U.S. patent application number 11/783325 was filed with the patent office on 2007-08-09 for antiallergic agents.
This patent application is currently assigned to Institute of Medicinal Molecular Design, Inc.. Invention is credited to Akiko Itai, Susumu Muto.
Application Number | 20070185059 11/783325 |
Document ID | / |
Family ID | 29727583 |
Filed Date | 2007-08-09 |
United States Patent
Application |
20070185059 |
Kind Code |
A1 |
Muto; Susumu ; et
al. |
August 9, 2007 |
Antiallergic agents
Abstract
A medicament for the preventive and/or therapeutic treatment of
allergic diseases and/or endometriosis and/or hysteromyoma which
comprises as an active ingredient a substance selected from the
group consisting of a compound represented by the following general
formula (I) and a pharmacologically acceptable salt thereof, and a
hydrate thereof and a solvate thereof: ##STR1## wherein X
represents a connecting group whose number of atoms in the main
chain is 2 to (said connecting group may be substituted), A
represents hydrogen atom or acetyl group, E represents an aryl
group which may be substituted or a hetero aryl group which may be
substituted, ring Z represents an arene which may have one or more
substitutents in addition to the group represented by formula --O-A
wherein A has the same meaning as that defined above and the group
represented by formula --X-E wherein each of X and E has the same
meaning as that defined above, or a heteroarene which may have one
or more substitutents in addition to the group represented by
formula --O-A wherein A has the same meaning as that defined above
and the group represented by formula --X-E wherein each of X and E
has the same meaning as that defined above.
Inventors: |
Muto; Susumu; (Tokyo,
JP) ; Itai; Akiko; (Tokyo, JP) |
Correspondence
Address: |
GREENBLUM & BERNSTEIN, P.L.C.
1950 ROLAND CLARKE PLACE
RESTON
VA
20191
US
|
Assignee: |
Institute of Medicinal Molecular
Design, Inc.
Tokyo
JP
|
Family ID: |
29727583 |
Appl. No.: |
11/783325 |
Filed: |
April 9, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10515623 |
Jun 20, 2005 |
|
|
|
PCT/JP03/07120 |
Jun 5, 2003 |
|
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11783325 |
Apr 9, 2007 |
|
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Current U.S.
Class: |
514/63 ;
514/237.8; 514/317; 514/365; 514/408; 514/448; 514/521;
514/620 |
Current CPC
Class: |
A61P 11/00 20180101;
C07D 295/192 20130101; A61P 19/02 20180101; A61K 31/498 20130101;
A61K 31/055 20130101; A61K 31/403 20130101; A61P 9/00 20180101;
A61P 43/00 20180101; A61K 31/165 20130101; A61K 31/63 20130101;
C07C 235/64 20130101; A61K 31/167 20130101; A61P 27/02 20180101;
A61P 11/02 20180101; A61P 7/00 20180101; A61K 31/606 20130101; A61K
31/5375 20130101; A61P 9/10 20180101; A61P 27/14 20180101; A61K
31/4453 20130101; A61K 31/18 20130101; A61K 31/609 20130101; A61K
31/616 20130101; A61P 13/10 20180101; A61K 31/427 20130101; A61K
31/422 20130101; A61K 31/357 20130101; A61P 1/04 20180101; A61K
31/40 20130101; A61P 17/00 20180101; A61K 31/404 20130101; A61P
35/00 20180101; A61P 27/16 20180101; A61K 31/137 20130101; A61K
31/445 20130101; A61K 31/4035 20130101; A61P 25/28 20180101; A61P
29/00 20180101; A61K 31/421 20130101; A61K 31/455 20130101; A61P
25/00 20180101; A61P 11/06 20180101; A61K 31/15 20130101; A61K
31/47 20130101; A61K 31/381 20130101; A61P 1/12 20180101; A61P
15/00 20180101; A61P 17/04 20180101; A61P 37/08 20180101 |
Class at
Publication: |
514/063 ;
514/237.8; 514/317; 514/408; 514/365; 514/521; 514/620;
514/448 |
International
Class: |
A61K 31/695 20060101
A61K031/695; A61K 31/5375 20060101 A61K031/5375; A61K 31/40
20060101 A61K031/40; A61K 31/445 20060101 A61K031/445; A61K 31/426
20060101 A61K031/426; A61K 31/277 20060101 A61K031/277; A61K 31/165
20060101 A61K031/165 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 6, 2002 |
JP |
2002-165148 |
Claims
1. A method for the prophylactic and/or therapeutic treatment of
allergic diseases and/or endometriosis and/or hysteromyoma in a
mammal, which comprises administering to a mammal a
prophylactically and/or therapeutically effective amount of a
substance selected from the group consisting of a compound
represented by the following general formula (I), a
pharmacologically acceptable salt thereof, a hydrate thereof, and
solvate thereof: ##STR1049## wherein X represents a connecting
group whose number of atoms in the main chain is 2 to 5 (said
connecting group may be substituted), A represents hydrogen atom or
acetyl group, E represents an aryl group which may be substituted
or a heteroaryl group which may be substituted, ring Z represents
an arene or heteroarene which may have one or more substitutents in
addition to the group represented by formula --O-A or --X-E,
provided that the compounds represented by the following (1) and
(2) are excluded: (1) The compounds represented by the
aforementioned formula (I) wherein X is a group represented by the
following formula: ##STR1050## wherein the bond at the left end
binds to ring Z and the bond at the right end binds to E, E is a
3,5-di-substituted phenyl group wherein at least one of said
substitutents is trifluoromethyl group, ring Z is a benzene ring
which may have one or more substitutents selected from the group
consisting of: a halogen atom; a nitro group; a cyano group; an
alkoxy group; an alkyl group which may be substituted with one or
more substitutents selected from the group consisting of a hydroxyl
group, an alkyl-oxy-imino group, and an aralkyl-oxy-imino group; an
alkenyl group which may be substituted with one or more
substitutents selected from the group consisting of: an aryl group,
a cyano group, an alkyl-oxy-carbonyl group, and a carboxy group; an
