Indian Patents
Title of Invention

"CARBOSTYRIL COMPOUND"
Abstract The present invention provides a carbostyril compound represented by General Formula (I)or a salt thereof wherein A is a direct bond a lower alkylene group or a lower alkylidene group X is an oxygen atom or a sulfur atom R4 and R5 each represent a hydrogen atom the bond between the 3 and 4 positions of the carbostyril skeleton is a single bond or a double bond R1 is a hydrogen atom etc R2 is a hydrogen atom etc and R3 is a hydrogen atom etc. The carbostyril compound or salt thereof of the present invention induces the production of TFF and thus is usable for the treatment and/or prevention of disorders such as alimentary tract diseases oral diseases upper respiratory tract diseases respiratory tract diseases eye diseases cancers and wounds.
Full Text DESCRIPTION
CARBOSTYRIL COMPOUND
TECHNICAL FIELD
The present invention relates to a carbostyril compound.
BACKGROUND OF THE INVENTION
The trefoil factor family (TFF) is a group of highly
stable peptides having a three-leaved clover-like structure
formed from six cysteine residues. Three TFF peptides (TFF1 TFF2
and TFF3) have been identified so far in humans. TFFs are present
in mucus-related tissues such as the alimentary tract and are
secreted mainly by mucus-secreting cells. The expression of TTF
peptides is up-regulated in the vicinity of damaged mucosa and in
regenerating glands. It is reported that the main functions of
TFF peptides lie in the augmentation of cell migration processes
(motogenic effects) protection of cells and suppression of
apoptosis [Nature Reviews Molecular Cell Biology Vol.
732(2003)].
TFF2 is a peptide of 106 amino acid residues initially
isolated from porcine pancreas. The TFF2 peptide is abundant in
the gastric mucous neck cells the pyloric region of the stomach
the mucosa surrounding ulcers the regenerative mucosa the
overlying mucus layer Brunner's glands and so forth.
It has been confirmed with experiments using rats that
TFF2 prevents the development of colitis and gastric ulceration
and also accelerates the healing thereof [Gastroenterology 108:
108-116(1995) Gastroenterology 110: 489-497(1996) Alim.
Pharmacol. Ther. 14: 1033-1040(2000) Gut 45: 516-522(1999)
Gut 44: 636-642 1999 and J. Leukoc. Biol. Vol. 75:
223(2004)].
Other experiments show that indomethacin-induced
gastric ulcers are exacerbated in TFF2 knockout mice [J. Clin.
Invest. Vol. 109: 193-204(2002)].
Eur. J. Clin. Invest. 32: 519-527(2002) discloses the
ability of TFF2 to stabilize mucus.
Am. J. Respir. Cell Mol. Biol. Vol. 29: 458-464(2003)
teaches that TFF2 might be involved in regulating the
proliferation of damaged airway epithelia.
It can be understood from the above that TFF2 plays key
roles in protection against and repair of mucosal injury. With
regard to diseases which are likely to be cured with TFF2
improved therapeutic effects are expected by a promotion of
endogenous TFF2 production.
Gastroenterology 126: 796-808(2004) discloses that
TFF3 is effective for curing alimentary tract mucositis such as
stomatitis induced by the administration of carcinostatics.
Science Vol. 274: 259-262(1996) and Gastroenterology 119: 691-
698(2000) conclude from the fact that stomach cancer was
developed in TFF1 knockout mice that the TFF1 gene may function
as a tumor suppressor gene. Nature Reviews Molecular Cell
Biology Vol. 4: 721-732(2003) and Int. J. Mol. Med. 12: 3-
9(2003) suggest that TFF2 may act in a similar way as TFF1 and
TFF3.
As compounds for up-regulating TFF2 expression ligands
for peroxisome proliferator-activated receptor-T (PPART) (e.g.
indomethacin aspirin prostaglandin Ja and troglitazone) are
known [FEES Lett. 488: 206-210(2001) Alim. Pharmacol. Ther. 18
(suppl. 1): 119-125(2003) FEES Lett. 558: 33-38(2004) and Can.
Res. 61: 2424-2428(2001)].
Among various proteins keratinocyte growth factor
(KGF) is reported to enhance TFF2 and TFF3 expressions in rat
lower gastrointestinal tracts [Am. J. Physiol. Regul. Integr.
Comp. Physiology. 284: R564-R573(2003)].
Some studies teach pharmacological actions of the TFF
peptides themselves and suggest the possibility of their
application in clinical medicine (W092/14837 WO02/102403 and
W002/46226).
W001/002377 and WO02/051419 disclose various compounds
having a substituent containing a 24-dioxo-thazolidinyl or 4-
oxo-2-thioxo-thiazolidinyl moiety on a heteroaryl skeleton such
as a quinoline. These documents also disclose that such compounds
exhibit telomerase inhibitory activity.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide a
novel compound capable of up-regulating TFF and to provide a
pharmaceutical composition for preventing and/or treating
alimentary tract diseases oral diseases upper respiratory tract
diseases respiratory tract diseases eye diseases cancers
and/or wounds by up-regulating TFF.
The present inventors carried out extensive research to
develop a novel compound capable of up-regulating endogenous TFF
and as a result they found that carbostyril compounds of the
following formula (1) can up-regulate endogenous TFF
particularly TFF2. The present invention has been accomplished
based on these findings.
The present invention provides a carbostyril compound
an agent comprising said compound a use of said compound a
method for treating a disorder and a process for producing said
compound as described in Items 1 to 35 below.
Item 1. A carbostyril compound represented by General
Formula (1)
or a salt thereof
wherein A is a direct bond a lower alkylene group or
a lower alkylidene group
X is an oxygen atom or a sulfur atom
the bond between the 3 and 4 positions of the
carbostyril skeleton is a single bond or a double bond
R4 and R5 each represent a hydrogen atom with the
proviso that when the bond between the 3 and 4 positions of the
carbostyril skeleton is a double bond R4 and R5 instead may be
linked together in the form of a -CH=CH-CH=CH- group
R1 is one of the following (1-1) to (1-29):
(1-1) a hydrogen atom
(1-2) a lower alkyl group
(1-3) a phenyl lower alkyl group optionally substituted on the
phenyl ring with one or more members selected from the group
consisting of a phenyl group lower alkyl groups lower alkoxy
groups halogen atoms - (B) iNR6R7 groups a nitro group a carboxy
group lower alkoxycarbonyl groups a cyano group phenyl lower
alkoxy groups a phenoxy group a piperidinyl lower
alkoxycarbonyl groups amino lower alkoxycarbonyl groups
optionally substituted with one or more cycloalkyl groups 2-
imidazolinylcarbonyl groups optionally substituted on the 2-
imidazoline ring with one or more lower alkylthio groups 3-
pyrrolinylcarbonyl groups optionally substituted on the 3-
pyrroline ring with one or more lower alkyl groups
thiazolidinylcarbonyl groups optionally substituted on the
thiazolidine ring with a phenyl group 3-
azabicyclo[3.2.2]nonylcarbonyl groups piperidinyl lower alkyl
groups anilino lower aklyl groups optionally substituted on the
amino group with one or more lower alkyl groups phenyl thio lower
alkyl groups indolinyl lower alkyl groups and
piperidinylcarbonyl groups optionally substituted on the
piperidine ring with one or more lower alkyl groups
(1-4) a cycloalkyl lower alkyl group
(1-5) a phenoxy lower alkyl group
(1-6) a naphthyl lower alkyl group
(1-7) a lower alkoxy lower alkyl group
(1-8) a carboxy lower alkyl group
(1-9) a lower alkoxycarbonyl lower alkyl group
(1-10) a pyridyl lower alkyl group optionally substituted on the
pyridine ring with one or more members selected from the group
consisting of halogen atoms piperidinyl groups a morpholino
group piperazinyl groups optionally substituted on the
piperazine ring with one or more members selected from the group
consisting of a phenyl group and lower alkyl group thienyl
groups a phenyl group pyridyl groups piperidinyl lower alkyl
groups phenyl thio lower alkyl groups biphenyl groups lower
alkyl groups optionally substituted with one or more halogen
atoms pyridylamino groups pyridylcarbonylamino groups lower
alkoxy groups anilino lower alkyl groups optionally substituted
on the amino group with one or more lower alkyl groups and
anilino groups optionally substituted on the amino group with one
or more lower alkyl groups
(1-11) a cyano lower alkyl group
( 1 - 12 ) an - Ai-CONRV group
(1-13) a group of the following formula
N-R10
(1-14) a phenyl group
(1-15) a quinolyl lower alkyl group
(1-16) a lower alkoxy lower alkoxy-substituted lower alkyl group
(1-17) a hydroxy-substituted lower alkyl group
(1-18) a thiazolyl lower alkyl group optionally substituted on
the thiazole ring with one or more members selected from the
group consisting of halogen atoms a phenyl group thienyl groups
and pyridyl groups
(1-19) a lower alkyl group optionally substituted with one or
more halogen atoms
(1-20) a lower alkylsilyloxy lower alkyl group
(1-21) a phenoxy lower alkyl group optionally substituted on the
phenyl ring with one or more members selected from the group
consisting of lower alkyl groups optionally substituted with one
or more halogen atoms lower alkoxy groups halogen atoms lower
-6-
alkenyl groups cycloalkyl groups a nitro group and a phenyl
group
(1-22) a phenylthio lower alkyl group optionally substituted on
the phenyl ring with one or more halogen atoms
(1-23) a piperidinyl lower alkyl groups optionally substituted on
the piperidine ring with one or more members selected from the
group consisting of phenyl lower alkyl groups and a phenyl group
(1-24) a piperazinyl lower alkyl group optionally substituted on
the piperazine ring with one or more phenyl groups
'(1-25) a 1234-tetrahydroisoquinolyl lower alkyl group
(1-26) a naphthyloxy lower alkyl group
(1-27) a benzothiazolyloxy lower alkyl group optionally
substituted on the benzothiazole ring with one or more alkyl
groups
(1-28) a lower alkyl group substituted with one or more members
selected from the group consisting of quinolyloxy groups and
isoquinolyloxy groups
(1-29) a pyridyloxy lower alkyl group optionally substituted on
the pyridine ring with one or more lower alkyl groups
R2 is one of the following (2-1) to (2-33):
(2-1) a hydrogen atom
(2-2) a lower alkoxy group
(2-3) a lower alkyl group
(2-4) a carboxy lower alkoxy group
(2-5) a lower alkoxycarbonyl lower alkoxy group
(2-6) a hydroxy group
(2-7) a phenyl lower alkoxy group optionally substituted on the
phenyl ring with one or more members selected from the group
consisting of halogen atoms lower alkyl groups optionally
substituted with one or more halogen atoms lower alkylthio
groups optionally substituted with one or more halogen atoms
lower alkoxy groups a nitro group lower alkylsulfonyl groups
lower alkoxycarbonyl groups phenyl lower alkenyl groups lower
alkanoyloxy groups and 123-thiadiazolyl groups
(2-8) a piperidinyl lower alkoxy group optionally substituted on
the piperldlne ring with one or more lower alkyl groups
(2-9) an amino-substituted lower alkoxy group optionally
substituted with one or more lower alkyl groups
(2-10) a lower alkenyloxy group
(2-11) a pyridyl lower alkoxy group optionally substituted on the
pyridine ring with one or more lower alkyl groups each lower
alkyl substituent optionally being substituted with one or more
halogen atoms
(2-12) a lower alkynyloxy group
(2-13) a phenyl lower alkynyloxy group
(2-14) a phenyl lower alkenyloxy group
(2-15) a furyl lower alkoxy group optionally substituted on the
furan ring with one or more lower alkoxycarbonyl groups
(2-16) a tetrazolyl lower alkoxy group optionally substituted on
the tetrazole ring with one member selected from the group
consisting of a phenyl group phenyl lower alkyl groups and
cycloalkyl lower alkyl groups
(2-17) a 124-oxadiazolyl lower alkoxy group optionally
substituted on the 124-oxadiazole ring with a phenyl group the
phenyl substituent optionally being substituted on the phenyl
ring with one or more lower alkyl groups
(2-18) an isoxazolyl lower alkoxy group optionally substituted on
the isoxazole ring with one or more lower alkyl groups
(2-19) a 134-oxadiazolyl lower alkoxy group optionally
substituted on the 134-oxadiazole ring with a phenyl group the
phenyl substituent optionally being substituted on the phenyl
ring with one or more lower alkyl groups
(2-20) a lower alkanoyl lower alkoxy group
(2-21) a thiazolyl lower alkoxy group optionally substituted on
the thiazole ring with one or more members selected from the
group consisting of lower alkyl groups and a phenyl group each
phenyl substituent optionally being substituted on the phenyl
ring with one or more halogen atoms
(2-22) a piperidinyloxy group optionally substituted on the
piperidine ring with one or more benzoyl groups each benzoyl
-8-
substltuent optionally being substituted on the phenyl ring with
one or more halogen atoms
(2-23) a thienyl lower alkoxy group
(2-24) a phenylthio lower alkoxy group
(2-25) a carbamoyl-substituted lower alkoxy group optionally
substituted with one or more lower alkyl groups
(2-26) a benzoyl lower alkoxy group
(2-27) a pyridylcarbonyl lower alkoxy group
(2-28) an imidazolyl lower alkoxy group optionally substituted on
the imidazole ring with one or more phenyl lower alkyl groups
(2-29) a phenoxy lower alkoxy group
(2-30) a phenyl lower alkoxy-substituted lower alkoxy group
(2-31) a 23-dihydro-IH-indenyloxy group
(2-32) an isoindolinyl lower alkoxy group optionally substituted
on the isoindoline ring with one or more oxo groups
(2-33) a phenyl group
R3 is one of the following (3-1) to (3-19):
(3-1) a hydrogen atom
(3-2) a lower alkyl group
(3-3) a hydroxy-substituted lower alkyl group
(3-4) a cycloalkyl lower alkyl group
(3-5) a carboxy lower alkyl group
(3-6) a lower alkoxycarbonyl lower alkyl group
(3-7) a phenyl lower alkyl group optionally substituted on the
phenyl ring with one or more members selected from the group
consisting of halogen atoms lower alkyl groups optionally
substituted with one or more halogen atoms lower alkoxy groups
optionally substituted with one or more halogen atoms a phenyl
group lower alkoxycarbonyl groups a phenoxy group lower
alkylthio groups lower alkylsulfonyl groups phenyl lower alkoxy
groups and amino groups optionally substituted with one or more
lower alkanoyl groups
(3-8) a naphthyl lower alkyl group
(3-9) a furyl lower alkyl group optionally substituted on the
furan ring with one or more lower alkoxycarbonyl groups.
-9-
(3-10) a thiazolyl lower alkyl group optionally substituted on
the thiazole ring with one or more members selected from the
group consisting of lower alkyl groups and a phenyl group each
phenyl substituent optionally being substituted on the phenyl
ring with one or more optionally halogen-substituted lower alkyl
groups
(3-11) a tetrazolyl lower alkyl group optionally substituted on
the tetrazole ring with one or more lower alkyl groups
(3-12) a benzothienyl lower alkyl group optionally substituted on
the benzothiophehe ring with one or more halogen atoms
(3-13) a lower alkynyl group
(3-14) a lower alkenyl group
(3-15) a phenyl lower alkenyl group
(3-16) a benzoimidazolyl lower alkyl group
(3-17) a pyridyl lower alkyl group
(3-18) an imidazolyl lower alkyl group optionally substituted on
the imidazole ring with one or more phenyl lower alkyl groups
(3-19) a quinolyl lower alkyl group
B is a carbonyl group or an -NHCO- group
1 is 0 or 1
R6 and R7 each independently represent one of the
following (4-1) to (4-79):
(4-1) a hydrogen atom
(4-2) a lower alkyl group
(4-3) a lower alkanoyl group
(4-4) a lower alkylsulfonyl group optionally substituted with one
or more halogen atoms
(4-5) an alkoxycarbonyl group optionally substituted with one or
more halogen atoms
(4-6) a hydroxy-substituted lower alkyl group
(4-7) a pyridylcarbonyl group optionally substituted on the
pyridine ring with one or more members selected from the group
consisting of pyrrolyl groups and halogen atoms
(4-8) a pyridyl group optionally substituted on the pyridine ring
with one or more members selected from the group consisting of
-10-
lower alkyl groups and lower alkoxy groups
(4-9) a pyridyl lower alkyl group
(4-10) a phenyl group optionally substituted on the phenyl ring
with one or more members selected from the group consisting of
halogen atoms lower alkyl groups optionally substituted with one
or more halogen atoms a phenoxy group lower alkoxy groups
optionally substituted with one or more halogen atoms lower
alkylthio groups lower alkylsulfonyl groups amino groups
optionally substituted with one or more members selected from the
group consisting of lower alkyl groups and lower alkanoyl groups
pyrrolidinyl groups optionally substituted on the pyrrolidine
ring with one or more oxo groups piperidinyl groups optionally
substituted on the piperidine ring with one or more lower alkyl
groups lower alkenyl groups an aminosulfonyl group a hydroxy
group carbamoyl groups optionally substituted with one or more
lower alkyl groups phenyl lower alkoxy groups and a cyano group
(4-11) a cycloalkyl group optionally substituted on the
cycloalkyl ring with one or more lower alkyl groups
(4-12) a benzoyl group optionally substituted on the phenyl ring
with one or more members selected from the group consisting of
halogen atoms a phenoxy group a phenyl group lower alkyl
groups optionally substituted with one or more halogen atoms
lower alkoxy groups lower alkanoyl groups a nitro group a
cyano group amino groups optionally substituted with one or more
members selected from the group consisting of a phenyl group and
lower alkyl groups pyrrolidinyl groups optionally substituted on
the pyrrolidine ring with one or more oxo groups pyrrolyl
groups pyrazolyl groups 124-triazolyl groups and imidazolyl
groups
(4-13) a benzoyl group substituted on the phenyl ring with one or
more lower alkylenedioxy groups
(4-14) a cycloalkylcarbonyl group
(4-15) a furylcarbonyl group
(4-16) a naphthylcarbonyl group
(4-17) a phenoxycarbonyl group optionally substituted on the
phenyl ring with one or more members selected from the group
consisting of lower alkoxy groups lower alkyl groups halogen
atoms and a nitro group
(4-18) a phenyl lower alkoxycarbonyl group optionally substituted
on the phenyl ring with one or more members selected from the
group consisting of halogen atoms and a nitro group
(4-19) a piperidinyl group optionally substituted on the
piperidine ring with one or more members selected from the group
consisting of lower alkyl groups lower alkanoyl groups benzoyl
groups optionally substituted on the phenyl ring with one or more
halogen atoms and phenyl groups optionally substituted on the
phenyl ring with one or more halogen atoms
(4-20) a tetrahydropyranyl lower alkyl group
(4-21) a cycloalkyl lower alkyl group
(4-22) a lower alkenyl group
(4-23) a phenyl lower alkyl group optionally substituted on the
alkyl group with one or more lower alkoxycarbonyl groups and
optionally substituted on the phenyl ring with one or more
members selected from the group consisting of halogen atoms
lower alkyl groups optionally substituted with one or more
halogen atoms lower alkoxy groups optionally substituted with
one or more halogen atoms and a hydroxy group
(4-24) a lower alkylenedioxy-substituted phenyl lower alkyl group
(4-25) a furyl lower alkyl group
(4-26) a carbamoyl lower alkyl group optionally substituted with
one or more members selected from lower alkyl groups and a phenyl
group each phenyl substituent optionally being substituted on
the phenyl ring with one or more lower alkyl groups
(4-27) a lower alkoxy lower alkyl group
(4-28) an imidazolyl lower alkyl group optionally substituted on
the lower alkyl group with one or more members selected from the
group consisting of a carbamoyl group and lower alkoxycarbonyl
groups
(4-29) an amino-substituted lower alkyl group optionally
substituted with one or more lower alkyl groups.
(4-30) a 2345-tetrahydrofuryl group optionally substituted on
the 2345-tetrahydrofuran ring with one or more oxo groups
(4-31) a lower alkoxycarbonyl lower alkyl group
(4-32) a pyrrolidinyl lower alkyl group optionally substituted on
the pyrrolidine ring with one or more lower alkyl groups
(4-33) a phenoxy lower alkanoyl group
(4-34) a morpholino lower alkyl group
(4-35) a indolyl group
(4-36) a thiazolyl group
(4-37) a 124-triazolyl group
(4-38) a pyridyl lower alkanoyl group
(4-39) a thienylcarbonyl group
(4-40) a thienyl lower alkanoyl group
(4-41) a cycloalkyl lower alkanoyl group
(4-42) an isoxazolylcarbonyl group optionally substituted on the
isoxazole ring with one or more lower alkyl groups
(4-43) a pyrazylcarbonyl group
(4-44) a piperidinylcarbonyl group optionally substituted on the
piperidine ring with one or more members selected from a benzoyl
group and lower alkanoyl groups
(4-45) a chromanylcarbonyl group
(4-46) an isoindolinyl lower alkanoyl group optionally
substituted on the isoindoline ring with one or more oxo groups
(4-47) a thiazolidinyl lower alkanoyl group optionally
substituted on the thiazolidine ring with one or more members
selected from an oxo group and a thioxo group
(4-48) a piperidinyl lower alkanoyl group
(4-49) a phenyl lower alkenylcarbonyl group optionally
substituted on the phenyl ring with one or more halogen atoms
(4-50) a phenyl lower alkenylcarbonyl group substituted on the
phenyl ring with one or more alkylenedioxy groups
(4-51) a pyridyl lower alkenyl carbonyl group
(4-52) a pyridylthio lower alkanoyl group
(4-53) an indolylcarbonyl group
(4-54) a pyrrolylcarbonyl group.
(4-55) a pyrrolidinylcarbonyl group optionally substituted on the
pyrrolidine ring with one or more oxo groups
(4-56) a benzofurylcarbonyl group
(4-57) an indolyl lower alkanoyl group
(4-58) a benzothienylcarbonyl group
(4-59) a phenyl lower alkanoyl group optionally substituted on
the phenyl ring with one or more halogen atoms
(4-60) a phenylsulfonyl group optionally substituted on the
phenyl ring with one or more members selected from the group
consisting of lower alkoxycarbonyl groups a cyano group a nitro
group amino groups optionally substituted with one or more
alkanoyl groups a hydroxy group a carboxyl group lower
alkoxycarbonyl lower alkyl groups halogen atoms lower alkyl
groups optionally substituted with one or more halogen atoms and
lower alkoxy groups optionally substituted with one or more
halogen atoms
(4-61) a thienylsulfonyl group optionally substituted on the
thiophene ring with one or more members selected from the group
consisting of halogen atoms and lower alkoxycarbonyl groups
(4-62) a quinolylsulfonyl group
(4-63) an imidazolylsulfonyl group optionally substituted on the
imidazole ring with one or more lower alkyl groups
(4-64) a phenylsulfonyl group optionally substituted on the
phenyl ring with one or more lower alkylenedioxy groups
(4-65) a lower alkenylsulfonyl group
(4-66) a cycloalkyl lower alkylsulfonyl group
(4-67) a 34-dihydro-2H-l4-benzoxazinylsulfonyl group optionally
substituted on the 34-dihydro-2H-l4-benzoxazine ring with one
or more lower alkyl groups
(4-68) a pyrazolylsulfonyl group optionally substituted on the
pyrazole ring with one or more members selected from halogen
atoms and lower alkyl groups
(4-69) an isoxazolylsulfonyl group optionally substituted on the
isoxazole ring with one or more lower alkyl groups
(4-70) a thiazolylsulfonyl group optionally substituted on the
thiazole ring with one or more members selected from the group
consisting of lower alkyl groups and an amino group each amino
substituent optionally being substituted with one or more
alkanoyl groups
(4-71) a phenyl lower alkylsulfonyl group
(4-72) a phenyl lower alkenylsulfonyl group
(4-73) a naphthyloxycarbonyl group
(4-74) a lower alkynyloxycarbonyl group
(4-75) a lower alkenyloxycarbonyl group
(4-76) a phenyl lower alkoxy-substituted lower alkoxycarbonyl
group
(4-77) a cycloalkyloxycarbonyl group optionally substituted on
the cycloalkyl ring with one or more lower alkyl groups
(4-78) a tetrazolyl group
(4-79) an isoxazolyl group optionally substituted on the
isoxazole ring with one or more lower alkyl groups or instead
R6 and R7 may be linked together to form together with
the nitrogen atom to which they are bound a 1234-
tetrahydroisoquinolyl group an isoindolinyl group or a 5- to 7-
membered saturated heterocyclic group the heterocydic group
optionally containing one or more additional heteroatoms and
optionally being substituted with one to three members from the
following (5-1) to (5-28):
(5-1) lower alkyl groups
(5-2) lower alkoxy groups
(5-3) an oxo group
(5-4) a hydroxy group
(5-5) pyridyl lower alkyl groups
(5-6) phenyl groups optionally substituted on the phenyl ring
with one or more members selected from the group consisting of
halogen atoms lower alkoxy groups optionally substituted with
one or more halogen atoms lower alkyl groups optionally
substituted with one or more halogen atoms a cyano group and a
hydroxy group
(5-7) lower alkylenedioxy-substituted phenyl lower alkyl groups.
(5-8) phenyl lower alkyl groups optionally substituted on the
phenyl ring with one or more halogen atoms
(5-9) pyrimidyl groups
(5-10) pyrazyl groups
(5-11) cycloalkyl groups
(5-12) phenyl lower alkoxy groups optionally substituted on the
phenyl ring with one or more halogen atoms
(5-13) benzoyl groups optionally substituted on the phenyl ring
with one or more halogen atoms
(5-14) benzoyl groups substituted on the phenyl ring with one or
more lower alkylenedioxy groups
(5-15) carbamoyl lower alkyl groups optionally substituted with
one or more members selected from the group consisting of a
phenyl group and lower alkyl groups
(5-16) benzoxazolyl groups
(5-17) lower alkoxycarbonyl groups
(5-18) a carbamoyl group
(5-19) phenyl lower alkylidene groups optionally substituted on
the phenyl ring with one or more halogen atoms
(5-20) phenyl lower alkoxycarbonyl groups
(5-21) pyridyl groups optionally substituted on the pyridine ring
with one or more members selected from the group consisting of a
cyano group and lower alkyl groups
(5-22) furyl lower alkyl groups
(5-23) tetrahydropyranyl groups
(5-24) imidazolyl lower alkyl groups
(5-25) naphthyl groups
(5-26) 23-dihydro-IH-indenyl groups
(5-27) 13-dioxolanyl lower alkyl groups
(5-28) - (A3) jra11!12 groups
AI is a lower alkylene group
R8 and R9 each independently represent one of the
following (6-1) to (6-25):
(6-1) a hydrogen atom
(6-2) a lower alkyl group.
(6-3) a phenyl group optionally substituted on the phenyl ring
with one or more members selected from the group consisting of
lower allcyl groups optionally substituted with one or more
halogen atoms lower allcylthio groups lower alkoxy groups
optionally substituted with one or more halogen atoms halogen
atoms a phenyl group lower alkylamino groups a cyano group a
phenoxy group cycloalkyl groups pyrrolidinyl groups optionally
substituted with one or more oxo groups 1234-
tetrahydroisoquinolylcarbonyl groups 1234-
tetrahydroquinolylcarbonyl groups optionally substituted with one
or more lower alkyl groups 1234-
tetrahydroquinoxalinylcarbonyl groups optionally substituted with
one or more lower alkyl groups thiazolyl groups optionally
substituted with one or more phenyl groups a carbamoyl group
phenyl lower alkoxy groups lower alkylsulfonylamino groups
anilino groups optionally substituted with one or more halogen
atoms phenyl lower alkyl groups and hydroxy-substituted lower
alkyl groups
(6-4) a cycloalkyl group
(6-5) a cycloakyl lower alkyl group
(6-6) a carbamoyl lower alkyl group
(6-7) a phenyl lower alkyl group optionally substituted on the
phenyl ring with one or more members selected from the group
consisting of lower alkyl groups optionally substituted with one
or more halogen atoms lower alkoxy groups optionally substituted
with one or more halogen atoms halogen atoms and a phenyl group
(6-8) lower alkyl-substituted amino lower alkyl group
(6-9) a naphthyl group
(6-10) a naphthyl lower alkyl group
(6-11) a tetrahydronaphthyl lower alkyl group
(6-12) a fluorenyl group
(6-13) a pyridyl group
(6-14) a pyridyl lower alkyl group
(6-15) a pyrimidinyl group
(6-16) a pyrazinyl lower alkyl group optionally substituted on
the pyrazine ring with one or more lower alkyl groups
(6-17) a thiazolyl group
(6-18) a pyrazolyl lower alkyl group optionally substituted on
the pyrazole ring with one or more lower alkyl groups
(6-19) a thienyl lower alkyl group
(6-20) a piperidinyl group optionally substituted on the
piperidine ring with one or more members selected from the group
consisting of lower alkyl groups a benzoyl group and phenyl
lower alkyl groups optionally substituted on the phenyl ring with
one or more members selected from the group consisting of halogen
atoms and lower alkyl groups
(6-21) an indolyl group
(6-22) an indazolyl group
(6-23) a 34-dihydrocarbostyril optionally substituted with one
or more lower alkyl groups
(6-24) a quinolyl group optionally substituted with one or more
lower alkyl groups
(6-25) a carbazolyl group optionally substituted with one or more
lower alkyl groups or
R8 and R9 may be linked together to form together with
the nitrogen atom to which they are bound a 5- to 8-membered
saturated heterocyclic group optionally containing one or more
additional heteroatoms and optionally substituted on the
heterocyclic ring with one or more members selected from the
group consisting of the following (6-28-1) to (6-28-24):
(6-28-1) lower alkyl groups
(6-28-2) phenyl lower alkyl groups optionally substituted on the
phenyl ring with one or more members selected from halogen atoms
and lower alkoxy groups optionally substituted with one or more
halogen atoms
(6-28-3) naphthyl lower alkyl groups
(6-28-4) phenyl lower alkylcarbamoyl lower alkyl groups
(6-28-5) phenylcarbamoyl lower alkyl groups
(6-28-6) phenyl lower alkoxycarbonyl groups
(6-28-7) phenoxy lower alkyl groups optionally substituted on the
phenyl ring with one or more members selected from the group
consisting of halogen atoms and lower alkyl groups optionally
substituted with one or more halogen atoms
(6-28-8) biphenyl groups
(6-28-9) phenyl groups optionally substituted on the phenyl ring
with one or more halogen atoms
(6-28-10) 23-dihydroindenyl groups optionally substituted with
one or more halogen atoms
(6-28-11) benzothiazolyl groups optionally substituted with one
or more halogen atoms
(6-28-12) pyridyl groups optionally substituted with one or more
halogen atoms
(6-28-13) benzothienyl groups
(6-28-14) benzoisothiazolyl groups
(6-28-15) thienopyridyl groups
(6-28-16) a carbamoyl group
(6-28-17) phenyl lower alkoxy groups optionally substituted on
the phenyl ring with one or more halogen atoms
(6-28-18) phenoxy groups optionally substituted with one or more
halogen atoms
(6-28-19) benzoyl groups optionally substituted on the phenyl
ring with one or more members selected from halogen atoms and
lower alkoxy groups
(6-28-20) anilino groups optionally substituted on the phenyl
ring with one or more lower alkyl groups each lower alkyl
substituent optionally being substituted with one or more halogen
atoms
(6-28-21) anilino groups substituted on the amino group with one
or more lower alkyl groups and optionally further substituted on
the phenyl ring with one or more halogen atoms
(6-28-22) benzofuryl groups
(6-28-23) naphthyl groups
(6-28-24) an oxo group or
R8 and R9 may be linked together to form together with
the nitrogen atom to which they are bound a 5- or 6-membered
unsaturated heterocyclic group the unsaturated heterocyclic
group optionally being substituted on the heterocyclic ring with
one or more members selected from the group consisting of the
following (6-29-1) to (6-29-3):
(6-29-1) phenyl groups optionally substituted with one or more
halogen atoms
(6-29-2) 23-dihydroindenyl groups
(6-29-3) benzothienyl groups or instead
R8 and R9 may be linked together to form together with the
nitrogen atom to which they are bound a 1234-
tetrahydroquinolyl group a 1234-tetrahydroisoquinolyl group
a 13-dihydroisoindolyl group an octahydropyrrolo[l2-
a]pyrazinyl group optionally substituted on the pyrazine ring
with one or more lower alkyl groups or an 8-
azabicyclo[3.2.1]octyl group optionally substituted on the 8-
azabicyclo[3.2.1]octyl group with one or more phenoxy groups
each phenoxy substituent optionally being substituted on the
phenyl ring with one or more halogen atoms
A2 is a lower alkylene group
R10 is one of the following (7-1) to (7-44):
(7-1) a hydrogen atom
(7-2) a lower alkyl group
(7-3) an alkoxycarbonyl group optionally substituted with one or
more halogen atoms
(7-4) a benzoyl group optionally substituted on the phenyl ring
with one or more members selected from the group consisting of
lower alkyl groups optionally substituted with one or more
halogen atoms a phenyl group halogen atoms a cyano group a
phenoxy group lower alkoxycarbonyl groups pyrazolyl groups and
lower alkoxy groups optionally substituted with one or more
halogen atoms
(7-5) an alkanoyl group
(7-6) a phenyl lower alkanoyl group optionally substituted on the
phenyl ring with one or more members selected from the group
consisting of halogen atoms and lower alkyl groups.
(7-7) a cycloalkyl lower alkanoyl group
(7-8) a phenyl group optionally substituted on the phenyl ring
with one or more lower alkyl groups
(7-9) a phenoxy lower alkanoyl group optionally substituted on
the phenyl ring with one or more halogen atoms
(7-10) a phenyl lower alkenylcarbonyl group
(7-11) a pyridylcarbonyl group optionally substituted on the
pyridine ring with one or more members selected from the group
consisting of halogen atoms and lower alkyl groups each lower
alkyl substituent optionally being substituted with one or more
halogen atoms
(7-12) a furylcarbonyl group
(7-13) a thienylcarbonyl group
(7-14) a piperidinylcarbonyl group optionally substituted on the
piperidine ring with one or more lower alkanoyl groups
(7-15) a pyrrolidinylcarbonyl group optionally substituted on the
pyrrolidine ring with one or more oxo groups
(7-16) a tetrahydropyranylcarbonyl group
(7-17) a naphthylcarbonyl group
(7-18) an indolylcarbonyl group
(7-19) a benzofurylcarbonyl group
(7-20) a benzothienylcarbonyl group optionally substituted on the
benzothiophene ring with one or more halogen atoms
(7-21) a furyl lower alkyl group
(7-22) a pyridyl lower alkyl group optionally substituted on the
pyridine ring with one or more members selected from the group
consisting of halogen atoms and lower alkyl groups each lower
alkyl substituent optionally being substituted with one or more
halogen atoms
(7-23) a thienyl lower alkyl group optionally substituted on the
thiophene ring with one or more halogen atoms
(7-24) a phenyl lower alkyl group optionally substituted on the
phenyl ring with one or more members selected from the group
consisting of lower alkoxy groups optionally substituted with one
or more halogen atoms a cyano group lower alkyl groups
optionally substituted with one or more halogen atoms amino
groups optionally substituted with one or more members selected
from the group consisting of lower alkyl groups and lower
alkanoyl groups halogen atoms lower alkoxycarbonyl groups
lower alkanoyloxy groups lower alkylsulfonyl groups lower
alkylthio groups and pyrrolidinyl groups
(7-25) a thiazolyl lower alkyl group
(7-26) an imidazolyl lower alkyl group optionally substituted on
the imidazole ring with one or more lower alkyl groups
(7-27) a pyrrolyl lower alkyl group optionally substituted on the
pyrrole ring with one or more lower alkyl groups
(7-28) a cycloalkyl lower alkyl group
(7-29) a lower alkylthio lower alkyl group
(7-30) a phenoxycarbonyl group optionally substituted on the
phenyl ring with one or more members selected from the group
consisting of halogen atoms lower alkyl groups and lower alkoxy
groups
(7-31) a phenyl lower alkoxycarbonyl group optionally substituted
on the phenyl ring with one or more halogen atoms
(7-32) a naphthyloxycarbonyl group
(7-33) a lower alkynyloxycarbonyl group
(7-34) a cycloalkylcarbonyl group
(7-35) a quinoxalinylcarbonyl group
(7-36) a -CO-NR13R14 group
(7-37) a piperidinyl group optionally substituted on the
piperidine ring with one or more lower alkyl groups
(7-38) a cycloalkyl group
(7-39) a tetrahydropyranyl group
(7-40) a lower alkoxy lower alkyl group
(7-41) a tetrahydro-2H-thiopyranyl group
(7-42) a naphthyl group
(7-43) a biphenyl group
(7-44) a lower alkylsilyl lower alkoxycarbonyl group
A3 is a lower alkylene group
m is 0 or 1
R11 and R12 each independently represent one of the
following (8-1) to (8-5):
(8-1) a hydrogen atom
(8-2) a lower alkyl group
(8-3) a lower alkanoyl group
(8-4) a phenyl lower alkanoyl group
(8-5) a phenyl group optionally substituted on the phenyl ring
with one or more halogen atoms or instead
R11 and R12 may be linked together to form together with
the nitrogen atom to which they are bound a 5- or 6-membered
saturated heterocyclic group which optionally contains one or
more additional heteroatoms the heterocyclic group optionally
being substituted with one to three members selected from the
group consisting of the following (9-1) and (9-2):
(9-1) lower alkyl groups
(9-2) a phenyl group and
R13 and R14 each independently represent one of the
following (10-1) to (10-3):
(10-1) a hydrogen atom
(10-2) a lower alkyl group
(10-3) a phenyl group or instead
R13 and R14 may be linked together to form together with
the nitrogen atom to which they are bound a 5- or 6-membered
saturated heterocyclic group which optionally contains one or
more additional heteroatoms.
Item 2. A carbostyril compound or a salt thereof
according to Item 1 wherein the bond between the 3 and 4
positions of the carbostyril skeleton is a single bond or a
double bond and R4 and R5 each represent a hydrogen atom.
Item 3. A carbostyril compound or a salt thereof
according to Item 2 wherein a group of the formula
_ 9
0
in which R3 A and X are as defined in Item 1 above is bound to
-23-
the 3 4 5 6 7 or 8 position of the carbostyril skeleton.
Item 4. A carbostyril compound or a salt thereof
according to Item 3 wherein the bond between the 3 and 4
positions of the carbostyril skeleton is a single bond and the
group of the formula
in which R3 A and X are as defined in Item 1 above is bound to
the 5 or 6 position of the carbostyril skelton.
Item 5. A carbostyril compound or a salt thereof
according to Item 3 or 4 wherein A is a lower alkylene group or
a lower alkylidene group.
Item 6. A carbostyril compound or a salt thereof
according to Item 5 wherein R1 is one of (1-2) (1-3) (1-4) (1-
6) (1-10) (1-12) (1-13) (1-18) and (1-21) as defined in Item
1 above.
Item 7. A carbostyril compound or a salt thereof
according to Item 6 wherein the group of the formula
in which R3 A and X are as defined in Item 1 above is bound to
the 5 position of the carbostyril skelton.
Item 8. A carbostyril compound or a salt thereof
according to Item 7 wherein R1 is a phenyl lower alkyl group
optionally substituted on the phenyl ring with one or more
members selected from the group consisting of a phenyl ring
halogen atoms -(B)iNR6R7 groups wherein B 1 R6 and R7 are as
defined in Item 1 lower alkoxycarbonyl groups and phenyl lower
alkoxy groups.
Item 9. A carbostyril compound or a salt thereof
according to Item 8 wherein A is a lower alkylene group R2 is a
hydrogen atom or a lower alkoxy group R3 is a hydrogen atom and
Itera 10. A carbostyril compound or a salt thereof
according to Item 7 wherein A is a lower alkylene group R1 is a
lower alkyl group R2 is a hydrogen atom or a lower alkoxy group
R3 is a hydrogen atom and X is an oxygen atom or a sulfur atom.
Item 11. A carbostyril compound or a salt thereof
according to Item 7 wherein A is a lower alkylene group R1 is a
naphthyl lower alkyl group R2 is a hydrogen atom or a lower
alkoxy group R3 is a hydrogen atom and X is an oxygen atom or a
sulfur atom.
Item 12. A carbostyril compound or a salt thereof
according to Item 7 wherein A is a lower alkylene group R1 is a
group of the formula
in which R10 and A2 are as defined in Item 1 above R2 is a
hydrogen atom or a lower alkoxy group R3 is a hydrogen atom and
X is an oxygen atom or a sulfur atom.
Item 13. A carbostyril compound or a salt thereof
according to Item 3 wherein the bond between the 3 and 4
positions of the carbostyril skeleton is a double bond and a
group of the formula
in which R3 A and X are as defined in Item 1 above is bound to
the 3 4 or 5 position of the carbostyril sleketon.
Item 14. A carbostyril compound or a salt thereof
according to Item 13 wherein R1 is one of (1-2) and (1-3) as
defined in Item 1.
Item 15. A carbostyril compound or a salt thereof
according to Item 14 wherein A is a lower alkylene group or a
lower alkylidene group and R2 is a hydrogen atom or a lower
alkoxy group.
Item 16. A carbostyril compound or a salt thereof
according to Item 1 wherein the bond between the 3 and 4
positions of the carbostyril skeleton is a double bond and R4 and
R5 are linked together in the form of a -CH=CH-CH«CH- group.
Item 17. A carbostyril compound or a salt thereof
according to Item 16 wherein a group of the formula
R3\ .0
S
in which R3 A and X are as defined in Item 1 above is bound to
the 7 position of the carbostyril skeleton.
Item 18. A carbostyril compound or a salt thereof
according to Item 17 wherein R1 is one of (1-2) and (1-3) as
defined in Item 1 above.
Item 19. A carbostyril compound or a salt thereof
according to Item 18 wherein A is a lower alkylene group or a
lower alkylidene group R2 and R3 are both hydrogen atoms and X
is an oxygen atom or a sulfur atom.
Item 20. A carbostyril compound or a salt thereof
according to Item 1 wherein A is a direct bond.
Item 21. A carbostyril compound or a salt thereof
according to Item 1 wherein A is a lower alkylene group.
Item 22. A carbostyril compound or a salt thereof
according to Item 1 wherein A is a lower alkylidene group.
Item 23. A carbostyril compound or a salt thereof
according to any one of Items 20 to 22 wherein the bond between
the 3 and 4 positions of the carbostyril skeleton is a single
bond or a double bond and R4 and R5 each represent a hydrogen
atom.
Item 24. A carbostyril compound or a salt thereof
according to any one of Items 20 to 22 wherein the bond between
the 3 and 4 positions of the carbostyril skeleton is a double
bond and R4 and R5 are linked together in the form of a -CH=CHCH=
CH- group.
Item 25. A carbostyril compound selected from the group
consisting of the following compounds:
-26-
-[1-(biphenyl-4-ylmethyl)-8-methoxy-2-oxo-l234-
tetrahydroquinolin-5-ylmethyl] thiazolidine-24-dlone
5-11- (4-chlorobenzyl) -8-methoxy- 2-oxo-l 234-tetrahydroquinolin-
5 -ylmethyl]thiazolidine-24-dione
5-[1-(4-bromobenzyl)-8-methoxy-2-oxo-1234-tetrahydroquinolin-
5-ylmethyl]thiazolidine-24-dione
5-[1-(2-naphthylmethyl)-8-methoxy-2-oxo-l234-
tetrahydroquinolin-5-ylmethyl]thiazolidine-24-dione
5-{l-[4-(heptyloxycarbonylamino)benzyl]-8-methoxy-2-oxo-l234-
tetrahydroquinolin-5-ylmethyl}thiazolidine-24-dione
5-[1-(1-biphenyl-4-ylpiperidin-4-ylmethyl)-2-oxo-l234-
tetrahydroquinolin-5-ylmethyl]thiazolidine-24-dione
5-{l-[l-(4-methylphenyl)piperidin-4-ylmethyl]-2-oxo-1234-
tetrahydroquinolin-5-ylmethyl}thiazolidine-24-dione
5-{l-[4-(2-chlorobenzyloxycarbonylamino)benzyl]-8-methoxy-2-oxo-
1234-tetrahydroquinolin-5-ylmethyl}thiazolidine-24-dione
1-(biphenyl-4-ylmethyl)-8-methoxy-5-( 4-oxo-2-thioxothiazolidin-5-
ylmethyl)-34-dihydro-lH-quinolin-2-one/
8 -methoxy-1 -methyl- 5 - (4 -oxo- 2 - thioxothiazolidin- 5 -ylmethyl) - 34 -
dihydro-1H-quinolin-2-one
8-methoxy-l-(3-methylbutyl)-5-(4-oxo-2-thioxothiazolidin-5-
ylmethyl)-34-dihydro-1H-quinolin-2-one
l-propyl-8-methoxy-5- (4-oxo-2-thioxothiazolidin-5-ylmethyl) -34-
dihydro-IH-quinolin-2-one
l-isobutyl-8-methoxy-5-(4-oxo-2-thioxothiazolidin-5-ylmethyl)-
34-dihydro-lH-quinolin-2-one
8-methoxy-1-phenethyl - 5-(4-oxo - 2 - thioxothiazolidin-5-ylmethyl )-
34-dihydro-lH-quinolin-2-one and
l-(4-phenylthiomethyl)benzyl-5-(4-oxo-2-thioxothiazolidin-5-
ylmethyl)-34-dihydro-lH-quinolin-2-one or a salt thereof.
Item 26. A pharmaceutical composition comprising as an
active ingredient a carbostyril compound or salt thereof
according to Item 1.
Item 27. A prophylactic and/or therapeutic agent for a
disorder on which TFF up-regulation has a prophylactic and/or
therapeutic effect comprising as an active ingredient a
carbostyril compound or salt thereof according to Item 1.
Item 28. A prophylactic and/or therapeutic agent
according to Claim 27 wherein the disorder on which TFF upregulation
has a prophylactic and/or therapeutic effect is an
alimentary tract disease oral disease upper respiratory tract
disease respiratory tract disease eye disease cancer or wound.
Item 29. A prophylactic and/or therapeutic agent
according to Claim 27 wherein the disorder on which TFF upregulation
has a prophylactic and/or therapeutic effect is a
drug-induced ulcer peptic gastric ulcer ulcerative colitis
Crohn's disease drug-induced enteritis ischemic colitis
irritable bowel syndrome ulcer developed after endoscopic
demucosation acute gastritis chronic gastritis reflux
esophagitis esophageal ulcer Barrett esophagus
gastrointestinal mucositis hemorrhoidal diseases stomatitis
SjSgren syndrome xerostomia rhinitis pharyngitis bronchial
asthma chronic obstructive lung disease dry eye or
keratoconjunctivitis.
Item 30. A prophylactic and/or therapeutic agent
according to Item 27 wherein the TFF is TFF2.
Item 31. A use of a carbostyril compound or salt
thereof according to Item 1 for manufacturing a prophylactic
and/or therapeutic agent for a disorder on which TFF upregulation
has a prophylactic and/or therapeutic effect.
Item 32. A method for preventing and/or treating a
disorder on which TFF up-regulation has a prophylactic and/or
therapeutic effect comprising administering to a patient an
effective amount of a carbostyril compound or salt thereof
according to Item 1.
Item 33. A prophylactic and/or therapeutic agent for
alimentary tract diseases oral diseases upper respiratory tract
diseases respiratory tract diseases eye diseases cancers or
wounds the agent comprising a compound that induces the
production of TFF.
Item 34. A prophylactic and/or therapeutic agent
according to Item 33 wherein the TFF is TFF2.
Item 35. A process for the production of a carbostyril
compound (1) of the following formula:
(1)
R1
or a salt thereof wherein R1 R2 R3 R4 R5 A X and
the bond between the 3 and 4 positions of the carbostyril
skeleton are as defined in Item 1
which comprises
(i) reacting a compound (2) of the formula:
R5
(2)
R' I1
or a salt thereof wherein R1 R2 R4 R5 and the bond
between the 3 and 4 positions of the carbostyril skeleton are as
defined above and R15 is a hydrogen atom or lower alkyl group
and A4 represents a direct bond or lower alkylene group
with a compound (3) of the formula:
or a salt thereof wherein R3 and X are as defined above
to give a compound (la) of the formula:
5
or a salt thereof wherein R1 R2 R3 R4 R5 R15 A4 and
the bond between the 3 and 4 positions of the carbostyril
skeleton are as defined above and
(ii) reducing the compound (la) defined above or a salt
thereof to give a compound (Ib) of the formula:
R'
or a salt thereof wherein R1 R2 R3 R4 R5 R15 A the bond between the 3 and 4 positions of the carbostyril
skeleton are as defined above.
Among carbostyril compounds represented by General
Formula (1) compounds wherein the bond between the 3 and 4
positions of the carbostyril skeleton is a single bond and a
double bond and R4 and R5 each represent a hydrogen atom are
preferable.
Among carbostyril compounds represented by General
Formula (1) compounds wherein a group of the formula
RxN--f0
X^S>-Ain
which R3 A and X are as defined in Item 1 above is bound to
the 3 4 5 6 7 or 8 position of the carbostyril skeleton are
preferable.
Among carbostyril compounds represented by General
Formula (1) compounds wherein the bond between the 3 and 4
positions of the carbostyril skeleton is a single bond and the
group of the formula
in which R3 A and X are as defined in Item 1 above is bound to
the 5 or 6 position of the carbostyril skelton are preferable.
Among carbostyril compounds represented by General
Formula ( 1 ) compounds wherein A is a lower alkylene group or a
lower alkylidene group are preferable.
Among carbostyril compounds represented by General
Formula (1) compounds wherein R1 is one of (1-2) (1-3) (1-4)
(1-6) (1-10) (1-12) (1-13) (1-18) and (1-21) as defined in
Item 1 above are preferable.
Among these preferable carbostyril compounds compounds
wherein the group of the formula
in which R3 A and X are as defined in Item 1 above is bound to
the 5 position of the carbostyril skelton are more preferable.
Compounds wherein R1 is a phenyl lower alkyl group
optionally substituted on the phenyl ring with one or more
members selected from a phenyl group halogen atoms -(B)iNR6R7
groups wherein B 1 R6 and R7 are as defined in Item 1 above
lower alkoxycarbonyl groups and phenyl lower alkoxy groups are
also more preferable
of such carbostyril compounds those wherein A is a
lower alkylene group R2 is a hydrogen atom or a lower alkoxy
group R3 is a hydrogen atom and X is an oxygen atom or a sulfur
atom are particularly preferable.
Among carbostyril compounds represented by General
Formula ( 1 ) compounds wherein R1 is a lower alkyl group are
preferable and further those wherein A is a lower alkylene
group R2 is a hydrogen atom or a lower alkoxy group R3 is a
hydrogen atom and X is an oxygen atom or a sulfur atom are more
preferable .
Among carbostyril compounds represented by General
Formula ( 1 ) compounds wherein R1 is a naphthyl lower alkyl group
are preferable and further those wherein A is a lower alkylene
group R2 is a hydrogen atom or a lower alkoxy group R3 is a
-31-
hydrogen atom and X is an oxygen atom or a sulfur atom are more
preferable.
Among carbostyril compounds represented by General
Formula (1) compounds wherein R1 is a group
in which R10 and A2 are as defined in Item 1 above are preferable
and further those wherein A is a lower alkylene group R2 is a
hydrogen atom or a lower alkoxy group R3 is a hydrogen atom and
X is an oxygen atom or a sulfur atom are preferable.
Among carbostyril compounds represented by General
Formula (1) compounds wherein the bond between the 3 and 4
positions of the carbostyril skeleton is a double bond and a
group of the formula
in which R3 A and X are as defined in Item 1 above is bound to
the 3 4 or 5 position of the carbostyril sleketon are preferable
and further those wherein R1 is (1-2) or (1-3) as defined in Item
1 are more preferable of such carbostyril compounds compounds
wherein A is a lower alkylene group or a lower alkylidene group
and R2 is a hydrogen atom or a lower alkoxy group are particularly
preferable.
Among carbostyril compounds represented by General
Formula (1) compounds wherein the bond between the 3 and 4
positions of the carbostyril skeleton is a double bond and R4 and
R5 are linked together in the form of a -CH=CH-CH=CH- group are
preferable
of such carbostyril compounds compounds wherein a
group of the formula
in which R3 A and X are as defined in Item 1 above is bound to
the 7 position of the carbostyril skeleton are more preferable
those wherein R1 is (1-2) or (1-3) as defined in Item 1 above are
still more preferable and those wherein A is a lower alkylene
group or a lower alkylidene group R2 and R3 are both hydrogen
atoms and X is an oxygen atom or a sulfur atom are particularly
preferable.
Examples of particularly preferable carbostyril
compounds of the present invention are as follows:
5-[1-(biphenyl-4-ylmethyl)-8-methoxy-2-oxo-l234-
tetrahydroquinolin- 5 -ylmethyl ] thiazolidine- 24 -dione
5 - [ 1 - (4 - chlorobenzyl) - 8 -me thoxy- 2 - oxo -1234-1 e trahydroquinolin -
5-ylmethyl]thiazolidine-24-dione
5 - [ 1 - (4 -bromobenzyl) - 8 -me thoxy- 2 -oxo-1234- tetrahydroquinolin-
5-ylmethyl]thiazolidine-24-dione
5-[1-(2-naphthylmethyl)-8-methoxy-2-oxo-l234-
tetrahydroquinolin- 5 -ylmethyl ] thiazolidine- 24 -dione
5-{l-[4-( heptyloxycarbonyland.no) benzyl ] - 8 -me thoxy- 2 - oxo -1234-
tetrahydroquinolin-5-ylmethyl}thiazolidine-24-dione
5- [ 1- (l-biphenyl-4-ylpiperidin-4-ylmethyl) -2-oxo-l 234-
tetrahydroquinolin- 5 -ylmethyl ] thiazolidine - 24-dione
5-{l-[l-(4-methylphenyl)piperidin-4-ylmethyl]-2-oxo-l234-
tetrahydroquinolin-5-ylmethyl}thiazolidine-24-dione
5-{l-[4-(2- chlorobenzyloxycarbonylamino) benzyl ] - 8 -methoxy- 2 -oxo -
1234-tetrahydroquinolin-5-ylmethyl} thiazolidine-24-dione
1-(biphenyl-4-ylmethyl )-8-methoxy-5-(4-oxo-2-thioxothiazolidin-5-
ylmethyl)-34-dihydro-lH-quinolin-2-one
8-me thoxy-1-me thyl-5-( 4-oxo-2- thioxothiazolidin-5-ylmethyl) -34-
dihydro-1H-quinolin-2-one
8 -methoxy-1 - (3 -methylbutyl) - 5 - (4 -oxo- 2 - thioxothiazolidin- 5 -
ylmethyl)-34-dihydro-lH-quinolin-2-one
l-propyl-8-methoxy-5- (4-oxo-2-thioxothiazolidin-5-ylmethyl) -34-
dihydro-lH-quinolin-2-one
l-isobutyl-8-methoxy-5- (4-oxo-2-thioxothiazolidin-5-ylmethyl) -
34-dihydro-lH-quinolin-2-one
-33-
8 -methoxy-1 -phenethyl - 5 - (4 - oxo - 2 - thioxothlazolidln - 5 -ylmethyl) -
34-dihydro-lH-quinolin-2-one and
1 - (4 - phenyl thiomethyl) benzyl - 5 - (4 - oxo - 2 - thioxothiazolidin - 5 -
ylmethyl)-34-dihydro-IH-quinolin-2-one.
Specific examples of groups in the above formula (1)
are as follows.
Examples of lower alkylene groups include straight and
branched Ci_6 alkylene groups such as methylene ethylene
dimethyltrimethylene 1-methyltrime thy lene methylmethylene
ethylmethylene tetramethylene pentamethylene and hexamethylene.
Examples of lower alkylidene groups include straight
and branched Ci-6 alkylidene groups such as methylidene
ethylidene propylidene butylidene pentylidene and hexylidene.
Examples of lower alkyl groups include straight and
branched Ci_6 alkyl groups such as methyl ethyl n-propyl
isopropyl n-butyl isobutyl tert-butyl sec-butyl n-pentyl
isopentyl neopentyl n-hexyl isohexyl and 3-methylpentyl.
Examples of lower alkoxy groups include straight and
branched Ci-6 alkoxy groups such as methoxy ethoxy n-propoxy
isopropoxy n-butoxy isobutoxy tert-butoxy sec-butoxy ripen
tyloxy isopentyloxy neopentyloxy n-hexyloxy isohexyloxy
and 3-methylpentyloxy.
Examples halogen atoms include fluorine chlorine
bromine and iodine.
Examples of lower alkoxycarbonyl groups include
alkoxycarbonyl groups wherein the alkoxy moiety is a straight or
branched Ci-6 alkoxy group such as methoxycarbonyl ethoxycarbonyl
n-propoxycarbonyl isopropoxycarbonyl n-butoxycarbonyl
isobutoxycarbonyl tert-butoxycarbonyl sec-butoxycarbonyl npentyloxycarbonyl
neopentyloxycarbonyl n-hexyloxycarbonyl
isohexyloxycarbonyl and 3-methylpentyloxycarbonyl.
Examples of phenyl lower alkoxy groups include
phenylalkoxy groups wherein the alkoxy moiety is a straight or
branched Ci-6 alkoxy group such as benzyloxy 2-phenylethoxy 1-
phenylethoxy 3-phenylpropoxy 4-phenylbutoxy 5-phenylpentyloxy
6-phenylhexyloxy 11-dimethyl-2-phenylethoxy and 2-methyl-3-
phenylpropoxy.
Examples of piperidinyl lower alkoxycarbonyl groups
include piperidinylalkoxycarbonyl groups wherein the alkoxy
moiety is a straight or branched Ci-e alkoxy group such as [(!-
2- 3- or 4-)piperidinyl]methoxycarbonyl 2-
[(!- 2- 3- or 4-)piperidinyl]ethoxycarbonyl 1-
[(!- 2- 3- or 4-)piperidinyl]ethoxycarbonyl 3-
[ (1 - 2- 3- or 4-)piperidinyl]propoxycarbonyl 4-
[(!- 2- 3- or 4-)piperidinyl]butoxycarbonyl 5-
[(!- 2- 3- or 4-)piperidinyl]pentyloxycarbonyl 6-
[(!- 2 - 3- or 4-) piperidinyl ] hexyloxycarbonyl 11- dimethyl - 2 -
[(!- 2- 3- or 4-)piperidinyl]ethoxycarbonyl and 2-methyl-3-
[(!- 2- 3- or 4-)piperidinyl]propoxy carbonyl.
Examples of cycloalkyl groups include C3-8 cycloalkyl
groups such as cyclopropyl cyclobutyl cyclopentyl cyclohexyl
cycloheptyl and cyclooctyl.
Examples of amino lower alkoxycarbonyl groups
optionally substituted with one or more cycloalkyl groups
include:
amino-substituted alkoxycarbonyl groups wherein the
alkoxy moiety is a straight or branched Ci-6 alkoxy group
optionally substituted with one or two C3.8 cycloalkyl groups
such as aminomethoxycarbonyl 2-aminoethoxycarbonyl
cyclopropylaminomethoxycarbony 1 2 - cyclohexylaminoethoxycarbonyl
1-cyclobutylaminoethoxycarbonyl 3-
cyclopen tylaminopropoxycarbonyl 4 - cycloheptylaminobut oxycarbonyl
5 - cyclooctylaminopentyloxycarbonyl 6 -
cyclohexylaminohexyloxycarbonyl 11- dimethyl - 2 -
cyclohexylaminoethoxycarbonyl 2-methyl-3-
cyclopropylaminopropoxycarbonyl and 2 - (N- cyclopropyl -Ncyclohexylamino)
ethoxycarbonyl.
Examples of lower alkylthio groups include straight and
branched Ci.6 alkylthio groups such as methylthio ethylthio n-
propylthio isopropylthio n-butylthio tert-butylthio npentylthio
and n-hexylthio.
Examples of 2-lmidazolinylcarbonyl groups optionally
substituted on the 2-imidazoline ring with one or more alkylthio
groups include 2-imidazolinylcarbonyl groups optionally
substituted on the 2-imidazoline ring with one to three lower
alkylthio groups such as (1- 2- 4- or 5-) 2-
imidazolinylcarbonyl 2-methylthio-(l- 4- or 5-)2-
imidazolinylcarbonyl 2-ethylthio-(l- 4- or 5-)2-
imidazolinylcarbonyl 4-propylthio-(l- 2- or 5-)2-
imidazolinylcarbonyl 5-isopropylthio-(1- 2- or 4-)2-
imidazolinylcarbonyl 2-n-butylthio-(l- 4- or 5-) 2-
imidazolinylcarbonyl 2-n-pentylthio-(1 - 4- or 5 -) 2
imidazolinylcarbonyl 2-n-hexylthio-(l- 4- or 5-)2-
imidazolinylcarbonyl 24-dimethylthio-(l- or 5-)2-
imidazolinylcarbonyl and 245-trimethylthio-(1-)2-
imidazolinylcarbonyl.
Examples of 3-pyrrolinylcarbonyl groups optionally
substituted on the 3-pyrroline ring with one or more lower alkyl
groups include 3-pyrrolinylcarbonyl groups optionally substituted
on the 3-pyrroline ring with one to three lower alkyl groups
such as (1- 2- or 3-)3-pyrrolinylcarbonyl 2-methyl-
(1- 2- 3- 4- or 5-)3-pyrrolinylcarbonyl 2-ethyl-
(1- 2- 3- 4- or 5-)3-pyrrolinylcarbonyl 3-propyl-
(1- 2- 4- or 5-)3-pyrrolinylcarbonyl 4-isopropyl-
(1- 2- 3- or 5-)3-pyrrolinylcarbonyl 5-n-butyl-
(1- 2- 3- 4- or 5-)3-pyrrolinylcarbonyl 2-n-pentyl-
(1- 2- 3- 4- or 5-)3-pyrrolinylcarbonyl 2-n-hexyl-
(1- 2- 3- 4- or 5-)3-pyrrolinylcarbonyl 25-dimethyl-
(1- 2- 3- 4- or 5-)3-pyrrolinylcarbonyl 24-dimethyl-
(1- 2- 3- or 5-)3-pyrrolinylcarbonyl 23-dimethyl-
(1- 2- 4- or 5-)3-pyrrolinylcarbonyl and 245-trimethylthio-
(1- 2- 3- or 5-)3-pyrrolinylcarbonyl.
Examples of thiazolidinylcarbonyl groups optionally
substituted on the thiazolidine ring with a phenyl group includes
-36-
(2- 3- 4- or 5-)thiazolidinylcarbonyl 2-phenyl-
(3- 4- or 5-)thiazolidlnylcarbonyl 3-phenyl-(2- 4- or 5-)
thiazolidinylcarbonyl 4-phenyl-(2- 3- or 5-)
thiazolidlnylcarbonyl and 5-phenyl-(2- 3- or 4-)
thiazolidinylcarbonyl.
Examples of piperidinyl lower alkyl groups include
piperidinylalkyl groups wherein the alkyl moiety is a straight or
branched Ci_6 alkyl group such as [(!- 2- 3- or 4-)
piperidinyl]methyl 2-[(l- 2- 3- or 4-)piperidinyl]ethyl 1-
[(!- 2- 3- or 4-)piperidinyl]ethyl 3-[(l- 2- 3- or 4-
piperidinyl]propyl 4-[(l- 2- 3- or 4-)piperidinyl]butyl 5-
[(!- 2- 3- or 4-)piperidinyl]pentyl 6-[(l- 2- 3- or 4-)
piperidinyl]hexyl ll-dimethyl-2-[(1- 2- 3- or 4-)
piperidinyl]ethyl and 2-methyl-3-[(1- 2- 3- or 4-)
piperidinyl]propyl.
Examples of anilino lower alkyl groups optionally
substituted on the amino group with one or more lower alkyl
groups include anilinoalkyl groups optionally substituted on the
amino group with one or more straight and/or branched Ci_6 alkyl
groups such as anilinomethyl N-methylanilinomethyl Nethylanilinomethyl
N-n-propylanilinomethyl Nisopropylanilinomethyl
N-n-butylanilinomethyl N-seebut
ylanilinomethyl N-tert-butylanilinomethyl N-npentylanilinomethyl
N-n-hexylanilinomethyl 2-anilinoethyl 2-
(N-methylanilino) ethyl 2 - (N-ethylanilino) ethyl 2 - (N-n -
propylanilino)ethyl 2-(N-isopropylanilino)ethyl 2-(N-nbutylanilino)
ethyl 2-(N-sec-butylanilino)ethyl 2-(N- tert -
butylanilino)ethyl 2-(N-n-pentylanilino)ethyl 2-(N-nhexylanilino)
ethyl 3-anilinopropyl 3-(N-methylanilino)propyl
4-(N-ethylanilino)butyl 4-(N-n-propylanilino)butyl 5-(Nisopropylanilino)
pentyl 5-(N-n-butylanilino)pentyl 6-(N-secbutylanilino)
hexyl 6-(N- tert -butylanilino)hexyl 6 - (N-n -
pentylanilino)hexyl and 6-(N-n-hexylanilino)hexyl.
Examples of phenylthio lower alkyl groups include
phenylthioalkyl groups wherein the alkyl moiety is a straight or
-37-
branched Ci_6 alky! group such as phenyl thiomethyl 2-
phenylthioethyl 1-phenylthioethyl 3-phenylthiopropyl 4-
phenylthiobutyl 5-phenylthiopentyl 6-phenylthiohexyl 11-
dimethyl-2-phenylthioethyl and 2-methyl-3-phenylthiopropyl.
Examples of indolinyl lower alkyl groups include
indolinylalkyl groups wherein the alkyl moiety is a straight or
branched Ci_6 alkyl group such as
[(!- 2- 3- 4- 5- 6- or 7-)indolinyl]methyl
2-[(l- 2- 3- 4- or 5-)indolinyl]ethyl
!-[(!- 2- 3- 4- 5- 6- or 7)indolinyl]ethyl
3-[(l- 2- 3- 4- 5- 6- or 7)indolinylIpropyl
4-[(l- 2- 3- 4- 5- 6- or 7)indolinyl]butyl
5-[(l- 2- 3- 4- 5- 6- or 7)indolinylJpentyl
6-[(l- 2- 3- 4- 5- 6- or 7)indolinyl]hexyl
ll-dimethyl-2-[(l- 2- 3- 4- 5- 6- or 7)indolinyl]ethyl
and 2-methyl-3-[(l- 2- 3- 4- 5- 6- or 7)indolinyl]propyl.
Examples of piperidinylcarbonyl groups optionally
substituted on the piperidine ring with one or more lower alkyl
groups include piperidinylcarbonyl groups optionally substituted
on the piperidine ring with one to three straight and/or branched
Ci-6 alkyl groups such as (1- 2- 3- or 4-)piperidinylcarbonyl
l-methyl-(2- 3- or 4-)piperidinylcarbonyl
1-ethyl-(2- 3- or 4-)piperidinylcarbonyl
l-n-propyl-(2- 3- or 4-)piperidinylcarbonyl
l-n-butyl-(2- 3- or 4-)piperidinylcarbonyl
l_n-pentyl-(2- 3.^ or 4-)piperidinylcarbonyl
l-n-hexyl-(2- 3- or 4-)piperidinylcarbonyl
12-dimethyl-(3- 4- 5- or 6-)piperidinylcarbonyl
l23-trimethyl-(4- 5- or 6-)piperidinylcarbonyl
2-n-propyl-(l- 3- 4- 5- or 6-)piperidinylcarbonyl
3-ethyl-(l- 2- 4- 5- or 6-) piperidinylcarbonyl and
2-methyl-4-isopropyl-(l- 3- 5- or 6-)piperidinylcarbonyl.
Examples of phenyl lower alkyl groups optionally
substituted on the phenyl ring with one or more members selected
from the group consisting of a phenyl group lower alkyl groups
-38-
lower alkoxy groups halogen atoms -(B)iNR6R7 groups a nitro
group a carboxy group lower alkoxycarbonyl groups a cyano
group phenyl lower alkoxy groups a phenoxy group piperidinyl
lower alkoxycarbonyl groups amino lower alkoxycarbonyl groups
optionally substituted with one or more cycloalkyl groups 2-
imidazolinylcarbonyl groups optionally substituted on the 2-
imidazoline ring with one or more lower alkylthio groups 3-
pyrrolinylcarbonyl groups optionally substituted on the pyrroline
ring with one or more lower alkyl groups a thiazolidinylcarbonyl
groups optionally substituted on the thiazolidine ring with a
phenyl group 3-azabicyclo[3.2.2] nonylcarbonyl groups
piperidinyl lower alkyl groups aniline lower alkyl groups
optionally substituted on the amino group with one or more lower
alkyl groups phenylthio lower alkyl groups indolinyl lower
alkyl groups and piperidinylcarbonyl groups optionally
substituted on the piperidine ring with one or more lower alkyl
groups include:
mono- and di-phenylalkyl groups wherein the alkyl
moiety is a straight or branched Ci-6 aklyl group optionally
substituted on the phenyl ring with one to three members selected
from the group consisting of a phenyl group the above-described
straight and branched Ci_6 alkyl groups the above-described
straight and branched Ci-6 alkoxy groups halogen atoms the belowdescribed
-(B)iNR6R7 groups a nitro group a carboxyl group the
above-described straight and branched Ci-6 alkoxycarbonyl groups
a cyano group the above-described phenylalkoxy groups wherein
the alkoxy moiety is a straight or branched Ci_6 alkoxy group a
phenoxy group the above-described piperidinylalkoxycarbonyl
groups wherein the alkoxy moiety is a straight or branched Ci_6
alkoxy group the above-described aminoalkoxycarbonyl groups
wherein the alkoxy moiety is a straight or branched Ci-6 alkoxy
group optionally substituted with one or two C3-8 cycloalkyl
groups the above-described 2-imidazolinylcarbonyl groups
optionally substituted on the 2-jjnidazoline ring with one to
three straight and/or branched Ci-6 alkylthio groups the above-
39-
described 3-pyrrolinylcarbonyl groups optionally substituted on
the 3-pyrroline ring with one to three straight and/or branched
Ci-6 alkyl groups thiazolidinylcarbonyl groups optionally
substituted on the thiazolidine ring with a phenyl group 3-
azabicyclo[3.2.2]nonylcarbonyl groups piperidinylalkyl groups
wherein the alkyl moiety is a straight or branched d-6 alkyl
group anilinoalkyl groups wherein the alkyl moiety is a straight
or branched Ci_6 alkyl group optionally substituted on the amino
group with one or two straight and/or branched Ci-6 alkyl groups
phenylthioalkyl groups wherein the alkyl moiety is a straight or
branched Ci.6 alkyl group indolinylalkyl groups wherein the alkyl
moiety is a straight or branched Ci-e alkyl group and the abovedescribed
piperidinylcarbonyl groups optionally substituted on
the piperidine ring with one to three straight and/or branched
Ci-e alkyl groups
such as benzyl 1-phenethyl 2-phenethyl 3-
phenylpropyl 2-phenylpropyl 4-phenylbutyl 5-phenylpentyl 4-
phenylpentyl 6-phenylhexyl 2-methyl-3-phenylpropyl 11-
dlmethyl-2-phenylethyl 11-diphenylmethyl 22-diphenylethyl
33-diphenylpropyl 12-diphenylethyl 4-[W-(3-pyridyl)
aminocarbonyl]benzyl 4-[N- (2-methoxyphenyl)aminocarbonyl]benzyl
4 - [ 2 - (2 - piperidinyl) ethoxycarbonyl ] benzyl 4 - [ 2 - (cyclohexylamino)
ethoxycarbonyl]benzyl 4-[4-(3-pyridylmethyl)-1-
piperaz inylcarbonyl]benzyl 4-[4-(4-pyridylmethyl)-1-
piperazinylcarbonyl]benzyl 4-[4-(2-pyridylmethyl)-1-
piperazinylcarbonyl]benzyl 4-[4-(2-pyridyl)-1-
piperazinylcarbonyl]benzyl 4-[4-(3-chlorophenyl)-1-
piperaz inylcarbonyl]benzyl 4-[4-(2-fluorophenyl) -1 -
piperazinylcarbonyl]benzyl 4-[4-(2-pyrimidyl)-1-
piperaz inylcarbonyl]benzyl 4-(4- cyclopentyl-1-
piperazinylcarbonyl)benzyl 4-[4-(2-methoxyphenyl)-1-
piperaz inylcarbonyl]benzyl 4-[4-(4-fluorophenyl)-1-
piperazinylcarbonyl]benzyl 4-[4-(34 -methylenedioxybenzyl)-1-
piperaz inylcarbonyl] benzyl 4- (//-cyclohexyl-Wmethylaminocarbonyl)
benzyl 4- (NN-di-n-butylaminocarbonyl)benzyl
-40-
4-[4-(1-piperidinyl)-1-piperidinylcarbonyl]benzyl 4-(1-
homopiperidinylcarbonyl)benzyl 4-[2-methylthlo-1 - (2 -
imidazolinyl)carbonyl]benzyl 4- {N-[2-(2-pyridyl)ethyl]-Nmethylaminocarbonyl}
benzyl 4- [N- (1 -methyl- 4 -piperidinyl) -Nmethylaminocarbonyl
] benzyl 4 - (N //-diisobutylaminocarbonyl) benzy
4 - [ N- (2 -1 e t rahydropyranyl) methyl -N- e thylaminocarbonyl ] ben zyl 4 -
(4-thiomorpholinocarbonyl)benzyl 4-[25-dimethyl-1 - (3 -
pyronyl)carbonyl]benzyl 4-(3-thiazolidinylcarbonyl)benzyl 4-(JVcyclopropylmethyl-
N-n-propylaminocarbonyl)benzyl 4-[l-(3-
azabicyclo[3.2.2]nonylcarbonyl)benzyl 4-(N-cyclopentyl-Nallylaminocarbonyl)
benzyl 4-[4-(4-pyridyl)-1-
piperazinylcarbonyl]benzyl 4-[4-(4-trifluoromethylphenyl)-1-
piperaz inylcarbonyl]benzyl 4-[4-(2-phenylethyl)-1-
piperazinylcarbonyl]benzyl 4-[4-(2-pyrazyl)-1-
piperazinylcarbonyl]benzyl 4-(N-n-butylaminocarbonyl)benzyl 4-
(N- cyclopropylaminocarbonyl) benzyl 4 - [N- (1 -methyl -1 - phenylethyl)
aminocarbonyl]benzyl 4- (W-benzylaminocarbonyl)benzyl 4-[AN (2-
chlorobenzyl)aminocarbonyl]benzyl 4- [N-(3-chlorobenzyl)
aminocarbonyl]benzyl 4-[N-(4-chlorobenzyl) aminocarbonyl]benzyl
4-[N-(2-pyridyl)methylaminocarbonyl]benzyl 4-[AM 3-pyridyl)
methylaminocarbonyl]benzyl 4-[(4-pyridyl)methylaminocarbonyl]
benzyl 4-[35-dimethyl-1-piperidinylcarbonyl]benzyl 4-[N- (2 -
furyl)methylaminocarbonyl]benzyl 4-[4-(2-fluorobenzyloxy) -1 -
piperidinylcarbonyl]benzyl 4-{4- [N-(2-phenylacetyl)-Nmethylamino]-
1-piperidinylcarbonyl}benzyl 4-[(4-methoxy-1-
piperidinyl)carbonyl]benzyl. 4-{[4-(34-dimethyl-1-piperazinyl)-
1-piperidinyl]carbonyl}benzyl 4-{[4-(4-chlorobenzoyl)-1-
piperidinyl]carbonyl}benzyl 4-{[4-(4-chlorobenzyl)-1-
piperidinyl]carbonyl}benzyl 4-[(4-ethylcarbamoylmethyl-lpiperidinyl)
carbonyl]benzyl 4-[(4-cyclohexyl-1-
piperidinyl)carbonyl]benzyl 4-{[4-(4-methoxyphenyl)-1-
piperidinyl]carbonyl}benzyl 4-{[4-(2-benzoxazolyl)-1-
piperazinyl]carbonyl}benzyl 4-[(4-anilinocarbonylmethyl-lpiperaz
inyl)carbonyl]benzyl 4-[(4-methyl-2-benzyl-1-
piperazinyl)carbonyl]benzyl 4-[(4-phenyl-3-oxo-l-
41-
piperazinyl)carbonyl]benzyl 4-[(4-tert-butyl-3-oxo-lpiperazinyl)
carbonyl]benzyl 4-[N-(l-benzoyl-4-piperidinyl)-Nmethylaminocarbonyl]
benzyl 4- [N-(1-acetyl-4-piperidlnyl)-Nmethylaminocarbonyl]
benzyl 4-{[4-(4-cyanophenyl) -1 -
piperazinyl]carbonyl}benzyl 4-[N-methylcarbamoylmethyl-Nben
zy laminocarbonyl ] benzyl 4 - [ N- benzyl -Ncyclohexylaminocarbonyl
] benzyl 4 - [ 2 - (N-methyl -Nphenylcarbamoyl)
ethyl -N-methylaminocarbonyl ] benzyl 4 - { [ 4 - (3 -
phenyl-1-pyrrolidinyl)-1-piperidinyl]carbonyl}benzyl 4-
[(1234-tetrahydroisoquinoline-2-yl)carbonyl]benzyl 4 - [ (4 -
benzyl-1-piperidinyl)carbonyl]benzyl 4-{[4-(34-
methylenedioxybenzoyl) -1 -piperazinyl] carbonyl}benzyl 4 - [Nme
thyl -N- (4 -me thylbenzyl) aminocarbonyl ] benzyl 4 - [ N-me thyl -N-
(34 -me thylenedioxybenzyl) aminocarbonyl ] benzyl 4 - [N-me thyl -N- (2 -
methoxybenzyl) aminocarbonyl ]benzyl 4 - [ (4-phenyl-1 -piperazinyl)
carbonyl] benzyl 4 - [ (4 -phenyl- 4-hydroxy-1 -piperidinyl) carbonyl ]
benzyl 4-(N-isopropyl-N-benzylaminocarbonyl) benzyl 4-(N-ethyl-
N-cyclohexylaminocarbonyl)benzyl 4- [N-ethyl-N- (4-pyridyl)
me thy laminocarbonyl ] benzyl 4 - (N-n - propy laminocarbonyl) benzyl 4 -
[ N- ethyl -N- (4 - ethoxybenzyl) aminocarbonyl ] benzyl 4 - (N- ethyl -Ncyclohexylmethylaminocarbonyl)
benzyl 4 - [N- (2-ethoxyethyl)
aminocarbonyl]benzyl 4-[N-(II-dimethyl-2-phenylethyl)
aminocarbonyl ] benzyl 4 - [ { 4 - [N-methyl -N- (4 - chlorophenyl) amino ] -1 -
piperidinyl}carbonyl ]benzyl 4- [N- (1 -methyl-1 -cyclopentyl)
aminocarbonyl ] benzyl 4- [N- (1 -methyl-1 -cyclohexyl) aminocarbonyl ]
benzyl 4-{N-[2-(3-methoxyphenyl)ethyl]aminocarbonyl}benzyl 4-
[N- (4 - trif luoromethoxybenzyl) aminocarbonyl ] benzyl 4 - {N- [ 2 - (4 -
chlorophenyl) ethyl ] aminocarbonyl }benzyl 4-[N- (34-
me thylenedioxybenzyl) aminocarbonyl ] benzyl 4 - (Ncyclohexylmethylaminocarbonyl)
benzyl 4 - [N- (4 -f luorobenzyl)
aminocarbonyl ] benzyl 4 - [N- (1 -phenylethyl) aminocarbonyl ] benzyl
4- [N-(3-phenylpropyl)aminocarbonyl]benzyl 4-{N-[3-(l-imidazolyl)
propyl]aminocarbonyl}benzyl 4-[N-(2-phenylethyl)aminocarbonyl]
benzyl 4 - [ 2 - (NN-diisopropylamino) ethylaminocarbonyl ]benzyl 4-
{N- [ 1 -me t hoxycarbonyl - 2 - (4 -hydroxyphenyl) ethyl ] aminocarbonyl}
benzyl 4-[N-(carbamoylmethyl)aminocarbonyl]benzyl 4-{N-[lcarbamoyl-
2-(5-imidazolyl)ethyl]amlnocarbonyl}benzyl 4-{W-[ 1-
methoxycarbonyl-2-(5-imidazolyl)ethyl]amlno carbonyl}benzyl 4-
[N-(2-oxo-2345-tetrahydrofuran-3-yl)aminocarbonyl]benzyl 4-
[(2-ethoxycarbonyl-1-piperidinyl)carbonyl]benzyl 4-(Nmethoxycarbonylmethyl
-W-methylaminocarbonyl) benzyl 4 - [ (2 -
carbamoyl-1-pyrrolidinyl)carbonyl]benzyl 4-{[N- (26-
dimethylbenzyl) -N-ethyl]aminocarbonyl}benzyl 4-{W- [
methylphenyl)carbamoylmethyl] -N-methylamlnocarbonyl}benzyl 4-[N-
(4-chlorobenzyl)-N-ethylaminocarbonyl]benzyl 4-[N- (4-
trif luoromethylbenzyl) -N-ethylaminocarbonyl ] benzyl 4 - [N- (3 -
bromobenzyl)-AT-ethylaminocarbonyl]benzyl 4-{[4-(2-chlorobenzyl)-
1-piperidinyl]carbonyl}benzyl 4-{[4-(3-chlorobenzyl)-lpiperidinyl]
carbonyl}benzyl 4-{[4-(2-chlorobenzylldene)-1-
piperidinyl]carbonyl}benzyl 4- [N-(2-methoxybenzyl)aminocarbonyl]
benzyl 4-{//-[2-(2-fluorophenyl)ethyl]aminocarbonyl}benzyl 4-{N-
[2-(3-fluorophenyl)ethyl]aminocarbonyl}benzyl 4-[(4-
benzyloxycarbonyl-1-piperazinyl)carbonyl]benzyl 4-{[4-(3-cyano-
2-pyridyl)-l-piperazinyl]carbonyl}benzyl 4-[(4-phenyl-lpiperidinyl)
carbonyl]benzyl 4-[{4-[(3-furyl)methyl] -1 -
piperazinyl}carbonyl]benzyl 4-{[4-(3-pyridyl)-1-piperazinyl]
carbonyl}benzyl 4-{[4-(4-tetrahydropyranyl)-1-piperazinyl]
carbonyl}benzyl 4-{[4-(2-fluorobenzyl)-1-piperidinyl]carbonyl}
benzyl 4-{[4-(4-morpholino)-1-piperidinyl]carbonyl}benzyl 4-{4-
[2-(l3-dioxolane-2-yl)ethyl]-l-piperazinyl}carbonyl]benzyl 4-
phenylbenzyl 2-phenylbenzyl 3-phenylbenzyl 4-tert-butylbenzyl
4-aminobenzyl 4-nitrobenzyl 4-methoxycarbonylbenzyl 4-
carboxybenzyl 3-methoxy-4-chlorobenzyl 4-methoxybenzyl 246-
trimethoxybenzyl 34-dichlorobenzyl 4-chlorobenzyl 4-
bromobenzyl 246-trifluorobenzyl 4-fluorobenzyl 4-cyanobenzyl
4-piperidinylcarbonylbenzyl 4-anilinocarbonylbenzyl. 4-(ATcyclohexylaminocarbonyl)
benzyl 4-(W-benzoylamino)benzyl 4-(Ncyclohexylamino)
benzyl 4-phenylcarbamoylaminobenzyl 4-
methylbenzyl 34-dimethylbenzyl 345-trimethylbenzyl 4-
benzyloxybenzyl 4-ethylcarbamoylaminobenzyl 4-
-43-
ethylaminocarbonylbenzyl 4-isopropylaminocarbonylbenzyl 4-[tf-
(2-hydroxyethyl)aminocarbonyl]benzyl 4- [N-(3-pyridyl)
amlnocarbonyl ] benzyl 4 - [N- (4 - chlorophenyl) aminocarbonyl ] benzyl
4- [N-(4-isopropylphenyl)aminocarbonyl]benzyl 4- [N-(4-
phenoxyphenyl) aminocarbonyl ] benzyl 4 - [N- (3 -phenoxyphenyl)
aminocarbonyl ] benzyl 4 - [N- (3 -phenoxybenzoyl) amino ] benzyl 4 - [N-
(4-phenoxybenzoyl)amino]benzyl 4-[Ar-(4-chlorobenzoyl)amino]
benzyl 4-[AT-(2-chlorobenzoyl)amino]benzyl 4-[N-(26-
dichlorobenzoyl)amino]benzyl 4-[AM 4-methoxyphenyl)
aminocarbonyl ] benzyl 4 -[//-(2 -furylcarbonyl) amino ] benzyl 4 - [N-
(4 -methoxybenzoyl) amino ] benzyl 4 - f N- (3 -methoxybenzoyl) amino ]
benzyl 4-[//-(2-methoxybenzoyl)amino]benzyl 4-phenoxybenzyl 4-
n- pentyloxycarbonylaminobenzyl 4-[N-(4-methoxyphenoxycarbonyl)
amino]benzyl 4-[ N- (4-methylphenoxycarbonyl)amino]benzyl 4-
benzyloxycarbonylaminobenzyl 4-ethanoylaminobenzyl 4-(Nacetylamino)
benzyl 4-methylsulfonylaminobenzyl
methoxycarbonylaminobenzyl 4-[AM 4-isopropylphenyl)
aminocarbonyl]benzyl 4-[4-{2-[(1- 2- or 3-)imidazolyl]ethyl}-
1-piperazinylcarbonyl]benzyl 4-{4-[3-methyl-(2- 3- or 4-)
pyridyl]-1-piperazinyl carbony1}benzyl 4-{4-[4-methyl-
(2- 3- or 4-)pyridyl]-l-piperazinylcarbonyl}benzyl 4-[4-{2-
[(2- 3- or 4-)pyridyl]ethyl}-l-piperazinylcarbonyl]benzyl 4-
{4-4-[(1- or 2-)naphthyl]-(l- 2- or 3-)piperazinylcarbonyl}
benzyl 4-[(l- 2- 3- or 4- piperazinylcarbonyl)] benzyl 4-[2-
methyl-(l- 3- 4- 5- or 6-)piperidinylcarbonyl]benzyl 4-[3-
ethoxycarbonyl-(l- 2- 4- 5- or 6-Jpiperidinyl]benzyl 4-[4-
(3-hydroxyphenyl)-(l- 2- 4- 5- or 6-)piperidinyl]benzyl 4-
[4-hydroxy-4-benzyl-(l- 2- or 3-)piperidinylcarbonyl]benzyl 4-
[3-acetylamino-(l- 2- 4- or 5-)pyrrolidinylcarbonyl]benzyl 4-
[Mr-{2-[l-ethyl-(2- or 3-)pyrrolidinyl]ethyl}aminocarbonyl]benzyl
4-[//-{2-[(2- or 3-Jpyrrolidinyl]ethyl}aminocarbonyl]benzyl 4-[W-
{2-([2- 3- or 4-]morpholino)ethyl}aminocarbonyl]benzyl 4-[N-
{3-([2- 3- or 4-]morpholino)propyl}aminocarbonyl]benzyl 4-
[26-dimethyl-(3- 4- or 5-Jmorpholinocarbonyl]benzyl 4-[4-(4-
trifluoromethylanilino)-(l- 2- or 3-)piperazinylcarbonyl]benzyl
-44-
4-{2-[(l- 2- 3- or 4-) piperidlnylmethyl]-(3- 4- 5- or 6-)
morpholinocarbonyDbenzyl 4 - (W-methyl-N-n -pentylaminocarbonyl)
benzyl 4-{4-[(l- 2- 4- or 5-)23-dihydro-lH-indenyl]-
(1- 2- or 3-)piperidinylcarbonyl}benzyl 4-[AM 2-
methylcyclohexyl) aminocarbonyl]benzyl 4-
isoindolinylcarbonylbenzyl 4-[2-phenyl-(l- 3- 4- or 5-)
pyrrolidinylcarbonyl]benzyl 4-{2-[(l- 2- 3- or 4-
morpholinomethyl)-(l- 3- 4- or 5-)pyrrolidinylcarbonyl]
benzyl 4-[2-dimethylaminomethyl-(l- 3- 4- or 5-)
pyrrolidinylcarbonyl]benzyl 4- {N-[1-(4-fluorobenzoyl)-
(2- 3- or 4-)piperidinyl]-W-methylaminocarbonyl} benzyl
4-[2-phenyl-(3- 4- or 5-)thiazolidinylcarbonyl]benzyl 4-[Nmethyl-(
2-methoxyanilino)carbonyl]benzyl 4-(3-
methylthioanilinocarbonyl)benzyl 4-(2-
methylthioanilinocarbonyl)benzyl 4-(34-
dichloroanilinocarbonyl)benzyl 4-(4-trifluoromethoxy-4-
anilinocarbonyl)benzyl 4-anilinocarbonylbenzyl 4-(4-
chloroanilinocarbonyl)benzyl 4-(4-methoxyanilinocarbonyl)benzyl
4-(3-methoxyanilinocarbonyl)benzyl 4 - (2 -
chloroanilinocarbonyl)benzyl 4-(4-methylanilinocarbonyl)benzyl
4-(24-dimethoxyanilinocarbonyl)benzyl 4-(4 -methoxy-5-
chloroanilinocarbonyl)benzyl 4-(2-methoxy-5-
acetylaminoanilinocarbonyl)benzyl 4-(34-
dimethoxyanilinocarbonyl) benzyl 4 - [ 2 - (1 -methylallyl)
anilinocarbonyl]benzyl 4-(3-trifluoromethoxyanilinocarbonyl)
benzyl 4-(2-methylanilinocarbonyl)benzyl 4-(2-
fluoroanilinocarbonyl)benzyl 4-(3-fluoroanilinocarbonyl)benzyl
4-(4-fluoroanilinocarbonyl)benzyl 4-(3-
dimethylaminoanilinocarbonyl)benzyl 4-(4-
ethoxyanilinocarbonyl)ben zyl 4-(3-
trifluoromethylanilinocarbonyl)benzyl 4-(4-
trifluoromethylanilinocarbonyl)benzyl 4-(3-
acetylaminoanilinocarbonyl)benzyl 4-(4-
acetylaminoanilinocarbonyl)benzyl 4-[(2- 3- or 4 -
pyridylaminocarbonyl) benzyl 4 - [AT-methyl - (3 -
methylanilino)carbonyl]benzyl 4-[3-methoxy-(2 - 4- 5- or 6-
)pyridylaminocarbonyl]benzyl 4-(2-phenoxyanilinocarbonyl)benzyl
4-(3-phenoxyanilinocarbonyl)benzyl 4-(4-phenoxyanilinocarbonyl)
benzyl 4-(35-dichloroanilinocarbonyl)benzyl 4-(23-
dimethylanilinocarbonyl)benzyl 4-(24-dimethylanilinocarbonyl)
benzyl 4-(35-dimethylanilinocarbonyl)benzyl 4 - (35 -
difluoroanilinocarbonyl)benzyl 4-
[(!- 2- 3- 4- 5- 6- or 7-)indolylaminocarbonyl]benzyl 4-
(3-fluoro-4-methoxyanilinocarbonyl)benzyl 4-(4-
aminosulfonylanilinocarbonyl)benzyl 4-(4-methyl-3-
methoxyanilinocarbonyl)benzyl 4-(3-chloro-4-
methoxyanilinocarbonyl)benzyl 4-(3-chloro-4-
methylanilinocarbonyl)benzyl 4-(3-methoxy-5-
trifluoromethylanilinocarbonyl)benzyl 4-(3-chloro-4-
fluoroanilinocarbonyl)benzyl 4-[3-methyl-(2- 4- 5- or 6-
)pyridylaminocarbonyl]benzyl 4-[(2- 4- or 5 -
thiazolylaminocarbonyl)benzyl 4-(3-chloro-4-
hydroxyanilinocarbonyl)benzyl 4-(2-chloro-5-
acetylaminoanilinocarbonyl)benzyl 4-(4-
methylthioanilinocarbonyl)benzyl 4-(4-
isopropylanilinocarbonyl)benzyl 4-(4-tertbutylanilinocarbonyl)
benzyl 4-[(2- or 4-)124-
triazolylaminocarbonyl]benzyl 4-{4-[2-oxo-(l- 3- 4- or 5-)
pyrrolidinyl]anilinocarbonyl}benzyl 4-(4-methylsulfonylamino)
benzyl 4-(4-methylcarbamoylanilinocarbonyl)benzyl
anilinocarbonylbenzyl 4-(2-benzyloxyanilinocarbonyl)benzyl 4-
(4-vinylanilinocarbonyl)benzyl 4-(4-acetylaminoanilinocarbonyl)
benzyl 4-(3-acetylaminoanilinocarbonyl)benzyl 4-(4-
trifluoromethylanilinocarbonyl)benzyl 4-{3-[(2- 3- or 4-)
pyridyl]propionylamino}benzyl 4-(3-phenoxypropionylamino)benzyl
4-[(2- 3- or 4-) pyridylcarbonylamino]benzyl 4-{2-[(2- 3- or
4-) pyridyl]acetylamino}benzyl 4-[(2- or 3-)furylcarbonylamino]
benzyl 4-[(2- or 3-)thienylcarbonylamino]benzyl 4-{2-
[(2- or 3-)thienyl]acetylamino}benzyl 4-{2-[(l- 2- or 3-)
pyrrolyl]-(3- 4- 5- or 6-)pyridyl carbonylamino}benzyl 4-
cyclopentylcarbonylaminobenzyl 4 - cyclohexylcarbonylaminobenzyl
4 - (2 -cyclopentylacetylaird.no) benzyl 4 - (2 -cyclohexylcarbonyland.no)
benzyl 4-[l-benzoyl-(2- 3- or 4-)piperidlnylcarbonylamino]
benzyl 4-[l-acetyl-(2- 3- or 4-)piperidinylcarbonylamlno]
benzyl 4-[(2- 3- 4- 5- 6- 7- or 8-)chromanyl]benzyl 4-(2-
nitrobenzoyland.no)benzyl 4-(3-nitrobenzoyland.no)benzyl 4-(4-
nitrobenzoylamino)benzyl 4-(2-phenylbenzoyland.no)benzyl 4-(2-
dimethylaminobenzoyland.no) benzyl 4 - (2 -anilinobenzoylartd.no) benzyl
4 - (26 -dichlorobenzoylamino) benzyl 4 - (2 -cyanobenzoylarrd.no) benzyl
4 - (3 -phenoxybenzoyland.no) benzyl 4 - (2 -phenoxybenzoylarrd.no) benzyl
4-(4-phenoxybenzoylarrd.no)benzyl 4-[(l- or 2-)
naphthylcarbonyland.no ] benzyl 4 - (2 -methyl- 3 -fluorobenzoylarrd.no)
benzyl 4-(34-methylenedioxybenzoylamino)benzyl 4-{2-[l3-
dioxo-(2- 4- or 5-)isoindolinyl]acetylamino}benzyl 4-{2-[2-
thioxo-4-oxothiazolidinyl]acetylamino}benzyl 4-{3-
[(!- 2- 3- or 4-)piperidinyl]propionylarrd.no}benzyl 4-(4-
acetylbenzoyland.no) benzyl 4 - (2 - trifluoromethylbenzoylarrd.no)
benzyl 4 - (3 - trifluoromethylbenzoyland.no) benzyl 4 - (4 -
trifluoromethyIbenzoylamino)benzyl 4-[2-(2-chlorophenyl)
acetylamino]benzyl 4-(2-chloro-4-fluorobenzoyland.no)benzyl 4-
(2-chlorocinnamoylamino)benzyl 4-(34-
me thy lenedioxycinnamoylarrd.no) ben zyl 4-[3-(2- 3- or 4-)
pyridylvinylcarbonyland.no]benzyl 4-[2-chloro-(3- 4- 5- or 6-)
pyridylcarbonylarrd.no]benzyl 4-{2-[(2- 3- or 4-)pyridylthio]
acetylamino}benzyl 4-[(2- 3- 4- 5- 6- or 7-)
indolylcarbonyland.no]benzyl 4-[(l- 2- or 3-)
pyrrolylcarbonyland.no]benzyl 4-[2-oxo-(l- 3- 4- or 5-)
pyrrolidinylcarbonylamino]benzyl 4-[(2- 3- 4- 5- 6 - or 7-)
benzofurylcarbonylamino]benzyl 4-[26-dichloro-(3- 4- or 5-)
pyridylcarbonylarrd.no ] benzyl 4 - { 2 -
[(!- 2- 3- 4- 5- 6- or 7-)indolyl]acetylamino}benzyl 4-
[(2- 3- 4- 5- 6- or 7-)benzothienylcarbonyland.no]benzyl 4-
{4-[2-oxo-(l- 3- 4- or 5-)pyrrolidinyl]benzoylamino}benzyl 4-
{4-[(l- 2- or 3-Jpyrrolyllbenzoylarrd.no}benzyl 4-{4-
[(!- 3- 4- or 5-) pyrazolyl]benzoylarrd.no}benzyl 4-{4-
-47-
[(!- 3- or 5-)l24-triazolyl]benzoylamino}benzyl 4-{4-
[(!- 2- 4- or 5-)lmidazolyl]benzoylamlno}benzyl 4-[4-(35-
dlmethyl-4-isoxazolyl)benzoylamino]benzyl 4-[(2- or 3-)
pyrazylcarbonylamlno ] benzyl 4 - (2 -methoxybenzoylamino) benzyl 4 -
(2-methoxy-5-chlorobenzoylamino)benzyl 4-(4-chlorobenzoylamino)
benzyl 4-(2-phenoxyacetylamino)benzyl 4-(3-phenylpropionyl)
benzyl 4-[(2- 3- or 4-)pyridylcarbonylamino]benzyl 4-
benzoylaminobenzyl 4-cinnamoylaminobenzyl
4-(4-methoxyphenylsulfonylamino)benzyl
4-(3-methoxyphenylsulfonylamino)benzyl
4 - (2 -methoxyphenylsulf onylamino) benzyl
4-(4-chlorophenylsulfonylamino)benzyl
4-(3-chlorophenylsulfonylamino)benzyl
4-(2-chlorophenylsulfonylamino)benzyl
4-(2 -methylphenylsulfonylamino)benzyl
4 - (3 -methylphenylsulfonylaird.no) benzyl
4 - (4 -methylphenylsulfonylaird.no) benzyl
4 - (4 - fluorophenylsulfonylarrd.no) benzyl
4 - (3-f luorophenylsulfonylarrd.no) benzyl
4 - (2 - fluorophenylsulfonylarrd.no) benzyl
4-(2-methoxy-5-chlorophenylsulfonylamino)benzyl
4-(2-trifluoromethylphenylsulfonylamino)benzyl
4 - (3 - trif luorome thy lphenylsulfonylarrd.no) benzyl
4-(4-trifluoromethylphenylsulfonylamino)benzyl
4-[(2- or 3-)thienylsulfonylaird.no]benzyl
4 - (2 - chlorophenylsulfonylarrd.no) benzyl
4 - (2 - trifluoromethoxyphenylsulfonylarrd.no) benzyl
4 - (3 - trifluoromethoxyphenylsulfonylarrd.no) benzyl
4 - (4 - trifluoromethoxyphenylsulfonylarrd.no) benzyl
4 - (2 -me thoxycarbonylphenylsulfonylarrd.no) benzyl
4 - (2 - cyanophenylsulfonylarrd.no) benzyl
4 - (3 -cyanophenylsulfonylarrd.no) benzyl.
4 - (4 -cyanophenylsulfonyland.no) benzyl
4 - (34 - dimethoxyphenylsulfonylatrd.no) benzyl
4-(25-dimethoxyphenylsulfonylamino)benzyl
4 - (2 -nitrophenylsulfonyland.no) benzyl
4 - (3 -nitrophenylsulfonyland.no) benzyl
4 - (4 -nitrophenylsulfonyland.no) benzyl
4-(4-bromophenylsulfonylamino)benzyl
4 - (3 -bromophenylsulfonyland.no) benzyl
4-(2-bromophenylsulfonylamino)benzyl
4-(4-n-butyIphenylsulfonylamino)benzyl
4 - (2 -methoxy- 5 -chlorophenylsulfonyland.no) benzyl
4-(26-dichlorophenylsulfonylamino)benzyl
4-[(l- 2- 3- 4- 5- 6- 7- or 8-)quinolylsulfonylamino]
benzyl 4-[l-methyl-(2- 4- or 5-)imidazolylsulfonylamino3benzyl
4-(23-dichlorophenylsulfonylamino)benzyl
4-(25-dichlorophenylsulfonylamino)benzyl
4-(24-dichlorophenylsulfonylamino)benzyl
4-(3-nitro-4-methyIphenylsulfonylamino)benzyl
4-(2-chloro-4-fluorophenylsulfonylamino)benzyl
4 - (24 - dichloro- 5 -me thy Iphenylsulf onylamino) benzyl
4-(2-methyl-5-nitrophenylsulfonylamino)benzyl
4-(2-chloro-5-nitrophenylsulfonylamino)benzyl
4-(2-chloro-4-cyanophenylsulfonylamino)benzyl
4-(246-trlmethyIphenylsulfonylamino)benzyl
4-(4-acetylaminophenylsulfonylamino)benzyl
4 - (35 - dichloro - 2 -hydroxyphenylsulf onylamino) benzyl
4-(4-methoxy-2-nitrophenylsulfonylamino)benzyl
4-(34-dichlorophenylsulfonylamino)benzyl
4-(4-tert-butylphenylsulfonylamino)benzyl
4-(4-carboxyphenylsulfonylamino)benzyl
4-(2-bromo-5-chlorophenylsulfonylamino)benzyl
4-(4-ethyIphenylsulfonylamino)benzyl
4-(25-dimethylsulfonylamino)benzyl
4-(4-n-butoxyphenylsulfonylamino)benzyl
4-(25-difluorophenylsulfonylamino)benzyl
4-(2-chloro-4-acetylaminophenylsulfonylamino)ben zyl
4-(24-difluorophenylsulfonylamino)benzyl
4-(2-methoxy-4-methylphenylsulfonyland.no)benzyl
-49-
4 - (2 -methyl - 3 - chlorophenylsulfonylamino) benzyl
4 - (26 -dif luorophenylsulf onylamino) benzyl
4-(34-difluorophenylsulfonylamino)benzyl
4 - (2 -methyl - 5 - f luorophenylsulf onylamino) benzyl
4 - (3 -methyl- 4 -chlorophenylsulfonylamino) benzyl
4-(2-methyl-6-chlorophenylsulfonylamino)benzyl
4-(4-isopropylphenylsulfonylamino)benzyl
4-(34-dichlorophenylsulfonylamino)benzyl
4 - (2 - f luoro - 4 - bromophenylsulf onylamino) benzyl
4- (4-methyl-3-chlorophenylsulf onylamino) benzyl
4 -vinylsulfonylaminobenzyl 4 - (3 -chloropropylphenylsulfonylamino)
benzyl 4 - cyclohexylmethylsulfonylaminobenzyl 4 - [ 2 - chloro -
(3 - 4 - or 5 -) thienylsulf onylamino ] benzyl 4 - (35 -
dichlorophenylsulfonyland.no) benzyl 4-{4-[2-(4-
methoxycarbonyl) ethyl ] phenylsulfonyland.no } benzyl 4 - [ 4 -methyl -
(2- 3- 4- 5- 6- 7- or 8-)34-dihydro-2H-l4-dihydro-2H-l4-
benzoxazinylsulfonyland.no ] benzyl 4 - (222 -
trifluoroethylsulfonyland.no)benzyl 4-(235-trimethyl-4-
methoxyphenylsulfonyland.no) benzyl 4 - [ (13 - dimethyl - 5 - chloro - 4 -
pyrazolyl)sulfonylamino]benzyl 4-[(35-dimethyl-4-isoxazolyl)
sulfonyland.no ] benzyl 4 - (3 -carboxy- 4-hydroxyphenylsulfonyland.no)
benzyl 4-{[23-dichloro-(4- or 5-)thienyl]sulfonylamino}benzyl
4-{[25-dichloro-(3- or 4-)thienyl]sulfonylamino}benzyl 4-{[2-
bromo-{3- 4- or 5-)thienyl]sulfonylamino}benzyl 4-(4-
carboxyphenylsulfonyland.no) benzyl 4 - (2 - acetylamino - 4 -methyl - 5 -
thiazolylsulfonyland.no) benzyl 4 - {[ 2 -methoxycarbonyl-
(3- 4- or 5-)thienyl]sulfonylamino}benzyl 4-
benzylsulfonylaminobenzyl 4-styrylsulfonylaminobenzyl 4-(245-
trifluorophenylsulfonyland.no) benzyl 4 -phenylsulfonylaminobenzyl
4-phenoxycarbonylaminobenzyl 4 - [ (4 -chlorophenoxy) carbonyland.no ]
benzyl 4 - [ (4 -bromophenoxy) carbonyland.no ] benzyl 4 -
benzyloxycarbonylaminobenzyl 4-methoxycarbonylaminobenzyl 4-nbutoxycarbonylaminobenzyl
4 - [ (4 -methoxyphenoxy) carbonylamino ]
benzyl 4-[(3-methoxyphenoxy)carbonylamino]benzyl 4-[(2-
methoxyphenoxy)carbonylamino]benzyl 4-[(l- or 2-)
-50-
naphthyloxycarbonylamino ] benzyl 4 - [ (4 - f luorophenoxy)
carbonylamino ] benzyl 4 - [ (4 -methylphenoxy) carbonylamino ] benzyl
4-[(2-chlorobenzyloxy)carbonylamino]benzyl 4 - [ 2 -
propynyloxycarbonylamino]benzyl 4- [ (4-nitrophenoxy)
carbonylamino]benzyl 4-(2-fluoroethoxycarbonylamino)benzyl 4-
(3 - butenyloxycarbonylamino) benzyl 4 - (4 -
chlorobutoxycarbonylamino) benzyl 4 - (2 - chloroethoxycarbonylamino)
benzyl 4-[2-(benzyloxy)ethoxycarbonylamino]benzyl 4-
propoxycarbonylaminobenzyl 4 -n -butoxycarbonylaminobenzyl 4 - (2 -
isopropyl- 5-methylcyclohexyloxycarbonylamino)benzyl 4- [ (4 -
nitrobenzyloxy)carbonylamino]benzyl 4-(2-
ethylhexyloxycarbonylamino) benzyl 4- [AT-methyl- (4 -
chloroanilino) carbonyl ] benzyl 4 - [ (2-chloroanilino) carbonyl ]
benzyl 4-[(3-cyanoanilino)carbonyl]benzyl 4-[(4-cyanoanilino)
carbonyl]benzyl 4-[(2-cyanoanilino)carbonyl]benzyl 4-[(2-
chloro-4-fluoroanilino)carbonyl]benzyl 4-[(l- or 5-)
tetrazolylaminocarbonyl ] benzyl 4 - [ 5 -methyl- (3 - or 4 -)
isoxazolylaminocarbonyl]benzyl 4-{4-[4-methyl-
(1- 2- 3- or 4-)piperazinyl]anilinocarbonyl}benzyl
(2- 3- or 4-)(l-piperidinylmethyl)benzyl (2- 3- or 4-)(/7-
methylanilinomethyl)benzyl (2- 3- or 4-)(phenylthiomethyl)
benzyl and (2- 3- or 4-)(1-indolylmethyl)benzyl.
Examples of cycloalkyl lower alkyl groups include C3.8
cycloalkylalkyl groups wherein the alkyl moiety is a straight or
branched Ci_6 alkyl group such as cyclopropylmethyl
cyclohexylmethyl 2-cyclopropylethyl 1-cyclobutylethyl
cyclopentylmethyl 3-cyclopentylpropyl 4-cyclohexylbutyl 5-
cycloheptylpentyl 6-cyclooctylhexyl 11-dimethyl-2-
cyclohexylethyl and 2-methyl-3-cyclopropylpropyl.
Examples of phenoxy lower alkyl groups include phenoxy
alkyl groups wherein the alkyl moiety is a straight or branched
Ci_6 alkyl group such as phenoxymethyl 2-phenoxyethyl 1-
phenoxyethyl 3-phenoxypropyl 4-phenoxybutyl 11-dimethyl-2-
phenoxyethyl 5-phenoxypentyl 6-phenoxyhexyl 1-phenoxyisopropyl
and 2-methyl-3-phenoxypropyl.
-51-
Examples of naphthyl lower alkyl groups include
naphthylalkyl groups wherein the alkyl moiety is a straight or
branched Ci_6 alkyl group such as (1- or 2-)naphthylmethyl
2-[(l- or 2-)naphthyl]ethyl !-[(!- or 2-)naphthyl]ethyl
3-[(l- or 2-)naphthyl]propyl 4-[(l- or 2-)naphthyl]butyl
5-[(l- or 2-)naphthyl]pentyl 6-[(l- or 2-)naphthylJhexyl 11-
dimethyl-2-[(l- or 2-)naphthyl]ethyl and 2-methyl-3-[(l- or 2-)
naphthyl]propyl.
Examples of lower alkoxy lower alkyl groups include
alkoxyalkyl groups wherein the alkyl moiety is a straight or
branched Ci-e alkyl group and the alkoxy moiety is a straight or
branched Ci-e alkoxy group such as methoxymethyl 2-methoxyethyl
1-ethoxyethyl 2-ethoxyethyl 3-n-butoxypropyl 4-n-propoxybutyl
1-methyl-3-isobutoxypropyl 11 - dime thyl - 2 -n- pentyloxye thyl 5-nhexyloxypentyl
6-methoxyhexyl 1-ethoxyisopropyl and 2-me thyl-
3-methoxypropyl.
Examples of carboxy lower alkyl groups include
carboxyalkyl groups wherein the alkyl moiety is a straight or
branched d-6 alkyl group such as carboxymethyl 2-carboxyethyl
1-carboxyethyl 3-carboxypropyl 4-carboxybutyl 5-carboxypentyl
6-carboxyhexyl ll-dimethyl-2-carboxyethyl and 2-methyl-3-
carboxypropyl.
Examples of lower alkoxycarbonyl lower alkyl groups
include alkoxycarbonylalkyl groups wherein the alkoxy moiety is a
straight or branched Ci_6 alkoxy group and the alkyl moiety is a
straight or branched Ci_6 alkyl group such as
methoxycarbonylmethyl ethoxycarbonylmethyl 2-
methoxycarbonylethyl. 2-ethoxycarbonylethyl 1-
ethoxycarbonylethyl 3-methoxycarbonylpropyl 3-
ethoxycarbonylpropyl 4-ethoxycarbonylbutyl 5-
isopropoxycarbonylpentyl 6-n-propoxycarbonylhexyl 11-dimethyl-
2-ii-butoxycarbonylethyl 2-methyl-3-tert-butoxycarbonylpropyl 2-
n-pentyloxycarbonylethyl and n-hexyloxycarbonyl methyl.
Examples of piperazinyl groups optionally substituted
on the piperazine ring with one or more members selected from the
-52-
group consisting of a phenyl group and lower alkyl groups
include:
piperazinyl groups optionally substituted on the
piperazine ring with one to three members selected from the group
consisting of a phenyl group and straight and branched Ci_6 alkyl
groups
such as (I- or 2-)piperazinyl 4-methyl-(l- 2- or 3-)
piperazinyl 4-ethyl-(l- 2- or 3-)piperazinyl 4-n-propyl-
1- 2- or 3-)piperazinyl 4-tert-butyl-(l- 2- or 3-)
piperazinyl 4-sec-butyl-(l- 2- or 3-) piperazinyl 4-n-butyl-
(1- 2- or 3-)piperazinyl 4-n-pentyl-(l- 2- or 3-)piperazinyl
4-n-hexyl-(l- 2- or 3-)piperazinyl 34-dimethyl-
(1- 2- 5- or 6-)piperazinyl 345-trimethyl-(l- or 2-)
piperazinyl 4-phenyl-(l- 2- or 3-)piperazinyl 24-diphenyl-
(1- 3- 5- or 6-)piperazinyl 234-triphenyl-(l- 5- or 6-)
piperazinyl and 4-phenyl-2-methyl-(l- 3- 5- or 6-)piperazinyl.
Examples of pyridylamino groups include (2- 3- or 4-)
pyridylamino.
Examples of pyridylcarbonylamino groups include
(2- 3- or 4-)pyridylcarbonylamino.
Examples of anilino groups optionally substituted on
the amino group with one or more lower alkyl groups include
anilino groups optionally substituted on the amino group with one
or more straight and/or branched Ci_6 alkyl groups such as anilino
N-methylanilino N-ethylanilino W-n-propylanilino Nisopropylanilino
tf-n-butylanilino W-sec-butylanilino N-tertbutylanilino
N-n-pentylanilino and N-n-hexylanilino.
Examples of pyridyl lower alkyl groups optionally
substituted on the pyridine ring with one or more members
selected from the group consisting of halogen atoms piperidinyl
groups a morpholino group piperazinyl groups optionally
substituted on the piperizine ring with one or more members
selected from the group consisting of a phenyl group and lower
alkyl groups thienyl groups a phenyl group pyridyl groups
piperidinyl lower alkyl groups phenylthio lower alkyl groups
-53-
biphenyl groups lower eilkyl groups optionally substituted with
one or more halogen atoms pyridylamino groups
pyridylcarbonylamino groups lower alkoxy groups aniline lower
alkyl groups optionally substituted on the amino group with one
or more lower alkyl groups and anilino groups optionally
substituted on the amino group with one or more lower alkyl
groups include:
pyridyl alkyl groups wherein the alkyl moiety is a Ci_6
straight or branched alkyl group optionally substituted on the
pyridine ring with one to three members selected from the group
consisting of the above-described halogen atoms piperidinyl
groups a morpholino group the above-described piperazinyl
groups optionally substituted on the piperazine ring with one to
three members selected from the group consisting of a phenyl
group and straight and branched Ci_6 alkyl groups thienyl groups
a phenyl group pyridyl groups piperidinylalkyl groups wherein
the alkyl moiety is a straight or branched Ci-e alkyl group
phenylthioalkyl groups wherein the alkyl moiety is a straight or
branched Ci-6 alkyl group biphenyl groups lower alkyl groups
wherein the alkyl moiety is a straight or branched Ci-6 alkyl
group optionally substituted with one to three halogen atoms
pyridylamino groups pyridylcarbonylamino groups straight and
branched Ci-6 alkoxy groups anilinoalkyl groups wherein the alkyl
moiety is a straight or branched Ci-6 alkyl group optionally
substituted on the amino group with one or two straight and/or
branched Ci-6 alkyl groups and the above-described anilino groups
optionally substituted on the amino group with one or more
straight and/or branched Ci-6 alkyl groups
such as (2- 3- or 4-)pyridyljnethyl
2-[(2- 3- or 4-)pyridyl]ethyl l-[(2- 3- or 4-) pyridyl]ethyl
3-t(2- 3- or 4-)pyridyl]propyl 4-[(2- 3- or 4-)pyridyl]butyl
ll-d±methyl-2-t(2- 3- or 4-)pyridyl]ethyl 5-[(2- 3- or 4-)
pyridyl]pentyl 6-[(2- 3- or 4-)pyridyl]hexyl 1-
[(2- 3- or 4-)pyridyl]isopropyl 2-methyl-3-[(2- 3- or 4-)
pyridyl]propyl (2-chloro-3-pyridyl)methyl [2-chloro-
54-
(3- 4- 5- or 6-)pyridyl]methyl [23-dichloro-(4- 5- or 6-)
pyridyl]methyl [2-bromo-(3- 4- 5- or 6-)pyridyl]methyl
[246-trifluoro-(3- 5- or 6-Jpyridyl] methyl [2-(lpiperidinyl)-(
3- 4- 5- or 6-Jpyridyl] methyl [2-(4-
morpholino)-(3- 4- 5- or 6-Jpyridyl]methyl [2-(4-methyl-lpiperazinyl)-(
3- 4- 5- or 6-)pyridyl]methyl 2-[2-(4-ethyl-lpiperazinyl)-(
3- 4- 5- or 6-)pyridyl]ethyl 3-[2-(4-isopropyll-
piperazinyl)-(3- 4- 5- or 6-) pyridylJpropyl 4-[2-(4-secbutyl-
l-piperazinyl)-(3- 4- 5- or 6-)pyridyl]butyl 5-[2-(4-npentyl-
l-piperazinyl)-(3- 4- 5- or 6-)pyridyl]pentyl 6-[2-(4-
n-hexyl-l-piperazinyl)-(3- 4- 5- or 6-)pyridyl]hexyl [2-(4-
phenyl-2-methyl-l-piperazinyl)-(3- 4- 5- or 6-)pyridyl]methyl
[2-(4-phenyl-l-piperazinyl)-(3- 4- 5- or 6-)pyridyl]methyl
[2-(3-thienyl)-(3- 4- 5- or 6-Jpyridyl]methyl [2-phenyl-
(3- 4- 5- or 6-Jpyridyl]methyl 2-[24-diphenyl-
(3- 5- or 6-)pyridyl]ethyl 3-[2-(2-pyridyl)-6-(3-thienyl)-
(3- 4- or 5-)pyridyl]propyl 4-(3-anilino-(2- 4- 5- or 6-)
pyridylbutyl 5-[2-(4-morpholino)-(3- 4- 5- or 6-)pyridyl]
pentyl 6-[2-(l-piperidinyl)-(3- 4- 5- or 6-)pyridyl]hexyl
[2-(2-pyridyl)-(3- 4- 5- or 6-Jpyridyl]methyl
(3- 4- 5- or 6-)(l-piperidinylmethyl)-2-pyridylmethyl
(3- 4- 5- or 6-)phenylthiomethyl-2-pyridylmethyl
(4- 5- or 6-)biphenyl-3-pyridylmethyl (4- 5- or 6-)
trifluoromethyl-3-pyridylmethyl (4- 5- or 6-)(2-pyridylamino)-
3-pyridylmethyl (4- 5- or 6-)[(2- or 3-)pyridylcarbonylamino]-
3-pyridylmethyl 35-dimethyl-4-methoxy-2-pyridylmethyl (3- 4-
5- or 6 -) (N-methylanilinomethyl) -2 -pyridylmethyl [ 2 - (Nmethylanilino)-(
3- 4- 5- or 6-)pyridyl]methyl 2-[2-(Nethylanilino)-(
3- 4- 5- or 6-)pyridyl]ethyl 3-[2-(N-npropylanilino)-(
3- 4- 5- or 6-)pyridyl]propyl 4-[2-(W-nbutylanilino)-(
3- 4- 5- or 6-)pyridyl]ethyl 5-[2-(N-npentylanilino)-(
3- 4- 5- or 6-)pyridyl]pentyl and 6-[2-(N-nhexylanilino)-(
3- 4- 5- or 6-)pyridyl]hexyl.
Examples of cyano lower alkyl groups include cyanoalkyl
groups wherein the alkyl moiety is a straight or branched Ci-6
-55-
alkyl group such as cyanomethyl 2-cyanoethyl 1-cyanoethyl 3-
cyanopropyl 4-cyanobutyl 11-dimethyl-2-cyanoethyl 5-
cyanopentyl 6-cyanohexyl 1-cyanoisopropyl and 2-methyl-3-
cyanopropyl.
Examples of quinolyl lower alkyl groups include
quinolylalkyl groups wherein the alkyl moiety is a straight or
branched d-6 alkyl group such as [(2- 3- 4- 5- 6- 7- or 8-)
quinolyl]methyl 2-[(2- 3- 4- 5- 6- 7- or 8-)quinolyl]ethyl
l-[(2- 3- 4- 5- 6- 7- or 8-)quinolyl]ethyl
3-[(2- 3- 4- 5- 6- 7- or 8-)quinolyl]propyl
4-[(2- 3- 4- 5- 6- 7- or 8-)quinolyl]butyl
ll-dimethyl-2-[(2- 3- 4- 5- 6- 7- or 8-)quinolyl]ethyl
5-[(2- 3- 4- 5- 6- 7- or 8-)quinolyl]pentyl
6-[(2- 3- 4- 5- 6- 7- or 8-)quinolyl]hexyl
l-[(2- 3- 4- 5- 6- 7- or 8-)quinolyl]isopropyl and
2-methyl-3-[(2- 3- 4- 5- 6- 7- or -8)quinolyl]propyl.
Examples of lower alkoxy lower alkoxy-substituted lower
alkyl groups include alkoxyalkoxy-substituted alkyl groups
wherein each of the two alkoxy moieties is a straight or branched
Ci-6 alkoxy group and the alkyl moiety is a straight or branched
Ci-e alkyl group such as methoxymethoxymethyl 2-
(methoxymethoxy)ethyl 1-(ethoxymethoxy)ethyl 3-(2-nbutoxyethoxy)
propyl 4-(3-n-propoxypropoxy)butyl 11-dimethyl-2-
(4-n-pentyloxybutoxy)ethyl 5-(5-n-hexyloxypentyloxy)pentyl 6-
(6-methoxyhexyloxy)hexyl 1-ethoxymethoxyisopropyl 2-methyl-3-
(2-methoxyethoxy)propyl and 33-dimethyl-3-(methoxymethoxy)
propyl.
Examples of hydroxy-substituted lower alkyl groups
include straight and branched Ci_6 alkyl groups substituted with
one to three hydroxy groups such as hydroxymethyl 2-
hydroxyethyl 1-hydroxyethyl 3-hydroxypropyl 23-
dihydroxypropyl 4-hydroxybutyl 34-dihydroxybutyl 11-
dimethyl-2-hydroxyethyl 5-hydroxypentyl 6-hydroxyhexyl 33-
dimethyl-3-hydroxypropyl 2-methyl-3-hydroxypropyl and 234-
trihydroxybutyl.
-56-
Examples of thiazolyl lower alkyl groups optionally
substituted on the thiazole ring with one or more members
selected from the group consisting of halogen atoms a phenyl
group thienyl groups and pyridyl groups include:
thiazolylalkyl groups wherein the alkyl moiety is a
straight or branched Ci-6 alkyl group optionally substituted on
the thiazole ring with one to three members selected from the
group consisting of halogen atoms a phenyl group thienyl groups
and pyridyl groups
such as t(2- 4- or 5-)thiazolyl]methyl 2-
[(2- 4- or 5-)thiazolyl]ethyl l-[(2- 4- or 5-)thiazolyl]
ethyl 3-[(2- 4- or 5-)thiazolyl]propyl 4-[(2- 4- or 5-)
thiazolyl]butyl 5-[(2- 4- or 5-)thiazolyl]pentyl 6-
[(2- 4- or 5-)thiazolylJhexyl 11-dimethyl-2-[(2- 4- or 5-)
thiazolyl]ethyl [2-methyl-3-[(2- 4- or 5-)thiazolyl]propyl
[2-chloro-(4- or 5-)thiazolyl]methyl 2-[2-chloro-(4- or 5-)
thiazolyl]ethyl l-[2-fluoro-(4- or 5-)thiazolyl]ethyl 3-[2-
bromo-(4- or 5-)thiazolylJpropyl 4-[2-iodo-(4- or 5-)
thiazolyl]butyl [2-phenyl-(4- or 5-)thiazolyl]methyl 2-[2-
phenyl-(4- or 5-)thiazolyl]ethyl l-[2-phenyl-(4- or 5-)
thiazolyl]ethyl 3-[2-phenyl-(4- or 5-)thiazolylJpropyl 4-[2-
phenyl-(4- or 5-)thiazolyl]butyl 5-[2-phenyl-(4- or 5-)
thiazolyl]pentyl 6-[2-phenyl-(4- or 5-)thiazolyl]hexyl 11-
dimethyl-2-[2-phenyl-(4- or 5-)thiazolyl]ethyl [2-methyl-3-[2-
phenyl-(4- or 5-)thiazolylJpropyl [2-(2- or 3-)thienyl-
(4- or 5-)thiazolyl]methyl 2-[2-(2- or 3-)thienyl-(4- or 5-)
thiazolylJethyl l-[2-(2- or 3-)thienyl-(4- or 5-)thiazolyl]
ethyl 3-[2-(2- or 3-)thienyl-(4- or 5-)thiazolylJpropyl 4-[2-
(2- or 3-)thienyl-(4- or 5-)thiazolylJbutyl 5-[2-(2- or 3-)
thienyl-(4- or 5-)thiazolyl]pentyl 6-[2-(2- or 3-)thienyl-
(4- or 5-)thiazolyl]hexyl ll-dimethyl-2-[2-(2- or 3-)thienyl-
(4- or 5-)thiazolyl]ethyl [2-methyl-3-[2-(2- or 3-)thienyl-(4-
or 5-) thiazolylJpropyl [2-(2- 3- or 4-)pyridyl-(4- or 5-)
thiazolyl]methyl 2-[2-(2- 3- or 4-)pyridyl-(4- or 5-)
thiazolyl]ethyl l-[2-(2- 3- or 4-)pyridyl-(4- or 5-)thiazolyl]
-57-
ethyl 3-[2-(2- 3- or 4-)pyridyl-(4- or 5-)thiazolyl]propyl 4-
[2-(2- 3- or 4-) pyridyl-(4- or 5-)thiazolyl]butyl 5-[2-
(2- 3- or 4-)pyridyl-(4- or 5-)thiazolyl]pentyl 6-[2-
(2- 3- or 4-)pyridyl-(4- or 5-)thiazolyl]hexyl 11-dimethyl-2-
[2-(2- 3- or 4-)pyridyl-(4- or 5-)thiazolyl]ethyl and [2-
methyl-3-[2-(2- 3- or 4-)pyridyl-(4- or 5-Jthiazolyl]propyl.
Examples of lower alkylsilyloxy lower alkyl groups
include alkylsilyloxyalkyl groups wherein each of the two alkyl
moieties is a straight or branched Ci-6 alkyl group such as
trimethylsilyloxymethyl (1- or 2-)(triethylsilyloxy)ethyl 3-
(trimethylsilyloxy)propyl dimethyl-tert-butylsilyloxymethyl 2-
(dimethyl- tert-butyls ilyloxy) ethyl 3-(dimethyl-tert -
butylsilyloxy)propyl 4-(dimethyl-tert-butylsilyloxy)butyl 5-
(dimethyl-tert-butylsilyloxy)pentyl and 6-(dimethyl-tertbutylsilyloxy)
hexyl.
Examples of phenoxy lower alkyl groups optionally
substituted on the phenyl ring with one or more members selected
from the group consisting of lower alkyl groups optionally
substituted with one or more halogen atoms lower alkoxy groups
halogen atoms lower alkenyl groups cycloalkyl groups a nitro
group and a phenyl group include:
phenoxy alkyl groups wherein the alkyl moiety is a
straight or branched Ci-6 alkyl group optionally substituted on
the phenyl ring with one to three members selected from the group
consisting of straight and branched Ci-6 alkyl groups optionally
substituted with one to three halogen atoms straight and
branched Ci.6 alkoxy groups halogen atoms straight and branched
C2-e alkenyl groups C3.8 cycloalkyl groups a nitro group and a
phenyl group
such as 3-[(2- 3- or 4-)methylphenoxy]propyl 3-[(2-
3- or 4-)propylphenoxy]propyl 3-[(2- 3- or 4-)
methoxyphenoxy]propyl 3-[(23- or 34-)dichlorophenoxy]propyl
3-[(23- or 34-)difluorophenoxy]propyl 3-[3-fluoro-4-
chlorophenoxy]propyl 3-[(2- 3- or 4-)trifluoromethylphenoxy]
propyl 3-[2-methoxy-4-propenylphenoxy]propyl 3-[2-chloro-4-
-58-
methoxyphenoxy]propyl. (2- 3- or 4-)cyclopentylphenoxypropyl
3-[(2- 3- or 4-Jnitrophenoxy]propyl 3-[(23- or 34-)
dimethylphenoxy]propyl and 3-[(2- 3- or 4-)phenylphenoxy]
propyl.
Examples of phenylthio lower alkyl groups optionally
substituted on the phenyl ring with one or more halogen atoms
include:
phenylthioalkyl groups wherein the alkyl moiety is a
straight or branched C^e alkyl group optionally substituted on
the phenyl ring with one to three halogen atoms
such as phenylthiomethyl 2-phenylthioethyl 1-
phenylthioethyl 3-phenylthiopropyl 4-phenylthiobutyl 5-
phenylthiopentyl 6-phenylthiohexyl 11-dimethyl-2-
phenylthioethyl 2-methyl-3-phenylthiopropyl (2- 3- or 4-)
chlorophenylthiomethyl 2-[(2- 3- or 4-)chlorophenylthio]ethyl
3-[(2- 3- or 4-)chlorophenylthio]propyl 4-[(2- 3- or 4-)
fluorophenylthio]butyl 5-[(2- 3- or 4-)bromophenylthio]pentyl
and 6-[(2- 3- or 4-)iodophenylthio]hexyl.
Examples of piperidinyl lower alkyl groups optionally
substituted on the piperidine ring with one or more members
selected from the group consisting of a phenyl group and phenyl
lower alkyl groups include:
piperidinylalkyl groups wherein the alkyl moiety is a
straight or branched d-6 alkyl group optionally substituted on
the piperidine ring with one to three members selected from the
group consisting of a phenyl group and phenylalkyl groups wherein
the alkyl moiety is a straight or branched Ci_6 alkyl group
such as [(!- 2- 3- or 4-)piperidinyl]methyl 2-
[(!- 2- 3- or 4-)piperidinyl]ethyl !-[(!- 2- 3-. or 4-)
piperidinyl]ethyl 3-[(l- 2- 3- or 4-)piperidinyl]propyl 4-
[(!- 2- 3- or 4-) piperidinyl]butyl 5-[(l- 2- 3- or 4-)
piperidinyl]pentyl 6-[(l- 2- 3- or 4-)piperidinyl]hexyl 11-
dimethyl-2-[(l- 2- 3- or 4-)piperidinyl]ethyl 2-methyl-3-
[(!- 2- 3- or 4-)piperidinyl]propyl [4-phenyl-1-piperidinyl]
methyl 3-[4-phenyl-l-piperidinyl]propyl [4-phenylmethyl-l-
59-
piperidinyl]methyl 3-[4-phenylmethyl-l-piperidlnyl]propyl 2-[4-
phenyl-(l- 2- or 3-)piperidinyl]ethyl 3-[4-phenylmethyl-
(1- 2- or 3-)piperidlnyl]propyl 4-[4-phenylethyl-
(1- 2- or 3-)piperidinyl]butyl 5-[4-phenyl-(l- 2- or 3-)
piperidinyl]pentyl and 6-[4-phenyl-(l- 2- or 3-)piperidinyl]
hexyl.
Examples of piperazinyl lower alkyl groups optionally
substituted on the piperazine ring with one or more phenyl groups
include:
piperazinylalkyl groups wherein the alkyl moiety is a
straight or branched Ci.6 alkyl group optionally substituted on
the piperazine ring with one to three phenyl groups
such as (1- or 2-)piperazinylmethyl 2-[(l- or 2-)
piperazinyl]ethyl [4-phenyl-(1- 2- or 3-)piperazinyl]methyl
2-[4-phenyl-(l- 2- or 3-)piperazinyl]ethyl 3-[4-phenyl-
(1- 2- or 3-)piperazinyl]propyl 4-[4-phenyl-(l- 2- or 3-)
piperazinyl]butyl 5-[4-phenyl-(1- 2- or 3-)piperazinyl]pentyl
and 6-[4-phenyl-(l- 2- or 3-)piperazinyl]hexyl.
Examples of 1234-tetrahydroisoquinolyl lower alkyl
groups include 1234-tetrahydroisoquinolylalkyl groups wherein
the alkyl moiety is a straight or branched Ci-6 alkyl group such
as (1234-tetrahydroisoquinolin-2-yljmethyl 2-(1234-
tetrahydroisoquinolin-2-yl)ethyl 3 - (1234 -
tetrahydroisoquinolin-2-yl)propyl 4-(1234-
tetrahydroisoquinolin-2-yl)butyl 5 - (1234 -
tetrahydroisoquinolin-2-yl)pentyl and 6-(1234-
tetrahydroisoquinolin-2-yl)hexyl.
Examples of naphthyloxy lower alkyl groups include
naphthyloxyalkyl groups wherein the alkyl moiety is a straight or
branched Ci-6 alkyl group such as 1-naphthyloxymethyl 2-(2-
naphthyloxy)ethyl 3-(l-naphthyloxy)propyl 3-(2-
naphthyloxy)propyl 4-(1-naphthyloxy)buty1 5-(2-
naphthyloxy)pentyl and 6-(1-naphthyloxy)hexyl.
Examples of benzothiazolyloxy lower alkyl group
optionally substituted on the benzothiazole ring with one or more
-60-
alkyl groups include:
benzothiazolyloxyalkyl groups wherein the alkyl moiety
is a straight or branched Ci_6 alkyl group optionally substituted
on the benzothiazoline ring with one to three straight and/or
branched Ci-6 alkyl groups
such as l-[benzothiazol-(2-4-5-6-or 7-)yloxy]methyl
2-[benzothiazol-(2-4-5-6-or 7-)yloxy]ethyl 3-[benzothiazol-
(2-4-5-6-or 7-)yloxy]propyl 3-[benzothiazol-(2-4-5-6-or 7-
) yloxy Jpropyl 4-[benzothiazol-(2-4-/5-6-or 7-)yloxy]butyl 5-
[benzothiazol-(2-4-5-6-or 7-)yloxy]pentyl 6-[benzothiazol-
(2-4-5-6-or 7-)yloxy]hexyl 2-methylbenzothiazol-5-yloxymethyl
2 - (2 -methylbenzothiazol-5-yloxy) ethyl 3 - (2 -methylbenzothiazol- 5-
yloxy)propyl 4-(2-ethylbenzothiazol-5-yloxy)butyl 5-(2-
ethylbenzothiazol-5-yloxy)pentyl and 6-(2-ethylbenzothiazol-5-
yloxy)hexyl.
Examples of lower alkyl groups substituted with one or
more members selected from the group consisting of quinolyloxy
groups and isoquinolyloxy groups include:
alkyl groups wherein the alkyl moiety is a straight or
branched Ci_6 alkyl group substituted with one to three members
selected from the group consisting of quinolyloxy groups and
isoquinolyloxy groups
such as (5-quinolyloxy)methyl 2-(5-quinolyloxy)ethyl
3-(5-quinolyloxy)propyl 4-(5-quinolyloxy)butyl 5-(5-
quinolyloxy)pentyl 6-(5-quinolyloxy)hexyl (5-isoquinolyloxy)
methyl 2-(5-isoquinolyloxy)ethyl 3-(5-isoquinolyloxyJpropyl
4-(5-isoquinolyloxy)butyl 5-(5-isoquinolyloxy)pentyl and 6-(5-
isoquinolyloxy)hexyl.
Examples of pyridyloxy lower alkyl groups optionally
substituted on the pyridine ring with one or more lower alkyl
groups include:
pyridyloxyalkyl groups wherein the alkyl moiety is a
straight or branched Ci_6 alkyl group optionally substituted on
the pyridine ring with one to three straight and/or branched d-6
alkyl groups
-61-
such as (2- 3- or 4-)pyridyloxymethyl 2-
[(2- 3- or 4-)pyridyloxy]ethyl l-[(2- 3-f or 4-)pyridyloxy]
ethyl 3-[(2- 3- or 4-)pyridyloxy]propyl 4-[(2- 3- or 4-)
pyridyloxy]butyl 11-dimethyl-2-[ (2- 3- or 4-)pyridyloxy]ethyl
5-1(2- 3- or 4-)pyridyloxy]pentyl 6-[(2- 3- or 4-)
pyridyloxy]hexyl [6-methyl-(2- 3- 4- or 5-)pyridyloxy]methyl
2-[6-ethyl-(2- 3- 4- or 5-)pyridyloxy]ethyl 3-[6-methyl-
(2- 3- 4- or 5-)pyridyloxy]propyl 4-[6-methyl-
(2- 3- 4- or 5-)pyridyloxy]butyl 5-[6-methyl-
(2- 3- 4- or 5-)pyridyloxy]pentyl and 6-[6-methyl-
(2- 3- 4- or 5-)pyridyloxy]hexyl.
Examples of carboxy lower alkoxy groups include
carboxyalkoxy groups wherein the alkoxy moiety is a straight or
branched Ci-e alkoxy group such as carboxymethoxy 2-carboxyethoxy
1-carboxyethoxy 3-carboxypropoxy 4-carboxybutoxy 5-
carboxypentyloxy 6-carboxyhexyloxy 11-dimethyl-2-carboxyethoxy
and 2-methyl-3-carboxypropoxy.
Examples of lower alkoxycarbonyl lower alkoxy groups
include alkoxycarbonylalkoxy groups wherein each of the two
alkoxy moieties is a straight or branched Ci-6 alkoxy group such
as methoxycarbonylmethoxy ethoxycarbonylmethoxy 2-
methoxycarbonylethoxy 2-ethoxycarbonylethoxy 1-
ethoxycarbonylethoxy 3-methoxycarbonylpropoxy 3-
ethoxycarbonylpropoxy 4-ethoxycarbonylbutoxy 5-
isopropoxycarbonylpentyloxy 6-n-propoxycarbonylhexyloxy 11-
dime thyl -2-n- but oxycarbonyle thoxy 2 -methyl - 3 - tert -
butoxycarbonylpropoxy 2-n-pentyloxycarbonylethoxy and nhexyloxycarbonylmethoxy.
Examples of lower alkyl groups optionally substituted
with one or more halogen atoms include straight and branched Ci_6
alkyl groups optionally substituted with one to three halogen
atoms such as in addition to the above-described lower alkyl
groups trifluoromethyl trichloromethyl chloromethyl
bromomethyl fluoromethyl iodomethyl difluoromethyl
dibromomethyl 2-chloroethyl 222-trifluoroethyl 222-
-62-
trichloroethyl 3-chloropropyl 23-dichloropropyl 444-
trichlorobutyl 4-fluorobutyl 444-trifluorobutyl 5-
chloropentyl 3-chloro-2-methylpropyl 5-bromohexyl and 56-
dibromhexyl.
Examples of lower alkylthio groups optionally
substituted with one or more halogen atoms include straight and
branched Ci-e alkylthio groups optionally substituted with one to
three halogen atoms such as in addition to the above-described
lower alkylthio groups trifluoromethylthio trichloromethylthio
chloromethylthio bromomethylthio fluoromethylthio
iodomethylthio difluoromethylthio dibromomethylthio 2-
chloroethylthio 222-trifluoroethylthio 222-
trichloroethylthio 3-chloropropylthio 23-dichloropropylthio
444-trichlorobutylthio 4-fluorobutylthio 444-
trifluorobutylthio 5-chloropentylthio 3-chloro-2-
methylpropylthio 5-bromohexylthio and 56-dibromohexylthio.
Examples of lower alkylsulfonyl groups include straight
and branched Ci_6 alkyl sulfonyl groups optionally substituted with
one to three halogen atoms such as methylsulfonyl ethylsulfonyl
n-propylsulfonyl isopropylsulfonyl n-butylsulfonyl
isobutylsulfonyl tert-butylsulfonyl sec-butylsulfonyl npentylsulfonyl
isopentylsulfonyl neopentylsulfonyl nhexylsulfonyl
isohexylsulfonyl and 3-methylpentylsulfonyl.
Examples of phenyl lower alkenyl groups include
phenylalkenyl groups containing one to three double bonds wherein
the alkenyl moiety is a straight or branched Ca-e alkenyl group
such as styryl 3-phenyl-2-propenyl (trivial name: cinnamyl) 4-
phenyl-2-butenyl 4-phenyl-3-butenyl 5-phenyl-4-pentenyl 5-
phenyl-3-pentenyl 6-phenyl-5-hexenyl 6-phenyl-4-hexenyl 6-
phenyl-3-hexenyl 4-phenyl-13-butadienyl and 6-phenyl-l35-
hexatrienyl.
Examples of lower alkanoyloxy groups include straight
and branched C2-e alkanoyloxy groups such as acetyloxy
propionyloxy butyryloxy isobutyryloxy pentanoyloxy tertbutylcarbonyloxy
and hexanoyloxy.
-63-
Examples of phenyl lower alkoxy groups optionally
substituted on the phenyl ring with one or more members selected
from the group consisting of halogen atoms lower alkyl groups
optionally substituted with one or more halogen atoms lower
alkylthio groups optionally substituted with one or more halogen
atoms lower alkoxy groups a nitro group lower alkylsulfonyl
groups lower alkoxycarbonyl groups phenyl lower alkenyl groups
lower alkanoyloxy groups and 123-thiadiazolyl groups include:
phenylalkoxy groups wherein the alkoxy moiety is a
straight or branched Ci-6 alkoxy group optionally substituted on
the phenyl ring with one to three members selected from the group
consisting of the above-described halogen atoms the abovedescribed
straight and branched d-6 alkyl groups optionally
substituted with one to three halogen atoms the above-described
straight and branched Ci_6 alkylthio groups optionally substituted
with one to three halogen atoms the above-described straight and
branched Ci_6 alkoxy groups a nitro group the above-described
straight and branched Ci_6 alkylsulfonyl groups the abovedescribed
straight and branched Ci_6 alkoxycarbonyl groups the
above-described phenylalkenyl groups containing one to three
double bonds wherein the alkenyl moiety is a straight or branched
C2-6 alkenyl group the above-described straight and branched Ci-6
alkanoyloxy groups and 123-thiadiazolyl groups
such as benzyloxy 2-phenylethoxy 1-phenylethoxy 3-
phenylpropoxy 4-phenylbutoxy 5-phenylpentyloxy 6-
phenylhexyloxy 1 l-dimethyl-2-phenylethoxy 2-methyl-3-
phenylpropoxy 4-chlorobenzyloxy 2-chlorobenzyloxy 3-
chlorobenzyloxy 3-fluorobenzyloxy 4-fluorobenzyloxy 24-
dibromobenzyloxy 246-trifluorobenzyloxy 3-
trifluoromethylbenzyloxy 4-trifluoromethylbenzyloxy 4-
methylbenzyloxy 3-methylbenzyloxy 24-dimethylbenzyloxy 246-
trimethylbenzyloxy 4-methoxycarbonylbenzyloxy 3-
methoxybenzyloxy 2-methoxybenzyloxy 3-methoxycarbonylbenzyloxy
23-dimethoxybenzyloxy 245-trimethoxybenzyloxy 3-
nitrobenzyloxy 2-(23-dinitrophenyl)ethoxy 3-(246-
-64-
trinitrophenyl)ethoxy 2-nitro-4-methylbenzyloxy 4-
methylsulfonylbenzyloxy 4-(4-ethylsulfonylphenyl)butoxy 5-(4-
propylsulf onylphenyl) pentyloxy 4 - ace tyloxybenzyloxy 6 - (4 -
propionyloxyphenyl)hexyloxy 4-styrylbenzyloxy 4 - (123 -
thiadiazol-4-yl)benzyloxy 4-trifluoromethylthiobenzyloxy 3-
methylthiobenzyloxy 24-dimethylthiobenzyloxy and 246-
trimethylthiobenzyloxy.
Examples of piperidinyl lower alkoxy groups optionally
substituted on the piperidine ring with one or more lower alkyl
groups include:
piperidinylalkoxy groups wherein the alkoxy moiety is a
straight or branched Ci-e alkoxy group optionally substituted on
the piperidine ring with one to three straight and/or branched
Ci-e alkyl groups
such as [(!- 2- 3- or 4-) piperidinyl]methoxy
2-[(l- 2- 3- or 4-)piperidinylJethoxy !-[(!- 2- 3- or 4-)
piperidinyl]ethoxy 3-[(l- 2- 3- or 4-)piperidinyl]propoxy 4-
[(!- 2- 3- or 4-)piperidinyl]butoxy 5-[(l- 2- 3- or 4-)
piperidinyl]pentyloxy 6-[(l- 2- 3- or 4-)piperidinyl]hexyloxy
ll-dimethyl-2-[(l- 2- 3- or 4-)piperidinylJethoxy 2-methyl-
3-[(l- 2- 3- or 4-)piperidinyl]propoxy [1-methyl-
(2- 3- or 4-)piperidinyl]methoxy 2-[l-ethyl-(2- 3- or 4-)
piperidinyl]ethoxy 3-[l-n-propyl-(2- 3- or 4-)piperidinyl]
propoxy 4-[l-n-butyl-(2- 3- or 4-piperidinyl)butoxy 5-[l-npentyl-(
2- 3- or 4-)piperidinyl]pentyloxy 6-[l-n-hexyl-(2- 3-
or 4-)piperidinyl]hexyloxy [l2-dimethyl-(3- 4- 5- or 6-)
piperidinyl]methoxy [l23-trimethyl-(4- 5- or 6-)piperidinyl]
methoxy 2-[2-n-propyl-(3- 4- 5- or 6-)piperidinyl]ethoxy
2-[3-ethyl-(2- 4- 5- or 6-)piperidinyl]ethoxy and [2-methyl-
4-isopropyl-(3-f 5- or 6-piperidinyl)methoxy.
Examples of amino-substituted lower alkoxy groups
optionally substituted on each amino group with one or more lower
alkyl groups include amino-substituted straight and branched d-6
alkoxy groups optionally substituted on the amino group with one
or two straight and/or branched Ci-e alkyl groups such as
-65-
aminomethoxy 2-aminomethoxy 1-aminoethoxy 3-aminopropoxy 4-
aminobutoxy 5-aminopentyloxy 6-aminohexyloxy 11-dimethyl-2-
aminoethoxy 2-methyl-3-aminopropoxy methylaminomethoxy 1-
ethylaminoethoxy 2-n-propylaminoethoxy 3-isopropylaminopropoxy
4-n-butylaminobutoxy 5-n-pentylaminopentyloxy 6-nhexylaminohexyloxy
dime thylaminome thoxy 3-dimethylaminopropoxy
2-diisopropylaminoethoxy (N-ethyl-//-.n-propylamino)methoxy and
2- (JV-methyl-W-n-hexylamino)ethoxy.
Examples of lower alkenyloxy groups include straight
and branched C2-e alkenyloxy groups containig one to three double
bonds such as vinyloxy 1-propenyloxy 1-methyl-l-propenyloxy
2-methyl-1-propenyloxy 2-propenyloxy 2-butenyloxy 1-butenyloxy
3-butenyloxy 2-pentenyloxy 1-pentenyloxy 3-pentenyloxy 4-
pentenyloxy 13-butadienyloxy 13-pentadienyloxy 2-penten-4-
yloxy 2-hexenyloxy 1-hexenyloxy 5-hexenyloxy 3-hexenyloxy 4-
hexenyloxy 33-dimethyl-l-propenyloxy 2-ethyl-1-propenyloxy
135-hexatrienyloxy 13-hexadienyloxy and 14-hexadienyloxy.
Examples of pyridyl lower alkoxy groups optionally
substituted on the pyridine ring with one or more lower alkyl
groups each lower alkyl substituent optionally being substituted
with one or more halogen atoms include:
pyridylalkoxy groups wherein the alkoxy moiety is a
straight or branched Ci_6 alkoxy group optionally substituted on
the pyridine ring with one to three above-described straight
and/or branched d-6 alkyl groups each alkyl substituent
optionally being substituted with one to three halogen atoms
such as [(2- 3- or 4-)pyridyl]methoxy 2-
[(2- 3- or 4-)pyridyl]ethoxy l-[(2- 3- or 4-) pyridyl]ethoxy
3-[(2- 3- or 4-)pyridyl]propoxy 4-[(2- 3- or 4-)pyridyl]
butoxy 5-[(2- 3- or 4-) pyridyl]pentyloxy 6-[(2- 3- or 4-)
pyridylJhexyloxy ll-dlmethyl-2-[(2- 3- or 4-)pyridyl]ethoxy
2-methyl-3-[(2- 3- or 4-)pyridyl]propoxy [2-trifluoromethyl-
