SiC>2; stepwise gradient from
95:5 to 4:1 hex:EtOAc) to obtain title compound (1.43 g,
65%).
(Figure Removed)A solution of Part A compound (1.01 g, 2.37 mmol)
and TFA (8 mL) in CH2C12 (30 mL) was stirred at RT for 4.5
h. The solution was concentrated in vacuo, and the
residue was dissolved in CH2C12 and filtered through a pad
of solid K2C03. The filtrate was concentrated in vacuo to
give the corresponding crude amine. To a solution of the
crude amine in THF (11.9 mL) were added pyridine (0.383
mL, 4.74 mmol) and 2,4-dinitrobenzenesulfonyl chloride
(0.85 g, 3.19 mmol) and the solution was stirred at RT
for 15h. Since' some starting material still remained at
this point, more sulfonyl chloride (0.32 g, 1.2 mmol) was
then added. After a further 4 h, HPLC analysis indicated
that all starting material had been consumed. The
reaction mixture was diluted with Et20, washed with IN aq
HC1, saturated aq NaHCO3 and brine, dried (MgSO4),
filtered and concentrated in vacuo to provide the crude
2, 4-dinitrobenzenesulfonamide
To a solution of the crude 2,4-dinitrobenzenesulfonamide
in CH3CN (3 mL) were added K2C03 (excess) and
tert-butyl bromoacetate (7.11 mmol). The reaction was
stirred at RT overnight. HPLC analysis indicated the
ratio of product to starting material was 2/1. More DMF
(3 mL) , K2C03 and tert-butyl bromoacetate were added to
the reaction mixture. The reaction was complete in 2 h.
The reaction mixture was diluted with Et20, washed with
IN aq HC1, saturated NaHC03 and brine, dried (MgS04) , and
concentrated in vacua to provide the crude tert-butyl
ester. This crude material was chromatographed (Si02;
hexanes/EtOAc; stepwise gradient from 9:1 to 2:1) to give
title compound (0.663 g, 42% overall).
(Figure Removed)To a solution of Part B compound (0.663 g, 0.995
mmol) in THF (2.5 mL) were-added Et3N (0.208 mL, 1.49
mmol) and mercaptoacetic acid (0.090 mL, 1.29 mmol). The
reaction was stirred at RT overnight. The reaction
mixture was then diluted with Et20, washed with IN aq
HC1, saturated NaHC03 and brine, dried (MgS04) , and
concentrated in vacua. The residue was chromatographed
(SiOa; hexanes/EtOAc; stepwise gradient from 9:1 to 2:1)
to give title compound (0.265 g, 61%).
D.
To a solution of Part C compound (0.015 g, 0.0344
mmol) in DCE (1 mL) were added 4-phenoxybenzaldehyde
(0.103 mmol) and NaBH(OAc)3 (0.0365 g, 0.172 mmol). The
reaction was stirred at RT for 15 h. The reaction
mixture was filtered through a cotton plug to provide a
clear solution, which was diluted with CH2C12/ washed with
saturated aq NaHC03 and brine, dried (MgS04), and
concentrated in vacua. The crude product was purified by
preparative HPLC (YMC S5 CDS 30x250 mm column: flow rate
25 mL/min, gradient 20%B to 100%B over 25 min, 100%B hold
for 15 min, Retention time = 29.1 min) to furnish the
tert-butyl ester. A solution of this material was
dissolved in CH2C12 (1.3 mL) and TFA (0.5 mL) was added
slowly. The reaction was stirred at RT overnight and was
then concentrated in vacuo. The residue was then
dissolved in CH2C12, washed with H20, saturated aq NaHCOa
and brine, dried (MgSC^) and concentrated in vacuo to
give title compound (0.012 g, 61%). LC/MS gave the
correct [M + H]+ = 563.3
Further analogs (as shown in the table below) were
synthesized by the same reductive amination procedure as
described in Example 459 Part D using Example 459 Part C
compound and different aromatic aldehydes. In addition
carbamate-acids such as Example 461 compound were also
synthesized using the general method described previously
for the synthesis of the Example 136 compound.
(Table Removed)
To a solution of the Example 230 acid (240 mg, 0.47
mmol) in DMF ( 2 . 0 mL) were added HOAT (68 mg, 0.49 mmol),
EDAC (94 mg, 0.49 mmol) and 2-cyanoethylamine (34 mg,
0.49 mmol). The solution was stirred at RT for 18 h;
- 192 -
analysis of the reaction by LC-MS showed that starting
material was still present. Additional 2-cyanoethylamine
(34 mg, 0.49 mmol) was added and the reaction mixture was
stirred at RT for 48 h. Volatiles were removed in vacua
and the residue was dissolved in CH2C12 (40 mL) and washed
successively with water (2 x 30 rnL) and brine (30 mL) .
The organic phase was dried (MgS04) and concentrated in
vacuo. The resulting white residue was dissolved in a
minimum amount of CH2C12 (3 mL) and precipitation by the
cautious addition of EtOAc furnished the amide product
title compound (184 mg; 70%) as a white solid.
B.
OCH3
To a 0°C solution of Part A compound (180 mg; 0.32
mmol) in CH2C12 (1.5 mL) were successively added Ph3P (83
mg; 0.32 mmol), DEAD (100 jiL, 0.64 mmol) and ,TMSN3 (85 uL,
0.64 mmol). The reaction mixture was stirred at RT for
24 h. LC-MS analysis showed that a significant amount of
starting material still remained. The reaction mixture
was then concentrated in vacuo to 2/3 of the original
volume and additional Ph3P, DEAD and TMSN3 (1 equivalent
of each reagent) were added. The reaction mixture was
stirred at RT for another 24h and then diluted with EtOAc
(40 mL) . The solution was treated with 5% aqueous CAN
solution (10 mL) and stirred for 15 min. The reaction
solution was washed with water (30 mL) and brine (30 mL) ,
dried (MgS04) and concentrated in vacuo. The residue was

chromatographed (Si02; ether:CH2C12 3:7) to furnish the
title compound (100 mg; 53%) as a white solid.
C.
To a solution of Part B compound (100 mg, 0.17 mmol)
in THF/l,4-dioxane (6:1, 1.4 mL) was added aqueous NaOH
solution (0.6 mL of a 1.0 M solution, 3.5 equiv) . The
mixture was stirred at RT for 14 h and then acidified to
~pH 2 with 1.0 M aqueous H3P04 solution. EtOAc (30 mL)
was added, and the organic phase was washed with water
(15 mL) and brine (15 mL), dried (MgS04) and concentrated
in vacuo. The residue was chromatographed (SiO2; 4%
MeOH/CH2Cl2) to give the title tetrazole (35 mg; 38%) as a
white foam. LC/MS (electrospray) gave the correct
molecular ion: [M + H]+ = 541.3
Example 464
O^CH3
A.
A mixture of 2-hydroxybenzaldehyde (500 mg, 4.09
mmol), glycine methyl ester hydrochloride (544 mg, 4.09
mmol) and Et3N (495 mg, 4.9 mmol) in dry MeOH (5 mL) was
stirred at RT for 3 h. NaBH4 (155 mg, 4.09 mmol) was
then added in three portions. The reaction was stirred
at RT for another 30 min. Saturated aqueous Na2C03 (1 mL)
was added to destroy the remaining NaBEU and then aqueous
HC1 (10 mL of a IN solution) was added. The aqueous
phase was washed with EtOAc (3 x 20 mL), then carefully
basified with IN aq NaOH to pH = 7-8. The aqueous phase
was then extracted with EtOAc (3 x 20 mL). The orangered
solution was concentrated in vacuo to give title
compound as a yellow viscous oil.
B.
Part A compound (38 mg, 0.195 mmol), 4-methoxyphenyl
chloroformate and pyridine (39 mg, 5 mmol) was dissolved
in 0.1 mL CH2C12, for 5 min. The reaction mixture was
then washed with aqueous HC1 (2 x 2 mL of a IN solution) .
The organic phase was washed with brine, dried (Na2S04) ,
concentrated in vacuo and chromatographed (SiQ2/'
hex:EtOAc = 7 :3) to give title compound (40 mg; 59%) as
a pale yellow oil.
c.
To a solution of Part B compound (40 mg, 0.116
iranol) , 2-[2-phenyl-5-methyl-oxazole-4-yl]-ethanol
(Maybridge; 24 mg, 0.116 iranol) and Ph3P (40 mg, 0.151
mmol) in dry THF (3 mL) was added dropwise DEAD (26 mg,
0.151 mmol). The solution was stirred at RT overnight.
The orange-red solution was concentrated in vacua and the
residue was purified by Prep-HPLC (continuous gradient'
from 50% A: 50% B to 100%B; A = 90% H20:10 %MeOH + 0.1%
TFA) ; (B = 90% MeOH/10% H20 + 0 . 1 % TFA) for 10 min; YMC
SH-343-5 ODS 20 x 100 mm (5 (jm) column) to provide title
compound (30 mg, 47%) as a yellow viscous oil.
D.
Part C compound was dissolved in MeOH (3 mL) and
(0.3 mL). To this solution was added LiOH (3 mg) and the
reaction was stirred at RT for 3 h. Volatiles were
removed in vacua and the solution was acidified with IN
aqueous HC1 to pH = ~3—4. The aqueous phase was
extracted with EtOAc (3 x 10 mL) . The combined organic
extracts were washed with brine, dried (Na2SC>4) and
concentrated in vacuo to give title compound as a white
solid (18 mg; 64%). LC/MS (electrospray) gave the
correct molecular ion [(M+H)+ = 516].
XH NMR (5): 2.27-2.32 (m, 3H) , 2.96-2.98 (m, 2H) , 3.65-
3.69 (d, 3H) , 4.06-4.20 (m, 4H) , 4.55-4.63 (d, 2H) , 6.74-
6.93 (m, 4H) , 7 . 19-7 . 35 (m, 2h) , 7.88-7.90 (m, 2H) .
Example 465
Ph-i
A.
A mixture of (3-alanine methyl ester hydrochloride
(51 mg; 0.363 mmol) , Et3N (50 uL; 0.363 mmol) and the
aldehyde (100 mg; 0.33 mmol)
Ph-4
in MeOH (1 mL) was stirred at RT for 3 h. NaBH4 (14 mg;
0.363 mmol) was then added and the reaction was stirred
at RT for another 1 h. Volatiles were removed in vacuo
and the residue was partitioned between saturated aqueous
Na2C03 and EtOAc (20 mL each) . The organic phase was
concentrated in vacuo to give Part A compound as a yellow
oil which was used in the next step without further
purification.
B.
To a solution of Part A compound (20 mg; 0.050
mmol) and pyridine (0.50 mL) in CH2C12 (2 mL) was added 3
chlorophenyl chloroformate (14 mg; 0.070 mmol). The
reaction was stirred at RT for 2 h, then volatiles were
removed in vacuo. The residue was purified by
preparative HPLC (YMC S5 ODS 20 x 75 mm reverse phase
column; continuous gradient from 50:50 A:B to 100% B,
where A = 90:10:0.1 H2O:MeOH:TFA and B = 90:10:0.1
MeOH :H2O :TFA) to give Part B compound.
C.
A solution of Part B compound and LiOH.H2O (5 mg)
in THF:H20 (4:1) was stirred at RT for 1 h. The reaction
solution was acidified to pH 3 with aqueous HCl/ then
extracted with EtOAc. The combined organic extracts were
concentrated in vacuo to give title compound (5 mg; 18%)
as a white solid. [M + H] + = 535.2; 537.2
Ex-amp 1 p
Title compound was synthesized using the same
sequence as in Example 465 with the exception that the
aldehyde
was used. [M + H]+ = 535.2; 537.2
Following procedures as described above, Examples
467 to 472 compounds were prepared.
Examples 467 to 469
(Figure Removed)Example No. R3
467 501.3
468 563.3
469 515.3
- 199 -
Examples 470 to 472
Example No. R3 [M+Hf
470 501.3
471 563.3
472 515.3
fixampl& 473
A.
OAc
A mixture of 3-iodophenol (2.0 g; 9.1 mmol), acetic
anhydride ( 4 .6 g; 45.5 mmol) and pyridine (3.6 g; 45.5
mmol} was stirred in CH2C12 (20 mL) for 3 h. The
resulting mixture was washed with saturated aqueous NH4Cl

(3 x 100 mL) , dried (MgS04) and concentrated in vacuo to
give Part A compound (2.30 g; 97%) as a yellow oil.
B.
(Figure Removed)
A mixture of Part A compound (1.00 g; 4.0 mmol),
trimethylsilylacetylene (780 mg; 8 mmol), Cul (15 mg;
0.08 mmol) and (Ph3P)2Pd2Cl2 (28 mg; 0.04 mmol) in
diethylamine (10 mL) was stirred at RT for 3 h.
Volatiles were removed in vacuo and the residue was
chromatographed (Si02; hexane.-EtOAc 4:1) to give crude
Part B compound, which was used in the next step without
further purification.
C.
(Figure Removed)
To a solution of crude Part B compound in CH2C12 (2
mL) were added pyridine (3 mL; 37 mmol) ) and acetic
anhydride (4 mL; 42 mmol) . The reaction was stirred at
RT for 2 h, then was partitioned between saturated
aqueous NH4C1 (30 mL) and CH2C12. The organic phase was
washed with additional saturated aqueous NH4C1 (30 mL) and
H20 (100 mL) , dried (Na2S04) and concentrated in vacuo to
give Part C compound, which was used in the next step
without further purification.
(Figure Removed)
A solution of crude Part C compound and Bu4NF (1.1
g; 12 mmol) in THF (10 mL) was stirred at RT for 1.7 h,
after which all starting material had been consumed. The
reaction solution was washed with H20, Celite" was added,
and volatiles were removed in vacuo. The solids were
chromatographed (Si02; hexane:EtOAc 9:1) to give Part D
compound (400 mg; 63% over 3 steps).
E.
(Figure Removed)