alkynyl group which may be substituted with one or more
substitutents selected from the group consisting of: an aryl group,
and a tri(alkyl)silyl group; a halogenated alkyl group; an aryl
group which may be substituted with one or more substitutents
selected from the group consisting of: a halogen atom, and a
halogenated alkyl group; an aralkyl group; a 5 to 9-membered
heteroaryl group which may be substituted with one or more alkyl
groups; an alkyl-carbonyl group; a 6-membered nonaromatic
heterocyclic-carbonyl group which may be substituted with one or
more aralkyl groups; a 5-membered heteroaryl-sulfonyl group; a
carboxy group; an alkyl-oxy-carbonyl group; a carbamoyl group which
may be substituted with one or more substitutents selected from the
group consisting of: an aryl group which may be substituted with
one or more halogenated alkyl groups, and an alkyl group; a
sulfamoyl group which may be substituted with one or more
substitutents selected from the group consisting of: an aryl group
which may be substituted with one or more halogenated alkyl groups,
and an alkyl group; an amino group which may be substituted with
one or more substitutents selected from the group consisting of: an
alkyl group, an alkyl-carbonyl group, an aryl-carbonyl group, an
alkyl-sulfonyl group, and an aryl-sulfonyl group; an ureido group
which may be substituted with one or more aryl groups; a thioureido
group which may be substituted with one or more aryl groups; a
diazenyl group which may be substituted with one or more aryl
groups wherein said aryl groups may be substituted with one or more
substitutents selected from the group consisting of: a nitro group,
and a 6-membered heteroaryl-sulfamoyl group; and a hydroxy group;
in addition to the group represented by formula --O-A and the group
represented by formula --X-E, and (2) The compounds represented by
the aforementioned formula (I) wherein X is a group represented by
the following formula: ##STR1051## wherein the bond at the left end
binds to ring Z and the bond at the right end binds to E, E is a
2,5-di-substituted phenyl group wherein at least one of said
substitutents is trifluoromethyl group, ring Z is a benzene ring
which may have one or more substitutents in addition to the group
represented by formula --O-A and the group represented by formula
--X-E.
2. The method according to claim 1, wherein: X is a group
represented by the following formula: ##STR1052## wherein the bond
at the left end binds to ring Z and the bond at the right end binds
to E, ring Z is a benzene ring which may have one or more
substitutents in addition to the group represented by formula --O-A
and the group represented by formula --X-E.
3. The method according to claim 2, wherein: E is a
3,5-bis(trifluoromethyl)-2-bromophenyl group, a
3,5-bis(trifluoromethyl)-2-methylphenyl group, a
2,6-dichloro-4-(trifluoromethyl)phenyl group, a
2,4-dimethoxy-5-(trifluoromethyl)phenyl group, a
2,4-difluoro-5-(trifluoromethyl)phenyl group, a
4-chloro-2-(4-chlorobenzenesulfonyl)-5-(trifluoromethyl)phenyl
group, a 5-chloro-2-nitro-4-(trifluoromethyl)phenyl group, a
2,3-difluoro-4-(trifluoromethyl)phenyl group, a
2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl group, a
4-chloro-2-(trifluoromethyl)phenyl group,
2-fluoro-3-(trifluoromethyl)phenyl group, a
4-fluoro-3-(trifluoromethyl)phenyl group, a
4-chloro-3-(trifluoromethyl)phenyl group,
4-nitro-3-(trifluoromethyl)phenyl group, a
4-cyano-3-(trifluoromethyl)phenyl group, a
2-methyl-3-(trifluoromethyl)phenyl group, a
4-methyl-3-(trifluoromethyl)phenyl group, a
4-methoxy-3-(trifluoromethyl)phenyl group, a
2-chloro-4-(trifluoromethyl)phenyl group, a
4-isopropyl-2-(trifluoromethyl)phenyl group, a
2-nitro-4-(trifluoromethyl)phenyl group, a
4-bromo-3-(trifluoromethyl)phenyl group, a
4-bromo-2-(trifluoromethyl)phenyl group, a
2-bromo-4-(trifluoromethyl)phenyl group, a
4-fluoro-2-(trifluoromethyl)phenyl group, a
4-isopropoxy-2-(trifluoromethyl)phenyl group, or a
4-cyano-2-(trifluoromethyl)phenyl group or
2,4-bis(trifluoromethyl)phenyl group, the following partial formula
(Iz-1) in the general formula containing ring Z ##STR1053## is
represented by the following formula (Iz-2): ##STR1054## wherein
R.sup.z represents a group selected from the following Substituent
Group .gamma.-2z, wherein Substituent Group .gamma.-2z is one of a
halogen atom, a nitro group, a cyano group, a methoxy group, a
methyl group, an isopropyl group, a tert-butyl group, a
1,1,3,3-tetramethylbutyl group, a 2-phenylethen-1-yl group, a
2,2-dicyanoethen-1-yl group, a
2-cyano-2-(methoxycarbonyl)ethen-1-yl group, a
2-carboxy-2-cyanoethen-1-yl group, a ethynyl group, a phenylethynyl
group, a (trimethylsilyl)ethynyl group, a trifluoromethyl group, a
pentafluoroethyl group, a phenyl group, a 4-(trifluoromethyl)phenyl
group, a 4-fluorophenyl group, a 2,4-difluorophenyl group, a
2-phenethyl group, a 1-hydroxyethyl group, a 1-(methoxyimino)ethyl
group, a 1-[(benzyloxy)imino]ethyl group, a 2-thienyl group, a
3-thienyl group, a 1-pyrrolyl group, a 2-methylthiazol-4-yl group,
an imidazo[1,2-a]pyridin-2-yl group, 2-pyridyl group, an acetyl
group, an isobutyryl group, a piperidinocarbonyl group, a
4-benzylpiperidinocarbonyl group, a (pyrrol-1-yl)sulfonyl group, a
carboxy group, a methoxycarbonyl group, a
N-[3,5-bis(trifluoromethyl)phenyl]carbamoyl group, a
N,N-dimethylcarbamoyl group, a sulfamoyl group, a
N-[3,5-bis(trifluoromethyl)phenyl]sulfamoyl group, a
N,N-dimethylsulfamoyl group, an amino group, a N,N-dimethylamino
group, an acetylamino group, a benzoylamino group, a
methanesulfonylamino group, a benzenesulfonylamino group, a
3-phenylureido group, a (3-phenyl)thioureido group, a
(4-nitrophenyl)diazenyl group, and a
{[4-(pyridin-2-yl)sulfamoyl]phenyl}diazenyl group.