(3- 4- 5- or 6-)pyridyl]methoxy [2-methyl-(3- 4- 5- or 6-)
pyridyl]methoxy [24-dimethyl-(3- 5- or 6-)pyridyl]methoxy
[246-trimethyl-(3- or 5-)pyridyl]methoxy) [2-trifluoromethyl-
66-
4-methyl-(3- 5- or 6-)pyridyl]methoxy 2-[3-ethyl-
(2- 4- 5- or 6-) pyridylJethoxy 3-[4-n-propyl-
(2- or 3-)pyridyl]propoxy 4-[3-n-butyl-(2- 4- 5- or 6-)
pyridyl]butyl 5-[3-trifluoromethyl-(2- 4- 5- or 6-)pyridyl]
pentyloxy 6-[2-n-pentyl-(3- 4- 5- or 6-)pyridyl]hexyloxy and
[2-n-hexyl-(3- 4- 5- or 6-)pyridyl]methoxy.
Examples of lower alkynyloxy groups include straight
and branched C2.6 alkynyloxy groups such as ethynyloxy 2-
propynyloxy 2-butynyloxy 3-butynyloxy 1-methyl-2-propynyloxy
2-pentynyloxy and 2-hexynyloxy.
Examples of phenyl lower alkynyloxy groups include
phenylalkynyloxy groups wherein the alkynyloxy moiety is a
straight or branched C2-e alkynyloxy group such as 2-
phenylethynyloxy 3-phenyl-2-propynyloxy 4-phenyl-2-butynyloxy
4-phenyl-3-butynyloxy 3-phenyl-1-methyl-2-propynyloxy 5-phenyl-
2-pentynyloxy and 6-phenyl-2-hexynyloxy.
Examples of phenyl lower alkenyloxy groups include
phenylalkenyloxy groups containing one to three double bonds
wherein the alkenyloxy moiety is a straight or branched C2.6
alkenyloxy group such as styryloxy 3-phenyl-1-propenyloxy 3-
phenyl-1 -methyl-1 -propenyloxy 3-phenyl-2-methyl-1 -propenyloxy
3-phenyl-2-propenyloxy 4-phenyl-2-butenyloxy 4-phenyl-lbutenyloxy
4-phenyl-3-butenyloxy 4-phenyl-2-pentenyloxy 5-
phenyl-1-pentenyloxy 5-phenyl-3-pentenyloxy 5-phenyl-4-
pentenyloxy 4-phenyl-l3-butadienyloxy 5-phenyl-l3-
pentadienyloxy 5-phenyl-2-penten-4-yloxy 6-phenyl-2-hexenyloxy
6-phenyl-1-hexenyloxy 6-phenyl-5-hexenyloxy 6-phenyl-3-
hexenyloxy 6-phenyl-4-hexenyloxy 3-phenyl-33-dimethyl-1-
propenyloxy 3-phenyl-2-ethyl-1-propenyloxy 6-phenyl-l35-
hexatrienyloxy 6-phenyl-l3-hexadienyloxy and 6-phenyl-14-
hexadienyloxy.
Examples of furyl lower alkoxy groups optionally
substituted on the furan ring with one or more lower
alkoxycarbonyl groups include:
furylalkoxy groups wherein the alkoxy moiety is a
-67-
straight or branched Ci-e alkoxy group optionally substituted on
the furan ring with one to three above-described alkoxycarbonyl
groups wherein the alkoxy moiety is a straight or branched Ci-6
alkoxy group
such as [(2- or 3-)furyl]methoxy 2-[(2- or 3-)furyl]
ethoxy l-[(2- or 3-)furyl]ethoxy 3-t(2- or 3-)furyl]propoxy 4-
[(2- or 3-)furyl]butoxy 5-[(2- or 3-)furyl]pentyloxy 6-
[(2- or 3-)furyl]hexyloxy ll-dimethyl-2-[(2- or 3-)furyl]ethoxy
2-methyl-3-[(2- or 3-)furyl]propoxy [2-ethoxycarbonyl-
(3- 4- or 5-)furyl]methoxy [2-methoxycarbonyl-(3- 4- or 5-)
furyl]methoxy [3-n-propoxycarbonyl-(2- 4- or 5-)furyl]methoxy
[2-n-butoxycarbonyl-(3- 4- or 5-)furyl]methoxy [3-npentyloxycarbonyl-(
2- 4- or 5-)furyl]methoxy [2-nhexyloxycarbonyl-(
3- 4- or 5-)furyl]methoxy [23-
diethoxycarbonyl-(4- or 5-)furyl]methoxy 234-
trimethoxycarbonyl-5-furyl)methoxy/ 2-[3-n-propoxycarbonyl-
(2- 4- or 5-)furyl]ethoxy 3-[2-n-butoxycarbonyl-
(3- 4- or 5-)furyl]propoxy 4-[3-n- pentyloxycarbonyl-
(2- 4- or 5-)furyl]butoxy 5-[2-n-hexyloxycarbonyl-
(3- 4- or 5-)furyl]pentyloxy and 6-[2-n-hexyloxycarbonyl-
(3- 4- or 5-)furyl]hexyloxy.
Examples of tetrazolyl lower alkoxy groups optionally
substituted on the tetrazole ring with one member selected from
the group consisting of a phenyl group phenyl lower alkyl groups
and cycloalkyl lower alkyl groups include:
tetrazolylalkoxy groups wherein the alkoxy moiety is a
straight or branched d.6 alkoxy group optionally substituted on
the tetrazole ring with one member selected from the group
consisting of a phenyl group the above-described phenylalkyl
groups wherein the alkyl moiety is a straight or branched Ci-6 alky
group and the above-descried C3.8 cycloalkyl alkylgroups wherein
the alkyl moiety is a straight or branched Ci_6 alkyl group
such as [(I- or 5-)tetrazolyl]methoxy 2-[(l- or 5-)
tetrazolyl]ethoxy !-[(!- or 5-)tetrazolyl]ethoxy
3-[(l- or 5-)tetrazolylJpropoxy 4-[(l- or 5-)tetrazolyl] butoxy.
-68-
5-[(l- or 5-)tetrazolylJpentyloxy 6-[(l- or 5-)
tetrazolylJhexyloxy ll-dimethyl-2-[(1- or 5-)tetrazolyl] ethoxy
2-methyl-3-[(1- or 5-) tetrazolyl]propoxy (1-benzyl-5-
tetrazolyl)methoxy (1-phenyl-5-tetrazolyl)methoxy (1-
cyclohexylmethyl-5-tetrazolyl)methoxy [5-(2-phenylethyl) -1 -
tetrazolyl]methoxy [l-(l-phenylethyl)-5-tetrazolyl]methoxy [1-
(3-phenylpropyl)-5-tetrazolyl]methoxy [5-(4-phenylbutyl)-1-
tetrazolylJmethoxy [l-(5-phenylpentyl)-5-tetrazolyl]methoxy [1-
(6-phenylhexyl)-5-tetrazolyl]methoxy [5-(2-cyclohexylethyl)-1-
tetrazolyl ] methoxy [ 1 - (1 - cyclopropylethyl) - 5 - tetrazolyl ] methoxy
[1-(3-cyclobutylpropyl)-5-tetrazolyl]methoxy [ 5 - (4 -
cyclopentylbutyl)-1-tetrazolyl]methoxy [1-(5-cycloheptylpentyl) -
5-tetrazolyl]methoxy [1-(6-cyclooctylhexyl) - 5 -tetrazolyl]methoxy
2-(l-phenyl-5-tetrazolyl)ethoxy 3-(1-cyclohexylmethyl-5-
tetrazolyDpropoxy 4- [5-(2-phenylethyl)-l-tetrazolyl]butoxy 5-
(1-benzyl-5-tetrazolyl)pentyloxy 6-(1-phenyl-5-
tetrazolylJhexyloxy and l-(l-cyclohexylmethyl-5-
tetrazolyl)ethoxy.
Examples of phenyl groups optionally substituted on the
phenyl ring with one or more lower alkyl groups include phenyl
groups optionally substituted on the phenyl ring with one to
three straight and/or branched Ci-e alkyl groups such as phenyl
2-methylphenyl 3-methylphenyl 4-methylphenyl 2-ethylphenyl 3-
ethylphenyl 4-ethylphenyl 4-isopropylphenyl 3-n-butylphenyl
4-n-pentylphenyl 4-n-hexylphenyl 34-dimethylphenyl 34-
diethylphenyl 24-dimethylphenyl 25-dimethylphenyl 26-
dimethylphenyl and 345-trimethylphenyl.
Examples of 124-oxadiazolyl lower alkoxy groups
optionally substituted on the 124-oxadiazole ring with a phenyl
group the phenyl substituent optionally being substituted on the
phenyl ring with one or more lower alkyl groups include:
124-oxadiazolylalkoxy groups wherein the alkoxy
moiety is a straight or branched Ci_6 alkoxy group optionally
substituted on the 124-oxadiazole ring with one of the abovedescribed
phenyl groups optionally substituted on the phenyl ring
-69-
with one to three straight and/or branched Ci-6 alkyl groups
such as [(3- or 5-) 124-oxadiazolyl] me thoxy
2-[(3- or 5-)l24-oxadiazolyl]ethoxy l-[(3- or 5-) 124-
oxadiazolyljethoxy 3-[(3- or 5-)124-oxadiazolyl] propoxy 4-
[(3- or 5-)124-oxadiazolyl]butoxy 5-[(3- or 5-) 124-
oxadiazolyl]pentyloxy 6-[(3- or 5-)124-oxadiazolyl] hexyloxy
ll-dimethyl-2-[(3- or 5-)124-oxadiazolyl]ethoxy 2-methyl-3-
[(3- or 5-)l24-oxadiazolyl]propoxy [3-(4-tert-butylphenyl)-5-
124-oxadiazolyl]methoxy [3-(3 -methylphenyl)-5-124-
oxadiazolyl]methoxy [5-(2-ethylphenyl)-3-124-oxadiaz olyl]
methoxy [3-(4-n-propylphenyl)-5-l24-oxadiazolyl]methoxy [5-
(3-n-pentylphenyl) -3-124-oxadiazolyl] me thoxy [3-(2-nhexylphenyl)-
5-124-oxadiazolyl]methoxy [ 3-(24-
dimethyIphenyl)-5-124-oxadiazolyl]methoxy [ 3 - (235 -
trimethyIphenyl)-5-124-oxadiazolyl]methoxy 2-[3-(4-tertbutyIphenyl)-
5-124-oxadiazolyl]ethoxy 1-[3-(3-methylphenyl)-5-
124-oxadiazolyl]ethoxy. 3-[5-(2-ethylphenyl)-3-124-
oxadiazolyl]propoxy 4-[3-(4-n-propyIphenyl)-5-124-oxadiazolyl]
butoxy 5-[5-(3-n-pentylphenyl)-3-124-oxadiazolyl]pentyloxy 6-
[3-(2-n-hexylphenyl)-5-124-oxadiazolyl]hexyloxy 2-[3-(24-
dimethylphenyl)-5-124-oxadiazolyl]ethoxy and l-[3-(235-
trimethyIphenyl)-5-124-oxadiazolyl]ethoxy.
Examples of isoxazolyl lower alkoxy groups optionally
substituted on the isoxazole ring with one or more lower alkyl
groups include:
isoxazolylalkoxy groups wherein the alkoxy moiety is a
straight or branched Ci-6 alkoxy group optionally substituted on
the isoxazole ring with one or two above-described straight
and/or branched Ci.6 alkyl groups
such as [(3- 4- or 5-)isoxazolyl]methoxy
2-[(3- 4- or 5-)isoxazolyl]ethoxy l-[(3- 4- or 5-)
isoxazolyl]ethoxy 3-[(3- 4- or 5-)isoxazolyl]propoxy 4-
[(3- 4- or 5-)isoxazolyl]butoxy 5-[(3- 4- or 5-)isoxazolyl]
pentyloxy 6-[(3- 4- or 5-)isoxazolyl]hexyloxy 11-dimethyl-2-
t(3- 4- or 5-)isoxazolyl]ethoxy 2-methyl-3-[(3- 4- or 5-)
-70-
isoxazolyl ] propoxy (35- dimethyl - 4 - isoxazolyl) methoxy [ 3 -
methyl-(4- or 5-) isoxazolyl]methoxy [3-ethyl-(4- or 5-)
isoxazolyl]methoxy [4-n-propyl-(3- or 5-)isoxazolyl]methoxy [5-
n-butyl-(3- or 4-)isoxazolyl]methoxy [3-n-pentyl-(4- or 5-)
isoxazolyl]methoxy [4-n-hexyl-(3- or 5-)isoxazolyl]methoxy 2-
[3-methyl-(4- or 5-)isoxazolylJethoxy l-[3-ethyl-(4- or 5-)
isoxazolyl]ethoxy 3-[4-/i-propyl-(3- or 5-) isoxazolyl]propoxy
4-[5-n-butyl-(3- or 4-)isoxazolyl]butoxy 5-[3-n-pentyl-
(4- or 5-)isoxazolyl]pentyloxy and 6-[4-n-hexyl-(3- or 5-)
isoxazolyl]hexyloxy.
Examples of 134-oxadiazolyl lower alkoxy groups
optionally substituted on the 134-oxadiazole ring with a phenyl
group the phenyl substituent optionally being substituted on the
phenyl ring with one or more lower alkyl groups include:
134-oxadiazolylalkoxy groups wherein the alkoxy
moiety is a straight or branched Ci-6 alkoxy group optionally
substituted on the 134-oxadiazole ring with one of the abovedescribed
phenyl groups optionally substituted on the phenyl ring
with one to three straight and/or branched Ci-e alkyl groups
such as [(2- or 5-) 134-oxadiazolyl]methoxy 2-
1(2- or 5-)134-oxadiazolyl]ethoxy l-[(2- or 5-)134-
oxadiazolyljethoxy 3-[(2- or 5-)134-oxadiazolyl]propoxy 4-
[(2- or 5-)134-oxadiazolyl]butoxy 5-[(2- or 5-)134-
oxadiazolyl]pentyloxy 6-[(2- or 5-)134-oxadiazolyl]hexyloxy
lrl-dimethyl-2-[(2- or 5-)l34-oxadiazolyl]ethoxy 2-methyl-3-
1(2- or 5-) 134-oxadiazolyl]propoxy [2-(4-tert-butylphenyl)-5-
134-oxadiazolylJmethoxy [2-(4-methylphenyl) - 5 -134 -
oxadiaz olyl]methoxy [5-(2-ethylphenyl)-2-134-oxadiazolyl]
methoxy [2-(4-n-propylphenyl)-5-l34-oxadiazolyl]methoxy [5-
(3-n-pentylphenyl)-2-l34-oxadiazolyl]methoxy [2-(2-nhexylphenyl)-
5-134-oxadiazolyl]methoxy [2-(24-
dimethylphenyl)-5-134-oxadiazolyl ] methoxy [2-(235-
trimethylphenyl)-5-134-oxadiazolyl]methoxy 2-[2-(4-tertbutylphenyl)-
5-134-oxadiazolylJethoxy 1-[2-(3-methylphenyl)-5-
134-oxadiazolylJethoxy 3-[5-(2-ethylphenyl)-2-134-
-71-
oxadiazolyl ] propoxy 4- [ 2 - (4-n-propylphenyl) - 5-134 -oxadiazolyl ]
butoxy 5-[5-(3-.n-pentylphenyl)-2-l34-oxadiazolyl]pentyloxy 6-
[2-(2-n-hexylphenyl)-5-134-oxadiazolyl]hexyloxy 2-[2-(24-
dimethylphenyl)-5-134-oxadiazolylJethoxy and l-[2-(235-
trimethylphenyl)-5-134-oxadiazolyl]ethoxy.
Examples of lower alkanoyl lower alkoxy groups include
alkanoylalkoxy groups wherein the alkanoyl moiety is a straight
or branched C2-e alkanoyl group and the alkoxy moiety is a
straight or branched Ci-6 alkoxy group such as acetylmethoxy
propionylmethoxy 2-acetylethoxy 2-propionylethoxy 1-
acetylethoxy 3-acetylpropoxy 3-propionylpropoxy 4-acetylbutoxy
5-butyrylpentyloxy 6-pentanoylhexyloxy 11-dimethyl-2-
hexanoylethoxy 2-methyl-3-acetylpropoxy 2-pentanoylethoxy and
hexanoylmethoxy.
Examples of phenyl groups optionally substituted on the
phenyl ring with one or more halogen atoms include phenyl groups
optionally substituted on the phenyl ring with one to three
halogen atoms such as phenyl 4-fluorophenyl 25-difluorophenyl
24-difluorophenyl 34-difluorophenyl 35-difluorophenyl 26-
difluorophenyl 2-chlorophenyl 3-chlorophenyl 4-chlorophenyl
23-dichlorophenyl 24-dichlorophenyl 25-dichlorophenyl 34-
dichlorophenyl 26-dichlorophenyl 3-fluorophenyl 2-
fluorophenyl 3-bromophenyl 4-iodophenyl 2-bromophenyl 4-
bromophenyl 35-dichlorophenyl 246-trifluorophenyl 34-
difluorophenyl 2-iodophenyl 3-iodophenyl 4-iodophenyl 23-
dibromophenyl 24-diiodophenyl and 246-trichlorophenyl.
Examples of thiazolyl lower alkoxy groups optionally
substituted on the thiazole ring with one or more members
selected from the group consisting of lower alkyl groups and a
phenyl group each phenyl substituent optionally being
substituted on the phenyl ring with one or more halogen atoms
include:
thiazolylalkoxy groups wherein the alkoxy moiety is a
straight or branched Ci-6 alkoxy group optionally substituted on
the thiazole ring with one or two members selected from the group
-72-
conslsting of the above-described straight and branched Ci-6 alkyl
groups and phenyl groups optionally substituted on the phenyl
ring with one to three halogen atoms
such as [(2- 4- or 5-)thiazolyl]methoxy 2-
[(2- 4- or 5-)thiazolyl]ethoxy l-[(2- 4- or 5-)thiazolyl]
ethoxy 3-[(2- 4- or 5-)thiazolyl]propoxy 4-[(2- 4- or 5-)
thiazolyl]butoxy 5 - [ (2 - 4- or 5-) thiazolyl]pentyloxy 6-
[(2- 4- or 5-)thiazolyl]hexyloxy 11-dimethyl-2-
[(2- 4- or 5-)thiazolyl]ethoxy 2-methyl-3-[(2- 4- or 5-)
thiazolyl]propoxy [2-phenyl-(4- or 5-)thiazolylJmethoxy [2-(4-
chlorophenyl) - 4 -methyl - 5 - thiazolyl ] methoxy [ 2 - (3 - bromophenyl) -
(4- or 5-)thiazolyl]methoxy [2-(2-fluorophenyl)-(4- or 5-)
thiazolyl]methoxy [2-(34-dichlorophenyl)-(4- or 5-)thiazolyl]
methoxy [2-(246-trifluorophenyl)-(4- or 5-)thiazolyl]methoxy
[2-methyl-(4- or 5-)thiazolyl]methoxy 2-[2-ethyl-(4- or 5-)
thiazolyl]methoxy 2-[4-phenyl-(2- or 5-)thiazolyl]ethoxy
3-[5-n-propyl-(2- or 4-)thiazolyl]propoxy 4-[4-n-butyl-
(2- or 5-)thiazolyl]butoxy 5-[2-n-pentyl-(4- or 5-)thiazolyl]
pentyloxy 6-[5-n-hexyl-(2- or 4-)thiazolyl]hexyloxy [24-
dimethyl-5-thiazolylJmethoxy and [24-diphenyl-5-thiazolyl]
methoxy.
Examples of benzoyl groups optionally substituted on
the phenyl ring with one or more halogen atoms include benzoyl
groups optionally substituted on the phenyl ring with one to
three halogen atoms such as benzoyl 4-fluorobenzoyl 25-
difluorobenzoyl 24-difluorobenzoyl 34-difluorobenzoyl 35-
difluorobenzoyl 26-difluorobenzoyl 2-chlorobenzoyl 3-
chlorobenzoyl 4-chlorobenzoyl 23-dichlorobenzoyl 24-
dichlorobenzoyl 25-dichlorobenzoyl 34-dichlorobenzoyl 26-
dichlorobenzoyl 3-fluorobenzoyl 2-fluorobenzoyl 3-bromobenzoyl
4-iodobenzoyl 2-bromobenzoyl 4-bromobenzoyl 35-
dichlorobenzoyl 246-trifluorobenzoyl 2-iodobenzoyl 3-
iodobenzoyl 4-iodobenzoyl 23-dibromobenzoyl 24-diiodobenzoyl
and 246-trichlorobenzoyl.
Examples of piperidinyloxy groups optionally
-73-
substituted on the piperidine ring with one or more benzoyl
groups each benzoyl substituent optionally being substituted on
the phenyl ring with one or more halogen atoms include:
piperidinyloxy groups optionally substituted on the
piperidine ring with one to three above-described benzoyl groups
each benzoyl substituent optionally being substituted on the
phenyl ring with one to three halogen atoms
such as (1- 2- 3- or 4-)piperidinyloxy l-(4-
chlorobenzoyl)-(2- 3- or 4-piperidinyloxy l-(3-bromobenzoyl)-
(2- 3- or 4-)piperidinyloxy 1-benzoyl-(2- 3- or 4-)
piperidinyloxy l-(2-fluorobenzoyl)-(2- 3- or 4-)piperidinyloxy
l-(24-dichlorobenzoyl)-(2- 3- or 4-)piperidinyloxy l-(246-
trifluorobenzoyl)-(2- 3- or 4-)piperidinyloxy 2-(3-
chlorobenzoyl)-(l- 3- or 4-)piperidinyloxy 3-(2-
chlorobenzoyl)-(l- 2- or 4-)piperidinyloxy 4-(23-
dibromobenzoyl)-(l- 2- or 3-)piperidinyloxy 12-dibenzoyl-
(3- or 4-)piperidinyloxy and l24-tribenzoyl-3-piperidinyloxy.
Examples of thienyl lower alkoxy groups include
thienylalkoxy groups wherein the alkoxy moiety is a straight or
branched Ci_6 alkoxy group such as [(2- or 3-)thienyl]methoxy
2-[(2- or 3-)thienyl]ethoxy l-[(2- or 3-)thienyl]ethoxy
3-[(2- or 3-)thienylJpropoxy 4-[(2- or 3-)thienylJbutoxy
5-[(2- or 3-) thienyl]pentyloxy 6-[(2- or 3-)thienyl]hexyloxy
ll-dimethyl-2-t(2- or 3-)thienyl]ethoxy and
2-methyl-3-[(2- or 3-)thienyl]propoxy.
Examples of phenylthio lower alkoxy groups include
phenylthioalkoxy groups wherein the alkoxy moiety is a straight
or branched Ci-6 alkoxy group such as phenylthiomethoxy 2-
phenylthioethoxy 1-phenylthioethoxy 3-phenylthiopropoxy 4-
phenylthiobutoxy 5-phenylthiopentyloxy 6-phenylthiohexyloxy
11-dimethyl-2-phenylthioethoxy and 2-methyl-3-phenylthiopropoxy.
Examples of carbamoyl-substituted lower alkoxy groups
optionally substituted with one or more lower alkyl groups
include:
carbamoyl-substituted straight and branched d-6 alkoxy
-74-
groups optionally substituted on the carbamoyl group with one or
two straight and/or branched Ci-6 alkyl groups
such as carbamoylmethoxy 2-carbamoylethoxy 1-
carbamoylethoxy 3-carbamoylpropoxy 4-carbamoylbutoxy 5-
carbamoylpentyloxy 6-carbamoylhexyloxy 11-dimethyl- 2 -
carbamoylethoxy 2-methyl-3-carbamoylpropoxy
methylcarbamoylmethoxy 1-ethylcarbamoylethoxy 2-npropylcarbamoylethoxy
3-isopropylcarbamoylpropoxy 4-nbutylcarbamoylbutoxy
5-n-pentylcarbamoylpentyloxy 6-nhexylcarbamoylhexyloxy
dimethylcarbamoylmethoxy 3-
dimethylcarbamoylpropoxy 2-diisopropylcarbamoylethoxy (W-ethyl-
N-n -propylcarbamoyl)methoxy and 2 - (//-methyl-N-nhexylcarbamoyl)
ethoxy.
Examples of benzoyl lower alkoxy groups include
benzoylalkoxy groups wherein the alkoxy moiety is a straight or
branched Ci-e alkoxy group such as benzoylmethoxy 2-benzoylethoxy
1-benzoylethoxy 3-benzoylpropoxy 4-benzoylbutoxy 5-
benzoylpentyloxy 6-benzoylhexyloxy 1l-dimethyl-2-benzoylethoxy
and 2-methyl-3-benzoylpropoxy.
Examples of pyridylcarbonyl lower alkoxy groups include
pyridylcarbonylalkoxy groups wherein the alkoxy moiety is a
straight or branched Ci_6 alkoxy group such as
[(2- 3- or 4-)pyridylcarbonyl]methoxy 2-[(2- 3- or 4-)
pyridylcarbonyl]ethoxy l-[(2- 3- or 4-)pyridylcarbonyl]
ethoxy 3-[(2- 3- or 4-)pyridylcarbonyl]propoxy
4-[(2- 3- or 4-)pyridylcarbonyl]butoxy 5-[(2- 3- or 4-)
pyridylcarbonyl]pentyloxy 6-[(2- 3- or 4-)pyridylcarbonyl]
hexyloxy 11-dimethyl-2-[(2- 3- or 4-)pyridylcarbonyl]ethoxy
and 2-methyl-3-[(2- 3- or 4-)pyridylcarbonyl] propoxy.
Examples of imidazolyl lower alkoxy groups optionally
substituted on the imidazole ring with one or more phenyl lower
alkyl groups include:
imidazolylalkoxy groups wherein the alkoxy moiety is a
straight or branched Ci.6 alkoxy group optionally substituted on
the imidazole ring with one to three phenylalkyl groups wherein
-75-
the alkyl moiety is a straight or branched Ci-6 alkyl group
such as [(!- 2- 4- or 5-)imidazolyl]methoxy 2-[(l-
2- 4- or 5-)imidazolyl]ethoxy !-[(!- 2- 4- or 5-)
imidazolyl] ethoxy 3-[(l- 2- 4- or 5-)imidazolyl]propoxy 4-
[(!- 2- 4- or 5-)imidazolyl]butoxy 5-[•(!- 2- 4- or 5-)
imidazolyl] pentyloxy 6-[(l- 2- 4- or 5-)imidazolyl] hexyloxy
ll-dimethyl-2-[(l- 2- 4- or 5-) imidazolyl] ethoxy 2-methyl-
3-[(l- 2- 4- or 5-)imidazolyl]propoxy [1-benzyl-
(2- 4- or 5-)imidazolyl]methoxy [l-(2-phenylethyl)-
(2- 4- or 5-)imidazolyl]methoxy 2-[2-(3-phenylpropyl)-
(1- 4- or 5-)imidazolyl]ethoxy 3-[4-(4-phenylbutyl)-
(1- 2- or 5-)imidazolyl]propoxy 5-[4-(5-phenylpentyl)-
(1 - 2 - or 4 -) imidazolyl ] pentyloxy 6 - [ 1 - (6 -phenylhexyloxy) -
(2- 4- or 5-)ImidazolylJhexyloxy [l2-dibenzyl-(4- or 5-)
imidazolyl]methoxy and [l24-tribenzyl-5-imidazolyl]methoxy.
Examples of phenoxy lower alkoxy groups include
phenoxyalkoxy groups wherein the alkoxy moiety is a straight or
branched Ci-6 alkoxy group such as phenoxymethoxy 2-phenoxyethoxy
1-phenoxyethoxy 3-phenoxypropoxy 4-phenoxybutoxy 5-
phenoxypentyloxy 6-phenoxyhexyloxy 11-dimethyl-2-phenoxyethoxy
and 2-methyl-3-phenoxypropoxy.
Examples of phenyl lower alkoxy-substituted lower
alkoxy groups include phenylalkoxy-substituted alkoxy groups
wherein each of the two alkoxy moieties is a straight or branched
Ci-6 alkoxy group such as phenylmethoxymethoxy 2-
(phenylmethoxy)ethoxy 1-(phenylmethoxy)ethoxy 3-(phenylmethoxy)
propoxy 4-(phenylmethoxyJbutoxy. 5-(phenylmethoxy)pentyloxy 6-
(phenylmethoxy) hexyloxy 11- dimethyl - 2 - (phenylmethoxy) ethoxy 2 -
methyl-3-(phenylmethoxy) propoxy l-(2-phenylethoxy)ethoxy 2-(lphenylethoxy)
ethoxy 3 - (3 -phenylpropoxy) propoxy 4 - (4 -
phenylbutoxy)butoxy 5-(5-phenylpentyloxy)pentyloxy 6-(6-
phenylhexyloxy)hexyloxy (11-dimethyl-2-phenylethoxy)methoxy
and 3-(2-methyl-3-phenylpropoxy)propoxy.
Examples of isoindolinyl lower alkoxy groups optionally
substituted on the isoindoline ring with one or more oxo groups
-76-
include:
isoindolinylalkoxy groups wherein the alkoxy moiety is
& straight or branched Ci-e alkoxy group optionally substituted on
the isoindoline ring with one or two oxo groups
such as [(!- 2- 4- or 5-)isoindolinyl]methoxy 2-
[(!- 2- 4- or 5-)isoindolinyl]ethoxy !-[(!- 2- 4- or 5-)
isoindolinylJethoxy 3-[(l- 2- 4- or 5-)isoindolinylJpropoxy
4-[(l- 2- 4- or 5-) isoindolinyl]butoxy
5-[(l- 2- 4- or 5-)isoindolinyl]pentyloxy
6-[(l- 2- 4- or 5-)isoindolinyl]hexyloxy 11-dimethyl-2-
[(!- 2- 4- or 5-)isoindolinyl]ethoxy 2-methyl-3-
[(!- 2- 4- or 5-)isoindolinyl]propoxy 3-[l3-dioxo-
(2- 4- or 5-) isoindolinylJpropoxy [1-oxo-
(2- 3- 4- 5- 6- or 7-)isoindolinyl]methoxy 2-[l3-dioxo-
(1- 4- or 5-)isoindolinyl]ethoxy 4-[l-oxo-
(2- 3- 4- 5- 6- or 7-)isoindolinyl]butoxy 5-[l3-dioxo-
(1- 4- or 5-)isoindolinyl]pentyloxy and 6-[l-oxo-
(2- 3- 4- 5- 6- or 7-)isoindolinylJhexyloxy.
Examples of lower alkoxy groups optionally substituted
with one or more halogen atoms include straight and branched Ci_6
alkoxy groups optionally substituted with one to three halogen
atoms such as in addition to the above-described lower alkoxy
groups trifluoromethoxy trichloromethoxy chloromethoxy
bromomethoxy fluoromethoxy iodomethoxy difluoromethoxy
dibromomethoxy 2-chloroethoxy 222-trifluoroethoxy 222-
trichloroethoxy 3-chloropropoxy 23-dichloropropoxy 444-
trichlorobutoxy 4-fluorobutoxy 5-chloropentyloxy 3-chloro-2-
methylpropoxy 5-bromohexyloxy and 56-dibromohexyloxy.
Examples of lower alkanoyl groups include straight and
branched Ci.6 alkanoyl groups such as formyl acetyl propionyl
butyryl isobutyryl pentanoyl tert-butylcarbonyl and hexanoyl.
Examples of amino groups optionally substituted with
one or more lower alkanoyl groups include amino groups optionally
substituted with one or two straight and/or branched Ci-6 alkanoyl
groups such as amino formylamino acetylamino propionylamino
-77-
butyrylami.no isobutyrylamino pentanoylamino tertbutylcarbonylamino
hexanoylamino ArJV-diacetylamino and Nacetyl-
W-propionylamino.
Examples of phenyl lower alkyl groups optionally
substituted on the phenyl ring with one or more members selected
from the group consisting of halogen atoms lower alkyl groups
optionally substituted with one or more halogen atoms lower
alkoxy groups optionally substituted with one or more halogen
atoms a phenyl group lower alkoxycarbonyl groups a phenoxy
group lower alkylthio groups lower alkylsulfonyl groups phenyl
lower alkoxy groups and amino groups optionally substituted with
one or more lower alkanoyl groups include:
mono- and di-phenylalkyl groups wherein the alkyl
moiety is a straight or branched Ci-e alkyl group optionally
substituted on the phenyl ring with one to three members selected
from the group consisting of the above-described halogen atoms
the above-described straight and branched Ci-6 alkyl groups
optionally substituted with one to three halogen atoms the
above-described straight and branched Ci-6 alkoxy groups optionally
substituted with one to three halogen atoms a phenyl group the
above-described alkoxycarbonyl groups wherein the alkoxy moiety
is a straight or branched Ci6 alkoxy group a phenoxy group the
above-described straight and branched Ci_6 alkylthio groups the
above-described straight and branched Ci-6 alkylsulfonyl groups
the above-described phenylalkoxy groups wherein the alkoxy moiety
is a straight or branched Ci-e alkoxy group and the abovedescribed
amino groups optionally substituted with one or two
straight and/or branched Ci.6 alkanoyl groups
such as benzyl 1-phenethyl 2-phenethyl 3-
phenylpropyl 2-phenylpropyl 4-phenylbutyl 5-phenylpentyl 4-
phenylpentyl 6-phenylhexyl 2-methyl-3-phenylpropyl 11-
dimethyl-2-phenylethyl 11-diphenylmethyl 22-diphenylethyl
33-diphenylpropyl 12-diphenylethyl 4-chlorobenzyl 2-
chlorobenzyl 3-chlorobenzyl 3-fluorobenzyl 4-fluorobenzyl
23-dichlorobenzyl 246-trifluorobenzyl 3-
-78-
trifluororaethylbenzyl 4-trifluororaethylbenzyl 2-methyIbenzyl
3-methylbenzyl 4-methylbenzyl 4-tert-butylbenzyl 24-
dlmethylbenzyl 246-trimethylbenzyl 2-phenylbenzyl 4-
phenylbenzyl 24-diphenylbenzyl 246-triphenylbenzyl 2-
trifluoromethoxybenzyl 3-1rifluoromethoxybenzyl 4 -
trifluoromethoxybenzyl 2-methoxybenzyl 3-methoxybenzyl 4-
methoxybenzyl 34-dlmethoxybenzyl 345-trimethoxybenzyl 4-
methoxycarbonylbenzyl 3 - ethoxycarbonyIbenzyl 2-npropoxycarbonylbenzyl
24 -dimethoxycarbonylbenzyl 246-
trime thoxycarbony Ibenzyl 4 - tert -butoxycarbony Ibenzyl 3 -
phenoxybenzyl 2-phenoxybenzyl 4-phenoxybenzyl 34-
diphenoxybenzyl 345-triphenoxybenzyl 4-methylthiobenzyl 3-
methylthiobenzyl 2-methylthiobenzyl 24-dimethylthiobenzyl
246- trime thy 1 thiobenzyl 4 -me thylsulf onylbenzyl 3 -
methylsulfonylbenzyl 2-methylsulfonylbenzyl 34-
dime thylsulf onylbenzyl 345- trimethylsulf onylbenzyl 4 -
benzyloxybenzyl 3-benzyloxybenzyl 2-benzyloxybenzyl 24-
dibenzyloxybenzyl 246-tribenzyloxybenzyl 4 -methoxy-3-
chlorobenzyl 4-(W-acetylamino)benzyl 3-aminobenzyl 2-
aminobenzyl 4-aminobenzyl 23-diaminobenzyl 345-
triaminobenzyl and 4-methyl-3-fluorobenzyl.
Examples of naphthyl lower alkyl groups include
naphthylalkyl groups wherein the alkyl moiety is a straight or
branched Ci_6 alkyl group such as [(1- or 2-)naphthyl]methyl 1-
[(1- or 2-)naphthyl]ethyl 2-[(l- or 2-)naphthyl]ethyl 3-
[(1- or 2-)naphthyl]propyl 2-[(l- or 2-)naphthyl]propyl 4-
[(1- or 2-)naphthyl]butyl 5-[(l- or 2-)naphthyl]pentyl 4-
[(1- or 2-) naphthyl] pen tyl 6-[(l- or 2-) naphthyl ]hexyl 2-
methyl-3-[(l- or 2-)naphthyl]propyl and 11-dimethyl-2-
[(1- or 2-)naphthyl]ethyl.
Examples of furyl lower alkyl groups optionally
substituted on the furan ring with one or more lower
alkoxycarbonyl groups include:
furylalkyl groups wherein the alkyl moiety is a
straight or branched Ci_6 alkyl group optionally substituted on
-79-
the furan ring with one to three alkoxycarbonyl groups wherein
the alkoxy moiety is a straight or branched Ci-6 alkoxy group
such as [(2- or 3-)furyl]methyl 2-[(2- or 3-)furyl]
ethyl l-[(2- or 3-)furyl]ethyl 3-[(2- or 3-)furyl]propyl 4-
[(2- or 3-)furyl]butyl 5-[(2- or 3-)furyl]pentyl 6-[(2- or 3-)
furyllhexyl ll-dimethyl-2-[(2- or 3-)furyl] ethyl 2-methyl-3-
[(2- or 3-)furyl]propyl [5-ethoxycarbonyl-(2- 3- or 4-)furyl]
methyl [5-methoxycarbonyl-(2- 3- or 4-)furyl]methyl [2-npropoxycarbonyl-(
3- 4- or 5-)furyl]methyl [3-tertbutoxycarbonyl-(
2- 4- or 5-)furyl]methyl [4-npentyloxycarbonyl-(
2- 3- or 5-)furyl]methyl [2-nhexyloxycarbonyl-(
3- 4- or 5-)furyl]methyl [25-
diethoxycarbonyl-(3- or 4-)furyl]methyl and [245-
triethoxycarbonyl-3-furyl]methyl.
Examples of phenyl groups optionally substituted on the
phenyl ring with one or more lower alkyl groups each lower alkyl
substituent optionally being substituted with one or more halogen
atoms include:
phenyl groups optionally substituted on the phenyl ring
with one to three straight and/or branched Ci-6 alkyl groups each
alkyl substituent optionally being substituted with one to three
above-described halogen atoms
such as phenyl 2-methylphenyl 3-methylphenyl 4-
methylphenyl 2-ethylphenyl 3-ethylphenyl 4-ethylphenyl. 4-
isopropylphenyl 3-n-butylphenyl 4-n-pentylphenyl 4-nhexylphenyl
34-dimethylphenyl 34-diethylphenyl 24-
dimethylphenyl 25-dimethylphenyl 26-dimethylphenyl 345-
trimethyIphenyl 2-trifluoromethylphenyl 3-trifluoromethylphenyl
4-trifluoromethylphenyl 35-difluoromethylphenyl 246-tri
(trifluoromethyl)phenyl and 2-methyl-4-trifluoromethylphenyl.
Examples of thiazolyl lower alkyl groups optionally
substituted on the thiazole ring with one or more members
selected from the group consisting of lower alkyl groups and a
phenyl group each phenyl substituent optionally being
substituted with one or more optionally halogen-substituted lower
-80-
alkyl groups include thiazolylalkyl groups wherein the alkyl
moiety is a straight or branched Ci.6 alkyl group. Such
thiazoylalkyl groups include those optionally substituted on the
thiazole ring with one or two members selected from the abovedescribed
straight and branched Ci-6 alkyl groups and the abovedescribed
phenyl groups optionally substituted on the phenyl ring
with one to three straight and/or branched d-6 alkyl groups each
alkyl substituent on the phenyl substituent optionally further
being substituted with one to three halogen atoms. More specific
examples of the thiazolyl lower alkyl groups are [(2- 4- or 5-)
thiazolyl]methyl 2-[(2- 4- or 5-) thiazolyl]ethyl
1-1(2- 4- or 5-)thiazolyl]ethyl 3-[(2- 4- or 5-)thiazolyl]
propyl 4-t(2- 4- or 5-)thiazolyl]butyl 5-[(2- 4- or 5-)
thiazolyl]pentyl 6-[(2- 4- or 5-)thiazolyl]hexyl 11-
dimethyl-2-[(2- 4- or 5-)thiazolyl]ethyl [2-methyl-(4- or 5-)
thiazolyl]methyl [2-(4-trifluoromethylphenyl)-[(4- or 5-)
thiazolyl]methyl 2-[4-ethyl-(2- or 5-)thiazolyl]ethyl l-[5-(3-
methylphenyl)-(2- or 4-)thiazolyl]ethyl 3-[5-isopropyl-
(2- or 4-)thiazolylJpropyl 4-[2-(24-dijnethylphenyl)-(4- or 5-)
thiazolyl]butyl 5-[2-n-butyl-(4- or 5-)thiazolyl]pentyl 6-[4-
(246-trimethylphenyl)-(2- or 5-)thiazolyl]hexyl (24-dimethyl-
5-thiazolyl)methyl [2-(4-trifluoromethylphenyl)-4-phenyl-5-
thiazolylJmethyl and (2-phenyl-4-thiazolyl)methyl.
Examples of tetrazolyl lower alkyl groups optionally
substituted on the tetrazole ring with one or more lower alkyl
groups include:
tetrazolylalkyl groups wherein the alkyl moiety is a
straight or branched Ci-6 alkyl group optionally substituted on
the tetrazole ring with one or more straight and/or branched d-6
alkyl groups
such as t(l- or 5-)tetrazolyl]methyl 2-[(l- or 5-)
tetrazolyl]ethyl !-[(!- or 5-)tetrazolyl]ethyl 3-[(l- or 5-)
tetrazolyl]propyl 4-[(l- or 5-)tetrazolyl]butyl 5-[(l- or 5-)
tetrazolyl]pentyl 6-[(l- or 5-)tetrazolyl]butyl 5-(l-methyl-5-
tetrazolyDpentyl 6-(l-methyl-5-tetrazolyl)hexyl (5-methyl-l-
81-
tetrazolyl)methyl 2-(5-ethyl-l-tetrazolyl)hexyl 11-dimethyl-2-
[(1- or 5-) tetrazolyl]ethyl 2-methyl-3-[(l- or 5-)tetrazolyl]
propyl (1-methyl-5-tetrazolyl)methyl (1-ethyl-5-tetrazolyl)
methyl 2-(l-n-propyl-5-tetrazolyl)ethyl l-(l-u-butyl-5-
tetrazolyl)ethyl 3-(1-n-pentyl-5-tetrazolyl)propyl 4-(l-Jihexyl-
4-tetrazolyl)butyl 3-(5-isopropyl-l-tetrazolyl)propyl 4-
(5-sec-butyl-l-tetrazolyl)butyl 5-(5-isopentyl-1-tetrazolyl)
pentyl and 6-(5-n-hexyl-l-tetrazolyl)hexyl.
Examples of benzothlenyl lower alkyl groups optionally
substituted on the benzothiophene ring with one or more halogen
atoms include:
benzothienylalkyl groups wherein the alkyl moiety is a
straight and branched Ci-6 alkyl group optionally substituted on
the benzothiophene ring with one to three halogen atoms
such as 1(2- 3- 4- 5- 6- or 7-)benzothienyl]
methyl 2-[(2- 3- 4- 5- 6- or 7-)benzothienyl]ethyl
l-[(2- 3- 4- 5- 6- or 7-)benzothienyl]ethyl
3-[(2- 3- 4- 5- 6- or 7-)benzothienyl]propyl
4-[(2- 3- 4- 5- 6- or 7-)benzothienyl]butyl
5-[(2- 3- 4- 5- 6- or 7-)benzothienyl]pentyl
6-[(2- 3- 4- 5- 6- or 7-)benzothienyl]hexyl
ll-dimethyl-2-[(2- 3- 4- 5- 6- or 7-)benzothienyl]ethyl
2-methyl-3-[(2- 3- 4- 5- 6- or 7-)benzothienyl]propyl
[5-chloro-(2- 3- 4- 6- or 7-)benzothienyl]methyl
[4-bromo-(2- 3- 5- 6- or 7-)benzothienyl]methyl
[6-fluoro-(2- 3- 4- 5- or 7-)benzothienyl]methyl
[7-iodo-(2- 3- 4- 5- or 6-)benzothienyl]methyl
[2-chloro-(3- 4- 5- 6- or 7-)benzothienyl]methyl
[45-dichloro-(2- 3- 6- or 7-)benzothienyl]methyl
[245-chloro-(3- 6- or 7-)benzothienyl]methyl
2-[6-fluoro-(2- 3- 4- 5- or 7-)benzothienyl]ethyl
l-[7-iodo-(2- 3- 4- 5- or 6-)benzothienyl]ethyl
3-[2-chloro-(3- 4- 5- 6- or 7-)benzothienyl]propyl
4-[45-dichloro-(2- 3- 6- or 7-)benzothienyl]butyl
5-[245-trichloro-(3- 6- or 7-)benzothienyl]pentyl and
6-[5-chloro-(2- 3- 4- 6- or 7-)benzothienyl]hexyl.
Examples of lower alkynyl groups include C2.6 straight
and branched alkynyl groups such as ethynyl 2-propynyl 2-
butynyl 3-butynyl 1-methyl-2-propynyl 2-pentynyl and 2-
hexynyl.
Examples of lower alkenyl groups include straight and
branched C2-e alkenyl groups containing one to three double bonds
such as vinyl 1-propenyl 1-methyl-1-propenyl 2-methyl-lpropenyl
2-propenyl 2-butenyl 1-butenyl 3-butenyl 2-
penthenyl 1-penthenyl 3-penthenyl 4-penthenyl 13-butadienyl
13-pentadienyl 2-penten-4-yl 2-hexenyl 1-hexenyl 5-hexenyl
3-hexenyl 4-hexenyl 33-dimethyl-1-propenyl 2-ethyl-1-propenyl
135-hexatrienyl 13-hexadienyl and 14-hexadienyl.
Examples of benzoimidazolyl lower alkyl groups include
benzoimidazolylalkyl groups wherein the alkyl moiety is a
straight or branched Ci_6 alkyl group such as [(!- 2- 4- or 5-)
benzoimidazolyl]methyl 2-[(l- 2- 4- or 5-)benzoimidazolyl]
ethyl !-[(!- 2- 4- or 5-)benzoimidazolyl]ethyl 3-
[(!- 2- 4- or 5-)benzoimidazolyl]propyl 4-
[(!- 2- 4- or 5-)benzoimidazolyl]butyl 5-[(l- 2- 4- or 5-)
benzoimidazolyl]pentyl 6-[(l- 2- 4- or 5-)benzoimidazolyl]
hexyl ll-dimethyl-2-[(1- 2- 4- or 5-)benzoimidazolyl]ethyl
and 2-methyl-3-[(l- 2- 4- or 5-)benzoimidazolyl]propyl.
Examples of pyridyl lower alkyl groups include
pyridylalkyl groups wherein the alkyl moiety is a straight or
branched Ci-6 alkyl group such as [(2- 3- or 4-)pyridyl]methyl
2-[(2- 3- or 4-)pyridyl]ethyl l-[(2- 3- or 4-)pyridyl]ethyl
3-[(2- 3- or 4-)pyridyl]propyl 4-[(2- 3- or 4-)pyridyl]butyl
ll-dimethyl-2-[(2- 3- or 4-)pyridyl]ethyl 5-[(2- 3- or 4-)
pyridyl]pentyl 6-[(2- 3- or 4-)pyridyl]hexyl
l-[(2- 3- or 4-)pyridyl]isopropyl and
2-methyl-3-[(2- 3- or 4-)pyridyl]propyl.
Examples of imidazolyl lower alkyl groups optionally
substituted on the imidazole ring with one or more phenyl lower
alkyl groups include:
-83-
imidazolylalkyl groups wherein the alkyl moiety is a
straight or branched Ci-6 alkyl group optionally substituted on
the imidazole ring with one to three above-described phenylalkyl
groups wherein the alkyl moiety is a straight or branched Ci-e
alkyl group
such as [(!- 2- 4- or 5-)imidazolyl]methyl
2-[(l- 2- 4- or 5-)imidazolyl]ethyl !-[(!- 2- 4- or 5-)
imidazolyl]ethyl 3-[(l- 2- 4- or 5-)imidazolylJpropyl 4-[(l-
2- 4- or 5-)imidazolyl]butyl 11-dimethyl-2-
[(!- 2- 4- or 5-)imidazolyl]ethyl 5-[(l- 2- 4- or 5-)
imidazolyl]pentyl 6-[(l- 2- 4- or 5-)imidazolyl]hexyl !-[(!-
2- 4- or 5-)imidazolyl]isopropyl 2-methyl-3-
[(!- 2- 4- or 5-)imidazolyl]propyl [l-benzyl-(2- 4- or 5-)
imidazolyl]methyl [l-(2-phenylethyl)-(2- 4- or 5-)imidazolyl]
methyl [l-(l-phenylethyl)-(2- 4- or 5-)imidazolyl]methyl
[l-(3-phenylpropyl)-(2- 4- or 5-)imidazolyl]methyl
[l-(4-phenylbutyl)-(2- 4- or 5-)imidazolyl]methyl
[l-(5-phenylpentyl)-(2- 4- or 5-)imidazolyl]methyl
[l-(6-phenylhexyl)-(2- 4- or 5-)imidazolyl]methyl
2-[2-benzyl-(l- 4- or 5-)imidazolyl]ethyl
l-[4-(4-phenylethyl)-(l- or 2-)imidazolyl]ethyl
3-[2-(2-phenylethyl)-(!- 4- or 5-)imidazolyl]methyl
4-[l-(3-phenylpropyl)-(2- 4- or 5-)imidazolyl]butyl
5-[l-(4-phenylbutyl)-(2- 4- or 5-)imidazolyl]pentyl
6-[l-(5-phenylpentyl)-(2- 4- or 5-)imidazolyl]hexyl
[l2-dibenzyl-(4- or 5-)imidazolyl]methyl and
(124-tribenzyl-5-imidazolyl)methyl.
Examples of lower alkylsulfonyl groups optionally
substituted with one or more halogen atoms include straight and
branched Ci-6 alkylsulfonyl groups optionally substituted with one
to three halogen atoms such as in addition to the abovedescribed
lower alkylsulfonyl groups trifluoromethylsulfonyl
trichloromethylsulfonyl chloromethylsulfonyl
bromomethylsulfonyl fluoromethylsulfonyl iodomethylsulfonyl
difluoromethylsulfonyl dibromomethylsulfonyl 2-
-84-
chloroethylsulfonyl 222-trifluoroethylsulfonyl 222-
trichloroethylsulfonyl 3-chloropropylsulfonyl 23-
dichloropropylsulfonyl 444-trichlorobutylsulfonyl 4-
fluorobutylsulfonyl 5-chloropentylsulfonyl 3-chloro-2-
methylpropylsulfonyl 5-bromohexylsulfonyl and 56-
dibromohexylsulfonyl.
Examples of alkoxycarbonyl groups optionally
substituted with one or more halogen atoms include:
alkoxycarbonyl groups wherein the alkoxy moiety is a
straight or branched CI-IQ alkoxy group optionally substituted
with one to three halogen atoms
such as in addition to the above-described lower
alkoxycarbonyl groups n-heptyloxycarbonyl n-octyloxycarbonyl
n-nonyloxycarbonyl n-decyloxycarbonyl 2-ethylhexyloxycarbonyl
trifluoromethoxycarbonyl trichloromethoxycarbonyl
chloromethoxycarbonyl bromomethoxycarbonyl
fluoromethoxycarbonyl iodomethoxycarbonyl
difluoromethoxycarbonyl dibromomethoxycarbonyl 2-
chloroethoxycarbonyl 2-fluoroethoxycarbonyl 222-
trifluoroethoxycarbonyl 222-trichloroethoxycarbonyl 3-
chloropropoxycarbonyl 23- dichloropropoxycarbonyl 444-
trichlorobutoxycarbonyl 4-fluorobutoxycarbonyl 4-
chlorobutoxycarbonyl 5-chloropentyloxycarbonyl 3-chloro- 2 -
me thylpropoxycarbonyl 5-bromohexyloxycarbonyl 56-
dibromohexyloxycarbonyl 776-trichloroheptyloxycarbonyl 8-
bromooctyloxycarbonyl 999-trifluorononyloxycarbonyl and
101010-trichlorodecyloxycarbonyl.
Examples of pyridylcarbonyl groups optionally
substituted on the pyridine ring with one or more members
selected from the group consisting of pyrrolyl groups and halogen
atoms include:
pyridylcarbonyl groups optionally substituted on the
pyridine ring with one to three members selected from the group
consisting of pyrrolyl groups and halogen atoms
such as (2- 3- or 4-)pyridylcarbonyl 2-chloro-
(3- 4- 5- or 6-)pyridylcarbonyl 26-dichloro-(3- 4- or 5-)
pyridylcarbonyl 2-(1-pyrrolyl)-(3- 4- 5- or 6-)
pyridylcarbonyl 2-bromo-(3- 4- 5- or 6-)pyridylcarbonyl 26-
difluoro-(3- 4- or 5-)pyridylcarbonyl 4-(1-pyrrolyl)-
(2- or 3-)pyridylcarbonyl 3-chloro-(2- 4- 5- or 6-)
pyridylcarbonyl 25-dibromo-(3- 4- or 6-)pyridylcarbonyl 2-
(1-pyrrolyl)-4-chloro-(3- 5- or 6-)pyridylcarbonyl 246-
trifluoro-(3- or 5-)pyridylcarbonyl and 24-di(1-pyrrolyl)-
(3- 5- or 6-)pyridylcarbonyl.
Examples of pyridyl groups optionally substituted on
the pyridine ring with one or more members selected from the
group consisting of lower alkyl groups and lower alkoxy groups
include:
pyridyl groups optionally substituted on the pyridine
ring with one to three members selected from the group consisting
of the above-described straight and branched Ci-6 alkyl groups and
the above-described straight and branched Ci-6 alkoxy groups
such as (2- 3- or 4-)pyridyl 2-methyl-
(3- 4- 5-. or 6-)pyridyl 3-methyl-(2- 4- 5- or 6-)pyridyl
2-methoxy-(3- 4- 5- or 6-)pyridyl 4-ethyl-(2- or 3-)pyridyl
3-n-propyl-(2- 4- 5- or 6-)pyridyl 2-tert-butyl-
(3- 4- 5- or 6-)pyridyl 2-n-pentyl-(3- 4- 5- or 6-)pyridyl
3-n-hexyl-(2- 4- 5- or 6-)pyridyl 24-dimethyl-
(3- 5- or 6-)pyridyl 246-trimethyl-(3- or 5-)pyridyl
3-ethoxy-(2- 4- 5- or 6-)pyridyl 2-isopropoxy-
(3- 4- 5- or 6-)pyridyl 2-n-butoxy-(3- 4- 5- or 6-)pyridyl
4-n-pentyloxy-(2- or 3-)pyridyl 2-n-hexyloxy-(3- 4- 5- or 6-)
pyridyl 23-dimethoxy-(4- 5- or 6-)pyridyl 3-methyl-
(2- 4- 5- or 6-)pyridyl 345-trimethoxy-(2- or 6-)pyridyl
and 2-methyl-3-methoxy-(4- 5- or 6-)pyridyl.
Examples of amino groups optionally substituted with
one or more members selected from the group consisting of lower
alkyl groups and lower alkanoyl groups:
include amino groups optionally substituted with one or
two members selected from the group consisting of straight and
-86-
branched d-6 alkyl groups and straight and branched d-6 alkanoyl
groups
such as amlno methylamlno ethylamlno n-propylamino
isopropylamino n-butylamino tert-butylamino n-pentylamino nhexylamlno
dimethylamlno diethylamino di-n-propylamlno di-nbutylamino
di-n-pentylamino di-n-hexylamino N-methyl-Nethylamino
N-ethyl-W-n-propylamino N-methyl-//-n-butylamino Nmethyl-
AT-n-hexylamino formylamino acetylamino propionylamino
butyrylamino isobutyrylamlno pentanoylamino tertbutylcarbonylamino
hexanoylamino AT W-diacetylami.no W-acetyl-Wpropionylamino
N-metlnyl-N-acetylamino and N-ethyl-Npropionylamino.
Examples of pyrrolidinyl groups optionally substituted
on the pyrrolidine ring with one or more oxo groups include
pyrrolidinyl groups optionally substituted with one or two oxo
groups such as (1- 2- or 3-)pyrrolidinyl 2-oxo-(l- 3- 4-
or 5-)pyrrolidinyl and 25-dioxo-(l- or 3-)pyrrolidinyl.
Examples of piperidinyl groups optionally substituted
on the piperidine ring with one or more lower alkyl groups
include piperidinyl groups optionally substituted on the
piperidine ring with one to three straight and/or branched Ci-6
alkyl groups such as (1- 2- 3- or 4-)piperidinyl 1-methyl-
(2- 3- or 4-)piperidinyl l-ethyl-(2- 3- or 4-)piperidinyl
l-n-propyl-(2- 3- or 4-)piperidinyl 1-isopropyl-
(2- 3- or 4-)piperidinyl l-n-butyl-(2- 3- or 4-)piperidinyl
l-n-pentyl-(2- 3- or 4-)piperidinyl l-n-hexyl-(2- 3- or 4-)
piperidinyl l2-dimethyl-(3- 4- 5- or 6-)piperidinyl 123-
trimethyl-(4- 5- or 6-)piperidinyl 2-n-propyl-
(1- 3- 4- 5- or 6-)piperidinyl 3-ethyl-
(1- 2- 4- 5- or 6-)piperidinyl and 2-methyl-4-isopropyl-
(1- 3-. 5- or 6-)piperidinyl.
Examples of carbamoyl groups optionally substituted
with one or more lower alkyl groups include carbamoyl groups
optionally substituted with one or two straight and/or branched
Ci-6 alkyl groups such as carbamoyl methylcarbamoyl
ethylcarbamoyl n-propyIcarbamoyl isopropylcarbamoyl nbutylcarbamoyl
tert-butylcarbamoyl n-pentyIcarbamoyl nhexylcarbamoyl
dime thy Icarbamoyl diethylcarbamoyl di-n-propyl
carbamoyl di-n-butylcarbamoyl di-n-pentylcarbamoyl di-nhexylcarbamoyl
N-methyl-N-ethylcarbamoyl N-ethyl-W-npropyIcarbamoyl
//-methyl-N-n-butylcarbamoyl and N-methyl-N-nhexyIcarbamoyl.
Examples of phenyl groups optionally substituted with
on the phenyl ring one or more members selected from the group
consisting of halogen atoms lower alkyl groups optionally
substituted with one or more halogen atoms a phenoxy group
lower alkoxy groups optionally substituted with one or more
halogen atoms lower alkylthio groups lower alkylsulfonyl
groups amino groups optionally substituted with one or more
members selected from the group consisting of lower alkyl groups
and lower alkanoyl groups pyrrolidinyl groups optionally
substituted on the pyrrolidine ring with one or more oxo groups
piperidinyl groups optionally substituted on the piperidine ring
with one or more lower alkyl groups lower alkenyl groups an
aminosulfonyl group a hydroxy group carbamoyl groups optionally
substituted with one or more lower alkyl groups phenyl lower
alkoxy groups and a cyano group include:
phenyl groups optionally substituted on the phenyl ring
with one to three members selected from the group consisting of
the above-described halogen atoms the above-described straight
and branched Ci-6 alkyl groups optionally substituted with one to
three halogen atoms a phenoxy group the above-described
straight and branched Ci.6 alkoxy groups optionally substituted
with one to three halogen atoms the above-described straight and
branched d-6 alkylthio groups the above-described straight and
branched Ci-6 alkylsulfonyl groups the above-described amino
groups optionally substituted with one or two members selected
from the group consisting of straight and branched Ci-6 alkyl
groups and straight and branched d-6 alkanoyl groups the abovedescribed
pyrrolidinyl groups optionally substituted on the
-88-
pyrrolidine ring with one or two oxo groups the above-described
piperidinyl groups optionally substituted on the piperidine ring
with one to three straight and/or branched Ci-6 alkyl groups the
above-described straight and branched C2-e alkenyl groups
containing one to three double bonds an aminosulfonyl group a
hydroxy group the above-described carbamoyl groups optionally
substituted with one or two straight and/or branched Ci-6 alkyl
groups the above-described phenylalkoxy groups wherein the
alkoxy moiety is a straight or branched d-6 alkoxy group and a
cyano group
such as phenyl 4-phenoxyphenyl 3-phenoxyphenyl 2-
phenoxyphenyl 4-isopropylphenyl 3-isopropylphenyl 2-
isopropylphenyl 4-tert-butylphenyl 4-methylphenyl 3-
methylphenyl 2-methylphenyl 23-dimethylphenyl 24-
dimethylphenyl 35-dimethylphenyl 246-trimethylphenyl 4-
methyl-3-methoxyphenyl 4-trifluoromethylphenyl 3-
trifluoromethylphenyl 2-trifluoromethylphenyl 4-methyl-3-
chlorophenyl 4-chlorophenyl 3-chlorophenyl 2-chlorophenyl 2-
fluorophenyl 3-fluorophenyl 4-fluorophenyl 3-bromophenyl 34-
dichlorophenyl 35-dichlorophenyl 345-trichlorophenyl 246-
trifluorophenyl 35-difluorophenyl 3-chloro-4-fluorophenyl 2-
chloro-5-fluorophenyl 3-fluoro-4-methoxyphenyl 3-chloro-4-
methoxyphenyl 3-chloro-4-hydroxyphenyl 4-methoxyphenyl 3-
methoxyphenyl 2-methoxyphenyl 24-dimethoxyphenyl 34-
dimethoxyphenyl 246-trimethoxyphenyl 2-methoxy-5-chlorophenyl
2-methoxy-5-acetylaminophenyl 2-chloro-5-acetylaminophenyl 4-
ethoxyphenyl 4-trifluoromethoxyphenyl 3-trifluoromethoxyphenyl
2-trifluoromethoxyphenyl 3-methoxy-5-trifluoromethylphenyl 4-
methylthiophenyl 3-methylthiophenyl 2-methylthiophenyl 2-(lmethyl-
1-vinyl)phenyl 4-vinylphenyl 3-dimethylaminophenyl 4-
methylaminophenyl 2-(W-methyl-AT-acetylamino) phenyl 3-
acetylaminophenyl 4-propionylaminophenyl 4-acetylaminophenyl
2-acetylaminophenyl 4-aminosulfonylphenyl 3-aminosulfonylphenyl
2-aminosulfonylphenyl 4-methylthiophenyl 3-methylthiophenyl 2-
methylthiophenyl 4-methylsulfonylphenyl 3-methylsulfonylphenyl
-89-
2-methylsulfonylphenyl 4-methylcarbamoylphenyl 3-
carbamoylphenyl 2-ethylcarbamoylphenyl 2-benzyloxyphenyl 3-
benzyloxyphenyl 4-benzyloxyphenyl 2-phenylphenyl 3-
phenylphenyl 4-phenylphenyl 2-cyanophenyl 3-cyanophenyl 4-
cyanophenyl 4-[2-oxo-(l- 3- 4- or 5-)pyrrolidinyl]phenyl 3-
[25-dioxo-(l- or 3-)pyrrolidinyl]phenyl 4-[4-methyl-
(1- 2- or 3-)piperazinyl]phenyl 3-[4-ethyl-(l- 2- or 3-)
piperazinyl]phenyl and 2-t4-isopropyl-(l- 2- or 3-)
piperazinyl]phenyl.
Examples of cycloalkyl groups optionally substituted on
the cycloalkyl ring with one or more lower alkyl groups include
Ca-a cycloalkyl groups optionally substituted on the cycloalkyl
ring with one to three straight and/or branched Ci_6 alkyl groups
such as in addition to the above-described cycloalkyl groups 1-
methylcyclopropyl 1-methylcyclopentyl 1-methylcyclohexyl 2-
methylcyclohexyl 1-methylcyclobutyl 1-ethylcyclooctyl 1-npropylcycloheptyl
12-dimethyIcyclohexyl 145-
trimethylcyclooctyl 1-n-butylcyclopropyl
1-n-pentylcyclopentyl and 1-n-hexyIcyclohexyl.
Examples of amino groups optionally substituted with
one or more members selected from the group consisting of a
phenyl group and lower alkyl groups include:
amino groups optionally substituted with one or two
members selected from the group consisting of a phenyl group and
straight and branched Ci_6 alkyl groups
such as amino methylamino ethylamino n-propylamino
isopropylamino n-butylamino tert-butylamino n-pentylamino nhexylamino
dimethylamino diethylamino di-n-propylamino di-nbutylamino
di-n-pentylamino di-n-hexylamino W-methyl-Wethylamino
N-ethyl-W-n-propylamino N-methyl-AT-n-butylamino Nmethyl-
AT-n-hexylamino phenylamino WW-diphenylamino N-methyl-
Af-phenylamino N-ethyl-N-phenylamino and N-n-propyl-Nphenylamino.
Examples of benzoyl groups optionally substituted on
the phenyl ring with one or more members selected from the group
-90-
conslsting of halogen atoms a phenoxy group a phenyl group
lower alkyl groups optionally substituted with one or more
halogen atoms lower alkoxy groups lower alkanoyl groups a
nitro group a cyano group amino groups optionally substituted
with one or more members selected from the group consisting of a
phenyl group and lower alkyl groups pyrrolidinyl groups
optionally substituted on the pyrrolidine ring with one or more
oxo groups pyrrolyl groups pyrazolyl groups 124-triazolyl
groups and imidazolyl groups include:
benzoyl groups optionally substituted on the phenyl
ring with one to three members selected from the group consisting
of halogen atoms a phenoxy group a phenyl group the abovedescribed
straight and branched Ci-6 alkyl groups optionally
substituted with one to three halogen atoms the above-described
straight and branched Ci.6 alkoxy groups the above-described
straight and branched Ci_6 alkanoyl groups a nitro group a cyano
group the above-described amino groups optionally substituted
with one or two members selected from the group consisting of a
phenyl group and straight and branched Ci-6 alkyl groups the
above-described pyrrolidinyl groups optionally substituted on the
pyrrolidine ring with one or two oxo groups pyrrolyl groups
pyrazolyl groups 124-triazolyl groups and imidazolyl groups
such as benzoyl 4-methoxybenzoyl 3-methoxybenzoyl 2-
methoxybenzoyl 24-dimethoxybenzoyl 345-trimethoxybenzoyl 2-
methoxy-5-chlorobenzoyl 4-phenoxybenzoyl 2-phenoxybenzoyl 3-
phenoxybenzoyl 4-chlorobenzoyl 3-chlorobenzoyl 2-chlorobenzoyl
26-dichlorobenzoyl 2-chloro-4-fluorobenzoyl 246-
trifluorobenzoyl 4-bromobenzoyl 3-fluorobenzoyl 4-
trifluoromethylbenzoyl 3-trifluoromethylbenzoyl 2-
trifluoromethylbenzoyl 3-fluoro-2-methylbenzoyl 4-methylbenzoyl
3-methylbenzoyl 2-methylbenzoyl 34-dimethylbenzoyl 245-
trimethylbenzoyl 2-phenylbenzoyl 3-phenylbenzoyl 4-
phenylbenzoyl 4-nitrobenzoyl 3-nitrobenzoyl 2-nitrobenzoyl 2-
dimethylaminobenzoyl 3-methylaminobenzoyl 4-(Wmethylanilino)
benzoyl 2-anilinobenzoyl 3-cyanobenzoyl 4-
-91-
cyanobenzoyl 2-cyanobenzoyl 4-acetylbenzoyl 2-propionylbenzoyl
3-butyrylbenzoyl 4-[(l- 2- or 3-)pyrrolyl]benzoyl 4-
[(!- 3- 4- or 5-)pyrazolyl]benzoyl 4-[(l- 3- or 5-)l24-
triazolyl]benzoyl 4-[(l- 2- 4- or 5 -)Imidazolyl]benzoyl and
4-[2-oxo-(l- 3- 4- or 5-)pyrrolidlnyl]benzoyl.
Examples of lower alkylenedloxy groups include straight
and branched Ci-4 alkylene groups such as methylenedioxy
ethylenedioxy trimethylenedioxy and tetramethylenedioxy.
Examples of benzoyl groups substituted on the phenyl
ring with one or more lower alkylenedioxy groups include:
benzoyl groups substituted on the phenyl ring with one
or more of the above-described straight and branched d-4
alkylenedioxy groups
such as 34-methylenedioxybenzoyl
23-ethylenedioxybenzoyl 34-trimethylenedioxybenzoyl and
23-tetramethylenedioxybenzoyl.
Examples of cycloalkylcarbonyl groups include
cycloalkylcarbonyl groups wherein the cydoalkyl moiety is a C3-8
cycloalkyl group such as cyclopropylcarbonyl cyclobutylcarbonyl
cyclopentylcarbonyl cyclohexylcarbonyl cycloheptylcarbonyl and
cyclooctylcarbonyl.
Examples of furylcarbonyl groups include (2- or 3-)
furylcarbonyl.
Examples of naphthylcarbonyl groups include (1- or 2-)
naphthylcarbonyl.
Examples of phenoxycarbonyl groups optionally
substituted on the phenyl ring with one or more members selected
from the group consisting of lower alkoxy groups lower alkyl
groups halogen atoms and a nitro group include:
phenoxycarbonyl groups optionally substituted on the
phenyl ring with one to three members selected from the group
consisting of the above-described straight and branched Ci_6 alkoxy
groups the above-described straight and branched Ci-6 alkyl groups
halogen atoms and a nitro group
such as phenoxycarbonyl 4-chlorophenoxycarbonyl 3-
-92-
chlorophenoxycarbonyl 2-chlorophenoxycarbonyl 34-
dichlorophenoxycarbonyl 246-trichlorophenoxycarbonyl 4-
fluorophenoxycarbonyl 3-fluorophenoxycarbonyl 2-
fluorophenoxycarbonyl 24-difluorophenoxycarbonyl 345-
trifluorophenoxycarbonyl 4-bromophenoxycarbonyl 2-chloro-4-
methoxyphenoxycarbonyl 3-fluoro-5-methylphenoxycarbonyl 4-
methoxyphenoxycarbonyl 3-methoxyphenoxycarbonyl 2-
me thoxyphenoxycarbonyl 34- dime thoxyphenoxycarbonyl 245-
trimethoxyphenoxycarbonyl 4-methylphenoxycarbonyl 3-
methylphenoxycarbonyl 2-methylphenoxycarbonyl 25-
dimethylphenoxycarbonyl 234-trimethylphenoxycarbonyl 4-
nitrophenoxycarbonyl 3-nitrophenoxycarbonyl 2-
nitrophenoxycarbonyl 24-dinitrophenoxycarbonyl and 246-
trini trophenoxycarbonyl.
Examples of phenyl lower alkoxycarbonyl groups
optionally substituted on the phenyl ring with one or more
members selected from the group consisting of halogen atoms and a
nitro group include:
phenylalkoxycarbonyl groups wherein the alkoxy moiety
is a straight or branched Ci-6 alkoxy group optionally substituted
on the phenyl ring with one to three members selected from the
group consisting of halogen atoms and a nitro group
such as benzyloxycarbonyl 2-phenylethoxycarbonyl 1-
phenylethoxycarbonyl 3-phenylpropoxycarbonyl 4-
phenylbutoxycarbonyl 5-phenylpentyloxycarbonyl 6-
phenylhexyloxycarbonyl 11 -dimethyl- 2-phenylethoxycarbonyl 2 -
methyl-3-phenylpropoxycarbonyl 4-chlorobenzyloxycarbonyl 3-
chlorobenzyloxycarbonyl 2-chlorobenzyloxycarbonyl 34-
dichlorobenzyloxycarbonyl 246-trichlorobenzyloxycarbonyl 4-
fluoroben zyloxycarbonyl 3-fluorobenzyloxycarbonyl 2-
fluorobenzyloxycarbonyl 24-difluorobenzyloxycarbonyl 345-
trifluorobenzyloxycarbonyl 4-bromobenzyloxycarbonyl 4-
nitrobenzyloxycarbonyl 3-nitrobenzyloxycarbonyl 2-
nitrobenzyloxycarbonyl 24-dinitrobenzyloxycarbonyl 246-
trinitrobenzyloxycarbonyl and 2-nitro-4-chlorobenzyloxycarbonyl.
-93-
Examples of piperidinyl groups optionally substituted
on the piperidine ring with one or more members selected from the
group consisting of lower alkyl groups lower alkanoyl groups
benzoyl groups optionally substituted on the phenyl ring with one
or more halogen atoms and phenyl groups optionally substituted
on the phenyl ring with one or more halogen atoms include:
piperidinyl groups optionally substituted on the
piperidine ring with one to three members selected from the group
consisting of the above-described straight and branched Ci-6 alkyl
groups the above-described straight and branched Ci-e alkanoyl
groups the above-described benzoyl groups optionally substituted
on the phenyl ring with one to three halogen atoms and the
above-described phenyl groups optionally substituted on the
phenyl ring with one to three halogen atoms
such as (1- 2- 3- or 4-)piperidinyl 1-methyl-
(2- 3- or 4-)piperidinyl l-acetyl-(2- 3- or 4-)piperidinyl
l-benzoyl-(2- 3- or 4-)piperidinyl l-(4-chlorobenzoyl)-
(2- 3- or 4-)piperidinyl l-(3-bromobenzoyl)-(2- 3- or 4-)
piperidinyl 1-benzoyl-(2- 3- or 4-)piperidinyl
l-(4-fluorobenzoyl)-(2- 3- or 4-)piperidinyl l-(24-dichloro
benzoyl)-(2- 3- or 4-)piperidinyl 1-(246-trifluorobenzoyl)-
(2- 3- or 4-)piperidinyl 2-(3-chlorobenzoyl)-(!- 3- or 4-)
piperidinyl 3-(2-chlorobenzoyl)-(!- 2- or 4-)piperidinyl 4-
(23-dibromobenzoyl)-{l- 2- or 3-)piperidinyl 12-dibenzoyl-
(3- or 4-)piperidinyl 124-tribenzoyl-3-piperidinyl 14-
dlmethyl-(2- 3- 5- or 6-)piperidinyl 124-trimethyl-
(3- 5- or 6-)piperidinyl 1-benzoyl-2-methyl-
(3- 4- 5- or 6-)piperidinyl l-phenyl-2-methyl-
(3- 4- 5- or 6-)piperidinyl l-acetyl-3-methyl-
(2- 4- 5- or 6-)piperidinyl l-phenyl-(2- 3- or 4-)
piperidinyl l-(4-chlorophenyl)-(2- 3- or 4-)piperidinyl
l-(3-bromophenyl)-(2- 3- or 4-)piperidinyl l-(4-iodophenyl)-
(2- 3- or 4-)piperidinyl 1-(4-fluorophenyl)-(2- 3- or 4-)
piperidinyl l-(24-dichlorophenyl)-(2- 3- or 4-)piperidinyl
1-(246-trifluorophenyl)-(2- 3- or 4-)piperidinyl
-94-
2-(3-chlorophenyl)-(l- 3- 4- 5- or 6-)piperidinyl
3-(2-chlorophenyl)-(l- 2- 4- 5- or 6-)piperidinyl
4-(23-dibromophenyl)-(l- 2- or 3-)piperidinyl 12-diphenyl-
(3-4- 5- or 6-)piperidinyl and l24-triphenyl-(3- 5- or 6-)
piperidinyl.
Examples of tetrahydropyranyl lower alkyl groups
include tetrahydropyranylalkyl groups wherein the alkyl moiety is
a straight or branched Ci_6 alkyl group such as
[(2- 3- or 4-)tetrahydropyranyl]methyl 2-[(2- 3- or 4-)
tetrahydropyranyl]ethyl l-[(2- 3- or 4-)tetrahydropyranyl]
ethyl 3-[(2- 3- or 4-)tetrahydropyranyl]propyl 4-
[(2- 3- or 4-)tetrahydropyranyl]butyl 11-dimethyl-2-
[(2- 3- or 4-)tetrahydropyranyl]ethyl 5-[(2- 3- or 4-)
tetrahydropyranyl]pentyl 6-[(2- 3- or 4-)tetrahydropyranyl]
hexyl l-[(2- 3- or 4-)tetrahydropyranyl]isopropyl and
2-methyl-3-[(2- 3- or 4-)tetrahydropyranyl]propyl.
Examples of phenyl lower alkyl groups optionally
substituted on the alkyl group with one or more lower
alkoxycarbonyl groups and optionally further substituted on the
phenyl ring with one or more members selected from the group
consisting of halogen atoms lower alkyl groups optionally
substituted with one or more halogen atoms lower alkoxy groups
optionally substituted with one or more halogen atoms and a
hydroxy group include:
mono- and di-phenylalkyl groups wherein the alkyl
moiety is a straight or branched Ci-6 alkyl group optionally
substituted on the alkyl group with one or more lower
alkoxycarbonyl groups wherein the alkoxy moiety is a straight or
branched Ci-6 alkoxy group and optionally further substituted on
the phenyl group with one to three members selected from the
group consisting of halogen atoms the above-described straight
and branched d-e alkyl groups optionally substituted with one to
three halogen atoms the above-described straight and branched
Ci-6 alkoxy groups optionally substituted with one to three
halogen atoms and a hydroxy group
-95-
such as benzyl 1-phenethyl 2-phenethyl 3-
phenylpropyl 2-phenylpropyl 4-phenylbutyl 5-phenylpentyl 4-
phenylpentyl 6-phenylhexyl 2-methyl-3-phenylpropyl 11-
dimethyl-2-phenylethyl 11-dimethyl-1-phenylmethyl 11-
diphenylmethyl 22-dlphenylethyl 33-diphenylpropyl 12-
diphenylethyl 4-chlorobenzyl 2-chlorobenzyl 3-chlorobenzyl 3-
fluorobenzyl 4-fluorobenzyl 3-bromobenzyl 23-dichlorobenzyl
26-dichlorobenzyl 246-trifluorobenzyl 2-(4-chlorophenyl)
ethyl 2-(2-fluorophenyl)ethyl 2-(3-fluorophenyl)ethyl 3-
trifluoromethylbenzyl 4-trifluoromethylbenzyl 2-methylbenzyl
3-methylbenzyl 4-methylbenzyl 4-te.rt-butylbenzyl 24-
dimethylbenzyl 246-trimethylbenzyl 2-trifluoromethoxybenzyl
3-trifluoromethoxybenzyl 4-trifluoromethoxybenzyl 2-
methoxybenzyl 3-methoxybenzyl 4-methoxybenzyl 4-ethoxybenzy
2-(3-methoxyphenyl)ethyl 34-dimethoxybenzyl 345-
trimethoxybenzyl 4-hydroxybenzyl 3-hydroxybenzyl 2-
hydroxybenzyl 24-dihydroxybenzyl 345-trlhydroxybenzyl 2-
methoxy-4-chlorobenzyl 3-methyl-5-fluorobenzyl 2 - (4
hydroxyphenyl)-1-methoxycarbonylethyl and 2-(4-chlorophenyl)-1-
ethoxycarbonylethyl.
Examples of lower alkylenedioxy-substituted phenyl
lower alkyl groups Include:
alkylenedioxy-substituted phenylalkyl groups wherein
the alkyl moiety is a straight or branched Ci_6 alkyl group
substituted on the phenyl ring with one or more of the abovedescribed
straight and branched Ci-4 alkylenedioxy groups
such as 34-methylenedioxybenzyl
34-1rimethylenedioxybenzyl 2-(23-ethylenedioxyphenyl)ethyl 1-
(34-trimethylenedioxyphenyl)ethyl 3 - (23 -
tetramethylenedioxyphenyl)propyl 4-(34-methylenedioxyphenyl)
butyl 5-(23-ethylenedioxyphenyl)penty1 6-(34-
trimethylenedioxyphenyl)hexyl 11-dimethyl-2-(23-
methylenedioxyphenyl)ethyl and 2-methyl-3-(34-
ethylenedioxyphenyl)propyl.
Examples of furyl lower alkyl groups include furylalkyl
groups wherein the alkyl moiety is a straight or branched Ci_6
alkyl group such as [(2- or 3-)furyl]methyl 2-[(2- or 3-)furyl]
ethyl l-[(2- or 3-)furylJethyl 3-t(2- or 3-)furyl]propyl 4-
1(2- or 3-)furyl]butyl 5-[(2- or 3-)furyl]pentyl 6-[(2- or 3-)
furyl]hexyl ll-dimethyl-2-[(2- or 3-)furyl]ethyl and 2-methyl-
3-[(2- or 3-)furyl]propyl.
Examples of carbamoyl lower alkyl groups optionally
substituted with one or more members selected from the group
consisting of lower alkyl groups and a phenyl group each phenyl
substituent optionally being substituted on the phenyl ring with
one or more lower alkyl groups include:
carbamoylalkyl groups wherein the alkyl moiety is a
straight or branched Ci-6 alkyl group optionally substituted with
one or two members selected from the group consisting of the
above-described straight and branched Ci_6 alkyl groups and the
above-described phenyl groups optionally substituted on the
phenyl ring with one to three straight and/or branched Ci-6 alkyl
groups
such as carbamoylmethyl 2-carbamoylethyl 1-
carbamoylethyl 3-carbamoylpropyl 4-carbamoylbutyl 5-
carbamoylpentyl 6 - carbamoylhexyl 11- dimethyl - 2 - carbamoylethyl
2-methyl-3-carbamoylpropyl 2-(AT-methyl-N-phenylcarbamoyl)ethyl
N- (4 -methylphenyl) carbamoylmethyl 2 - [N-methyl-N- (3 -methylphenyl)
carbamoyl ] ethyl N- (2 -methylphenyl) carbamoylmethyl 2 - [ N- ethyl -N-
(34- dimethylphenyl) carbamoyl ] ethyl N- (246 - trimethylphenyl)
carbamoylmethyl NN-dimethylcarbamoylmethyl NNdiphenylcarbamoylmethyl
W-methyl-N-ethylcarbamoylmethyl Nmethylcarbamoylmethyl
and 2-
(//-methylcarbamoyl) ethyl.
Examples of imidazolyl lower alkyl groups optionally
substituted on the lower alkyl group with one or more members
selected from the group consisting of a carbamoyl group and lower
alkoxycarbonyl groups include:
imidazolylalkyl groups wherein the alkyl moiety is a
straight or branched Ci-e alkyl group optionally substituted on
the lower alkyl group with one or more members selected from the
group consisting of a carbamoyl group and alkoxycarbonyl groups
wherein the alkoxy moiety is a straight or branched Ci-6 alkoxy
group
such as in addition to the above-described imidazolyl
lower alkyl groups 1-carbamoyl-2-[(!- 2- 4- or 5-)imidazolyl]
ethyl l-methoxycarbonyl-2-[(l- 2- 4- or 5-)imidazolyl]ethyl
l-carbamoyl-l-[(l- 2- 4- or 5-)imidazolyl]methyl 1-
ethoxycarbonyl-l-[(l- 2- 4- or 5-)imidazolyl]methyl 1-
carbamoyl-3-[(1- 2- 4- or 5-)imidazolyl]propyl 1-npropoxycarbonyl-
4-[(!- 2- 4- or 5-)imidazolyl]butyl 1-
carbamoyl-5-t (1- 2- 4- or 5-)Imidazolyl]pentyl and 1-tertbutoxycarbonyl-
6-[(l- 2- 4- or 5-)imidazolyl]hexyl.
Examples of amino-substituted lower alkyl groups
optionally substituted on each amino group with one or more lower
alkyl groups include:
amino-subsituted straight and branched Ci_6 alkyl groups
optionally substituted on the amino group with one or two
straight and/or branched Ci-e alkyl groups
such as aminomethyl 2-aminoethyl 1-aminoethyl 3-
aminopropyl 4-aminobutyl 5-aminopentyl 6-aminohexyl
dimethyl-2-aminoethyl 2-methyl-3-aminopropyl methylaminomethyl
2-ethylaminoethyl 3-n-propylaminopropyl 3-isopropylaminopropyl
4-n-butylaminobutyl 5-n-pentylaminopentyl 6-n-hexylaminohexyl
dimethylaminoethyl 2-diisopropylaminopropyl 3-
diisopropylaminopropyl (N- e thyl -N-n- propylamino) me thyl and
2- (N-me thyl -W-n-hexy lamino )me thyl.
Examples of 2345-tetrahydrofuryl groups optionally
substituted on the 2345-tetrahydrofuran ring with one or more
oxo groups include:
2345-tetrahydrofuryl groups optionally substituted
on the 2345-tetrahydrofuran ring with one or two oxo groups
such as (2- or 3-)2345-tetrahydrofuryl 2-oxo-
(3- 4- or 5-)2345-tetrahydrofuryl 3-oxo-(2- 4- or 5-)
2345-tetrahydrofuryl and 25-dioxo-(3- or 4-)2345-
tetrahydrofuryl.
Examples of pyrrolidinyl lower alkyl groups optionally
substituted on the pyrrolidine ring with one or more lower alkyl
groups include:
pyrrolidinylalkyl groups wherein the alkyl moiety is a
straight or branched Ci-6 alkyl group optionally substituted on
the pyrrolidine ring with one to three above-described straight
and/or branched Ci-e alkyl groups
such as [(!- 2- or 3-)pyrrolidinyl]methyl 2-
[(!- 2- or 3-)pyrrolidinyl]ethyl !-[(!- 2- or 3-)
pyrrolidinyl]ethyl 3-[(1- 2 - or 3-)pyrrolidinyl]propyl 4-
[(!- 2- or 3-)pyrrolidinyl]butyl 5-[(l- 2- or 3-)
pyrrolidinyl]pentyl 6-[(l- 2- or 3-)pyrrolidinyl]hexyl 11-
dimethyl-2-[(l- 2- or 3-)pyrrolidinyl]ethyl 2-methyl-
[(!- 2- or 3-)pyrrolidinyl]propyl l-ethyl-[(2- or 3-)
pyrrolidinyl]methyl 1-ethyl-[(2- or 3-)pyrrolidinyl]methyl 2-
methyl-[(l- 3- 4- or 5-)pyrrolidinylJmethyl 3-n-propyl-
[(!- 2- 4- or 5-)pyrrolidinyl Jmethyl l-.n-butyl-[ (2- or 3-)
pyrrolidinyl]methyl 2-n-pentyl-[(1- 3- 4- or 5-)pyrrolidinyl]
methyl l-n-hexyl-[(2- or 3-)pyrrolidinyl]methyl 12-dimethyl-
[(3- 4- or 5 -) pyrrolidinyl]methyl and 123-(Table Remove)trimethyl-
[(4- or 5-)pyrrolidinyl]methyl.
Examples of phenoxy lower alkanoyl groups include
phenoxyalkanoyl groups wherein the alkanoyl moiety is a straight
or branched C2-e alkanoyl group such as 2-phenoxyacetyl 3-
phenoxypropionyl 2-phenoxypropionyl 4-phenoxybutyryl 5-
phenoxypentanoyl 6-phenoxyhexanoyl 22-dimethyl-3-
phenoxypropionyl and 2-methyl-3-phenoxypropionyl.
Examples of morpholino lower alkyl groups include
morpholinoalkyl groups wherein the alkyl moiety is a straight or
branched Ci_6 alkyl group such as [(2- 3- or 4-)
morpholino]methyl 2-[(2- 3- or 4-)morpholino]ethyl
l-[(2- 3- or 4-)morpholino]ethyl 3-[(2- 3- or 4-)
morpholino]propyl 4-[(2- 3- or 4-)morpholino]butyl
5-[(2- 3- or 4-)morpholino]pentyl 6-[(2- 3- or 4-)
morpholinolhexyl 11-dimethyl-2-[(2- 3- or 4-)morpholino]ethyl
and 2-methyl-3-[(2- 3- or 4-)morpholino]propyl.
Examples of pyridyl lower alkanoyl groups include
pyridylalkanoyl groups wherein the alkanoyl moiety is a straight
or branched C2-e alkanoyl group such as 2-
[(2- 3- or 4-)pyridyllacetyl 3-[(2- 3- or 4-)pyridyl]
propionyl 2-[(2- 3- or 4-)pyridyl]propionyl 4-
[(2- 3- or 4-)pyridylJbutyryl 5-[(2- 3- or 4-)pyridyl]
pentanoyl 6-[(2- 3- or 4-)pyridyl]hexanoyl 22-dimethyl-3-
[(2- 3- or 4-)pyridyl]propionyl and 2-methyl-3-
[(2- 3- or 4-)pyridyl]propionyl.
Examples of thienylcarbonyl groups include 2-
thienylcarbonyl and 3-thienylcarbonyl.
Examples of thienyl lower alkanoyl groups include
thienylalkanoyl groups wherein the alkanoyl moiety is a straight
or branched C2.6 alkanoyl group such as 2-[(2- or 3-)
thienyl]acetyl 3-[(2- or 3-)thienyl]propionyl 2-[(2- or 3-)
thienyl]propionyl 4-[(2- or 3-)thienyl]butyryl 5-[(2- or 3-)
thienyl]pentanoyl 6-[(2- or 3-)thienyl]hexanoyl 22-dimethyl-3-
[ (2- or 3-)thienyl]propionyl and 2-methyl-3-[ (2- or 3-)thienyl]
propionyl.
(Table Remove)Examples of cycloalkyl lower alkanoyl groups include
C3-e cycloalkylalkanoyl groups wherein the alkanoyl moiety is a
straight or branched C2_6 alkanoyl group such as 2-
cyclopropylacetyl 2-cyclohexylacetyl 3-cyclopropylpropionyl 2-
cyclobutylpropionyl 2-cyclopentylacetyl 3-cyclopentylpropionyl
4-cyclohexylbutyryl 5-cycloheptylpentanoyl 6-cyclooctylhexanoyl
22-dimethyl-3-cyclohexylpropionyl and 2-methyl-3-
cyclopropylpropionyl.
Examples of isoxazolylcarbonyl groups optionally
substituted on the isoxazole ring with one or more lower alkyl
groups include isoxazoylcarbonyl groups optionally substituted on
the isoxazole ring with one or two straight and/or branched Ci_6
alkyl groups such as (3- 4- or 5-)isoxazolylcarbonyl
[35-dimethyl-4-isoxazolyl]carbonyl [3-ethyl-(4- or 5
isoxazolyl]carbonyl [4-n-propyl-(3- or 5-)isoxazolyl]carbonyl
[5-n-butyl-(3- or 4-Jisoxazolyl]carbonyl [3-n-pentyl-(4- or 5-)
isoxazolyllcarbonyl and [4-n-hexyl-(3- or 5-)isoxazolyl]carbonyl.
Examples of pyrazylcarbonyl groups include 2-
pyrazylcarbonyl.
Examples of piperidinylcarbonyl groups optionally
substituted on the piperidine ring with one or more members
selected from the group consisting of a benzoyl group and lower
alkanoyl groups include:
piperidinylcarbonyl groups optionally substituted on
the piperidine ring with one to three members selected from the
group consisting of a benzoyl group and the above-described
straight and branched Ci_6 alkanoyl groups
such as (1- 2- 3- or 4-)piperidinylcarbonyl [1-
acetyl-(2- 3- or 4-)piperidinyl]carbonyl [1-benzoyl-
(2- 3- or 4-)piperidinyl]carbony1 [2-propionyl-
(1- 3- 5- or 6-)piperidinyl]carbonyl [3-butyryl-
(1- 2 - 5- or 6-)piperidinyl]carbonyl [4-pentanoyl-
(1- 2- or 3-)piperidinyl]carbonyl [l-hexanoyl-(2- 3- or 4-)
(Table Remove)piperidinyl]carbonyl [l-acetyl-4-benzoyl-(2- 3- 5- or 6-)
piperidinyl]carbonyl and [l24-triacetyl-(3- 5- or 6-)
piperidinyl]carbonyl.
Examples of chromanylcarbonyl groups include
2-chromanylcarbonyl 3-chromanylcarbonyl 4-chromanylcarbonyl
5-chromanylcarbonyl 6-chromanylcarbonyl 7-chromanylcarbonyl
and 8-chromanylcarbonyl.
Examples of isoindolinyl lower alkanoyl groups
optionally substituted on the isoindoline ring with one or more
oxo groups include:
isoindolinyl lower alkanoyl groups wherein the alkanoyl
moiety is a straight or branched C2-e alkanoyl group optionally
substituted on the isoindoline ring with one or two oxo groups
such as 2-[(l- 2- 4- or 5-)isoindolinylJacetyl 3-
isoindolinyl]pentanoyl 6-[(l- 2- 4- or 5-isoindolinyl]
hexanoyl 22-dimethyl-3-[(1- 2- 4- or 5-)isoindolinyl]
propionyl 2-methyl-3-[(l- 2- 4- or 5-isoindolinyl]propionyl
[l3-dioxo-2-(2- 4- or 5-)isoindolinyl]acetyl and [l-oxo-2-
(2- 3- 4- 5- 6- or 7-)isoindolinyl]acetyl.
Examples of thiazolidinyl lower alkanoyl groups
optionally substituted on the thiazolidine ring with one or more
members selected from the group consisting of an oxo group and a
thioxo group include:
thiazolidinylalkanoyl groups wherein the alkanoyl
moiety is a straight or branched C2-e alkanoyl group optionally
substituted on the thiazolidine ring with one or two members
selected from the group consisting of an oxo group and a thioxo
group
such as 2-[(2- 3- 4- or 5-)thiazolidinyl]acetyl 3-
[(2- 3- 4- or 5-)thiazolidinyl]propionyl 2-
[(2- 3- 4- or 5-)thiazolidinyl]propionyl 4-
[(2- 3- 4- or 5-)thiazolidinyl]butyryl 5-[(2- 3- 4- or 5-)
thiazolidinylJpentanoyl 6-[(2- 3-. 4- or 5-)thiazolidinyl]
hexanoyl 22-dimethyl-3-[(2- 3- 4- or 5-)thiazolidinyl]
propionyl 2-methyl-3-[(2-. 3- 4- or 5-)thiazolidinyl]propionyl
[2-thioxo-4-oxo-2-(3- or 5-)thiazolidinyl]acetyl [2-thioxo-2-
(3- 4- or 5-)thiazolidinyl]acetyl [2-oxo-2-(3- 4- or 5-)
thiazolidinyl]acetyl [24-dithioxo-2-(3- or 5-)thiazolidinyl]
acetyl and [24-dioxo-2-(3- or 5-)thiazolidinyl]acetyl.
Examples of piperidinyl lower alkanoyl groups include
piperidinylalkanoyl groups wherein the alkanoyl moiety is a
straight or branched C2-e alkanoyl group such as
2-[(l- 2-. 3- or 4-)piperidinyl]acetyl 3-[(l- 2- 3- or 4-)
piperidinyl]propionyl 2-[(l- 2- 3- or 4-)piperidinyl]
(Table Remove)propionyl 4-[(l- 2- 3- or 4-)piperidinyl]butyryl 5-
[(!- 2- 3- or 4-)piperidinyl]pentanoyl 6-[(l- 2- 3- or 4-)
piperidinyl]hexanoyl 22-dimethyl-3-[(1- 2- 3- or 4-)
piperidinyl]propionyl and 2-methyl-3-[(l- 2- 3- or 4
piperidinyl]propionyl.
Examples of phenyl lower alkenylcarbonyl groups
optionally substituted on the phenyl ring with one or more
halogen atoms include:
phenylalkenylcarbonyl groups containing one to three
double bonds wherein the alkenyl moiety is a straight or branched
C2-e alkenyl group optionally substituted on the phenyl ring with
one to three halogen atoms
such as styrylcarbonyl (trivial name: cinnamoyl group)
3-phenyl-2-propenylcarbonyl 4-phenyl-2-butenylcarbonyl 4-
phenyl-3-butenylcarbonyl 5-phenyl-4-pentenylcarbonyl 5-phenyl-
3-pentenylcarbonyl 6-phenyl-5-hexenylcarbonyl 6-phenyl-4-
hexenylcarbonyl 6-phenyl-3-hexenylcarbonyl 4-phenyl-
butadienylcarbonyl 6 -phenyl-135-hexatrienylcarbonyl
chlorostyrylcarbonyl 3- (4 -bromophenyl) - 2-propenylcarbonyl 4 - (3 -
fluorophenyl)-2-butenylcarbonyl 4-(24-dichlorophenyl)-3-
butenylcarbonyl 5-(246-trifluorophenyl)-4-pentenylcarbonyl 5-
(4-iodopheny1)-3-pentenylcarbonyl 6-(3-chlorophenyl)-
hexenylcarbony1 6-(4-chlorophenyl)-4-hexenylcarbony 1
dichlorophenyl)-3-hexenylcarbonyl 4-(3-chloro-4-fluorophenyl)-
13-butadienylcarbonyl and 6-(26-difluorophenyl) -135
hexatrienylcarbonyl.
Examples of phenyl lower alkenylcarbonyl groups
optionally substituted on the phenyl ring with one or more lower
alkylenedioxy groups include:
phenylalkenylcarbonyl groups containing one to three
double bonds wherein the alkenyl moiety is a straight or branched
C2-e alkenyl group optionally substituted on the phenyl ring with
one or more of the above-described straight and branched Ci-4
alkylenedioxy groups
such as 34-methylenedioxystyrylcarbonyl 3-(23-
ethylenedioxyphenyl)-2-propenylcarbonyl 4 - (34 -
trimethylenedioxyphenyl)-2-butenylcarbonyl 4 - (23 -
tetramethylenedioxyphenyl)-3-butenylcarbonyl 5-(23-
methylenedioxyphenyl)-4-pentenylcarbonyl 5-(34-
ethylenedioxyphenyl)-3-pentenylcarbonyl 6 - (23 -
tetramethylenedioxyphenyl)-4-hexenylcarbonyl 6-(23-
methylenedioxyphenyl)-3-hexenylcarbonyl 4 - (34 -
methylenedioxyphenyl)-13-butadienylcarbonyl and
6-(23-methylenedioxyphenyl)-135-hexatrienylcarbonyl.
Examples of pyridyl lower alkenylcarbonyl groups
include pyridylalkenylcarbonyl groups containing one to three
double bonds wherein the alkenyl moiety is a straight or branched
C2-e alkenyl group such as 2-[(2- 3- or 4-)pyridyl]
vinylcarbony1 3-[(2- 3- or 4-)pyridyl]-2-propenylcarbonyl 4-
t(2-f 3- or 4-)pyridyl]-2-butenylcarbonyl 4-[(2- 3- or 4-)
pyridyl]-3-butenylcarbonyl 5-[(2- 3- or 4-)pyridyl]-4-pentenyl
carbonyl 5-[(2- 3- or 4-)pyridyl]-3-pentenylcarbonyl
[(2- 3- or 4-)pyridyl]-5-hexenylcarbonyl 6-[(2- 3- or
pyridyl]-4-hexenylcarbonyl 6-[(2- 3- or 4-)pyridyl]- (Table Remove)3-
hexenylcarbonyl 4-phenyl-l3-butadienylcarbonyl and 6-
t(2- 3- or 4-)pyridyl]-135-hexatrienylcarbonyl.
Examples of pyridylthio lower alkanoyl groups include
pyridylthioalkanoyl groups wherein the alkanoyl moiety is a
straight or branched C2-e alkanoyl group such as 2-
[(2- 3- or 4-)pyridylthio]acetyl 3-[(2- 3- or 4-)
pyridylthio]propionyl 2-[(2- 3- or 4-)pyridylthio]propionyl
4-[(2- 3- or 4-) pyridylthio]butyryl 5-[(2- 3- or 4-)
pyridylthio]pentanoyl 6-[(2- 3- or 4-)pyridylthio]hexanoyl
methyl-3-[(2- 3- or 4-)pyridylthio]propionyl.
Examples of indolylcarbonyl groups include 1-
indolylcarbonyl 2-indolylcarbonyl 3-indolylcarbonyl 4-
indolylcarbonyl 5-indolylcarbonyl 6-indolylcarbonyl and 7-
indolylcarbonyl.
Examples of pyrrolylcarbonyl groups include 2-
pyrrolylcarbonyl and 3-pyrrolylcarbonyl.
Examples of pyrrolidinylcarbonyl groups optionally
substituted on the pyrrolidine ring with one or more oxo groups
-104-
include pyrrolidlnylcarbonyl groups optionally substituted on the
pyrrolidine ring with one or two oxo groups such as
(1- 2- or 3-)pyrrolidinylcarbonyl 2-oxo-(l- 3- 4- or
pyrrolidinylcarbonyl 3-oxo-(l- 2- 4- or 5-)pyrrolidinyl
carbonyl 25-dioxo-(l- or 3-)pyrrolidinylcarbonyl and
dioxo-(l- 4- or 5-)pyrrolidinyl carbonyl.
Examples of benzofurylcarbonyl groups include 2-
benzofurylcarbonyl 3-benzofurylcarbonyl 4-benzofurylcarbonyl
5-benzofurylcarbonyl 6-benzofurylcarbonyl and
7-benzofurylcarbonyl.
Examples of indolyl lower alkanoyl groups include
indolylalkanoyl groups wherein the alkanoyl moiety is a straight
or branched C2-6 alkanoyl group such as 2-
[(!- 2- 3- 4- 5- 6- or 7-)indolyl]acetyl 3-
[(!- 2- 3- 4- 5- 6- or 7-)indolyl]propionyl 2-
[(!- 2- 3- 4- 5- 6- or 7-)indolyl]propionyl 4-
[(!- 2- 3- 4- 5- 6- or 7-)indolyl]butyryl 5-
[(!- 2- 3- 4- 5- 6- or 7-)indolyl]pentanoyl 6-
[(!- 2- 3- 4- 5- 6-. or 7-)indolyl]hexanoyl 22-dimethyl-3-
[(!- 2- 3- 4- 5- 6- or 7-)indolyl]propionyl and 2-methyl-
3-[(l- 2- 3- 4- 5- 6- or 7-)indolyl]propionyl.
Examples of benzothienylcarbonyl groups include 2-
benzothienylcarbonyl 3-benzothienylcarbonyl 4-
benzothienylcarbonyl 5-benzothienylcarbonyl 6-
benzothienylcarbonyl and 7-benzothienylcarbonyl.
Examples of phenyl lower alkanoyl groups optionally
substituted on the phenyl ring with one or more halogen atoms
include:
phenylalkanoyl groups wherein the alkanoyl moiety is a
straight or branched C2-e alkanoyl group optionally substituted
on the phenyl ring with one to three halogen atoms
such as 2-phenylacetyl 3-phenylpropionyl 2-
phenylpropionyl 4-phenylbutyryl 5-phenylpentanoyl 6-
phenylhexanoyl 22-dimethyl-3-phenylpropionyl 2-methyl-3-
phenylpropiony1 2-(4-fluorophenyl)acetyl 3-(25-
difluorophenyl)propionyl 2-(24-difluorophenylJpropionyl 4-
(34-difluorophenyl)butyryl 5-(35-difluorophenyl)pentanoyl 6-
(26-difluorophenyl)hexanoyl 2-(2-chlorophenyl)acetyl
chlorophenyl)propionyl 2-(4-chlorophenyl)propiony 1 4-(23-
dichlorophenyl) propionyl 5 - (24 -dichlorophenyl) pentanoyl 6 -
(25-dichlorophenyl)hexanoyl 2-(34-dichlorophenyl)acetyl 3-
(26-dichlorophenyl) propionyl 2 - (3 -fluorophenyl) propionyl 4 - (2 -
fluorophenyl)butyryl 5-(3-bromophenyl)pentanoyl 6 -
iodophenyl)hexanoyl 2-(2-bromophenyl)acetyl 3-(4-bromophenyl)
propionyl 2-(35-dichlorophenyl)propionyl 4-(246-trifluoro
phenyl)butyryl 5-(34-difluorophenyl)pentanoyl 6-(2-iodophenyl)
hexanoyl 2-(3-iodophenyl)acetyl 3-(4-iodophenyl)propionyl 2-
(23-dibromophenyl)propionyl 4-(24-diiodophenyl)butyryl and 2-
(246-trichlorophenyl)acetyl.
Examples of phenylsulfonyl groups optionally
substituted on the phenyl ring with one or more members selected
from the group consisting of lower alkoxycarbonyl groups a cyano
group a nitro group amino groups optionally substituted with
one or more lower alkanoyl groups a hydroxy group a carboxyl
group lower alkoxycarbonyl lower alkyl groups halogen atoms
lower alkyl groups optionally substituted with one or more
halogen atoms and lower alkoxy groups optionally substituted
with one or more halogen atoms include:
phenylsulfonyl groups optionally substituted on the
phenyl ring with one to five members selected from the group
consisting of the above-described lower alkoxycarbonyl groups
wherein the alkoxy moiety is a straight or branched Ci-e alkoxy
group a cyano group a nitro group the above-described amino
groups optionally substituted with one or two straight and/or
branched Ci-e alkanoyl groups a hydroxy group a carboxyl group
the above-described alkoxycarbonylalkyl groups wherein the alkoxy
moiety is a straight or branched Ci_6 alkoxy group and the alkyl
moiety is a straight or branched Ci.6 alkyl group halogen atoms
the above-described straight and branched d-6 alkyl groups
optionally substituted with one to three halogen atoms and the
-106-
above-described straight and branched Ci_6 alkoxy groups optionally
substituted with one to three halogen atoms
such as phenylsulfonyl 4-methoxyphenylsulfonyl
3-methoxyphenylsulfonyl 2-methoxyphenylsulfonyl 2-
trifluoromethoxyphenylsulfonyl 3 - trifluoromethoxyphenylsulfonyl
4 - trif luoromethoxyphenylsulf onyl 34- dime thoxyphenylsulf onyl
25-dimethoxyphenylsulfonyl 246-trime thoxyphenylsulf onyl 4-nbutoxyphenylsulfonyl
2 -methoxy- 5 - chlorophenylsulfonyl 2 -
methoxy- 5 -methylphenylsulfonyl 2 -methoxy- 4 -methylphenylsulfonyl
4-chlorophenylsulfonyl 3-chlorophenylsulfonyl 2-
chlorophenylsulfonyl 4-fluorophenylsulfonyl 3-
fluorophenylsulfonyl 2-fluorophenylsulfonyl 4-
bromophenylsulfonyl 3-bromophenylsulfonyl 2-bromophenylsulfonyl
26-dichlorophenylsulfonyl 23-dichlorophenylsulfonyl
dichlorophenylsulfonyl 24-dichlorophenylsulfonyl 34-
dichlorophenylsulfonyl 35-dichlorophenylsulfonyl 2-chloro-4-
fluorophenylsulfonyl 2-bromo-5-chlorophenylsulfonyl 25-
difluorophenylsulfonyl 24-difluorophenylsulfonyl 26-
difluorophenylsulfonyl 34-difluorophenylsulfonyl 24-dichloro-
5-methylphenylsulfonyl 245-trifluorophenylsulfonyl 23456-
pentafluorophenylsulfonyl 3-chloro-4-fluorophenylsulfonyl 2-
chloro-6-methylphenylsulfonyl 24-dichloro-6-
methylphenylsulfonyl 2-methyl-3-chlorophenylsulfonyl 2-methyls'
methyl- 5 - f luorophenylsulf onyl 2 -methyl- 4 -bromophenylsulf onyl 2 -
f luoro-4-bromophenylsulfonyl 25-dimethyl-4-chloropheny Isulf onyl
2 -methylphenylsulfonyl 3-methylphenylsulfonyl 4-
methylphenylsulfonyl 25-dimethylphenylsulfonyl 246-
trimethylphenylsulfonyl 236-trimethyl-4-methoxyphenylsulfonyl
4-tert-butylphenylsulfonyl 4-ethylphenylsulfonyl 4-
isopropylphenylsulfonyl 2-trifluoromethylphenylsulfonyl 3-
trifluoromethylphenylsulfonyl 4-trifluoromethylphenylsulfonyl
-
cyanophenylsulfonyl 4-cyanophenylsulfonyl 3-nitrophenylsulfonyl
methylphenylsulfonyl 3-nitro-6-methylphenylsulfonyl 3-nitro-6-
chlorophenylsulfonyl 2-chloro-4-cyanophenylsulfonyl 4-
acetylamlnophenylsulfonyl 3-chloro-4-acetylaminophenylsulfonyl
2-hydroxy-35-dlchlorophenylsulfonyl 2-hydroxyphenylsulfonyl 3-
hydroxyphenylsulfonyl 4-hydroxyphenylsulfonyl 2-nitro-4-
methoxyphenylsulfonyl 3-carboxyphenylsulfonyl 4-
carboxyphenylsulfonyl 2-carboxyphenylsulfonyl 4 - (2 -
methoxycarbonylethyl)phenylsulfonyl 3-carboxy-4-
hydroxyphenylsulfonyl 3-aminophenylsulfonyl 2-
aminophenylsulfonyl and 4-aminophenylsulfonyl.
Examples of thienylsulfonyl groups optionally
substituted on the thiophene ring with one or more members
selected from the group consisting of halogen atoms and lower
alkoxycarbonyl groups include:
thienylsulfonyl groups optionally substituted on the
thiophene ring with one to three members selected from halogen
atoms and the above-described alkoxycarbonyl groups wherein the
alkoxy moiety is a straight or branched Ci-e alkoxy group
such as (2- or 3-)thienylsulfonyl [2-chloro-
(3- 4- or 5-)thieny1]sulfonyl [23-dichloro-(4- or 5-)
thienyl]sulfonyl [25-dichloro-(3- or 4-)thienyl]sulfonyl [2-
bromo-(3- 4- or 5-)thienyl]sulfonyl [2-fluoro-(3- 4- or 5-)
thienyl]sulfonyl (234-trichloro-5-thienyl)sulfonyl [2-
methoxycarbonyl-(3- 4- or 5-)thienyl]sulfonyl [3-
ethoxycarbonyl-(2- 4- or 5-)thienyl]sulfonyl [3-npropoxycarbonyl-(
2- 4- or 5-)thienyl]sulfonyl [2-tertbutoxycarbonyl-(
3- 4- or 5-)thienyl]sulfonyl [2-npentyloxycarbonyl-(
3- 4- or 5-)thienyl]sulfonyl [3-nhexyloxycarbonyl-(
2- 4- or 5-)thienyl]sulfonyl [23-
dimethoxycarbonyl-(4- or 5-)thienyl]sulfonyl and [2-chloro-3-
methoxycarbonyl-(4- or 5-)thienyl]sulfonyl.
Examples of quinolylsulfonyl groups include
2-quinolylsulfonyl 3-quinolylsulfonyl 4-quinolylsulfonyl
5-quinolylsulfonyl 6-quinolylsulfonyl 7-quinolylsulfonyl and
8-quinolylsulfonyl.
-108-
Examples of imidazolylsulfonyl groups optionally
substituted on the imidazole ring with one or more lower alkyl
groups include imidazolylsulfonyl groups optionally substituted
on the imidazole ring with one to three above-described straight
and branched Ci_6 alkyl groups such as
(1- 2- 4- or 5-)imidazolylsulfonyl [l-methyl-(2- 4- or 5-)
imidazolyl]sulfonyl [2-ethyl-(l- 4- or 5-)imidazolyl]sulfonyl
[l-isopropyl-(2- 4- or 5-)imidazolyl]sulfonyl [4-n-butyl-
(1- 2- or 5-)imidazolyl]sulfonyl [5-n-pentyl-(l- 2- or 4-)
imidazolyl]sulfonyl [l-n-hexyl-(2- 4- or 5-)imidazolyl]
sulfonyl [12-dimethyl-(4- or 5-)imidazolyl]sulfonyl and
(124-trimethyl-5-imidazolyl)sulfonyl.
Examples of phenylsulfonyl groups optionally
substituted on the phenyl ring with one or more lower
alkylenedioxy groups include phenylsulfonyl groups optionally
substituted on the phenyl ring with one or more one to three the
above-described straight and branched Ci_4 alkylenedioxy groups
such as (34-ethylenedioxyphenyl)sulfonyl (23-
methylenedioxyphenyl)sulfonyl (34-
trimethylenedioxyphenyl)sulfonyl and (23-
tetramethylenedioxyphenyl)sulfonyl.
Examples of lower alkenylsulfonyl groups include
straight and branched C2.6 alkenylsulfonyl groups containing one to
three double bonds such as vinylsulfonyl 1-propenylsulfonyl 1-
methyl-1-propenylsulfonyl 2-methyl-1-propenylsulfonyl 2-
propenylsulfonyl 2-butenylsulfonyl 1-butenylsulfonyl 3-
butenylsulfonyl 2-pentenylsulfonyl 1-pentenylsulfonyl 3-
pentenylsulfonyl 4-pentenylsulfonyl 1 3-butadienylsulfonyl
13-pentadienylsulfonyl 2-pentene-4-ynylsulfonyl 2-
hexenylsulfonyl 1-hexenylsulfonyl 5-hexenylsulfonyl 3-
hexenylsulfonyl 4-hexenylsulfonyl 33-dimethyl-1-
propenylsulfonyl 2-ethyl-1-propenylsulfonyl 135-
hexatrienylsulfonyl 13-hexadienylsulfonyl and 14-
hexadienylsulfonyl.
Examples of cycloalkyl-substituted lower alkylsulfonyl
-109-
groups include C3_8 cycloalkyl-substituted alkylsulfonyl groups
wherein the alkyl moiety is a straight or branched Ci-6 alkyl group
such as cyclopropylmethylsulfonyl cyclohexylmethylsulfonyl 2-
cyclopropyle thylsulf onyl 1 - cyclobutylethylsulf onyl
cyclopentylmethylsulfonyl 3-cyclopentylpropylsulfonyl 4-
cyclohexylbutylsulfonyl 5-cycloheptylpentylsulfonyl 6-
cyclooctylhexylsulfonyl 11-dimethyl-2-cyclohexylethylsulfonyl
and 2-methyl-3-cyclopropylpropylsulfonyl.
Examples of 34-dihydro-2H-l4-benzoxazinylsulfonyl
groups optionally substituted on the
34-dihydro-2H-l4-benzoxazine ring with one or more lower alkyl
groups include 34-dihydro-2H-l4-benzoxazinylsulfonyl groups
optionally substituted on the 34-dihydro-2H-l4-benzoxazine ring
with one to three above-described straight and/or branched Ci-6
alkyl groups such as (2- 3- 4- 5- 6- 7- or 8-)34-dihydro-
2H-l4-benzoxazinylsulfonyl [4-methyl-(2- 3- 5- 6- 7- or 8-)
34-dihydro-2H-l4-benzoxazinyl]sulfonyl [5-ethyl-
(2- 3- 4- 6- 7- or 8-)34-dihydro-2H-14-benzoxazinyl]
sulfonyl [6-n-propyl-(2- 3- 4- 5- 7- or 8-)34-dihydro-2H-
14-benzoxazinyl]sulfonyl [7-n-butyl-(2- 3- 5- 6- 7- or 8-)
34-dihydro-2H-14-benzoxaz inyl]sulfonyl [8-n-pentyl-
(2- 3- 5- 6- 7- or 8-)34-dihydro-2H-l4-benzoxazinyl]
sulfonyl [2-n-hexyl-(3- 4- 5- 6- 7- or 8-)34-dihydro-2H-
14-benzoxazinyl]sulfonyl [3-methyl-(2- 4- 5- 6- 7- or 8-)
34-dihydro-2H-14-benzoxazinyl]sulfonyl [46-dimethyl-
(2- 3- 5- 7- or 8-)34-dihydro-2H-14-benzoxazinyl]sulfonyl
and [456-trimethyl-(2- 3- 7- or 8-)34-dihydro-2H-l4-
benzoxazinyl]sulfonyl.
Examples of pyrazolylsulfonyl groups optionally
substituted on the pyrazole ring with one or more members
selected from the group consisting of halogen atoms and lower
alkyl groups include:
pyrazolylsulfonyl groups optionally substituted on the
pyrazole ring with one to three members selected from the group
consisting of halogen atoms and the above-described straight and
-110-
branched Ci-e alkyl groups
such as (1- 3- 4- or 5-)pyrazolylsulfonyl (13-
dimethyl-5-chloro-4-pyrazolyl)sulfonyl [l-ethyl-(3- 4- or 5-)
pyrazolyl]sulfonyl [3-n-propyl-(l- 4- or 5-)pyrazolyl]sulfonyl
[4-n-butyl-(3- 4- or 5-)pyrazolyl]sulfonyl [5-n-pentyl-
(1- 3- or 4-)pyrazolyl]sulfonyl [l-n-hexyl-(3- 4- or 5-)
pyrazolyl]sulfonyl [13-dimethyl-(4- or 5-)pyrazolyl]sulfonyl
(135-trimethyl-4-pyrazolyl)sulfonyl [3-bromo-(l- 4- or 5-)
pyrazolyl]sulfonyl [4-fluoro-(l- 3- or 5-)pyrazolyl]sulfonyl
[5-iodo-(l- 3- or 4-)pyrazolyl]sulfonyl [34-dichloro-
(1- or 5-)pyrazolyl]sulfonyl and (345-trichloro-4-pyrazolyl)
sulfonyl.
Examples of isoxazolylsulfonyl groups optionally
substituted on the isoxazole ring with one or more lower alkyl
groups include isoxazolylsulfonyl groups optionally substituted
on the isoxazole ring with one or two above-described straight
and/or branched d-6 alkyl groups such as (3- 4- or 5-)
isoxazolylsulfonyl (35-dimethyl-4-isoxazolyl)sulfonyl [3-
methyl-(4- or 5-)isoxazolyl]sulfonyl [3-ethyl-(4- or 5-)
isoxazolyl]sulfonyl [4-n-propyl-(3- or 5-)isoxazolyl]sulfonyl
[5-n-butyl-(3- or 4-)isoxazolyl]sulfonyl [3-n-pentyl-(4- or 5-)
isoxazolyl]sulfonyl and [4-n-hexyl-(3- or 5-)isoxazolyl]sulfonyl.
Examples of thiazolylsulfonyl groups optionally
substituted on the thiazole ring with one or more members
selected from the group consisting of lower alkyl groups and an
amino group each amino substituent optionally being substituted
with one or more lower alkanoyl groups include:
thiazolylsulfonyl groups optionally substituted on the
thiazole ring with one or two members selected from the group
consisting of the above-described straight or branched d-6 alkyl
groups and the above-described amino groups optionally
substituted with one or two straight and/or branched Ci-6 alkanoyl
groups
such as (2- 4- or 5-)thiazolylsulfonyl
(2-acetylamino-4-methyl-5-thiazolyl)sulfonyl [2-ethyl-(4- or 5-)
-111-
thiazolyl]sulfonyl [4-n-propyl-(2- or 5-)thiazolyl]sulfonyl
[5-n-butyl-(2- or 4-)thiazolyl]sulfonyl [2-n-pentyl-(4- or 5-)
thiazolyl]sulfonyl [4-n-hexyl-(2- or 5-)thiazolyl]sulfonyl
(24-dimethyl-5-thiazolyl)sulfonyl [2-amino-(4- or 5-)
thiazolyl]sulfonyl [2-formylamlno-(4- or 5-)thiazolyl]sulfonyl
[4-n-propionylamino-(2- or 5-)thiazolyl]sulfonyl [5-n-butyryl
amino-(2- or 4-)thiazolyl]sulfonyl [2-n-pentanoylamino-
(4- or 5-)thiazolyl]sulfonyl [4-.n-hexanoylamino-(2- or 5-)
thiazolyl]sulfonyl (24-diacetyl-5-thiazolyl)sulfonyl and
[2-(WN-diacetylamino)-(4- or 5-)thiazolyl]sulfonyl.
Examples of phenyl lower alkylsulfonyl groups include
mono- and di-phenylalkyl groups wherein the alkyl moiety is a
straight or branched Ci_6 alkyl group such as benzylsulfonyl 1-
phenethylsulfonyl 2-phenethylsulfonyl 3-phenylpropylsulfonyl
2-phenylpropylsulfonyl 4-phenylbutylsulfonyl 5-
phenylpentylsulfonyl 4-phenylpentylsulfonyl 6-
phenylhexylsulfonyl 2-methyl-3-phenylpropylsulfonyl 11-
dimethyl-2-phenylethylsulfonyl 11-dimethyl-1-
phenylmethylsulfonyl 11- diphenylmethylsulfonyl 22-
diphenylethylsulfonyl 33-diphenylpropylsulfonyl and 12-
diphenylethylsulfonyl.
Examples of phenyl lower alkenylsulfonyl groups
include:
phenylalkenylsulfonyl groups containing one to three
double bonds wherein the alkenyl moiety is a straight or branched
C2-e alkenyl group optionally substituted on the phenyl ring with
one to three halogen atoms
such as styrylsulfonyl 3-phenyl-2-propenylsulfonyl 4-
phenyl-2-butenylsulfonyl 4-phenyl-3-butenylsulfonyl 5-phenyl-4-
pentenylsulfonyl 5-phenyl-3-pentenylsulfonyl 6-phenyl-5-
hexenylsulfonyl 6-phenyl-4-hexenylsulfonyl 6-phenyl-3-
hexenylsulfonyl 4-phenyl-l3-butadienylsulfonyl 6-phenyl-l35-
hexatrienylsulfonyl 2-chlorostyrylsulfonyl 3-(4-bromophenyl)-2-
propenylsulfonyl 4-(3-fluorophenyl)-2-butenylsulfonyl 4-(24-
dichlorophenyl)-3-butenylsulfonyl 5-(246-trifluorophenyl)-4-
-112-
pentenylsulfonyl 5-(4-iodophenyl)-3-pentenylsulfonyl 6-(3-
chlorophenyl)-5-hexenylsulfonyl 6-(4- chlorophenyl) - 4 -
hexenylsulfonyl 6-(34-dichlorophenyl)-3-hexenylsulfonyl 4 - (3 -
chloro-4-fluorophenyl)-l 3-butadienylsulfonyl and 6-(26-
difluorophenyl)-135-hexatrienylsulfonyl.
Examples of naphthyloxycarbonyl groups include 1-
naphthyloxycarbonyl and 2-naphthyloxycarbonyl.
Examples of lower alkynyloxycarbonyl groups include
alkynyloxycarbonyl groups wherein the alkynyl moiety is a
straight or branched C2.6 alkynyl group such as
ethynyloxycarbonyl 2-propynyloxycarbonyl 2-butynyloxycarbonyl
3 -butynyloxycarbonyl 1 -methyl- 2 -propynyloxycarbonyl
2-pentynyloxycarbonyl and 2-hexynyloxycarbonyl.
Examples of lower alkenyloxycarbonyl groups include
alkenyloxycarbonyl groups containing one to three double bonds
wherein the alkenyl moiety is a straight or branched C2.6 alkenyl
group such as vinyloxycarbonyl 1-propenyloxycarbonyl 1-methyl-
1-propenyloxycarbonyl 2-methyl-1-propenyloxycarbonyl 2-
propenyloxycarbonyl 2-butenyloxycarbonyl 1-butenyloxycarbonyl
3-butenyloxycarbonyl 2-pentenyloxycarbonyl 1-
pentenyloxycarbonyl 3-pentenyloxycarbonyl 4-pentenyloxycarbonyl
13-butadienyloxycarbonyl 13 -pentadienyloxycarbonyl 2-pentene-
4-ynyloxycarbonyl 2-hexenyloxycarbonyl 1-hexenyloxycarbonyl 5-
hexenyloxycarbonyl 3-hexenyloxycarbonyl 4-hexenyloxycarbonyl
33-dimethyl-1-propenyloxycarbonyl 2-ethyl-1-propenyloxycarbonyl
1.35-hexatrienyloxycarbonyl 13-hexadienyloxycarbonyl and 14-
hexadienyloxycarbonyl.
Examples of phenyl lower alkoxy-substituted lower
alkoxycarbonyl groups include phenylalkoxy-substituted
alkoxycarbonyl groups wherein each of the two alkoxy moieties is
a straight or branched Ci-e alkoxy group such as
phenylmethoxymethoxycarbonyl 2-(pheny line thoxy)ethoxycarbonyl 1-
(phenylmethoxy)ethoxycarbonyl 3-(phenylmethoxy)propoxycarbonyl
4 - (phenylme thoxy) but oxycarbonyl 5 - (phenylme thoxy)
pentyloxycarbonyl 6-(phenylmethoxy)hexyloxycarbonyl 11-
-113-
dimethyl - 2 - (phenylmethoxy) ethoxycarbonyl 2 -methyl - 3 -
(phenylmethoxy) propoxycarbonyl 1 - (2 - phenyle thoxy) ethoxycarbonyl
2 - (1 - phenyle thoxy) ethoxycarbonyl 3 - (3 - phenylpropoxy) propoxy
carbonyl 4-(4-phenylbutoxy)butoxycarbonyl 5-(5-phenylpentyloxy)
pentyloxycarbonyl 6-(6-phenylhexyloxy)hexyloxycarbonyl (11-
dime thy 1 - 2 - phenyle thoxy) me thoxycarbonyl and 3 - (2 -methyl - 3 -
phenylpropoxy)propoxycarbonyl.
Examples of cycloalkyloxycarbonyl groups optionally
substituted on the cydoalkyl ring with one or more lower alkyl
groups include:
cycloalkyloxycarbonyl groups wherein the cycloalkoxy
moiety is a C3-8 cycloalkoxy group optionally substituted on the
cycloalkyl ring with one to three above-described straight and
branched Ci-6 alkyl groups
such as cyclopropyloxycarbonyl cyclobutyloxycarbonyl
cyclopentyloxycarbonyl cyclohexyloxycarbonyl
cycloheptyloxycarbonyl cyclooctyloxycarbonyl 3-methyl-6-
isopropylcyclohexyloxycarbonyl 2-ethylcyclopropyloxycarbonyl 2-
n-propylcyclobutyloxycarbonyl 3-n-butylcycloheptyloxycarbonyl
3-n-pentylcyclooctyloxycarbonyl 2-methylcyclopentyloxycarbonyl
and 236-trimethylcyclohexyloxycarbonyl.
Examples of isoxazolyl groups optionally substituted on
the isoxazole ring with one or more lower alkyl groups include
isoxazolyl groups optionally substituted on the isoxazole ring
with one or two straight and/or branched Ci-e alkyl groups such as
(3- 4- or 5-)isoxazolyl 5-methyl-(3- or 4-) isoxazolyl 35-
dimethyl-4-isoxazolyl 3-ethyl-(4- or 5-) isoxazolyl 4-n-propyl-
(3- or 5-)isoxazolyl 5-n-butyl-(3- or 4-) isoxazolyl 3-npentyl-(
4- or 5-)isoxazolyl and 4-n-hexyl-
(3- or 5-)isoxazolyl.
Examples of 5- to 7-membered saturated heterocyclic
rings formed from R6 and R7 being linked together together with
the nitrogen atom to which they are bound the heterocyclic ring
optionally containing one or more additional heteroatoms
include:
-114-
5- to 7-membered saturated heterocyclic rings formed
from R6 and R7 being linked together together with the nitrogen
atom to which they are bound the heterocyclic group optionally
containing one or more additional heteroatoms selected from
oxygen sulfur atom and nitrogen atom
such as pyrrolidine piperazine piperidine morpholine
thiomorpholine homopiperazine homopiperidine imidazolidine
thiazolidine isothiazolidine oxazolidine isoxazolidine
isothiazolidine and pyrazolidine.
Examples of phenyl groups optionally substituted on the
phenyl ring with one or more members selected from the group
consisting of halogen atoms lower alkoxy groups optionally
substituted with one or more halogen atoms lower alkyl groups
optionally substituted with one or more halogen atoms a cyano
group and a hydroxy group include:
phenyl groups optionally substituted on the phenyl ring
with one to three members selected from the group consisting of
halogen atoms the above-described straight and branched d-6
alkoxy groups optionally substituted with one to three halogen
atoms the above-described straight and branched Ci-e alkyl groups
optionally substituted with one to three halogen atoms a cyano
group and a hydroxy group
such as phenyl 4-isopropylphenyl 3-isopropylphenyl
2-isopropylphenyl 4-tert-butylphenyl 4-methylphenyl 3-
methylphenyl 2-methylphenyl 23-dlmethylphenyl 24-
dimethylphenyl 35-dimethylphenyl 246-trimethylphenyl 4-
methyl-3-methoxyphenyl 4-trifluoromethylphenyl 3 -
trifluoromethylphenyl 2-trifluoromethylphenyl 4-methyl-3-
chlorophenyl 4-chlorophenyl 3-chlorophenyl 2-chlorophenyl 2-
fluorophenyl 3-fluorophenyl 4-fluorophenyl 3-bromophenyl 34-
dichlorophenyl 35-dichlorophenyl 345-trichlorophenyl 246-
trifluorophenyl 35-difluorophenyl 3-chloro-4-fluorophenyl 2-
chloro-5-fluorophenyl 3-fluoro-4-methoxyphenyl 3-chloro-4-
methoxyphenyl 3-chloro-4-hydroxyphenyl 4-methoxyphenyl 3-
methoxyphenyl 2-methoxyphenyl 24-dimethoxyphenyl 34-
-115-
diraethoxyphenyl 246-trimethoxyphenyl 2-methoxy-5-chlorophenyl
4-ethoxyphenyl 4-trifluoromethoxyphenyl 3-
trifluoromethoxyphenyl 2-trifluoromethoxyphenyl 3-methoxy-5-
trifluoromethyl phenyl 2-cyanophenyl 3-cyanophenyl 4-
cyanophenyl 3-hydroxyphenyl 2-hydroxyphenyl and 4-
hydroxyphenyl.
Examples of phenyl lower alkyl groups optionally
substituted on the phenyl ring with one or more halogen atoms
include:
mono- and di-phenylalkyl groups wherein the alyl moiety
is a straight or branched Ci-6 alkyl group optionally substituted
on each phenyl ring with one to three halogen atoms
such as benzyl 1-phenethyl 2-phenethyl 3-
phenylpropyl 2-phenylpropyl 4-phenylbutyl 5-phenylpentyl 4-
phenylpentyl 6-phenylhexyl 2-methyl-3-phenylpropyl 11-
dimethyl-2-phenylethyl 11-diphenylmethyl 22-diphenylethyl
33-diphenylpropyl 12-diphenylethyl 4-chlorobenzyl 2-
chlorobenzyl 3-chlorobenzyl 2-fluorobenzyl 3-fluorobenzyl 4-
fluorobenzyl 23-dichlorobenzyl and 246-trifluorobenzyl.
Examples of phenyl lower alkoxy groups optionally
substituted on the phenyl ring with one or more halogen atoms
include:
phenylalkoxy groups wherein the alkoxy moiety is a
straight or branched Ci_6 alkoxy group optionally substituted on
the phenyl ring with one to three halogen atoms
such as benzyloxy 2-phenylethoxy 1-phenylethoxy 3-
phenylpropoxy 4-phenylbutoxy 5-phenylpentyloxy 6-
phenylhexyloxy 1l-dimethyl-2-phenylethoxy 2-methyl-3-
phenylpropoxy 4-chlorobenzyloxy 2-chlorobenzyloxy 3-
chlorobenzyloxy 2-fluorobenzyloxy 3-fluorobenzyloxy 4-
fluorobenzyloxy 24-dibromobenzyloxy and 246-
trifluorobenzyloxy.
Examples of carbamoyl lower alkyl groups optionally
substituted with one or more members selected from the group
consisting of phenyl group and lower alkyl groups include:
-116-
carbamoylalkyl groups wherein the alkyl moiety is a
straight or branched Ci-e alkyl group optionally substituted with
one or two members selected from the group consisting of a phenyl
group and the above-described straight and branched Ci-e alkyl
groups
such as carbamoylmethyl 2-carbamoylethyl 1-
carbamoylethyl 3-carbamoylpropyl 4-carbamoylbutyl 5-
carbamoylpentyl 6 - carbamoylhexyl 11- dimethyl - 2 - carbamoylethyl
2-methyl- 3-carbamoylpropyl 2 - (W-methyl-N-phenylcarbamoyl) ethyl
Af-phenylcarbamoyljnethyl 2-(ATW-dimethylcarbamoyl)ethyl 3-(Nphenylcarbamoyl)
propyl 2 - (N- ethyl -N- phenylcarbamoyl) ethyl N Ndimethylcarbamoylmethyl
Ar-methyl-N-ethylcarbamoylmethyl Nmethylcarbamoylmethyl
and 2 - (W-methylcarbamoyl) ethyl.
Examples of phenyl lower alkylidene groups optionally
substituted on the phenyl ring with one or more halogen atoms
include:
phenylalkylidene groups wherein the alkylidene moiety
is a straight or branched Ci-6 alkylidene group optionally
substituted on the phenyl ring with one to three halogen atoms
such as phenylmethylidene phenylethylidene
phenylpropylidene phenylisopropylidene phenylbutylidene
phenylpentylidene phenylhexylidene 2 - chlorophenylmethylidene
3 - chlorophenylmethylidene 4 - chlorophenylmethylidene 2 -
fluorophenylmethylidene 3 - fluorophenylmethyl idene 4 -
fluorophenylme thylidene 2 -bromophenylme thylidene 3 -
bromophenylme thylidene 4 - bromophenylme thylidene 2 -
iodophenylmethylidene 23- dichlorophenylme thylidene 24-
dif luorophenylme thylidene 246- trichlorophenylmethylidene
235-trifluorophenylmethylidene and 2-fluoro-4-
chlorophenylmethylidene.
Examples of phenyl lower alkoxycarbonyl groups include
phenylalkoxycarbonyl groups wherein the alkoxy moiety is a
straight or branched Ci_6 alkoxy group such as benzyloxycarbonyl
2-phenylethoxycarbonyl 1-phenylethoxycarbonyl 3-phenylpropoxy
carbonyl 4-phenylbutoxycarbonyl 5-phenylpentyloxycarbonyl 6-
-117-
phenylhexyloxycarbonyl ll-dimethyl-2-phenylethoxycarbonyl and
2-methyl-3-phenylpropoxycarbonyl.
Examples of pyridyl groups optionally substituted on
the pyridine ring with one or more members selected from the
group consisting of a cyano group and lower alkyl groups include
pyridyl groups optionally substituted on the pyridine
ring with one to three members selected from the group consisting
of a cyano group and the above-described straight and branched
Ci_6 alkyl groups
such as (2- 3-. or 4-)pyridyl 2-methyl-
(3- 4- 5- or 6-)pyridyl 3-methyl-(2- 4- 5- or 6-)pyridyl
4-methyl-(2- or 3-)pyridyl 2-cyano-(3- 4- 5- or 6-)pyridyl
3-cyano-(2- 4- 5- or 6-)pyridyl 4-cyano-(2- or 3-)pyridyl
23-dimethyl-(4- 5- or 6-)pyridyl 345-trimethyl-(2- or 6-)
pyridyl 24-dicyano-(3- 5- or 6-)pyridyl 245-tricyano-
(3- or 6-)pyridyl and 2-methyl-4-cyano-(3- 5- or 6-)pyridyl.
Examples of 13-dioxolanyl lower alkyl groups include
13-dioxolanylalkyl groups wherein the alkyl moiety is a straight
or branched Ci-e alkyl group such as [(2- or 4-)13-
dioxolanyl]methyl 2-[(2- or 4-)13-dioxolanyl]ethyl 1-
[(2- or 4-)l3-dioxolanyl]ethyl 3-[(2- or 4-)l3-dioxolanyl]
propyl 4-[(2- or 4-)13-dioxolanyl]butyl 11-dimethyl-2-
[(2- or 4-)1.3-dioxolanyl]ethyl 5-[(2- or 4-)13-dioxolanyl]
pentyl 6-[(2- or 4-)l3-dioxolanyl]hexyl l-[(2- or 4-)l3-
dioxolanyl]isopropyl and 2-methyl-3-[(1- 2- or 4-)l3-
dioxolanyl]propyl.
Examples of 5- to 8-membered saturated heterocyclic
rings formed from R8 and R9 being linked together together with
the nitrogen atom to which they are bound the heterocyclic ring
optionally containing one or more additional heteroatoms
include:
5- to 8-membered saturated heterocyclic rings formed
from R8 and R9 being linked together together with the nitrogen
atom to which they are bound the heterocyclic ring optionally
containing one or more additional heteroatoms selected from
-118-
oxygen nitrogen and sulfur atom
such as pyrrolidine piperazine piperidine morpholine
thiomorpholine imidazolidine thiazolidine isothiazolidine
oxazolidine isoxazolidine isothiazolidine pyrazolidine
perhydroazepine and perhydroazocine.
Examples of octahydropyrrolo[12-a]pyrazinyl groups
optionally substituted on the pyrazine ring with one or more
lower alkyl groups include octahydropyrrolo[12-a]pyrazinyl
groups optionally substituted on the pyrazine ring with one to
three straight and/or branched Ci-e alkyl groups.
Examples of 8-azabicyclo[3.2.1]octyl groups optionally
substituted on the 8-azabicyclo[3.2.1]octyl group with one or
more phenoxy groups each phenoxy substituent optionally being
substituted on the phenyl ring with one or more halogen atoms
include 8-azabicyclo[3.2.1]octyl groups optionally substituted on
the 8-azabicyclo[3.2.1]octyl group with one to three phenoxy
groups each phenoxy substituent optionally being substituted on
the phenyl ring with one to three halogen atoms.
Examples of 5- or 6-membered saturated heterocyclic
rings formed from R11 and R12 or R13 and R14 being linked together
together with the nitrogen atom to which they are bound the
heterocyclic ring optionally containing one or more additional
heteroatoms include:
5- or 6-membered saturated heterocyclic rings formed
from R11 and R12 or R13 and R14 being linked together together
with the nitrogen atom to which they are bound the heterocyclic
ring optionally containing one or more additional heteroatoms
selected from oxygen nitrogen and sulfur atom
such as pyrrolidine piperazine piperidine morpholine
thiomorpholine imidazolidine thiazolidine isothiazolidine
oxazolidine isoxazolidine isothiazolidine and pyrazolidine.
Examples of phenyl groups optionally substituted on the
phenyl ring with one or more members selected from the group
consisting of lower alkyl groups optionally substituted with one
or more halogen atoms lower alkylthio groups lower alkoxy
-119-
groups optionally substituted with one or more halogen atoms
halogen atoms a phenyl group lower alkylamino groups a cyano
group a phenoxy group cycloalkyl groups pyrrolidinyl groups
optionally substituted with one or more oxo groups 1234-
tetrahydroisoquinolylcarbonyl groups 1234-
tetrahydroquinolylcarbonyl groups optionally substituted with one
or more lower alkyl groups 1234-
tetrahydroquinoxalinylcarbonyl groups optionally substituted with
one or more lower alkyl groups thiazolyl groups optionally
substituted with one or more phenyl groups a carbamoyl group
phenyl lower alkoxy groups lower alkylsulfonylamino groups
anilino groups optionally substituted with one or more halogen
atoms phenyl lower alkyl groups and hydroxy-substituted lower
alkyl groups include:
phenyl groups optionally substituted on the phenyl ring
with one to three members selected from the group consisting of
straight and branched C1.6 alkyl groups optionally substituted
with one to three halogen atoms straight and branched Ci_6
alkylthio groups straight and branched Ci-6 alkoxy groups
optionally substituted with one to three halogen atoms halogen
atoms a phenyl group amino groups optionally substituted with
one or two straight and/or branched Ci-e alkyl groups a cyano
group a phenoxy group C3.8 cycloalkyl groups pyrrolidinyl
groups optionally substituted with one or two oxo groups
1234-tetrahydroisoquinolylcarbonyl groups 1234-
tetrahydroquinolylcarbonyl groups optionally substituted with one
to three straight and/or branched Ci-6 alkyl groups 1234-
tetrahydroquinoxalinylcarbonyl groups optionally substituted with
one to three straight and/or branched Ci-6 alkyl groups thiazolyl
groups optionally substituted with one to three phenyl groups a
carbamoyl group phenyl alkoxy groups wherein the alkoxy moiety
is a straight or branched Cj.6 alkoxy group straight and branched
Ci-e alkylsulfonylamino groups anilino groups optionally
substituted with one to three halogen atoms phenyl alkyl groups
wherein the alkyl moiety is a straight or branched Ci-e alkyl
-120-
group and hydroxy-substituted alkyl groups wherein the alkyl
moiety is a straight or branched Ci-e alkyl group substituted with
one to three hydroxy groups
such as (2- 3- or 4-)trifluoromethylphenyl
(2- 3- or 4-)methylthiophenyl (2- 3- or 4-)
trifluoromethoxyphenyl (2- 3- or 4-)ethylphenyl
(2- 3- or 4-)propylphenyl (2- 3- or 4-)butylphenyl
(2- 3- or 4-)pentylphenyl (2- 3- or 4-)hexylphenyl
(2- 3- or 4-)isopropylphenyl (2- 3- or 4-)chlorophenyl
(2- 3- or 4-)fluorophenyl (2- 3- or 4-)phenylphenyl
(2- 3- or 4-)dimethylaminophenyl (2- 3- or 4-)cyanophenyl
(2- 3- or 4-)phenyloxyphenyl (34- 23- 26- or 35-)
dimethylphenyl (34- 23- 26- or 35-)difluorophenyl 2-
chloro-4-methylphenyl (2- 3- or 4-)cyclohexylphenyl
(2- 3- or 4-)benzyloxyphenyl (2- 3- or 4-)
methylsulfonylaminophenyl (2- 3- or 4-)anilinophenyl (34-
23- 26- or 35-)dimethoxyphenyl 3-chloro-4-methoxyphenyl 3-
chloro - 4 -methylphenyl 3 -methoxy- 5 - trif luoromethylphenyl 2 -
chloro-5-trifluoromethylphenyl 2-chloro-6-cyanophenyl 2-chloro-
5-carbamoylphenyl (2- 3- or 4-)phenylmethylphenyl (2- 3- or
4-)pyrrolidinylphenyl (2- 3- or 4-)[(l- 2- 3- or 4-)
(1234-tetrahydroisoquinolylcarbonyl)]phenyl (2- 3- or 4-)
[(!- 2- 3- or 4-)(6-methyl-l234-tetrahydroquinolyl
carbonyl)]phenyl (2- 3- or 4-)(4-fluoroanilino)phenyl (2- 3-
or 4-)[4-methyl-1-(1234-tetrahydroquinoxalinyl)carbonyl]phenyl
and (2- 3- or 4-) [(4- or 5-) phenylthiazolyl-2-yl]phenyl.
Examples of phenyl lower alkyl groups optionally
substituted on the phenyl ring with one or more members selected
from the group consisting of lower alkyl groups optionally
substituted with one or more halogen atoms lower alkoxy groups
optionally substituted with one or more halogen atoms halogen
atoms and a phenyl group include:
phenyl alkyl groups wherein the alkyl moiety is a
straight or branched Ci-e alkyl group optionally substituted on
the phenyl ring with one to three members selected from the group
-121-
consisting of straight and branched Ci-6 alkyl groups optionally
substituted with one to three halogen atoms straight and
branched Ci-6 alkoxy groups optionally substituted with one to
three halogen atoms halogen atoms and a phenyl group
such as benzyl 1-phenethyl 2-phenethyl 3-
phenylpropyl 2-phenylpropyl 4-phenylbutyl 5-phenylpentyl 4-
phenylpentyl 6-phenylhexyl 2-methyl-3-phenylpropyl 11-
dimethyl-2-phenylethyl 11-diphenylmethyl 22-diphenylethyl
33-diphenylpropyl 12-diphenylethyl 4-chlorobenzyl 2-
chlorobenzyl 3-chlorobenzyl 3-fluorobenzyl 4-fluorobenzyl
(2- or 4-)bromobenzyl 23-dichlorobenzyl 24-dichlorobenzyl 3-
chloro-4-fluorobenzyl 246-trifluorobenzyl 3-
trifluoromethylbenzyl 4-trifluoromethylbenzyl 2-methylbenzyl
3-methylbenzyl 4-methylbenzyl 4-te.rt-butylbenzyl 24-
dimethylbenzyl 246-trimethylbenzyl 2-phenylbenzyl 3-
phenylbenzyl 4-phenylbenzyl 24-diphenylbenzyl 246-
triphenylbenzyl 2-trifluoromethoxybenzyl 3-
trifluoromethoxybenzyl 4-trifluoromethoxybenzyl 3-chloro-4-
difluoromethoxybenzyl 4-chloro-3-trifluoromethylbenzyl 2-
methoxybenzyl 3-methoxybenzyl 4-methoxybenzyl 34-
dimethoxybenzyl 345-trimethoxybenzyl 2-(4-methoxyphenyl)ethyl
2-(2 -methoxyphenyl)ethyl and 2-(4- chlorophenyl)ethyl.
Examples of lower alkyl-substituted amino lower alkyl
groups include:
aminoalkyl groups wherein the alkyl moiety is a
straight or branched Ci_6 alkyl group having on the amino group
one or two straight and/or branched Ci_6 alkyl groups
such as tf-methylaminomethyl NN-diethylaminomethyl
NN-Ai-n- propylaminoe thyl NW-diisopropylaminoethyl 3-(NNdimethylamino)
propyl 4-(NN~dimethylamino)butyl 5- (N Ndimethylamino)
pentyl and 6 - (N N- dime thylamino) hexyl.
Examples of pyrazinyl lower alkyl groups optionally
substituted on the pyrazine ring with one or more lower alkyl
groups include:
pyrazinylalkyl groups wherein the alkyl moiety is a
-122-
straight or branched d-6 alkyl group optionally substituted on
the pyrazine ring with one to three straight and/or branched Ci_6
alkyl groups
such as (2- or 3-)pyrazinylmethyl (1- or 2-)(2- or 3-
pyrazinyl)ethyl 3-(2- or 3-)pyrazinylpropyl 4-(2- or 3-)
pyrazinylbutyl 5-(2- or 3-)pyrazinylpentyl 6-(2- or 3-)
pyrazinylhexyl 2-methyl-5-pyrazinylmethyl (1- or 2-) (2-methyl-
5-pyrazinyl)ethyl 3-(2-methyl-5-pyrazinyl)propyl 4-(2-ethyl-5-
pyrazinyl)butyl 5-(2-ethyl-5-pyrazinyl)pentyl and 6-(2-methyl-
5 -pyrazinyl)hexyl.
Examples of pyrazolyl lower alkyl groups optionally
substituted on the pyrazoline ring with one or more lower alkyl
groups include:
pyrazolylalkyl groups wherein the alkyl moiety is a
straight or branched C1.6 alkyl group optionally substituted on
the pyrazoline ring with one to three straight and/or branched
Ci-6 alkyl groups
such as (3- 4- or 5-Jpyrazolylmethyl (1- or 2-)
(3- 4- or 5-)pyrazolylethyl 3-(3- 4- or 5-)pyrazolylpropyl
4-(3- 4- or 5-)pyrazolylbutyl 5-(3- 4- or 5-)pyrazolylpentyl
6-(3- 4- or 5-)pyrazolylhexyl [1-methyl-(3- 4- or 5-)
pyrazolyl]methyl [15-dimethyl-(3- or 4-)pyrazolyl]methyl and
[15-dimethyl-(3- or 4-)pyrazolyl]ethyl.
Examples of piperidinyl groups optionally substituted
on the piperidine ring with one or more members selected from the
group consisting of lower alkyl groups a benzoyl group and
phenyl lower alkyl groups optionally substituted on the phenyl
ring with one or more members selected from halogen atoms and
lower alkyl groups include:
piperidinyl groups optionally substituted on the
piperidine ring with one to three members selected from the group
consisting of straight and branched d-6 alkyl groups a benzoyl
group and phenyl lower alkyl groups wherein the alkyl moiety is
a straight or branched Ci-e alkyl group optionally substituted on
the phenyl ring with one to three members selected from the group
-123-
consistlng of halogen atoms and straight and branched Ci_6 alkyl
groups
such as N-methyl-(2- 3- or 4-)piperidinyl W-ethyl-
(2- 3- or 4-)piperidinyl W-n-propyl-(2- 3- or 4-)piperidinyl
W-benzoyl-(2- 3- or 4-)piperidinyl 1-benzyl-4-piperidinyl 1-
phenylethyl-4-piperidinyl l-(2- 3- or 4-)chlorophenylmethyl-4-
piperidinyl and l-(2- 3- or 4-)methylphenylmethyl-4-
piperidinyl l23-trimethyl-(4- 5- or 6-)piperidinyl 1-
benzyl-3-methyl-(2- 4- 5-or 6-)piperidinyl and l-benzoyl-2-
benzyl-(3- 4- 5- or 6-)piperidinyl.
Examples of 34-dihydrocarbostyril groups optionally
substituted with one or more lower alkyl groups include 34-
dihydrocarbostyril groups optionally substituted with one to
three straight and/or branched Ci.6 alkyl groups such as 34-
dihydro-(5- 6- 7- or 8-)carbostyril and (6- 7- or 8-)methyl-
34-dihydro-5-carbostyril.
Examples of quinolyl groups optionally substituted with
one or more lower alkyl groups include quinolyl groups optionally
substituted with one to three straight and/or branched Ci.6 alkyl
groups such as (2- 3- 4- 5- 6- 7- or 8-)quinolyl and 2-
methyl-4-quinolyl.
Examples of carbazolyl groups optionally substituted
with one or more lower alkyl groups include carbazolyl groups
optionally substituted with one to three straight and branched
Ci-e alkyl groups such as N-methyl-(2- 3- 4- or 5-)carbazolyl
and W-ethyl-(2- 3- 4- or 5-)carbazolyl.
Examples of phenyl lower alkylcarbamoyl lower alkyl
groups include phenylalkylcarbamoylalkyl groups wherein each of
the two alkyl moieties is a straight or branched Ci_6 alkyl group
such as phenylmethylcarbamoylmethyl (1- or 2-)phenylethyl
carbamoylmethyl (1- or 2-)phenylethylcarbamoylethyl 3-(2-
phenylethylcarbamoyl)propyl 4-(2-phenylethylcarbamoyl)butyl
5-(2-phenylethylcarbamoyl)pentyl and 6-(2-phenylethylcarbamoyl)
hexyl.
Examples of phenylcarbamoyl lower alkyl groups include
-124-
phenylcarbamoylalkyl groups wherein the alkyl moiety is a
straight or branched Ci_6 alkyl group such as
phenylcarbamoylmethyl (1- or 2-)phenylcarbamoylethyl 3-
(phenylcarbamoyl) propyl 4 - (phenylcarbamoyl) butyl 5 -
(phenylcarbamoyl) pentyl and 6 - (phenylcarbamoyl) hexyl.
Examples of anilino groups optionally substituted on
the phenyl ring with one or more lower alkoxy groups each lower
alkoxy substituent optionally being substituted with one or more
halogen atoms include:
anilino groups optionally substituted on the phenyl
ring with one to three straight and/or branched Ci-6 alkoxy groups
each alkoxy substituent optionally being substituted with one to
three halogen atoms
such as (2- 3- or 4-)chloromethoxyanilino and
(2- 3- or 4-)trifluoromethoxyanilino.
Examples of anilino groups substituted on the amino
group with one or more lower alkyl groups and further substituted
on the phenyl ring with one or more halogen atoms include:
anilino groups substituted on the amino group with one
to three straight and/or branched Ci-6 alkyl groups and further
substituted on the phenyl ring with one to three halogen atoms
such as W-methyl-(2- 3- or 4-)chloroanilino W-ethyl-
(2- 3- or 4-)chloroanilino //-methyl-(2- 3- or 4-)
bromoanilino W-methyl-(2- 3- or 4-)fluoroanilino AT-ethyl-(2-
3- or 4-)iodoanilino and N-n-propyl-(2- 3- or 4-)
chloroanilino.
Examples of 5- and 6-membered unsaturated heterocyclic
rings formed from R8 and R9 being linked together together with
the nitrogen atom to which they are bound include (2- or 3-)
pyrroline 12-dihydropyridine 23-dihydropyridine 1234-
tetrahydropyridine and 1256-tetrahydropyridine.
Examples of benzoyl groups optionally substituted on
the phenyl ring with one or more members selected from the group
consisting of lower alkyl groups optionally substituted with one
or more halogen atoms a phenyl group halogen atoms a cyano
-125-
group a phenoxy group lower alkoxycarbonyl groups pyrazolyl
groups and lower alkoxy groups optionally substituted with one
or more halogen atoms include:
benzoyl groups optionally substituted on the phenyl
ring with one to three members selected from the group consisting
of the above-described straight and branched Ci-e alkyl groups
optionally substituted with one to three halogen atoms a phenyl
group halogen atoms a cyano group a phenoxy group the abovedescribed
straight and branched Ci-6 alkoxycarbonyl groups
pyrazolyl groups and the above-described straight and branched
Ci-e allcoxy groups optionally substituted with one to three halogen
atoms
such as benzoyl 4-methylbenzoyl 3-methylbenzoyl
2-methylbenzoyl 4-tert-butylbenzoyl 24-dimethylbenzoyl
246-trimethylbenzoyl 3-trifluoromethylbenzoyl 4-
trifluoromethylbenzoyl 2-trifluoromethylbenzoyl 4-phenylbenzoyl
4-chlorobenzoyl 3-chlorobenzoyl 2-chlorobenzoyl 4-
fluorobenzoyl 3-fluorobenzoyl 2-fluorobenzoyl 3-bromobenzoyl
2-bromobenzoyl 4-bromobenzoyl 34-dichlorobenzoyl 23-
dichlorobenzoyl 2-chloro-4-fluorobenzoyl 2-methoxy-5-
chlorobenzoyl 4-methoxybenzoyl 3-methoxybenzoyl 2-
methoxybenzoyl 34-dimethoxybenzoyl 345-trimethoxybenzoyl 3-
trifluoromethoxybenzoyl 4-trifluoromethoxybenzoyl 2-
trifluoromethoxybenzoyl 3-cyanobenzoyl 4-cyanobenzoyl 2-
cyanobenzoyl 3-phenoxybenzoyl 2-phenoxybenzoyl 4-
phenoxybenzoyl 4-methoxycarbonylbenzoyl 3-ethoxycarbonylbenzoyl
2-tert-butoxycarbonylbenzoyl and 4-(1-pyrazolyl)benzoyl.
Examples of alkanoyl groups include straight and
branched CI-IQ alkanoyl groups such as in addition to the abovedescribed
lower alkanoyl groups heptanoyl octanoyl nonanoyl
decanoyl and 2-ethyl-hexanoyl.
Examples of phenyl lower alkanoyl groups optionally
substituted on the phenyl ring with one or more members selected
from the group consisting of halogen atoms and lower alkyl groups
include:
-126-
phenylalkanoyl groups wherein the alkanoyl moiety is a
straight or branched C2-6 alkanoyl group optionally substituted
on the phenyl ring with one to three members selected from the
group consisting of halogen atoms and straight and branched Ci_6
alkyl groups
such as 2-phenylacetyl 3-phenylpropionyl 2-
phenylpropionyl 4-phenylbutyryl 5-phenylpentanoyl 6-
phenylhexanoyl 22-dimethyl-3-phenylpropionyl 2-methyl-3-
phenylpropionyl 2-(4-fluorophenyl)acetyl 3 - (25 -
difluorophenyl)propionyl 2-(24-difluorophenyl)propionyl 4-
(34- difluorophenyl)butyry1 5-(35-difluorophenyl)pentanoy1 6-
(26- dif luorophenyl) hexanoyl 2 - (2 - chlorophenyl) acetyl 3 - (3 -
chlorophenyl)propionyl 2-(4-chlorophenyl)propionyl 4-(23-
dichlorophenyl)propionyl 5-(24-dichlorophenyl)pentanoyl 6-
(25-dichlorophenyl)hexanoyl 2-(34-dichlorophenyl)acetyl 3-
(26- dichlorophenyl) propionyl 2 - (3 - f luorophenyl) propionyl 4 - (2 -
fluorophenyl)butyryl 5-(3-bromophenyl)pentanoyl 6-(4-
iodophenyl)hexanoyl 2-(2-bromophenyl)acetyl 3 - (4 -
bromophenyl)propionyl 2-(35-dichlorophenyl)propionyl 4 - (246 -
tr if luorophenyl) butyryl 5 - (34 - dif luorophenyl) pen tanoyl 6 - (2 -
iodophenyl)hexanoyl 2-(3-iodophenyl)acetyl 3-(4-
iodophenyl)propionyl 2-(23-dibromophenyl)propionyl 4 - (24 -
diiodophenyl)butyryl 2-(246-trichlorophenyl)acetyl 2-(4-
methylphenyl)acetyl 3-(25-dimethylphenyl)propionyl 2-(24-
diethylphenyl)propionyl 4-(34-di-n-propylphenyl)butyryl 2 - (2 -
ethylphenyl)acetyl 3-(3-n-propylphenyl)propionyl 2-(4-tertbutylphenyl)
propionyl 2-(246-trimethylphenyl)acetyl 2-(25-
dichloro-4-methylphenyl)acetyl 2-(3 -methyl-4-chlorophenyl)acetyl
4-(2-n-butylphenyl)butyryl 5-(3-n-pentylphenyl)pentanoyl and 6-
(4-n-hexylphenyl)hexanoyl.
Examples of phenoxy lower alkanoyl groups optionally
substituted on the phenyl ring with one or more halogen atoms
include:
phenoxyalkanoyl groups wherein the alkanoyl moiety is a
straight or branched €2-6 alkanoyl group optionally
on the phenyl ring with one to three halogen atoms
such as in addition to the above-described phenoxy
lower alkanoyl groups 2-(4-chlorophenoxy)acetyl 2-(4-
fluorophenoxy)acetyl 3-(25-difluorophenoxy)propionyl 2-(24-