A mixture of Part D compound (400 mg; 2.5 mmol) and
Pd/CaCo3/Pb catalyst (40 mg; Aldrich) in MeOH (20 mL) was
stirred under an atmosphere of H2 for 30 min. The mixture
was filtered through Celite® and the filtrate was
concentrated in vacuo. The residue was chromatographed
(Si02; hexane:EtOAc 95:5) to give Part E compound (310 mg;
77%) as a colorless oil.
F.
(Figure Removed)
To a 0°C solution of Part E compound (310 mg; 1.9
mmol) in DCE (10 mL) were successively added dropwise
neat diethylzinc (491 juL; 4.8 mmol; Aldrich) and ICH2C1
(700 uL; 9.6 mmol). The reaction mixture was allowed to
- 202 -
warm to RT and then stirred at RT for 3 h, after which it
was partitioned between saturated aqueous NH4C1 and EtOAc
(50 mL each). The organic phase was washed with
saturated aqueous NH4C1 and H2O (50 mL each) and
concentrated in vacuo. The residue was chromatographed
(SiO2; hexanerEtOAc 9:1) to furnish Part F compound (230
mg; 69%) as a colorless oil.
G.
A mixture of Part F compound (100 mg; 0.57 mmol)
and K2CO3 (157 mg; 1.1 mmol) in MeOH (5 mL) was stirred at
RT overnight (no reaction). Aqueous LiOH (1.1 mL of a
1 M solution; 1.1 mmol) was added and the solution was
stirred at RT overnight. Volatiles were removed in vacuo
and the residue was partitioned between aqueous 1 M HC1
and EtOAc. The organic phase was concentrated in vacuo
and the residue was chromatographed (Si02; hexane:EtOAc
4:1) to furnish Part G compound (70 mg; 92%) as a yellow
oil.
(Figure Removed)
To a solution of Part G compound (6 mg; 0.045 mmol)
in DMF ( 0 . 2 mL) was added potassium t-butoxide (5 mg;
0.05 mmol) . The reaction was stirred for 2 min at RT,
after which the carbamoyl chloride (20 mg; 0.045 mmol)
(Figure Removed)
was added and the reaction was stirred at RT for a
further 15 min. Volatiles were then removed in vacuo and
the residue was chromatographed (Si02; hexane:EtOAc 7:3)
to furnish Part H compound (11 mg; 45%) as a yellow oil.
I.
(Figure Removed)
A solution of Part H compound and LiOH.H2O in
MeOH/H2O (10 mL of a 9:1 mixture) was stirred at RT
overnight. The solution was then acidified to pH ~3 with
aqueous HCl and extracted with EtOAc. The combined
organic extracts were concentrated in vacuo and purified
by preparative HPLC to give title compound (10.1 mg; 95%)
as an off-white lyophilate. [M + H]+ = 527.3
Ph- A.
Example 474
(Figure Removed)
A mixture of 3-benzyloxybenzaldehyde (2.00 g; 1.0
mmol) , ethyl bromoacetate (1.67 g/ 1.0 mtnol) and Cs2CO3
(3.25 g; 1.0 mmol) in DMF (20 mL) was stirred at RT for 8
h. The reaction mixture was partitioned between H2O (300
mL) and EtOAc (100 mL). The aqueous phase was extracted
with EtOAc (2 x 100 mL). The combined organic extracts
were washed with brine, dried (Na2S04) and concentrated in
vacuo. The residue was chromatographed (Si02; 85:15
hex:EtOAc) to obtain Part A compound (3.48 g; >100%) as a
colorless oil.
B.
To a solution of Part A compound (3.4 g; 11.9 mmol)
in dry THF (50 mL) under Ar was added LiAlH4 (36 mL of a
0.5 M solution in THF; 17.8 mmol) dropwise. The reaction
was stirred at RT for 1 h. The reaction was quenched by
slow addition of saturated aqueous NH4C1 (1 mL) .
Volatiles were removed in vacuo and the residue was
partitioned between EtOAc (100 mL) and 1 M aqueous HC1.
The organic phase was dried (Na2SO4) and concentrated in
vacuo to give Part B compound (2.4 g; 98%) as a white
solid.
C.
To a solution of Part B compound (2.4 g; 9.8 mmol)
and Ph3P (3.1 g; 14.7 mmol) in CH2C12 was added CBr4 (4.80
g/ 14.7 mmol). The reaction was stirred at RT overnight,
then concentrated in vacuo. The residue was
chromatographed (Si02; 95:5 hex:EtOAc) to give Part C
compound ( 2 . 8 g; 93%) as a white solid.
D.
A mixture of Part C compound (310 mg; 1.0 mmol) and
potassium tert-butoxide (113 mg; 2.0 mmol) in toluene (20
mL) was heated at 105°C for 20 min. Additional KOtBu
(56 mg; 1.0 mmol) was added and the reaction heated at
105°C for another 10 min. The mixture was cooled to RT
and partitioned between H20 (100 mL) and EtOAc (100 mL) .
The organic phase was washed with H20 (2 x 100 mL) , dried
(Na2SO4) and concentrated in vacuo. The reaction was
repeated with additional Part C compound (500 mg; 1.63
mmol) and KOtBu (182 mg; 16 mmol). The combined crude
reaction products were chromatographed (SiO2; hexane) to
give Part D compound (590 mg; 89%) as a colorless oil.
E.
To a 0°C solution of Part D compound (1.4 g; 62
mmol) in DCE (100 mL) was added neat diethylzinc (1.6 mL;
16 mmol) dropwise, followed by ICH2C1 (5.46 g; 31 mmol) .
The reaction mixture was allowed to warm to RT and
stirred at RT overnight, then washed with 1M aqueous HCl.
The organic phase was dried (Na2S04) and concentrated in
vacuo. The crude residue was chromatographed twice (SiO2;
hexane) to give Part E compound (510 mg; 30%) in addition
to recovered starting material Part D compound (250 mg;
18%) .
F.
To a -78°C solution of Part E compound (510 mg; 2.2
mmol) in liquid NH3 (30 mL) was added Na (500 mg; 22
mmol). The dark blue solution was stirred at -78°C for
4 h, then was allowed to warm to RT overnight. The
remaining solid residue was partitioned between 1 M
aqueous HC1 and EtOAc (50 mL each). The organic phase
was dried (Na2SO4) and concentrated in vacuo. The crude
product was chromatographed (Si02; 9:1 hexane: EtOAc) to
give Part F compound (240 mg; 75%) as a yellow oil.
G.
(Figure Removed)
To a solution of Part F compound (150 mg; 1.0 mmol)
in DMF (10 mL) were successively added KOtBu (112 mg; 1.0
mmol) and a solution of the following carbamoyl chloride
(44 mg; 1.0 mmol) in DMF (0.5 mL).
(prepared as described in
Examples 5 and 139) . The reaction was stirred at RT for
15 min, after which analytical HPLC indicated that all
starting material had been consumed. The mixture was
partitioned between H2O and EtOAc (100 mL each) . The
organic phase was washed with H20 (2 x 100 mL) , dried
(Na2SO4) and concentrated in vacuo. The crude product was
chromatographed (Si02; 9:1 hexane:EtOAc) to give impure
Part G compound as a yellow oil.
H.'
A solution of Part G compound (556 mg; 1.0 mmol)
and LiOH.H20 (116 mg; 2.8 mmol) in 10:1 MeOH:H2O (10 mL)
was stirred at RT for 2 h. Volatiles were removed in
vacuo and the residue was acidified to pH 2 with aqueous
1 M HC1, then extracted with EtOAc (3 x 40 mL) . The
combined organic extracts were dried (Na2SO4) and
concentrated in vacuo. The crude product was purified by
preparative HPLC (YMC S5 ODS 50 x 250 mm column; flow
rate = 25 mL/min; continuous 20 min gradient from 70:30
B:A to 100% B, where A = 90:10:0.1 H2O:MeOH:TFA and B =
90:10:0.1 MeOH:H2O:TFA) to give (120 mg; 30% over 2 steps)
as a colorless oil. [M + H] + = 543.2
(Figure Removed)
Title compound was synthesized from Example 474
Part F compound (150 mg; 1.0 mmol) and the carbamoyl
chloride (440 mg; 1.0 mmol)
- 208 -
Ph- LiOH/H2O hydrolysis in the same manner as in Example 474 .
The title compound was isolated and purified as a
colorless oil (340 mg; 92% over 2 steps) . [M + H]+ =
543.3
Following the procedures described above, the
Examples 476 to 494 compounds were prepared.
Examples 476 to 484
(Table Removed)
ExamDle
Example 492 was synthesized according to the
procedures described hereinbefore.
*H NMR (CDC13; 400 MHz): 8 0.68 (t, J = 4.4 Hz; 2H) , 0.94
(t, J = 4.4 Hz; 2H), 1.87 (m, 1H), 2.42 (s, 3H) , 3.06 (s,
2H), 4.02 (t, J = 5.2 Hz, 2H), 4.22 (t, J = 5.2 Hz, 2H),
4.60 (2 peaks, 2H) , 6.84-6.89 (m, 4H), 7.15-7.26 (m, 4H) ,
7.40-7.47 (m, 3H), 7.98-8.00 (m, 2H).
The required (commercially unavailable) phenols and
chloroformates for the synthesis of the above carbamateacid
analogs were prepared as follows:
3-Fluoro-4-methyl-phenyl nhloroformate
(Figure Removed)
A mixture of 5-methoxy-2-methyl aniline (5.0 g; 36
mmol), HC1 (7.6 mL of a 12 M solution; 91 mmol) and H2O
(11 mL) was heated at 60°C for 15 min until complete
dissolution had occurred. The reaction was cooled to 0°C
and an aqueous solution of NaN02 (2.5 g; 36 mmol) was
added dropwise (internal temperature was stirred at 0°C for 30 min and a 0°C solution of HBF4
(5.3 mL of a 48% solution; 40 mmol) was added cautiously.
The reaction was stirred at 0°C for 20 min, and the
resultant brown solid was filtered, washed with ice water
(3 x 10 mL) and H20 (2 x 10 mL) . The solid was dried
under high vacuum for 20 h, then heated (heat gun) until
evolution of BF3 (white fumes) had ceased. The resulting
brown oil was partitioned between EtOAc and H2O. The
organic phase was dried (Na2S04) , concentrated in vacuo
and distilled by Kugelrohr to give 3-fluoro-4-tnethyl
anisole (1.6 g; 31%) as a colorless oil.
B.
To a -70°C solution of 3-fluoro-4-methyl anisole
(1.62 g; 11.6 mmol) in CH2C12 (10 mL) was added dropwise
BBr3 (10 mL; 12 mmol) . The reaction mixture was stirred
at -70°C for 10 min, then allowed to warm to 0°C and
stirred at 0°C for 2 h. The reaction was allowed to warm
to RT and concentrated in vacuo and the residue was
partitioned between H2O and EtOAc. The organic phase was
washed with H2O, dried (Na2S04) and concentrated in vacuo
to give 3-fluoro-4-methyl phenol (1.1 g; 75%) as an oil.
c.
A solution of 3-fluoro-4-methyl phenol (1.1 g; 8.7
tnmol) , phosgene (5.9 mL of a 1.93 M solution in toluene;
8.7 tnmol) , DMF (10 |iL) and N,N-dimethylaniline (1.27 g;
8.7 mmol) in chlorobenzene (10 mL) in a sealed tube was
stirred at RT for 2h, then at 80°C for 2 h. The reaction
was cooled to RT, stirred for RT for 1 h, then was
concentrated in vacuo. The residue was distilled by
Kugelrohr to furnish 3-fluoro-4-methyl phenyl
chloroformate (800 mg; 49%) as a clear oil.
3 -chloiro-4-methyl-phenyl chloroform a te
3-chloiro-4-methyl phenyl chloroformate (600 mg; 45%
overall for 2 steps) was synthesized from 3-chloro-4-
methyl anisole (1.0 g) using the same route (BBr3-mediated
methyl ether cleavage followed by treatment with
phosgene) as above.
^-hr-nmn-4-met-hyl-phenyl To a 0°C mixture of 3-bromo-4-methyl aniline (5 g;
27 mmol) and H2S04 (5.5 mL of a 16 M solution) in H20 (7.5
mL) was added dropwise a solution of aqueous NaN02 (1.93
g; 28 mmol in 7.5 mL H20) . The reaction was stirred at
0°C for 30 min, then was heated at 50°C for 2 h, then was
cooled to RT and extracted with EtOAc (2x) . The combined
organic extracts were washed with H20, dried (Na2S04) and.
concentrated in vacuo to give 3-bromo-4-methyl phenol
(1.72 g; 34%) as an oil. This phenol was converted to 3 -
bromo-4-methyl phenyl chloroformate (1.9 g; 82%) using
the same procedure (phosgene/ dimethylaniline/heat) as
for 3-fluoro-4-methyl phenyl chloroformate above.
2-Methoxyphenyl chloroformate. (1.5 g) and 3-
methoxyphenyl chloroformate (1.5 g) were both synthesized
in the same way as for 3-fluoro-4-methyl phenyl
chloroformate (phosgene/dimethylaniline/heat) from 2-
methoxyphenol (2 g) and 3-methoxyphenol (2 g)
respectively.
3-chloro-4-mefchoyy phenol
To a 0°C solution of 3-chloro-4-methoxy aniline
(1.0 g; 6.4 mmol) in 1:1 H20:conc. H2S04 (100 mL) was
added very slowly a solution of NaN02 (0.5 g; 7.6 mmol) in
H20 (10 mL) . Thick yellow fumes were emitted, and the
black solution was then heated to reflux for 30 min. The
mixture was extracted with EtOAc (4 x 50 mL) and the
combined extracts were concentrated in vacuo. The
residue was chromatographed (Si02; 4:1 hex: EtOAc) to
obtain 3-chloro-4-methoxy phenol (300 mg; 30%) as a
yellow oil.