4. The method according to claim 1, wherein the substance has
inhibitory activity against production of IgE, inhibitory activity
against degranulation from an activated mast cell, and/or
inhibitory activity against proliferation of a mast cell.
5. A compound represented by the general formula (I-1), a salt
thereof, a hydrate thereof, or a solvate thereof: ##STR1055##
wherein Z.sup.1 represents a 2-hydroxyphenyl group which may be
substituted in the 5-position or a 2-acetoxyphenyl group which may
be substituted in the 5-position, E.sup.1 represents a phenyl group
which may be substituted, provided that the compounds represented
by the following (1) and (2) are excluded: (1) The compounds
represented by the aforementioned formula (I-1) wherein Z.sup.1 is
2-hydroxyphenyl group which may be substituted with a substitutent
selected from the group consisting of: a halogen atom; a nitro
group; a cyano group; an alkoxy group; an alkyl group which may be
substituted with one or more substitutents selected from the group
consisting of: a hydroxyl group, an alkyl-oxy-imino group, and an
aralkyl-oxy-imino group; an alkenyl group which may be substituted
with one or more substitutents selected from the group consisting
of: an aryl group, a cyano group, an alkyl-oxy-carbonyl group, and
a carboxy group; an alkynyl group which may be substituted with one
or more substitutents selected from the group consisting of: an
aryl group, and a tri(alkyl)silyl group; a halogenated alkyl group;
an aryl group which may be substituted with one or more
substitutents selected from the group consisting of: a halogen
atom, and a halogenated alkyl group; an aralkyl group; a 5 to
9-membered heteroaryl group which may be substituted with one or
more alkyl groups; an alkyl-carbonyl group; a 6-membered
nonaromatic heterocyclic-carbonyl group which may be substituted
with one or more aralkyl groups; a 5-membered heteroaryl-sulfonyl
group; a carboxy group; an alkyl-oxy-carbonyl group; a carbamoyl
group which may be substituted with one or more substitutents
selected from the group consisting of: an aryl group which may be
substituted with one or more halogenated alkyl groups, and an alkyl
group; a sulfamoyl group which may be substituted with one or more
substitutents selected from the group consisting of: an aryl group
which may be substituted with one or more halogenated alkyl groups,
and an alkyl group; an amino group which may be substituted with
one or more substitutents selected from the group consisting of: an
alkyl group, an alkyl-carbonyl group, an aryl-carbonyl group, an
alkyl-sulfonyl group, and an aryl-sulfonyl group; an ureido group
which may be substituted with one or more aryl groups; a thioureido
group which may be substituted with one or more aryl groups; and a
diazenyl group which may be substituted with one or more aryl
groups wherein said aryl groups may be substituted with one or more
substitutents selected from the group consisting of: a nitro group,
and a 6-membered heteroaryl-sulfamoyl group in the 5-position or
2-acetoxyphenyl group which may be substituted with a substitutent
selected from the group consisting of: a halogen atom; a nitro
group; a cyano group; an alkoxy group; an alkyl group which may be
substituted with one or more substitutents selected from the group
consisting of: a hydroxyl group, an alkyl-oxy-imino group, and an
aralkyl-oxy-imino group; an alkenyl group which may be substituted
with one or more substitutents selected from the group consisting
of: an aryl group, a cyano group, an alkyl-oxy-carbonyl group, and
a carboxy group; an alkynyl group which may be substituted with one
or more substitutents selected from the group consisting of: an
aryl group, and a tri(alkyl)silyl group; a halogenated alkyl group;
an aryl group which may be substituted with one or more
substitutents selected from the group consisting of: a halogen
atom, and a halogenated alkyl group; an aralkyl group; a 5 to
9-membered heteroaryl group which may be substituted with one or
more alkyl groups; an alkyl-carbonyl group; a 6-membered
nonaromatic heterocyclic-carbonyl group which may be substituted
with one or more aralkyl groups; a 5-membered heteroaryl-sulfonyl
group; a carboxy group; an alkyl-oxy-carbonyl group; a carbamoyl
group which may be substituted with one or more substitutents
selected from the group consisting of: an aryl group which may be
substituted with one or more halogenated alkyl groups, and an alkyl
group; a sulfamoyl group which may be substituted with one or more
substitutents selected from the group consisting of: an aryl group
which may be substituted with one or more halogenated alkyl groups,
and an alkyl group; an amino group which may be substituted with
one or more substitutents selected from the group consisting of: an
alkyl group, an alkyl-carbonyl group, an aryl-carbonyl group, an
alkyl-sulfonyl group, and an aryl-sulfonyl group; an ureido group
which may be substituted with one or more aryl groups; a thioureido
group which may be substituted with one or more aryl groups; and a
diazenyl group which may be substituted with one or more aryl
groups wherein said aryl groups may be substituted with one or more
substitutents selected from the group consisting of: a nitro group,
and a 6-membered heteroaryl-sulfamoyl group in the 5-position,
E.sup.1 is a 3,5-bis(trifluoromethyl)phenyl group, and (2) The
compounds represented by the aforementioned formula (I-1) wherein
Z.sup.1 is a 2-hydroxyphenyl group which may be substituted in the
5-position or a 2-acetoxyphenyl group which may be substituted in
the 5-position, E.sup.1 is a 2,5-bis(trifluoromethyl)phenyl
group.