difluorophenoxy)propionyl 4-(34-difluorophenoxy)butyryl 5-
(35- difluorophenoxy)pentanoyl 6-(26-difluorophenoxy)hexanoyl.
2-(2-chlorophenoxy)acetyl 3-(3-chlorophenoxy)propionyl 2-(4-
chlorophenoxy)propionyl 4-(23-dichlorophenoxy)propionyl 5-
(24- dichlorophenoxy)pentanoyl 6-(25-dichlorophenoxy)hexanoyl
2-(34-dichlorophenoxy)acetyl 3-(26-dichlorophenoxy)propionyl
2-(3-fluorophenoxy)propionyl 4-(2-fluorophenoxy)butyryl 5-(3-
bromophenoxy)pentanoyl 6-(4-iodophenoxy)hexanoyl 2 - (2 -
bromophenoxy)acetyl 3-(4-bromophenoxy)propionyl 2 - (35 -
dichlorophenoxy)propionyl 4-(246-trifluorophenoxy)butyryl 5-
(34-difluorophenoxy)pentanoyl 6-(2-iodophenoxy)hexanoyl 2-(3-
iodophenoxy)acetyl 3-(4-iodophenoxy)propionyl 2-(23-
dibromophenoxy) propionyl 4 - (24 - diiodophenoxy) butyryl and
2-(246-trichlorophenoxy)acetyl.
Examples of phenyl lower alkenylcarbonyl groups include
phenylalkenylcarbonyl groups containing one to three double bonds
wherein the alkenyl moiety is a straight or branched C2-e alkenyl
group such as styrylcarbonyl (trivial name: cinnamoyl) 3-
phenyl-2-propenylcarbonyl 4-phenyl-2-butenylcarbonyl 4-phenyl-
3-butenylcarbonyl 5-phenyl-4-pentenylcarbonyl 5-phenyl-3-
pentenylcarbonyl 6-phenyl-5-hexenylcarbonyl 6-phenyl-4-
hexenylcarbonyl 6-phenyl-3-hexenylcarbonyl 4-phenyl-l3-
butadienylcarbonyl and 6-phenyl-135-hexatrienylcarbonyl.
Examples of pyridylcarbonyl groups optionally
substituted on the pyridine ring with one or more members
selected from the group consisting of halogen atoms and lower
alkyl groups each lower alkyl substituent optionally being
substituted with one or more halogen atoms include:
pyridylcarbonyl groups optionally substituted on the
pyridine ring with one to three members selected from the group
consisting of halogen atoms and the above-described straight and
-128-
branched Ci_6 alkyl groups optionally substituted with one to three
halogen atoms
such as (2- 3- or 4-)pyridylcarbonyl 2-chloro-
(3- 4- 5- or 6-)pyridylcarbonyl 26-dichloro-(3- 4- or 5-)
pyridylcarbonyl 23-dichloro-(4- 5- or 6-)pyridylcarbonyl 2-
trifluoromethyl-(3- 4- 5- or 6-)pyridylcarbonyl 2-bromo-
(3- 4- 5- or 6-)pyridylcarbonyl 26-difluoro-(3- 4- or 5-)
pyridylcarbonyl 4-methyl-(2- 3- 5- or 6-)pyridylcarbonyl 3-
chloro-(2- 4- 5- or 6-)pyridylcarbonyl 25-dibromo-
pyridylcarbonyl 246-trifluoro-(3- or 5-)pyridylcarbonyl 24-
dimethyl-(3- 5- or 6-)pyridylcarbonyl 246-trimethyl-
(3- or 5-)pyridylcarbonyl and 2-methyl-4-chloro-(3- 5- or 6-)
pyridylcarbonyl.
Examples of piperidinylcarbonyl groups optionally
substituted on the piperidine ring with one or more lower
alkanoyl groups include piperidinylcarbonyl groups optionally
substituted on the piperidine ring with one to three straight
and/or branched Ci.6 alkanoyl groups such as
(2- 3- or 4-)piperidinylcarbonyl l-acetyl-(2- 3- or
piperidinylcarbonyl l-n-propanoyl-(2- 3- or 4-)
piperidinylcarbonyl l-isopropanoyl-(2- 3- or 4-)
piperidinylcarbonyl l-n-butyryl-(2- 3- or 4-)
piperidinylcarbonyl l-n-pentanoyl-(2- 3- or 4-)
piperidinylcarbonyl 1-n-hexanoyl-(2- 3- or 4-)
piperidinylcarbonyl l2-diacetyl-(3- 4- 5- or 6-)
piperidinylcarbonyl l23-triacetyl-(4- 5- or 6-)
piperidinylcarbonyl 2-acetyl-(l- 3- 4- 5- or 6-)
piperidinylcarbonyl 3-propanoyl-(l- 2- 4- 5- or 6-)
30 piperidinylcarbonyl and 2-formyl-4-propanoyl-(l- 3- 5- or 6-)
piperidinylcarbonyl.
Examples of tetrahydropyranylcarbonyl groups include 2-
tetrahydropyranylcarbonyl 3-tetrahydropyranylcarbonyl and 4-
tetrahydropyranylcarbonyl.
35 Examples of benzothienylcarbonyl groups optionally
-129-
substituted on the benzothiophene ring with one or more halogen
atoms include benzothienylcarbonyl groups optionally substituted
on the benzothiophene ring with one to three halogen atoms such
as (2- 3- 4- 5- 6- or 7-)benzothienylcarbonyl [3-chloro-(2-
4- 5- 6- or 7-)benzothienyl]carbonyl [4-bromo-(2- 3- 5- 6-
or 7-)benzothienyl]carbonyl [5-fluoro-
(2- 3- 4- 6- or 7-)benzothienyl]carbonyl [6-iodo-
(2- 3- 4- 5- or 7-)benzothienyl]carbonyl [7-chloro-
(2- 3- 4- 5- or 6-)benzothienyl]carbonyl [2-chloro-
(3- 4- 5- 6- or 7-)benzothienyl]carbonyl [23-dichloro-
(4- 5- 6- or 7-)benzothienyl]carbonyl and [346-trichloro-
(2- 5- or 7-)benzothienyl]carbonyl.
Examples of pyridyl lower alkyl groups optionally
substituted on the pyridine ring with one or more members
selected from the group consisting of halogen atoms and lower
alkyl groups each lower alkyl substituent optionally being
substituted with one or more halogen atoms include:
pyridylalkyl groups wherein the alkyl moiety is a
straight or branched Ci-e alkyl group optionally substituted on
the pyridine ring with one to three members selected from the
group consisting of halogen atoms and the above-described
straight and branched Ci.6 alkyl groups optionally substituted with
one to three halogen atoms
such as (2- 3- or 4-)pyridylmethyl 2-
[(2- 3- or 4-)pyridyl]ethyl l-[(2- 3- or 4-)pyridyl]ethyl
3-[(2- 3- or 4-)pyridyl]propyl 4-1(2- 3- or 4-)pyridyl]butyl
ll-dimethyl-2-[(2- 3- or 4-)pyridyl]ethyl 5-[(2- 3- or 4-)
pyridyl]pentyl 6-[(2- 3- or 4-)pyridyl]hexyl 1-
[(2- 3- or 4-)pyridyl]isopropyl 2-methyl-3-[(2- 3- or 4-)
pyridyl]propyl [2-chloro-(3- 4- 5- or 6-)pyridyl]methyl
[23-dichloro-(4- 5- or 6-)pyridyl]methyl [2-bromo-
(3- 4- 5- or 6-)pyridyl]methyl [2.46-trifluoro-
(3- 5- or 6-)pyridyl]methyl [2-trifluoromethyl-
(3- 4- 5- or 6-)pyridyl]methyl [2-methyl-(3- 4- 5- or 6-)
pyridyl]methyl [2-ethyl-(3- 4- 5- or 6-)pyridyl]methyl 2-[2-
-130-
n-propyl-(3- 4- 5- or 6-)pyridyl]ethyl 3-[2-n-butyl-
(3- 4- 5- or 6-)pyridyi]propyl 4-[2-n-pentyl-
(3- 4- 5- or 6-)pyridyl]butyl 5-[2-n-hexyl-
(3- 4- 5- or 6-)pyridyl]pentyl 6-[2-isopropyl-
(3- 4- 5- or 6-)pyridyl]hexyl [2-cert-butyl-
(3- 4- 5- or 6-Jpyridyl]methyl [24-dimethyl-(3- 5- or 6-)
pyridyl]methyl [246-trimethyl-(3- or 5-Jpyridyl]methyl [24-
ditrifluoromethyl-(3- 5- or 6-)pyridyl]methyl 2-(24-
bistrifluoromethyl)-(3- 5- or 6-)pyridyl)ethyl and 3-[2-
methyl-6-chloro-(3- 4- or 5-)pyridyl]propyl.
Examples of thienyl lower alkyl groups optionally
substituted on the thiophene ring with one or more halogen atoms
include:
thienylalkyl groups wherein the alkyl moiety is a
straight or branched Ci-6 alkyl group optionally substituted on
the thiophene ring with one to three halogen atoms
such as [(2- or 3-)thienyl]methyl 2-[(2- or 3-)
thienyl]ethyl l-[(2- or 3-)thienyl]ethyl 3-[(2- or 3-)thienyl]
propyl 4-[(2- or 3-)thienyl]butyl 5-[(2- or 3-)thienyl]pentyl
6-[(2- or 3-)thienyl]hexyl 11-dimethyl-2-[(2- or 3-)thienyl]
ethyl 2-methyl-3-[(2- or 3-)thienyl]propyl [2-chloro-
(3- 4- or 5-)thienyl]methyl [4-bromo-(2- 3- or 5-)thienyl]
methyl [5-fluoro-(2- 3- or 4-) thienyl]methyl [3-iodo-
(2- 4- or 5-)thienyl]methyl [23-dichloro-(4- or 5-)thienyl]
methyl (245-trichloro-3-thienyl)methyl 2-[2-fluoro-
(3- 4- or 5-)thienyl]ethyl l-[4-iodo-(2- 3- or 5-)thienyl]
ethyl 3-[3-chloro-(2- 4- or 5-) thienyl]propyl 4-[45-
dichloro-(2- or 3-)thienyl]butyl 5-(245-trichloro-3-thienyl)
pentyl and 6-[2-chloro-(3- 4- or 5-)thienyl]hexyl.
Examples of amino groups optionally substituted with
one or more members selected from the group consisting of lower
alkyl groups and lower alkanoyl groups include:
amino groups optionally substituted with one or two
members selected from the group consisting of straight and
branched Ci-e alkyl groups and straight and branched Ci-6 alkanoyl
groups
such as amlno forraylamino acetylamino propionylamino
butyrylamino isobutyrylamino pentanoylamino tertbutylcarbonylamino
hexanoylamino WAr-diacetylamino N-acetyl-Npropionylamino
methylamino ethylamino n-propylamino
isopropylamino n-butylamino n-pentylamino n-hexylamino
dimethylamino 3-diethylamino diisopropylamino N-ethyl-N-npropylamino
W-methyl-W-n-hexylamino N-methyl-AT-acetylamino and
N- ethyl -N- acetylamino.
Examples of phenyl lower alkyl groups optionally
substituted on the phenyl ring with one or more members selected
from the group consisting of lower alkoxy groups optionally
substituted with one or more halogen atoms a cyano group lower
alkyl groups optionally substituted with one or more halogen
atoms amino groups optionally substituted with one or more
members selected from the group consisting of lower alkyl groups
and lower alkanoyl groups halogen atoms lower alkoxycarbonyl
groups lower alkanoyloxy groups lower alkylsulfonyl groups
lower alkylthio groups and pyrrolidinyl groups include:
mono- and di-phenylalkyl groups wherein the alkyl
moiety is a straight or branched Ci_6 alkyl group optionally
substituted on the phenyl ring with one to three members selected
from the group consisting of the above-described straight and
branched Ci_6 alkoxy groups optionally substituted with one to
three halogen atoms a cyano group the above-described straight
and branched Ci-e alkyl groups optionally substituted with one to
three halogen atoms the above-described amino groups optionally
substituted with one or two members selected from the group
consisting of straight and branched Ci-6 alkyl groups and straight
and branched d-6 alkanoyl groups halogen atoms the abovedescribed
straight and branched Ci-6 alkoxycarbonyl groups the
above-described straight and branched C2-6 alkanoyloxy groups the
above-described straight and branched Ci.6 alkylsulfonyl groups
the above-described straight and branched Ci-6 alkylthio groups
and pyrrolidinyl groups
such as benzyl 1-phenethyl 2-phenethyl
3-phenylpropyl 2-phenylpropyl 4-phenylbutyl 5-phenylpentyl 4-
phenylpentyl 6-phenylhexyl 2-methyl-3-phenylpropyl 11-
dimethyl-2-phenylethyl 11-diphenylmethyl 22-diphenylethyl
33-dlphenylpropyl 12-diphenylethyl 4-chlorobenzyl 2-
chlorobenzyl 3-chlorobenzyl 3-fluorobenzyl 4-fluorobenzyl 2-
fluorobenzyl 4-bromobenzyl 3-bromobenzyl 2-bromobenzyl l-(2-
chlorophenyl)ethyl 23-dichlorobenzyl 246-trifluorobenzyl 2-
trifluoromethylbenzyl 3-trifluoromethylbenzyl 4-
trifluoromethylbenzyl 2-methylbenzyl 3-methylbenzyl 4-
methylbenzyl 4-tert-butylbenzyl 4-n-butylbenzyl 24-
dimethylbenzyl 246-trimethylbenzyl 2-phenylbenzyl 4-
phenylbenzyl 24-diphenylbenzyl 246-triphenylbenzyl 2-
trifluoromethoxybenzyl 3-trifluoromethoxybenzyl 4-
trifluoromethoxybenzy1 4-difluoromethoxybenzyl 2-methoxybenzyl
3-methoxybenzyl 4-methoxybenzyl 4-n-butoxybenzyl 4-tertbutoxybenzyl
l-(3-methoxyphenyl)ethyl l-(4-methoxyphenyl)ethyl
1-(2-methoxyphenyl)ethyl 34-dimethoxybenzyl 345-
trlmethoxybenzyl 4-methoxycarbonylbenzyl 3-ethoxycarbonylbenzyl
2 -n -propoxycarbonylbenzyl 24-dimethoxycarbonylbenzyl 246-
trimethoxycarbonylbenzyl 1-(4-n-butoxyphenyl)ethyl 4-tertbutoxycarbonylbenzyl
4-methylthiobenzyl 3-methylthiobenzyl 2-
methylthiobenzyl 4-ethylthiobenzyl 24-dimethylthiobenzyl
246-trimethyl thiobenzyl 4-methylsulfonylbenzyl 3-
methylsulfonylbenzyl 2-methylsulfonylbenzyl 34-
dimethylsulfonylbenzyl 345-trlmethylsulfonylbenzyl 4-methoxy-
3 -chlorobenzyl 4 - (AT-acetylamino) benzyl 4 - (N Ndiethylamino)
benzyl 4-(AT/N-dimethylamino)benzyl 4-(Nmethylamino)
benzyl 3-aminobenzyl 2-aminobenzyl 4-aminobenzyl
4-acetyloxybenzyl 23-diaminobenzyl 345-triaminobenzyl
methyl-3-fluorobenzyl 4-cyanobenzyl 3-cyanobenzyl 2-
cyanobenzyl 4-(1-pyrrolidinyl)benzyl 4-methoxy-2-chlorobenzyl
and 3-chloro-5-methylbenzyl.
Examples of thiazolyl lower alkyl groups include
thiazolylalkyl groups wherein the alkyl moiety is a straight or
branched Ci.6 alkyl group such as [(2- 4- or 5-)thiazolyl]methyl
2-[(2- 4- or 5-)thiazolyl]ethyl l-[(2- 4- or 5-)thiazolyl]
ethyl 3-[(2- 4- or 5-)thiazolyl]propyl 4-[(2- 4- or 5-)
thiazolyl]butyl 5-[(2- 4- or 5-)thiazolyl]pentyl 6-
[(2- 4- or 5-)thiazolyl]hexyl ll-dimethyl-2-[(2- 4- or 5-)
thiazolyl]ethyl and [2-methyl-3-[(2- 4- or 5-)thiazolyl]propyl.
Examples of imidazolyl lower alkyl groups optionally
substituted on the imidazole ring with one or more lower alkyl
groups include:
imidazolylalkyl groups wherein the alkyl moiety is a
straight or branched Ct.6 alkyl group optionally substituted on
the imidazole ring with one to three above-described straight and
branched Ci-6 alkyl groups
such as [(!- 2- 4- or 5-)imidazolyl]methyl 2-
[(!- 2- 4- or 5-)imidazolyl]ethyl !-[(!- 2- 4- or 5-)
imidazolyl]ethyl 3-[(l- 2- 4- or 5-)imidazolylJpropyl 4-
[(!- 2- 4- or 5-)imidazolyl]butyl 11-dimethyl-2-
[(!- 2- 4- or 5-)imidazolyl]ethyl 5-[(l- 2- 4- or 5-)
imidazolyl]pentyl 6-[(l- 2- 4- or 5-)imidazolyl]hexyl 1-
[(!- 2- 4- or 5-)imidazolyl]isopropyl 2-methyl-3-
[(!- 2- 4- or 5-)imidazolyl]propyl [1-methyl-
(2- 4- or 5-)imidazolylJmethyl [l-ethyl-(2- 4- or 5-)
imidazolyl]methyl [l-n-propyl-(2- 4- or 5-)imidazolyl]methyl
[l-n-butyl-(2- 4- or 5-)imidazolyl]methyl [1-n-pentyl-
(2- 4- or 5-)imidazolyl]methyl [l-n-hexyl-(2- 4- or
imidazolyl]methyl 2-[2-methyl-(l- 4- or 5-)imidazolyl]ethyl
l-[l-ethyl-(2- 4- or 5-)imidazolyl]ethyl 3-[l-ethyl-
(2- 4- or 5-)imidazolyl]methyl 4-[l-n-propyl-(2- 4- or 5-)
imidazolyl]butyl 5-[l-n-butyl-(2- 4- or 5-)imidazolyl]pentyl
6-[l-n-pentyl-(2- 4- or 5-)imidazolyl]hexyl [12-dimethyl-
(4- or 5-)imidazolyl]methyl and (124-trimethyl-5-imidazolyl)
methyl.
Examples of pyrrolyl lower alkyl groups optionally
substituted on the pyrrole ring with one or more lower alkyl
groups include:
-134-
pyrrolylalkyl groups wherein the alkyl moiety is a
straight or branched Ci-6 alkyl group optionally substituted on
the pyrrole ring with one to three above-described straight and
branched Ci-6 alkyl groups
such as [(!- 2- or 3-Jpyrrolyl]methyl
2-[(l- 2- or 3-)pyrrolyl]ethyl !-[(!- 2- or 3-)pyrrolyl]
ethyl 3-[(l- 2- or 3-)pyrrolyl]propyl 4-[(l- 2- or 3-)
pyrrolyl]butyl ll-dimethyl-2-[(l- 2- or 3-)pyrrolyl]ethyl 5-
[(!- 2- or 3-)pyrrolyl]pentyl 6-[(l- 2- or 3-)pyrrolyl]hexyl
!-[(!- 2- or 3-)pyrrolyl]isopropyl 2-methyl-3-[(1- 2- or 3-)
pyrrolylJpropyl [l-methyl-(2- or 3-)pyrrolyl]methyl [1-ethyl-
(2- or 3-)pyrrolyl]methyl [l-n-propyl-(2- or 3-)pyrrolyl]methyl
[l-n-butyl-(2- or 3-Jpyrrolyl]methyl [l-n-pentyl-(2- or 3-)
pyrrolyl]methyl [l-n-hexyl-(2- or 3-)pyrrolyl]methyl 2-[2-
methyl-(l- 3- 4- or 5-)pyrrolyl]ethyl l-[l-ethyl-(2- or 3-)
pyrrolyl]ethyl 3-[l-ethyl-(2- or 3-)pyrrolyl]methyl 4-[l-npropyl-(
2- or 3-)pyrrolyl]butyl 5-[l-n-butyl-(2- or 3-)pyrrolyl]
pentyl 6-[l-n-pentyl-(2- or 3-)pyrrolyl]hexyl [12-dimethyl-
(3- 4- or 5-Jpyrrolyl]methyl and [l24-trimethyl-(3- or 5-)
pyrrolyl]methyl.
Examples of lower alkylthio lower alkyl groups include
alkylthioalkyl groups wherein each of the two alkyl moieties is a
straight or branched Ci_6 alkyl group such as methylthiomethyl 2-
methylthioethyl 1-ethylthioethyl 2-ethylthioethyl 3-nbutylthiopropy1
4-n-propylthiobutyl 11-dimethyl-2-npentylthioethyl
5-n-hexylthiopentyl 6-methylthiohexyl 1-
ethylthioisopropyl and 2-methyl-3-methylthiopropyl.
Examples of phenoxycarbonyl groups optionally
substituted on the phenyl ring with one or more members selected
from the group consisting of halogen atoms lower alkyl groups
and lower alkoxy groups include:
phenoxycarbonyl groups optionally substituted on the
phenyl ring with one to three members selected from the group
consisting of halogen atoms the above-described straight and
branched Ci-6 aklyl groups and the above-described straight and
-135-
branched Ci-6 alkoxy groups
such as phenoxycarbonyl 4-chlorophenoxycarbonyl 3-
chlorophenoxycarbonyl 2-chlorophenoxycarbonyl 34-
dichlorophenoxycarbonyl 246-trichlorophenoxycarbonyl 4-
fluorophenoxycarbonyl 3-fluorophenoxycarbonyl 2-
fluorophenoxycarbonyl 24-difluorophenoxycarbonyl 345-
trifluorophenoxycarbonyl 4-bromophenoxycarbonyl 2-chloro-4-
methoxyphenoxycarbonyl 3-fluoro-5-methylphenoxycarbonyl 4-
methoxyphenoxycarbonyl 3-methoxyphenoxycarbonyl 2-
methoxyphenoxycarbonyl 34-dimethoxyphenoxycarbonyl
trlmethoxyphenoxycarbonyl 4-methylphenoxycarbonyl 3-
methylphenoxycarbonyl 2-methylphenoxycarbonyl 25-
dimethylphenoxycarbonyl and 234-trimethylphenoxycarbonyl.
Examples of phenyl lower alkoxycarbonyl groups
optionally substituted on the phenyl ring with one or more
halogen atoms include:
phenylalkoxycarbonyl groups wherein the alkoxy moiety
is a straight or branched Ci-6 alkoxy group optionally substituted
on the phenyl ring with one to three halogen atoms
such as benzyloxycarbonyl 2-phenylethoxycarbonyl 1-
phenylethoxycarbonyl 3-phenylpropoxycarbonyl 4-
phenylbutoxycarbonyl 5-phenylpentyloxycarbonyl 6-
phenylhexyloxycarbonyl 11- dimethyl - 2 -phenylethoxycarbonyl 2 -
methyl - 3 - phenylpropoxycarbonyl 2 - chlorobenzyloxycarbonyl 3 -
chlorobenzyloxycarbonyl 2-chlorobenzyloxycarbonyl 34-
dichlorobenzyloxycarbonyl 246-trichlorobenzyloxycarbonyl 4-
fluorobenzyloxycarbonyl 3-fluorobenzyloxycarbonyl 2-
fluorobenzyloxycarbonyl 24-difluorobenzyloxycarbonyl 345-
trifluorobenzyloxycarbonyl 4-bromobenzyloxycarbonyl 4-
nitrobenzyloxycarbonyl and 3-nitrobenzyloxycarbonyl.
Examples of quinoxalinylcarbonyl groups include 2-
quinoxalinylcarbonyl 5-quinoxalinylcarbonyl and 6-
quinoxalinylcarbonyl.
Examples of phenyl lower alkanoyl groups include
phenylalkanoyl groups wherein the alkanoyl moiety is a straight
or branched C2-6 alkanoyl group such as 2-phenylacetyl 3-
phenylpropionyl 2-phenylpropionyl 4-phenylbutyryl 5-
phenylpentanoyl 6-phenylhexanoyl 22-dimethyl-2-phenylpropionyl
and 2-methyl-3-phenylpropionyl.
The compounds of the present invention can be produced
according to for example. Reaction Schemes 1 to 16. All the
starting materials and target compounds shown in Reaction Schemes
1 to 16 may be in the form of suitable salts. Examples of such
salts are as described for carbostyril compound of Formula (1)
below.
wherein R1 R2 R3 R4 R5 X and the bond between the 3- and 4-
positions of the carbostyril skeleton are as defined above R15 is
a hydrogen atom or lower alkyl group and A4 represents a direct
bond or lower alkylene group provided that the total number of
carbon atoms of the group substituting the carbostyril skeleton
i.e. -CH(R15)-A4- is no greater than 6.
The reaction of Compound (2) with Compound (3) is
carried out in a suitable solvent in the presence of a basic
compound or acid.
Examples of solvents usable herein are aromatic
hydrocarbons such as benzene toluene and xylene ethers such as
diethyl ether tetrahydrofuran dioxane monoglyme and diglyme
halogenated hydrocarbons such as dlchloromethane dichloroethane
chloroform and carbon tetrachloride lower alcohols such as
methanol ethanol isopropanol butanol tert-butanol and
ethylene glycol aliphatic acids such as acetic acid esters such
as ethyl acetate and methyl acetate ketones such as acetone and
methyl ethyl ketone acetonitrile pyridine dimethyl sulfoxide
NW-dimethylformamide hexamethylphosphoric triamide mixed
solvents of such solvents etc.
Examples of basic compounds are carbonates such as
sodium carbonate potassium carbonate sodium hydrogencarbonate
potassium hydrogencarbonate and cesium carbonate metal
hydroxides such as sodium hydroxide potassium hydroxide and
calcium hydroxide sodium hydride potassium hydride potassium
sodium sodium amide metal alcoholates such as sodium methylate
sodium ethylate and sodium n-butoxide piperidine pyridine
imidazole N- ethyldiisopropylamine dimethylaminopyridine
triethylamine trimethylamine dimethylaniline Nme
thylmorpholine 15- diaz abicydo [4.3.0] nonene - 5 (DBN) 18-
diazabicyclo[5.4.0]undecene-7 (DBU) 14-
diazabicyclo[2.2.2]octane (DABCO) and like organic bases and
mixtures thereof.
Examples of acids are organic acids such as ptoluenesulfonic
acid and like sulfonic acids and acetic acid
trifluoroacetic acid trichloroacetic acid and like aliphatic
acids inorganic acids such as hydrochloric acid sulfuric acid
hydrobromic acid and phosphoric acid and mixtures thereof.
In the present invention a basic compound and an acid
may be used in combination.
Basic compound or acid is usually used in a catalytic
amount and preferably about 0.01 to about 1 mol per mol of
Compound (2).
Compound (3) Is usually used In an amount of at least 1
mol and preferably about 1 to about 2 mol per mol of Compound
(2).
The reaction is usually carried out at about room
temperature to about 200°C and preferably about room temperature
to about 150°C. The reaction is usually finished in about 0.5 to
about 20 hours.
The reaction for producing Compound (Ib) from Compound
(la) is carried out for example either without a solvent or in
a suitable solvent in the presence of a reducing agent.
Examples of solvents usable herein are water lower
alcohols such as methanol ethanol isopropanol butanol tertbutanol
and ethylene glycol acetonitrile aliphatic acids such
as formic acid and acetic acid ethers such as diethyl ether
tetrahydrofuran dioxane monoglyme and diglyme aromatic
hydrocarbons such as benzene toluene and xylene halogenated
hydrocarbons such as dichloromethane dichloroethane chloroform
and carbon tetrachloride NN-dimethylformamide mixtures of such
solvents etc.
Examples of reducing agents are mixtures of silicon
dioxide and pyridine compounds such as diethyl l4-dihydro-26-
dimethyl-35-pyridinedicarboxylate sodium borohydride lithium
borohydride sodium cyanoborohydride sodium triacetoxy
borohydride aluminium lithium hydride and like hydride reducing
agents mixtures of such hydride reducing agents palladium black
palladium carbon platinum oxide platinum black Raney nickel
and like catalytic hydrogenation reducing agent etc.
When a mixture of a pyridine compound and silicon
dioxide is used as a reducing agent a suitable reaction
temperature is usually about room temperature to about 200°C and
preferably about room temperature to about 150°C. The reaction is
usually finished in about 0.5 to about 50 hours. The pyridine
compound is usually used in an amount of at least 1 mol and
preferably 1 to 3 mol per mol of Compound (la). Silicon dioxide
is usually used in an amount of at least 1 mol and preferably 1
-139-
to 10 mol per mol of Compound (la).
When a hydride reducing agent is used a suitable
reaction temperature is usually about -80 to about 100° C and
preferably about -80 to about 70°C. The reaction is usually
finished in about 30 minutes to about 60 hours. The hydride
reducing agent is usually used in an amount of about 0.1 to about
20 mol and preferably about 0.1 to about 6 mol per mol of
Compound (Ib). In particular when lithium aluminium hydride is
used as a hydride reducing agent it is preferable to use diethyl
ether tetrahydrofuran dioxane monoglyme diglyme and like
ethers and benzene toluene xylene and like aromatic
hydrocarbons as solvents. Cobalt(II) chloride cobalt(III)
chloride cobalt(II) acetate or like cobalt compound may be
added to the reaction system of the reaction in the presence of
pyridine trimethylamine triethylamine W-ethyldiisopropylamine
or like amine sodium hydroxide or like inorganic base and/or
dimethylglyoxime 22'-bipyridyl 110-phenanthroline or like
ligand.
When a catalytic hydrogenation reducing agent is used
the reaction is usually carried out at about -30 to about 100" C
and preferably about 0 to about 100°C in a hydrogen atmosphere
of about atmospheric pressure to about 20 atm and preferably
about atmospheric pressure to about 10 atm or in the presence of
formic acid ammonium formate cyclohexene hydrazine hydrate or
like hydrogen donor. The reaction is usually finished in about 1
to about 12 hours. The catalytic hydrogenation reducing agent is
usually used in an amount of about 0.01 to about 5 times and
preferably about 1 to about 3 times the weight of
wherein R1 R2 R4 R5 and the bond between the 3- and 4-positions
of the carbostyril skeleton are as defined above and R16 is a
lower alkyl group.
Compound (Ic) is produced by reacting Compound (4) and
Compound (5) in a suitable solvent in the presence of a basic
compound followed by acid treatment. This acid treatment is
hereinafter referred to as "Acid Treatment A".
Examples of solvents usable herein are water aromatic
hydrocarbons such as benzene toluene and xylene ethers such as
diethyl ether tetrahydrofuran dioxane 2-methoxyethanol
monoglyme and diglyme halogenated hydrocarbons such as
dichloromethane dichloroethane chloroform and carbon
tetrachloride lower alcohols such as methanol ethanol
isopropanol butanol tert-butanol and ethylene glycol aliphatic
acids such as acetic acid esters such as ethyl acetate and
methyl acetate ketones such as acetone and methyl ethyl ketone
acetonitrile pyridine dimethyl sulfoxide NW-dijnethylformamide
hexamethylphosphoric triamide mixed solvents of such solvents
etc.
Examples of basic compounds are carbonates such as
sodium carbonate potassium carbonate sodium hydrogencarbonate
-141-
potasslum hydrogencarbonate and cesium carbonate metal
hydroxides such as sodium hydroxide potassium hydroxide and
calcium hydroxide sodium hydride potassium hydride potassium
sodium sodium amide metal alcoholates such as sodium methylate
sodium ethylate and sodium n-butoxide sodium acetate piperidine
pyridine imidazole N-ethyldiisopropylamine
dimethylaminopyridine triethylamine trimethylamine
dimethylaniline W-methylmorpholine DBN DBU DABCO other
organic bases and mixtures thereof.
Basic compound is usually used in an amount of at least
about 1 mol and preferably about 1 to about 3 mol per mol of
Compound (4).
Compound (5) is usually used in an amount of at least
about 1 mol and preferably about 1 to about 2 mol per mol of
Compound (4).
The reaction is usually carried out at about room
temperature to about 200°C and preferably about room temperature
to about 150°C. The reaction is usually finished in about 0.5 to
about 10 hours.
Examples of acids usable in acid-treating the reaction
product are inorganic acids such as hydrochloric acid sulfuric
acid hydrobromic acid and the like. Such acids are usually used
in a large excess relative to the reaction product to be treated.
Examples of solvents usable in the acid treatment
include those that are usable in the reaction of Compound (4)
with Compound (5) above.
The acid treatment is usually carried out at about room
temperature to about 200°C and preferably about room temperature
to about 150"C. The acid treatment is usually finished in about
0.5 to about 30 hours.
The reaction of Compound (4) with Compound (6) is
carried out under the same conditions selected for the reaction
of Compound (4) with Compound (5).
Reaction Scheme 3
-142-
(le)
wherein R1 R2 R4 R5 X A and the bond between the 3- and 4-
positions of the carbostyril skeleton are as defined above Xi is
a halogen atom and R3a is a group other than a hydrogen atom as
defined in connection with R3 above.
The reaction of Compound (le) and Compound (7) is
carried out in a suitable inert solvent in the presence of a
basic compound.
Examples of inert solvents usable herein are aromatic
hydrocarbons such as benzene toluene and xylene ethers such as
diethyl ether tetrahydrofuran dioxane 2-methoxyethanol
monoglyme and diglyme halogenated hydrocarbons such as
dichloromethane dichloroethane chloroform and carbon
tetrachloride lower alcohols such as methanol ethanol
isopropanol butanol tert-butanol and ethylene glycol aliphatic
acids such as acetic acid esters such as ethyl acetate and
methyl acetate ketones such as acetone and methyl ethyl ketone
acetonitrile pyridine dimethyl sulfoxide NW-dimethylformamide
hexamethylphosphoric triamide mixed solvents of such solvents
etc.
Examples of basic compounds are carbonates such as
sodium carbonate potassium carbonate sodium hydrogencarbonate
potassium hydrogencarbonate and cesium carbonate metal
hydroxides such as sodium hydroxide potassium hydroxide and
calcium hydroxide sodium hydride potassium hydride potassium
sodium sodium amide metal alcoholates such as sodium methylate
sodium ethylate sodium n-butoxide sodium tert-butoxide and
potassium tert-butoxide pyridine imidazole Nethyldiisopropylamine
dimethylaminopyridine triethylamine
trimethylamine dime thy laniline N-methylmorpholine DBN DBU
DABCO other organic bases and mixtures thereof.
Basic compound is usually used in an amount of at least
1 mol and preferably 1 to 10 mol per mol of Compound (le).
Compound (7) is usually used in an amount of at least 1
mol and preferably 1 to 10 mol per mol of Compound (le).
The reaction is usually carried out at about 0 to about
200°C and preferably 0 to about 150°C. The reaction is usually
finished in about 5 minutes to about 80 hours.
Sodium iodide potassium iodide or like alkali metal
halide compound may be introduced into the reaction system of the
reaction.
When a Compound (le) in which X is sulfur is used in
the reaction of Compound (le) with Compound (7) a compound
represented by the formula:
wherein R1 R2 R4 R5 R3a A and the bond between the 3- and 4-
positions of the carbostyril skeleton are as defined above
is sometimes generated. This compound can be easily separated
from the reaction mixture.
Reaction Scheme 4
wherein R1 R2 R4 R5 A4 R15 R16 xlr and the bond between the 3-
and 4-positions of the carbostyril skeleton are as defined above
and R17 is a lower alkyl group.
The reaction to produce Compound (9) from Compound (8)
is carried out by hydrolyzing Compound (8).
This hydrolysis reaction is performed for example
either in a suitable solvent or without a solvent in the
presence of an acid or basic compound.
Examples of usable solvents are water lower alcohols
such as methanol ethanol isopropanol and tert-butanol ketones
such as acetone and methyl ethyl ketone ethers such as diethyl
ether dioxane tetrahydrofuran monoglyme and diglyme aliphatic
acids such as acetic acid and formic acid esters such as methyl
acetate and ethyl acetate halogenated hydrocarbons such as
chloroform dichloroethane dichloromethane carbon tetrachloride
dimethyl sulfoxide ArW-dimethylformamide hexamethylphosphoric
triamide mixed solvents of such solvents etc.
Examples of acids are mineral acids such as
hydrochloric acid sulfuric acid and hydrobromic acid and
organic acids such as formic acid acetic acid trifluoroacetic
-acid p-toluenesulfonic acid and like sulfonic acids. Such acids
may be used singly or as a combination of two or more such acids.
Examples of basic compounds are carbonates such as
sodium carbonate potassium carbonate sodium hydrogencarbonate
and potassium hydrogencarbonate metal hydroxides such as sodium
hydroxide potassium hydroxide calcium hydroxide and lithium
hydroxide etc. Such basic compounds may be used singly or as a
combination of two or more such compounds.
The hydrolysis reaction advantageously proceeds usually
at about 0 to about 200"C and preferably about 0 to about 150°C.
The reaction is usually finished in about 10 minutes to about 30
hours.
Compound (Ig) can be produced by reacting Compound (8)
with Compound (5) in a suitable solvent in the presence or
absence of basic compound and then acid-treating the reaction
product. Alternatively Compound (Ig) can be produced by reacting
Compound (9) with Compound (5) in a suitable solvent in the
presence or absence of basic compound and then acid-treating the
reaction product.
Examples of solvents for use in the reaction of
Compound (8) with Compound (5) and the reaction of Compound (9)
with Compound (5) include in addition to sulfolane those that
are usable in the reaction of Compound (4) with Compound (5)
shown in Reaction Scheme 2 presented above.
Examples of usable basic compounds include those that
are usable in the reaction of Compound (4) with Compound (5)
shown in Reaction Scheme 2 presented above.
Basic compound is usually used in an amount of at least
1 mol and preferably 1 to 2 mol per mol of Compound (5).
Compound (8) and Compound (9) are usually used in amounts of at
least 1 mol and preferably 1 to 5 mol per mol of Compound (5).
The reaction is usually carried out at about room
temperature to about 200°C and preferably about room temperature
to about 150" C. The reaction is usually finished in about 0.5 to
about 10 hours.
The subsequent acid treatment is carried out under the
same conditions as described with respect to "Acid Treatment A"
in Reaction Scheme 2 above.
Reaction Scheme 5
RlaXi
(10)
wherein R1 R2 R3 R4 R5 X A Xi and the bond between the 3-
and 4-positions of the carbostyril skeleton are as defined above
and Rla is a group other than a hydrogen atom as defined in
connection with R1.
The reaction of Compound (Ih) with Compound (10) is
carried out under the same conditions as described in connection
with the reaction of Compound (le) with Compound (7) shown in
Reaction Scheme 3 above.
Reaction Scheme 6
(Ik)
wherein R2 R3 R4 R5 X A R8 R9 AI and the bond between the
3- and 4-positions of the carbostyril skeleton are as defined
above.
A wide variety of reaction conditions selected for an
ordinary amide bond formation reaction are applicable to the
reaction of Compound (Ij) with Compound (11) such as in
particular (a) a mixed acid anhydride process in which
Carboxylic Acid (Ij) is reacted with an alkyl halocarboxylate to
-147-
form a mixed acid anhydride and reacting this anhydride with
Amine (11) (b) an activated ester process in which Carboxylic
Acid (Ij) is activated into an activated ester such as phenyl
ester p-nitrophenyl ester AT-hydroxysuccinimide ester 1-
hydroxybenzotriazole ester etc. or into an activated amide with
benzoxazoline-2-thione and then reacted with Amine (11) (c) a
carbodiimide process in which Carboxylic Acid (Ij) and Amine (11)
are subjected to a condensation reaction in the presence of an
activating agent such as dicyclohexylcarbodiimide l-(3-
dime thylaminopropyl) - 3 - ethylcarbodiimide (WSC)
carbonyldiimidazole or the like (d) other processes for
example in which Carboxylic Acid (Ij) is converted into a
Carboxylic anhydride using a dehydration agent such as acetic
anhydride and reacting this carboxylic anhydride with Amine
(11) an ester of Carboxylic Acid (Ij) formed with a lower
alcohol is reacted with Amine (11) at a high temperature and high
pressure an acid halide of Carboxylic Acid (Ij) i.e. a
carboxylic acid halide is reacted with Amine (11) and like
processes.
A mixed acid anhydride for use in the mixed acid
anhydride process described above can be obtained by an ordinary
Schotten-Baumann reaction and the reaction product is usually
used for the reaction with Amine (11) to give the desired
compound of Formula (Ik) without isolation from the reaction
mixture.
The above-described Schotten-Baumann reaction is
usually carried out in the presence of a basic compound.
Such basic compounds include any conventional basic
compounds for use in Schotten-Baumann reactions for example
triethylamine trimethylamine pyridine dimethylaniline. Nethyldiisopropylamine
dimethylaminopyridine AT-methylmorpholine
DBN DBU DABCO and like organic bases and carbonates such as
sodium carbonate potassium carbonate sodium hydrogencarbonate
and potassium hydrogencarbonate metal hydroxides such as sodium
hydroxide potassium hydroxide and calcium hydroxide potassium
-148-
hydride sodium hydride potassium sodium sodium amide metal
alcoholates such as sodium methylate and sodium ethylate and
like inorganic bases. Such basic compounds are used singly or as
a combination of two or more such compounds. The reaction is
usually carried out at about -20 to about 100°C and preferably
about 0 to about 50°C. The reaction time is about 5 minutes to
about 10 hours and preferably about 5 minutes to about 2 hours.
The reaction of the resulting mixed acid anhydride with
Amine (11) is usually carried out at about -20 to about 150°C
and preferably about 10 to about 50°C. The reaction time is about
5 minutes to about 10 hours and preferably about 5 minutes to
about 5 hours.
The mixed acid anhydride process is usually carried out
in a solvent. Examples of solvents are those that are commonly
used in connection with mixed acid anhydride processes. Specific
examples are chloroform dichloromethane dichloroethane carbon
tetrachloride and like halogenated hydrocarbons benzene
toluene xylene and like aromatic hydrocarbons diethyl ether
diisopropyl ether tetrahydrofuran dimethoxyethane and like
ethers methyl acetate ethyl acetate isopropyl acetate and
like esters W//-dimethylformamide dimethyl sulfoxide
hexamethylphosphoric triamide and like aprotic polar solvents
mixtures of such solvents etc.
Examples of alkyl halocarboxylates usable in the mixed
anhydride process are methyl chloroformate methyl bromoformate
ethyl chloroformate ethyl bromoformate isobutyl chloroformate
etc.
In the mixed acid anhydride process Carboxylic Acid
(lj) an alkyl halocarboxylate and Amine (11) are preferably
used equimolar to each other. However an alkyl halocarboxylate
and Amine (11) are each usable in an amount of about 1 to about
1.5 mol per mol of Carboxylic Acid (lj).
Process (c) in which a condensation reaction carried
out in the presence of an activating agent as described above is
performed in a suitable solvent either in the presence or absence
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of a basic compound. Examples of solvents and basic compounds
usable herein are those that are usable in the process in which a
carboxylic acid halide is reacted with Amine (Ib) as described in
Processes (d) below. The amount of activating agent is usually
used in an amount of at least 1 mol and preferably 1 to 5 mol
per mol of Compound (Ij). When WSC is used as an activating agent
the reaction advantageously progresses by introducing 1-
hydroxybenzotriazole into the reaction system. The reaction is
usually carried out at about -20 to 180"C and preferably about 0
to about 150°C. The reaction usually completes in about 5 minutes
to about 90 hours.
Among Processes (d) if a process in which a carboxylic
acid halide is reacted with Amine (11) is selected this reaction
is carried out in the presence of a basic compound in a suitable
solvent. Examples of basic compounds for use include a wide
variety of known compounds such as those described above in
connection with the Schotten-Baumann reaction. Examples of
solvents include in addition to those usable in the
aforementioned mixed acid anhydride process methanol ethanol
isopropanol propanol butanol 3-methoxy-1-butanol ethyl
cellosolve methyl cellosolve and like alcohols acetonitrile
pyridine acetone water etc. The ratio of carboxylic acid
halide to Amine (11) is not limited and can be suitably selected
from a broad range. It is usually such that per mol of the
former the latter is used in an amount of at least about 1 mol
and preferably about 1 to about 5 mol. The reaction is usually
carried out at about -20 to about 180°C and preferably about 0
to about 150°C. The reaction is usually finished in about 5
minutes to about 30 hours.
Moreover the amide bond formation reaction shown in
Reaction Scheme 6 can be carried out by reacting Carboxylic Acid
(Ij) and Amine (11) in the presence of a condensing agent
composed of a phosphorus compound such as triphenylphosphine
diphenylphosphinyl chloride phenyl-JV-phenylphosphoramide
chloridate diethyl chlorophosphate diethyl cyanophosphate
-150-
diphenyl azidophosphate bis(2-oxo-3-oxazolidinyl)phosphinic
chloride etc. Such condensing agents can be used singly or as a
combination of two or more such agents.
The reaction is usually carried out at about -20 to
about 150"C and preferably about 0 to about 100°C using a
solvent and basic compound that are also usable in the
aforementioned process in which a carboxylic acid halide and
Amine (11) are reacted. The reaction is usually finished in about
5 minutes to about 30 hours. Condensing agent and Amine (11) are
each used in an amount of at least about 1 mol and preferably
about 1 to about 2 mol per mol of Carboxylic Acid (lj).
Reaction Scheme 7
(11) (1m)
wherein R2 R3 R4 R5 X A and the bond between the 3- and 4-
positions of the carbostyril skeleton are as defined above Rlb is
a group as defined in (1-9) in connection with R1 above and Rlc
is a group as defined in (1-8) in connection with R1 above.
The reaction for producing Compound (1m) from Compound
(11) is carried out under conditions as described in connection
with the reaction for producing Compound (9) from Compound (8)
shown in Reaction Scheme 4 above.
The reaction for producing Compound (11) from Compound
(1m) can be carried out by reacting Compound (1m) with a compound
represented by the formula
R23OH (50)
wherein R23 is a lower alkyl group.
Conditions usually selected for esterification
reactions are applicable to the reaction. For example it may be
carried out in the presence of hydrochloric acid sulfuric acid.
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or like a mineral acid or thionyl chloride phosphorus
oxychloride phosphorus pentachloride phosphorus trichloride or
like halogenating agent. Compound (50) is used in a large excess
relative to Compound (1m). The reaction advantageously progresses
usually at about 0 to about 150" C and preferably about 50 to
about 100" C. The reaction is usually finished in about 1 to about
10 hours.
Reaction Scheme 8
do)
wherein R2 R3 R4 R5 X A A2 and the bond between the 3- and
4-positions of the carbostyril skeleton are as defined above and
R10a is a group as defined in (7-3) and (7-44) in connection with
R10 above.
The reaction for producing Compound (lo) from Compound
(In) is carried out under the same conditions as described in
connection with the reaction for producing Compound (9) from
Compound (8) shown in Reaction Scheme 4 above.
When R10a of Compound (In) is a group as defined in (7-
44) the above-presented reaction may be carried out in the
presence of a fluorine compound. Examples of fluorine compounds
are ammonium tetrafluoride tetra-N-butyl ammonium fluoride
pyridine hydrofluoride etc. Among such examples tetra-W-butyl
ammonium fluoride is preferable. Fluorine compound is usually
used in at least 1 mol and preferably 1 to 2 mol per herein R2 R3 R4 R5 X A A2 Xi and the bond between the
and 4-positions of the carbostyril skeleton are as defined above
iob is a group as defined in (7-3) to (7-7) (7-9) to (7-20) (7-
30) to (7-35) and (7-44) in connection with R110U above
10C is a group as defined in (7-2) (7-8) (7-21) to (7-29) and
(7-37) to (7-43) in connection with R110U above
R10d is a group as defined in (7-1) (7-2) (7-21) to (7-29) and
(7-40) in connection with R10 above furyl group pyridyl group
optionally substituted on the pyridine ring with one
members selected from the group consisting of halogen atoms and
lower alkyl groups each lower alkyl substituent optionally being
substituted with one or more halogen atoms thienyl group
optionally substituted on the thiophene ring with one or more
halogen atoms phenyl group optionally substituted on the phenyl
ring with one or more members selected from the group consisting
of lower alkoxy groups optionally substituted with one or more
halogen atoms a cyano group lower alkyl groups optionally
substituted with one or more halogen atoms amino groups
optionally substituted with one or more members selected from the
group consisting of lower alkyl groups and lower alkanoyl groups
halogen atoms lower alkoxycarbonyl groups lower alkanoyloxy
groups lower alkylsulfonyl groups lower alkylthio groups and
pyrrolidinyl groups thiazolyl group imidazolyl group optionally
substituted on the imidazole ring with one or more lower alkyl
groups pyrrolyl group optionally substituted on the pyrrole ring
with one or more lower alkyl groups or cycloalkyl group
R14a is a group as defined in (10-1) to (10-3) in connection with
R14 above and
R18 is a hydrogen atom or lower alkyl group
provided that the total number of carbon atoms of the group
CH(Rlod)R18 of Compound (Ir) is not greater than 6.
The reaction of Compound (lo) with Compound (12) is
carried out under the same conditions as described in connection
with the reaction of Compound (Ij) with Compound (11) shown in
Reaction Scheme 6 above provided that with respect to the
reaction of Compound (lo) with Compound (12) the amounts of
alkyl halocarboxylate Carboxylic Acid (12) activating agent
condensing agent carboxylic acid halide etc. are relative to
Compound (lo).
The reaction of Compound (lo) with Compound (13) is
carried out under the same conditions as described in connection
with the reaction of Compound (le) with Compound (7) shown in
Reaction Scheme 3 above.
The reaction of Compound (lo) with Compound (14) may be
-154-
carried out for example either in a suitable solvent or without
a solvent in the presence of a reducing agent.
Examples of solvents usable herein are water lower
alcohols such as methanol ethanol isopropanol butanol tertbutanol
and ethylene glycol acetonitrile aliphatic acids such
as formic acid and acetic acid ethers such as diethyl ether
tetrahydrofuran dioxane monoglyme and diglyme aromatic
hydrocarbons such as benzene toluene and xylene halogenated
hydrocarbons such as dichloromethane dichloroethane chloroform
carbon tetrachloride mixtures of such solvents etc.
Examples of reducing agents are aliphatic acids such as
formic acid aliphatic acid alkali metal salts such as sodium
formate and sodium acetate hydride reducing agents such as
sodium borohydride sodium cyanoborohydride sodium
triacetoxyborohydride and aluminium lithium hydride mixtures of
such hydride reducing agents catalytic hydrogenation reducing
agent such as palladium black palladium carbon platinum oxide
platinum black Raney nickel etc.
When an aliphatic acid such as formic acid or an
aliphatic acid alkali metal salt such as sodium formate or sodium
acetate is used as a reducing agent a suitable reaction
temperature is usually about room temperature to about 200" C and
preferably about 50 to about 150"C. The reaction is usually
finished in about 10 minutes to about 10 hours. Such aliphatic
acids and aliphatic acid alkali metal salts are usually used in a
large excess relative to Compound (lo).
When a hydride reducing agent is used a suitable
reaction temperature is usually about -80 to about 100°C and
preferably about -80 to about 70°C. The reaction is usually
finished in about 30 minutes to about 60 hours. The hydride
reducing agent is usually used in an amount of about 1 to about
20 mol and preferably about 1 to about 6 mol per mol of
Compound (lo). In particular when aluminium lithium hydride is
used as a hydride reducing agent it is preferable to use diethyl
ether tetrahydrofuran dioxane monoglyme diglyme or like
-155-
ether or benzene toluene xylene or like aromatic hydrocarbon
as a solvent. Trimethylamine triethylamine Nethyldiisopropylamine
or like amine or molcular sieves 3A (MS-
3A) molcular sieves 4A (MS-4A) or like molcular sieves may be
introduced into the reaction system of the reaction.
When a catalytic hydrogenation reducing agent is used
the reaction is usually carried out at about -30 to about 100°C
and preferably about 0 to about 60°C in a hydrogen atmosphere
usually of about atmospheric pressure to about 20 atm and
preferably about atmospheric pressure to about 10 atm or in the
presence of formic acid ammonium formate cyclohexene hydrazine
hydrate or like hydrogen donor. The reaction is usually finished
in about 1 to about 12 hours. The catalytic hydrogenation
reducing agent is usually used in an amount of about 0.1 to about
40 wt.% and preferably about 1 to about 20 wt.% relative to
Compound (lo).
In the reaction of Compound (lo) with Compound (14)
Compound (14) is usually used in an amount at least eguimolar
and preferably equimolar to a large excess relative to Compound
do).
The reaction of Compound (lo) with Compound (15) is
carried out in the presence or absence of basic compound but
preferably in the absence of basic compound in a suitable inert
solvent or without a solvent.
Examples of inert solvents and basic compounds include
those that are for use in one of the Processes (d) in which a
carboxylic acid halide is reacted with Amine (11) for the
reaction of Compound (lo) with Compound (12) (amide bond
formation reaction).
The amount of Compound (15) is usually about 1 to about
5 mol and preferably about 1 to about 3 mol per mol of Compound
do).
The reaction advantageously proceeds usually at about 0
to about 200°C and preferably about room temperature to about
150°C. The reaction is usually finished in about 5 minutes to
about 30 hours.
Boron trifluoride diethyl ether complex or like boron
compound may be introduced into the reaction system
wherein R2 R3 R4 R5 X A A2 Xi R14a and the bond between the
3- and 4-positions of the carbostyril skeleton are as defined
above and R14b is a group as defined in (10-2) and (10-3) in
connection with R14 above.
The reaction of Compound (Is) with Compound (16) is
carried out under the same conditions as described in connection
with the reaction of Compound (le) with Compound (7) shown in
Reaction Scheme 3 above.
Reaction Scheme 11
wherein R2 R3 R4 R5 X A and the bond between the 3- and 4-
positions of the carbostyril skeleton are as defined above Rld is
a group as defined in (1-3) in connection with R1 above except for
having at least one lower alkoxycarbonyl group on the phenyl
ring and Rle is a group as defined in (1-3) in connection with R1
above except for having at least one carboxy group on the phenyl
ring.
The reaction for producing Compound (Iv) from Compound
(lu) is carried out under the same conditions as described in
connection with the reaction for producing Compound (9) from
Compound (8) shown in Reaction Scheme 4 above.
The reaction for producing Compound (lu) from Compound
(Iv) is carried out under the same conditions as described in
connection with the reaction for producing Compound (11) from
Compound (1m) shown in Reaction Scheme 7 above.
Reaction Scheme 12
. R3 R4 R5 X A R6 R7 Rle and the bond between the
3- and 4-positions of the carbostyril skeleton are as defined
above and Rlf is a group as defined in (1-3) in connection with
R1 above except for having at least one -CONR6R7 group on the
phenyl ring.
-158-
The reaction of Compound (Iv) with Compound (17) is
carried out under the same conditions as described in connection
with the reaction of Compound (Ij) with Compound (11) shown in
Reaction Scheme 6 above.
Reaction Scheme 13
(laa)
wherein R2 R3 R4 R5 X A Xlf R18 and the bond between the 3-
and 4-positions of the carbostyril skeleton are as defined above
Rlg is a group as defined in (1-3) in connection with R1 above
except for having at least one -(BhNHR7a group on the phenyl ring
provided that 1 is as defined above
R111 is a group as defined in (1-3) in connection with R1 above
except for having at least one -(B)iN(R6a)R7a group on the phenyl
ring
R11 is a group as defined in (1-3) in connection with R1 above
except for having at least one -(B)iN(R6b)R7a group on the phenyl
ring
R13 is a group as defined in (1-3) in connection with R1 above
except for having at least one -(BhN[CH(R6c)R18]R7a group on the
-159-
phenyl ring provided that the total number of carbon atoms of
CH(R6c)R18 is no greater than 6
1 is as defined above
R7a is a group as defined in (4-1) to (4-79) in connection with R7
above
R6a is a group as defined in (4-2) (4-4) (4-6) (4-8) to (4-11)
(4-19) to (4-32) (4-34) to (4-37) (4-60) (4-62) to (4-72) (4-
78) and (4-79) in connection with R6 above
R6b is a group as defined in (4-3) (4-5) (4-7) (4-12) to (4-18)
(4-33) (4-38) to (4-59) (4-61) (4-73) to (4-77) in connection
with R6 above and
R6c is a group as defined in (4-1) (4-2) (4-6) (4-9) (4-20)
(4-21) (4-23) to (4-29) (4-31) (4-32) and (4-34) pyridyl
group tetrahydropyranyl group cycloalkyl group phenyl group
optionally substituted on the phenyl ring with one or more
members selected from the group consisting of halogen atoms
lower alkyl groups optionally substituted with one or more
halogen atoms lower alkoxy groups optionally substituted with
one or more halogen atoms and hydroxy groups lower
alkylenedioxy-substituted phenyl group furyl group imidazolyl
group optionally substituted on the imidazole ring with one or
more members selected from the group consisting of a carbamoyl
group and lower alkoxycarbonyl groups pyrrolidinyl group
optionally substituted on the pyrrolidine ring with one or more
lower alkyl groups or morpholino group.
The reaction of Compound (Ix) with Compound (18) is
carried out under the same conditions as described in connection
with the reaction of Compound (lo) with Compound (12) shown in
Reaction Scheme 9 above.
The reaction of Compound (Ix) with Compound (19) is
carried out under the same conditions as described in connection
with the reaction of Compound (lo) with Compound (13) shown in
Reaction Scheme 9 above.
The reaction of Compound (Ix) with Compound (20) is
carried out under the same conditions as described in connection
-160-
with the reaction of Compound (lo) with Compound (14) shown in
Reaction Scheme 9 above.
Reaction Scheme 14
(Ibb) (Ice)
wherein R2 R3 R4 R5 X A and the bond between the 3- and 4-
positions of the carbostyril skeleton are as defined above R1 is
a group as defined in (1-3) in connection with R1 above except for
having at least one nitro group on the phenyl ring and R11 is a
group as defined in (1-3) in connection with R1 above except for
having at least one amino group on the phenyl ring.
The reaction for producing Compound (Ice) from Compound
(Ibb) can be carried out by for example (1) reducing Compound
(Ibb) in a suitable solvent using a catalytic hydrogenation
reducing agent or (2) reducing Compound (Ibb) in a suitable
inert solvent using as a reducing agent a mixture of an acid with
a metal or metal salt a mixture of a metal or metal salt with an
alkali metal hydroxide sulfide or ammonium salt or the like.
When using Method (1) above examples of usable
solvents are water acetic acid alcohols such as methanol
ethanol and isopropanol hydrocarbons such as n-hexane and
cyclohexane ethers such as dioxane tetrahydrofuran diethyl
ether and diethylene glycol dimethyl ether esters such as ethyl
acetate and methyl acetate aprotic polar solvents such as NNdimethylformamide
mixtures of such solvents etc. Examples of
usable catalytic hydrogenation reducing agent include palladium
palladium black palladium carbon platinum carbon platinum
platinum oxide copper chromite Raney nickel etc. Such reducing
agent may be used singly or as a combination of two or more such
agents. Reducing agent is usually used in an amount of about 0.02
-161-
times to equal to the weight of Compound (Ibb). The reaction
temperature is usually about -20 to about 150"C and preferably
about 0 to about 100°C. The hydrogen pressure is usually about 1
to 10 atm. The reaction is usually finished in about 0.5 to about
100 hours. An acid such as hydrochloric acid may be introduced
into the reaction system of the reaction.
When using Method (2) above a mixture of iron zinc
tin or tin(II) chloride with a mineral acid such as
hydrochloric acid or sulfuric acid or a mixture of iron
iron(II) sulfate zinc or tin with an alkali metal hydroxide
such as sodium hydroxide a sulfide such as ammonium sulfide
aqueous ammonia or an ammonium salt such as ammonium chloride
or the like can be used as a reducing agent. Examples of inert
solvents are water acetic acid alcohols such as methanol and
ethanol ethers such as dioxane mixtures of such solvents etc.
Conditions for the reduction reaction can be suitably selected
according to the reducing agent to be used. For example when a
mixture of tin(II) chloride and hydrochloric acid is used as a
reducing agent it is advantageous to carry out the reaction at
about 0 to about 150° C for about 0.5 to about 10 hours. Reducing
agent is used in an amount of at least 1 mol and usually about 1
to 5 mol per mol of Compound (Ibb).
Reaction Scheme 15
wherein R2 R3 R4 R5 X A and the bond between the 3- and 4-
positions of the carbostyril skeleton are as defined above
R1" is a group as defined in (1-10) in connection with R1 above
except for having at least one halogen atom on the pyridine ring
R1" is a group as defined in (1-10) in connection with R1 above
except for having on the pyridine ring at least one member
selected from piperidinyl groups morpholino group piperazinyl
group optionally substituted on the piperazine ring with one or
more members selected from the group consisting of a phenyl group
and lower alkyl groups anilino group optionally substituted on
the amino group with one or more lower alkyl groups pyridylamino
group or pyridylcarbonylamino group
R10 is a group as defined in (1-10) in connection with R1 above
except for having at least one member selected from thienyl
groups a phenyl group pyridyl groups and a biphenyl group
R19 is a piperidinyl group morpholino group piperazinyl group
optionally substituted on the piperazine ring with one or more
members selected from the group consisting of a phenyl group and
lower alkyl groups anilino group optionally substituted on the
amino group with one or more lower alkyl groups pyridylamino
group or pyridylcarbonylamino group
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R20 is a thienyl group phenyl group pyridyl group or biphenyl
group
M is an alkali metal such as lithium potassium sodium or the
like -MgXi (Xi is as defined above) -ZnXi (Xi is as defined
above) or -B(OH)2
Y is a lower alkyl group
q is 1 to 4 and
r is 1 to 3 provided that q + r equals 4.
The reaction of Compound (Idd) with Compound (21) is
carried out in a suitable solvent in the presence of a basic
compound and a catalyst.
Examples of solvents and basic compounds usable herein
include those that are usable in the reaction of Compound (le)
with Compound (7) shown in Reaction Scheme 3 above.
Examples of catalysts are
bis(tributyltin)/bis(dibenzylideneacetone)palladium Rtris(
dibenzylideneacetone)dipalladium Stris(
dibenzylideneacetone)dipalladium palladium(II) acetate and
like palladium compounds R-22'-bis(diphenylphosphino
binaphthyl (K-BINAP) S-22'-bis(diphenylphosphino)-
binaphthyl (S-BINAP) RAC-22'-bis(diphenylphosphino
binaphthyl (JZAC-BINAP) 22-bis(diphenylimidazolidinylidene) and
like compounds 45-bis(diphenylphosphino)-99-dimethylxanthene
and like xanthene compounds tert-butylphosphine tertbutylphosphine
tetrafluoroborate and like alkylphosphines salts
thereof mixtures thereof etc.
Basic compound is usually used in an amount of at least
1 mol and preferably 1 to 2 mol per mol of Compound (Idd).
Catalyst is used in a typical catalytic amount relative
to Compound (Idd).
Compound (21) is usually used in an amount of at least
1 mol and preferably 1 to 2 mol per mol of Compound (Idd).
The reaction is usually carried out at about room
temperature to about 200" C and preferably about room temperature
to about 150°C. The reaction is usually finished in about 0.5 to
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about 20 hours.
The reaction of Compound (Idd) with Compound (22a) or
(22b) is carried out in a suitable solvent in the presence of a
basic compound and a catalyst.
Solvents usable herein include in addition to water
those that are usable in the reaction of Compound (le) with
Compound (7) shown in Reaction Scheme 3 above.
Basic compounds usable herein include those that are
usable in the reaction of Compound (le) with Compound (7) shown
in Reaction Scheme 3 above.
Examples of catalysts are
tetrakis(triphenylphosphine)palladium(0)
dichlorobis(triphenylphosphine)palladium(II) and like palladium
compounds.
Basic compound is usually used in an amount of at least
1 mol and preferably 1 to 5 mol per mol of Compound (Idd).
Catalyst is usually used in an amount of 0.001 to 1 mol
per mol of Compound (Idd) and preferably 0.01 to 0.5 mol per
mol of Compound (Idd).
Compound (21) is usually used in an amount of at least
1 mol and preferably 1 to 5 mol per mol of Compound (Idd).
The reaction is usually carried out at about -30 to
about 200'C and preferably about 0 to about 150°C. The reaction
is usually finished in about 0.5 to about 20 hours.
With respect to the reaction when M is an alkali metal
salt or MgXi the reaction proceeds in the absence of basic
wherein R1 R3 R4 R5 X A Xi and the bond between the 3- and
4-positions of the carbostyril skeleton are as defined above
R2a is a group as defined in (2-2) (2-4) (2-5) and (2-7) to (2-
32) in connection with R2 above and
R21 is a lower alkyl group carboxy lower alkyl group lower
alkoxycarbonyl lower alkyl phenyl lower alkyl group optionally
substituted on the phenyl ring with one or more members selected
from the group consisting of halogen atoms lower alkyl groups
optionally substituted with one or more halogen atoms lower
alkylthio groups optionally substituted with one or more halogen
atoms lower alkoxy groups a nitro group lower alkylsulfonyl
groups lower alkoxycarbonyl groups phenyl lower alkenyl groups
lower alkanoyloxy groups and 123-thiodiazolyl groups
piperidinyl lower alkyl group optionally substituted on the
piperidine ring with one or more lower alkyl groups atninosubstituted
lower alkyl group optionally substituted with one or
more lower alkyl groups lower alkenyl group pyridyl lower alkyl
group optionally substituted on the pyridine ring with one or
more lower alkyl groups each lower alkyl substituent optionally
being substituted with one or more halogen atoms lower alkynyl
group phenyl lower alkynyl group phenyl lower alkenyl group
furyl lower alkyl group optionally substituted on the furan ring
with one or more lower alkoxycarbonyl groups tetrazolyl lower
alkyl group optionally substituted on the tetrazole ring with a
substituent selected from the group consisting of a phenyl group
phenyl lower alkyl groups and cycloalkyl lower alkyl groups
124-oxadiazolyl lower alkyl group optionally substituted on the
124-oxadiazole ring with a phenyl group the phenyl substituent
optionally being substituted on the phenyl ring with one or more
lower alkyl groups isooxazolyl lower alkyl group optionally
substituted on the isoxazole ring with one or more lower alkyl
groups 134-oxadiazolyl lower alkyl group optionally
substituted on the 134-oxadiazole ring with a phenyl group the
phenyl substituent optionally being substituted on the phenyl
ring with one or more lower alkyl groups lower alkanoyl lower
alkyl group thiazolyl lower alkyl group optionally substituted
on the thiazole ring with one or more members selected from the
group consisting of lower alkyl groups and phenyl groups each
phenyl substituent optionally being substituted on the phenyl
ring with one or more halogen atoms piperidinyl group optionally
substituted on the piperidine ring with one or more benzoyl
groups each benzoyl substituent optionally being substituted on
the phenyl ring with one or more halogen atoms thienyl lower
alkyl group phenylthio lower alkyl group carbamoyl-substituted
lower alkyl group optionally substituted with one or more lower
alkyl groups benzoyl lower alkyl group pyridylcarbonyl lower
alkyl group imidazolyl lower alkyl group optionally substituted
on the imidazole ring with one or more phenyl lower alkyl groups
phenoxy lower alkyl group phenyl lower alkoxy-substituted lower
alkyl group 23-dihydro-1H-indeny 1 group or isoindolinyl lower
alkyl group optionally substituted on the isoindoline ring with
one or more oxo groups.
The reaction of Compound (Igg) with Compound (23) is
carried out under the same conditions as described in connection
with the reaction of Compound (le) with Compound (7) shown in
Reaction Scheme 3 above.
Compounds (2) (4) and (8) used as starting materials
as shown in the reaction scheme given above can be produced
according to for example the reaction scheme below.
Reaction Scheme 17
positions of the carbostyril skeleton are as defined above R22 is
a lower alkylsulfonyl group optionally having at least one
halogen atom X2 is a halogen atom and m is 1 to 4.
The reaction of Compound (24) with Compound (25) or
(26) and the reaction of Compound (30) with Compound (25) or (26)
can be carried out under the same conditions as described in one
of the Processes (d) in which an acid halide of Carboxylic Acid
(Ij) i.e. a carboxylic acid halide is reacted with Amine (11)
for the reaction of Compound (Ij) with Compound (11) shown in
Reaction Scheme 6 above.
The reaction for producing Compound (28) from Compound
(27) and the reaction for producing Compound (32) from Compound
(31) can be achieved by reacting Compound (27) with a metal
cyanide and Compound (31) with a metal cyanide respectively in
a suitable solvent in the presence of a catalyst.
Examples of metal cyanides are sodium cyanide
potassium cyanide silver cyanide zinc cyanide cuprous cyanide
etc.
Examples of solvents and catalysts usable in these
reactions include those that are usable in the reaction of
Compound (Idd) with Compound (22) shown in Reaction Scheme 15
above.
Catalyst is usually used in an amount of 0.01 to I mol
and preferably 0.01 to 0.5 mol per mol of Compound (27) or (31).
Metal cyanide is usually used in an amount of at least
1 mol and preferably 1 to 3 mol per mol of Compound (27) or
(31).
The reactions are usually carried out at about room
temperature to 200°C and preferably about room temperature to
about 150 C. The reactions are usually finished in about 1 hour
to about 1 week.
The reaction for producing Compound (2a) from Compound
(28) and the reaction for producing Compound (2b) from Compound
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(32) are carried out in a suitable solvent in the presence of a
reducing agent.
Examples of solvents usable herein are formic acid and
like aliphatic acids dioxane tetrahydrofuran diethyl ether
diethylene glycol dimethyl ether and like ethers benzene
toluene xylene and like aromatic hydrocarbons dichloromethane
dichloroethane chloroform carbon tetrachloride and like
halogenated hydrocarbons and mixtures of such solvents.
Examples of reducing agents are diisobutylaluminum
hydride and like alkylaluminum hydrides Raney nickel etc.
Reducing agent is usually used in an amount at least equal to
and preferably equal to to 5 times the weight of Compound (28)
or (32).
The reactions are usually carried out at about room
temperature to 200° C and preferably about room temperature to
about 150° C. The reactions are usually finished in about 0.5 to
about 20 hours.
Compounds (2a) and (2b) can be produced by reducing
compounds (28) and (32) respectively under the same conditions
as described in connection with the reaction as shown in
Reaction scheme 1 for producing Compound (Ib) from Compound (la)
when a catalytic hydrogenation reducing agent is used. It is
desirable to introduce an inorganic acid such as hydrochloric
acid or sulfuric acid into the reaction system usually in an
amount of at least 1 mol and preferably 1 to 2 mol per mol of
compounds (28) or (32).
The reaction for producing Compound (29) from Compound
(2a) and the reaction for producing Compound (33) from Compound
(2b) are carried out in a suitable solvent in the presence of an
acid by separately reacting Compound (2a) and Compound (2b) with
an alcohol compound represented by
HO-(CH2)ra-OH (51)
wherein m is as defined above.
Solvents and acids usable herein include those that are
usable in the reaction of Compound (2) with Compound (3) shown in
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Reactlon Scheme 1 above.
It is usually advantageous to use an acid in a
catalytic amount. The amount of Compound (51) is usually at least
1 mol and preferably 1 to 5 mol per mol of Compound (2a) or
(2b).
The reactions are usually carried out at about room
temperature to 200°C and preferably about room temperature to
about 150"C. The reactions are usually finished in about 0.5
hours to about 10 hours.
The reaction of Compound (24) with Compound (10) the
reaction of Compound (27) with Compound (10) the reaction of
Compound (28) with Compound (10) the reaction of Compound (2a)
with Compound (10) and the reaction of Compound (29) with
Compound (10) are carried out under the same conditions as
described in connection with the reaction of Compound (le) with
Compound (7) shown in Reaction scheme 3.
The reaction for producing Compound (2a) from Compound
(29) and the reaction for producing Compound (2b) from Compound
(33) are carried out under the same conditions as described in
connection with the reaction for producing Compound (9) from
Compound (8) shown in Reaction scheme 4. In these reactions
pyridinium p-toluenesulfonate and like sulfonates are
wherein Rla R2 R4 R5 R15 XL and the bond between the 3- and 4-
positions of the carbostyril skeleton are as defined above.
The reaction for producing from Compound (34)
Compound (2c) wherein R15 is a hydrogen atom and the reaction for
producing from Compound (35) Compound (2d) wherein R15 is a
hydrogen atom are carried out in a suitable solvent in the
presence of a catalyst by separately reacting Compound (34) and
Compound (35) with a compound represented by
Xi(X2)CHOR24 (52)
wherein Xi and X2 are as defined above and R24 is a lower alkyl
group.
Solvents usable herein include those that are usable in
the reaction of Compound (Idd) with Compound (22) shown in
Reaction Scheme 15 above.
Examples of catalysts are titanium tetrachloride and
like titanium compounds tin(IV) chloride and like tin compounds
aluminium chloride and like aluminium compounds etc. Catalyst is
usually used in an amount of at least 1 mol and preferably 1 to
5 mol per mol of Compound (34) or (35).
Compound
(52) is usually used in an amount of at least 1 mol and
preferably 1 to 5 mol per mol of Compound (34) or (35).
The reaction is usually carried out at about 0 to about
70" C and preferably about 0 to about 50'C. The reaction is
usually finished in about 1 minute to about 1 hour.
The reaction for producing from Compound (34)
Compound (2c) wherein R15 is a hydrogen atom and the reaction for
producing from Compound (35) Compound (2d) wherein R15 is a
hydrogen atom can be carried out in the presence of a
halogenating agent and an acid by separately reacting Compound
(34) and Compound (35) with p-formaldehyde and then
hexamethylenetetramine.
Examples of halogenating agents usable herein are
hydrochloric acid hydrobromic acid etc. Examples of acids are
sulfuric acid phosphoric acid and like inorganic acids ptoluenesulfonic
acid formic acid acetic acid and like organic
acids and mixtures of such acids. Halogenating agent and acid
are usually used in large excess.
p-Formaldehyde is usually used in an amount at least
0.1 times and preferably 0.1 times to equal to. Compound (34) or
(35).
Hexamethylenetetramine is usually used in an amount of
at least 1 mol and preferably 1 to 5 mol per mol of compound
(34) or (35).
The reaction is usually carried out at about room
temperature to about 1508C and preferably about room temperature
to about 100°C. The reaction is usually finished in about 0.5 to
about 10 hours.
The reaction for producing from Compound (34)
Compound (2c) wherein R15 is a hydrogen atom and the reaction for
producing from Compound (35) Compound (2d) wherein R15 is a
hydrogen atom can be carried out in a suitable solvent in the
presence of an acid by separately reacting Compound (34) and
Compound (35) with hexamethylenetetramine.
These reactions are generally called Duff reactions.
Acids usable herein are those that are preferably used in Duff
reactions for example acetic acid boric acid/anhydrous
glycerol trifluoroacetic acid etc. Acid is usually used in an
amount at least equimolar and preferably equimolar to a large
excess per mol of Compound (34) or (35).
Solvents usable herein include those that are usable in
the reaction of Compound (Idd) with Compound (22) shown in
Reaction Scheme 15 above.
The reactions are usually carried out at about room
temperature to about 200°C and preferably about room temperature
to about 150° C. The reactions are usually finished in about 0.5
to about 10 hours.
Compound (2c) wherein R15 is a lower alkyl group and
Compound (2d) wherein R15 is a lower alkyl group are produced by
separately reacting in a suitable solvent in the presence of an
acid reacting Compound (34) and Compound (35) with a compound
represented by
XiCOR15a (53)
wherein Xi is as described above and R1Sa is a lower alkyl group.
These reactions are generally called Friedel-Crafts
reactions and performed in a suitable solvent in the presence of
a Lewis acid.
Lewis acids usable herein include any Lewis acids
typically used in such Friedel-Crafts reactions and examples are
aluminium chloride zinc chloride iron chloride tin(IV)
chloride boron tribromide boron trifluoride concentrated
sulfuric acid etc.
Examples of usable solvents are carbon disulfide
nitrobenzene chlorobenzene and like aromatic hydrocarbons
dichloromethane dichloroethane carbon tetrachloride
tetrachloroethane and like halogenated hydrocarbons nitroethane
nitromethane and like aliphatic nitro compounds mixed solvents
of such solvents etc.
Lewis acid is usually used in an amount of 1 to 6 mol
per mol of compounds (34) or (35).
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Compound (53) is usually used in an amount of at least
1 mol and preferably 1 to 5 mol per mol of Compound (34) or
(35).
The reactions are usually carried out at about 0 to
about 150°C and preferably about 0 to about 100°C. The reactions
are usually finished in about 0.5 to about 25 hours.
The reaction of Compound (34) with Compound (10) and
the reaction of Compound (2c) with Compound (10) are carried out
under the same conditions as described in connection with the
reaction of Compound (le) with Compound (7) shown in
wherein Rla R2 R4 R5 Xi X2 and the bond between the 3- and 4-
positions of the carbostyril skeleton are as defined above.
The reaction for producing Compound (2e) from Compound
(36) and the reaction for producing Compound (2f) from Compound
(37) are carried out by reacting Compound (36) with carbon
monoxide gas and Compound (37) with carbon monoxide gas
respectively in a suitable solvent in the presence of a catalyst
and an acid alkali metal salt.
Examples of solvents and catalysts usable in these
reactions include those that are usable in the reaction of
Compound (Idd) with Compound (22) shown in Reaction Scheme 15
above.
Examples of acid alkali metal salts are sodium formate
potassium formate sodium acetate potassium acetate etc. Acid
alkali metal salt is usually used in an amount of at least 1 mol
and preferably 1 to 5 mol per mol of Compound (36) or (37).
Catalyst is usually used in an amount of 0.01 to 1 mol
per mol of Compound (36) or (37).
Carbon monoxide gas is usually used in a large excess
relative to Compound (36) or (37).
The reactions are usually carried out at about room
temperature to about 200°C and preferably about room temperature
to about 150°C. The reactions are usually finished in about 0.5
to about 10 hours.
The reaction of Compound (36) with Compound (10) and
the reaction of Compound (2e) with Compound (10) are carried out
under the same conditions as described in connection with the
reaction of Compound (le) with Compound (7) shown in.
wherein R1 R2 R4 R5 XL R16 X2 and the bond between the 3- and
4-positions of the carbostyril skeleton are as defined above.
The reaction of Compound (38) with Compound (39) is
carried out under the same conditions as described in connection
with the reaction of Compound (34) with Compound (53) shown in
Reaction Scheme 18 above.
The reaction for producing Compound (41) from Compound
(40) is carried out by reducing Compound (40) under the same
conditions as described in connection with the reaction for
producing Compound (Ib) from Compound (la) using a hydride
reducing agent shown in Reaction Scheme 1 above.
The reaction for producing Compound (4a) from Compound
(41) is carried out by reacting Compound (41) with a halogenating
agent either in a suitable solvent or without a solvent.
Examples of halogenating agents are hydrochloric acid
hydrobromic acid and like mineral acids N/V-diethyl-l22-
trichlorovinylazide phosphorus pentachloride phosphorus
pentabrond.de phosphorus oxychloride thionyl chloride and
mixtures of sulfonyl halide compounds (mesyl chloride tosyl
chloride and the like) with basic compounds etc.
Basic compounds usable herein are those that are usable
in the reaction of Compound (2) with Compound (3) shown in
Reaction Scheme 1 above.
Examples of usable solvents are dioxane
tetrahydrofuran diethyl ether and like ethers chloroform
methylene chloride carbon tetrachloride and like halogenated
hydrocarbons etc.
When a mixture of sulfonyl halide compound and basic
compound is used as a halogenating agent sulfonyl halide
compound is usually used in an amount of at least 1 mol and
preferably 1 to 2 mol per mol of Compound (41). Basic compound
is usually used in a catalytic amount and preferably a catalytic
to equimolar amount relative to Compound (41). When other
halogenating agents are used the halogenating agent is usually
used in an amount of at least 1 mol and preferably 1 to 10 mol
per mol of Compound (41).
The reaction advantageously proceeds usually at room
temperature to 150°C and preferably room temperature to 100°C.
The reaction is usually finished in about 1 to about
wherein RI R2 R4 R5 Xi R15 R16 R17 A4 and the bond between
the 3- and 4-positions of the carbostyril skeleton are as defined
above.
The reaction of Compound (42) with Compound (46) is
carried out under the same conditions as described in connection
with the reaction of Compound (le) with Compound (7) shown in
Reaction Scheme 3 above.
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The reaction for producing Compound (8) from Compound
(43) is carried out in a suitable solvent in the presence of a
halogenating agent either in the presence or absence of a basic
compound.
Examples of halogenating agents usable herein are Br2
C12 and like halogen molecules iodine chloride sulfuryl
chloride copper compounds such as copper(I) bromide Nbromosuccinimide
and like W-halosuccinimides etc.
Examples of usable solvents are diethyl ether
tetrahydrofuran dioxane 2-methoxyethanol monoglyme diglyme
and like ethers dichloromethane dichloroethane chloroform
carbon tetrachloride and like halogenated hydrocarbons acetic
acid propionic acid and like aliphatic acids carbon disulfide
etc.
Examples of basic compounds include those that are
usable in the reaction of Compound (2) with Compound (3) shown in
Reaction Scheme 1 presented above.
Halogenating agent is usually used in an amount of 1 to
10 mol and preferably 1 to 5 mol per mol of Compound (43).
Basic compound is usually used in an amount of 1 to 10
mol and preferably 1 to 5 mol per mol of Compound (43).
The reaction is usually carried out at about 0 to about
200°C and preferably about 0 to about 100°C. The reaction is
usually finished in about 5 minutes to about 20 hours.
The reaction of Compound (44) with Compound (46) is
carried out in a suitable solvent in the presence of a basic
compound.
Examples of basic compounds usable herein are sodium
hydroxide potassium hydroxide calcium hydroxide sodium
carbonate potassium carbonate and like inorganic basic
compounds sodium acetate and like aliphatic acid alkali metal
salts piperidine triethylamine trimethylamine pyridine
dimethylaniline N-ethyldiisopropylamine dimethylaminopyridine
W-methylmorpholine DBN DBU DABCO and like organic bases etc.
Such basic compounds may be used singly or as a combination of
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two or more such compounds.
Any inert solvents are usable insofar as they do not
adversely affect the reaction for example water aromatic
hydrocarbons such as benzene toluene and xylene ethers such as
diethyl ether tetrahydrofuran dioxane monoglyme and diglyme
halogenated hydrocarbons such as dichloromethane dichloroethane
chloroform and carbon tetrachloride lower alcohols such as
methanol ethanol isopropanol butanol tert-butanol and
ethylene glycol aliphatic acids such as acetic acid esters such
as ethyl acetate and methyl acetate ketones such as acetone and
methyl ethyl ketone acetonitrile pyridine dimethyl sulfoxide
NW-dimethylformamide hexamethylphosphoric triamide mixtures of
such solvents etc.
Basic compound is usually used in an amount of about
0.1 to about 5 mol per mol of Compound (45).
Compound (46) is usually used in an amount of at least
1 mol and preferably about 1 to about 5 mol per mol of Compound
(45).
The reaction temperature is usually about room
temperature to about 200°C and preferably about 50 to about
150" C. The reaction is usually finished in about 5 minutes to
about 30 hours.
The reaction for producing Compound (43) from Compound
(46) is carried out by reducing Compound (46) under the same
conditions as described in connection with the reaction for
producing Compound (Ib) from Compound (la) shown in Reaction
Scheme 1 in which a catalytic hydrogenation reducing agent is
used.
Reaction Scheme 22
wherein R1"1. R1" R10 R2 R4 R5 M m and the bond between the 3-
and 4-positions of the carbostyril skeleton are as defined above.
The reaction of Compound (47) with Compound (21) is
carried out under the same conditions as described in connection
with the reaction of Compound (Idd) with Compound (21) shown in
Reaction Scheme 15 above.
The reaction of Compound (47) with Compound (22) is
carried out under the same conditions as described in connection
with the reaction of Compound (Idd) with Compound (21) shown in
Reaction Scheme 15 above.
By reacting Compound (23) with starting Compounds (24)
(34) (36) (38) (42) and (47) in which R2 is a hydroxyl group
the corresponding compounds in which R2 is a group as defined in
(2-2) (2-4) (2-5) and (2-7) to (2-32) can be produced. These
reactions are carried out under the same conditions as described
in connection with the reaction of Compound (Igg) with Compound
(23) shown in Reaction Scheme 16 above.
By reacting Compound (10) with starting Compounds (38)
and (42) in which R1 is a hydrogen atom the corresponding
compounds in which R1 is a group as defined in (1-2) to (1-29) can
be produced. These reactions are carried out under the same
-181-
conditions as described in connection with the reaction of
Compound (Ih) with Compound (10) shown in Reaction Scheme 5 above.
Each of the objective compounds obtained according to
the above reaction schemes can be isolated and purified from the
reaction mixture by for example after cooling the reaction
mixture performing an isolation procedure such as filtration
concentration extraction etc. to separate a crude reaction
product and then subjecting the crude reaction product to a
usual purification procedure such as column chromatography
recrystallization etc.
The carbostyril compound of Formula (1) according to
the present invention includes stereoisomers and optical isomers
and solvents such as hydrate etc.
Among the compounds of the present invention those
having a basic group or groups can easily form salts with common
pharmaceutically acceptable acids. Examples of such acids include
hydrochloric acid hydrobromic acid nitric acid sulfuric acid
phosphoric acid and other inorganic acid methansulfonic acid ptoluenesulfonic
acid acetic acid citric acid tartric acid
maleic acid fumaric acid malic acid lactic acid and other
organic acid etc.
Among the compounds of the present invention those
having an acidic group or groups can easily form salts by
reacting with pharmaceutically acceptable basic compounds.
Examples of such basic compounds include sodium hydroxide
potassium hydroxide calcium hydroxide sodium carbonate
potassium carbonate sodium hydrogencarbonate potassium
hydrogencarbonate etc.
The following is an explanation of pharmaceutical
preparations comprising the compound of the present invention as
an active ingredient.
Such pharmaceutical preparations are obtained by
formulating the compound of the present invention into usual
pharmaceutical preparations using usually employed diluents or
-182-
excipients such as fillers extenders binders wetting agents
disintegrants surfactants lubricants etc.
The form of such pharmaceutical preparations can be
selected from various forms according to the purpose of therapy.
Typical examples include tablets pills powders solutions
suspensions emulsions granules capsules suppositories
injections (solutions suspensions etc.) and the like.
To form tablets any of various known carriers can be
used including for example lactose white sugar sodium
chloride glucose urea starch calcium carbonate kaolin
crystalline cellulose and other excipients water ethanol
propanol simple syrup glucose solutions starch solutions
gelatin solutions carboxymethylcellulose shellac
methylcellulose potassium phosphate polyvinylpyrrolidone and
other binders dry starch sodium alginate agar powder
laminaran powder sodium hydrogencarbonate calcium carbonate
fatty acid esters of polyoxyethylenesorbitan sodium
laurylsulfate stearic acid monoglyceride starch lactose and
other disintegrants white sugar stearin cacao butter
hydrogenated oils and other disintegration inhibitors quaternary
ammonium base sodium lauryl sulfate and other absorption
promoters glycerin starch and other wetting agents starch
lactose kaolin bentonite colloidal silicic acid and other
adsorbents purified talc stearates boric acid powder
polyethylene glycol and other lubricants etc.
Such tablets may be coated with usual coating materials
as required to prepare for example sugar-coated tablets
gelatin-coated tablets enteric-coated tablets film-coated
tablets double- or multi-layered tablets etc.
To form pills any of various known carriers can be
used including for example glucose lactose starch cacao
butter hydrogenated vegetable oils kaolin talc and other
excipients gum arable powder tragacanth powder gelatin
ethanol and other binders laminaran agar and other
disintegrants etc.
-183-
To form suppositories any of various known carriers
can be used including for example polyethylene glycol cacao
butter higher alcohols esters of higher alcohols gelatin
semisynthetic glycerides etc.
To form an injection a solution emulsion or
suspension is sterilized and preferably made isotonic with blood.
Any of various known widely used diluents can be employed to
prepare the solution emulsion or suspension. Examples of such
diluents include water ethanol propylene glycol ethoxylated
isostearyl alcohol polyoxylated isostearyl alcohol fatty acid
esters of polyoxyethylene sorbitan etc. In this case the
pharmaceutical preparation may contain sodium chloride glucose
or glycerin in an amount sufficient to prepare an isotonic
solution and may contain usual solubilizers buffers analgesic
agents etc. and further if necessary coloring agents
preservatives flavors sweetening agents etc. and/or other
medicines.
The proportion of the compound of the present invention
in the pharmaceutical preparation is not limited and can be
suitably selected from a wide range. It is usually preferable
that the pharmaceutical preparation contain the compound of the
present invention in a proportion of 1 to 70 wt.%.
The route of administration of the pharmaceutical
preparation according to the present invention is not limited
and the preparation is administered by a route suitable for the
form of the preparation patient's age and sex conditions of the
disease and other conditions. For example tablets pills
solutions suspensions emulsions granules and capsules are
administered orally. Injections are intravenously administered
singly or as mixed with usual injection transfusions such as
glucose solutions amino acid solutions or the like or singly
administered intramuscularly intracutaneously subcutaneously or
intraperitoneally as required. Suppositories are administered
intrarectally.
The dosage of the pharmaceutical preparation is
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suitably selected according to the method of use patient's age
and sex severity of the disease and other conditions and is
usually about 0.001 to about 100 mg/kg body weight/day and
preferably 0.001 to 50 mg/kg body weight/day in single or
divided doses.
Since the dosage varies depending on various conditions
a dosage smaller than the above range may be sufficient or a
dosage larger than the above range may be required.
The carbostyril derivative of the present invention
induces TFF production such as TFF2 production and thus is
useful as an active ingredient of a TFF inducer (up-regulator)
particularly TFF2 inducer.
The compound of the present invention can be used
based on its TFF production inducing activity as an agent for
preventing or treating various diseases for example mucosal
injury in human and veterinary medicines. Specific examples of
diseases for which preventive or therapeutic effects can be
obtained based on TFF production inducing activity particularly
TFF2 production inducing activity include acute and chronic
alimentary tract diseases of various origins (e.g. drug-induced
ulcers peptic gastric ulcers ulcerative colitis Crohn's
disease drug-induced enteritis ischemic colitis irritable
bowel syndrome ulcers developed after endoscopic demucosation
acute gastritis chronic gastritis reflux esophagitis
esophageal ulcer Barrett esophagus gastrointestinal mucositis
(such as gastrointestinal mucositis caused by chemotherapy
radiotherapy etc) hemorrhoidal diseases etc.) oral diseases
(e.g. stomatitis (such as stomatitis caused by chemotherapy or
radiotherapy aphthous stomatitis etc) SjSgren syndrome
xerostomia etc.) upper respiratory tract diseases (e.g.
rhinitis pharyngitis etc.) respiratory tract diseases (e.g.
bronchial asthma chronic obstructive lung diseases etc.) eye
diseases (e.g. dry eye keratoconjunctivitis etc.) cancers
wounds etc.
The compound of the present invention has few side
-185-
effects and is highly safe.
The carbostyrll compounds of Formula (1) and salts
thereof encompassed by the present invention can be administered
in combination with TFF peptides (TFF1 TFF2 TFF3 etc) other
type of compounds having an inducing activity of TFF production
and/or other drugs (such as anti-inflammatory agents anti-ulcer
drugs etc).
The patents patent applications and publications cited
herein are incorporated by reference.
BRIEF DESCRIPTION OF DRAWINGS
Fig. 1 shows a comparison between the nucleotide sequence
of the PCR product cloned to the plasmid pCR-Blunt-TFF2pro
(Sequence Number 1 in Sequence Listing) and the counterpart of
the hTFF2 promoter region reported in a gene bank (GenBank
accession AB038162).
BEST MODE FOR CARRYING OUT THE INVENTION
The following Examples are intended to illustrate the
present invention in further detail.
Reference Example 1
Synthesis of 8-me thoxy-1-methyl-2-oxo-12-dihydroquinoline-5-
carboxaldehyde
8-Methoxy-l-methyl-lH-quinolin-2-one (21.14 g 0.11
mol) and paraformaldehyde (10.6 g) were suspended in concentrated
hydrochloric acid (105 ml) and 4 ml of concentrated sulfuric
acid was added followed by stirring at 70 to 80" C for 2.5 hours.
After cooling to room temperature ice water was added to the
reaction mixture and extraction with dichloromethane was
performed. The organic layer was washed with a saturated sodium
chloride solution and dried over anhydrous sodium sulfate. The
solvent was then distilled off under reduced pressure. The
residue was dissolved in 400 ml of chloroform and
hexamethylenetetramine (4.25 g 0.03 mol) was added followed by
-186-
heating under reflux for 2.5 hours. After cooling to room
temperature the solvent was distilled off under reduced pressure.
50% acetic acid (110 ml) was added to the residue and stirring
was carried out at 100"C for 2 hours. After cooling to room
temperature water was added and the insoluble matter was
collected by filtration and dried to thereby obtain 13.81 g
(yield: 57%) of 8-methoxy-l-methyl-2-oxo-l2-dihydroquinoline-5-
carboxaldehyde as a light yellow powder.
-NMRfDMSO-de) dppm:
3.80 (3Hs) 4.01 (3Hs) 6.79 (lHdJ=9.9Hz) 7.45
(lHdJ=8.4Hz) 7.86 (lHdJ=8.4Hz) 9.05 (lHdJ=9.9Hz)
10.14(lHs)
Reference Example 2
Synthesis of diethyl 2-(8-methoxy-1-methyl-2-oxo-12-
dihydroquinolin-5-ylmethylene)malonate
8-Methoxy-1-methyl-2-oxo-12-dihydroquinoline-5-
carboxaldehyde (18.9 g) diethyl malonate (26.5 ml) and
piperidine (2.7 ml) were added to pyridine (90 ml) and the
resulting mixture was stirred at 90 to 100°C for 6 hours. After
cooling to room temperature the reaction mixture was added to
cold concentrated hydrochloric acid and the precipitated solid
was collected by filtration washed with water and dried to
thereby obtain 16.62 g (yield: 53%) of diethyl 2-(8-methoxy-lmethyl-
2-oxo-l2-dihydroquinolin-5-ylmethylene)malonate as a
yellow powder.
1H-NMR(DMSO-d6) dppm:
1.10 (3HtJ=7.2Hz) 1.28 (3HtJ=7.2Hz) 3.80 (3Hs) 3.92
(3Hs) 4.05-4.3 (4Hm) 6.69 (lHdJ=9.8Hz) 7.18 (lHdJ=8.5Hz)
7.30 (lHdJ=8.5Hz) 7.84 (lHdJ=9.8Hz) 8.14(lHs)
Reference Example 3
Synthesis of diethyl 2-(8-methoxy-l-methyl-2-oxo-l2-
dihydroquinolin-5-ylmethyl)malonate
Diethyl 2-(8-methoxy-1-methyl-2-oxo-12-
-187-
dihydroquinolin-5-ylinethylene)malonate (16.62 g) and 10%
palladium carbon (1.6 g) were added to 300 ml of ethanol
followed by catalytic hydrogenation at room temperature and
atmospheric pressure for 6 hours. The catalyst was filtered off
and the filtrate was concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (ethyl
acetatem-hexane = 1:1) to thereby obtain 13.59 g (yield: 81%) of
diethyl 2-(8-methoxy-1-methyl-2-oxo-12-dihydroquinolin-5-
ylmethyl)malonate as a light yellow oil.
hl-NMIUCDCla) dppm:
1.15-1.3 (6Hm). 3.45 (2HdJ=7.6Hz) 3.60 (lHtJ=7.6Hz) 3.89
(3Hs) 3.95 (3Hs) 4.1-4.25 (4Hm) 6.75 (IH.dJ=9.8Hz) 6.96
(lHdJ=8.3Hz) 7.04 (lHdJ=8.3Hz) 7.86 (lHdJ=9.8Hz)
Reference Example 4
Synthesis of diethyl 2-chloro-2-(8-methoxy-l-methyl-2-oxo-l2-
dihydroquinolin-5-ylmethyl)malonate
Sodium hydride (60% in oil) (1.0 g) was added under ice
cooling to a tetrahydrofuran (THF) solution (140 ml) of 13.59 g
of diethyl 2-(8-methoxy-1-methyl-2-oxo-12-dihydroquinolin-5-
ylmethyl)malonate and stirring was carried out until the
generation of hydrogen stopped. N-chlorosuccinimide (5.6 g) was
added followed by stirring for 1 hour. The reaction mixture was
added to cold hydrochloric acid and extraction with
dichloromethane was performed. After drying over anhydrous sodium
sulfate the dry product was concentrated under reduced pressure
diisopropyl ether was added to the residue and the precipitated
solid was collected by filtration and dried to thereby obtain
12.77 g (yield: 86%) of diethyl 2-chloro-2-(8-methoxy-l-methyl-2-
oxo-12-dihydroquinolin-5-ylmethyl)malonate as a light yellow
powder.
1H-NMR(CDC13) dppm:
1.28 (3HtJ=7.2Hz) 3.86(2Hs) 3.89(3Hs) 3.92(3Hs) 4.2-4.3
(4Hm) 6.71 (lHdJ=9.8Hz) 6.98 (IH.dJ=8.4Hz) 7.10
(lHdJ=8.4Hz) 7.93 (lHdJ=9.8Hz)
-188-
Reference Example 5
Synthesis of 2-chloro-3-(8-methoxy-l-methyl-2-oxo-l2-
dihydroquinolin-5-yl)propionic acid
Diethyl 2-chloro-2-(8-methoxy-l-methyl-2-oxo-l2-
dihydroquinolin-5-ylmethyl)malonate (5.1 g) was added to a
mixture of 20 ml of acetic acid and 15 ml of 6N hydrochloric acid
followed by heating under reflux for 9 hours. After cooling to
room temperature water was added to the reaction mixture
followed by cooling with ice. The precipitated solid was
collected by filtration washed with water and dried to thereby
obtain 3.1 g of 2-chloro-3-(8-methoxy-l-methyl-2-oxo-l2-
dihydroquinolin-5-yl)propionic acid as a light yellow powder.
-NMRfDMSO-ds) dppm:
3.45-3.65 (2Hm) 3.77 (3Hs) 3.86 (3Hs) 4.5-4.65 (lHm) 6.62
(lHdJ=9.8Hz) 7.14 (!HdJ=8.3Hz) 7.21 (lHdJ=8.3Hz) 8.03
(lHdJ=9.8Hz) 13.4 (!Hbrs)
Reference Example 6
Synthesis of diethyl 2-[2-(8-methoxy-l-methyl-2-oxo-l2-
dihydroquinolin-5-yl)ethyl]malonate
Sodium hydride (60% in oil) (0.5 g) was added under ice
cooling to a tetrahydrofuran (THF) solution (30 ml) of diethyl
malonate (2.2 ml) and stirring was carried out until the
generation of hydrogen stopped. 5-(2-iodoethyl)-8-methoxy-lmethyl-
2-oxo-l2-dihydroquinoline (1.54 g) was added followed by
stirring at room temperature overnight. The reaction mixture was
added to cold hydrochloric acid and extraction with
dichloromethane was performed. After drying over anhydrous sodium
sulfate the dry product was concentrated under reduced pressure
and the residue was purified by silica gel column chromatography
(dichloromethane:methanol = 50:1 -» 40:1). The purified product
was under reduced pressure to thereby obtain 1.73 g (yield:
quantitative) of diethyl 2-[2-(8-methoxy-l-methyl-2-oxo-l2-
dihydroquinolin-5-yl)ethyl]malonate as a yellow oil.
1.2-1.4 (6Hm) 2.1-2.25 (2Hm) 2.8-3.0 (2Hm) 3.3-3.5(lHm)
3.88 (3Hs) 3.93 (3Hs) 4.1-4.4 (4Hm) 6.75 (lHdJ=9.7Hz)
6.9-7.1 (2Hm) 7.92 (lHdJ=9.7Hz)
Reference Example 7
Synthesis of diethyl of 2-chloro-2-[2-(8-methoxy-l-methyl-2-oxo-
12-dihydroquinolin-5-yl)ethyl]malonate
Sodium hydride (60% in oil) (0.21 g) was added under
ice cooling to a THF solution (30 ml) of 1.79 g of diethyl 2-[2-
(8 -me thoxy-1 -methyl - 2 - oxo -12- dihydroquinolin - 5 -yl) ethyl ] malonate
and stirring was carried out until the generation of hydrogen
stopped. N-chlorosuccinimide (0.7 g) was added followed by
stirring for 1.5 hours. The reaction mixture was added to cold
hydrochloric acid and extraction with dichloromethane was
performed. The extract was dried over anhydrous sodium sulfate
and concentrated under reduced pressure to thereby obtain 2.38 g
(yield: quantitative) of diethyl 2-chloro-2-[2-(8-methoxy-lmethyl-
2-oxo-12-dihydroquinolin-5-yl)ethyl]malonate as a yellow
oil.
-NMRtCDCla) dppm:
1.31 (6HtJ=7.1Hz) 2.47 (2HtJ=8.7Hz) 2.98 (2HtJ=8.7Hz)
3.88 (3Hs) 3.93 (3Hs) 6.75 (lHdJ=9.7Hz) 6.9-7.1 (2Hm)
7.87 (lHdJ=9.7Hz)
Reference Example 8
Synthesis of 2-chloro-4-(8-methoxy-l-methyl-2-oxo-l2-
dihydroquinolin-5-yl)butyric acid
Diethyl 2-chloro-2-[2-(8-methoxy-l-methyl-2-oxo-l2-
dihydroquinolin-5-yl)ethyl]malonate (2.38 g) was added to a
mixture of acetic acid (10 ml) and 6N hydrochloric acid (15 ml)
and the resulting mixture was heated under reflux overnight.
After cooling to room temperature water and a small quantity of
ethanol was added to the reaction mixture followed by ice
cooling. The precipitated solid was collected by filtration
washed with water and dried to thereby obtain 0.99 g (yield: 55%)
of 2-cdiloro-4-(8-methoxy-l-methyl-2-oxo-l2-dihydroquinolin-5-
yl)butyric acid as a gray powder.
-NMRtDMSO-ds) dppm:
1.9-2.3 (2Hm) 2.8-3.1 (2Hm) 3.77 (3Hs) 3.85 (3Hs) 4.4-4.6
(lHm) 6.61 (lHdJ=9.7Hz) 7.05 (lHdJ=7.IHz) 7.18
(lHdJ=7.1Hz) 7.98 (lHdJ=9.7Hz) 13.4 (lHbrs)
Reference Example 9
Synthesis of diethyl 2-[3-(8-methoxy-l-methyl-2-oxo-l2-
dihydroquinolin-5-yl)propyl]malonate
Sodium hydride (60% in oil) (0.39 g) was added under
ice cooling to a THF solution (30 ml) of diethyl malonate (1.85
ml) and stirring was carried out until the generation of
hydrogen stopped. 5-(3-Iodopropyl)-8-methoxy-l-methyl-2-oxo-l2-
dihydroquinoline (2.89 g) was added followed by stirring at room
temperature for 4.5 hours. The reaction mixture was added to cold
hydrochloric acid and extraction with dichloromethane was
performed. After drying over anhydrous sodium sulfate the dry
product was concentrated under reduced pressure and the residue
was purified by silica gel column chromatography
(dichloromethane:methanol = 20:1). The purified product was
concentrated under reduced pressure to thereby obtain 2.94 g
(yield: 93%) of diethyl 2-[3-(8-methoxy-l-methyl-2-oxo-l2-
dihydroquinolin-5-yl)propylJmalonate as a yellow oil.
-NMRfCDCla) dppm:
1.27 (6HtJ=7.1Hz) 1.6-1.8 (2Hm) 1.95-2.1 (2Hm) 2.87
(2HtJ=7.7Hz) 3.56 (1Ht.J=7.5Hz) 3.89(3Hs) 3.95(3Hs) 4.1-
4.4 (4Hm) 6.73 (lHdJ=9.8Hz) 7.00 (2Hs) 7.84(lHdJ=9.8Hz)
Reference Example 10
Synthesis of diethyl 2-chloro-2-[3-(8-methoxy-l-methyl-2-oxo-l2-
dihydroquinolin-5-yl)propyl]malonate
Sodium hydride (60% in oil) (0.33 g) was added under
ice cooling to a THF solution (30 ml) of diethyl 2-[3-(8-methoxy1-
methyl-2-oxo-12-dihydroquinolin-5-yl)propyl]malonate (2.94 g)
and stirring was carried out until the generation of hydrogen
stopped. N-chlorosuccinimide (1.2 g) was added followed by
stirring for 2 hours. The reaction mixture was added to cold
hydrochloric acid and extraction with dichloromethane was
performed. The extract was dried over anhydrous sodium sulfate
and concentrated under reduced pressure to thereby obtain 4.02 g
(yield: quantitative) of diethyl 2-chloro-2-[3-(8-methoxy-lmethyl-
2-oxo-12-dihydroquinolin-5-yl)propyl]malonate as a yellow
oil.
1H-NMR(CDC13) dppm:
1.26 (6HtJ=7.1Hz) 1.6-1.9 (2Hm) 2.31 (2HtJ=8.0Hz) 2.88
(2HtJ=7.7Hz) 3.88 (3Hs) 3.94 (3Hs) 6.72(lHdJ=9.8Hz)
6.99 (2Hs) 7.79(lHdJ=9.8Hz)
Reference Example 11
Synthesis of 2-chloro-5-(8-methoxy-l-methyl-2-oxo-l2-
dihydroquinolin-5-yl)valeric acid
Diethyl 2-chloro-2-[3-(8-methoxy-1-methyl-2-oxo-12-
dihydroquinolin-5-yl)propyl]malonate (4.02 g) was added to a
mixture of acetic acid (15 ml) and 6N hydrochloric acid (20 ml)
followed by heating under reflux for 24 hours. After cooling to
room temperature water was added to the reaction mixture
followed by cooling with ice. The precipitated solid was
collected by filtration washed with water and dried to thereby
obtain 2.30 g (yield: 75%) of 2-chloro-5-(8-methoxy-1-methyl-2-
oxo-12-dihydroquinolin-5-yl)valeric acid as a light yellow
powder.
-NMRfDMSO-de) dppm:
1.6-2.2 (4Hm) 2.7-3.l(2Hm) 3.77(3Hs) 3.84(3Hs) 4.5-4.65
(lHm) 6.59 (!H.dJ=9.7Hz) 7.05 (lHdJ=8.IHz) 7.17
(lHdJ=8.1Hz) 7.99 (lHdJ=9.7Hz) 13.2 (lHbrs)
Reference Example 12
Synthesis of 8-methoxy-2-oxo-l234-tetrahydroquinoline-5-
8-Methoxy-34-dihydro-lH-quinolin-2-one (5 g) was
dissolved in dichloromethane (100 ml) and dichloromethyl methyl
ether (6.4 ml) was added at room temperature followed by cooling
in an ice water bath. Titanium tetrachloride (85 ml) was added
dropwise at a temperature not higher than 10°C and the resulting
mixture was stirred at room temperature overnight. The reaction
mixture was poured into ice water and the aqueous layer was
subjected to extraction with dichloromethane. The organic layer
was dried over sodium sulfate filtered and concentrated under
reduced pressure. Diethyl ether was added to the residue and the
produced solid was collected by filtration and dried to thereby
obtain 5.2 g (yield: 90%) of 8-methoxy-2-oxo-l234-
tetrahydroquinoline-5-carboxaldehyde.
-NMRfCDCla) dppm:
2.63 (2HtJ=7.4Hz) 3.54 (2HtJ=7.4Hz) 3.97(3Hs) 6.92
(lHdJ=8.5Hz) 7.50 (lHdJ=8.5Hz) 7.84 (lHbrs) 10.02 (lHs)
Reference Example 13
Synthesis of 8-methoxy-l-ethyl-2-oxo-l234-tetrahydroquinoline-
5-carboxaldehyde
8-Methoxy-2-oxo-l234-tetrahydroquinoline-5-
carboxaldehyde (2.0 g) was dissolved in DMF (20 ml) and 0.43 g
of sodium hydride (60% in oil) was added under ice cooling. After
the addition stirring was carried out at room temperature until
the generation of hydrogen stopped. The resulting mixture was
cooled in an ice water bath again 1.2 ml of ethyl iodide was
added dropwise and stirring was carried out at room temperature
for 8 hours. The reaction mixture was poured into iced aqueous
hydrochloric acid extraction with methylene chloride was
performed and the organic layer was dried over sodium sulfate
filtered and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography to thereby
obtain 2.1 g (yield: 91%) of 8-methoxy-l-ethyl-2-oxo-l234-
tetrahydroquinoline-5-carboxaldehyde.
dppm:
1.15 (3HtJ=7.1Hz) 2.51 (2HtJ=7.0Hz) 3.36 (2HtJ=7.0Hz)
3.97 (3Hs) 4.01 (2HtJ=7.4Hz) 6.98 (lHdJ=8.6Hz) 7.60
(lHdJ=8.6Hz) 10.06 (1HS)
Reference Example 14
Synthesis of 8-methoxy-l-methyl-34-dihydro-lH-quinolin-2-one
8-Methoxy-34-dihydro-lH-quinolin-2-one (15 g) was
dissolved in DMF (150 ml) and 3.6 g of sodium hydride (60% in
oil) was added under ice cooling. After the addition stirring
was carried out at room temperature until the generation of
hydrogen stopped. The resulting mixture was cooled with ice water
again and 5.8 ml of methyl iodide was added dropwise followed
by stirring at room temperature overnight. The solvent was
distilled off under reduced pressure and the residue was
purified by silica gel column chromatography to thereby obtain
16.7 g (yield: 96%) of 8-methoxy-l-methyl-34-dihydro-lHquinolin-
2-one.
-NMRfCDCla) dppm:
2.5-2.6 (2Hm) 2.8-2.9(2Hm). 3.39(3Hs) 3.85(3Hs) 6.75-6.9
(2Hm) 7.0-7.05 (lHm)
Reference Example 15
Synthesis of 8-methoxy-l-methyl-2-oxo-l234-
tetrahydroquinoline-5-carboxaldehyde
8-Methoxy-l-methyl-34-dihydro-lH-quinolin-2-one (1.5
g) was dissolved in dichloromethane (15 ml) and dichloromethyl
methyl ether (0.86 ml) was added at room temperature followed by
cooling with ice water. Titanium tetrachloride (10.5 ml) was
added dropwise and the resulting mixture was stirred at room
temperature overnight. Further dichloromethyl methyl ether (1.29
ml) and titanium tetrachloride (15.8 ml) were added and stirring
was carried out at room temperature for 5 hours. The reaction
mixture was poured into ice water and the aqueous layer was
subjected to extraction with dichloromethane. The organic layer
was dried over sodium sulfate filtered and concentrated under
reduced pressure. Hexane was added to the residue and the
produced insoluble matter was collected by filtration and dried
to thereby obtain 1.37 g (yield: 80%) of 8-methoxy-l-methyl-2-
oxo -1234-1 etrahydroquinoline - 5 - carboxaldehyde.
-NMRfCDCla) dppm:
2.5-2.55 (2Hm) 3.3-3.45 (2Hm) 3.96 (3Hs) 6.99
(lHdJ=8.6Hz) 7.60 (lHdJ=8.6Hz) 10.06(lHs)
Reference Example 16
Synthesis of l-(4-biphenylmethyl)-6-bromo-34-dihydro-lHquinolin-
2-one
Sodium hydride (60% in oil) (0.49 g) was added at 0° C
to a DMF solution (20 ml) of 6-bromo-34-dihydro-lH-quinolin-2-
one (2.54 g) followed by stirring for 30 minutes. 4-
Bromomethylbiphenyl (3.05 g) was added and the resulting mixture
was stirred at room temperature overnight. Water was added to the
reaction mixture extraction with ethyl acetate was performed
and the extract was dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (ethyl acetate:n-hexane = 1:6 -•
1:2). The purified product was recrystallized from a chloroformdiisopropyl
ether mixed solvent to thereby obtain 4.06 g (yield:
92%) of l-(4-biphenylmethyl)-6-bromo-34-dihydro-lH-quinolin-2-
one as a white powder.
1H-NMR(DMSO-d6) dppm:
2.65-2.78 (2Hm) 2.89-3.03 (2Hm) 5.17(2Hs) 6.90 (lHdJ=8.7
Hz) 7.23-7.39 (4Hm) 7.39-7.50 (3Hm) 7.50-7.71 (4Hm)
Reference Example 17
Synthesis of l-(4-biphenylmethyl)-2-oxo-l234-
tetrahydroquinoline-6-carboxaldehyde
A DMF solution (30 ml) of l-(4-biphenylmethyl)-6-bromo-
34-dihydro-lH-quinolin-2-one (2.80 g) sodium formate (0.171 g)
and bistriphenylphosphine palladium chloride (0.25 g) was stirred
under a carbon monoxide atmosphere at 100°C for 4 hours. Water
was added to the reaction mixture extraction with ethyl acetate
was performed and the extract was dried over anhydrous sodium
sulfate and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (ethyl acetate:nhexane
= 1:4 -»• 1:2). The purified product was recrystallized
from a chloroform-diethyl ether mixed solvent to thereby obtain
1.95 g (yield: 78%) of l-(4-biphenylmethyl)-2-oxo-
tetrahydroquinoline-6-carboxaldehyde as a white powder.
1H-NMR(DMSO-d6) dppm:
2.78 (2HtJ=8.0Hz) 3.07(2HtJ=8.0Hz) 5.24(2Hs) 7.15
(lHdJ=8.4Hz) 7.25-7.49(5Hm) 7.55-7.82 (6Hm) 9.84(lHs)
Reference Example 18
Synthesis of 1-(4-chlorobenzyl)-2-oxo-l2-dihydroquinoline-4-
carboxaldehyde
Sodium hydride (60% in oil) (1.3 g) was added at 0°C to
a DMF solution (50 ml) of 2-oxo-l2-dihydroquinoline-
carboxaldehyde (5.13 g) followed by stirring for 30 minutes. 4-
chlorobenzylbromide (7.0 g) was added and the resulting mixture
was stirred at room temperature overnight. Water was added to the
reaction mixture extraction with ethyl acetate was performed
and the extract was dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (ethyl acetate:n-hexane =1:10
1:4). The purified product was recrystallized from a
chloroform-diisopropyl ether-n-hexane mixed solvent to thereby
obtain 4.13 g (yield: 47%) of l-(4-chlorobenzyl)-2-oxo-l2-
dihydroquinoline-4-carboxaldehyde as a white powder.
-NMRfDMSO-ds) dppm:
5.55 (2Hs) 7.24 (2HdJ=8.5Hz) 7.28-7.39 (4Hm) 7.45
(lHdJ=8.4Hz) 7.50-7.64 (lHm) 8.68 (lHddJ-l.38.IHz)
10.24(lHs)
Reference Example 19
Synthesls of l-(4-chlorobenzyl)-2-oxo-l2-dihydroquinoline-3-
carboxaldehyde
Sodium hydride (60% in oil) (1.3 g) was added at 0°C to
a DMF solution (50 ml) of 2-oxo-l2-dihydroquinoline-3-
carboxaldehyde (5.13 g) followed by stirring for 30 minutes. 4-
chlorobenzyl bromide (7.0 g) was added and the resulting mixture
was stirred at room temperature overnight. Water was added to the
reaction mixture extraction with ethyl acetate was performed
and the extract was dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (ethyl acetate :n-hexane = 1:10
- 1:4). The purified product was recrystallized from a
chloroform- diisopropyl ether mixed solvent to thereby obtain 6 . 57
g (yield: 72%) of l-(4-chlorobenzyl)-2-oxo-l2-dihydroquinoline-
3-carboxaldehyde as a white powder.
-NMRtDMSO-ds) dppm:
5.56 (2Hs) 7.21-7.39 (5Hm) 7.44 (lHd J=8.6Hz) 7.61-7.72
(lHm) 8.02 (lHddJ=1.47.8Hz) 8.59 (lHs) 10.31(lHs)
Reference Example 20
Synthesis of 5-trifluoromethanesulfonyloxy-34-dihydro-lHquinolin
- 2 - one
Pyridine (30 ml) and trifluoromethanesulfonic anhydride
(25 g) were added with stirring at O'C to an anhydrous
dichlorome thane solution (200 ml) of 5-hydroxy-34-dihydro-lHquinolin-
2-one (15.9 g) followed by stirring for 2 hours. The
resulting mixture was concentrated under reduced pressure water
was added to the residue and extraction with dichloromethane was
performed. The extract was washed with water an aqueous
potassium hydrogensulfate solution and water in this order and
dried over anhydrous sodium sulfate. After concentration under
reduced pressure the residue was recrystallized from an ethyl
acetate-diisopropyl ether mixed solvent to thereby obtain 28 g
(yield: 97%) of 5-trifluoromethanesulfonyloxy-34-dihydro-lHquinolin-
2-one as a light brown powder.
H-NMR(CDCl3) dppm:
2.67 (2HddJ=6.3HzJ=8.8Hz) 3.07 (2HtJ=7.2Hz) 6.80-
6.90(lHm) 6.90-7.02(lHm) 7.16-7.32 (lHm) 8.95(lHbrs)
Reference Example 21
Synthesis of 5-cyano-34-dihydro-lH-quinolin-2-one
5-Trif luoromethanesulf onyloxy-34-dihydro-IH-quinolin-
2-one (1.5 g) zinc cyanide (1.3 g) and
tetrakis(triphenylphosphine) palladium (0.59 g) were suspended in
DMF (20 ml) and the suspension was stirred at 100° C for 2 hours.
The insoluble matter was filtered off and ethyl acetate was
added to the filtrate followed by washing with water. The
resulting mixture was dried over anhydrous magnesium sulfate and
concentrated under reduced pressure and the residue was
recrystallized from an ethyl acetate-diethyl ether mixed solvent
to thereby obtain 0.71 g (yield: 81%) of 5-cyano-34-dihydro-lHquinolin-
2-one as a light brown powder.
Hl-NMRfDMSO-de) dppm:
2.45-2.60 (2Hm) 3.05(2HtJ=7.2Hz)7.08-7.18(lHm)7.28-7.40
(2Hm)10.37 (lHbrs)
Reference Example 22
Synthesis of 2-oxo-1234 -tetrahydroquinoline-5-carboxaldehyde
5-Cyano-34-dihydro-lH-quinolin-2-one (100 mg) and
Raney nickel (100 mg) were suspended in formic acid (10 ml) and
the suspension was heated under reflux for 2 hours. An additional
100 mg of Raney nickel was added followed by heating under
reflux for 1 hour. The reaction mixture was filtered to remove
the insoluble matter and the filtrate was concentrated. Ethyl
acetate and water were added to the residue and after stirring
the mixture was filtered through Celite. The filtrate was
separated into layers and the organic layer was washed with
water and dried over anhydrous sodium sulfate. After
concentration under reduced pressure the residue was
recrystallized from an ethyl acetate-n-hexane mixed solvent to
thereby obtain 77 mg (yield: 76%) of 2-oxo-l234-
tetrahydroquinoline-5-carboxaldehyde as a light brown powder.
xH-NMR(DMSO-d6) dppm:
2.39-2.51 (2Hm) 3.35 (2HtJ=7.4Hz) 7.10-7.17 (lHm) 7.31-
7.41 (lHm) 7.44-7.50 (lHm) 10.18 (lHs) 10.26(lHbrs)
Reference Example 23
Synthesis of l-(4-biphenylmethyl)-2-oxo-l234-
tetrahydroquinoline-5-carboxaldehyde
Sodium hydride (60% in oil) (0.25 g) was added at 0°C
to a DMF solution (10 ml) of 2-oxo-l234-tetrahydroquinoline-5-
carboxaldehyde (1.0 g) followed by stirring for 30 minutes. 4-
bromomethylbiphenyl (1.69 g) was added and the resulting mixture
was stirred at room temperature for 1 hour. Water was added to
the reaction mixture and extraction with ethyl acetate was
performed. The extract was washed with a saturated sodium
chloride solution dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (ethyl acetate:n-hexane = 1:4 -
1:2). The purified product was recrystallized from a chloroformdiisopropyl
ether mixed solvent to thereby obtain 1.11 g (yield:
56%) of l-(4-biphenylmethyl)-2-oxo-l234-tetrahydroquinoline-5-
carboxaldehyde as a colorless plate crystals.
hl-NMRfDMSO-de) dppm:
2.65-2.78 (2Hm) 3.45 (2HtJ=7.6Hz) 5.24 (2Hs) 7.21-7.49
(7Hm) 7.49-7.57 (lHm) 7.57-7.70 (4Hm) 10.24(lHs)
Reference Example 24
Synthesis of 5-(l3-dioxolan-2-yl)-8-methoxy-34-dihydro-lHquinolin-
2-one
8-Methoxy-2-oxo-l234-tetrahydroquinoline-5-
carboxaldehyde (42 g) was suspended in toluene (400 ml) and
ethylene glycol (33.7 ml) and p-toluenesulfonic acid monohydrate
(0.78 g) were added and the resulting mixture was heated under
reflux in a Dean-Stark apparatus for 4.5 hours. The reaction
-199-
mixture was cooled and 10 ml of an aqueous solution containing
1.72 g of sodium bicarbonate was added. Stirring was carried out
for some time and the produced solid was collected by filtration.
The solid was washed with water and toluene and dried at 60° C to
thereby obtain 35.5 g (yield: 70%) of 5-(l3-dioxolan-2-yl)-8-
methoxy-34-dihydro-lH-quinolin-2-one as white crystals.
-NMRfDMSO-de) dppm:
2.33-2.44 (2Hm) 2.85-2.98 (2Hm) 3.79 (3Hs) 3.86-4.08 (4Hm)
5.78 (!Hs) 6.86 (IH.d J=8.5Hz) 7.07 (lHd J=8. 5Hz) . 8.97
Reference Example 25
Synthesis of l-(6-chloropyridin-3-ylmethyl)-5-(l3-dioxolan-2-
yl)-8-methoxy-34-dihydro-lH-quinolin-2-one
Sodium hydride (55% in oil) (2.1 g) was added in small
portions under ice cooling to a DMF solution (70 ml) of 5- (13-
dioxolan-2-yl)-8-methoxy-34-dihydro-lH-quinolin-2-one (10 g)
and stirring was carried out at room temperature until the
generation of hydrogen stopped. The resulting mixture was cooled
with ice again and a DMF solution (30 ml) of 2-chloro-5-
chloromethyl pyridine (9.74 g) was added dropwise. After stirring
at room temperature for 4 hours the reaction mixture was poured
into ice water and the produced insoluble matter was collected
by filtration. The solid was washed with water and diethyl ether
and dried to thereby obtain 11.84 g (yield: 79%) of
chloropyridin-3-ylmethyl) -5- ( 1 3 -dioxolan- 2 -yl) -8-methoxy-3 4-
dihydro-lH-quinolin-2-one as a light yellow solid.
-NMRfDMSO-de) dppm:
2.47-2.53 (2Hm) 2.88-2.94 (2Hm) 3.63 (3Hs) 3.91-4.04 (4Hm)
5.08 (2Hs) 5.80 (lHs) 6.88 (lHd J=8.6Hz) 7. 19(lHd J=8.6Hz)
7.38 (!HdJ=8.3Hz) 7.60 (lHdd Ji=2.3Hz J2=8.3Hz) 8.19
(lHdJ=2.3Hz)
Reference Example 26
Synthesis of 5-(l3-dioxolan-2-yl)-8-methoxy-l-[6-(N-methyl-N-
phenylamino)pyridin-3-ylmethyl]-34-dihydro-IH-quinolin-2-one
1-(6-Chloropyridin-3-ylmethyl)-5-[13]dioxolan-2-yl-8-
methoxy-34-dihydro-lH-quinolin-2-one (0.4 g)
tris(dibenzylideneacetone)dipalladium (48.8 mg) 45-
bis(diphenylphosphino)-99-dimethylxanthene (92.6 mg) and sodium
tert-butoxide (0.15 g) were suspended in toluene (10.6 ml). Nmethylaniline
(0.17 g) was added and the resulting mixture was
heated under reflux in an argon atmosphere for 13 hours. After
concentration under reduced pressure the residue was purified by
silica gel column chromatography (ethyl acetate:n-hexane =
dichloromethane:methanol = 20:1). The purified product was
concentrated under reduced pressure to thereby obtain 0.45 g
(yield: 95%) of 5-(l3-dioxolan-2-yl)-8-methoxy-l-[6-(N-methyl-Nphenylamino)
pyridin-3-ylmethyl]-34-dihydro-lH-quinolin-2-one as
an amorphous solid.
Hl-NMRfCDCla) dppm:
2.52-2.58 (2Hm) 2.74-2.80 (2Hm) 3.40 (3Hs) 3.83(3Hs)
3.98-4.12 (4Hm) 5.22 (2Hs) 5.81 (!Hs) 6.39 (IH.dJ=8.7Hz)
6.76 (lHd J=8.7Hz) 7.13-7.26 (4Hm) 7.33-7.39 (3Hm) 7.99
(lH.dJ=2.0Hz)
Reference Example 27
Synthesis of 8-methoxy-l-[6-(N-methyl-N-phenylamino)pyridin-3-
ylmethyl]-2-oxo-1234-tetrahydroquinoline-5-carboxaldehyde
Pyridinium p-toluene sulfonate (PPTS) (0.54 g) was
added to a mixed solution of 5-(l3-dioxolan-2-yl)-8-methoxy-l-
[6-(N-methyl-N-phenylamino)pyridin-3-ylmethyl]-34-dihydro-1Hquinolin-
2-one (0.95 g) in acetone (19 ml) and water (9.5 ml)
followed by heating under reflux for 2 hours. An aqueous sodium
hydrogencarbonate solution was added to the reaction mixture and
extraction with ethyl acetate was performed. The extract was
washed twice with water washed with a saturated sodium chloride
solution dried over sodium sulfate filtered and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (ethyl acetate:n-hexane = 1:1). The