A solution of 3'-fluoro-4'-methoxyacetophenone (10
g; 59 mmol) and m-chloroperbenzoic acid (50% purity; 30
g; 89 mmol) in CH2C12 (300 mL) was stirred at RT
overnight. The solution was washed with saturated
aqueous Na2C03, then filtered through a pad of SiO2 (CH2C12
as eluent) and finally chromatographed (SiO2; hex:EtOAc
4:1) to give the crude product (3'-fluoro-4'-methoxy
phenyl acetate; 63 g). A solution of this crude material
and LiOH.H20 (5 g; 120 mmol) in MeOH:H2O (100 mL of a 9:1
mixture) was stirred at RT overnight. Volatiles were
removed in vacuo, and the residue was partitioned between
excess aqueous 1 M HC1 and EtOAc (aqueous layer pH~3).
The aqueous phase was extracted with EtOAc (2x) . The
combined organic extracts were dried (Na2SO4) and
concentrated in vacuo to give 3-fluoro-4-methoxy phenol
(6.1 g; 72%) as an oil.
3-bromo-4-methoxy phenol (4.39 g; 47% for 2 steps)
was synthesized using the exact analogous sequence
starting from 3-bromo-4-methoxy benzaldehyde.
3-propyl phenol
(Figure Removed)
A mixture of 3-iodoanisole (2 g; 8.5 mmol),
trimethyl- silylacetylene (1.67 g; 17 mmol), Cul (32 mg;
0.17 mmol) and (Ph3P)2PdCl2 (59 mg; 0.085 mmol) in
diethylamine (10 mL) was stirred at RT for 1 h.
Volatiles were removed in vacuo, and the residue was
partitioned between EtOAc and brine. The organic phase
was washed with brine (2 x 10 mL) and then filtered
through a pad of Si02. Volatiles were removed in vacuo to
give the crude product (3-trimethylsilylethynyl anisole)
as a light yellow oil. A solution of this crude product
and tetrabutylammonium fluoride (6.6 g; 26 mmol) in THF
(10 mL) was stirred at RT for 15 min. Volatiles were
removed in vacuo and the residue was chromatographed
(Si02; 9:1 hex:EtOAc) to furnish Part A compound (1.0 g;
89%) as a yellow oil.
(Figure Removed)
To a 0°C solution of Part A compound (1.0 g; 7.6
mmol) in anhydrous THF (5 mL) was added dropwise n-BuLi
(4.5 mL of a 2.0 M solution in hexane; 9.1 mmol) . The
resulting yellow solution was stirred at 0°C for 30 min.
Methyl iodide (1.6 g; 11.4 mmol) was then added and the
reaction was allowed to warm to RT and stirred at RT for
30 min. Volatiles were removed in vacuo and the residue
was partitioned between aqueous IN HCl and EtOAc. The
aqueous phase was extracted with EtOAc (3x20 mL), and
the combined organic extracts were dried (MgSO4) and
concentrated in vacuo to give Part B compound (1.0 g;
92%) as a yellow oil.
C.
A solution of Part B compound (1.0 g) in MeOH (5
mL) was stirred over 10% Pd/C (10 mg) under an atmosphere
of H2 overnight. The catalyst was removed by filtration
through a pad of Celite® and the filtrate was
concentrated in vacuo to give Part C compound (1.0 g;
100%) as a yellow oil.
D.
To a -78°C solution of Part C compound (1.0 g; 6.6
mmol) in CH2C12 (10 mL) was added BBr3 (4.8 mL of a 1 M
solution in CH2C12) . The reaction was allowed to warm to
RT and was stirred at RT for 3 h, after which it was
cautiously partitioned between aqueous 1 M HCl and CH2C12.
The organic phase was washed with aqueous NH4C1, dried
(MgS04) and concentrated in vacuo to give 3-propyl phenol
(900 mg; 100%) as a yellow oil.
Example 495
(Figure Removed)
A mixture of benzoic acid (1.22 g; 10 mmol),
me thane sulfonyl chloride (1.15 g; 10 mmol), K2CO3 (5.52 g;
40 mmol) and benzyltriethylammonium chloride (O.23 g; 1
mmol) in toluene was stirred at 80°C for 2 h. Ethyl
hydrazine acetate hydrochloride (1.55 g; 10 mmol) was
then added and the reaction was stirred for a further 30
min, then cooled to RT. Solids were filtered off and the
filtrate was concentrated in vacuo. The residue was
chromatographed (Si02/- stepwise gradient from 3:1 to 1:1
hexane:EtOAc) to give Part A compound (350 mg; 16%) as a
white solid.
B.
(Figure Removed)
To a 0°C solution of Part A compound (49 mg; 0.22
mmol) and the aldehyde (50 mg; 010 mmol)
CHO
in DCE (3 mL) was added NaBH(OAc)3 (30 mg; 0.42 mmol).
The reaction was allowed to warm to RT and stirred at RT
for 2 h, then at 60°C for 18 h. The mixture was cooled
to RT and concentrated in vacuo. The residue was
purified by preparative HPLC (YMC S5 ODS 30 x 250 mm
column; flow rate = 25 mL/min; 20 min continuous gradient
from 70:30 B:A to 100% B, where solvent A = 90:10:0.1
H20:MeOH:TFA and solvent B = 90:10:0.1 MeOH: H2O: TFA) to
give Part B compound.
C.
(Figure Removed)
A solution of crude Part B compound in THF (1 mL)
and aqueous LiOH (0.3 mL of a 1 M solution; 0.3 mmol) was
stirred at RT for 3 h, then acidified to pH ~3 with
aqueous 1 M HCl. The aqueous phase was extracted with
EtOAc (2x); the combined organic extracts were
concentrated in vacuo. The residue was purified by
preparative HPC (YMC S5 CDS 30 x 250 mm column; flow rate
= 25 mL/min; 22 min continuous gradient from 70:30 B:A to
100% B, where solvent A = 90:10:0.1 H20:MeOH:TFA and
solvent B = 90:10:0.1 MeOH:H2O:TFA) to give title compound
(26 mg; 33% yield over 2 steps) as a white solid.
[M + H]+ = 486.3
Example 496
A.
(Figure Removed)
To a 0°C solution of the aldehyde (200 mg; 0.65
mmol)
in MeOH (2 mL) was added portionwise NaBH4 (24 mg; 0.65
mmol) , after which the reaction was allowed warm to RT
and stirred at RT for 1 h. Volatiles were removed in
vacuo and the residue was partitioned between H20 and
EtOAc. The organic phase was dried (Na2S04) and
concentrated in vacuo to give the intermediate alcohol as
an oil. A solution of the alcohol in CH2C12 (2 mL) and
PBr3 (1 mL of a 1M solution in CH2C12) was stirred at RT
for 30 min. Volatiles were removed in vacuo and the
residue was partitioned between aqueous saturated NaHCO3
and EtOAc. The organic phase was washed with H20, dried
(Na2S04) and concentrated in vacuo to give Part A compound
(150 mg; 62%) as an oil.
B.
(Figure Removed)
A solution of Part A compound (42 mg; 0.11 mmol),
Example 500 Part A compound (25 mg; 0.11 mmol) and K2CO3
(100 mg; 0.71 mmol) in DMF (1 mL) was stirred at RT for 3
days. The reaction mixture was partitioned between EtOAc
and H20. The organic phase was washed with H2O (2x) and
concentrated in vacuo. The residual oil was dissolved in
THF (1 mL) and aqueous LiOH (0.3 mL of a 1 M solution)
was added. The reaction was stirred at RT for 3 h, then
acidified to pH ~3 with aqueous 1 M HC1. The aqueous
phase was extracted with EtOAc (2x) ; the combined organic
extracts were concentrated in vacuo. The residue was
purified by preparative HPC (YMC S5 ODS 30 x 250 mm
column; flow rate = 25 mL/min; 20 min continuous gradient
from 70:30 B:A to 100% B, where solvent A = 90:10:0.1
H2O:MeOH:TFA and solvent B = 90:10:6.1 MeOH: H2O: TFA) to
give title compound (15 mg; 27% yield over 2 steps) as a
white solid. [M + H] + = 486.4
Example 497
(Figure Removed)
A mixture of 3 -hydroxyacetophenone (650 mg; 4.78
mmol) , K2C03 (660 mg; 4.78 mmol) and'the 2-phenyl-5-
methyl- 4 -oxazole-ethanol mesylate (1.12 g; 3.98 mmol)
(Figure Removed)
in MeCN (40 mL) was refluxed overnight. Volatiles were
removed in vacuo, and the residue was partitioned between
EtOAc (100 mL) and 1.0 M aqueous NaOH (80 mL) . The
organic phase was washed with brine (100 mL) , dried
(MgS04) and concentrated in vacuo. The residue was
chromatographed (Si02; hexaneiEtOAc 3:1) to give Part A
compound (850 g; 67%) as a yellow solid.
B.
(Figure Removed)
To a solution of Part A compound (850 mg, 2.65
mmol) in DCE (15 mL) were successively added glycine
methyl ester hydrochloride (333 mg, 2.65 mmol) , Et3N (554
uL, 4.0 mmol), NaBH(OAc)3 (786 mg; 3.7 mmol) and acetic
acid (152 uL; 2.65 mmol) . The reaction mixture was
stirred at RT for 6 days, then partitioned between
aqueous I M NaOH and CH2C12. The aqueous phase was washed
with H2O, then concentrated in vacuo. The residue was
partitioned between EtOAc and 1 M aqueous HC1. The
organic phase was washed with brine, dried (MgSOj and
concentrated in vacuo to give recovered starting material
(Part A compound). The pH of the aqueous HC1 phase was
adjusted to 10 with excess solid NaOH. This aqueous
phase was extracted with EtOAc (60 mL). The organic
extract was washed with brine (60 mL) , dried (MgS04) and
concentrated in vacuo to give the crude Part B compound
(400 mg; 39%) as an oil, which was used in the next step
without further purification.
C.
To a solution of Part B compound (29 mg; 0.074
mmol) in pyridine (1.0 mL) were added 4-tolyl
chloroformate (14 nL; 0.089 mmol) and DMAP (10 mg) . The
solution was heated at 61°C for 2h, then cooled to RT and
concentrated in vacuo to give crude Part C compound (36
mg) as a syrup.
D.
A solution of crude Part C compound (36 mg; Q.68
mmol) and LiOH.H20 (12 mg; 0.28 mmol) in THF:MeOH:H20 (1
mL of a 1:1:1 solution) was stirred at RT for 2 h.
Volatiles were removed in vacuo and the residue was
acidified to pH 2 with aqueous 1 M HC1, then extracted
with EtOAc (3 x 40 mL). The combined organic extracts
were dried (Na2SO4) and concentrated in vacuo. The crude
product was purified by preparative HPLC (YMC S5 ODS 50 x
250 mm column; flow rate =25 mL/min; continuous 20 min
gradient from 70:30 B:A to 100% B, where A = 90:10:0.1
H20:MeOH:TFA and B = 90:10:0.1 MeOH:H20:TFA) to give title
compound (28 mg; 72% over 2 steps) as a white solid.
[M + H]+ = 515.3
Example* A98
OCH3
A.
A solution of (S)-1-(4-methoxyphenyl) ethylamine
(11.9 g, 79 mmol), methyl bromoacetate (11.5 g; 75 mmol)
and Et3N (12.6 mL; 90 mmol) in THF (156 mL) was stirred at
RT for 15 h. The reaction was partitioned between EtOAc
and H2O. The organic phase was washed with brine, dried
(MgSO4) , and concentrated in vacuo to give crude Part A
compound, which was used in the next step without further
purification.

To a 0°C solution of the crude Part A compound from
above in CH2C12 (198 mL) was slowly added dropwise BBr3
(12.0 mL; 127 mmol) . The reaction was stirred at 0°C for
3 h, then poured cautiously into a 0°C mixture of
saturated aqueous NH4C1 and EtOAc. The aqueous phase was
neutralized by slow addition of solid NaHC03, then
extracted with EtOAc (2x) . The combined organic extracts
were washed with brine, dried (MgSO4) and concentrated in
vacuo to furnish Part B compound (7.29 g; 44% over 2
steps) .
C.
To a solution of Part B compound (6.13 g; 29.3
mmol) in dioxane:H20 (98 mL of a 1:1 solution) were
successively added NaHC03 (3.2 g; 38 mmol) and 4-methoxyphenyl
chloroformate (3.92 mL; 26.4 mmol). The reaction
was stirred at RT for 2 h, then partitioned'between EtOAc
and H2O. The organic phase was washed with brine, dried
(MgSO4) , and concentrated in vacuo to give crude Part C
compound (10.0 g; 95%) .
(Figure Removed)
To a solution of Part C compound in MeCN (59 mL)
were successively added K2CO3 (2.43 g; 17.6 mmol) and the
mesylate (4.93 g; 17.6 mmol).
Ph-i
The reaction was heated at 90°C for 20 h, then cooled to
RT. The mixture was partitioned between EtOAc and H2O.
The organic phase was washed with brine, dried (MgSOj and
concentrated in vacuo. The residue was chromatographed
(SiO2; stepwise gradient from 8:1 to 3:1 to 1:1
hexane:EtOAc) to give Part D compound (3.4 g; 36%).
E.
To a solution of Part D compound (3.4 g; 6.25 mmol)
in THF:H20 (31 mL of a 2:1 solution) was added LiOH.H20
(0.525 g; 125 mmol). The reaction was stirred at RT
overnight for 14 h. EtOAc was added and the solution was
acidified with 1 N HCl solution to pH ~2. The organic
phase was washed with brine, dried (MgS04) and
concentrated in vacuo. The residue was purified by
preparative HPLC (YMC S5 ODS 30 x 250 mm column; flow
rate =25 mL/min; 22 min continuous gradient from 70:30
B:A to 100% B, where solvent A = 90:10:0.1 H20:MeOH:TFA
and solvent B = 90:10:0.1 MeOH:H2O:TFA; retention time =
17.8 min) to give the title compound (2.1 g; 63% yield)
as a white solid. [M + H]+ = 531.3; XH NMR (DMSO-d6; 400
MHz): 8 1.50 (2d, J = 6.6 Hz; 3H), 2.37 (s, 3H), 2.94
(t, J = 7.0 Hz, 2H) , 3.74 (S/ 3H) , 3.81 (m; 2H) , 4.21 (t,
J = 6.2 Hz, 2H), 5.36 (m, 1H), 6.93 (m, 6H), 7.28 (m,
2H), 7.50 (m, 3H), 7.91 (m, 2H)
Exampl p> 4QQ
(Figure Removed)
The synthesis of title compound was done using the
identical sequence described for Example 498 compound
except that (R)-4-methoxy-a-methyl benzylamine was used
instead of the (S) isomer. [M + H] * = 531.3;
XH NMR (DMSO-ds; 400 MHz): 8 1.50 (2d, J = 7.0 Hz; 3H) ,
2.37 (s, 3H), 2.94 (t, J = 6.6 Hz, 2H) , 3.74 (s, 3H),
3.84 (m; 2H) , 4.21 (t, J = 6.6 Hz, 2H), 5.35 (m, 1H),
6.93 (m, 6H) , 7.29 (m, 2H) , 7.50 (m, 3H) , 7.91 (m, 2H)
Ph- Example 500
(Figure Removed)
A mixture of 4-hydroxyphenyl butyl ketone (2.50 g;
14.0 mmol) , 2-phenyl 5-methyl oxazole-4-ethanol mesylate
(3.30 g; ll.v mmol) and K2C03 (1.94 g; 14.0 mmol) in
acetonitrile (50 mL) was refluxed under Ar for 18 h.
Volatiles were removed in vacuo and the residue was
partitioned between H2O and EtOAc. The aqueous phase was
extracted with EtOAc. The combined organic extracts were
washed with aqueous 1M NaOH and H20, dried (MgSOj and
concentrated in vacuo. The residue was chromatographed
(Si02; stepwise gradient from 3:1 to 9:1 hex: EtOAc) to
give Part A compound (3.42 g; 80%) as a white solid.
B.
A mixture of Part A compound (3.42 g; 9.42 mmol)/
glycine methyl ester HCl salt (1.18 g; 9.42 mmol), Et3N
(1.97 mL; 14.1 mmol), NaBH(OAc)3 (2.80 g; 13.2 mmol) and
HOAc (0.54 mL; 9.42 mmol) in DCE (20 mL) was stirred at
RT for 6 days. At this point the reaction was
incomplete, but was not progressing any further. The
reaction was quenched with saturated aqueous NaHC03 (6
mL) , then concentrated in vacuo. The residue was
partitioned between saturated aqueous NaHCO3 and EtOAc.
The organic phase was washed with saturated aqueous NaHC03
and H2O, then extracted with 1M aqueous HCl (the unreacted
starting material remained in the organic phase) . The
aqueous phase was basified with NaOH, then extracted with
EtOAc. The organic phase was washed with H20 and brine,

dried (MgSOj and concentrated in vacuo to give Part B
compound (365 mg; 9%) as an oil.
C.
To a solution of Part C compound (50 mg; 0.11 mmol)
in pyridine (1 mL) was added 4-methoxyphenyl
chloroformate (40 ^L) and DMAP (5 mg) . The reaction
mixture was heated at 60°C for 6 h, ' then was cooled to RT
and volatiles were removed in vacuo. The residue was
dissolved in THF/MeOH/H20 (1 mL of a 2:2:1 mixture) and
LiOH (30 mg) was added. The reaction was stirred at RT
for 18 h, then was acidified with aqueous 1 M HCl to pH
2. The mixture was extracted with EtOAc (30 mL) , washed
with H2O and brine (15 mL each) , dried (MgS04) and
concentrated in vacuo to give the crude product. This
material was purified by preparative HPLC (YMC S5 ODS 30
x 250 mm column; continuous gradient from 60:40 A:B to
100% B over 30 min) to give, 'after lyophilization from
MeOH/H2O, the title compound (52 mg; 79%) as a white
solid. [M + H]+ = 573.3
P.yamp If* 5 Q i
CO2H
OCH3