6. The compound according to claim 5, wherein: Z.sup.1 is a
2-hydroxyphenyl group substituted with a substitutent selected from
the following Substituent Group .gamma..sup.1-1z in the 5-position,
wherein Substituent Group .gamma..sup.1-1z is a halogen atom, a
nitro group, a cyano group, a methoxy group, a methyl group, an
isopropyl group, a tert-butyl group, a 1,1,3,3-tetramethylbutyl
group, a 2-phenylethen-1-yl group, a 2,2-dicyanoethen-1-yl group, a
2-cyano-2-(methoxycarbonyl)ethen-1-yl group, a
2-carboxy-2-cyanoethen-1-yl group, an ethynyl group, a
phenylethynyl group, a (trimethylsilyl)ethynyl group, a
trifluoromethyl group, a pentafluoroethyl group, a phenyl group, a
4-(trifluoromethyl)phenyl group, a 4-fluorophenyl group, a
2,4-difluorophenyl group, a 2-phenethyl group, a 1-hydroxyethyl
group, a 1-(methoxyimino)ethyl group, a 1-[(benzyloxy)imino]ethyl
group, a 2-thienyl group, a 3-thienyl group, a 1-pyrrolyl group, a
2-methylthiazol-4-yl group, an imidazo[1,2-a]pyridin-2-yl group,
2-pyridyl group, an acetyl group, an isobutyryl group, a
piperidinocarbonyl group, a 4-benzylpiperidinocarbonyl group, a
(pyrrol-1-yl)sulfonyl group, a carboxy group, a methoxycarbonyl
group, a N-[3,5-bis(trifluoromethyl)phenyl]carbamoyl group, a
N,N-dimethylcarbamoyl group, a sulfamoyl group, a
N-[3,5-bis(trifluoromethyl)phenyl]sulfamoyl group, a
N,N-dimethylsulfamoyl group, an amino group, a N,N-dimethylamino
group, an acetylamino group, a benzoylamino group, a
methanesulfonylamino group, a benzenesulfonylamino group, a
3-phenylureido group, a (3-phenyl)thioureido group, a
(4-nitrophenyl)diazenyl group, or a
{[4-(pyridin-2-yl)sulfamoyl]phenyl}diazenyl group, E.sup.1 is a
group selected from the following Substituent Group
.delta..sup.1-1e and .delta..sup.1-2e, wherein Substituent Group
.delta..sup.1-1e is a 3,5-bis(trifluoromethyl)-2-bromophenyl group,
a 3,5-bis(trifluoromethyl)-2-methylphenyl group, a
2,6-dichloro-4-(trifluoromethyl)phenyl group, a
2,4-dimethoxy-5-(trifluoromethyl)phenyl group, a b
2,4-difluoro-5-(trifluoromethyl)phenyl group, a b
4-chloro-2-(4-chlorobenzenesulfonyl)-5-(trifluoromethyl)phenyl
group, a 5-chloro-2-nitro-4-(trifluoromethyl)phenyl group, a
2,3-difluoro-4-(trifluoromethyl)phenyl group, or a
2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl group, and wherein
Substituent Group .delta..sup.1-2e is a
4-chloro-2-(trifluoromethyl)phenyl group, a
2-fluoro-3-(trifluoromethyl)phenyl group, a
4-fluoro-3-(trifluoromethyl)phenyl group, a
4-chloro-3-(trifluoromethyl)phenyl group, a
4-nitro-3-(trifluoromethyl)phenyl group, a
4-cyano-3-(trifluoromethyl)phenyl group, a
2-methyl-3-(trifluoromethyl)phenyl group, a
4-methyl-3-(trifluoromethyl)phenyl group, a
4-methoxy-3-(trifluoromethyl)phenyl group, a
2-chloro-4-(trifluoromethyl)phenyl group, a
4-isopropyl-2-(trifluoromethyl)phenyl group, a
2-nitro-4-(trifluoromethyl)phenyl group, a
4-bromo-3-(trifluoromethyl)phenyl group, a
4-bromo-2-(trifluoromethyl)phenyl group, a
2-bromo-4-(trifluoromethyl)phenyl group, a
4-fluoro-2-(trifluoromethyl)phenyl group, a
4-isopropoxy-2-(trifluoromethyl)phenyl group, a
4-cyano-2-(trifluoromethyl)phenyl group, or a
2,4-bis(trifluoromethyl)phenyl group.
7. A compound represented by the general formula (I-3), a salt
thereof, a hydrate thereof, or a solvate thereof: ##STR1056##
wherein Z.sup.3 represents a 2-hydroxyphenyl group which may be
substituted in the 5-position or a 2-acetoxyphenyl group which may
be substituted in the 5-position, E.sup.3 represents a group
represented by the following formula: ##STR1057## wherein one of
R.sup.3e2 and R.sup.3e3 represents a hydrogen atom and the other
represents a hydrocarbon group which may be substituted or a
hydroxyl group which may be substituted, and R.sup.3e5 represents a
C.sub.2 to C.sub.6 hydrocarbon group which may be substituted.
8. The compound according to claim 7, a salt thereof, a hydrate
thereof, or a solvate thereof, wherein Z.sup.3 is a 2-hydroxyphenyl
group which is substituted with a halogen atom in the 5-position or
a 2-acetoxyphenyl group which is substituted with a halogen atom in
the 5-position.