(Table Remove)purifled product was concentrated under reduced pressure to
thereby obtain 0.69 g (yield: 81%) of 8-methoxy-l-[6-(N-methyl-Nphenylamino)
pyridin - 3 -ylme thyl ] - 2 - oxo -1234-
tetrahydroquinoline-5-carboxaldehyde as a light yellow amorphous
solid.
-NMRfCDCla) dppra:
2.53-2.59 (2Hm) 3.28-3.34 (2Hm) 3.39 (3Hs) 3.95 (3Hs)
5.23(2Hs) 6.37 (lHdJ=8.8Hz) 6.90 (lHdJ=8.6Hz) 7.09
(lHdd/J1=2.4HzJ2=8.8Hz)7.16-7.21 (3Hm) 7.33-7.39 (2Hm) 7.54
(lHdJ=8.6Hz) 7.94 (!HdJ=2.4Hz) 10.00 (IH.s)
Reference Example 28
Synthesis of 5-(l3-dioxolan-2-yl)-8-methoxy-l-(6-thiophen-3-
yIpyridin-3-ylme thy1)-34-dihydro-1H-quinolin-2-one
1-(6-Chloropyridin-3-ylmethyl)-5-(13-dioxolan-2-yl)-8-
methoxy-34-dihydro-lH-quinolin-2-one (0.4 g)
tetrakis(triphenylphosphine) palladium (0.12 g) and a 2N aqueous
solution of sodium carbonate (2.5 ml) were suspended in 8 ml of
12-dimethoxyethane and 0.20 g of 3-thiopheneboronic acid was
added followed by heating under reflux in an argon atmosphere
for 4 hours. Water was added to the reaction mixture and
extraction with ethyl acetate was performed. The extract was
washed twice with water washed with a saturated sodium chloride
solution dried over sodium sulfate filtered and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (ethyl acetate:n-hexane = 1:1). The
purified product was concentrated under reduced pressure to
thereby obtain 0.45 g (yield: 95%) of 5-(l3-dioxolan-2-yl)-8-
methoxy-1-(6-thiophen-3-ylpyridin-3-ylmethyl)-34-dihydro-1Hquinolin-
2-one as a light brown amorphous solid.
(Table Remove)1H-NMR(DMSO-d6) dppm:
2.49-2.51 (2Hm) 2.89-2.91 (2Hm) 3.71 (3Hs) 3.91-4.04 (4Hm)
5.19 (2Hs) 5.79 (IH.s) 6.87 (lHdJ=8.8Hz) 7.16
(lHdJ=8.8Hz) 7.51-7.74 (4Hm) 8.09-8.10 (lHm) 8.32
(!HdJ=2.0Hz)
Reference Example 29
Synthesis of 8-methoxy-l-(6-thiophen-3-ylpyrldin-3-ylmethyl)-2-
oxo-1234-tetrahydroquinoline-5-carboxaldehyde
Pyridinium p-toluenesulfonate (PPTS) (0.24 g) was added
to a mixed solution of 5-(l3-dioxolan-2-yl)-8-methoxy-l-(6-
thiophen-3-ylpyridin-3-ylmethyl)-34-dihydro-lH-quinolin-2-one
(0.4 g) in acetone (8 ml) and water (4 ml) followed by heating
under reflux 1.5 hours. The resulting mixture was concentrated
under reduced pressure subjected to extraction with
dichloromethane washed with water washed with a saturated
sodium chloride solution dried over sodium sulfate filtrated
and concentrated under reduced pressure to thereby obtain 0.4 g
(yield: quantitative) of 8-methoxy-l-(6-thiophen-3-ylpyridin-3-
ylmethyl)-2-oxo-l234-tetrahydroquinoline-5-carboxaldehyde as a
light brown amorphous solid.
1H-NMR(DMSO-d6) dppm:
2.51-2.58 (2Hm) 3.34-3.41 (2Hm) 3.81 (3Hs) 5.19 (2Hs)
7.09 (lHd J=8.8Hz) 7.54-7.74 (5Hm) 8.09-8.10 (lHm) 8.35
(lHdJ=1.8Hz) 10.03 (lHs)
Reference Example 30
Synthesis of 5-(l3-dioxolan-2-yl)-l-phenyl-34-dihydro-lHquinolin-
2-one
5-(13-Dioxolan-2-yl)-34-dihydro-lH-quinolin-2-one
(2.30 g 10.5 mmol) iodobenzene (3.5 ml 31.5 mmol) copper(I)
iodide (4 00 mg 2.10 mmol) trans-12-diaminocyclohexane (0.129
ml 1.05 mmol) and cesium carbonate (6.84 g 21.0 mmol) were
stirred in 30 ml of 14-dioxane under reflux for three days.
After cooling the insoluble matter was filtered off through a
Celite pad. Ethyl acetate and water were added to the filtrate
and the resulting mixture was washed (twice with water and once
with a saturated sodium chloride solution) dried (MgSO4) and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (ethyl acetate:n-hexane = 1:3 -»
-203-
1:1) to thereby obtain 2.91 g (yield: 92%) of 5-(l3-dioxolan-2-
yl)-l-phenyl-34-dihydro-lH-quinolin-2-one as a white solid.
-NMRfCDCla) dppm:
2.75-2.90 (2Hm) 3.11-3.27 (2Hm) 3.98-4.25 (4Hm) 5.99 (lHs)
6.39 (lHdJ=7.6Hz) 7.05 (lHtJ=8.0Hz) 7.16-7.30 (3Hm) 7.35-
7.56 (3Hm)
Reference Example 31
Synthesis of l-phenyl-2-oxo-l234-tetrahydroquinoline-5-
carboxaldehyde
2N Hydrochloric acid (5 ml) was added to a solution of
5-(13-dioxolan-2-yl)-1-phenyl-34-dihydro-1H-quinolin-2-one
(2.60 g) in THF (30 ml) followed by stirring at room temperature
overnight. After distilling off THF under reduced pressure ethyl
acetate-water was added and the resulting mixture was washed
(twice with water and once with a saturated sodium chloride
solution) dried (MgS04) and concentrated under reduced pressure.
The obtained solid was recrystallized from chloroform-diethyl
ether to thereby obtain 1.93 g (yield: 87%) of 1-phenyl-2-oxo-
1234- tetrahydroquinoline-5-carboxaldehyde as a beige powder.
1H-NMR(CDC13) dppm:
2.75-2.89 (2Hm) 3.53-3.68 (2Hm) 6.65 (lHddJ=0.9HzJ=8.2Hz)
7.15-7.20 (3Hm) 7.39-7.61 (4Hm) 10.24 (lHs)
Reference Example 32
Synthesis of 5-methoxy-2-oxo-l234-tetrahydroquinoline-8-
carboxaldehyde
5-Methoxy-34-dihydro-lH-quinolin-2-one (5.00 g 26
mmol) was dissolved in dichloromethane (100 ml) and
dichloromethyl methyl ether (7.65 ml 85 mmol) was added at OQC.
Titanium tetrachloride (12.4 ml 113 mmol) was added dropwise at
a temperature not higher than IQOC. Stirring was carried out at
room temperature for 2 hours and the reaction mixture was poured
into ice water and separated into layers. The aqueous layer was
subjected to extraction with dichloromethane. The organic layers
were combined and washed twice with water washed with a
saturated sodium chloride solution dried over sodium sulfate
filtered and concentrated under reduced pressure. The residue
was dissolved in dichloromethane diethyl ether was added and
the produced insoluble matter was collected by filtration and
dried to thereby obtain 5.32 g (yield: 92%) of 5-methoxy-2-oxol
234-tetrahydroquinoline-8-carboxaldehyde as a light brown
powder.
-NMRfCDCla) dppm:
2.55-2.67 (2Hm) 2.90-3.04 (2Hm) 3.94 (3Hs) 6.69
(lHdJ=8.6Hz) 7.53 (lHdJ=8.6Hz) 9.79 (lHs) 10.60 (lHbrs)
Reference Example 33
Synthesis of 5-methoxy-8-methyl-34-dihydro-lH-quinolin-2-one
5-Methoxy-2-oxo-1234-tetrahydroquinoline-8-
carboxaldehyde (1.00 g) and 10% palladium carbon (100 mg) were
added to a mixed solvent of acetic acid (10 ml) and ethanol (10
ml) followed by catalytic reduction at 50QC for 1 hour. The
catalyst was filtered off and the filtrate was (Table Remove)concentrated
under reduced pressure. The residue was subjected to extraction
with ethyl acetate and the extract was washed twice with water
washed with a saturated sodium chloride solution dried over
sodium sulfate filtered and concentrated under reduced pressure.
The residue was recrystaliized from an ethyl acetate-diethyl
ether mixed solvent to thereby obtain 826 mg (yield: 89%) of 5-
methoxy-8-methyl-34-dihydro-lH-quinolin-2-one as a white powder.
hl-NMRfCDCla) dppm:
2.04 (3Hs) 2.54-2.65 (2Hm) 2.89-3.02 (2Hm) 3.81 (3Hs)
6.51 (IH.d J=8.4Hz) 6.97 (lHdJ=8.4Hz) 7.37 (lHbrs)
Reference Example 34
Synthesis of 5-hydroxy-8-methyl-34-dihydro-lH-quinolin-2-one
A 2N dichloromethane solution (52 ml) of boron
tribromide was added dropwise at -20QC to a dichloromethane
solution (100 ml) of 5-methoxy-8-methyl-34-dihydro-lH-quinolin-
2-one (10.0 g). After stirring for 1 hour the reaction mixture
was poured into ice water and separated into layers. The organic
layer was washed twice with water washed with a saturated sodium
chloride solution dried over sodium sulfate filtered and
concentrated under reduced pressure. The residue was
recrystallized from an ethyl acetate-diethyl ether mixed solvent
to thereby obtain 9.4 g (yield: quantitative) of 5-hydroxy-8-
methyl-34-dihydro-lH-quinolin-2-one as a white powder.
Hl-NMRfCDCla) dppm:
2.14 (3Hs) 2.60-2.65 (2Hm) 2.94-2.99 (2Hm) 5.50 (lHbrs)
6.45 (lHdJ=8.2Hz) 6.88 (!HdJ=8.2Hz) 7.40 (lHbrs)
Reference Example 35
Synthesis of 8-methyl-5-trifluoromethanesulfonyloxy-34-dihydro-
1H-quinolin-2-one
Pyridine (6.2 ml) and trifluoromethanesulfonic
anhydride (10.3 ml) were added with stirring at OQC to an
anhydrous dichloromethane solution (30 ml) of 5-hydroxy-8-methyl-
34-dihydro-lH-quinolin-2-one (9.0 g) followed by stirring for 1
hour. The resulting mixture was concentrated under reduced
pressure water was added to the residue and extraction with
dichloromethane was performed. The extract was washed with water
an aqueous potassium hydrogensulfate solution and water in this
order and dried over anhydrous sodium sulfate. After
concentration under reduced pressure the residue was
recrystallized from an ethyl acetate-diisopropyl ether mixed
solvent to thereby obtain 28 g (yield: 97%) of 8-methyl-5-
trifluoromethanesulfonyloxy-34-dihydro-lH-quinolin-2-one as a
light brown powder.
-NMRfCDCla) dppm:
2.26 (3Hs) 2.60-2.73 (2Hm) 2.99-3.12 (2Hm) 6.89
(lHdJ=8.5Hz) 7.11 (lHdJ=8.5Hz) 7.67 (lHbrs)
Reference Example 36
Synthesis of 5-cyano-8-methyl-34-dihydro-lH-quinolin-2-one
8-Methyl-5-trif luoromethanesulf onyloxy-34-dihydro-lHquinolin-
2-one (4.0 g) zinc cyanide (3.34 g) and
tetrakis(triphenylphosphine) palladium (0.299 g) were suspended
in DMF (40 ml) and the suspension was stirred at 100QC for 4
hours. The insoluble matter was filtered off and ethyl acetate
was added to the filtrate followed by washing with water. After
drying over anhydrous magnesium sulfate the dry product was
concentrated and the residue was recrystallized from a DMFethanol
mixed solvent to thereby obtain 2.1 g (yield: 87%) of 5-
cyano-8-methyl-34-dihydro-lH-quinolin-2-one as a light brown
powder.
-NMRtCDCla) dppm:
2.31 (3Hs). 2.64-2.75 (2Hm) 3.15-3.27 (2Hm) 7.14
(!HdJ=7.9Hz) 7.24 (lHdJ=7.9Hz) 7.67(lHbrs)
Reference Example 37
Synthesis of 8-methyl-2-oxo-l234-tetrahydroquinoline-
carboxaldehyde
5-Cyano-8-methyl-34-dihydro-lH-quinolin-2-one (2.0 g)
and Raney nickel (10 g) were suspended in formic acid (40 ml)
and the suspension was heated under reflux for 6 hours. The
reaction mixture was filtered to remove the insoluble matter and
the filtrate was concentrated. Ethyl acetate and water were added
to the residue and after stirring the mixture was filtered
through Celite. The filtrate was separated into layers and the
organic layer was washed with water and dried over anhydrous
sodium sulfate. After concentration under reduced pressure the
residue was recrystallized from an ethyl acetate-diethyl ether
mixed solvent to thereby obtain 1.29 g (yield: 62%) of 8-methyl-
2-oxo-1234-tetrahydroquinoline-5-carboxaldehyde as a light
brown powder.
-NMRfDMSO-de) dppm:
2.30 (3Hs) 2.37-2.50 (2Hm) 3.28-3.43 (2Hm) 7.26
(lHdJ=7.8Hz) 7.44 (lHdJ=7.8Hz) 9.56 (IH.s) 10.15 (lHs)
Reference Example 38
Synthesis of 5-methoxy-8-phenyl-34-dihydro-lH-quinolin-2-one
8-Bromo-5-methoxy-34-dihydro-lH-quinolin-2-one (10.0
g) tetrakis(triphenylphosphine) palladium (0.45 g) and potassium
carbonate (5.4 g) were suspended in dioxane (100 ml) and
phenylboronic acid (5.24 g) was added followed by heating under
reflux in an argon atmosphere for 2 hours. The reaction mixture
was concentrated under reduced pressure water was added to the
residue and the resulting mixture was subjected to extraction
with ethyl acetate. The extract was washed twice with water
washed with a saturated sodium chloride solution dried over
magnesium sulfate filtered and concentrated under reduced
pressure. The residue was recrystallized from an ethyl acetate-nhexane
mixed solvent to thereby obtain 8.3 g (yield: 84%) of
methoxy-8-phenyl-34-dihydro-lH-quinolin-2-one as a light yellow
powder.
-NMRfCDCla) dppm:
2.57-2.64 (2Hm) 2.97-3.04 (3Hm) 3.88 (2Hs) 6.66
(lHdJ=8.5Hz) 7.09 (lHdJ=8.5Hz) 7.27-7.52 (6Hm)
Reference Example 39
Synthesis of 1-(biphenyl-4-ylmethyl)-5-methoxy-8-phenyl-34-
dihydro-IH-quinolin-2-one
Sodium hydride (60% in oil) (0.87 g) was added at 0" C
to a DMF solution (50 ml) of 5-methoxy-8-phenyl-34-dihydro-lHquinolin-
2-one (5.0 g) followed by stirring for 30 minutes. 4-
Bromomethylbiphenyl (5.37 g) was added and the resulting mixture
was stirred at room temperature for 1 hour. Water was added to
the reaction mixture and extraction with ethyl acetate was
performed. The extract was washed with a saturated sodium
chloride solution dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (ethyl acetate:n-hexane =1:10
— 1:5). The purified product was recrystallized from an ethyl
acetate-n-hexane-diethyl ether mixed solvent to thereby obtain
6.8 g (yield: 82%) of l-(biphenyl-4-ylmethyl)-5-methoxy-8-phenyl-
34-dihydro-lH-guinolin-2-one as a white powder.
-NMRfCDCla) dppm:
2.64-2.70 (2Hm) 2.84-2.96 (2Hm) 3.86 (3Hs) 4.49 (2Hs)
6.73 (lHd J=8.6Hz) 6.91 (2HdJ=8.1Hz) 7.13 (lHdJ=8.6Hz)
7.24-7.55 (12Hm)
Reference Example 40
Synthesis of l-(biphenyl-4-ylmethyl)-5-hydroxy-8-phenyl-34-
dihydro-IH-quinolin-2-one
A dichloromethane solution (12 nil) of 2N boron
tribromide was added dropwise at -20° C to a dichloromethane
solution (50 ml) of l-(biphenyl-4-ylmethyl)-5-methoxy-8-phenyl-
34-dihydro-lH-quinolin-2-one (5.00 g). After stirring for 4
hours the reaction mixture was poured into ice water and
separated into layers. The organic layer was washed twice with
water washed with a saturated sodium chloride solution dried
over sodium sulfate filtered and concentrated under reduced
pressure. The residue was recrystallized from a dichloromethanediisopropyl
ether mixed solvent to thereby obtain 5.01 g (yield:
quantitative) of l-(biphenyl-4-ylmethyl)-5-hydroxy-8-phenyl-3/4-
dihydro-lH-quinolin-2-one as a white powder.
-NMRfCDCla) dppm:
2.66-2.74 (2Hm) 2.84-2.90 (2Hm) 4.48 (2Hs) 5.84 (lHbrs)
6.61 (lHd J=8.4Hz) 6.92 (2HdJ=8.2Hz) 7.01 (lHdJ=8.4Hz)
7.22-7.54 (12Hm)
Reference Example 41
Synthesis of l-(biphenyl-4-ylmethyl)-8-phenyl-5-
trif luoromethanesulf onyloxy-34-dihydro-lH-quinolin-2-one
Pyridine (1.12 ml) and trifluoromethanesulfonic
anhydride (1.99 ml) were added with stirring at 0° C to an
anhydrous dichloromethane solution (40 ml) of l-(biphenyl-4-
ylmethyl) - 5 -hydroxy- 8 -phenyl- 34 -dihydro- IH-quinolin - 2 -one (4.0
g) followed by stirring for 1 hour. The resulting mixture was
concentrated under reduced pressure water was added to the
residue and extraction with dichloromethane was performed. The
extract was washed with water an aqueous potassium
hydrogensulfate solution and water in this order dried over
anhydrous sodium sulfate and concentrated under reduced pressure
to thereby obtain 5.45 g (yield: quantitative) of l-(biphenyl-4-
ylmethyl) - 8 -phenyl - 5 - trif luoromethanesulf onyloxy- 34 -dihydro- 1Hquinolin-
2-one as a white amorphous solid.
-NMRfCDCla) dppm:
2.67-2.81 (2Hm) 2.90-3.03 (2Hm) 4.48 (2Hs) 6.85
(2HdJ=8.2Hz) 7.05-7.15 (lHm) 7.20-7.58 (13Hm)
Reference Example 42
Synthesis of l-(biphenyl-4-ylmethyl)-5-cyano-8-phenyl-34-
dihydro-lH-quinolin-2-one
1-(Biphenyl-4-ylmethyl)-8-phenyl-5-
trifluoromethanesulfonyloxy-34-dihydro-lH-quinolin-2-one (5.2 g)
zinc cyanide (2.50 g) and tetrakis(triphenylphosphine) palladium
(0.224 g) were suspended in DMF (50 ml) followed by stirring at
100" C for 4 hours. The insoluble matter was filtered off and
ethyl acetate was added to the filtrate and the resulting
mixture was washed with water. After drying over anhydrous
magnesium sulfate the dry product was concentrated to thereby
obtain 2.1 g (yield: 90%) of l-(biphenyl-4-ylmethyl)-5-cyano-8-
phenyl-34-dihydro-lH-quinolin-2-one as a white amorphous solid.
-NMRfCDCla) dppm:
2.75-2.82 (2Hm) 3.09-3.15 (2Hm) 4.48(2Hs) 6.85
(2HdJ=8.3Hz) 7.20-7.57 (14Hm)
Reference Example 43
Synthesis of l-(biphenyl-4-ylmethyl)-8-phenyl-2-oxo-l234-
tetrahydroquinoline-5-carboxaldehyde
1-(Biphenyl-4-ylmethyl)-5-cyano-8-phenyl-34-dihydrolH-
quinolin-2-one (3.0 g) and Raney nickel (15 g) were suspended
in formic acid (60 ml) and the suspension was heated under
-210-
reflux for 11 hours. The reaction mixture was filtered to remove
the insoluble matter and the filtrate was concentrated. Ethyl
acetate and water were added to the residue and after stirring
the mixture was filtered through Celite. The filtrate was
separated into layers and the organic layer was washed with
water dried over anhydrous sodium sulfate and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (ethyl acetate:n-hexane = 1:10 - 1:3). The
purified product was concentrated to thereby obtain 0.44 g
(yield: 15%) of 1-(biphenyl-4-ylmethyl)-8-phenyl-2-oxo-1234-
tetrahydroquinoline-5-carboxaldehyde as a white amorphous solid.
-NMRfCDCla) dppm:
2.69-2.75 (2Hm) 2.37-2.43 (2Hm) 4.48 (2Hs) 6.87
(2HdJ«=8.3Hz) 7.25-7.55 (13Hm) 7.61 (lHdJ=8.OHz) 10.20
(IH.s)
Reference Example 44
Synthesis of l-benzyl-8-methoxy-2-oxo-l234-
tetrahydroquinoline-5-carboxaldehyde
Sodium hydride (60% in oil) (1.07 g) was added at 0"C
to a DMF solution (50 ml) of 8-methoxy-2-oxo-l234-
tetrahydroquinoline-5-carboxaldehyde (5.0 g) followed by
stirring for 30 minutes. Benzyl bromide (3.47 ml) was added and
the resulting mixture was stirred at room temperature for 1 hour.
Water was added to the reaction mixture and extraction with
ethyl acetate was performed. The extract was washed with a
saturated sodium chloride solution dried over anhydrous
magnesium sulfate and concentrated under reduced pressure. The
residue was recrystallized from an ethyl acetate-n-hexane mixed
solvent to thereby obtain 6.6 g (yield: 92%) of l-benzyl-8-
methoxy-2-oxo-1234-tetrahydroquinoline-5-carboxaldehyde as a
white powder.
-NMRfCDCla) dppm:
2.60 (2HtJ=7.0Hz) 3.38 (2HtJ=7.0Hz) 3.82 (3Hs) 5.29
(2Hs) 6.82 (!HdJ=8.6Hz) 7.0-7.3 (5Hm) 7.5 (lHdJ=8.6Hz).
-211-
10.00(lHs)
Reference Example 45
Synthesis of l-benzyl-8-hydroxy-2-oxo-l234-
tetrahydroquinoline-5-carboxaldehyde
1-Benzyl-8-methoxy-2-oxo-1234-tetrahydroquinoline-5-
carboxaldehyde (3.0 g) and sodium 4-methylbenzenethiolate (3.27
g) were added to DMSO (30 ml) followed by stirring at 100° C for
40 minutes. Water and an aqueous solution of potassium
hydrogensulfate were added to the reaction mixture and
extraction with ethyl acetate was performed. The extract was
washed with a saturated sodium chloride solution dried over
anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was recrystallized from an ethyl acetate-nhexane
mixed solvent to thereby obtain 6.6 g (yield: 92%) of 1-
benzyl-8-methoxy-2-oxo-l234-tetrahydroquinoline-5-
carboxaldehyde as a light brown powder.
-NMRfDMSO-ds) dppm:
2.42-2.59 (2Hm) 3.19-3.40 (2Hm) 5.31 (2Hs) 6.85
(lHdJ=8.5Hz) 7.05-7.27 (5Hm) 7.43 (!HdJ=8.5Hz) 9.94
(1H.S) 11.12 (1HS)
Reference Example 46
Synthesis of 1-(4-carbomethoxybenzyl)-8-methoxy-2-oxo-1234-
tetrahydroquinoline-5-carboxaldehyde
Sodium hydride (60% in oil) (2.87 g) was added at 0°C
to a DMF solution (100 ml) of 8-methoxy-2-oxo-1234-
tetrahydroquinoline-5-carboxaldehyde (13.4 g) followed by
stirring for 30 minutes. Methyl 4-bromomethyl benzoate (18.0 g)
was added and the resulting mixture was stirred at room
temperature overnight. Water was added to the reaction mixture
and extraction with ethyl acetate was performed. The extract was
washed with a saturated sodium chloride solution dried over
anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (ethyl acetate:n-hexane = 1:4 -» 1:2). The
purified product was recrystallized from a chloroform-diisopropyl
ether mixed solvent to thereby obtain 14.43 g (yield: 62%) of 1-
(4-carbomethoxybenzyl)-8-methoxy-2-oxo-1234-
tetrahydroquinoline-5-carboxaldehyde as a white powder.
-NMRfDMSO-de) dppm:
2.50-2.61 (2Hm) 3.29-3.41 (2Hm) 3.71 (3Hs) 3.79 (3Hs)
5.18(2Hs) 7.06 (lHdJ=8.7Hz) 7.25 (2HdJ=8.2Hz) 7.60
(lHdJ=8.7Hz) 7.81 (2HdJ=8.2Hz) 10.02(lHs)
Using appropriate starting materials and following the
procedure of Reference Example 41 the compounds of Reference
Examples 47 to 50 were synthesized.
Reference Example 47
8-Chloro-5-trifluoromethanesulfonyloxy-34-dihydro-lH-quinolin-2-
one
-NMRfCDCla) dppm:
2.63-2.75 (2Hm) 3.02-3.15 (2Hm) 6.94 (lHdJ=8.9Hz) 7.34
(lHdJ=8.9Hz) 7.85(lHbrs)
Reference Example 48
6-Trifluoromethanesulfonyloxy-34-dihydro-lH-quinolin-2-one
-NMRfCDCla) dppm:
2.60-2.73 (2Hm) 3.01 (2HtJ=8.0Hz) 6.81-6.92 (lHm). 7.00-
7.12 (2Hm) 9.09 (lHbrs)
Reference Example 49
7-Trifluoromethanesulfonyloxy-34-dihydro-lH-quinolin-2-one
-NMRfCDdo) dppm:
2.60-2.71 (2Hm) 3.00 (2HtJ=8.0Hz) 6.70-6.77 (IH.m) 6.84-
6.95 (lHm) 7.16-7.30 (lHm) 8.80 (lHbrs)
Reference Example 50
8-Trifluoromethanesulfonyloxy-34-dihydro-lH-quinolin-2-one
dppm:
-213-
2.63-2.75 (2Hm) 3.05 (2HtJ=7.9Hz) 7.03 (1HtJ=7.9Hz) 7.12-
7.28 (2Hm) 7.78(lHbrs)
Reference Example 51
Synthesis of 6-oxo-56-dihydrophenanthridine-2-carbonitrile
2-(44-Dimethyl-[132]dioxaboronan-2-yl)-benzoic acid
ethyl ester (19.84 g) 2-iodo-4-cyanoaniline (18.47 g)
tetrakis(triphenylphosphine) palladium (8.75 g) and potassium
phosphate (35.36 g) were added to dioxane (360 ml) and the
resulting mixture was heated under reflux overnight. The reaction
solvent was cooled and the produced solid was collected by
filtration washed with water and dried to thereby obtain 17.3 g
(yield: quantitative) of the title compound as a yellow solid.
-NMRtDMSO-de) dppm:
7.47 (lHdJ=8.5Hz) 7.6-8.0 (3Hm) 8.1-8.2 (lHm) 8.3-8.4
(lHm) 8.98 (lHs) 12.05(lHbrs)
Reference Example 52
Synthesis of 5-benzyl-6-oxo-56-dihydrophenanthridine-2-
carbonitrile
6-Oxo-56-dihydrophenanthridine-2-carbonitrile (1 g)
was suspended in DMF (20 ml) 60% sodium hydride (0.2 g) was
added under ice cooling and stirring was carried out until the
generation of hydrogen stopped. Benzyl bromide (0.59 ml) was
added followed by stirring at room temperature for 1 hour. Water
was added and the produced solid was collected by filtration and
purified by silica gel chromatography (dichloromethanem-hexane
=1:1) to thereby obtain 0.68 g (yield: 48%) of the title compound
as colorless crystals.
-NMRfDMSO-dfi) dppm:
5.57 (2Hs) 7.1-7.5 (6Hm) 7.6-7.95 (3Hm) 8.27 (IH.dJ=8.3Hz)
8.58 (lHdJ=1.8Hz) 8.63(lHddJ=8.3HzJ=1.8Hz)
Using appropriate starting materials and following the
procedure of Reference Example 52 the compounds of Reference
-214-
Examples 53 to 54 were synthesized.
Reference Example 53
5-Ethyl-6-oxo-56-dihydrophenanthridlne-2-carbonitrile
-NMRfDMSO-dJ dppm:
1.43 (3HtJ=7.1Hz) 4.47 (2HtJ=7.1Hz) 7.35-7.9 (4Hm) 8.27
(lH.dJ=8.3Hz) 8.5-8.65 (2Hm)
Reference Example 54
5-(l-Biphenyl-4-ylmethyl)-6-oxo-56-dihydrophenanthridine-2-
carbonitrile
-NMRfDMSO-ds) dppm:
5.57 (2Hs) 7.1-7.5 (6Hm) 7.6-7.95 (3Hm) 8.27 (lHdJ=8.3Hz)
8.58 (lHdJ=1.8Hz) 8.63 (lHddJ=8.3HzJ=l.8Hz)
Reference Example 55
Synthesis of 5-benzyl-6-oxo-56-dihydrophenanthridine-2-
carboxaldehyde
5-Benzyl-6-oxo-56-dihydrophenanthridine-2-carbonitrile
(1.24 g) and Raney nickel (0.8 g) were suspended in 75% formic
acid (25 ml). The suspension was heated under reflux for 1 hour
and 40 minutes and filtered while hot. The filtrate was
concentrated and purified by silica gel chromatography (methylene
chloride:methanol = 50:1) to thereby obtain 1.08 g (yield: 80%)
of the title compound as a colorless crystals.
1H-NMR(DMSO-d6) dppm:
5.69 (2Hs) 7.15-7.35 (6Hm) 7.5-8.05 (3Hm)
8.47(lHdJ=7.9Hz) 8.70 (lHdJ=8.IHz) 8.63 (lHdJ=l.4Hz)
10.08 (lHs)
Using appropriate starting materials and following the
procedure of Reference Example 55 the compound of Reference
Example 56 was synthesized.
Reference Example 56
5-Ethyl-6-oxo-56-dihydrophenanthridine-2-carboxaldehyde
-215-
1H-NMR(DMSO-d6) dppm:
1.45 (3HtJ=7.1Hz) 4.50 (2HtJ=7.1Hz) 7.15-7.35 (6Hm) 7.5-
8.15 (4Hm) 8.39 (lHdJ=8.IHz) 8.56 (lHddJ=8.1HzJ=1.3Hz)
8.81 (lHdJ=1.8Hz) 10.11 (lHs)
Using appropriate starting materials and following the
procedure of Reference Example 13 the compounds of Reference
Examples 104 to 130 133 134 and 137 to 141 were synthesized.
Using appropriate starting materials and following the
procedure of Reference Example 19 the compounds of Reference
Examples 147 and 148 were synthesized.
Using appropriate starting materials and following the
procedure of Reference Example 21 the compounds of Reference
Examples 57 to 63 were synthesized.
Using appropriate starting materials and following the
procedure of Reference Example 23 the compounds of Reference
Examples 144 to 145 and 152 to 156 were synthesized.
Using appropriate starting materials and following the
procedure of Reference Example 24 the compounds of Reference
Examples 70 71 and 81 were synthesized.
Using appropriate starting materials and following the
procedure of Reference Example 25 the compounds of Reference
Examples 64 to 69 72 79 80 82 and 83 were synthesized.
Using appropriate starting materials and following the
procedure of Reference Example 26 the compounds of Reference
Examples 75 to 77 were synthesized.
Using appropriate starting materials and following the
procedure of Reference Example 28 the compounds of Reference
Examples 74 and 78 were synthesized.
Using appropriate starting materials and following the
procedure of Reference Example 29 the compounds of Reference
Examples 98 99 100 to 103 131 135 136 and 146 were
synthesized.
Using appropriate starting materials and following the
procedure of Reference Example 31 the compounds of Reference
-216-
Examples 84 to 97 and 142 were synthesized.
Using appropriate starting materials and following the
procedure of Reference Example 37 the compounds of Reference
Examples 149 to 151 were synthesized.
In the above Tables Me represents methyl and tBu
represents tert-butyl.
Reference Example 158
Synthesis of 5-(l3-dioxolan-2-yl)-l-{4-[(N-methyl-N-
10 phenylamino)methyl]benzyl}-34-dihydro-lH-quinolin-2-one
1-(4-Chloromethylbenzyl)-5-(13-dioxolan-2-yl)-34-
dihydro-lH-quinolin-2-one (100 mg 0.28 mmol) Nmethylaniline
(0.045 ml 0.42 mmol) and potassium carbonate
(57.9 mg 0.42 mmol) were added to acetonitrile (1 ml)
15 followed by heating under reflux for 4 hours. After cooling
to room temperature water was added to the reaction mixture
and extraction with dichloromethane was performed. The
organic layer was washed with water and a saturated sodium
chloride solution and dried over anhydrous sodium sulfate.
20 The dry product was concentrated under reduced pressure and
the residue was purified by preparative silica gel thin layer
chromatography (n-hexane:ethyl acetate = 1:1). The purified
product was concentrated to dryness under reduced pressure to
thereby obtain 80 mg (yield: 67%) of 5-(l3-dioxolan-2-yl)-l-{4 -[(N-methyl-N-phenylamino)methyl]benzyl}-34-dihydro-1Hquinolin-
2-one as a light yellow amorphous solid.
-NMRfCDCla) dppm: 2.72-2.78 (2Hm) 2.98 (3Hs) 3.08-3.12
(2Hm) 4.06-4.16 (4Hm) 4.48 (2Hs) 5.15 (2Hs) 5.94
(lHs) 6.67-6.74 (3Hm) 6.90 (!Hd J=8. IHz) . 7.09-7.26
(8Hm)
Reference Example 159
Synthesis of 5-(13-dioxolan-2-yl)-l-(6-
piperidinomethylpyridin-2-ylmethyl)-34-dihydro-lH-quinolin-
2-one
1-(6-Chloromethylpyridin-2-ylmethyl) - 5 - (1 3 -
dioxolan-2-yl)-34-dihydro-lH-quinolin-2-one (1.0 g 2.8
mmol) was added to piperidine (2 ml) followed by stirring in
an argon atmosphere at 100" C for 2 hours. After cooling to
room temperature water and a small quantity of acetic acid
were added to the reaction mixture and extraction with ethyl
acetate was performed twice. The organic layers were
combined washed twice with water and once with a saturated
sodium chloride solution and dried over anhydrous sodium
sulfate. The dry product was concentrated under reduced
pressure and the residue was purified by silica gel column
chromatography (dichloromethane:methanol = 20:1). The
purified product was concentrated to dryness under reduced
pressure to thereby obtain 0.73 g (yield: 64%) of 5-(13-
dioxolan-2-yl)-1-(6-piperidinomethylpyridin-2-ylmethyl)-34-
dihydro-lH-quinolin-2-one as a light yellow amorphous solid.
-NMRfCDCla) dppm: 1.44-1.49 (2Hm) 1.56-1.65 (4Hm) 2.42-
2.46 (4Hm) 2.74-2.80 (2Hm) 3.09-3.15 (2Hm) 3.64 (2Hs)
4.01-4.17 (4Hm) 5.27 (2HS) 5.95 (lHs) 6.95-7.02 (2Hm)
7.11 (lHtJ=7.9Hz) 7.23-7.31 (2Hm) 7.54 (1HtJ=7.7Hz)
Reference Example 160
Synthesis of 5-(l3-dioxolan-2-yl)-l-(4-
phenylsulfanylbenzyl)-34-dihydro-IH-quinolin-2-one
-240-
1-(4-Chloromethylbenzyl)-5-(13-dioxolan-2-yl)-34-
dihydro-lH-quinolin-2-one (1.0 g 2.79 mmol) thiophenol
(0.37 ml 3.63 mmol) and l8-diazabicyclo[5.4.0]undecene-7
(DBU) (0.84 ml 5.59 mmol) were added to THF (30 ml)
followed by heating under reflux for 7 hours. After cooling
to room temperature the reaction mixture was concentrated
under reduced pressure. The residue was purified by silica
gel column chromatography (n-hexane:ethyl acetate = 1:1).
The purified product was concentrated to dryness under
reduced pressure to thereby obtain 1.13 g (yield: 94%) of 5-
(13-dioxolan-2-yl)-1-(4-phenylsulfanylbenzyl)-34-dihydrolH-
quinolin-2-one as a white solid.
H-NMRtCDCla) dppm: 2.73-2.79 (2Hm) 3.06-3.12 (2H.m) 4.01-
4.17 (6Hm) 5.14 (2Hs) 5.95 (IH.s) 6.85-6.88 (IH.ra)
709-7.17 (4Hm) 7.19-7.32 (7Hm)
Reference Example 161
Synthesis of l-[2-(l-biphenyl-4-ylpiperidin-4-yl)ethyl]-2-
oxo-1234-tetrahydroguinoline-5-carboxaldehyde
Palladium acetate (34 mg 0.15 mmol) tri-tertbutylphosphine
tetrafluoroborate (66 mg 0.23 mmol) and
sodium tert-butoxide (218 mg 2.27 mmol) were added to a
toluene solution (10 ml) of 5-(l3-dioxolan-2-yl)-l-(2-
piperidin-4-ylethyl)-34-dihydro-lH-guinolin-2-one (500 mg
1.52 mmol) and 4-bromobiphenyl (424 rag 1.82 mmol) followed
by stirring in an argon atmosphere at 100°C for 7.5 hours.
After cooling to room temperature water was added to the
reaction mixture and extraction with ethyl acetate was
performed. The extract was dried over sodium sulfate and
concentrated under reduced pressure and the residue was
purified by basic silica gel column chromatography (nhexane:
ethyl acetate = 2:1). The purified product was
concentrated under reduced pressure and the residue was
dissolved in acetone (10 ml). p-Toluenesulfonic acid
monohydrate (104 mg) and water (2 ml) were added followed by
heating under reflux for 15 minutes. The resulting mixture
was cooled to room temperature and concentrated under reduced
pressure. The residue was rendered basic by adding an
aqueous solution of potassium carbonate and washed for 10
minutes in an ultrasonic washing machine. The produced
insoluble matter was collected by filtration washed with
water and dried to thereby obtain 213 mg (yield: 32.1%) of 1-
[2-(l-biphenyl-4-ylpiperidin-4-yl)ethyl]-2-oxo-1234-
tetrahydroquinoline-5-carboxaldehyde as a colorless solid.
-NMR (CDC13) dppm: 1.2-2.3 (7Hm) 2.6-2.7 (2Hm) 3.0-3.25
(2H m) 3.4-3.55 (2Hm) 3.65-3.8 (2Hm) 3.95-4.1 (2Hm)
7.18 (1H dJ=8.0Hz) 7.25-7.7 (10Hm) 7.84 (lHdJ=8.IHz)
10.22 (lHs)
Reference Example 162
Synthesis of 1-[3-(4-chlorophenylsulfanyl)propyl]-2-oxo-
123.4-tetrahydroquinoline-5-carboxaldehyde
1-(3-Bromopropyl)-5-(13-dioxolan-2-yl)-34-
dihydro-lH-quinolin-2-one (797 mg 2.34 mmol) 4-
chlorothiophenol (407 mg 2.81 mmol) and potassium carbonate
(421 mg 3.05 mmol) were added to acetonitrile (16 ml)
followed by heating under reflux for 5 hours. After cooling
to room temperature water was added to the reaction mixture
and extraction with ethyl acetate was performed. The extract
was dried over sodium sulfate and concentrated under reduced
pressure and the residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate = 3:1 - 2:1). The
purified product was concentrated under reduced pressure and
the residue was dissolved in acetone (16 ml) p-
Toluenesulfonic acid monohydrate (53.5 mg) and water (3 ml)
were added followed by stirring at room temperature
overnight. An aqueous solution of potassium carbonate was
added to the reaction mixture and extraction with
dichloromethane was performed. The organic layer was washed
with a saturated sodium chloride solution dried over
anhydrous sodium sulfate and concentrated under reduced
pressure to thereby obtain 700 mg (yield: 83%) of l-[3-(4-
chlorophenylsulfanyl)propyl]-2-oxo-1234-
tetrahydroquinoline-5-carboxaldehyde as a colorless oil.
1H-NMR(CDC13) dppm: 1.9-2.05 (2Hm) 2.55-2.65 (2Hm) 2.9-
3.05 (4Hm) 4.0-4.2 (6Hm) 5.94 (lHs) 6.96 (lHdJ=7.9Hz)
7.2-7.35 (6H m)
Reference Example 163
Synthesis of 1-[3-(4-benzylpiperidin-l-yl)propyl]-2-oxo-
1234-tetrahydroquinoline-5-carboxaldehyde
1-(3-Bromopropyl)-5-(13-dioxolan-2-yl)-34-
dihydro-lH-quinolin-2-one (790 mg 2.32 mmol) 4-
benzylpiperidine (0.49 ml 2.79 mmol) and potassium carbonate
(142 mg 1.03 mmol) were added to acetonitrile (15 ml)
followed by heating under reflux for 1.5 hours. After
cooling to room temperature the reaction mixture was
filtered to remove the insoluble matter. The solid was
washed with acetonitrile and the filtrate and washing were
combined and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (nhexane:
ethyl acetate = 3:1 -» ethyl acetatetmethanol = 50:1).
The purified product was concentrated under reduced pressure
and the residue was dissolved in acetone (15 ml) p-
Toluenesulfonic acid monohydrate (368 mg) was added and the
resulting mixture was heated under reflux for 2 hours. An
aqueous solution of potassium carbonate was added to the
reaction mixture followed by concentration under reduced
pressure. Water was added to the residue and extraction
with dichloromethane was performed. The organic layer was
washed with a saturated sodium chloride solution dried over
anhydrous sodium sulfate and concentrated under reduced
pressure to thereby obtain 672 mg (yield: quantitative) of 1-
[3 -(4-ben zylpiperidin-1-yl)propyl]-2-oxo-1234-
dppm: 1.2-1.95 (9Hm) 2.35 (2HtJ=7.OHz)
2.4-2.7 (4Hm) 2.8-3.1 (4Hm) 3.9-4.2 (6Hm) 5.94 (lHs)
7.1-7.4 (8Hm)
Using appropriate starting materials and following
the procedure of Reference Example 24 the compounds of
Reference Examples 178 and 185 shown below were synthesized.
Using appropriate starting materials and following
the procedure of Reference Example 25 the compounds of
Reference Examples 164 165 167 to 172 176 177 179 183
and 184 shown below were synthesized.
Using appropriate starting materials and following
the procedure of Reference Example 26 the compounds of
Reference Examples 186 to 190 192 193 197 198 203 and
206 to 209 shown below were synthesized.
Using appropriate starting materials and following
the procedure of Reference Example 27 the compounds of
Reference Examples 166 and 180 to 182 shown below were
synthesized.
Using appropriate starting materials and following
the procedure of Reference Example 30 the compounds of
Reference Examples 73 196 200 201 and 210 shown below were
synthesized.
Using appropriate starting materials and following
the procedure of Reference Example 158 the compound of
Reference Example 175 shown below was synthesized.
Using appropriate starting materials and following
the procedure of Reference Example 159 the compounds of
Reference Examples 173 and 174 shown below were synthesized.
Using appropriate starting materials and following
the procedure of Reference Example 161 the compounds of
Reference Examples 202 204 205 and 214 shown below were
synthesized.
Using appropriate starting materials and following
the procedure of Reference Example 162 the compounds of
Reference Examples 191 and 195 shown below were synthesized.
Using appropriate starting materials and following
the procedure of Reference Example 163 the compounds of
Reference Examples 194 199 and 211 to 213 shown below were
synthesized.
Using appropriate starting materials and following
the procedure of Reference Example 32 the compounds of
Reference Example 132 shown below was synthesized.
Using appropriate starting materials and following
the procedure of Reference Example 41 the compounds of
Reference Example 143 shown below was synthesized.
Using appropriate starting materials and following
the procedure of Reference Example 22 the compounds of
Reference Example 157 shown below was synthesized.
Synthesis of 5-(8-methoxy-l-methyl-2-oxo-l2-
dihydroquinolin-5-ylmethyl)thiazolidine-24-dione
1.0 g of 2-chloro-3-(8-methoxy-l-methyl-2-oxo-l2-
dihydroquinolin-5-yl)propionic acid 0.45 g of thiourea and
0.4 g of sodium acetate were added to 20 ml of methoxy
ethanol and the mixture was stirred at 110°C for 7.5 hours.
The reaction mixture was concentrated under reduced pressure
an aqueous sodium hydrogencarbonate solution was added to the
residue to precipitate a solid and the precipitated solid
was collected by filtration. The filtrate was extracted with
dichloromethane and the extract was dried over anhydrous
sodium sulfate and concentrated. The concentrated residue
and the solid collected by filtration were combined and added
to a mixed solvent of 10% hydrochloric acid and ethanol
followed by heating and refluxing overnight. The solvent was
distilled off under reduced pressure and the residue was
recrystallized from an aqueous DMF giving 0.41 g of 5-(8-
methoxy-1-methyl-2-oxo-12-dihydroquinolin-5-
ylmethyl)thiazolidine-24-dione as a yellow powder.
Melting point: 254°C-255°C
Example 2
Synthesis of 5-[2-(8-methoxy-l-raethyl-2-oxo-l2-
dihydroquinolin-5-yl)ethyl]thiazolidine-24-dione
912 mg of 2-chloro-4-(8-methoxy-1-methyl-2-oxo-12-
dihydroquinolin-5-yl)butyric acid 390 mg of thiourea and
394 mg of sodium acetate were added to 20 ml of
methoxyethanol followed by stirring at 110°C for 4 hours.
The reaction mixture was concentrated under reduced pressure.
Water was added to the residue and the mixture was extracted
with dichloromethane. The extract was dried over anhydrous
sodium sulfate and concentrated. The residue was added to a
mixed solvent of 10 ml of 10% hydrochloric acid and 10 ml of
ethanol followed by heating and refluxing overnight. The
-258-
solvent was distilled off under reduced pressure and the
residue was recrystallized from a DMF-ethanol mixed solvent
giving 332 mg (31% yield) of 5-[2-(8-methoxy-l-methyl-2-oxo-
12-dihydroquinolin-5-yl)ethyl]thiazolidine-24-dione as a
yellow powder.
Melting point: 222°C to 224°C
Example 3
Synthesis of 5-[3-(8-methoxy-l-methyl-2-oxo-l2-
dihydroquinolin-5-yl)propyl]thiazolidine-24-dione
1 g of 2-chloro-5-(8-methoxy-l-methyl-2-oxo-l2-
dihydroquinolin-5-yl)valeric acid 380 mg of thiourea and
380 mg of sodium acetate were added to 20 ml of
methoxyethanol followed by stirring at 110°C for 5 hours.
The reaction mixture was concentrated under reduced pressure
and water and a small amount of ethanol were added to the
residue to precipitate a solid. The precipitated solid was
collected by filtration. The solid collected by filtration
was added to a mixed solvent of 10 ml of 10% hydrochloric
acid and 10 ml of ethanol followed by heating and refluxing
overnight. The solvent was distilled off under reduced
pressure and the residue was extracted with dichloromethane.
The extract was dried over anhydrous sodium sulfate and
concentrated. The concentrated residue was purified by
silica gel column chromatography (dichloromethane:methanol of
100:1 -+ 10:1) and recrystallized from an ethanol-ether
mixed solvent giving 332 mg (29% yield) of 5-[3-(8-methoxy-
1-methyl-2-oxo-12-dihydroquinolin-5-yl)propyl]thiazolidine-
24-dione as a light yellow powder.
Melting point: 172°C to 175°C
Example 4
Synthesis of 5-(8-methoxy-l-methyl-2-oxo-l2-
dihydroquinolin-5-yl)thiazolidine-24-dione
3.02 g of ethyl chloro-(8-methoxy-l-methyl-2-oxo-
259-
12-dihydroquinolin-5-yl)acetate 1.4 g of thiourea and 2 g
of sodium acetate were added to 50 ml of methoxyethanol
followed by stirring at 110°C for 2.5 hours. The reaction
mixture was concentrated under reduced pressure. Water was
added to the residue to precipitate a solid and the
precipitated solid was collected by filtration. The
collected solid was added to a mixed solvent of 30 ml of 10%
hydrochloric acid and 30 ml of ethanol followed by heating
and refluxing overnight. The resultant was concentrated to
half its original volume under reduced pressure. Water was
added thereto and the mixture was cooled with ice to
precipitate a solid. The precipitated solid was collected by
filtration. The solid was recrystallized from a DMF-ethanol
mixed solvent giving 1.68 g (57% yield) of 5-(8-methoxy-lmethyl-
2-oxo-l2-dihydroquinolin-5-yl)thiazolidine-24-dione
as a gray powder.
Melting point: 255°C (decomposition)
Example 5
Synthesis of 5-[1-(4-chlorobenzyl)-2-oxo-l2-
dihydroquinolin-4-ylmethylidene]thiazolidine-24-dione
1.50 g of l-(4-chlorobenzyl)-2-oxo-l2-
dihydroquinolin-4-carboxaldehyde and 0.826 g of 24-
thiazolidinedione were suspended in 30 ml of toluene. Five
drops of piperidine and five drops of acetic acid were added
followed by heating and refluxing for 6 hours. The resultant
was allowed to cool to precipitate a solid and the
precipitated solid was collected by filtration and dried
giving 1.01 g (50% yield) of 5-[l-(4-chlorobenzyl)-2-oxo-l2-
dihydroquinolin-4-ylmethylidene]thiazolidine-24-dione as a
light-brown powder.
-NMRfDMSO-de) dppm:
5.53 (2H s) 6.76 (1H s). 7.11-7.49 (6H m) 7.53-7.64 (1H
m) 7.81 (1H d J=8.1Hz) 8.04 (1H. s) 12.21-13.32 (1H br)
-260-
Example 6
Synthesis of 5-[l-(4-chlorobenzyl)-2-oxo-l2-
dihydroquinolin-3-ylmethylidene]thiazolidine-24-dione
1.50 g of l-(4-chlorobenzyl)-2-oxo-12-
dihydroquinolin-3-carboxaldehyde and 0.826 g of 24-
thiazolidinedione were suspended in 30 ml of toluene and
five drops of piperidine and five drops of acetic acid were
added followed by heating and refluxing for 6 hours. The
resultant was allowed to cool to precipitate a solid. The
precipitated solid was collected by filtration and dried
giving 1.36 g of 5-[l-(4-chlorobenzyl)-2-oxo-l2-
dihydroquinolin-3-ylmethylidene]thiazolidine-24-dione as a
yellow powder (68% yield).
1H-NMR(DMSO-d6) dppm:
5.55 (2H s) 7.18-7.45 (6H m) 7.53-7.65 (1H m) 7.88-8.00
(2H m) 8.21 (1H s) 12.59 (1H brs)
Using appropriate starting materials the same
procedure as in Example 6 was conducted giving compounds of
the following Examples 7 to 13.
Example 7
5-[1-(l-Biphenyl-4-ylmethyl-2-oxo-l2-
dihydroquinolin-4-yljmethylidene]thiazolidine-24-dione
Hl-NMRtDMSO-de) dppm:
5.59 (2H brs) 6.78 (1H s) 7.18-7.70 (12H m) 7.82 (1H d
J=8.0Hz) 8.05 (1H s) 12.81 (1H brs)
Example 8
5-[l-(l-Biphenyl-4-ylmethyl-2-oxo-l2-
dihydroquinolin-3-yl)methylidene]thiazolidine-24-dione
-NMRfDMSO-de) dppm:
5.61 (2H brs) 7.21-7.51 (7H m) 7.51-7.68 (5H m) 7.87-
8.00 (2H m) 8.22 (1H s) 12.60 (1H brs)
-261-
Example 9
5-[l-(8-Methoxy-l-methyl-2-oxo-l2-dihydroquinolin-
5-yl)methylidene]thiazolidine-24-dione
Melting point: 300°C or higher
-NMRfDMSO-de) dppm:
3.80 (3H s) 3.95 (3H s) 6.70 (1H d J=9.8Hz) 7.35-7.45
(2H m) 8.05 (1H d J=9.8Hz) 8.14 (1H s) 12.63 (IE brs)
Example 10
5-[1-(8-Methoxy-l-methyl-2-oxo-l2-dihydroquinolin-
5-yl)methylidene]-3-methylthiazolidine-24-dione
Melting point: 270°C (decomposition)
Example 11
5-{1-[8-Methoxy-1-(4-bromoben zyl)-2-oxo-12-
dihydroquinolin-5-yl]methylidene}thiazolidine-24-dione
-NMRfDMSO-de) dppm:
3.65 (3H s) 5.67 (2H s) 6.80 (1H d J=9.8Hz) 7.03 (2H
d J=8.5Hz) 7.25-7.40 (2H m) 7.40-7.52 (2H m) 8.16 (2H
d J=10.9Hz) 12.64 (1H brs)
Example 12
5-[l-(l-Biphenyl-4-ylmethyl-2-oxo-l234-
tetrahydroquinolin-7-yl)methylidene]thiazolidine-24-dione
-NMRfDMSO-de) dppm:
2.70-2.84 (2H m) 2.97-3.09 (2H m) 5.22 (2H brs) 7.12
(1H s) 7.15-7.25 (1H m) 7.25-7.49 (6H m) 7.56-7.71 (5H
m) 12.52 (1H brs)
Example 13
5-[1-(1-Biphenyl-4-ylme thy1-2-oxo-1234-
tetrahydroquinolin-8-yl)methylidene]thiazolidine-24-dione
-NMRCDMSO-dfi) dppm:
2.55-2.68 (2H m) 2.80-2.94 (2H m) 4.98 (2H s) 6.98-7.16
(3H m) 7.22-7.63 (9H m) 7.75 (1H s) 12.57 (1H brs)
Example 14
Synthesis of 5-[l-(4-chlorobenzyl)-2-oxo-l2-
dihydroquinolin-4-ylmethyl]thiazolidine-24-dione
0.96 g of 5-[l-(4-chlorobenzyl)-2-oxo-l2-
dihydroquinolin-4-ylmethylidene]thiazolidine-24-dione 0.735
g of diethyl l4-dihydro-26-dimethyl-35-
pyridinedicarboxylate and 0.96 g of silica gel were added to
30 ml of toluene followed by heating and refluxing overnight.
The solvent was distilled off and the residue was purified
by silica gel column chromatography (dichloromethane:ethyl
acetate of 10:1 -»• 3:1) and the purified product was
recrystallized from a chloroform-ether mixed solvent giving
0.87 g (91% yield) of 5-[1-(4-chlorobenzyl)-2-oxo-l2-
dihydroquinolin-4-ylmethyl]thiazolidine-24-dione as a white
powder.
Melting point: 142.1°C to 143.7°C
Example 15
Synthesis of 5-[1-(4-chlorobenzyl)-2-oxo-l2-
dihydroquinolin-3-ylmethyl]thiazolidine-24-dione
1.207 g of 5-[l-(4-chlorobenzyl)-2-oxo-l2-
dihydroquinolin-3-ylmethylidene]thiazolidine-24-dione 0.924
g of diethyl l4-dihydro-26-dimethyl-35-
pyridinedicarboxylate and 1.2 g of silica gel were added to
30 ml of toluene followed by heating and refluxing overnight.
0.77 g of diethyl 14-dihydro-26-dimethyl-35-pyridine
dicarboxylate was further added to the reaction liquid
followed by heating and refluxing overnight. The solvent was
distilled off and the residue was purified by silica gel
column chromatography (dichloromethane:ethyl acetate of
3:1). The purified product was recrystallized from a
chloroform-ether mixed solvent giving 0.74 g (61% yield)
5-[1-(4-chlorobenzyl)-2-oxo-12-dihydroquinolin-4-
ylmethyl]thiazolidine-24-dione as a white powder.
-263-
Melting point: 230.7°C to 231.9°C
Using appropriate starting materials the same
procedure as in Example 15 was conducted giving compounds of
the following Examples 16 to 19.
Example 16
5-(2-Oxo-l2-dihydroquinolin-3-
ylmethyl)thiazolidine-24-dione
-NMRfDMSO-de) dppm:
2.45-2.55 (1H m) 3.35-3.5 (1H m) 4.9-5.0 (1H m) 7.15-
7.7 (4H m) 7.84 (1H s) 11.91 (1H brs) 12.08 (1H brs)
Example 17
5-[1-(Biphenyl-4-ylmethyl)-2-oxo-l2-
dihydroquinolin-3-ylmethyl]thiazolidine-24-dione
Melting point: 220.4°C to 221.8°C
Example 18
5-[1-(Biphenyl-4-ylmethyl)-2-oxo-1234-
tetrahydroquinolin-7-ylmethyl]thiaz olidine-24-dione
Melting point: 213.2°C to 213.7°C
Example 19
5 -[1-(Biphenyl-4-ylmethyl)-2-oxo-1234-
tetrahydroquinolin-8-ylmethyl]thiazolidine-24-dione
-NMRfDMSO-dfi) dppm:
2.40-2.53 (2H m) 2.70-2.85 (2H m) 3.09-3.25 (1H m)
3.50-3.64 (1H m) 4.79-4.90 (1H m) 4.90-5.16 (2H m) 7.02
(1H t J=7.5Hz) 7.08-7.21 (4H m) 7.28-7.64 (7H m) 12.04
(1H s)
Example 20
Synthesis of 5-[8-methoxy-l-(4-nitrobenzyl)-2-oxo-
12 34-tetrahydroquinolin-5-ylmethyl]thiazolidine-24-dione
600 mg of 5-[8-methoxy-l-(4-nitrobenzyl)-2-oxo-
1234-tetrahydroquinolin-5-ylmethylidene]thiazolidine-24-
dione 415 mg of diethyl l4-dihydro-26-dimethyl-35-
pyridinedicarboxylate and 600 mg of silica gel were added to
20 ml of toluene followed by heating and refluxing for 14
hours. The solvent was distilled off and the residue was
purified by silica gel column chromatography (n-hexane:ethyl
acetate=4:l -» 1:1). The purified product was recrystallized
from an ethyl acetate-ether mixed solvent giving 585 mg (97%
yield) of 5-[8-methoxy-l-(4-nitrobenzyl)-2-oxo-l234-
tetrahydroquinolin-5-ylmethyl]thiazolidine-24-dione as a
white powder.
Melting point: 246.5°C to 246.6°C.
Example 21
Synthesis of 5-[1-(4-aminobenzyl)-8-methoxy-2-oxo-
1234-tetrahydroquinolin-5-ylmethyl]thiazolidine-24-dione
10 g of 10% palladium carbon was added to a DMF
solution (100 ml) of 10.0 g of 5-[8-methoxy-l-(4-
nitrobenzyl)-2-oxo-1234-tetrahydroquinolin-5-
ylmethyl]thiazolidine-24-dione and the mixture was
subjected to a catalytic reduction at 40°C for 5 hours. The
catalyst was removed by filtration and the filtrate was
concentrated. Ethyl acetate and water were added to the
residue and celite filtration was carried out. The filtrate
was washed with water and dried over magnesium sulfate
followed by concentration. The residue was purified by
silica gel chromatography (n-hexane:ethyl acetate=4:l -» 1:4)
and the purified product was recrystallized from ethyl
acetate giving 7.98 g (86% yield) of 5-[l-(4-aminobenzyl)-8-
methoxy-2-oxo-l234-tetrahydroquinolin-5-
ylmethyl]thiazolidine-24-dione as a white powder.
Melting point: 174.1°C to 174.8°C
Example 22
Synthesis of 5-{8-methoxy-1-[4-(2-
naphthoylamino)benzyl]-2-oxo-1234-1 etrahydroquinolin-5-
ylmethyl}thiazolidine-24-dione
0.52 g of triethylamine and 0.42 g of
diethylphosphoro cyanidate (DEPC) were added with ice cooling
to a DMF solution (14 ml) of 0.7 g of 5-[l-(4-aminobenzyl)-8-
methoxy-2-oxo-1234-tetrahydroquinolin-5-
ylmethyl]thiazolidine-24-dione and 0.59 g of 2-naphthoic
acid followed by stirring for 16 hours. Water and ethyl
acetate were added to the reaction liquid and the insoluble
matter thus formed was collected by filtration. The
collected insoluble matter was dissolved in a
dichloromethane-methanol mixed solvent and concentrated. The
residue was washed with diethylether and diisopropyl ether.
The residue was dried under reduced pressure giving 0.74 g
(77% yield) of 5-{8-methoxy-l-[4-(2-naphthoylamino)benzyl]-2-
oxo-1234-tetrahydroquinolin-5-ylmethyl}thiazolidin-24-
dione as a white amorphous solid.
Melting point: 202°C to 208°C
-NMRfDMSO-de) dppm:
2.44-2.52 (2H m) 2.82-2.88 (2H m) 3.03-3.13 (1H m)
3.35-3.45 (1H m) 3.73 (3H s) 4.79 (1H dd Jx=4.1Hz
J2=9.9Hz) 5.20 (2H s) 6.83 (1H d J=8.6Hz) 6.91 (1H d
J=8.6Hz) 7.05 (2H d J=8.4Hz) 7.58-7.66 (4H m) 7.95-8.08
(4H m) 8.52 (1H s) 10.33 (1H s) 12.06 (1H s)
Example 23
Synthesis of 5-[1-(4-pentyloxycarbonylaminobenzyl)-
8-methoxy-2-oxo-1234-tetrahydroquinolin-5-
ylmethyl]thiazolidine-24-dlone
0.6 g of 5-[l-(4-aminobenzyl)-8-methoxy-2-oxo-
1234-tetrahydroquinolin-5-ylmethyl]thiazolidine-24-dione
was suspended in dichloromethane (6 ml) and 4 ml of pyridine
was added with ice cooling to form a solution. 0.26 g of
amyl chloroformate was added to this solution followed by
-266-
stirring for 1 hour. 1 N hydrochloric acid was added to the
reaction liquid and extracted with ethyl acetate. The
extract was washed twice with water and once with saturated
sodium chloride solution dried over anhydrous sodium sulfate
and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (n-hexane:ethyl
acetate=2:l - 1:1) and recrystallized from diisopropyl
ether giving 3.75 g (97% yield) of 5-[l-(4-
pentyloxycarbonylaminobenzyl)-8-methoxy-2-oxo-1234-
tetrahydroquinolin-5-ylmethyl]thiazolidine-24-dione as a
white powder.
Melting point: 98°C to 102°C.
Example 24
Synthesis of 5-[8-methoxy-l-(4-
methoxycarbonylbenzyl)-2-oxo-1234-tetrahydroquinolin-5-
ylmethylidene]thiazolidine-24-dione
7.0 g of 8-methoxy-l-(4-methoxycarbonylbenzyl)-2-
oxo- 1234-tetrahydroquinoline-5-carboxaldehyde and 3.25 g
of 24-thiazolidinedione were suspended in 70 ml of toluene.
Ten drops of piperidine and ten drops of acetic acid were
added followed by heating and refluxing for 4 hours. The
resultant was allowed to cool to precipitate a solid and the
precipitated solid was collected by filtration and dried
giving 8.0 g (90% yield) of 5-[8-methoxy-l-(4-
methoxycarbonylbenzyl)-2-oxo-1234-tetrahydroquinolin-5-
ylmethylidene]thiazolidine-24-dione as a light yellow powder.
-NMRtDMSO-de) dppm:
2.52-2.66 (2H m) 2.91-3.05 (2H m) 3.65 (3H s) 3.79 (3H
S) 5.17 (2H s) 7.02 (1H d J=8.7Hz) 7.16 (1H d J=8.7
Hz) 7.25 (2H d J=8.3Hz) 7.74- 7.90 (3H m) 12.55 (1H
brs)
Example 25
Synthesis of 5-[8-methoxy-l-(4-
-267-
methoxycarbonylbenzyl)-2-oxo-1234-tetrahydroquinolin- 5 -
ylmethyl]thiazolidine-24-dione
7.0 g of 10% palladium carbon was added to a DMF
solution (70 ml) of 7.0 g of 5-[8-methoxy-l-(4-
methoxycarbonyl benzyl)-2-oxo-1234-tetrahydroquinolin-5-
ylmethylidene]thiazolidine-24-dione and a catalytic
reduction was carried out at 40°C for 5 hours. The catalyst
was removed by filtration and the filtrate was concentrated.
The residue was purified by silica gel column chromatography
(n-hexane:ethyl acetate=4:l - 1:1). The purified product
was recrystallized from an ethyl acetate-diethyl ether mixed
solvent giving 5.23 g (74% yield) of 5-[8-methoxy-l-(4-
methoxycarbonylbenzyl)-2-oxo-1234-tetrahydroquinolin- 5-
ylmethyl]thiazolidine-24-dione as a white powder.
Melting point: 193.1°C to 195.5°C
Example 26
Synthesis of 5-[8-methoxy-l-(4-carboxybenzyl)-2-
oxo-1234-tetrahydroquinolin-5-ylmethyl]thiazolidine-24-
dione
35 ml of an aqueous 1 N-lithium hydroxide solution
was added to a mixed ethanol (200 ml) and THF (200 ml)
solution of 4.0 g of 5-[8-methoxy-l-(4-
methoxycarbonylbenzyl)-2-oxo-1234-tetrahydroquinolin-5-
ylmethyl]thiazolidine-24-dione followed by stirring at room
temperature overnight. The solvent was distilled off under
reduced pressure hydrochloric acid was added to the residue
and the insoluble matter thus formed was collected by
filtration. The collected insoluble matter was purified by
silica gel column chromatography (n-hexane:ethyl acetate=l:l
-• 1:3) and recrystallized from ethyl acetate giving 3.75 g
(97% yield) of 5-[8-methoxy-l-(4-carboxybenzyl)-2-oxo-
1234-tetrahydroquinolin-5-ylmethyl]thiazolidine-24-dione
as a white powder.
dppm:
2.42-2.61 (2H m) 2.70-2.94 (2H m) 3.01-3.15 (1H m)
3.34-3.48 (1H m) 3.56 (3H s) 4.78 (1H dd J=4.4 9.8Hz)
5.17 (2H brs) 6.81 (1H d J=8.6Hz) 6.90 (1H d J=8.6Hz)
7.17 (2H d J=8.2Hz) 7.77 (2H d J=8.2Hz) 12.06 (1H brs)
12.76 (1H brs)
Example 27
Synthesis of 5-{l-[4-(4-isopropylphenylamino
carbonyl)benzyl]-8-methoxy-2-oxo-1234-tetrahydroquinolin-
5-ylmethyl}thiazolidine-24-dione
0.34 g of triethylamine and 0.28 g of diethyl
phosphorocyanidate (DEPC) were added with ice cooling to a
DMF solution (10 ml) of 0.5 g of 5-[8-methoxy-l-(4-
carboxybenzyl)-2-oxo-1234-tetrahydroquinolin-5-
ylmethyl]thiazolidine-24-dione and 0.23 g of 4-
isopropylaniline followed by stirring for 0.5 hours. Water
was added to the reaction liquid and the mixture was
extracted with ethyl acetate. The organic layer was washed
twice with water and once with saturated sodium chloride
solution and dried over anhydrous sodium sulfate. The
solvent was distilled off under a reduced pressure the
residue was purified by silica gel column chromatography
(dichloromethane:methanol=100:l -» 20:1) and recrystallized
from a mixed solvent of ethyl acetate and n-hexane giving
0.57 g (64% yield) of 5-{l-[4-(4-
isopropylphenylaminocarbonyl)benzyl]-8-methoxy-2-oxo-1234-
tetrahydroquinolin-5-ylmethyl}thiazolidine-24-dione as a
white powder.
Melting point: 243°C to 244°C.
Using appropriate starting materials the same
procedure as in Example 27 was conducted giving compounds of
the following Examples 28 and 29.
Example 28
-269-
5-{8-Methoxy-1-[4-(piperidine-1-carbonyl)benzyl] - 2 -
oxo-1234-tetrahydroquinolin-5-ylmethyl}thiazolidine-24-
dione
-NMRfDMSO-de) dppm:
1.25-1.80 (6H m) 2.39-2.62 (2H m) 2.72-2.95 (2H m).
2.95- 3.72 (9H m) 4.77 (1H dd J=4.3 9.6Hz) 5.16 (2H s)
6.81 (1H d J=8.6Hz) 6.90 (1H d J=8.6Hz) 7.09 (2H d
J=8.0Hz) 7.18 (2H d J=8.0Hz) 12.05 (1H brs)
Example 29
5-[l-(4-Cyclohexylaminocarbonylbenzyl)-8-methoxy-2-
oxo-1234-tetrahydroquinolin-5-ylmethyl]thiazolidine-24-
dione
-NMRfDMSO-de) dppm:
0.95-1.85 (10H m) 2.39-2.60 (2H m) 2.70-2.94 (2H m) .
3.00-3.19 (1H m) 3.23-3.50 (1H m) 3.63 (3H s) 3.80-3.99
(1H m) 4.64-4.88 (1H m) 5.19 (2H s) 6.80 (1H d
J=8.6Hz) 6.89 (1H d J=8.6Hz) 7.11 (2H d J=8.0Hz) 7.65
(2H d J=8.0Hz) 8.03 (1H d J=7.8Hz) 12.06 (1H brs)
Example 30
Synthesis of 5-(l-benzyl-8-hydroxy-2-oxo-l234-
tetrahydroquinolin-5-ylmethylidene)thiazolidine-24-dione
2.0 g of l-benzyl-8-hydroxy-2-oxo-l234-
tetrahydroquinoline-5-carboxaldehyde and 0.874 g of 24-
thiazolidinedione were suspended in 20 ml of toluene. Ten
drops of piperidine and ten drops of acetic acid were added
followed by heating and refluxing for 8 hours. The resultant
was allowed to cool to precipitate a solid and the
precipitated solid was collected by filtration and dried
giving 2.7 g (92% yield) of 5-(l-benzyl-8-hydroxy-2-oxo-
1234-tetrahydroquinolin-5-ylmethylidene)thiazolidine-24-
dione as a yellow powder.
1H-NMR(DMSO-d6) dppm:
2.41-2.60 (2H m) 2.75-2.98 (2H m) 5.31 (2H s) 6.84 (1H
d J=8.6Hz) 7.00-7.30 (6H m) 7.81 (1H s) 10.72 (1H s)
12.48 (1H brs)
Example 31
Synthesis of 5-(l-benzyl-8-hydroxy-2-oxo-l234-
tetrahydroquinolin-5-ylmethyl)thiazolidine-24-dione
2.2 g of 10% palladium carbon was added to a DMF
solution (20ml) of 2.2 g of 5-(l-benzyl-8-hydroxy-2-oxo-
1234-tetrahydroquinolin-5-ylmethylidene)thiazolidine-24-
dione and the mixture was subjected to catalytic reduction
at room temperature for 2 hours. The catalyst was removed by
filtration and the filtrate was concentrated. The residue
was dissolved in ethyl acetate washed with water and
saturated sodium chloride solution and concentrated. The
residue was purified by silica gel column chromatography
(dichloromethane:methanol=50:l). The purified product was
recrystallized from a dichloromethane-ether mixed solvent
giving 1.9 g (88% yield) of 5-(l-benzyl-8-hydroxy-2-oxo-
1234-tetrahydroquinolin-5-ylmethyl)thiazolidine-24-dione
as a white powder.
Melting point: 213.2°C to 213.7°C
Example 32
Synthesis of 5-(l-benzyl-8-butoxy-2-oxo-l234-
tetrahydroquinolin-5-ylmethyl)thiazolidine-24-dione
55.5 mg of potassium tert-butoxide was added to a
DMSO solution (1 ml) of 90 mg of 5-(l-benzyl-8-hydroxy-2-oxo-
1234-tetrahydroquinolin-5-ylmethyl)thiazolidine-24-dione
followed by stirring at room temperature for 1 hour. 29.8 (il
of 4-iodobutane was added thereto followed by stirring at
room temperature for 2 hours. Water was added to the
reaction liquid potassium hydrogensulfate was added to the
mixture and the mixture was extracted with ethyl acetate.
After washing with water the extract was dried over
anhydrous magnesium sulfate and concentrated. The residue
was purified by preparative silica gel thin layer
chromatography (dichloromethane:methanol=20:l) giving 42 mg
(41% yield) of 5-(l-benzyl-8-butoxy-2-oxo-l234-
tetrahydroquinolin-5-ylmethyl)thiazolidine-24-dione as a
colorless amorphous solid.
Hl-NMRfCDCla) dppm:
0.93 (3H t J=7.3Hz) 1.35-1.50 (2H m) 1.57-1.73 (2H m)
2.52-2.67 (2H m) 2.67-2.95 (2H m)
3.05 (1H dd J=10.1Hz J=14.0Hz) 3.51 (1H dd J=4.0Hz
J=14.0Hz) 3.89 (2H t J=6.6Hz) 4.39 (1H dd J=4.0Hz
J=10.1Hz) 5.32 (2H s) 6.71 (1H d J=8.6Hz) 6.87 (1H d
J=8.6Hz) 7.02-7.25 (5H m) 9.15 (1H brs)
Example 33
Synthesis of 5-(l-benzyl-8-benzyloxy-2-oxo-l234-
tetrahydroquinolin-5-ylmethyl)thiazolidine-24-dione
55.5 mg of potassium tert-butoxide was added to a
DMSO solution (1 ml) of 90 mg of 5-(l-benzyl-8-hydroxy-2-oxo-
1234-tetrahydroquinolin-5-ylmethyl)thiazolidine-24-dione
followed by stirring at room temperature for 1 hour. 30 1
of benzyl bromide was added thereto followed by stirring at
room temperature for 1 hour. Water was added to the reaction
liquid potassium hydrogensulfate was added to the mixture
and the mixture was extracted with ethyl acetate. The
extract was washed with water dried over anhydrous magnesium
sulfate and concentrated. The residue was purified by
preparative silica gel thin layer chromatography
(dichloromethane:methanol=20:1) giving 84.5 mg (76% yield)
of 5-(1-benzyl-8-benzyloxy-2-oxo-1234-tetrahydroquinolin-
5-ylmethyl) thiazolidine -2 4 -dione as a colorless amorphous
solid.
-NMRfCDCla) dppm:
2.49-2.65 (2H m) 2.65-2.94 (2H m) 3.07 (1H dd J=10.0Hz
J=14.5Hz) 3.51 (1H dd J=4.1Hz J=14.5Hz) 4.39 (1H dd
J=4.1Hz J=10.0Hz) 4.97 (2H s) 5.32 (2H s) 6.76 (1H d.
J=8.6Hz) 6.86 (1H d J=8.6Hz) 6.93-7.02 (2H m) 7.03-7.19
(3H m) 7.29- 7.45 (5H m) 9.07 (1H brs)
Example 34
Synthesis of 5-(l-carboxymethyl-8-methoxy-2-oxo-
1234-tetrahydroquinolin-5-ylmethyl)thiazolidine-24-dione
4.16 g of l-tert-butoxycarbonylmethyl-8-methoxy-2-
oxo-l234-tetrahydroquinolin-5-carboxaldehyde and 1.66 g of
24-thiazolidinedione (1.00 eq.) were suspended in 40 ml of
toluene and two drops of acetic acid and two drops of
piperidine were added followed by heating and refluxing for
13 hours using a Dean Stark trap. After cooling crystals
were separated by filtration and washed with toluene. The
crystals obtained were suspended in 3.15 g of silica gel
2.09 g of dihydropyridine and 60 ml of toluene followed by
heating and refluxing overnight. 3.15 g of silica gel was
added the solvent was distilled off under reduced pressure
and the residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate=2:l) and
recrystallized from ethyl acetate-hexane giving 2.13 g (38%
yield) of 5-(l-carboxymethyl-8-methoxy-2-oxo-l234-
tetrahydroquinolin-5-ylmethyl)thiazolidine-24-dione as a
white powder.
Melting point: 251°C to 255°C
Example 35
Synthesis of 5-{l-[N-(3-trifluoromethyl
phenyl)amino]carbonylmethyl-8-methoxy-2-oxo-1234-
tetrahydroquinolin- 5-ylmethyl}thiazolidine-24-dione
potassium salt
500 mg of 5-(1-carboxymethyl-8-methoxy-2-oxo-
1234 -tetrahydroquinolin-5-ylmethyl)thiazolidine-24-dione
was dissolved in 5 ml of DMF. 0.35 ml of 3-trifluoromethyl
aniline 0.32 g of l-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride(WSC) and 0.25 g of 1-
hydroxybenzotriazole (HOBT) were added to the solution
followed by stirring at room temperature overnight. Water
was added to the reaction liquid and the solid thus obtained
was separated by filtration. The solid was dissolved in
methylene chloride washed with sodium chloride solution and
dried over sodium sulfate. After filtration the filtrate
was concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (methylene
chloride:methanol=50:1) giving 412 mg of 5-{l-[N-(3-
trifluoromethylphenyl)amino]carbonylmethyl-8-methoxy-2-oxo-
1234-tetrahydroquinolin-5-ylmethyl}thiazolidine-24-dione.
The 5-{l-[N-(3-trifluoromethyl
phenyl)amino]carbonylmethyl-8-methoxy-2-oxo-1234-
tetrahydroquinolin-5-ylmethyl}thiazolidine-24-dione thus
obtained was dissolved in 4 ml of THF. 84.5 mg of potassium
t-butoxide was added to dissolve the solid. Diethyl ether
was added and trituration was carried out. The crystals
produced were separated by filtration and dried giving 340
mg (49% yield) of 5-{l-[N-(3-trifluoromethyl
phenyl)amino]carbonylmethyl-8-methoxy-2-oxo-1234-
tetrahydroquinolin-5-ylmethyl}thiazolidine-24-
dionepotassium salt as a brown powder.
Melting point: 135°C to 139.5°C.
Example 36
Synthesis of 5-(8-methoxy-l-piperidin-4-ylmethyl-2-
oxo-1234-tetrahydroquinolin-5-ylmethyl)thiazolidine-24-
dione
1.7 g of 5-[8-methoxy-l-(l-tert-butoxycarbonyl
piperidin-4-ylmethyl)-2-oxo-1234-1etrahydroquinolin- 5-
ylmethyl]thiazolidine-24-dione was added to 50 ml of a 4 Nhydrogen
chloride ethyl acetate solution followed by
stirring at room temperature for 6 hours. The resultant was
concentrated under reduced pressure and an aqueous sodium
hydrogencarbonate solution was added to the residue. The
insoluble matter thus formed was collected by filtration and
dried giving 1.5 g (yield: quantitative) of 5-(8-methoxy-lpiperidin-
4-ylmethyl-2-oxo-l234-tetrahydroquinolin-5-
ylmethyl)thiazolidine-24-dione as a white powder.
1H-NMR(DMSO-d6) dppm:
1.05-1.3(2H m) 1.4-1.7(3H m) 2.3-2.9(6H m) 3.0-3.25(3H
m) 3.82(3H s) 4.00(2H d J=6.8Hz) 4.63(1H dd J=8.7Hz
J=4.2Hz) 6.9-7.05 (2H m)
Example 37
Synthesis of 5-(l-{2-[l-(4-methylbenzoyl)piperidin-
4-yl]ethyl}-2-oxo-l234-tetrahydroquinolin-5-
ylmethyl)thiazolidine-24-dione
2 ml of DMF was added to 100 mg of 5-{l-[2-(lpiperidin-
4-yl)ethyl]-2-oxo-1234-tetrahydroquinolin-5-
ylmethyl}thiazolidine-24-dione 42.2 mg of p-toluic acid
59.4 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (WSC) and 43.5 mg of 1-hydroxybenzotriazole
(HOBt) followed by stirring at room temperature for 2.5
hours. Water was added the mixture was stirred for a while
and the solid thus produced was collected by filtration. The
collected solid was dissolved in methylene chloride and
purified by silica gel chromatography (methylene
chloride:methanol=20:1) giving 68.4 mg (97% yield) of the
target compound as a white solid.
Melting point: 60°C to 65°C.
Example 38
Synthesis of 5-[l-(5-benzyl-6-oxo-56-
dihydrophenanthridin-2-yl)methylidene]thiazolidine-24-dione
592 mg of 5-benzyl-6-oxo-56-dihydrophenanthridine-
2-carboxaldehyde and 221 mg of 24-thiazolidinedione were
suspended in 10 ml of toluene. Two drops of acetic acid and
two drops of piperidine were added to the suspension
followed by heating and refluxing overnight. The reaction
liguid was cooled and the solid thus obtained was collected
by filtration. The collected solid was washed with toluenediethyl
ether and dried giving 620 mg (80% yield) of 5-[l-
(5-benzyl-6-oxo-56-dihydrophenanthridin-2-
yl)methylidene]thiazolidine-24-dione as a yellow solid.
-NMRtDMSO-de) dppm:
5.67 (2H s) 7.0-8.0 (10H m) 8.45 (1H dd J=8.0Hz l.SHz).
8.60 (1H d J=8.0Hz) 8.80 (1H d J=1.8Hz) 12.6 (1H brs)
Example 39
Synthesis of 5-[l-(5-benzyl-6-oxo-56-
dihydrophenanthridin-2-yl)methyl]thiazolidine-24-dione
620 mg of 5-[1-(5-benzyl-6-oxo-56-
dihydrophenanthridin-2-yl)methylidene]thiazolidine-24-dione
was dissolved in 2.31 ml of THF. 2.31 ml of pyridine and
2.31 ml of a THF solution of 2 M lithium borohydride were
added to the solution followed by heating and refluxing for
4 hours. The reaction liquid was cooled acidified with
diluted hydrochloric acid and extracted with dichloromethane.
The organic layer was washed with water then with saturated
sodium chloride solution and dried over sodium sulfate.
After filtration the solvent was distilled off under reduced
pressure the residue was crystallized using dichloromethane
and the solid thus obtained was separated by filtration. The
solid separated by filtration was air-dried giving 232 mg
(36% yield) of 5-[1-(5-benzyl-6-oxo-56-dihydrophenanthridin-
2-yl)methyl]thiazolidine-24-dione as white crystals.
-NMRfDMSO-de) dppm:
3.1-3.7 (2H m) 5.04 (1H dd J=13.8Hz J=4.8Hz) 5.76 (2H
s) 7.1-7.45 (5H m) 7.6-8.0 (2H m) 8.3-8.6 (3H m) 12.0
(1H brs)
Example 40
Synthesis of 5-{8-methoxy-l-[l-(2-
methylbenzyl)piperidin-4-yl]methyl-2-oxo-1234-
-276-
tetrahydroquinolin-5-ylmethyl}thiazolldine-24-dione
To 5-(8-methoxy-l-piperidin-4-ylmethyl-2-oxo-
1234-tetrahydroquinolin-5-ylmethyl)thiazolidine-24-dione
(20 funol 1.0 eq.) was added a DMF (200 1) solution of 2-
methylbenzaldehyde (24 fjinol 1.2 eq) and acetic acid (10 fil).
Si-sodium cyanoborohydride was added further thereto. The
solution was shaken for several minutes
diisopropylethylamine (30 jil) was added and a reaction was
carried out at room temperature overnight. The resin was
removed by filtration and washed with dichloromethane. The
solvent was distilled off from the filtrate in a nitrogen gas
stream and the residue was purified by HPLC (UV-trigger
column : CAPCELL PAR C18 UG 120 S-5 20 mm x 50 mm 0.05%
trifluoroacetic acid-H2O 0.05% trifluoroacetic acid-CHaCN) .
The structure was confirmed by LC-MS and freeze-drying was
conducted giving 5-{8-methoxy-l-[l-(2-
methylbenzyl)piperidin-4-yl]methyl-2-oxo-1234-
tetrahydroquinolin-5-ylmethyl}thiazolidine-24-dione in 50.5%
yield.
MS: 508 (M+1)
Example 41
Synthesis of 5-{8-methoxy-l-[l-(tetrahydropyran-4-
yl)piperidin-4-yl]methyl-2-oxo-1234 -tetrahydroquinolin-5-
ylmethyl}thiaz olidine-24-dione
To 5-(8-methoxy-l-piperidin-4-ylmethyl-2-oxo-
1234-tetrahydroquinolin-5-ylmethyl)thiazolidine-24-dione
(20 imol 1.0 eq.) was added a DMF (200 nl) solution of
tetrahydropyran-4-one (24 junol 1.2 eq.) and acetic acid (10
(il). MP-sodium triacetoxy borohydride was added further.
After this solution was shaken for several minutes DIEA (30
Hi) was added and a reaction was carried out at 60°C
overnight. The resin was removed by filtration and washed
with methylene chloride. The solvent was distilled off with
nitrogen gas and the residue was purified by HPLC (UV-
277-
trigger column:CAPCELL PAR C18 UG 120 S-5 20 mm x 50 mm
0.05% trofluoroacetic acid-H2O 0.05% trofluoroacetic acid-
CH3CN). The structure was confirmed by LC-MS and freezedrying
was conducted giving 5-{8-methoxy-l-[l-
(tetrahydropyran-4-yl)piperidin-4-yl]methyl-2-oxo-l234-
tetrahydroquinolin-5-ylmethyl}thiazolidine-24-dione in 30%
yield.
MS: 488 (M+1)
Example 42
Synthesis of 5-[l-(4-methanesulfonylaminobenzyl)-8-
methoxy-2-oxo-1234-tetrahydroquinolin- 5 -
ylmethyl]thiazolidine-24-dione
To a dichloromethane (20 ml) solution of 1.00 g
(0.00243 mM) of 5-[1-(4-aminobenzyl)-8-methoxy-2-oxo-1234-
tetrahydroquinolin-5-ylmethyl]thiazolidine-24-dione were
successively added pyridine (2.0 ml) and 0.21 ml (0.0027 mM)
of methanesulfonyl chloride under ice cooling with stirring.
The mixture was stirred at the same temperature for 30
minutes and water was added to stop the reaction. The
resultant was washed (twice with water and once with
saturated sodium chloride solution) dried (magnesium
sulfate) and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography
(dichloromethane:ethyl acetate=l:10 -• 1:1) giving 1.1 g
(92% yield) of the target compound as a white amorphous solid.
-NMRfDMSO-de) dppm:
2.39-2.54 (2H m) 2.72-2.87 (2H m) 2.88 (3H s) 3.05 (1H
dd J=10.0Hz J-14.4HZ) 3.39 (1H dd J=4.0Hz J=14.4Hz)
3.67 (3H s) 4.76 (1H dd J=4.0Hz J=10.0Hz) 5.13 (2H s)
6.80 (1H d J=8.6Hz) 6.89 (1H d J=8.6Hz) 6.93-7.06 (4H
m) 9.57 (1H s) 12.05 (1H s)
Example 43
Synthesis of 3-methoxycarbonylmethyl-5-(8-methoxy-
278-
1-methyl-2-oxo-12-dihydroquinolin-5-ylmethyl)thiazolidine-
24-dione
350 mg of 5-(8-methoxy-l-methyl-2-oxo-l2-
dihydroquinolin-5-ylmethyl)thiazolidine-24-dione was
dissolved in 5 ml of DMF. 0.156 ml of methyl bromoacetate
and 0.25 g of potassium carbonate were added to the solution
followed by stirring at room temperature overnight. Water
was added and the mixture was extracted with methylene
chloride. The organic layer was washed with saturated sodium
chloride solution and dried over sodium sulfate. After
filtration the solvent was distilled off under reduced
pressure. The residue was purified by silica gel
chromatography and recrystallized from methanol-acetone
giving 245 mg (57% yield) of 3-methoxycarbonylmethyl-5-(8-
methoxy-1-methyl-2-oxo-12-dihydroquinolin-5-
ylmethyl)thiazolidine-24-dione as white crystals.
Melting point: 182°C to 184°C
Example 44
Synthesis of 1-(biphenyl-4-ylmethyl)-5-(4-oxo-2-
thioxothiazolidine-5-ylidenemethyl)-34-dihydro-lH-quinolin-
2-one
1.50 g of l-(biphenyl-4-ylmethyl)-2-oxo-1234-
tetrahydroquinoline-5-carboxaldehyde and 0.761 g of 2-thioxol
3-thiazolidin-4-one were suspended in 20 ml of toluene.
Two drops of piperidine and two drops of acetic acid were
added to the suspension followed by heating and refluxing
for 4 hours. After allowing to cool the solid thus
precipitated was collected by filtration and dried giving
2.34 g (91% yield) of 1-(biphenyl-4-ylmethyl)-5-(4-oxo-2-
thioxothiazolidine-5-ylidenemethyl)-34-dihydro-IH-quinolin-
2-one as a yellow powder.
-NMRfDMSO-de) dppm:
2.76-2.81 (2H m) 3.04-3.09 (2H m) 5.23 (2H m) 7.10-7.47
(8H m) 7.54 (1H s) 7.59-7.65 (4H m) 13.78 (1H brs)
-279-
Using an appropriate starting material the same
procedure as in Example 44 was performed giving a compound
of the following Example 45.
Example 45
l-(4-Bromobenzyl)-5-(4-oxo-2-thioxothiazolidine-5-
ylidenemethyl)-34-dihydro-lH-quinolin-2-one
1H-NMR(DMSO-d6) dppm:
2.67-2.80 (2H m) 2.93-3.09 (2H m) 5.14 (2H s) 7.04 (1H
d J=8.6Hz) 7.10-7.25 (2H m) 7.32-7.57 (5H m) 13.77 (1H
brs)
Example 46
Synthesis of 1-(biphenyl-4-ylmethyl)-5-
(4-oxo-2-thioxothiazolidin-5-ylmethyl)-34-dihydro-1Hquinolin-
2-one
To 20 ml of toluene were added 1.4 g of 1-(biphenyl-
4-ylmethyl)-5-(4-oxo-2-thioxothiazolidine-5-ylidenemethyl)-
34-dihydro-lH-quinolin-2-one 1.01 g of diethyl 14-dihydro-
26-dimethyl-35-pyridine dicarboxylate and 1.4 g of silica
gel followed by heating and refluxing overnight. The
solvent was distilled off and the residue was purified by
silica gel column chromatography (n-hexane:ethyl acetate=4:l
- 2:1). The purified product was recrystallized from
toluene giving 0.84 g (60% yield) of 1-(biphenyl-4-
ylmethyl)-5-(4-oxo-2-thioxothiazolidin-5-ylmethyl)-34-
dihydro-lH-quinolin-2-one as a white powder.
Melting point: 186.3°C to 187.1°C
Example 47
Synthesis of l-(4-bromobenzyl)-5-(4-oxo-2-
thioxothiazolidin-5-ylmethyl)-34-dihydro-IH-quinolin-2-one
50 mg of l-(4-bromobenzyl)-5-(4-oxo-2-
thioxothiazolidine-5-ylidenemethyl)-34-dihydro-IH-quinolin-
2-one was suspended in a mixed solvent of 0.15 ml of methanol.
0.1 ml of water 0.08 ml of an aqueous 1 N-sodlum hydroxide
solution and 0.1 ml of THF. 0.03 ml of a DMF (5 ml)
solution of 42 mg of cobalt chloride 6-hydrate and 250 mg of
dimethylglyoxime was further added to the suspension and the
mixture was heated to 30°C to 40°C. An aqueous solution (0.1
ml) of 15 mg of sodium borohydride was added followed by
stirring for 30 minutes. A saturated aqueous potassium
hydrogensulfate solution was added the mixture was extracted
with ethyl acetate and the extract was washed with water.
The extract was dried over anhydrous magnesium sulfate and
concentrated. The residue was purified by preparative silica
gel thin layer chromatography (ethyl acetate:n-hexane=l:1) to
give 44.7 mg (89% yield) of 1-(4-bromobenzyl)-5-(4-oxo-2-
thioxothiazolidin-5-ylmethyl)-34-dihydro-lH-quinolin-2-one
as a colorless amorphous solid and further recrystallized
from ethyl acetate-diethyl ether giving a white powder.
Melting point: 191.3°C to 192.1°C
Using an appropriate starting material the same
procedure as in Example 47 was conducted giving a compound
of the following Example 48.
Example 48
1-(6-Chloropyridin-3-ylmethyl)-5-(4-oxo- 2 -
thioxothiazolidin-5-ylmethyl)-34-dihydro-IH-quinolin-2-
one hydrochloride
Melting point: 70°C to 80°C
Using appropriate starting materials the same
procedure as in Example 6 was conducted giving compounds of
the following Examples 49 to 110.
Using appropriate starting materials the same
procedure as in Example 15 was conducted giving compounds of
the following Examples 111 to 119 121 to 131 134 to 138
140 to 144 148 150 to 153 156 to 159 161 to 165 173 177
to 182 184 to 188 859 to 860 965 to 969 975 to 976 and
986 to 1001.
Using appropriate starting materials the same
procedure as in Example 21 was conducted giving compounds of
the following Examples 120 and 133.
Using appropriate starting materials the same
procedure as in Example 22 was conducted giving compounds of
the following Examples 189 to 225 and 258 to 291.
Using appropriate starting materials the same
procedure as in Example 23 was conducted giving compounds of
the following Examples 228 to 257 292 to 309 656 to 658
664 666 to 667 681 to 686 and 690 to 694.
Using appropriate starting materials the same
procedure as in Example 27 was conducted giving compounds of
the following Examples 176 310 to 545 and 1034.
Using appropriate starting materials the same
procedure as in Example 32 was conducted giving compounds of
the following Examples 546 to 606.
Using appropriate starting materials the same
procedure as in Example 35 was conducted giving compounds of
the following Examples 607 to 613 614 to 655 659 to 663
665 668 to 680 and 687 to 689.
Using appropriate starting materials the same
procedure as in Example 38 was conducted giving compounds of
the following Examples 695 to 699 and 921 to 959.
Using appropriate starting materials the same
procedure as in Example 39 was conducted giving compounds of
the following Examples 139 145 to 147 154 to 155 166 to
172 174 to 175 700 to 704 913 to 920 960 to 964 970 to
972 and 977 to 985.
Using appropriate starting materials the same
procedure as in Example 40 was conducted giving compounds of
the following Examples 705 to 759.
Using appropriate starting materials the same
procedure as in Example 42 was conducted giving compounds of
the following Examples 760 to 855.
Using appropriate starting materials the same
procedure as in Example 43 was conducted giving compounds of
the following Examples 857 and 861 to 912.
Using appropriate starting materials the same
procedure as in Example 6 was conducted giving compounds of
Examples 1002 to 1031.
Using appropriate starting materials the same
procedure as in Example 15 was conducted giving compounds of
Examples 1032 to 1033 1038 1041 to 1045 1047 1050 to 1055
1057 to 1058 1069 to 1070 1076 to 1079 and 1088.
Using appropriate starting materials the same
procedure as in Example 23 was conducted giving a compound
of Example 1059.
Using appropriate starting materials the same
procedure as in Example 35 was conducted giving compounds of
Examples 1115 to 1314.
Using appropriate starting materials the same
-283-
procedure as in Example 36 was conducted giving compounds of
Examples 160 and 1056.
Using appropriate starting materials the same
procedure as in Example 47 was conducted giving compounds of
Examples 974 1035 to 1037 1039 to 1040 1048 1060 to 1068
1071 to 1075 1080 to 1087 and 1089 to 1090.
The same procedure as in Example 1 was conducted
giving compound of Example 856.
Using appropriate starting materials the same
procedure as in Example 1317 was conducted giving compounds
of Examples 1049 and 1091 to 1114.
Using appropriate starting materials the same
procedure as in Example 25 was conducted giving compounds of
the following Examples 226 227 and 1046.
Using appropriate starting materials the same
procedure as in Example 26 was conducted giving compounds of
the following Examples 149 858 and 973.
Using an appropriate starting material the same
procedure as in Example 31 was conducted giving a compound
of the following Example 183.
Using an appropriate starting material the same
procedure as in Example 34 was conducted giving a compound