A.
rt _Cri4 -x?^ j""^s. ^-v.
CO2CH3
A mixture of glycine methyl ester hydrochloride
(245 mg; 1.95 mmol) , Et3N (271 uL; 1.95 mmol) and the
aldehyde
CHO
O
(400 mg; 1.3 mmol) and anhydrous MgS04 (200 mg) in THF (4
mL) was stirred at RT overnight, then filtered. The
filtrate was concentrated in vacuo to give crude Part A
compound, which was used in the next step without further
purification.
B.
CO2CH3
A mixture of indium metal (448 mg; 3.9 mmol) and
allyl bromide (334 |aL; 3.9 mmol) in anhydrous DMF (2 mL)
was stirred at 0°C for 50 min. A solution of the crude
Part A compound (from above) in anhydrous DMF (2 mL) was
added to this mixture, and the reaction was stirred
vigorously at RT for 3 h. Analytical HPLC/MS showed that
the reaction was complete at this point. The reaction
was partitioned between saturated aqueous NH4C1 and EtOAc.
The organic phase was washed with H20 (an emulsion formed)
and brine, dried (MgS04) and concentrated in vacuo to give
crude Part B compound (300 mg; 55% for 2 steps) . This
material was used in the next step without further
purification.
(Figure Removed)
To a 0°C solution of Part B compound (150 mg; 0.36
mmol) and Et3N (51 ^L; 0.36 mmol) in CH2C12 (4 mL) was
added dropwise 4-methoxyphenyl chloroformate (53 jaL; 0.36
mmol). The reaction was allowed to warm to RT and
stirred at RT for 1 h, then concentrated in vacuo. The
residue was chromatographed (SiO2; hexane:EtOAc 2:1) to
give Part C compound (200 mg; 98%) as an oil.
D.
A solution of Part C compound (100 mg, 0.18 mmol)
and LiOH.H2O (30 mg, 0.72 mmol) in THF:MeOH:H2O (1 mL of a
1:1:1 solution) was stirred at RT for 2 h. The reaction
mixture was then acidified to pH ~ 2 with aqueous IN HCl.
The aqueous phase was extracted with EtOAc (2x) . The
combined organic extracts were dried (Na2SO4) ,
concentrated in vacuo and lyophilized from dioxane to
provide title compound (80 mg; 82%) as a white solid.
[M + H] + = 557.2
Examp]P 502
(Figure Removed)
A solution of Example 501 Part C compound (100 mg;
0.18 mmol) in MeOH (10 mL) in the presence of 10% Pd/C
(50 mg) was stirred under an H2 atmosphere for 2 h at RT.
The catalyst was then filtered off using a pad of
Celite®. The filtrate was concentrated in vacuo to give
Part A compound (100 mg; 100%) as an oil.
B.
OCH3
Title compound (87 mg; 90%; white solid lyophilate)
was obtained from Part A compound in the same way as
Example 501 compound was synthesized from Example 501
Part C compound. [M + H]+ = 559.2
A.
OSO2CH3
To a solution of 5-methyl 2-phenyl-thiazol-4-ylethanol
(50 mg; 0.23 mmol) in CH2C12 (3 mL) were
successively added Et3N (50 uL; 0.36 mmol) and
methanesulfonyl chloride (20 uL; 0.26 mmol). The
reaction was stirred at RT for 2 h, then was partitioned
between CH2C12 and aqueous. 1 M HCl. The organic phase was
washed with brine, dried (Na2S04) , and concentrated in
vacuo to give Part A compound (68 mg; 100%) as a
colorless oil. This material was used in the next step
without further purification.
B.
A mixture of the phenol (prepared using the
identical procedures as described for the synthesis of
Example 498 Part C compound except that ethyl
bromoacetate was used instead of methyl bromoacetate)
(Figure Removed)
(18 mg; 0.048 mmol) and K2CO3 (30 mg; 0.22 mol) in MeCN (2
mL) was heated at 60°C overnight, then cooled to RT and
partitioned between EtOAc and excess aqueous 1 M HC1.
The aqueous phase was extracted with EtOAc (2x); the
combined organic extracts were dried (Na2SOj and
concentrated in vacuo. The residue was purified by
preparative HPLC (as described for Example 498) to
provide Part B compound (12 mg; 43%).
C.
A solution of Part B compound (12 mg; 0.02 mmol) and
LiOH.H2O (10 mg; 0.24 mmol) in THF (2 mL) and H2O (1 mLi)
was stirred at RT for 4 h. The reaction mixture was
acidified with excess aqueous 1 M HCl and extracted with
EtOAc (3x). The combined organic extracts were dried
(Na2SO4) and concentrated in vacuo; the residue was
purified by preparative HPLC (as described for Example
498) to give the title compound (3 mg; 26%) as a
colorless oil. [M + H] + = 547.2
Example 504
(Figure Removed)
The title compound was prepared in exactly the same
way as for Example 503 except that the [S] -enantiomer
QH3
I, HO^^ 0^0
was used for the alkylation step. [M + H]+ = 547.2
Example; 505
A.
H3CO
To a solution of 1- (4-methoxyphenyl) -1-cyclopropanecarboxylic
acid (250 mg; 1.3 mmol) in dioxane (8 ml) were
successively added Et3N (198 ^L; 1.43 mmol) and diphenylphosphoryl
azide (307 \JLl>; 1.43 mmol). The reaction was
stirred at RT for 5 min, then heated to 80°C for 3 h.
Volatiles were removed in vacuo, and the residue was
partitioned between EtOAc and H2O. The organic phase was
dried (Na2S04) and concentrated in vacuo to give the crude
product (presumably the corresponding isocyanate). This
material was dissolved in aqueous 8 M HC1 (1.8 mL),
stired at RT for 5 min, then heated to 100°C for 1 h.
After cooling to RT, Et20 was added, and the solution was
cautiously basified with excess solid NaOH. The aqueous
phase was extracted with Et2O (3 x 15 mL) , dried (MgSO4)
and concentrated in vacuo to provide compound A (100 mg;
47%) as an oil. This material was used in the next step
without further purification.
(Figure Removed)
A solution of Part A Compound (100 mg; 0.61 mmol),
methyl bromoacetate (103 mg; 0.67 mmol) and Et3N (102 JJ.L;
0.73 mmol) in THF was stirred at RT for 16 h. The
reaction mixture was partitioned between EtOAc and H20.
The organic phase was washed with brine, dried (MgS04) ,
and concentrated in vacuo. The residue was
chromatographed (Si02; CH2Cl2:MeOH 9:1) to give Part B
compound (90 mg; 62%) as an oil.
C.
To a 0°C solution of Part B compound (90 mg; 0.38
mmol) in CH2C12 (12.7 mL) was slowly added neat BBr3 (82
uL; 0.87 mmol) The reaction was stirred at 0°C- for 3 h,
then was partitioned between ice cold saturated aqueous
NH4C1 and EtOAc. The organic phase was discarded and the
aqueous layer was neutralized by addition of NaHC03, then
extracted with EtOAc (2x). The combined organic extracts
were washed with brine, dried (MgS04) , and concentrated in
vacuo to give Part C compound (50 mg/ 59%).
D.
A mixture of Part C compound (50 mg; 0.22 mmol), 4-
methoxyphenyl chloroformate (33 mg; 0.22 mol) and NaHCO3
(25 mg; 0.29 mmol) in 1:1 aqueous dioxane (7.5 mL) was
stirred at RT for 2 h. The reaction mixture was
partitioned between EtOAc and H2O. The organic phase was
washed with brine, dried (MgSO4) and concentrated in vacuo
to give Part D compound (45 mg; 52%) .
E.
(Figure Removed)
A mixture of Part D compound (45 mg; 0.12 mmol),
K2C03 (30 mg; 0.22 mol) and the mesylate (33 mg; 0.12
mmol)
(Figure Removed)
in MeCN (4 mL) was heated at 90°C for 20 h. The reaction
was cooled to RT and partitioned between EtOAc and H2O.
The aqueous phase was extracted with EtOAc (2x) ; the
combined organic extracts were dried (MgSO4) and
concentrated in vacuo. The residue was chroma tographed
(Si02; stepwise gradient from 9:1 to 1:1 hex: EtOAc) to
provide Part E compound (42 mg; 65%) .
F.
A solution of Part E compound (42 mg; 0.08 mmol) and
LiOH.H2O (6 mg; 0.15 mmol) in 2:1 THF:H20 (3.8 mL) was
stirred at RT overnight. The reaction mixture was
acidified to pH 2 with excess aqueous 1 M HCl and
extracted with EtOAc (2x). The combined organic extracts
were dried (Na2SO4) and concentrated in vacuo; the residue
was purified by preparative HPLC (as described for
Example 498) to give the title compound (28 mg; 68%) as a
colorless oil. [M + H]+ = 543.2
Following procedures as described above, the
Examples 506 to 518 compounds were prepared.
(Table Removed)
Example 505
XH NMR (DMSO-d6; 400 MHz): S 1.47 and 1.54 (2d, J = 7.5
Hz; 3H) , 2.29 (s, 3H), 2.37 (s, 3H), 2.93 (t, J = 6.6 Hz,
2H) , 3.81 (2d, J = 18 Hz; 2H) , 4.21 (t, J = 6.6 Hz, 2H) ,
5.3 (m, IH) , 6.94 (m, 4H) , 7.18 (d, J = 8.4 Hz, 2H) , 7.31
(m, 2H), 7.49 (m, 2H)
Example 50 S
OCH3
XH NMR (DMSO-ds; 400 MHz): 8 1.47 and 1.54 (2d, J = 7.5
Hz; 3H), 2.37 (s, 3H), 2.94 (t, J = 6.6 Hz, 2H), 3.74
(s, 3H), 3.81 (m, 2H), 4.21 (t, J = 6.6 Hz, 2H), 5.36
(m, IH) , 6.94 (m, 4H) , 7.29 (m, 2H) , 7.49 (m, 3H) , 7.91
(tn, 2H)
(Figure Removed)
The synthesis of Examples 513-518 involved the use
of Example 541 Part B compound as the alkylating agent.
(Table Removed)
Example No. Structure [M+H]
A mixture of methyl cx-aminoisobutyrate.
hydrochloride (108 mg; 0.7 mmol) , Et3N (146 ^L; 111 mmol),
NaBH(OAc)3 (222 mg; 11 mmol) and the aldehyde (215 mg; O7
mmol)
Ph- CHO
in DCE (5 mL) was stirred at RT for 21 h. Some starting
material remained, so the reaction was heated at 55°C for
4 h (no further reaction). Saturated aqueous NaHC03 was
added, and volatiles were removed in vacuo. The residue
was partitioned between H20 and EtOAc. The aqueous phase
was extracted with EtOAc (2x). The combined organic
extracts were washed with brine and extracted with
aqueous 1 M HC1. The aqueous phase was basified with
solid NaOH and extracted with EtOAc (2x). The organic
extracts were dried (Na2S04) and concentrated in vacuo to
give crude Part A compound (174 mg; 61%).
B.
A solution of Part A compound (120 mg; 0.29 mmol)
aqueous LiOH (2.0 mL of a 0.3 M solution of a 1:1:1
mixture of THF:MeOH:H2O) was stirred at RT overnight. The
reaction was acidified to pH ~ 2 with aqueous 1 M HC1,
then was concentrated in vacuo and purified by
preparative HPLC (YMC S5 ODS 30 x 250 mm column; flow
rate = 25 mL/min; continuous gradient from 40:60 B:A to
100% B over 30 min, where solvent A = 90:10:0.1
H20:MeOH:TFA; solvent B = 90:10:0.1 MeOH: H20: TFA) to
furnish Part B compound (60 mg/ 53%) as a syrup.
C.
H3C CH3
OCH3
A solution of Part B compound (25 mg; 0.06 mmol),
4-methoxyphenyl chloroformate (20 uL) in pyridine (1 mL)
was heated at 60°C for 6 h. Volatiles were removed in
vacuo and the residue was partitioned between EtOAc (2
mL) and aqueous 1 M HC1 (1 mL). The organic phase was
concentrated in vacuo and the residue was purified by
preparative HPLC (YMC 35 CDS 30 x 250 mm column; flow
rate = 25 mL/min/ continuous gradient from 40:60 B:A to
100% B over 20 min, where solvent A = 90:10:0.1 H20:MeOH:
TFA; solvent B = 90:10:0.1 MeOH:H2O: TFA) to furnish title
compound (4 mg; 12%) as a white foam. [M + H] + = 545.3
Following the procedures as set out hereinbefore,
the following Examples 520 to 535 compounds were
prepared.
Examples 520 to 535
(Table Removed)
To a 0°C solution of (R)-(-)-lactate (3.0 g; 29
mmol) and Et3N (4.8 mL; 35 mmol) in CH2C12 (60 mL) was
added methanesulfonyl chloride (2.67 mL; 35 mmol). The
mixture was stirred at 0°C for 1 h, then partitioned
between CH2C12 and 1M aqueous HC1 (100 mL each) . The
organic phase was washed with H2O and brine, dried
(MgSO4) , and concentrated in vacuo without heating to give
Part A compound as an oil (4.5 g; 86%), which was used in
the next step without further purification.
B.
(Figure Removed)
A mixture of Part A compound (1.42 g; 6.0 mmol),
(R)-4-methoxy-a-methyl benzylamine (300 mg, 2.0 mmol),
and K2CO3 (828 mg; 6.0 mmol) in MeCN (20 mL) was heated at
70°C for 17 h (some amine starting material still
remained). The reaction cooled to RT, filtered, and the
volatiles were removed in vacuo. The residue was
partitioned between EtOAc and H20. The organic phase was
washed with brine, dried (MgS04) , and concentrated in
vacuo. The residue was chromatographed (Si02; stepwise
gradient from 99:1 to 97:3 CHC13 :MeOH) to give Part B
compound (330 mg; 70%) as an oil.
(Figure Removed)
To a 0°C solution of Part B compound (330 mg; 1.39
mmol) in CH2C12 (3 mL) was slowly added dropwise BBr3 ( 3 . 0
mL of a 1 M solution in CH2C12; 30 mmol). The reaction
was stirred at 10°C for 3 h, then quenched by cautious
addition of saturated aqueous NH4C1 and CH2C12. The
isolated aqueous phase was neutralized by slow addition
of solid NaHC03/ then extracted with EtOAc (2x) . The
combined organic extracts were washed with brine, dried
(MgS04) and concentrated in vacuo to furnish crude Part C
compound (150 mg; 48%) , which was used in the next
reaction without further purification.
D.
(Figure Removed)
To a solution of Part C compound (300 mg; 1.35
mmol) in dioxane:H20 (6 mL of a 1:1 solution) were
successively added NaHC03 (500 mg; 5.95 mmol) and 4-
methoxyphenyl chloroformate (300 ^L; 2.0 mmol) slowly.
The reaction was stirred at RT for 1 h, then partitioned
between EtOAc and H20. The organic phase was washed with
brine, dried (MgS04) , and concentrated in vacuo to give a
crude residue, which was chromatographed (Si02; stepwise
gradient from 3:1 to 1:1 hexanerEtOAc) to furnish Part D
compound (330 mg; 66%).
E.
To a solution of Part D compound (330 mg; 0.88
mmol) in MeCN (20 mL) were successively added K2CO3 (165
mg; 1.2 mmol) and the mesylate (337 mg; 1.2 mmol).
The reaction mixture was heated at 95°C for 16 h, then
cooled to RT and filtered. The filtrate was concentrated
in vacuo and then partitioned between EtOAc and H20. The
organic phase was washed with brine, dried (MgSO4) and
concentrated in vacuo. The residue was chromatographed
(Si02; 3:1 hexane:EtOAc) to give Part E compound (350 mg;
71%) .
To a solution of Part E compound (350 mg; 0.62
mmol) in THF:H2O (15 mL of a 2:1 solution) was added
LiOH.H2O (52 mg; 1.2 mmol). The reaction was stirred at
RT overnight for 14 h; then EtOAc was added and the
solution acidified with 1 N HC1 solution to pH ~ 2 . The
organic phase was washed with brine, dried (MgSO4) and
concentrated in vacuo. The residue was purified by
preparative HPLC (YMC S5 CDS 30 x 250 mm column; flow
rate =25 mL/min; 20 min continuous gradient from 50:50
B:A to 100% B, where solvent A = 90:10:0.1 H2O:MeOH:TFA
and solvent B = 90:10:0.1 MeOH:H20:TFA; retention time =
26 min) and lyophilized from dioxane to give the title
compound (208 mg; 61% yield) as a white solid.
[M + H]+ = 545.3
537 to 539
Followng the procedures set out hereinbefore, the
Examples 537 to 539 compounds were prepared.
Example No. Structure [M+H]+
537
(Figure Removed)
Example 540
A.
To a 0°C solution of 5-methyl-2-phenyl-oxazol-4-yl
ethanol (5.0 g; 24.6 mmol), acetone cyanohydrin (3.35 mL;
36.9 mmol) and Ph3P (7.5 g; 29.5 mmol) in THF (60 mL) was
added DEAD (6.0 mL; 36.9 mmol) dropwise. After addition
was complete, the reaction mixture was warmed to RT and
stirred overnight at RT. Volatiles were removed in
vacuo, and the residue was chromatographed (SiO2;
hexane:EtOAc 2:1) to give Part A compound (4.5 g; 86%) as
an oil.
B.
A solution of Part A compound (4.5 g; 21.2 mmol)
and H2SO4 (concentrated; 20 mL) in EtOH (100 mL) was
heated under reflux overnight. The solution was
concentrated in vacuo to 1/3 its original volume, then
EtOAc (150 mL) and H20 (100 mL) were cautiously added.
The organic phase was washed with saturated aqueous NaHCO3
(2 x 100 mL) and brine (150 mL) , dried (MgS04) , and
concentrated in vacuo to give a crude oil. This material
was chroma tographed (Si02; hexane:EtOAc 2:1) to give Part
B compound (2.1 g; 38%) as a crystalline solid.
C.
Ph- To a -78°C solution of Part B compound (2.1 g; 8.1
mmol) in THF (6 mL) was added dropwise LiAlH4 (16 mL of a
1.0 M solution in THF; 16 mmol) under an atmosphere of N2.
The mixture was allowed to warm to 0°C and stirred at 0°C
for 30 min, after which the reaction was determined to be
complete by TLC (hex:EtOAc 1:1). Aqueous HCl (1.0 mL of
a 1 M solution; 1 mmol) and saturated aqueous sodium
potassium tartrate (10 mL) were successively added and
the mixture was stirred at RT for 30 min. The mixture
was extracted with EtOAc (100 mL), washed with H20 and
brine, dried (Na2S04) and concentrated in vacuo to give
crude Part C compound (1.78 g; 97%) as a white solid,
which was used in the next step without further
purification.
D.
Ph— ,OSO2CH3
To a solution of Part C compound (670 mg; 3.09
mmol) and Et3N (516 uL; 3.71 mmol) in CH2C12 (4 mL) was
added methanesulfonyl chloride (286 jlL; 3.71 mmol). The
reaction mixture was stirred at RT for 30 min, at which
point the reaction was complete by TLC (hex:EtOAc 2:1) .
The mixture was partitioned between CH2C12 (60 mL) and H2O
(40 mL) . The organic phase was washed with brine (40
mL) , dried (MgSO4) , and concentrated in vacuo to give Part
D compound (910 mg; 100%) which was used in the next step
without further purification.
E.
.CHO
A mixture of Part D compound (380 mg; 1.29 mmol),
4-hydroxybenzaldehyde (188 mg; 1.55 mmol) and K2C03 (214
mg; 1.55 mg) in MeCN (12 mL) was refluxed in an oil bath
for 17 h. At this point all starting Part D compound had
been consumed (but there was a. significant quantity of
the hydrolysis by-product, Part C compound) by HPLC/MS.
The reaction was cooled to RT and the solid precipitates
were filtered off. The filtrate was concentrated in
vacuo and partitioned between EtOAc (60 mL) and H20 (40
mL). The organic phase was washed with brine (40 mL) ,
dried (MgSOJ , and concentrated in vacuo to give the crude
product. This material was chromatographed (SiO2;
stepwise gradient from 4:1 to 1:2 hex:EtOAc) to give Part
E compound (150 mg; 36%) as an oil in addition to Part C
compound (100 mg; 36%).
F.
A mixture of Part E compound (150 mg; 0.50 mmol) ,
glycine methyl ester hydrochloride (75 mg; 0.60 mmol) and
Et3N (84 uL; 0.60 mmol) in MeOH (5 mL) was stirred at RT
for 6 h, after which NaBH4 (50 mg) was added cautiously
portionwise. The reaction mixture was stirred at RT
overnight, after which volatiles were removed in vacuo.
The residue was partitioned between EtOAc and H20. The
organic phase was washed with brine, dried (Na2SO4) and
concentrated in vacuo to give Part F compound (180 mg;
97%) as an oil.
G.
A mixture of Part F compound (23 mg; 0.060 mmol),
Et3N (10 uL; 0.66 mmol) and 4-tolyl chloroformate (10 (4,L;
0.066 mmol) in CH2C12 (1 mL) was stirred at RT for 2 h.
Volatiles were removed in vacuo and the residue was
dissolved in a solution of THF/MeOH/H2O (1 mL of a 2:2:1
mixture); LiOH.H20 (14 mg; 0.33 mmol) was added, and the
reaction was stirred at RT for 2 h. Volatiles were
removed in vacuo, and the residue was partitioned between
aqueous 1 M HC1 and EtOAc. The organic extract was
concentrated in vacuo and the residue was purified by
preparative HPLC (YMC ODS S5 30 mm x 250 mm column,
continuous 25 minute gradient from 40% B:60% A to 100% B,
hold at 100% B for 15 min, where solvent A = 90:10:0.1
H20: MeOH: TFA and solvent B = 90:10:0.1 MeOH:H2O :TFA; flow
rate = 2 5 mL/min) to give the title compound as a white
solid (13 mg; 45% over 2 steps). [M + H]+ = 515.3
Kxample 541