9. A compound represented by the general formula (I-4), a salt
thereof, a hydrate thereof, or a solvate thereof: ##STR1058##
wherein Z.sup.4 represents 2-hydroxyphenyl group which may be
substituted in the 5-position or 2-acetoxyphenyl group which may be
substituted in the 5-position, E.sup.4 represents a group
represented by the following formula: ##STR1059## wherein R.sup.4e4
represents a hydrocarbon group which may be substituted, R.sup.4e5
represents a halogen atom, a cyano group, an acyl group which may
be substituted, or a heterocyclic group which may be
substituted.
10. The compound according to claim 9, a salt thereof, a hydrate
thereof, or a solvate thereof, wherein Z.sup.4 is a 2-hydroxyphenyl
group which is substituted with a halogen atom in the 5-position or
2-acetoxyphenyl group which is substituted with a halogen atom in
the 5-position.
11. The method according to claim 1, wherein the mammal is a human.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a divisional application of
copending U.S. application Ser. No. 10/515,623, which is
incorporated by reference herein in its entirety, and which is a
National Stage Application of International Application No.
PCT/JP03/07120, filed Jun. 5, 2003, which claims priority under the
Paris Convention from Japanese Patent Application No. 2002-165148,
filed Jun. 6, 2002.
FIELD OF INVENTION
[0002] The present invention relates to pharmaceutical compositions
effective for preventive and/or therapeutic treatment of allergic
diseases such as pollinosis, bronchial asthma, atopic dermatitis,
urticaria; endometriosis, and hysteromyoma.
BACKGROUND ART
[0003] Allergic diseases are understood to be caused by production
of IgE by an antigen stimulation invaded in a body, and successive
release of various chemical mediators such as inflammatory
cytokine, histamine, leukotriene and the like by a degranulation
from an activated mast cell stimulated by a complex of the antigen
and IgE, thereby constriction of airway, accentuation of vascular
permeability, inflammation of skin, bronchi and the like are
induced. Accordingly, antiallergic agents are understood mainly as
drugs inhibiting allergic reaction type I and successively induced
allergic inflammation, particularly as drugs inhibiting the
production and release of the mediators from mast cells, or those
as being antagonists against the aforementioned actions. At
present, steroids, antihistaminic drugs, suppressants or inhibitors
of the release of mediators and the like have been used as
antiallergic agents. Although steroids are very effective drugs,
they have a problem of side effects. Antihistaminic drugs are only
for symptomatic therapies and fail to achieve radical therapy.
Suppressants or inhibitors of the release of mediators are
considered to have a high effectiveness. However, some of them lack
immediate effectiveness or have central side effects. Accordingly,
the antiallergic drugs currently available are not fully
satisfactory as they are.
[0004] Patients with endometriosis are increasing in recent years,
and currently, 10 to 14% of females are considered to be suffered
from the disease. Endometriosis has been focused as a cause of
sterility, as well as the disease lowers the quality of life of
patients with severe pains during menstruation and coitus. For a
treatment of the disease, a therapy by using a hormone drug has
been currently applied as a pseudo menopausal therapy. However, the
aforementioned therapy induces strong side effects, and it also has
a risk of causing osteoporosis during a long-term administration.
Therefore, at present, a drug or a method for treatment with safety
and high efficacy is not available.
[0005] In recent years, it was found that mast cells exist
apparently with high density in the lesion of endometriosis
(American Journal of Reproductive Immunology (New York: 1998),
(Denmark), Vol. 40, No. 4, p. 291-294), and that mast cells are
activated to lead degranulation (Nikkei Medical, 2002, No. 415, p.
28; Fertility and Sterility, (USA), 2002, Vol. 78, No. 4, p.
782-786). Furthermore, a relation between endometriosis and allergy
is strongly suggested, because interstitial hyperplasia, which is a
major step of infiltration and lesion of mast cells, is
significantly inhibited by the administration of a leukotriene
antagonist having antiallergic action to an endometriosis model rat
(Nikkei Medical, 2002, No. 415, p. 28; Fertility and Sterility,
(USA), 2002, Vol. 78, No. 4, p. 782-786).
[0006] Therefore, an antiallergic drug, which strongly inhibits
activation of mast cells and can be used as a therapeutic agent for
radical treatment of allergic diseases, is usable as an effective
therapeutic agent for endometriosis.
[0007] 45% of patients with endometriosis are suffered from
hysteromyoma, which suggests a relation of hysteromyoma and allergy
in the same manner as endometriosis. Accordingly, it is highly
probable that an antiallergic agent, which can be used as a
therapeutic agent for radical treatment of allergic diseases, is
useful as a therapeutic agent for hysteromyoma.
[0008] N-phenylsalicylamide derivatives are disclosed as a plant
growth inhibitor in the specification of U.S. Pat. No. 4,358,443.
As medicaments, said derivatives are disclosed as anti-inflammatory
agents in the specification of European Patent No. 0,221,211,
Japanese Patent Unexamined Publication (KOKAI) No. (Sho)62-99329,
and the specification of U.S. Pat. No. 6,117,859. Furthermore, they
are disclosed as NF-.kappa.B inhibitors in the pamphlets of
International Publication WO99/65499, International Publication
WO02/49632, and International Publication WO02/076918, and as
inhibitors against the production of cytokines in the pamphlet of
International Publication WO02/051397.