(Table Remove)Synthesis of 8-methoxy-l-(3-methylbutyl)-5-(4-oxo-
thioxothiazolidin-5-ylmethyl)~3,4-dihydro-lH-quinolin-2-one
3.0 g of 8-methoxy-l-(3-methylbutyl)-4-ylmethyl-2-oxo-
5 l,2,3,4-tetrahydroquinoline-5-carboxaldehyde and 1.53 g of 2-
thioxo-l,3-thiazolidin-4-one were suspended in 30 ml of
toluene. Five drops of piperidine and five drops of acetic
acid were added, followed by heating and refluxing for
overnight. After allowing to cool, the solid thus
10 precipitated was collected by filtration, and dried, and then
suspended in 16 ml of toluene. 2.29 g of diethyl 1,4-
dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate and 4.0 g of
silica gel were added to the suspension, followed by heating
and refluxing overnight. The solvent was distilled off from
15 the reaction mixture, and the residue was purified by silica
gel column chromatography (n-hexane:ethyl acetate=3:l -» 1:1),
The purified product was recrystallized from an ethyl
acetate-n-hexane mixed solvent, giving 2.11 g (55.2% yield)
of 8-methoxy-1-(3-methylbutyl)-5 -(4-oxo-2-thioxothiazolidin-
20 5-ylmethyl)-3,4-dihydro-lH-quinolin-2-one as a yellow powder.
Melting point: 139.5°C to 141°C
Example 1316
Synthesis of 5-[l-(3-hydroxypropyl)-2-oxo-l,2,3,4-
25 tetrahydroquinolin-5-ylmethyl]-3-tritylthiazolidine-2,4-dione
A DMF solution (10 ml) of 1.0 g (2.99 mmol) of 5-[l-
(3-hydroxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-5-
ylmethyl]thiazolidine-2,4-dione and 0.455 g (3.29 mmol) of
potassium carbonate was cooled with ice, and 0.876 g (3.04
30 mmol) of triphenylmethylchloride was added thereto, followed
by stirring at room temperature overnight. Water was added
to the reaction liquid and the mixture was extracted with
ethyl acetate. The organic layer was washed twice with water
and once with saturated sodium chloride solution, and
35 concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (n-hexane:ethyl
acetate=2:l -» ethyl acetate). The purified product was
concentrated under reduced pressure and evaporated to dryness,
giving 700 mg (40.6% yield) of 5-[l-(3-hydroxypropyl)-2-oxo-
5 1,2,3,4-tetrahydroquinolin-5-ylmethyl]-3-tritylthiazolidine-
2,4-dione as a colorless amorphous solid.
Example 1317
Synthesis of 5-{l-[3-(4-methylphenoxy)propyl]-2-oxo-
10 1,2,3,4-tetrahydroquinolin-5-ylmethyl}thiazolidine-2,4-dione
A THF solution (2 ml) of 100 mg (0.18 mmol) of 5-[l-
(3-hydroxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-5-
ylmethyl]-3-trityl thiazolidine-2,4-dione, 0.0363 ml(0.347
mmol) of p-cresol, and 91.1 mg (0.35 mmol) of
15 triphenylphosphine was cooled with ice. 0.158 ml of
azodicarboxylic acid diethyl (2.2 M toluene solution) was
added to the solution in an argon atmosphere. The mixture
was stirred at room temperature for two hours, and ethyl
acetate was added to the reaction liquid. After washing with
20 water, the organic layer was concentrated under reduced
pressure, and the residue was purified by preparative silica
gel thin layer chromatography (n-hexane:ethyl acetate=l:1).
The purified product was concentrated under reduced pressure,
and 2 ml of a solution of 4N-hydrogen chloride/ethyl acetate
25 was added to the residue. The mixture was stirred at room
temperature overnight, and further stirred at 70°C for 1.5
hours. The mixture was concentrated under reduced pressure,
and the residue was purified by preparative silica gel thin
layer chromatography (n-hexane:ethyl acetate=l:1). The
30 purified product was concentrated under reduced pressure and
evaporated to dryness, giving 27.1 mg (34.4% yield) of 5 (Table Remove) [ 3 - (4-methylphenoxy)propyl]-2-oxo-1,2,3,4-tetrahydroquinolin-
5-ylmethyl}thiazolidine-2,4-dione as a colorless amorphous
solid.
35 1H-NMR(DMSO-d6) dppm:
2.0-2.2 (2H, m), 2.28 (3H, s), 2.55-3.25 (5H, m), 3.68 (1H,
dd, Ji=3.7Hz, J2=14.4Hz), 4.02 (2H, t, J=5.9Hz), 4.14 (2H, t,
J=7.0Hz), 4.46 (1H, dd, J^S.VHz, J2=10.5Hz), 6.92 (2H, d,
J=7.5Hz), 7.08 (IE, d, J=8.0Hz), 7.05-7.4 (4H, m)
5
Preparation Example 1
1 - Methyl-8-methoxy-5-(4-oxo-2-thioxo-5-thiazolidinyl)
methyl-3,4-dihydro-lH-quinolin-2-one 5 mg
Starch 132 mg
10 Magnesium stearate 18 mg
Lactose 45 mg
Total 200 mg
Tablets containing the above composition per tablet are
15 prepared in the conventional manner.
Preparation Example 2
1-(2-Phenylethy1)-8-methoxy-5-(4 -oxo-2-thioxo-5-
thiazolidinyl)methyl-3,4-dihydro-lH-quinolin-2-one 5 g
20 Polyethyleneglycol (molecular weight: 4000) 0.3 g
Sodium chloride 0.9 g
Polyoxyethylenesorbitan monooleate 0.4 g
Sodium metabisulfite 0.1 g
Methyl-paraben 0.18 g
25 Propyl-paraben 0.02 g
Distilled water for injection 100 ml
The above parabens, sodium metabisulfite and sodium
chloride are dissolved into distilled water at 80°C with
agitation. The obtained solution is cooled to 40°C, and (Table Remove)the
30 compound of the invention, polyethyleneglycol and
Polyoxyethylenesorbitan monooleate are dissolved into the
above solution. Further distilled water for injection is
then added to the solution to adjust the solution to the
final amount. The resultant solution is subjected to filter
sterilization using an appropriate filter paper, and 1 ml of
5 the filtered solution is dispensed into ampules to prepare
injectable solutions.
Test Example 1
Transcription promoting activity on human Trefoil
10 Factor 2 (hTFF2) gene of test compounds was evaluated by
means of an hTFF2 gene reporter assay.
(l)Preparation of hTFF2 gene reporter vector pGL3-
hTFF2pro
15 DNA was extracted from HeLa cells (CCL-2, DAINIPPON
PHARMACEUTICAL CO., LTD.) using a deoxyribonucleic acid (DNA)
extraction kit (DNeasy™ Tissue Kit, manufactured by QIAGEN).
The hTFF2 promoter region was amplified using the extracted
DNA as a template by means of the polymerase chain reaction
20 (PCR). The oligomers 5'-CACGCGTCAGACTGGCAACCCCCTGTC-3' and
5'-GAAGCTTCTAGCTCAGCTGCACCCCAG-3' were selected as PCR
primers to be amplified, based on the report by Beck et al.
(Beck S., Sommer P., Blin N., Gott P., 5'-flanking motifs
control cell-specific expression of trefoil factor genes
25 (TFF), Int. J. Mol. Med. 2(3), 353-361 (1998)). Platinum®
Pfx DNA polymerase was used as DNA polymerase. The PCR was
performed under the conditions of denaturing for 30 seconds
at 95°C, annealing for 30 seconds at 55°C and extending for
75 seconds at 68°C, and the procedures were repeated for 32
30 cycles.
The PCR products were separated and purified by 1 %
agarose gel electrophoresis, and cloned to a pCR-Bluntll-(Table Remove)TOPO
vector attached to a cloning kit (Zero Blunt® TOPO® PCR
Cloning Kit, manufactured by Invitrogen Corporation). The
5 produced plasmid pCR-Blunt-TFF2pro was introduced into E.coll
for transformation (TOP 10 Ultracomp™ Cells, manufactured by
Invitrogen Corporation), and transformant strain pCR-Blunt-
TFF2pro/TOP10 was selectively cultured in LB agar medium
containing 30[xg/ml of Zeocin (Zeocin, manufactured by
10 Invitrogen Corporation). The pCR-Blunt-TFF2pro/TOP10 was
subjected to shaking culture in 50 ml of LB medium containing
30(ig/ml of Zeocin at 37°C over night, and a plasmid was
prepared using a plasmid preparation kit (Concert™ High
Purity Midiprep System, manufactured by GIBCO BRL).
15
The nucleotide sequence of the PCR product cloned to
the plasmid pCR-Blunt-TFF2pro was determined. The determined
nucleotide sequence was compared with the counterpart of
hTFF2 promoter region reported in a gene bank (GenBank
20 accession AB038162). The nucleotide sequence of the Mlul-
GenBank accession AB038162 (Fig. 1).
Fig. 1 shows in the upper register the nucleotide
25 sequence and nucleotide numbering of the hTFF2 promoter
region reported in GenBank (accession AB038162). The lower
register shows the nucleotide sequence (see appended Sequence
Number 1 shown in Sequence Listing) of the PCR product cloned
in the plasmid pCR-Blunt-TFF2pro. The underlined portions
30 indicate the recognition sequence (ACGCGT) of the restriction
restriction enzyme Hindlll. The nucleotide sequences of the
MluI-Hindlll region are identical between the hTFF2 promoter
region reported in GenBank and the PCR product cloned to the
plasmid pCR-Blunt-TFF2pro. ATG enclosed in the box is the
5 translation start codon and the arrow shows the transcription
initiation site.
The plasmid pCR-Blunt-hTFF2pro was cleaved by the
restriction enzymes Mlul and Hindlll, fractionated by 1%
10 agarose gel electrophoresis, and the hTFF2 promoter region
was purified using a nucleic acid purification kit (Concert™
Matrix Gel Extraction System, manufactured by GIBCO BRL).
The hTFF2 promoter region was inserted into the Mlul-Hindlll
region of a commercial plasmid pGL-Basic (manufactured by
15 Promega Corporation) using a ligation kit (Ligation high,
manufactured by TOYOBO CO., LTD.) to produce pGL3-hTFF2pro.
The plasmid pGL3-hTFF2pro was introduced into E. coll for
transformation (DH5a Competent Cell, manufactured by TOYOBO
CO., LTD.) and transformant strain pGL3-hTFF2pro/DH5a was
20 selectively cultured in LB agar medium containing lOOj-ig/ml of
ampicillin.
The pGL3-hTFF2pro/DH5a was inoculated into a 2-liter
Erlenmeyer flask containing 400ml of LB medium containing
25 100fAg/ml ampicillin, and subjected to 200 rpm shaking culture
at 37°C in a rotary shaker overnight. The plasmid pGL3-
hTFF2pro was extracted and purified from the cultured cells
using a plasmid preparation kit (EndoFree Plasmid Maxi Kit,
manufactured by QIAGEN).
A commercial vector, pWLneo (manufactured by
Stratagene), containing a drug-selection marker was
introduced into E. coll for transformation (DHSct Competent
Cell, manufactured by TOYOBO CO., LTD.) and transformant
strain pWLneo/DH5a was selectively cultured in LB agar
5 medium containing 100ng/ml of ampicillin. The pWLneo/DHSa
was inoculated into a 1-liter Erlenmeyer flask containing
150ml of LB medium containing 100ng/ml of ampicillin, and
subjected to 200 rpm shaking culture at 37°C in a rotary
shaker overnight. The plasmid pWLneo was extracted and
10 purified from the cultured cells using a plasmid preparation
kit (EndoFree Plasmid Maxi Kit, manufactured by QIAGEN).
(2preparation of cell line pGL3-hTFF2pro-pWL-neo/MKN-
45 #6-2 for hTFF2 gene reporter assay
15 Human gastric cancer cell line MKN-45 (JCRB0254, Health
Science Research Resources Bank) was cultured in medium (IMDM
medium) composed of 500 ml of medium (Iscove's Modified
Dulbecco's Medium, manufactured by SIGMA), 50 ml of fetal
bovine serum (manufactured by SIGMA) immobilized by heating
20 at 56°C for 30 minutes, 5 ml of Penicillin-Streptomycin
liquid (manufactured by SIGMA) and 20 ml of 200 mM L-glutamin
(manufactured by SIGMA), using a culture dish having a
diameter of 10 cm (CORNING Incorporated) placed in a 5% CO2
incubator at 37°C. The cells were washed with buffer
25 (Dulbecco's Phosphate Buffered Saline, manufactured by SIGMA)
and subjected to trypsin (0.25% Tripsin-lmM EDTA'4Na,
manufactured by SIGMA) treatment for suspension. The cells
were suspended in the IMDM medium, stained using Trypan Blue
Stain, 0.4% (tradename, Invitrogen Corporation) and the
30 number of cells which did not stain was counted as live cells
using a hemocytometer. The cells were washed once with
buffer (Dulbecco's Phosphate Buffered Saline, manufactured by
SIGMA) and 106 live cells were suspended in a solution for
gene transfer (0.25 M Mannitol/0.1 mM CaCl2/0.1 mM MgCl2/0.2
mM Tris-HCl, pH7.2 to 7.4) to which 10 fxg of the prepared
5 plasmid pGL3-hTFF2pro and 2 ng of the plasmid pWLneo were
added. The plasmid-added cell suspension was transferred to
a 1mm cuvette (manufactured by Bio-Rad Laboratories, Inc.)
and gene introduction into cells was performed by means of
electroporation using an SSH-1 cell fusion apparatus
10 (Shimadzu Corporation). The cells were suspended in the IMDM
medium, inoculated in a culture dish having a diameter of 10
cm (CORNING Incorporated) and cultured in a 5% CO2 incubator
at 37°C for 2 days. Selective culturing was then carried out
using IMDM medium containing 400 pig/ml of Geneticin
15 (manufactured by Invitrogen Corporation). 100 \tl of the
culture medium was then first inoculated into each well of a
96-well plate (manufactured by BD Falcon), and proliferated
cells were sequentially subjected to passaged culturing in a
24-well plate (manufactured by BD Falcon) and further in a 6-
20 well plate (manufactured by BD Falcon) to prepare pGL3-
hTFF2pro-pWL-neo/MKN-45 #6 cells. The obtained pGL3-
hTFF2pro'pWL-neo/MKN-45 #6 cells were suspended in IMDM
medium containing 400 [ig/ml of Geneticin, inoculated into a
96-well plate by means of limiting dilution for cloning to
25 obtain single clone pGL3-hTFF2pro-pWL-neo/MKN-45 #6-2 cells.
The pGL3-hTFF2prod-pWL-neo/MKN-45 #6-2 cells were
proliferated in a 10 cm culture dish, harvested and
cryopreserved.
30 (3) The hTFF2 genetic reporter assay using pGL3-
hTFF2pro • pWL-neo/MKN-45 #6-2 cell line
pGL3-hTFF2pro • pWL-neo/MKN-45 #6-2 was thawed from the
frozen state for use. The cells were inoculated into IMDM
medium containing 400 ng/ml of Geneticin in a 10 cm culture
dish and sequentially passaged every 3 to 5 days. During the
5 passage culturing, the cells were washed with buffer
(Dulbecco's Phosphate Buffered Saline, manufactured by SIGMA),
and tripsin (0.25% Tripsin-lmM EDTA-4Na, manufactured by
SIGMA) was added to separate the cells by treatment for 5
minutes at 37°C. The cell suspension was collected by adding
10 IMDM medium, and the cells were stained using Trypan Blue
Stain, 0.4% (tradename, Invitrogen Corporation) and the
number of cells which did not stain was counted as live cells
using a hemocytometer. A cell survival rate of 90 % or
higher was confirmed prior to the live cells being used for
15 the hTFF2 genetic reporter assay.
A day before test compounds were added, 100 \il of the
cell suspension containing about 7.5 x 104 cells was
inoculated into each well of 96-well plates (manufactured by
20 COSTAR) and cultured in a 5 % CO2 incubator at 37 °C. The
test compounds were prepared to have a concentration 200
times the final measurement concentration with
dimethylsulfoxide (Wako Pure Chemical Industries, Ltd.). The
test compounds having a predetermined concentration were
25 respectively diluted 100 times with IMDM medium, and 100 \il
of the diluted compounds was dispensed into wells of the 96-
well plates. Demethylsulfoxide was diluted 100 times with
IMDM medium and added to those wells to which test compounds
were not added. After the test compounds were added, the
30 cells were cultured in a 5 % C02 incubator at 37 °C for 24
hours. When the culturing was completed, the culture
supernatant was removed and the 96-well plates were frozen in
a deep freezer (manufactured by SANYO Electric Co., Ltd.).
The 96-well plates were thawed at room temperature when the
luciferase activity was measured, and 100 (xl of PicaGene
5 LT2.0 (Wako Pure Chemical Industries, Ltd.) diluted two times
with buffer (Dulbecco's Phosphate Buffered Saline,
manufactured by SIGMA) was added to each well. The plates
were allowed to stand at room temperature for at least 30
minutes and the luciferase activity was measured using a
10 Labsystems Luminoskan (manufactured by ICN Biomedicals Inc.).
Taking the average measurement of the
dimethylsulfoxide-added well groups in each plate as 100%, a
percentage for each test compound to the demethylsulfoxide-
15 added well groups (control %) was calculated.
The results are shown in the table below.
In the above table, a TFF2 production promoting
5 activity of 1000% or higher at a test compound concentration
of 10"6 M is indicated as "++" and a TFF2 production promoting
activity of 300% or higher at a test compound concentration
of 10'6 M as " + ".
The above results show that the concentration of
10 compound of the present invention for showing 300 % or higher
TFF2 production promoting activity is less than 10"5 M, and
more preferably less than 10"6 M.
Test Example 2
15 Healing effects on rat models with acetic acid-induced
gastric ulcers
(1) Production of gastric ulcer by acetic acid
Rats were fasted from the previous day. A celiotomy
was done in each rat under ether anesthesia, and the
acetic acid solution was injected into the submucosa at the
junction of the body of the glandular stomach and the
pyloric antrum using a disposable syringe to produce a
gastric ulcer.
(2) Test compound administration
5 Each test compound was suspended in a 0.5%
carboxymethylcelullose (CMC) solution at concentrations of
0.75 or 2.5 mg/ml. The rats were orally administrated once a
day for 8 days starting with the forth day from operation at
doses of 3 or 10 mg/kg. A gastric tube and a syringe were
10 used for the oral administration. The volumes of each test
compound and vehicle (0.5% CMC) were 4 ml/kg.
(3) Dissection
On the next day the vehicle and the test compound were
15 finally administrated to the rats, the rats were sacrificed
by exsanguination under anesthesia with ether, and each
stomach was removed. The removed stomachs were fixed in 1
formalin for 15 minutes, dissected along the greater
curvature of stomach to expose the ulcer, and the ulcerated
20 area was measured.
(4) Measurement of the ulcerated area
The ulcerated area was measured under a stereo
microscope (10 x) with an ocular micrometer (1 mmVgrid), and
25 the percentage healing ratio was calculated. The test
results were shown in the Table 184. The percentage healing
ratio was calculated by the following formula.
average ulcerated average ulcerated area
30 area of control group of test compound group
Healing ratio (%) = x 100
average ulcerated area of control group