A.
To a solution of benzaldehyde (23.8 g, 234 mmol) in
EtOAc (150 mL; pre-saturated with HCl gas) was added 2,3-
butanedione mono-oxime (25.0 g, 234 mmol) in one portion
and the resulting solution was stirred at RT for 12 h.
Analytical HPLC indicated that all starting materials had
been consumed. The reaction mixture was concentrated in
vacuo to yield Part A compound as a white solid, which
was used in the next step without further purification.
B.
To a solution of Part A compound in CHC13 (200 mL)
was added dropwise POC13 (30 mL, 320 mmol) . The reaction
was stirred for 12 h at 50°C, then was concentrated in
vacuo. The brown residue was partitioned between EtOAc
(300 mL) and IN aqeuous NaOH. The organic phase was
washed with brine, dried, (MgS04) and concentrated in
vacuo. The residue was chromatographed (Si02; Et20) to
give Part B compound (41.5 g; 86%) as a light brown solid
(>95% pure by analytical HPLC and ^-NMR analysis) .
C.
A solution of 4-hydroxybenzaldehyde (20 g, 160
mmol) , glycine methyl ester hydrochloride (22 g, 180
mmol) and Et3N (25 mL, 180 mmol) in MeOH (200 mL) was
stirred at RT for 12 h. The reaction mixture was cooled
to 0°C and NaBH4 (9.0 g, 240 mmol) was added portionwise
while maintaining the reaction temperature at reaction mixture was stirred for 5 h, then was
concentrated in vacuo to give crude Part C compound,
which was used in the next step without further
purification.
D.
To a solution of crude Part C compound in Et20 (300
mL ) and H20 (200 mL) were added NaHCO3 (20 g, 240 mmol,
in a single portion) and 4-tolyl chloroformate (15 mL,
150 mmol; dropwise). The biphasic reaction mixture was
stirred for 12 h at RT. The aqueous phase was then
extracted with Et2O (2 x 200 mL) . The combined organic
extracts were washed with brine (2 x 50 mL), dried
(MgSO4) and concentrated in vacuo. The residue was
chromatographed (Si02; stepwise gradient from 3:1 to 1:1
hexane:EtOAc) to give Part D compound (40.8 g; 76% over 2
steps) as an oil.
E.
A solution of Part B compound (14.5 g, 70 mmol),
Part C compound (21.6 g, 67 mmol) and K2C03 (18.4 g, 134
mmol) in CH3CN (150 mL) was stirred at 80°C for 12 h. The
reaction was cooled to RT and volatiles were removed in
vacuo. The brown oily residue was partitioned between
- 256 -
EtOAc (250 mL) and brine (100 mL) . The aqueous layer was
extracted with EtOAc (3 x 100 mL) . The combined organic
extracts were dried (MgS04) and concentrated in vacuo.
The residue was chromatographed (Si02; stepwise gradient
from 3:1 to 1:1 hexane: EtOAc) to give Part D compound
(23.6 g; 71%) as a colorless oil.
F.
A solution of Part D compound .(23.6 g, 47.4 mmol)
and LiOH.H2O (4.0 g, 95 mmol) in THF (200 mL) and H20 (120
mL) was stirred at RT for 4 h. The reaction mixture was
then acidified to pH ~ 2 with aqueous IN HCl. The
aqueous phase was extracted with EtOAc (3 x 200 mL) . The
combined organic extracts were dried (MgSO4) and
concentrated in vacuo to yield an oily residue, which was
recrystallized from EtOAc to provide title compound (19.4
g; 84%) as a white solid. [M + H]+ = 487.23;
*H NMR (CD3OD; 400 MHz): 6.2.32 (s, 3H) , 2.46 (s, 3H) ,
3.99 & 4.04 (2s, 2H) , 4.47 & 4.54 (2s, 2H) , 5.01 and 5.00
(2s, 2H) , 6.99 (d, J = 8.4 Hz, 2H) , 7.05 (m, 2H) , 7.17
(d, J = 8.4 Hz, 2H) , 7.31 (m, 2H) ; 7.49 (m, 3H) , 8.01 (m,
2H) ;
*H NMR (CDC13; .400 MHz): 5 2.31 (s, 3H) , 2.44 (s, 3H) ,
4.00 (s, 2H) , 4.55 (2s, 2H) , 5.00 (2s, 2H) ; 6.99 (m, 4H) ;
7.13 (m, 2H) , 7.21 (d, J = 8.8 Hz, 2H) ; 7.31 (m, 2H) ;
7.44 (s, 3H) ; 8.01 (s, 2H)