DISCLOSURE OF THE INVENTION
[0009] An object of the present invention is to provide medicaments
that enable radical preventive and/or therapeutic treatment of
allergy by an inhibition of allergic reactions. To achieve the
aforementioned object, the inventors of the present invention
conducted various researches on the antiallergic actions of
salicylamide derivatives which are generally believed to have low
toxicity. As a result, they found that N-substituted salicylamide
derivatives, particularly N-arylsalicylamide derivatives,
specifically N-phenylsalicylamide derivatives wherein aniline
moiety is substituted in both of 2- and 5-positions or in both of
3- and 5-positions, and N-thiazol-2-yl-salicylamide derivatives
wherein thiazole ring is substituted in both of 4- and 5-positions
have extremely superior activity in inhibitory action against the
proliferation of mast cells, inhibitory action against the
degranulation from mast cells by antigen and IgE stimulation, and
inhibitory action against the production of IgE from activated B
cells, and that radical preventive and/or therapeutic treatment of
allergic diseases can be achieved. The inventors also conducted
researches on hydroxyaryl derivatives which are analogous compounds
thereof. The present invention was achieved on the basis of these
findings.
[0010] The present invention thus provides: (1) A medicament for
preventive and/or therapeutic treatment of allergic diseases and/or
endometriosis and/or hysteromyoma which comprises as an active
ingredient a substance selected from the group consisting of a
compound represented by the following general formula (I) and a
pharmacologically acceptable salt thereof, and a hydrate thereof
and a solvate thereof: ##STR2## wherein X represents a connecting
group whose number of atoms in a main chain is 2 to 5 (said
connecting group may be substituted), A represents hydrogen atom or
acetyl group, E represents an aryl group which may be substituted
or a heteroaryl group which may be substituted, ring Z represents
an arene which may have one or more substitutents in addition to
the group represented by formula --O-A wherein A has the same
meaning as that defined above and the group represented by formula
--X-E wherein each of X and E has the same meaning as that defined
above, or a heteroarene which may have one or more substitutents in
addition to the group represented by formula --O-A wherein A has
the same meaning as that defined above and the group represented by
formula X-E wherein each of X and E has the same meaning as that
defined above.
[0011] Examples of preferred medicaments provided by the present
invention include:
[0012] (2) the aforementioned medicament which comprises as an
active ingredient a substance selected from the group consisting of
the compound and a pharmacologically acceptable salt thereof, and a
hydrate thereof and a solvate thereof, wherein X is a group
selected from the following connecting group .alpha. (said group
may be substituted): [Connecting group .alpha.] The groups of the
following formulas: ##STR3## wherein a bond at the left end binds
to ring Z and a bond at the right end binds to E; (3) the
aforementioned medicament which comprises as an active ingredient a
substance selected from the group consisting of the compound and a
pharmacologically acceptable salt thereof, and a hydrate thereof
and a solvate thereof, wherein X is a group represented by the
following formula (said group may be substituted): ##STR4## wherein
a bond at the left end binds to ring Z and a bond at the right end
binds to E; (4) the aforementioned medicament which comprises as an
active ingredient a substance selected from the group consisting of
the compound and a pharmacologically acceptable salt thereof, and a
hydrate thereof and a solvate thereof, wherein A is a hydrogen
atom; (5) the aforementioned medicament which comprises as an
active ingredient a substance selected from the group consisting of
the compound and a pharmacologically acceptable salt thereof, and a
hydrate thereof and a solvate thereof, wherein ring Z is a C.sub.6
to C.sub.10 arene which may have one or more substitutents in
addition to the group represented by formula --O-A wherein A has
the same meaning as that defined in the general formula (I) and the
group represented by formula --X-E wherein each of X and E has the
same meaning as that defined in the general formula (I), or a 5 to
13-membered heteroarene which may have one or more substitutents in
addition to the group represented by formula --O-A wherein A has
the same meaning as that defined in the general formula (I) and the
group represented by formula --X-E wherein each of X and E has the
same meaning as that defined in the general formula (I); (6) the
aforementioned medicament which comprises as an active ingredient a
substance selected from the group consisting of the compound and a
pharmacologically acceptable salt thereof, and a hydrate thereof
and a solvate thereof, wherein ring Z is a ring selected from the
following ring group .beta.: [Ring Group .beta.] benzene ring,
naphthalene ring, thiophene ring, pyridine ring, indole ring,
quinoxaline ring, and carbazole ring wherein said ring may have one
or more substitutents in addition to the group represented by
formula --O-A wherein A has the same meaning as that defined in the
general formula (I) and the group represented by formula --X-E
wherein each of X and E has the same meaning as that defined in the
general formula (I); (7) the aforementioned medicament which
comprises as an active ingredient a substance selected from the
group consisting of the compound and a pharmacologically acceptable
salt thereof, and a hydrate thereof and a solvate thereof, wherein
ring Z is a benzene ring which may have one or more substitutents
in addition to the group represented by formula --O-A wherein A has
the same meaning as that defined in the general formula (I) and the
group represented by formula --X-E wherein each of X and E has the
same meaning as that defined in the general formula (I); (8) the
aforementioned medicament which comprises as an active ingredient a
substance selected from the group consisting of the compound and a
pharmacologically acceptable salt thereof, and a hydrate thereof
and a solvate thereof, wherein ring Z is a benzene ring which is
substituted with halogen atom(s) in addition to the group
represented by formula --O-A wherein A has the same meaning as that
defined in the general formula (I) and the group represented by
formula --X-E wherein each of X and E has the same meaning as that
defined in the general formula (I); (9) the aforementioned
medicament which comprises as an active ingredient a substance
selected from the group consisting of the compound and a
pharmacologically acceptable salt thereof, and a hydrate thereof
and a solvate thereof, wherein ring Z is a naphthalene ring which
may have one or more substitutents in addition to the group
represented by formula --O-A wherein A has the same meaning as that
defined in the general formula (I) and the group represented by
formula --X-E wherein each of X and E has the same meaning as that
defined in the general formula (I); (10) the aforementioned
medicament which comprises as an active ingredient a substance
selected from the group consisting of the compound and a
pharmacologically acceptable salt thereof, and a hydrate thereof
and a solvate thereof, wherein E is a C.sub.6 to C.sub.10 aryl
group which may be substituted or a 5 to 13-membered heteroaryl
group which may be substituted; (11) the aforementioned medicament
which comprises as an active ingredient a substance selected from
the group consisting of the compound and a pharmacologically
acceptable salt thereof, and a hydrate thereof and a solvate
thereof, wherein E is a phenyl group which may be substituted; (12)
the aforementioned medicament which comprises as an active
ingredient a substance selected from the group consisting of the
compound and a pharmacologically acceptable salt thereof, and a
hydrate thereof and a solvate thereof, wherein E is
3,5-bis(trifluoromethyl)phenyl group; (13) the aforementioned
medicament which comprises as an active ingredient a substance
selected from the group consisting of the compound and a
pharmacologically acceptable salt thereof, and a hydrate thereof
and a solvate thereof, wherein E is a 5-membered heteroaryl group
which may be substituted.