CLAIM
1. A carbostyril compound represented by General Formula (1) a salt thereof
wherein A is a direct bond a lower alkylene group or a lower alkylidene group is an oxygen atom or a sulfur atom the bond between the 3 and 4 positions of the carbostyril skeleton is a single bond or a double bondR4 and R5 each represents a hydrogen atom with the proviso that when the bond between the 3 and 4 positions of the carbostyril skeleton is a double bond R4 and R5 instead may be linked together in the form of a -CH=CH-CH=CH- group
R1 is one of the following (1-1) to (1-29): (1-1) a hydrogen atom (1-2) a lower alkyl group
(1-3) a phenyl lower alkyl group optionally substituted on the phenyl ring with one or more members selected from the group consisting of a phenyl group lower alkyl groups lower alkoxy groups halogen atoms -(B)iNR6R7 groups a nitro group a carboxy group lower alkoxycarbonyl groups a cyano group phenyl lower alkoxy groups a phenoxy group a piperidinyl lower alkoxycarbonyl groups amino lower alkoxycarbonyl groups optionally substituted with one or more cycloalkyl groups 2-imidazolinylcarbonyl groups optionally substituted on the 2-imidazoline ring with one or more lower alkylthio groups 3-pyrrolinylcarbonyl groups optionally substituted on
the 3-pyrroline ring with one or more lower alkyl groups thiazolidinylcarbonyl groups optionally substituted on the thiazolidine ring with a phenyl group 3-azabicyclo[3.2.2]nonylcarbonyl groups piperidinyl lower alkyl groups anilino lower aklyl groups optionally substituted on the amino group with one or more lower alkyl groups phenylthio lower alkyl groups indolinyl lower alkyl groups and piperidinylcarbonyl groups optionally substituted on the piperidine ring with one or more lower alkyl groups (1-4) a cycloalkyl lower alkyl group (1-5) a phenoxy lower alkyl group (1-6) a naphthyl lower alkyl group (1-7) a lower alkoxy lower alkyl group (1-8) a carboxy lower alkyl group (1-9) a lower alkoxycarbonyl lower alkyl group (1-10) a pyridyl lower alkyl group optionally substituted on the pyridine ring with one or more members selected from the group consisting of halogen atoms piperidinyl groups a morpholino group piperazinyl groups optionally substituted on the piperazine ring with one or more members selected from the group consisting of a phenyl group and lower alkyl group thienyl groups a phenyl group pyridyl groups piperidinyl lower alkyl groups phenylthio lower alkyl groups biphenyl groups lower alkyl groups optionally substituted with one or more halogen atoms pyridylamino groups pyridylcarbonylamino groups lower alkoxy groups anilino lower alkyl groups optionally substituted on the amino group with one or more lower alkyl groups and anilino groups optionally substituted on the amino group with one or more lower alkyl groups (1-11) a cyano lower alkyl group (1-12) an -Ai-CONR8R9 group (1-13) a group of the following formula
(1-14) a phenyl group
(1-15) a quinolyl lower alkyl group
(1-16) a lower alkoxy lower alkoxy-substituted lower alkyl
group
(1-17) a hydroxy-substituted lower alkyl group
(1-18) a thiazolyl lower alkyl group optionally substituted
on the thiazole ring with one or more members selected from
the group consisting of halogen atoms a phenyl group
thienyl groups and pyridyl groups
(1-19) a lower alkyl group optionally substituted with one or
more halogen atoms
(1-20) a lower alkylsilyloxy lower alkyl group
(1-21) a phenoxy lower alkyl group optionally substituted on
the phenyl ring with one or more members selected from the
group consisting of lower alkyl groups optionally substituted
with one or more halogen atoms lower alkoxy groups halogen
atoms lower alkenyl groups cycloalkyl groups a nitro
group and a phenyl group
(1-22) a phenylthio lower alkyl group optionally substituted
on the phenyl ring with one or more halogen atoms
(1-23) a piperidinyl lower alkyl groups optionally
substituted on the piperidine ring with one or more members
selected from the group consisting of phenyl lower alkyl
groups and a phenyl group
(1-24) a piperazinyl lower alkyl group optionally substituted
on the piperazine ring with one or more phenyl groups
(1-25) a 1234-tetrahydroisoquinolyl lower alkyl group
(1-26) a naphthyloxy lower alkyl group
(1-27) a benzothiazolyloxy lower alkyl group optionally
substituted on the benzothiazole ring with one or more alkyl
groups
(1-28) a lower alkyl group substituted with one or more
members selected from the group consisting of quinolyloxy
groups and isoquinolyloxy groups.
(1-29) a pyridyloxy lower alkyl group optionally substituted on the pyridine ring with one or more lower alkyl groups
R2 is one of the following (2-1) to (2-33): (2-1) a hydrogen atom (2-2) a lower alkoxy group (2-3) a lower alkyl group (2-4) a carboxy lower alkoxy group (2 -5) a lower alkoxycarbonyl lower alkoxy group (2-6) a hydroxy group
(2-7) a phenyl lower alkoxy group optionally substituted on the phenyl ring with one or more members selected from the group consisting of halogen atoms lower alkyl groups optionally substituted with one or more halogen atoms lower alkylthio groups optionally substituted with one or more halogen atoms lower alkoxy groups a nitro group lower alkylsulfonyl groups lower alkoxycarbonyl groups phenyl lower alkenyl groups lower alkanoyloxy groups and 123-thiadiazolyl groups
(2-8) a piperidinyl lower alkoxy group optionally substituted on the piperidine ring with one or more lower alkyl groups (2-9) an amino-substituted lower alkoxy group optionally substituted with one or more lower alkyl groups (2-10) a lower alkenyloxy group
(2-11) a pyridyl lower alkoxy group optionally substituted on the pyridine ring with one or more lower alkyl groups each lower alkyl substituent optionally being substituted with one or more halogen atoms (2-12) a lower alkynyloxy group (2-13) a phenyl lower alkynyloxy group (2-14) a phenyl lower alkenyloxy group
(2-15) a furyl lower alkoxy group optionally substituted on the furan ring with one or more lower alkoxycarbonyl groups (2-16) a tetrazolyl lower alkoxy group optionally substituted on the tetrazole ring with one member selected from the group consisting of a phenyl group phenyl lower alkyl groups and
cycloalkyl lower alkyl groups
(2-17) a 124-oxadiazolyl lower alkoxy group optionally
substituted on the 124-oxadiazole ring with a phenyl group
the phenyl substituent optionally being substituted on the
phenyl ring with one or more lower alkyl groups
(2-18) an isoxazolyl lower alkoxy group optionally
substituted on the isoxazole ring with one or more lower
alkyl groups
(2-19) a 134-oxadiazolyl lower alkoxy group optionally
substituted on the 134-oxadiazole ring with a phenyl group
the phenyl substituent optionally being substituted on the
phenyl ring with one or more lower alkyl groups
(2-20) a lower alkanoyl lower alkoxy group
(2-21) a thiazolyl lower alkoxy group optionally substituted
on the thiazole ring with one or more members selected from
the group consisting of lower alkyl groups and a phenyl group
each phenyl substituent optionally being substituted on the
phenyl ring with one or more halogen atoms
(2-22) a piperidinyloxy group optionally substituted on the
piperidine ring with one or more benzoyl groups each benzoyl
substituent optionally being substituted on the phenyl ring
with one or more halogen atoms
(2-23) a thienyl lower alkoxy group
(2-24) a phenylthio lower alkoxy group
(2-25) a carbamoyl-substituted lower alkoxy group optionally
substituted with one or more lower alkyl groups
(2-26) a benzoyl lower alkoxy group
(2-27) a pyridylcarbonyl lower alkoxy group
(2-28) an imidazolyl lower alkoxy group optionally
substituted on the imidazole ring with one or more phenyl
lower alkyl groups
(2-29) a phenoxy lower alkoxy group
(2-30) a phenyl lower alkoxy-substituted lower alkoxy group
(2-31) a 23-dihydro-lH-indenyloxy group
(2-32) an isoindolinyl lower alkoxy group optionally