Example 542
OCH3
A.
A mixture of 2-phenyl-5-methyl-oxazole-4-acetic
acid (470 mg; 2.17 mmol; Maybridge) pyridine N-oxide (830
mg; 8.74 mmol) and acetic anhydride (350 mg; 3.57 mmol}
in toluene (10 mL) was heated at 90°C for 12 h, then
concentrated in vacuo. The residue was then partitioned
between EtOAc and 1M aqueous HCl. The organic phase was
washed with saturated aqueous NaHCO3, brine, dried
(Na2SO4) and concentrated in vacuo to give a dark brown
oil. This material was chromatographed (Si02; 4:1
hex:EtOAc) to give Part A compound (143 mg; 35%) as an
oil.
B.
To a 0°C solution of Part A compound (600 mg; 3.21
mmol) and Ph3P (3.37 g; 12.9 mmol) in CH2C12 (50 ml) was
added dropwise a solution of CBr4 (2.13 g; 6.4 mmol) in
CH2C12 (20 mL) . The solution was stirred at 0°C for 2 h,
then allowed to warm to RT and stirred at RT overnight.
Volatiles were removed in vacuo and the residue was
chromatographed (85:15 hexane .-EtOAc) to furnish Part B
compound (1.08 g; 98%) as a pale yellow solid.
(Figure Removed)
To a -78°C solution of Part B compound (1.12 g;
3.26 mmol) in THF (60 mL) was added n-butyllithium
dropwise (4.2 mL of a 1.6 M solution in hexane; 6.72
mmol) over 25 min, while maintaining the internal
temperature at for 1 h, then allowed to warm slowly to 0°C.
Paraformaldehyde (305 g) was then added in one portion
and the reaction was stirred at 0°C for 3 h and then
quenched with saturated aqueous NH4C1. The aqueous phase
was extracted with EtOAc (2x); the combined organic
extracts were washed with brine, dried (Na2SO4) and
concentrated in vacuo to give a dark oil. This material
was chromatographed (Si02; 3:2 hex:EtOAc) to give Part C
compound (466 mg; 67%) as a yellow solid.
D.
To a 0°C solution of Part C compound (466 mg; 2.19
mmol) and Et3N in CH2C12 was added dropwise
methanesulfonyl chloride (190 uL; 2.45 mmol) and the
reaction was stirred at 0°C for 1 h. The mixture was
then partitioned between CH2C12 and cold 1M aqueous HCl.
The organic phase was washed with brine, dried (Na2SO4)
and concentrated in vacuo. The crude product was
chromatographed (Si02; 3:2 hex:EtOAc) to give Part D
compound (533 mg; 84%) as an off-white solid.
(Figure Removed)
A mixture of Part D compound (198 mg; 0.68 mmol),
4-hydroxybenzaldehyde (96 mg; 0.79 mmol) and K2C03 (141
mg; 1.02 mmol) in CH3CN (13 mL) was heated at 70°C for
3 h, then stirred at RT overnight. Volatiles were
removed in vacuo, and the residue was partitioned between
EtOAc and 1 M aqueous NaOH. The organic phase was washed
with brine, dried (Na2S04) and concentrated in vacuo to
give crude Part E compound (190 mg; 88%) as a yellow oil,
which was used in the next step without further
purification.
F.
(Figure Removed)
A mixture of Part E compound (123 mg; 0.39 mmol) ,
glycine methyl ester hydrochloride (248 mg; 1.98 mmol)
and Et3N (600 uL; 4.3 mmol) in DCE (15 mL) was stirred at
RT for 15 min, after which NaBH(OAc)3H (262 mg; 1.2 mmol)
was added in one portion. The reaction was stirred for
16 h at RT, after which additional NaBH(OAc)3H (200 mg;
0.94 mmol) was added. Stirring was continued for 3 h,
after which still more NaBH(OAc)3H (200 mg; 0.94 mmol) was
added. The reaction was stirred at RT for 48 h, after
which all Part E compound had been consumed. The
reaction mixture was partitioned between CH2C12 and
aqueous NaHCO3. The aqueous phase was extracted with
CH2C12 (2x) . The combined organic extracts were washed
with brine, dried (Na2S04) and concentrated in vacuo. The
crude product was chroma tographed (Si02; stepwise gradient
from 1:1 to 2:3 hex:EtOAc) to give Part F compound (120
mg; 79%) as a colorless oil which solidified on standing
G.
~ ^NX^C02CH3
OCH3
To a solution of Part F compound (180 mg; 0.46
mmol) and pyridine (100 \iL; 1.24 mmol) in CH2C12 (10 mL)
was added 4-methoxyphenyl chloroformate (105 uXi; 0.71
mmol). The reaction was stirred at RT for 3.5 h, then
partitioned between aqueous NaHC03 and EtOAc. The aqueous
phase was extracted with EtOAc (2x) . The combined organic
extracts were washed with brine, dried (Na2S04) and
concentrated in vacuo. The crude product was
chromatographed (Si02; hex:EtOAc 3:2) to give Part G
compound (232 mg; 93%) as a colorless oil.
H.
(Figure Removed)
To a solution of Part G compound (232 mg; 0.43
mmol) in THF:H20 (12 mL of a 5:1 mixture) was added
LiOH.H2O (1.3 mmol). The solution was stirred at RT
overnight, then acidified with aqueous 1M HC1 and
extracted with EtOAc (2x) . The combined organic extracts
were washed with brine, dried (Na2S04) and concentrated in
vacuo. The crude product was purified by preparative
HPLC (YMC S5 ODS 30 x 75 mm column, flow rate = 20
rnL/min; continuous gradient from 70:30 B:A to 100% B,
where solvent A = 90:10:0.1 H2O:MeOH:TFA and solvent B
90:10:0.1 MeOH:H20:TFA) to give title compound (160 mg;
71%) as a white solid. [M + H]+ = 527.2
Example* 543
OCH3
A solution of 5-methyl-2-phenyloxazole-4-yl-acetic
acid (4.0 g; 18 mmol) and concentrated HCl (2 mL) in MeOH
(60 mL) was heated at reflux overnight. Volatiles were
removed in vacuo; the residue was partitioned between H2O
and EtOAc. The organic phase was washed with brine,
dried (MgS04) and concentrated in vacuo to give crude Part
A compound as a colorless oil (4.00 g/ 94%) which was
used in the next step without further purification.
B.
(Figure Removed)
To a -78°C solution of LDA (15.0 mL of a 2.0 M
solution in heptane/THF; 30 mmol; Aldrich) were
successively added dropwise a solution of Part A compound
(2.3 g; 10 mmol) in THF (6 mL) and HMPA (500 JJ.L; 2.9
mmol) . The solution was stirred at -78°C for 30 min,
after which methyl iodide (1.87 mL; 30 mmol) was added
dropwise. The solution was stirred at -78°C for 1 h,
then was allowed to warm to 0°C and stirred at 0°C for 1
h. The reaction solution was partitioned between
saturated aqueous NH4C1 and EtOAc. The aqueous phase was
extracted with EtOAc (2 x 50 mL). The combined organic
extracts were dried (MgS04) and concentrated in vacuo to
give crude Part B compound (1.90 g; 78%) as a colorless
oil, which was used in the next step without further
purification.
C.
To a -78°C solution of LDA (7.0 mL of a 2.0 M in
heptane/THF; 14 mmol; Aldrich) were successively added
dropwise a solution of Part B compound (1.8 g/ 7.3 mmol)
in THF (5 mL) and HMPA (500 uL; 2.9 mmol) . The solution
was stirred at -78°C for 1 h, then a solution of methyl
iodide (l mL; 11 mmol) was added dropwise. The solution
was stirred at -78°C for 1 h, then was allowed to warm to
0°C and stirred at 0°C for 1 h. The reaction solution was
then partitioned between saturated aqueous NH4C1 and
EtOAc. The aqueous phase was extracted with EtOAc (2 x
50 mL) . The combined organic extracts were dried (MgSO4)
and concentrated in vacuo. The crude product was
combined with the product from another reaction (from 670
mg of Part B compound) and chromatographed (Si02; 9:1
hexane:EtOAc) to give Part C compound (2.60 g; 95%) as a
colorless oil.
D.
(Figure Removed)
To a -78°C solution of Part C compound (1.2 g; 4.63
mmol) in THF (3 ttiL) under an atmosphere of N2 was added
dropwise a solution of LiAlH4 (1.0 mL of a 1.0 M solution
in THF). The reaction was stirred at -78°C for 1 h, then
was allowed to warm to 0°C and stirred at 0°C for 30 min.
The reaction was quenched by cautious addition of 1M
aqueous potassium sodium tartrate followed by H20. The
aqueous phase was extracted with EtOAc. The combined
organic extracts were washed with H20, dried (MgS04) and
concentrated in vacuo to give crude Part D compound (1.01
g; 94%) as an oil, which was used in the next step
without further purification.
E.
To an 80°C solution of Part D compound (700 mg; 3.0
mmol), Ph3P (1.2 g; 4.6 mmol) and 4 -hydroxybenz aldehyde
(406 mg; 3.3 mmol) in THF (10 mL) was added DEAD (720 JJ.L;
mmol) in two portions over 5 min. The solution was
stirred at 80°C for 1 h (starting material still
remained), then was concentrated in vacuo. The residue
was chromatographed (Si02; stepwise gradient from 9:1 to
5:1 hexane : EtOAc ) to give Part E compound (160 mg; 16%) .
F.
A solution of Part E compound (250 mg; 0.75 mmol) ,
glycine methyl ester hydrochloride (141 mg; 1.13 mmol)
and Et3N (157 (J.L; 1.13 mmol) in MeOH (30 mL) was stirred
at RT overnight. Excess solid NaBH4 was added cautiously;
the reaction was stirred at RT for 1 h, then concentrated
in vacuo. The residue was partitioned between H20 and
EtOAc. The organic phase was washed with brine, dried
(MgS04) and concentrated in vacuo to give crude Part F
compound (300 mg; 98%) which was used in the next
reaction without further purification.
G.
(Figure Removed)
To a 0°C solution of Part F compound (150 mg; 0.37
mmol) and Et3N (51 fiL; 0.37 mmol) in CH2C12 (5 mL) was
added 4-methoxyphenyl chloroformate (55 fiL; 0.37 mmol) .
The reaction was allowed to warm to RT and stirred at RT
for 2 h. Volatiles were removed in vacuo and the residue
was chromat ographe d (SiCX; 5:1 hexane:EtOAc) to furnish
Part G compound (130 mg; 63%).
H.
OCH3
A solution of Part G compound (130 mg) and LiOH.H2O
(39 mg) in H20/THF/MeOH (2 mL of a 1:2:2 mixture) was
stirred at RT for 2 h. Volatiles were removed in vacuo,
and the residue was acidified with 1.0 M aqueous HCl,
then extracted with EtOAc. The organic phase was dried
(Na2SO4) and concentrated in vacuo to give a residue,
which was purified by preparative HPLC (YMC S5 ODS
reverse phase CIS, 30-x 250 mm column; flow rate = 25
mL/min; continuous gradient from 50% A:B to 100% B over
20 min, where solvent A = 90:10:0.1 H2O:MeOH:TFA, B =
90:10:0.1 MeOH:H20:TFA) , then lyophilized from dioxane to
give the title compound (58 mg; 46%) as a white
lyophilate. [M + H]+ = 545.4
Example 544
OCH3
CO2H
Title compound was prepared in analogous fashion to
Example 543 except that 3 -hydroxybenz aldehyde was used
instead of 4-hydroxybenzaldehyde (in the preparation of
Example 543 Part E compound) . [M + H]+ = 545.4
545
A.
(Figure Removed)
A mixture of the acetylene (38 mg; 0.065 tnmol)
I -r N ^CO2t-Bu
O' ^
OCH3
(synthesized in a completely analogous fashion to Example
542 Part G compound with glycine tert-butyl ester
hydrochloride instead of glycine methyl ester
hydrochloride), guinoline (80 mg; 0.62 mmol) and
Lindlar's catalyst (8 mg; Pd/CaC03; Aldrich) in MeOH (8
mL) was stirred under an atmosphere of H2 at 0°C for 20
min. Additional Lindlar's catalyst (8 mg; Pd/CaC03;
Aldrich) was then added and stirring was continued under
an atmosphere of H2 at 0°C for 25 min, after which
reaction was complete. The mixture was filtered, and the
filtrate was concentrated in vacuo. The residue was
purified by preparative HPLC (YMC S5 ODS 20 x 100 mm
column; flow rate = 20 mL/min; continuous 20 min gradient
from 80:20 B:A to 100% B, where A = 90:10:0.1 H2O:MeOH:TFA
and B = 90:10:0.1 MeOH:H2O:TFA) to give Part A compound
(22 mg; 56%) as a colorless oil.
B.
(Figure Removed)
To a solution of Part A compound (3 mg; 0.005 mmol)
in CH2C12 (0.5 mL) was added dropwise TFA (0.25 mL) and
the reaction was stirred for 2 h at RT. Volatiles were
removed in vacuo; the residue was dissolved in CDC13/
- 267 -
filtered through a cotton plug and concentrated in vacuo
to give the title compound (1.5 mg; 55%) as a colorless
oil. [M + Na]+ = 551.0
Following procedures set out above, Examples 546 to
556 compounds were prepared.
Examples 546 to '556
CH3 ^CO2H
Example No. Structure [M+H]
(Figure Removed)
Example No. Structure [M+H]
556 511.4
Examp]g 555
N^.CO2H
A mixture of the mesylate (124 mg; 0.43 mmol) ,
OSO2CH3
3-hydroxybenzaldehyde (62 mg; 0.51 mmol) and K2C03 (94 mg;
0.68 mmol) in CH3CN (10 mL) were heated at 70°C for 48 h.
The reaction was cooled to RT, EtOAc was added, and the
mixture was washed with aq 1M NaOH and brine. The
organic phase was dried (Na2SO4) and concentrated in
vacuo. The residue was chroma t ographed (SiO2; hex:EtOAc
4:1) to give Part A compound (71 mg; S2%) as a colorless
oil. [M + H]+ = 318.2
(Figure Removed)
To a mixture of Part A compound (71 mg; 0.22 mmol),
glycine.HCl (140 mg; 1.11 mmol) and Et3N (0.3 mL; 2.16
mmol) in 1,2 dichloroethane (10 mL) was added NaBH(OAc)3
(150 mg). After stirring at RT for 16 h (reaction
incomplete), more NaBH(OAc)3 (150 mg) was added. A final
addition of NaBH(OAc)3 (150 mg; in total 2.12 mmol) was
made after another 3 h and the reaction stirred for 48 h
at RT. The reaction was complete at this point;
saturated aqueous NaHCO3 was added and the aqueous phase
was extracted with CH2C12 (2x) . The combined organic
extracts were washed with brine, dried (Na2S04) and
concentrated in vacuo. The residue was chromatographed
(Si02; hex.-EtOAc = 4:6) to give Part B compound (81 mg;
93%) as a colorless oil.
c.
OCH3
To a solution of Part B compound (10 mg; 0.026
mmol) in CH2C12 (2 mL) were successively added pyridine
(10 p.L; 0.12 mmol) and 4-methoxypheny 1 chloroformate (10
^L; 0.067 mmol) (each in 0.1 mL CH2C12) . The reaction was
stirred at RT for 16 h, then partitioned between aqueous
IN HC1 and EtOAc. The organic phase was washed, with
brine, dried (Na2S04) , and concentrated in vacuo. The
residue was purified by preparative HPLC (YMC S5 ODS 30 x
- 271 -
75 mm column, flow rate =20 mL/min; continuous gradient
from 70:30 A:B to 100% B, where solvent A = 90:10:0.1
H20:MeOH:TFA and solvent B = 90:10:0.1 MeOH:H20:TFA) to
give Part C compound (9 mg; 65%).
D.
(Figure Removed)
A solution of Part C compound (9 mg; 0.017 mmol) in
2:1 THF:H20 (3 mL) was added LiOH (6 mg; 0.14 mmol). The
solution was stirred at RT for 4 h, then acidified with
excess 1M HCl (aq) . The solution was extracted with
EtOAc (2x5 mL). The combined organic extracts were
washed with brine, dried (Na2SO4) , and concentrated in
vacuo. The crude product was purified by preparative
*.
HPLC using the same conditions as above to give title
compound (6 mg; 68%) as a colorless film.
[M + H]+ = 527.2
Title compound was synthesized using the same
sequence as Example 555 compound from Example 555 Part B
compound. Acylation with 4-methyl chlorof ormate (67%
after HPLC purification) followed by LiOH hydrolysis
furnished title compound (5 mg; 57% after HPLC
purification). [M + H]+ = 511.4
Examp]P 557
A.
A solution of 2-amino-5-cresol (5.0 g/ 40 mmol) ,
KOH (3.2 g; 57 mmol) was refluxed in EtOH (50 mL) and CS2
(40 tnL) for 8 h, after which the reaction mixture was
concentrated in vacuo. The residue was partitioned
between aq 1M HCl (100 mL) and EtOAc (200 mL) . The
organic phase was washed with water (2 x 100 mL), dried
(MgSO4) and concentrated in vacuo to give Part A compound
(4.0 g; 60%) as a white powder.
B.
A solution of Part A compound (3.2 g; 19 mmol) and
PC15 (3.75 g; 19 mmol) in toluene (150 mL) was heated at
reflux for 2 h. The reaction mixture was washed
successively with water and aqueous NaHC03/ then dried
(Na2S04) and concentrated in vacuo to give Part B compound
(4.0 g) as a crude oil. This material was used in the
next step without further purification.
(Figure Removed)
A solution of the 1,3 benzyl glycine aminoester
(150 mg; 0.39 mmol), Part B compound (100 mg; 0.59 mmol)
and triethylamine (0.2 mL; 1.98 mmol) in THF (5 mL) was
heated at 100°C in a sealed tube for 4 days. At this
point LC/MS showed that all starting material had been
consumed. Aqueous LiOH (0.5 mL of a 1 M solution) was
added and the solution was stirred at RT for 5 h. The
mixture was concentrated in vacuo to give an oil, which
was purified by preparative HPLC (as for Example 495) to
give the title compound (72 mg; 37%) as a solid.
Example 55 fi
A solution of the 1,4 benzyl glycine aminoester (50
mg; 0.13 mmol), Example 557 Part B compound (100 mg; 0.59
mmol) and triethylamine (0.2 mL; 1.98 mmol) in THF (5 mL)
was heated at 100°C in a sealed tube for 4 days. At this
point LC/MS showed that all starting material had been
consumed. Aqueous LiOH (0.5 mL of a 1 M solution) was
added and the solution was stirred at RT for 5 h. The
mixture was concentrated in vacuo to give an oil, which
was purified by preparative HPLC (as for Example 495) to
give the title compound (26 mg; 40%) as a solid.
Example
(Figure Removed)
To a solution of methyl propionylacetate (4.6 g, 35
mmol) in CHC13 (40 mL) was added dropwise a solution of
Br2 (5.6 g; 35 mmol) in CHC13 (10 mL) and the resulting
mixture was stirred at 0°C for, 0.5 h. The reaction was
allowed to warm to RT and then air was bubbled into the
mixture for 1 h. Volatiles were then removed in vacuo to
yield an oily residue, which was partitioned between
EtOAc (100 mL) and saturated aqueous NaHCO3. The organic
phase was washed with brine, dried (MgS04) and
concentrated in vacuo to provide crude Part A compound
(7.4 g, >95% yield; >90% purity) as an oil which was used
in the next reaction without further purification.
B.
A mixture of Part A compound (1.5 g, 7.2 mmol) and
4-methoxybenzamide (1.0 g, 6.6 mmol) was heated at 100°C
for 2.5 h. The reaction mixture was chromatographed
(Si02; 5% acetone/CH2C!2) to yield Part B compound (0.57
g, 33%).
C.
To a solution of the ester (0.57 g, 2.3 mmol) in THF
(10 mL) was added LiAH4 (2.5 mL of a 1 M solution in THF,
2.5 mmol) dropwise over 10 min and the reaction was
stirred at RT for 0.5 h. The reaction was quenched by
adding a few drops of water and then partitioned between
EtOAc (50 mL) and brine (10 mL) . The organic phase was
dried (MgS04) and concentrated in vacuo to give Part C
(0.52 g, >95%) as an oil which was used in the following
reaction without further purification.
A mixture of Part C compound (0.52 g, 2.3 mmol),
CH3SO2C1 (0.25 ml, 3.3 mmol) and Et3N (0.5 ml, 3.6 mmol)
in CH2C12 (10 mL) was stirred at RT for 12 h. Volatiles
were removed in vacuo, and the residue was
chroma t ogr aphed (Si02; 4% acetone/CH2C!2) to provide Part
D compound (0.61 g, 85% for 2 steps) as a colorless oil.
E.
To a mixture of crude Example 541 Part C compound
(synthesized using 4 -hydroxybenz aldehyde [2.0 g; 16 mmol]
and glycine methyl ester hydrochloride [2.3 g; 18 mmol])
in dioxane:H2O (100 mL of a 1:1 mixture) were successively
added NaHC03 (2.5 g; 30 mmol; in one portion) and 4-
methoxyphenyl chloroformate (2.0 mL; 14 mmol) dropwise.
The reaction was stirred at RT for 12 h and then
extracted with EtOAc (4 x 150 mL) . The combined organic
extracts were dried (MgS04) and concentrated in vacuo.
The residue was chromatographed (Si02; 3% acetone/CH2Cl2)
to provide Part E compound (2.4 g; 44%) as a colorless
oil .
P.
(Figure Removed)
A mixture of Part E compound (86 mg, 0.25 mmol) ,
Part D compound (60 mg, 0.20 mmol) and K2CO3 (50 mg, 3.7
mmol) in DMF (3 mL) was heated at 80°C for 12 h. The
reaction was cooled to RT and filtered. Volatiles were
removed in vacuo and the residue was chromatographed
(SiO2; 7:3 hexane :EtOAc) to provide title compound (41 mg;
36%) as a colorless oil.
G.
(Figure Removed)
A solution of Part F 'compound (41 mg, 0.071 mmol)
and LiOH.H20 (34 mg; 0.8 mmol) in THF-H2O (2 mL of a 2:1
mixture) was stirred at RT for 2 h. The reaction mixture
was acidified to pH ~ 2 with 1 M aqueous HC1, then was
extracted with EtOAc . The combined organic extracts were
concentrated in vacuo and the residue was purified by
preparative HPLC (YMC S5 ODS 30 x 250 mm column; flow
rate = 25 mL/min; 30 min continuous gradient from 50%
A:50% B to 100% B, where solvent A = 90:10:0.1
H2O:MeOH:TFA and solvent B = 90:10:0.1 MeOH : H2O : TFA) to
provide title compound (17 mg, 40%) as a colorless oil.
[M + H]+ = 547.23
Example
A.
OCH3
A mixture of the mesylate (18 mg; 0061 mmol)
the ester,
[described in the synthesis of Example 503 Part B
compound (50 mg/ 0.13 mmol)], K2C03 (17 mg; 0.34 mmol) in
CH3CN (1 mL) were heated at 70°C for 24 h. Additional
K2C03 (30 mg) and CH3CN (1 mL) were added and the mixture
was heated at 75°C for another 48 h. The reaction was
cooled to RT, EtOAc was added, and the mixture was washed
with ag 1M NaOH and brine. The organic phase was dried
(Na2S04) and concentrated in vacuo to give the crude
product. This was purified by preparative HPLC (YMC S5
ODS 50 x 75 mm column; continuous gradient from 70:30 B:A
to 100% B, where A = 90:10:0.1 H20:MeOH:TFA and B =
90:10:0.1 MeOH:H20 :TFA) to give Part A compound (13 mg;
35%) as a colorless oil.
B.
OCH3
To a solution of Part A compound (12 mg; 0.021
mmol) in 2:1 THF:H20 (1.5 mL) was added LiOH (8 mg; 0.19
mmol) . The solution was stirred at RT for 24 h, then
acidified with excess 1M HCl (aq) . The solution was
extracted with EtOAc (2x5 mL) . The combined organic
extracts were washed with brine, dried (Na2S04) , and
concentrated in vacuo. The crude product was purified by
preparative HPLC using the same conditions as above to
give title compound ( 6 . 4 mg) as a colorless film.
[M + H]+ = 541.3
Example 561
A.
OCH3
OCH3
A mixture of the mesylate (18 mg; 0061 mmol)
Ph- OCH3
K2C03 (17 mg; 0.34 mmol) in CH3CN (1 mL) were heated at
70°C for 24 h. Additional K2C03 (30 mg) and CH3CN (1 mL)
were added and the mixture was heated at 75°C for another
48 h. The reaction was cooled to RT, EtOAc was added,
and the mixture was washed with ag 1M NaOH and brine.
- 280 -
The organic phase was dried (Na2SO4) and concentrated in
vacuo to give the crude product. This was purified by
preparative HPLC (YMC 55 ODS 50 x 75 mm column;
continuous gradient from 70:30 B:A to 100% B, where A =
90:10:0.1 H20:MeOH:TFA and B = 90:10:0.1 MeOH :H2O: TFA) to
give Part A compound (13 mg; 35%) as a colorless oil.
B.
To a solution of Part A compound (12 mg; 0.021 mmol)
in 2:1 THF:H2O (1.5 mL) was added LiOH (8 mg; 0.19 mmol) .
The solution was stirred at RT for 24 h, then acidified
with excess 1M HCl (ag) . The solution was extracted with
EtOAc (2x5 mL). The combined organic extracts were
washed with brine, dried (Na2S04) , and concentrated in
vacuo. The crude product was purified by preparative
HPLC using the same conditions as above to give title
compound. [M + H]+ = 541.3
Example 562
(Figure Removed)
A solution of 4-iodobenzaldehyde (1.0 g; 4.31 mmol)
and glycine methyl ester hydrochloride (0.65 g; 5.17
mmol) and Et3N (0.50 g/ 4.95 mmol) in MeOH (15 mL) was
stirred at RT for 4 h. The mixture was cooled to 0°C and
a solution of NaBH4 (230 mg; 6.0 mmol) in MeOH was added
portionwise. The mixture was allowed to warm to RT and
stirred overnight at RT. Volatiles were removed in vacuo
(without heating) and the residue was partitioned between
aq NaHCO3 and EtOAc. The aqueous phase was extracted with
EtOAc (3x). The combined organic extracts were dried
(Na2S04) and concentrated in vacuo to give Part A compound
as an oil. This material was used in the next step
without further purification.
B.
To a solution of the crude Part A compound and Et3N
(0.80 g; 8.00 mmol) in CH2C12 was added a solution of 4-
methoxyphenyl chloroformate (0.93 g; 5.00 mmol) in CH2C12-
The reaction mixture was stirred at RT overnight, then
partitioned between saturated aq NaHCO3 and EtOAc. The
aqueous phase was extracted with EtOAc (2x) ; the combined
organic extracts were dried (Na2S04) and concentrated in
vacuo to give a residue, which was chromatographed (SiO2;
hex:EtOAc 3:1) to give Part B compound (1.2 g; 61%) as an
oil.
C.
To a 0°C solution of DL-propargyl glycine (3.0 g;
26.5 mmol) in pyridine (20 mL; 247 mmol) was added
dropwise benzoyl chloride (3.73 g; 26.5 mmol). The
solution was allowed to warm to RT and stirred at RT for
1 h. Acetic anhydride (10 mL) was added and the mixture
was stirred at 90°C for 2 h. The reaction mixture was
diluted with H20 (35 mL) and extracted with EtOAc (3x) ;
the combined organic extracts were washed with aqueous IN
HCl, H2O, aqueous NaHCO3, and finally water. The organic
phase was dried (Na2SO4) and concentrated in vacuo. The
crude product was chromatographed (SiO2; stepwise gradient
from 5:1 to 3:1 hex:EtOAc) to give Part C compound (1.0
g; 17%) as an orange solid.
D.
A solution of Part C compound (1.0 g; 4.65 mmol),
trifluoroacetic anhydride (3 mL) and TFA (3 mL) in a
sealed tube was heated at 40°C for 8 h. Volatiles were
removed in vacuo and the residue was dissolved in EtOAc
(50 mL) . The solution was washed repeatedly with
saturated aq NaHC03 (until all acid had been removed from
the organic phase) , then brine, dried (Na2S04) and
concentrated in vacuo. The residue was chromatographed
(Si02; 6:1 hex:EtOAc) to give Part D compound (800 mg;
87%; >98% pure by HPLC) as an oil.
E.
(Figure Removed)
A mixture of Part D compound (100 mg; 0.507 mmol),
Part B compound (254 mg; 0.558 mmol), Cul (2 mg; 0.01
mmol) and (Ph3P)2PdCl2 (4 mg; 0.005 mmol) in diethylamine
(2 mL) was stirred at RT for 3h under N2. At this point
HPLC/MS showed that all starting material had been
consumed and the presence of a peak which corresponded to
the desired product. The reaction mixture was filtered
and the filtrate was concentrated in vacuo. The residue
was chromatographed (Si02; stepwise gradient from 5:1 to
2:1 hex:EtOAc) to provide Part E compound (200 mg; 75%)
as an oil.
F.