[0013] From another aspect, the present invention provides use of
each of the aforementioned substances for manufacture of the
medicament according to the aforementioned (1) to (13).
[0014] The present invention further provides a method for
preventive and/or therapeutic treatment of allergic diseases and/or
endometriosis and/or hysteromyoma in a mammal including a human,
which comprises the step of administering preventively and/or
therapeutically effective amount of the aforementioned substances
to a mammal including a human.
[0015] The present invention further provides: (1) a compound
represented by the general formula (I-1) or a salt thereof, or a
hydrate thereof or a solvate thereof: ##STR5## wherein Z.sup.1
represents 2-hydroxyphenyl group which may be substituted in the
5-position or 2-acetoxyphenyl group which may be substituted in the
5-position, and E.sup.1 represents a phenyl group which may be
substituted.
[0016] Preferably, provided is:
(2) the compound or a salt thereof, or a hydrate thereof or a
solvate thereof, wherein E.sup.1 is 2,5-bis(trifluoromethyl)phenyl
group or 3,5-bis(trifluoromethyl)phenyl group, except that the
following compounds are excluded:
[0017] N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide,
[0018]
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide,
[0019]
N-[3,5-bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide,
[0020]
N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide, and
[0021]
N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-nitrobenzamide.
[0022] More preferably, provided is:
[0023] (3) the compound or a salt thereof, or a hydrate thereof or
a solvate thereof, wherein Z.sup.1 is 2-hydroxyphenyl group which
is substituted with a halogen atom in the 5-position or
2-acetoxyphenyl group which is substituted with a halogen atom in
the 5-position.
[0024] Moreover, the present invention provides: (1) a compound
represented by the general formula (I-2) or a salt thereof, or a
hydrate thereof or a solvate thereof: ##STR6## wherein Z.sup.2
represents 2-hydroxyphenyl group which may be substituted in the
5-position or 2-acetoxyphenyl group which may be substituted in the
5-position, E.sup.2 represents a 2,5-di-substituted phenyl group
wherein one of said substitutents is trifluoromethyl group or a
3,5-di-substituted phenyl group wherein one of said substitutents
is trifluoromethyl group, provided that the following compounds are
excluded: [0025]
5-chloro-N-[5-chloro-3-(trifluoromethyl)phenyl]-2-hydroxybenzamide,
[0026]
5-fluoro-2-hydroxy-N-[2-(2,2,2-trifluoroethoxy)-5-(trifluoromethy-
l)phenyl]benzamide, [0027]
5-fluoro-2-hydroxy-N-[2-(6,6,6-trifluorohexyloxy)-5-(trifluoromethyl)phen-
yl]-benzamide, [0028]
5-chloro-N-[2-(4-chlorophenoxy)-5-(trifluoromethyl)phenyl]-2-hydroxybenza-
mide, [0029]
5-chloro-2-hydroxy-N-[2-(4-methylphenoxy)-5-(trifluoromethyl)phenyl]benza-
mide, [0030]
5-chloro-N-[2-(4-chlorophenyl)sulfanyl-5-(trifluoromethyl)phenyl]-2-hydro-
xybenzamide, [0031]
5-chloro-2-hydroxy-N-[2-(1-naphthyloxy)-5-(trifluoromethyl)phenyl]benzami-
de, and [0032]
5-chloro-2-hydroxy-N-[2-(2-naphthyloxy)-5-(trifluoromethyl)phenyl]benzami-
de.
[0033] Preferably, provided is:
[0034] (2) the compound or a salt thereof, or a hydrate thereof or
a solvate thereof, wherein Z.sup.2 is 2-hydroxyphenyl group which
is substituted with a halogen atom in the 5-position or
2-acetoxyphenyl group which is substituted with a halogen atom in
the 5-position.
[0035] Moreover, the present invention provides: (1) a compound
represented by the general formula (I-3) or a salt thereof, or a
hydrate thereof or a solvate thereof: ##STR7## wherein Z.sup.3
represents 2-hydroxyphenyl group which may be substituted in the
5-position or 2-acetoxyphenyl group which may be substituted in the
5-position, E.sup.3 represents a group represented by the following
formula: ##STR8## wherein one of R.sup.3e2 and R.sup.3e3 represents
hydrogen atom and the other represents a hydrocarbon group which
may be substituted or hydroxyl group which may be substituted, and
R.sup.3e5 represents a C.sub.2 to C.sub.6 hydrocarbon group which
may be substituted.
[0036] Preferably, provided is:
[0037] (2) the compound according to claim 18 or a salt thereof, or
a hydrate thereof or a solvate thereof, wherein Z.sup.3 is
2-hydroxyphenyl group which is substituted with a halogen atom in
the 5-position or 2-acetoxyphenyl group which is substituted with a
halogen atom in the 5-position.