substituted on the isoindoline ring with one or more oxo
groups
(2-33) a phenyl group
R3 is one of the following (3-1) to (3-19): (3-1) a hydrogen atom (3-2) a lower alkyl group
(3-3) a hydroxy-substituted lower alkyl group (3-4) a cycloalkyl lower alkyl group (3-5) a carboxy lower alkyl group (3-6) a lower alkoxycarbonyl lower alkyl group (3-7) a phenyl lower alkyl group optionally substituted on the phenyl ring with one or more members selected from the group consisting of halogen atoms lower alkyl groups optionally substituted with one or more halogen atoms lower alkoxy groups optionally substituted with one or more halogen atoms a phenyl group lower alkoxycarbonyl groups a phenoxy group lower alkylthio groups lower alkylsulfonyl groups phenyl lower alkoxy groups and amino groups optionally substituted with one or more lower alkanoyl groups (3-8) a naphthyl lower alkyl group
(3-9) a furyl lower alkyl group optionally substituted on the furan ring with one or more lower alkoxycarbonyl groups (3-10) a thiazolyl lower alkyl group optionally substituted on the thiazole ring with one or more members selected from the group consisting of lower alkyl groups and a phenyl group each phenyl substituent optionally being substituted on the phenyl ring with one or more optionally halogen-substituted lower alkyl groups
(3-11) a tetrazolyl lower alkyl group optionally substituted on the tetrazole ring with one or more lower alkyl groups (3-12) a benzothienyl lower alkyl group optionally substituted on the benzothiophene ring with one or more halogen atoms
(3-13) a lower alkynyl group (3-14) a lower alkenyl group.
v3-15) a phenyl lower alkenyl group
(3-16) a benzoimidazolyl lower alkyl group
(3-17) a pyridyl lower alkyl group
(3-18) an imidazolyl lower alkyl group optionally substituted
on the imidazole ring with one or more phenyl lower alkyl
groups
(3-19) a quinolyl lower alkyl group
B is a carbonyl group or an -NHCO- group
1 is 0 or 1
R6 and R7 each independently represent one of the following (4-1) to (4-79): (4-1) a hydrogen atom (4-2) a lower alkyl group (4-3) a lower alkanoyl group
(4-4) a lower alkylsulfonyl group optionally substituted with one or more halogen atoms
(4-5) an alkoxycarbonyl group optionally substituted with one or more halogen atoms
(4-6) a hydroxy-substituted lower alkyl group (4-7) a pyridylcarbonyl group optionally substituted on the pyridine ring with one or more members selected from the group consisting of pyrrolyl groups and halogen atoms (4-8) a pyridyl group optionally substituted on the pyridine ring with one or more members selected from the group consisting of lower alkyl groups and lower alkoxy groups (4-9) a pyridyl lower alkyl group
(4-10) a phenyl group optionally substituted on the phenyl ring with one or more members selected from the group consisting of halogen atoms lower alkyl groups optionally substituted with one or more halogen atoms a phenoxy group lower alkoxy groups optionally substituted with one or more halogen atoms lower alkylthio groups lower alkylsulfonyl groups amino groups optionally substituted with one or more members selected from the group consisting of lower alkyl groups and lower alkanoyl groups pyrrolidinyl groups
optionally substituted on the pyrrolidine ring with one or
more oxo groups piperidinyl groups optionally substituted on
the piperidine ring with one or more lower alkyl groups
lower alkenyl groups an aminosulfonyl group a hydroxy
group carbamoyl groups optionally substituted with one or
more lower alkyl groups phenyl lower alkoxy groups and a
cyano group
(4-11) a cycloalkyl group optionally substituted on the
cycloalkyl ring with one or more lower alkyl groups
(4-12) a benzoyl group optionally substituted on the phenyl
ring with one or more members selected from the group
consisting of halogen atoms a phenoxy group a phenyl group
lower alkyl groups optionally substituted with one or more
halogen atoms lower alkoxy groups lower alkanoyl groups a
nitro group a cyano group amino groups optionally
substituted with one or more members selected from the group
consisting of a phenyl group and lower alkyl groups
pyrrolidinyl groups optionally substituted on the pyrrolidine
ring with one or more oxo groups pyrrolyl groups pyrazolyl
groups 124-triazolyl groups and imidazolyl groups
(4-13) a benzoyl group substituted on the phenyl ring with
one or more lower alkylenedioxy groups
(4-14) a cycloalkylcarbonyl group
(4-15) a furylcarbonyl group
(4-16) a naphthylcarbonyl group
(4-17) a phenoxycarbonyl group optionally substituted on the
phenyl ring with one or more members selected from the group
consisting of lower alkoxy groups lower alkyl groups
halogen atoms and a nitro group
(4-18) a phenyl lower alkoxycarbonyl group optionally
substituted on the phenyl ring with one or more members
selected from the group consisting of halogen atoms and a
nitro group
(4-19) a piperidinyl group optionally substituted on the
piperidine ring with one or more members selected from the