A solution of. Part E compound (20 mg; 0.038 mol) in
HOAc/conc HC1 (1 mL of a 10:1 solution) was stirred at
45°C overnight. Volatiles were removed in vacuo and the
residue was purified by preparative HPLC (YMC S5 ODS
reverse phase column; 30 x 250 mm; flow rate = 25 mL/min;
30 min continuous gradient from 50:50 A:B to 100% B,
where solvent A = 90:10:0.1 H2O:MeOH:TFA and solvent B =
90:10:0.1 MeOH:H20:TFA) to give the title compound (6.8
mg; 35%) as a lyophilate. [M + H] + = 511.2
Exampl P
(Figure Removed)
(38 mg; 0.072 mmol) in MeOH (5 mL) was stirred under an
atmosphere of H2 in the presence of 10% Pd/C catalyst (10
mg) at RT for 2 h. The catalyst was filtered off and the
filtrate was concentrated in vacuo to give Part A
compound (35 mg; 92%) as an oil.
B.
(Figure Removed)
A solution of Part A compound (35 mg; 0.066 mmol)
in aqueous LiOH (1 mL of a 1M solution) and THF (5 mL)
was stirred at RT for 2h. The reaction was acidified to
pH 3 with excess aqueous 1M HCl and extracted with EtOAc
(2x5 mL) . The combined organic extracts were dried
(Na2SO4) and concentrated in vacuo. The residue was
purified by preparative HPLC (YMC S5 ODS reverse phase
column; 30 x 250 mm; flow rate = 25 mL/min; 30 min
continuous gradient from 50:50 A:B to 100% B, where
solvent A = 90:10:0.1 H20:MeOH:TFA and solvent B =
- 285 -
90:10:0.1 MeOH:H20:TFA) to give, after lyophilization from
dioxane, the title compound (31 mg; 87%) as a white
solid. [M + H]+ = 515.9
Example 564
OCH3
A solution of Example 562 Part E compound
"N^CO2CH3
N-^X^^v^ o^O
OCH3
(20 mg/ 0.038 mmol) and aqueous LiOH (1 mL of a 1 M
solution; 1 mmol) in THF (2 mL) was stirred at RT for 2
h. The reaction mixture was acidified with excess
aqueous 1 M HCl and extracted with EtOAc. The combined
organic extracts were concentrated in vacuo. The residue
was purified by preparative HPLC ( (YMC S5 ODS reverse
phase column; 30 x 250 mm; flow rate = 25 mL/min; 30 min
continuous gradient from 50:50 A:B to 100% B, where
solvent A = 90:10:0.1 H20:MeOH:TFA and solvent B =
90:10:0.1 MeOH:H20:TFA) to give (9 mg; 46%) as a white
solid. [M + H]* = 511.2
(Figure Removed)
A mixture of Example 562 Part E compound
(80 mg; 0.15 mmol) , quinoline (2 }J,L; 0.01 mmol) and
Lindlar's catalyst (7 mg; 5% Pd/CaC03) in toluene (2 mL)
was stirred under an atmosphere of H2 for 2 h. More
Lindlar's catalyst (20 mg) was then added and stirring
was continued under H2 for another 2 h, after which the
reaction was complete by analytical HPLC. The reaction
mixture was filtered (Celite®) and the filtrate was
concentrated in vacuo. The residue was c hr oma t ogr aphe d
(Si02; stepwise gradient from 3:1 to 2:1 hexane: EtOAc) to
give Part A compound.
B.
OCH3
A solution of Part A compound and aqueous LiOH (1 mL
of a l M solution; 1 mmol) in THF was stirred at RT
overnight. The reaction mixture was acidified with
excess aqueous 1 M HCl and extracted with EtOAc (2x) .
The combined organic extracts were concentrated in vacuo .
The residue was purified by preparative HPLC (as for
Example 495) to give the title compound (14 mg; 18%) as a
white solid. [M + H] + = 513.3
Example 566
A.
(Figure Removed)
To a 0°C solution of Example 565 Part A compound
OCH3
(60 mg; 0.11 mmol) in DCE (3 mL) was added dropwise
diethylzinc (43 uL; 0.29 mmol) . The solution was stirred
at 0°C for 10 min and iodochloromethane (244 jiL; 0.57
mmol) was then added. The reaction was allowed to warm
to RT and stirred at RT for 3 h, then was cautiously
quenched by addition of aqueous HCl (1 mL of a 1- M
solution) . The aqueous layer was extracted with EtOAc
(2x) ; the combined organic extracts were dried (Na2S04)
and concentrated in vacuo. The residue was
chroma tographed (Si02; stepwise gradient from 3:1 to 2:1
hexane:EtOAc) to give crude Part A compound, which was
used in the next step without further purification.
B.
A solution of crude Part A compound and aqueous
LiOH (1 mL of a 1 M solution; 1 mmol) in THF was stirred
at RT overnight. The reaction mixture was acidified with
excess aqueous 1 M HCl and extracted with EtOAc. The
combined organic extracts were concentrated in vacuo.
The residue was purified by preparative HPLC (conditions)
to give the title compound (7 mg/ 12% over 2 steps) as a
white solid. [M + H]+ = 527.2.
Example 567
OCH3
A.
O^CH3 ph-4 T ,
N-^^^i Br
A mixture of Example 562 Part D compound
Ph- (300 mg; 1.52 mmol) , N-bromo-succinimide (297 mg; 1.67
mmol) and AgNO3 (28 mg; 0.19 mmol} in acetone (2 mL) was
stirred at RT for 30 min. The mixture was filtered and
the filtrate was concentrated in vacuo. The residue was
chromatographed (Si02; hexanerEtOAc 5:1) to give Part A
compound (320 mg; 76%) as yellow crystals.
B.
N-"\"-
H
To a solution of Part A compound (320 mg; 1.2
mmol), Ph3P (13 mg; 0.05 mmol) and Tris (dibenzylideneacetone)
dipalladium(0) (5 mg; 0.006 mmol) in THF (1 mL)
was added Bu3SnH (700 )J.L; 2.5 mmol) dropwise under an
atmosphere of N2. The mixture was stirred at RT for 2 h,
then was quenched by addition of aqueous KF (7 mL of a 1
M solution) . The mixture was stirred vigorously
overnight, then extracted with EtOAc (2x) . The combined
organic extracts were washed with H20, dried (Na2S04) and
concentrated in vacuo. The residual oil was
chromatographed (Si02; hexane:EtOAc 3:1) to give Part B
compound (200 mg; 35%) as an oil. In addition, the
byproduct vinyl compound
(Figure Removed)
A solution of Part B compound (100 mg/ 0.020 mmol)
and Example 562 Part B compound
N CO2CH3
0^0
OCH3
(100 mg; 0.22 mmol) and (Ph3P)4Pd° (3 mg; 0.002 mmol) in
toluene was heated at 100°C overnight under an atmosphere
of N2. Volatiles were removed in vacuo and the residue
was chromatographed (Si02; stepwise. gradient from 3:1 to
2:1 hexane:EtOAc) to give Part C compound.
D.
A solution of crude Part C compound (in aqueous
LiOH (1 mL of a 1M solution) and THF (5 mL) was stirred
at RT overnight. The reaction was acidified to pH 3 with
excess aqueous 1 M HCl and extracted with EtOAc (2x5
mL) . The combined organic extracts were dried (Na2S04)
and concentrated in vacuo. The residue was purified by
preparative HPLC (YMC S5 ODS reverse phase column; 30 x
250 mm; flow rate = 25 mL/min; 30 min continuous gradient
from 50:50 A:B to 100% B, where solvent A = 90:10:0.1
H2O:MeOH:TFA and solvent B = 90:10:0.1 MeOH: H20: TFA) to
give, after lyophilization from dioxane, title compound
(23 mg; 20%) as a white solid. [M + H]+ = 513.3
Examples 568 to 572
Following the procedures set out hereinbefore and
in the working Examples, the following compounds were
prepared.
Example No Structure [M-J-H]
(Figure Removed)
To a mixture of the amino-ester (27 mg; 0.073 mmol)
5-methyl-2-phenyl-thiazol-4-yl-ethanol (25 mg; 0.11 mmol;
Maybridge) resin-bound Ph3P (27 mg; 0.081 mmol) in CH2C12
( 0 .5 mL) was added DEAD (20 |4.L; 0.13 mmol) . The reaction
was stirred at RT for 6 h, then was filtered. The
filtrate was concentrated in vacuo and the residue was
purified by preparative HPLC (YMC S5 CDS 30 x 100 mm
column; flow rate = 50 mL/min; continuous gradient from
30:70 B.-A to 100% B, where solvent A = 90:10:0.1
H2O:MeOH:TFA and solvent B = 90:10:0.1 MeOH:H2O : TFA) to
furnish. Part A compound.
B.
CO2H
A solution of Part A compound in TFA (1 mL) was
stirred at RT overnight, then was concentrated in vacuo
to furnish title compound (11 mg; 26%) as a brown oil
(94% purity by analytical HPLC). [M + H]+ = 517.2
A.
To a mixture of the amino-ester (31 mg; 0.082 mmol)
5-methyl-2-phenyl-thiazol-4-yl-ethanol (25 mg; 0.11 mmol;
Maybridge) resin-bound Ph3P (32 mg; 0.096 mmol) in CH2Cl2
(0.5 mL) was added DEAD (20 jaL; 0.13 mmol). The reaction
was stirred at RT for 6 h, then was filtered. The
filtrate was concentrated in vacuo to give crude Part A
compound.
B.
A solution of crude Part A compound and LiOH.H20
(20 mg; 0.48 raraol) in THF : MeOH : H2O (1 tnL of a 3:1:1
mixture) was stirred at RT overnight. The reaction was
acidified to pH ~4 with aqueous IN HCl, then was
extracted with EtOAc (2x) . The combined organic extracts
were concentrated in vacuo and the residue was purified
by preparative HPLC (YMC S5 CDS 30 x 100 mm column; flow
rate = 50 mL/min; 10 min continuous gradient from 30:70
B:A to 100% B, where solvent A = 90:10:0.1 H20: MeOH: TFA
and solvent B = 90:10:0.1 MeOH : H2O : TFA) to furnish title
compound (16 mg; 34%) as a brown oil (95% purity by
analytical HPLC) . [M + H]+ = 565.2
To a solution of 2,4-dibromo-3-pentanone (Avocado
Chemicals, 19.6 g, 80 mmol) in CH2C12 (50 mL) was added
dropwise Et3N (30 mL, 210 mmol) over 30 min; th.e resulting
solution was heated to reflux for 12 h. The. reaction
mixture was cooled to RT, then was poured into ice and
- 295 -
acidified with concentrated HCl. The organic phase was
concentrated in vacuo to give an oil, which was
fractionally distilled (b.p. = 42°-45°C at 13 mm Hg) to
give Part A compound (6.0 g, 46%; with ~20% of the
starting material) as an oil.
B.
N CO2CH3
0^0
OCH3
A mixture of Example 559 Part E compound (0.60 g,
1.7 mmol),
OCH3
Part A compound (0.60 g, 3.7 mmol) and K2CO3 (1.0 g, 7.3
mmol) in benzene (20 tnL) was stirred at RT for 12 h. TLC
at this point indicated that ~50% of the starting
material had been consumed and that the reaction had
stalled. The reaction mixture was filtered and the
filtrate was concentrated in vacuo. The residue was
chroma tographed (Si02; 3% acetone/CH2C!2) to provide Part
B compound (0.41 g; 47%) as an oil.
C.
(Figure Removed)
A solution of Part B compound (40 mg, 0.080 mmol)
and thioisonicotinamide (50 mg, 0.36 mmol) in toluene-
EtOH (3 mL of a 1:1 mixture) was heated at 55°C for 12 h.
The reaction was cooled to RT and volatiles were removed
in vacuo. The crude product was purified by preparative
HPLC (YMC S5 ODS 30 x 250 mm, continuous 30 min gradient
from 30% B:70% A to 100% B at 30 min, where solvent A =
90:10:0.1 H2O:MeOH:TFA and solvent B = 90:10:0.1
MeOH:H20:TFA) to give Part C compound (17; 39%) as an oil
D.
OCH3
A solution of Part C compound (17 mg, 0.031 mmol)
and LiOH.H20 (40 mg, 1 mmol) in THF-H20 (3 mL of a 2:1
mixture) was stirred at RT for 2 h. The reaction mixture
was acidified by addition of acetic acid and then
partitioned between H2O (2 mL) and EtOAc (5 mL) . The
organic phase was dried (MgS04) and concentrated in vacuo
to provide the title compound (13.7 mg, 81%) as a white
solid. [M + H]+ = 534.2
Examples 576 to 580
Following the procedures set out hereinbefore and
in the working Examples,•the following compounds were
prepared.
Example No. Structure [M+H] *
576 551.2; 553.2
OCHj
577
HjCO
547.2
OCHj
578
CHj
531.2
N O
C02H
579 535.2; 537.2
CI
580 551.2; 553.2
. OCH,
- 298 -
Examples 581 and 582 were synthesized according to
the general procedures described for Examples 313 and
314.
Example Structure [M+Hf
581 499.2
582 499.1
Examples 583 and 584 were synthesized according to
the general methods described hereinbefore (e.g. for
Example 139) using 4-methoxy thiophenol.
Example Structure
583
OCH3
533.3
584
OCHj
533.3
- 299 -
Example 584
OCH3
*H NMR (CDC13; 400 MHz) : 6 2.42 (s, 3H) , 3.04 (br s; 2H) ,
3.79 (s, 3H), 4.03 (br s, 2H), 4.25 (br s, 2H), 4.70 (br
s, 2H), 6.8-7.0 (m, 5H), 7.15-7.30 (m, 1H), 7.35-7.50 (m,
5H), 7.95-8.05 (m, 2H); 8.95 (br s, 1H)






We claim;
1. A heterocyclic phenyl or pyridyl amino acid compound of the structure
(Formula Removed)
wherein x is 1,2, 3or 4; la is 1 or 2; n is 1 or 2;
R2 is H, alkyl, alkoxy, halogen, amino or amino; substituted with one or two substituents, which may be the same or different, selected from alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl or
thioalkyl, whereby these substituents may be further substituted with a carboxylic acid and/or any of halo F3' alkoxy' aryl,Woxy, aryl(aryl)
or diaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amino, hydroxy, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy, cycloheteroalkyl, arylheteroaryl, arylalkoxycarbonyl, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, nitro, cyano, thiol, haloalkyl,
trihaloalkyl and/or alkylthio and/or any of H, alkyl, arylalkyl, aryloxycarbonyl,
alkyloxycarbonyl, alkynyloxycarbonyl, alkenyloxycarbonyl, arylcarbonyl,. alkylcarbonyl, aryl, heteroaryl, alkyl(halo)aryloxycarbonyl, alkyloxy(halo)aryloxycarbonyj cycloalkylaryloxycarbonyl, cycloalkyloxyaryloxycarbonyl, cycloheteroalkyl, heteroarylcarbonyl, heteroaryl-heteroarylalkyl, alJcylcarbonylamino, arylcarbonylamino, heteroarylcarbonyland.no, alkoxycarbonyland.no, aryloxycarbonylamino, heteroaryloxycarbonylami.no, heteroaryl-heteroarylcarbonyl, alkylsulfonyl, alkenylsulfonyl, heteroaryloxycarbonyl, cycloheteroalkyloxycarbonyl, heteroarylalkyi, aminocarbonyl, substituted aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylalkenyl, cycloheteroalkylheteroarylalkyl, hydroxyalkyl, alkoxy, alkoxyaryloxycarbonyl, arylalkyloxycarbonyl, alkylaryloxycarbonyl, arylheteroarylalkyl, arylalkylarylalkyl, aryloxyarylalkyl, :alkynyloxycarbonvl, haloalkoxyaryloxycarbonyl, alkoxycarbonylaryloxycarbonyl, aryloxyaryloxycarbonyl/ arylsulfJLnylarylcarbonyl, arylthioarylcarbonyl, alkoxycarbonylaryloxycarbonyl, arylalkenyloxycarbonyl, heteroaryloxyarylalkyl, aryloxyarylcarbonyl, aryloxyarylalkyloxycarbonyl, arylalkenyloxycarbonyl, arylalkylcarbonyl, aryloxyalkyloxycarbonyl arylalkylsulfonyl,
arylthiocarbonyl, arylalkenylsulfonyl, hateroarylsulfonyl, arylsulfonyl, alkoxyarylalkyl, heteroarylalkoxycarbonyl, arylheteroarylalkyl, alkoxyarylcarbonyl, aryloxyheteroarylalkyl, heteroarylalkyloxyarylalkyl, arylarylalkyl,
..arylalkenylarylalkyl, aryla-lkoxyarylalkyl, arylcarbonylarylalkyl, alkylaryloxyarylalkyl, arylalkoxycarbonylheteroarylalkyl, heteroarylarylalkyl, arylcarbonylheteroarylalkyl, heteroaryloxyarylalkyl, arylalkenylheteroarylalkyl, arylaminoarylalkyl or aminocarbonylarylaiylalkyl; and, the amino substituents may be taken with a
nitrogen atom to which they are attached to form 1 -pyrrolidinyl, 1 -
piperidinyl, 1-azepinyl, 4-morpholinyl, 4-
thiaraorpholinyl, l--piperazinyl, 4-alkyl-l-piperazinyl, 4-arylalkyl-1-piperazinyl, 4-diarylalkyl-l-piperazinyl; 1-pyrrolidinyl, 1-piperidinyl, or 1-azepinyl, optionally substituted with al'kyl, alkoxy, alkylthio, halo, trifluoromethyl or hydroxy. R3 is aryloxycarbonyl, R4 is H or alkyl; wherein (CH2)x, (CH2)m or (CH2)n may also be
(Formula Removed)
and wherein aryl as employed herein alone or as part of another group refers to monocyclic and bicyclic aromatic groups containing 6 to 10 carbons in the ring portion and may optionally include one to three additional rings fused to a carbocyclic ring or a heterocyclic ring
and may be optionally substituted through available carbon atoms with 1, 2, or 3 groups selected from hydrogen, halo, haloalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl,- trifluoromethyl, trifluoromethpxy, alkynyl, cycloalkyl-alkyl, cycloheteroaikyl, cycloheteroalkyialkyl, aryl, heteroaryl, arylalkyl, -aryloxy, aryloxyalkyl, arylalkoxy, alkoxycarbonyl, arylcarbonyl, arylalkehyl, amindcarbonylaryl,' arylthiio, arylsulfinyl, arylazo, heteroarylalkyl,
heterbarylalkenyl, heteroarylheteroaryl, heteroaryloxy, • hydroxy, nitro, cyanb, am±nof substituted amino wherein, the amino. includes 1 or 2 substituents. which are. alkyl or ajyl , thiol, alkylthio, a-rylthio, heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl, arylcarbonyl, alkylaminocarbotiyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcaxbonylamino; arylcarbonylamino, .arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino or "
arylsulfonaminocarbonyl an4/or any oJhalo, CF3, alkoxy, aryl, aryloxy, aryl(aryl)
or diaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amino, hydroxy, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy, cycloheteroaikyl, arylheteroaryl, arylalkoxycarbonyl, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylaniino, nitro, cyano, thiol, haloalkyl, trihaloalkyl and/or alkylthio and/or any of
H, alkyl, arylalkyl, aryloxycarbonyl,
alkyloxycarbonyl, alkynyloxycarbonyl, alkenyloxycarbonyl arylcarbonyl,. alkylcarbonyl, aryl, heteroaryl, alkyl(halo)aryloxycarbonyl, alkyloxy(halo)aryloxycarbonyl cycloalkylaryloxycarbonyl, cycloalkyioxyaryloxycarbonyl ' cycloheteroalkyl, heteroarylcarbonyl, heteroaryl-heteroarylalkyl, alkylcarbonylamino, arylcarbonylanino heteroarylcarbonylamino, alkoxycarbonylamino,
aryloxycarbonylamino, heteroaryloxycarbonylamino, heteroaryl-heteroarylcarbonyl, alkylsulfonyl, alkenylsulfonyl, heteroaryloxycarbonyl, cycloheteroalkyloxycarbonyl, heteroarylalkyi, aminocarbonyl, substituted aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylalkenyl, cycloheteroalkylheteroarylalkyl, hydroxyalkyl, alkoxy, alkoxyaryloxycarbonyl, arylalkyloxycarbonyl, alkylaryloxycarbonyl, arylheteroarylalkyl, arylalkylarylalkyl, aryloxyarylalkyl, 'alkynyloxycarbonyl,
haloalkoxyaryloxycarbonyl, alkoxycarbonylaryloxycarbonyl, aryloxyaryloxycarbonyl, arylsulfinylarylcarbonyl, arylthioarylcarbonyl, alkoxycarbonylaryloxycarbonyl, arylalkenyloxycarbonyl, heteroaryloxyarylalkyl, aryloxyarylcarbonyl, aryloxyarylalkyloxycarbonyl, arylalkenyloxycarbonyl, arylalkylcarbonyl, aryloxyalkyloxycarbonyl arylalkylsulfonyl, arylthiocarbonyl, arylalkenylsulfonyl, . hateroarylsulfonyl, arylsulfonyl, alkoxyarylalkyl, heteroarylalkoxycarbonyl, arylheteroarylalkyl, alkoxyarylcarbonyl, aryloxyheteroarylalkyl, heteroarylalkyloxyarylalkyl, arylarylalkyl,
..arylalkenylarylalkyl, aryla-lkoxyarylalkyl, arylcarbonylary1alkyl, alkylaryloxyarylalkyl, arylalkoxycarbonylheteroarylalkyl, heteroarylarylalkyl, arylcarbonylheteroarylalkyl, heteroaryloxyarylalkyl, arylalkenylheteroarylalkyl, arylaminoarylalkyl or
aminocarbonylarylarylalkyl;
2. The compound as claimed in claim 1 wherein (CH2)x is alkylene, alkenylene.
3. The compound as claimed in claim 1 wherein
(Formula Removed)
R2 is H and R4 is H.
4. The compound as claimed in claim 1 wherein x is 2, m is 1, and n is 1.
5. The compound as claimed in claim 1 having the structure
(Structure Removed)
6 The compound as claimed in claim 1 having the structure
(Structure Removed)
7. The compound as claimed in claim 1 having the structure
(Structure Removed)
8. The compound as claimed in claim 1 having the structure
(Structure Removed)
9. The compound as claimed in claim 1 having the structure
(Structure Removed)
10. The compound as claimed in claim 1 having the structure


(Structure Removed)
11. The compound as claimed in claim 1 having the structure
(Structure Removed)
12. The compound as claimed in claim 1 having the structure
(Structure Removed)
13. The compound as claimed in claim 1 having the structure
(Structure Removed)
14. The compound as claimed in claim 1 having the structure
(Structure Removed)
15. The compound as claimed in claim 1 having the structure
(Structure Removed)
16. The compound as claimed in claim 1 having the structure
(Structure Removed)
17. The compound as claimed in claim 1 having the structure
(Structure Removed)
18. The compound as claimed in claim 1 having the structure
(Structure Removed)
19. The compound as claimed in claim 1 having the structure
(Structure Removed)
20. The compound as claimed in claim 1 having the structure
(Structure Removed)
21. The compound as claimed in claim 1 having the structure
(Structure Removed)
22. The compound as claimed in claim 1 having the structure
(Structure Removed)
23. The compound as claimed in claim 1 having the structure
(Structure Removed)
24. A pharmaceutical composition as and when prepared using a compound as
claimed in claim 1.

Documents:

IN-PCT-2002-00107-DEL-Abstract-(01-10-2008).pdf

IN-PCT-2002-00107-DEL-Abstract-(17-11-2008).pdf

in-pct-2002-00107-del-abstract.pdf

IN-PCT-2002-00107-DEL-Claims-(01-10-2008).pdf

IN-PCT-2002-00107-DEL-Claims-(17-11-2008).pdf

in-pct-2002-00107-del-claims.pdf

IN-PCT-2002-00107-DEL-Correspondence-Others-(01-10-2008).pdf

in-pct-2002-00107-del-correspondence-others.pdf

IN-PCT-2002-00107-DEL-Description (Complete)-(01-10-2008).pdf

IN-PCT-2002-00107-DEL-Description (Complete)-(17-11-2008).pdf

in-pct-2002-00107-del-description (complete).pdf

IN-PCT-2002-00107-DEL-Form-1-(01-10-2008).pdf

in-pct-2002-00107-del-form-1.pdf

in-pct-2002-00107-del-form-18.pdf

IN-PCT-2002-00107-DEL-Form-2-(01-10-2008).pdf

in-pct-2002-00107-del-form-2.pdf

IN-PCT-2002-00107-DEL-Form-3-(01-10-2008).pdf

in-pct-2002-00107-del-form-3.pdf

in-pct-2002-00107-del-form-5.pdf

IN-PCT-2002-00107-DEL-GPA-(01-10-2008).pdf

in-pct-2002-00107-del-gpa.pdf

IN-PCT-2002-00107-DEL-Others-Document-(01-10-2008).pdf

in-pct-2002-00107-del-pct-101.pdf

in-pct-2002-00107-del-pct-202.pdf

in-pct-2002-00107-del-pct-210.pdf

in-pct-2002-00107-del-pct-220.pdf

IN-PCT-2002-00107-DEL-PCT-304-(01-10-2008).pdf

in-pct-2002-00107-del-pct-401.pdf

IN-PCT-2002-00107-DEL-Petition-137-(01-10-2008).pdf

IN-PCT-2002-00107-DEL-Petition-138-(01-10-2008).pdf

IN-PCT-2002-107-DEL-Description (Complete)-(26-11-2008).pdf


Patent Number 226086
Indian Patent Application Number IN/PCT/2002/00107/DEL
PG Journal Number 01/2009
Publication Date 02-Jan-2009
Grant Date 08-Dec-2008
Date of Filing 28-Jan-2002
Name of Patentee BRISTOL-MYERS SQUIBB COMPANY
Applicant Address P.O.BOX 4000, PRINCETON, NEW JERCY 08543-4000, U.S.A.
Inventors:
# Inventor's Name Inventor's Address
1 HAO ZHANG 7 REID AVENUE, BELLE MEAD, NJ 08502,
2 PETER T. W. CHENG 63 MAIDENHEAD ROAD, PRINCETON, NJ 08540,USA
3 PRATIK DEVASTHALE 93 MARION DRIVE, PLAINSBORO, NJ 08540
4 YOON T. JEON 10 SADDLEWOOD COURT, BELLE MEAD, NJ 08540 USA.
5 SEAN CHEN 143 YORK DRIVE, PRINCETON, NJ 08540 USA.
PCT International Classification Number C07D 263/32
PCT International Application Number PCT/US00/25710
PCT International Filing date 2000-09-19
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/155,400 1999-09-22 U.S.A.