group consisting of lower alkyl groups lower alkanoyl
groups benzoyl groups optionally substituted on the phenyl
ring with one or more halogen atoms and phenyl groups
optionally substituted on the phenyl ring with one or more
halogen atoms
(4-20) a tetrahydropyranyl lower alkyl group
(4-21) a cycloalkyl lower alkyl group
(4-22) a lower alkenyl group
(4-23) a phenyl lower alkyl group optionally substituted on
the alkyl group with one or more lower alkoxycarbonyl groups
and optionally substituted on the phenyl ring with one or
more members selected from the group consisting of halogen
atoms lower alkyl groups optionally substituted with one or
more halogen atoms lower alkoxy groups optionally
substituted with one or more halogen atoms and a hydroxy
group
(4-24) a lower alkylenedioxy-substituted phenyl lower alkyl
group
(4-25) a furyl lower alkyl group
(4-26) a carbamoyl lower alkyl group optionally substituted
with one or more members selected from lower alkyl groups and
a phenyl group each phenyl substituent optionally being
substituted on the phenyl ring with one or more lower alkyl
groups
(4-27) a lower alkoxy lower alkyl group
(4-28) an imidazolyl lower alkyl group optionally substituted
on the lower alkyl group with one or more members selected
from the group consisting of a carbamoyl group and lower
alkoxycarbonyl groups
(4-29) an amino-substituted lower alkyl group optionally
substituted with one or more lower alkyl groups
(4-30) a 2345-tetrahydrofuryl group optionally substituted
on the 2345-tetrahydrofuran ring with one or more oxo
groups
(4-31) a lower alkoxycarbonyl lower alkyl group.

(4-32) a pyrrolidinyl lower alkyl group optionally
substituted on the pyrrolidine ring with one or more lower
alkyl groups
(4-33) a phenoxy lower alkanoyl group
(4-34) a morpholino lower alkyl group
(4-35) a indolyl group
(4-36) a thiazolyl group
(4-37) a 124-triazolyl group
(4-38) a pyridyl lower alkanoyl group
(4-39) a thienylcarbonyl group
(4-40) a thienyl lower alkanoyl group
(4-41) a cycloalkyl lower alkanoyl group
(4-42) an isoxazolylcarbonyl group optionally substituted on
the isoxazole ring with one or more lower alkyl groups
(4-43) a pyrazylcarbonyl group
(4-44) a piperidinylcarbonyl group optionally substituted on
the piperidine ring with one or more members selected from a
benzoyl group and lower alkanoyl groups
(4-45) a chromanylcarbonyl group
(4-46) an isoindolinyl lower alkanoyl group optionally
substituted on the isoindoline ring with one or more oxo
groups
(4-47) a thiazolidinyl lower alkanoyl group optionally
substituted on the thiazolidine ring with one or more members
selected from an oxo group and a thioxo group
(4-48) a piperidinyl lower alkanoyl group
(4-49) a phenyl lower alkenylcarbonyl group optionally
substituted on the phenyl ring with one or more halogen atoms
(4-50) a phenyl lower alkenylcarbonyl group substituted on
the phenyl ring with one or more alkylenedioxy groups
(4-51) a pyridyl lower alkenyl carbonyl group
(4-52) a pyridylthio lower alkanoyl group
(4-53) an indolylcarbonyl group
(4-54) a pyrrolylcarbonyl group
(4-55) a pyrrolidinylcarbonyl group optionally substituted on

the pyrrolidine ring with one or more oxo groups
(4-56) a benzofurylcarbonyl group
(4-57) an indolyl lower alkanoyl group
(4-58) a benzothienylcarbonyl group
(4-59) a phenyl lower alkanoyl group optionally substituted
on the phenyl ring with one or more halogen atoms
(4-60) a phenylsulfonyl group optionally substituted on the
phenyl ring with one or more members selected from the group
consisting of lower alkoxycarbonyl groups a cyano group a
nitro group amino groups optionally substituted with one or
more alkanoyl groups a hydroxy group a carboxyl group
lower alkoxycarbonyl lower alkyl groups halogen atoms lowe
alkyl groups optionally substituted with one or more halogen
atoms and lower alkoxy groups optionally substituted with
one or more halogen atoms
(4-61) a thienylsulfonyl group optionally substituted on the
thiophene ring with one or more members selected from the
group consisting of halogen atoms and lower alkoxycarbonyl
groups
(4-62) a quinolylsulfonyl group
(4-63) an imidazolylsulfonyl group optionally substituted on
the imidazole ring with one or more lower alkyl groups
(4-64) a phenylsulfonyl group optionally substituted on the
phenyl ring with one or more lower alkylenedioxy groups
(4-65) a lower alkenylsulfonyl group
(4-66) a cycloalkyl lower alkylsulfonyl group
(4-67) a 34-dihydro-2H-l4-benzoxazinylsulfonyl group
optionally substituted on the 34-dihydro-2H-l4-benzoxazine
ring with one or more lower alkyl groups
(4-68) a pyrazolylsulfonyl group optionally substituted on
the pyrazole ring with one or more members selected from
halogen atoms and lower alkyl groups
(4-69) an isoxazolylsulfonyl group optionally substituted on
the isoxazole ring with one or more lower alkyl groups
(4-70) a thiazolylsulfonyl group optionally substituted on

the thiazole ring with one or more members selected from the
group consisting of lower alkyl groups and an amino group
each amino substituent optionally being substituted with one
or more alkanoyl groups
(4-71) a phenyl lower alkylsulfonyl group
(4-72) a phenyl lower alkenylsulfonyl group
(4-73) a naphthyloxycarbonyl group
(4-74) a lower alkynyloxycarbonyl group
(4-75) a lower alkenyloxycarbonyl group
(4-76) a phenyl lower alkoxy-substituted lower alkoxycarbonyl
group
(4-77) a cycloalkyloxycarbonyl group optionally substituted
on the cycloalkyl ring with one or more lower alkyl groups
(4-78) a tetrazolyl group
(4-79) an isoxazolyl group optionally substituted on the
isoxazole ring with one or more lower alkyl groups or
instead
R6 and R7 may be linked together to form together with the nitrogen atom to which they are bound a 1234-tetrahydroisoquinolyl group an isoindolinyl group or a 5-to 7-membered saturated heterocyclic group the heterocyclic group optionally containing one or more additional heteroatoms and optionally being substituted with one to three members from the following (5-1) to (5-28): (5-1) lower alkyl groups (5-2) lower alkoxy groups (5-3) an oxo group (5-4) a hydroxy group (5-5) pyridyl lower alkyl groups
(5-6) phenyl groups optionally substituted on the phenyl ring with one or more members selected from the group consisting of halogen atoms lower alkoxy groups optionally substituted with one or more halogen atoms lower alkyl groups optionally substituted with one or more halogen atoms a cyano group and a hydroxy group

(5-7) lower alkylenedioxy-substituted phenyl lower alkyl
groups
(5-8) phenyl lower alkyl groups optionally substituted on the
phenyl ring with one or more halogen atoms
(5-9) pyrimidyl groups
(5-10) pyrazyl groups
(5-11) cycloalkyl groups
(5-12) phenyl lower alkoxy groups optionally substituted on
the phenyl ring with one or more halogen atoms
(5-13) benzoyl groups optionally substituted on the phenyl
ring with one or more halogen atoms
(5-14) benzoyl groups substituted on the phenyl ring with one
or more lower alkylenedioxy groups
(5-15) carbamoyl lower alkyl groups optionally substituted
with one or more members selected from the group consisting
of a phenyl group and lower alkyl groups
(5-16) benzoxazolyl groups
(5-17) lower alkoxycarbonyl groups
(5-18) a carbamoyl group
(5-19) phenyl lower alkylidene groups optionally substituted
on the phenyl ring with one or more halogen atoms
(5-20) phenyl lower alkoxycarbonyl groups
(5-21) pyridyl groups optionally substituted on the pyridine
ring with one or more members selected from the group
consisting of a cyano group and lower alkyl groups
(5-22) furyl lower alkyl groups
(5-23) tetrahydropyranyl groups
(5-24) imidazolyl lower alkyl groups
(5-25) naphthyl groups
(5-26) 23-dihydro-lH-indenyl groups
(5-27) 13-dioxolanyl lower alkyl groups
(5-28) -(A3)nNRllR12 groups
AI is a lower alkylene group
R8 and R9 each independently represent one of the following (6-1) to (6-25):

(6-1) a hydrogen atom
(6-2) a lower alkyl group
(6-3) a phenyl group optionally substituted on the phenyl
ring with one or more members selected from the group
consisting of lower alkyl groups optionally substituted with
one or more halogen atoms lower alkylthio groups lower
alkoxy groups optionally substituted with one or more halogen
atoms halogen atoms a phenyl group lower alkylamino
groups a cyano group a phenoxy group cycloalkyl groups
pyrrolidinyl groups optionally substituted with one or more
oxo groups 1234-tetrahydroisoquinolylcarbonyl groups
1234-tetrahydroquinolylcarbonyl groups optionally
substituted with one or more lower alkyl groups 1234-
tetrahydroquinoxalinylcarbonyl groups optionally substituted
with one or more lower alkyl groups thiazolyl groups
optionally substituted with one or more phenyl groups a
carbamoyl group phenyl lower alkoxy groups lower
alkylsulfonylamino groups anilino groups optionally
substituted with one or more halogen atoms phenyl lower
alkyl groups and hydroxy-substituted lower alkyl groups
(6-4) a cycloalkyl group
(6-5) a cycloakyl lower alkyl group
(6-6) a carbamoyl lower alkyl group
(6-7) a phenyl lower alkyl group optionally substituted on
the phenyl ring with one or more members selected from the
group consisting of lower alkyl groups optionally substituted
with one or more halogen atoms lower alkoxy groups
optionally substituted with one or more halogen atoms
halogen atoms and a phenyl group
(6-8) lower alkyl-substituted amino lower alkyl group
(6-9) a naphthyl group
(6-10) a naphthyl lower alkyl group
(6-11) a tetrahydronaphthyl lower alkyl group
(6-12) a fluorenyl group
(6-13) a pyridyl group

(6-14) a pyridyl lower alkyl group
(6-15) a pyrimidinyl group
(6-16) a pyrazinyl lower alkyl group optionally substituted
on the pyrazine ring with one or more lower alkyl groups
(6-17) a thiazolyl group
(6-18) a pyrazolyl lower alkyl group optionally substituted
on the pyrazole ring with one or more lower alkyl groups
(6-19) a thienyl lower alkyl group
(6-20) a piperidinyl group optionally substituted on the
piperidine ring with one or more members selected from the
group consisting of lower alkyl groups a benzoyl group and
phenyl lower alkyl groups optionally substituted on the
phenyl ring with one or more members selected from the group
consisting of halogen atoms and lower alkyl groups
(6-21) an indolyl group
(6-22) an indazolyl group
(6-23) a 34-dihydrocarbostyril optionally substituted with
one or more lower alkyl groups
(6-24) a quinolyl group optionally substituted with one or
more lower alkyl groups
(6-25) a carbazolyl group optionally substituted with one or
more lower alkyl groups or
R8 and R9 may be linked together to form together with the nitrogen atom to which they are bound a 5- to 8-membered saturated heterocyclic group optionally containing one or more additional heteroatoms and optionally substituted on the heterocyclic ring with one or more members selected from the group consisting of the following (6-28-1) to (6-28-24):
(6-28-1) lower alkyl groups
(6-28-2) phenyl lower alkyl groups optionally substituted on the phenyl ring with one or more members selected from halogen atoms and lower alkoxy groups optionally substituted with one or more halogen atoms (6-28-3) naphthyl lower alkyl groups.

(6-28-4) phenyl lower alkylcarbamoyl lower alkyl groups
(6-28-5) phenylcarbamoyl lower alkyl groups
(6-28-6) phenyl lower alkoxycarbonyl groups
(6-28-7) phenoxy lower alkyl groups optionally substituted on
the phenyl ring with one or more members selected from the
group consisting of halogen atoms and lower alkyl groups
optionally substituted with one or more halogen atoms
(6-28-8) biphenyl groups
(6-28-9) phenyl groups optionally substituted on the phenyl
ring with one or more halogen atoms
(6-28-10) 23-dihydroindenyl groups optionally substituted
with one or more halogen atoms
(6-28-11) benzothiazolyl groups optionally substituted with
one or more halogen atoms
(6-28-12) pyridyl groups optionally substituted with one or
more halogen atoms
(6-28-13) benzothienyl groups
(6-28-14) benzoisothiazolyl groups
(6-28-15) thienopyridyl groups
(6-28-16) a carbamoyl group
(6-28-17) phenyl lower alkoxy groups optionally substituted
on the phenyl ring with one or more halogen atoms
(6-28-18) phenoxy groups optionally substituted with one or
more halogen atoms
(6-28-19) benzoyl groups optionally substituted on the phenyl
ring with one or more members selected from halogen atoms and
lower alkoxy groups
(6-28-20) anilino groups optionally substituted on the phenyl
ring with one or more lower alkyl groups each lower alkyl
substituent optionally being substituted with one or more
halogen atoms
(6-28-21) anilino groups substituted on the amino group with
one or more lower alkyl groups and optionally further
substituted on the phenyl ring with one or more halogen atoms
(6-28-22) benzofuryl groups

(6-28-23) naphthyl groups. (6-28-24) an oxo group or
R8 and R9 may be linked together to form together with the nitrogen atom to which they are bound a 5- or 6-membered unsaturated heterocyclic group the unsaturated heterocyclic group optionally being substituted on the heterocyclic ring with one or more members selected from the group consisting of the following (6-29-1) to (6-29-3): (6-29-1) phenyl groups optionally substituted with one or more halogen atoms (6-29-2) 23-dihydroindenyl groups (6-29-3) benzothienyl groups or instead
R8 and R9 may be linked together to form together with the nitrogen atom to which they are bound a 1234-tetrahydroquinolyl group a 1234-tetrahydroisoquinolyl group a 13-dihydroisoindolyl group an
octahydropyrrolo[l2-a]pyrazinyl group optionally substituted on the pyrazine ring with one or more lower alkyl groups or an 8-azabicyclo[3.2.1]octyl group optionally substituted on the 8-azabicyclo[3.2.1]octyl group with one or more phenoxy groups each phenoxy substituent optionally being substituted on the phenyl ring with one or more halogen atoms
A2 is a lower alkylene group
R10 is one of the following (7-1) to (7-44): (7-1) a hydrogen atom (7-2) a lower alkyl group
(7-3) an alkoxycarbonyl group optionally substituted with one or more halogen atoms
(7-4) a benzoyl group optionally substituted on the phenyl ring with one or more members selected from the group consisting of lower alkyl groups optionally substituted with one or more halogen atoms a phenyl group halogen atoms a cyano group a phenoxy group lower alkoxycarbonyl groups pyrazolyl groups and lower alkoxy groups optionally substituted with one or more halogen atoms.

(7-5) an alkanoyl group
(7-6) a phenyl lower alkanoyl group optionally substituted on
the phenyl ring with one or more members selected from the
group consisting of halogen atoms and lower alkyl groups
(7-7) a cycloalkyl lower alkanoyl group
(7-8) a phenyl group optionally substituted on the phenyl
ring with one or more lower alkyl groups
(7-9) a phenoxy lower alkanoyl group optionally substituted
on the phenyl ring with one or more halogen atoms
(7-10) a phenyl lower alkenylcarbonyl group
(7-11) a pyridylcarbonyl group optionally substituted on the
pyridine ring with one or more members selected from the
group consisting of halogen atoms and lower alkyl groups
each lower alkyl substituent optionally being substituted
with one or more halogen atoms
(7-12) a furylcarbonyl group
(7-13) a thienylcarbonyl group
(7-14) a piperidinylcarbonyl group optionally substituted on
the piperidine ring with one or more lower alkanoyl groups
(7-15) a pyrrolidinylcarbonyl group optionally substituted on
the pyrrolidine ring with one or more oxo groups
(7-16) a tetrahydropyranylcarbonyl group
(7-17) a naphthylcarbonyl group
(7-18) an indolylcarbonyl group
(7-19) a benzofurylcarbonyl group
(7-20) a benzothienylcarbonyl group optionally substituted on
the benzothiophene ring with one or more halogen atoms
(7-21) a furyl lower alkyl group
(7-22) a pyridyl lower alkyl group optionally substituted on
the pyridine ring with one or more members selected from the
group consisting of halogen atoms and lower alkyl groups
each lower alkyl substituent optionally being substituted
with one or more halogen atoms
(7-23) a thienyl lower alkyl group optionally substituted on
the thiophene ring with one or more halogen atoms.

(7-24) a phenyl lower alkyl group optionally substituted on
the phenyl ring with one or more members selected from the
group consisting of lower alkoxy groups optionally
substituted with one or more halogen atoms a cyano group
lower alkyl groups optionally substituted with one or more
halogen atoms amino groups optionally substituted with one
or more members selected from the group consisting of lower
alkyl groups and lower alkanoyl groups halogen atoms lower
alkoxycarbonyl groups lower alkanoyloxy groups lower
alkylsulfonyl groups lower alkylthio groups and
pyrrolidinyl groups
(7-25) a thiazolyl lower alkyl group
(7-26) an imidazolyl lower alkyl group optionally substituted
on the imidazole ring with one or more lower alkyl groups
(7-27) a pyrrolyl lower alkyl group optionally substituted on
the pyrrole ring with one or more lower alkyl groups
(7-28) a cycloalkyl lower alkyl group
(7-29) a lower alkylthio lower alkyl group
(7-30) a phenoxycarbonyl group optionally substituted on the
phenyl ring with one or more members selected from the group
consisting of halogen atoms lower alkyl groups and lower
alkoxy groups
(7-31) a phenyl lower alkoxycarbonyl group optionally
substituted on the phenyl ring with one or more halogen atoms
(7-32) a naphthyloxycarbonyl group
(7-33) a lower alkynyloxycarbonyl group
(7-34) a cycloalkylcarbonyl group
(7-35) a quinoxalinylcarbonyl group
(7-36) a -CO-NR13R14 group
(7-37) a piperidinyl group optionally substituted on the
piperidine ring with one or more lower alkyl groups
(7-38) a cycloalkyl group
(7-39) a tetrahydropyranyl group
(7-40) a lower alkoxy lower alkyl group
(7-41) a tetrahydro-2H-thiopyranyl group.

(7-42) a naphthyl group (7-43) a biphenyl group (7-44) a lower alkylsilyl lower alkoxycarbonyl group
A3 is a lower alkylene group
m is 0 or 1
R11 and R12 each independently represent one of the following (8-1) to (8-5): (8-1) a hydrogen atom (8-2) a lower alkyl group (8-3) a lower alkanoyl group (8-4) a phenyl lower alkanoyl group
(8-5) a phenyl group optionally substituted on the phenyl ring with one or more halogen atoms or instead
R11 and R12 may be linked together to form together with the nitrogen atom to which they are bound a 5- or 6-membered saturated heterocyclic group which optionally contains one or more additional heteroatoms the heterocyclic group optionally being substituted with one to three members selected from the group consisting of the following (9-1) and (9-2):
(9-1) lower alkyl groups (9-2) a phenyl group and
R13 and R14 each independently represent one of the following (10-1) to (10-3): (10-1) a hydrogen atom (10-2) a lower alkyl group (10-3) a phenyl group or instead
R13 and R14 may be linked together to form together with the nitrogen atom to which they are bound a 5- or 6-membered saturated heterocyclic group which optionally contains one or more additional heteroatoms.
2. A carbostyril compound or a salt thereof according to Claim 1 wherein the bond between the 3 and 4 positions of the carbostyril skeleton is a single bond or a double bond and R4 and R5 each represent a hydrogen atom.
3. A carbostyril compound or a salt thereof according to Claim 2 wherein a group of the formula
in which R3 A and X are as defined in Claim 1 above is bound to the 3 4 5 6 7 or 8 position of the carbostyril skeleton.
4. A carbostyril compound or a salt thereof according to Claim 3 wherein the bond between the 3 and 4 positions of the carbostyril skeleton is a single bond and the group of the formulain which R3 A and X are as dfined in Claim I above is bound to the 5 or 6 position of the carbostyril skelton.
5. A carbostyril compound or a salt thereof
according to Claim 3 or 4 wherein A is a lower alkylene
group or a lower alkylidene group.
6. A carbostyril compound or a salt thereof
according to Claim 5 wherein R1 is one of (1-2) (1-3) (1-
4) (1-6). (1-10) (1-12) (1-13) (1-18) and (1-21) as
defined in Claim 1 above.
7. A carbostyril compound or a salt thereof
according to Claim 6 wherein the group of the formula
in which R3 A and X are as defined in Claim 1 above is bound to the 5 position of the carbostyril skelton.
8. A carbostyril compound or a salt thereof according to Claim 7 wherein R1 is a phenyl lower alkyl group optionally substituted on the phenyl ring with one or more members selected from the group consisting of a phenyl
ring halogen atoms -(B)iNR6R7 groups wherein B 1 R6 and R7 are as defined in Claim 1 lower alkoxycarbonyl groups and phenyl lower alkoxy groups.
9. A carbostyril compound or a salt thereof
5 according to Claim 8 wherein A is a lower alkylene group R2 is a hydrogen atom or a lower alkoxy group R3 is a hydrogen atom and X is an oxygen atom or a sulfur atom.
10. A carbostyril compound or a salt thereof
according to Claim 7 wherein A is a lower alkylene group R1
10 is a lower alkyl group R2 is a hydrogen atom or a lower
alkoxy group R3 is a hydrogen atom and X is an oxygen atom or a sulfur atom.
11. A carbostyril compound or a salt thereof
according to Claim 7 wherein A is a lower alkylene group R1
15 is a naphthyl lower alkyl group R2 is a hydrogen atom or a lower alkoxy group R3 is a hydrogen atom and X is an oxygen atom or a sulfur atom.
12. A carbostyril compound or a salt thereof
according to Claim 7 wherein A is a lower alkylene group R1
20 is a group of the formula
in which R10 and A2 are as defined in Claim 1 above R2 is a
hydrogen atom or a lower alkoxy group R3 is a hydrogen atom
and X is an oxygen atom or a sulfur atom.
25 13. A carbostyril compound or a salt thereof
according to Claim 3 wherein the bond between the 3 and 4 positions of the carbostyril skeleton is a double bond and a group of the formula
30 in which R3 A and X are as defined in Claim 1 above is
bound to the 3 4 or 5 position of the carbostyril sleketon
14. A carbostyril compound or a salt thereof
according to Claim 13 wherein R1 is one of (1-2) and (1-3)
as defined in Claim 1.
15. A carbostyril compound or a salt thereof
5 according to Claim 14 wherein A is a lower alkylene group or a lower alkylidene group and R2 is a hydrogen atom or a lower alkoxy group.
16. A carbostyril compound or a salt thereof
according to Claim 1 wherein the bond between the 3 and 4
10 positions of the carbostyril skeleton is a double bond and R4 and R5 are linked together in the form of a -CH=CH-CH=CH-group.
17. A carbostyril compound or a salt thereof
according to Claim 16 wherein a group of the formula
5 in which R3 A and X are as defined in Claim 1 above is bound to the 7 position of the carbostyril skeleton.
18. A carbostyril compound or a salt thereof
according to Claim 17 wherein R1 is one of (1-2) and (1-3)
20 as defined in Claim 1 above.
19. A carbostyril compound or a salt thereof
according to Claim 18 wherein A is a lower alkylene group or
a lower alkylidene group R2 and R3 are both hydrogen atoms
and X is an oxygen atom or a sulfur atom.
25 20. A carbostyril compound or a salt thereof
according to Claim 1 wherein A is a direct bond.
21. A carbostyril compound or a salt thereof
according to Claim 1 wherein A is a lower alkylene group.
22. A carbostyril compound or a salt thereof
30 according to Claim 1 wherein A is a lower alkylidene group.
23. A carbostyril compound or a salt thereof
according to any one of Claims 20 to 22 wherein the bond
between the 3 and 4 positions of the carbostyril skeleton is
ylmethyl)-34-dihydro-IH-quinolin-2-one
8-methoxy-1-phenethyl-5-(4-oxo-2-thioxothiazolidin-5-
ylmethyl)-34-dihydro-IH-quinolin-2-one and
1-(4-phenylthiomethyl)benzyl-5-(4-oxo-2-thioxothiazolidin-5-
ylmethyl)-3.4-dihydro-IH-quinolin-2-one or a salt thereof.
26. A pharmaceutical composition comprising as an
active ingredient a carbostyril compound or salt thereof
according to Claim 1.
27. A prophylactic and/or therapeutic agent for a
disorder on which TFF up-regulation has a prophylactic and/or
therapeutic effect comprising as an active ingredient a
carbostyril compound or salt thereof according to Claim 1.
28. A prophylactic and/or therapeutic agent
according to Claim 27 wherein the disorder on which TFF up-
regulation has a prophylactic and/or therapeutic effect is an
alimentary tract disease oral disease upper respiratory
tract disease respiratory tract disease eye disease cancer
or wound.
29. A prophylactic and/or therapeutic agent
according to Claim 27 wherein the disorder on which TFF up-
regulation has a prophylactic and/or therapeutic effect is a
drug-induced ulcer peptic gastric ulcer ulcerative colitis
Crohn's disease drug-induced enteritis ischemic colitis
irritable bowel syndrome ulcer developed after endoscopic
demucosation acute gastritis chronic gastritis reflux
esophagitis esophageal ulcer Barrett esophagus
gastrointestinal mucositis hemorrhoidal diseases stomatitis
syndrome xerostomia rhinitis pharyngitis
bronchial asthma chronic obstructive lung disease dry eye
or keratoconjunctivitis.
30. A prophylactic and/or therapeutic agent
according to Claim 27 wherein the TFF is TFF2.
31. A use of a carbostyril compound or salt thereof
according to Claim 1 for manufacturing a prophylactic and/or
therapeutic agent for a disorder on which TFF up-regulation
has a prophylactic and/or therapeutic effect.
32. A method for preventing and/or treating a
disorder on which TFF up-regulation has a prophylactic and/or
therapeutic effect comprising administering to a patient an
effective amount of a carbostyril compound or salt thereof
according to Claim 1.
33. A prophylactic and/or therapeutic agent for
alimentary tract diseases oral diseases upper respiratory
tract diseases respiratory tract diseases eye diseases
cancers or wounds the agent comprising a compound that
induces the production of TFF.
34. A prophylactic and/or therapeutic agent
according to Claim 33 wherein the TFF is TFF2.
35. A process for the production of a carbostyril compound (1) of the following formula:

or a salt thereof wherein R1 R2 R3 R4 R5 A X and the bond between the 3 and 4 positions of the carbostyril skeleton are as defined in Claim 1 which comprises
) reacting a compound (2) of the formula: 5
or a salt thereof wherein R1 R2 R4 R5 and the bond between the 3 and 4 positions of the carbostyril skeleton are as defined above and R15 is a hydrogen atom or lower alkyl group and A4 represents a direct bond or lower alkylene group
or a salt thereof wherein R3 and X are as defined above to give a compound (la) of the formula:

or a salt thereof wherein R1 R2 R3 R4 R5 R15 A4 and the bond between the 3 and 4 positions of the carbostyril skeleton are as defined above and
(ii) reducing the compound (la) defined above or a salt thereof to give a compound (Ib) of the formula:

rein R1 R2 R3 R4 R5 R15 A4 and the bond between the 3 and 4 positions of the carbostyril skeleton are as defined above.

Documents:

1824-delnp-2007-Abstract-(18-12-2012).pdf

1824-delnp-2007-abstract.pdf

1824-delnp-2007-Claims-(18-12-2012).pdf

1824-delnp-2007-claims.pdf

1824-delnp-2007-Correspondence Others-(09-05-2013).pdf

1824-delnp-2007-Correspondence Others-(12-02-2014).pdf

1824-delnp-2007-Correspondence Others-(17-05-2013).pdf

1824-delnp-2007-Correspondence Others-(18-12-2012).pdf

1824-delnp-2007-Correspondence-others (19-08-2008).pdf

1824-delnp-2007-Correspondence-Others-(10-08-2013).pdf

1824-delnp-2007-correspondence-others.pdf

1824-delnp-2007-description (complete).pdf

1824-delnp-2007-form-1.pdf

1824-delnp-2007-Form-18 (19-08-2008).pdf

1824-delnp-2007-form-2.pdf

1824-delnp-2007-Form-3-(09-05-2013).pdf

1824-delnp-2007-Form-3-(18-12-2012).pdf

1824-delnp-2007-form-3.pdf

1824-delnp-2007-form-5.pdf

1824-delnp-2007-GPA-(10-08-2013).pdf

1824-delnp-2007-GPA-(12-02-2014).pdf

1824-delnp-2007-GPA-(18-12-2012).pdf

1824-delnp-2007-pct-101.pdf

1824-delnp-2007-pct-210.pdf

1824-delnp-2007-pct-304.pdf

1824-delnp-2007-pct-308.pdf

1824-delnp-2007-Petition-137-(18-12-2012).pdf


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Patent Number 261015
Indian Patent Application Number 1824/DELNP/2007
PG Journal Number 23/2014
Publication Date 06-Jun-2014
Grant Date 30-May-2014
Date of Filing 08-Mar-2007
Name of Patentee OTSUKA PHARMACEUTICAL CO.,LTD.
Applicant Address 9,KANDATSUKASA-CHO 2-CHOME, CHIYODA-KU, TOKYO 101-8535,JAPAN
Inventors:
# Inventor's Name Inventor's Address
1 TAE FUKUSHIMA, TAKAHIRO TOMOYASU, HIRONOBU ISHIYAMA, KAZUHIDE OHTA, MASAAKI TAKANO AND TAKUMI SUMIDA 463-10, KAGASUNO, KAWAUCHI-CHO, TOKUSHIMA 7710192,JAPAN
2 TAKESHI KURODA, TAKAHITO YAMAUCHI, TOMOICHI SHINOHARA,KUNIO OSHIMA, CHIHARU KITAJIMA, HITOSHI NAGAO 463-10, KAGASUNO, KAWAUCHI-CHO, TOKUSHIMA-SHI, TOKUSHIMA 7710192, JAPAN
PCT International Classification Number C07D 417/06
PCT International Application Number PCT/JP2005/018217
PCT International Filing date 2005-09-26
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 2004-282814 2004-09-28 Japan