[0038] The present invention also provides: (1) a compound
represented by the general formula (I-4) or a salt thereof, or a
hydrate thereof or a solvate thereof: ##STR9## wherein Z.sup.4
represents 2-hydroxyphenyl group which may be substituted in the
5-position or 2-acetoxyphenyl group which may be substituted in the
5-position, E.sup.4 represents a group represented by the following
formula: ##STR10## wherein R.sup.4e4 represents a hydrocarbon group
which may be substituted, R.sup.4e5 represents a halogen atom,
cyano group, an acyl group which may be substituted, or a
heterocyclic group which may be substituted.
[0039] Preferably, provided is:
[0040] (2) the compound or a salt thereof, or a hydrate thereof or
a solvate thereof, wherein Z.sup.4 is 2-hydroxyphenyl group which
is substituted with a halogen atom in the 5-position or
2-acetoxyphenyl group which is substituted with a halogen atom in
the 5-position.
BRIEF EXPLANATION OF THE DRAWINGS
[0041] FIG. 1 shows inhibitory effect of the medicament of the
present invention (compound No. 50) against immediate type
allergy.
[0042] FIG. 2 shows inhibitory effect of the medicament of the
present invention (compound No. 50) against dermatitis with an
atopic dermatitis model.
BEST MODE FOR CARRYING OUT THE INVENTION
[0043] Reference to the disclosure of the pamphlet of International
Publication WO02/49632 is useful for better understanding of the
present invention. The entire disclosure of the aforementioned
pamphlet of International Publication WO02/49632 is incorporated by
reference in the disclosures of the present specification.
[0044] The terms used in the present specification have the
following meanings.
[0045] As the halogen atom, any of fluorine atom, chlorine atom,
bromine atom, or iodine atom may be used unless otherwise
specifically referred to.
[0046] Examples of the hydrocarbon group include, for example, an
aliphatic hydrocarbon group, an aryl group, an arylene group, an
aralkyl group, a bridged cyclic hydrocarbon group, a spiro cyclic
hydrocarbon group, and a terpene hydrocarbon.
[0047] Examples of the aliphatic hydrocarbon group include, for
example, alkyl group, alkenyl group, alkynyl group, alkylene group,
alkenylene group, alkylidene group and the like which are straight
chain or branched chain monovalent or bivalent acyclic hydrocarbon
groups; cycloalkyl group, cycloalkenyl group, cycloalkanedienyl
group, cycloalkyl-alkyl group, cycloalkylene group, and
cycloalkenylene group, which are saturated or unsaturated
monovalent or bivalent alicyclic hydrocarbon groups.
[0048] Examples of the alkyl group include, for example, methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,
tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl,
neopentyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl,
4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl,
3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl,
1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl,
2-ethylbutyl, 1-ethylbutyl, 1-ethyl-1-methylpropyl, n-heptyl,
n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl,
n-tetradecyl, and n-pentadecyl, which are C.sub.1 to C.sub.15
straight chain or branched chain alkyl groups.
[0049] Examples of the alkenyl group include, for example, vinyl,
prop-1-en-1-yl, allyl, isopropenyl, but-1-en-1-yl, but-2-en-1-yl,
but-3-en-1-yl, 2-methylprop-2-en-1-yl, 1-methylprop-2-en-1-yl,
pent-1-en-1-yl, pent-2-en-1-yl, pent-3-en-1-yl, pent-4-en-1-yl,
3-methylbut-2-en-1-yl, 3-methylbut-3-en-1-yl, hex-1-en-1-yl,
hex-2-en-1-yl, hex-3-en-1-yl, hex-4-en-1-yl, hex-5-en-1-yl,
4-methylpent-3-en-1-yl, 4-methylpent-3-en-1-yl, hept-1-en-1-yl,
hept-6-en-1-yl, oct-1-en-1-yl, oct-7-en-1-yl, non-1-en-1-yl,
non-8-en-1-yl, dec-1-en-1-yl, dec-9-en-1-yl, undec-1-en-1-yl,
undec-10-en-1-yl, dodec-1-en-1-yl, dodec-11-en-1-yl,
tridec-1-en-1-yl, tridec-12-en-1-yl, tetradec-1-en-1-yl,
tetradec-13-en-1-yl, pentadec-1-en-1-yl, and pentadec-14-en-1-yl,
which are C.sub.2 to C.sub.15 straight chain or branched chain
alkenyl groups.
[0050] Examples of the alkynyl group include, for example, ethynyl,
prop-1-yn-1-yl, prop-2-yn-1-yl, but-1-yn-1-yl, but-3-yn-1-yl,
1-methylprop-2-yn-1-yl, pent-1-yn-1-yl, pent-4-yn-1-yl,
hex-1-yn-1-yl, hex-5-yn-1-yl, hept-1-yn-1-yl, hept-6-yn-1-yl,
oct-1-yn-1-yl, oct-7-yn-1-yl, non-1-yn-1-yl, non-8-yn-1-yl,
dec-1-yn-1-yl, dec-9-yn-1-yl, undec-1-yn-1-yl, undec-10-yn-1-yl,
dodec-1-yn-1-yl, dodec-11-yn-1-yl, tridec-1-yn-1-yl,
tridec-12-yn-1-yl, tetradec-1-yn-1-yl, tetradec-13-yn-1-yl,
pentadec-1-yn-1-yl, and pentadec-14-yn-1-yl, which are C.sub.2 to
C.sub.15 straight chain or branched chain alkynyl groups.
[0051] Examples of the alkylene group include, for example,
methylene, ethylene, ethane-1,1-diyl, propane-1,3-diyl,
propane-1,2-diyl, propane-2,2-diyl, butane-1,4-diyl,
pentane-1,5-diyl, hexane-1,6-diyl, and
1,1,4,4-tetramethylbutane-1,4-diyl group, which are C.sub.1 to
C.sub.8 straight chain or branched chain alkylene groups.
[0052] Examples of the alkenylene group include, for example,
ethene-1,2-diyl, propene-1,3-diyl, but-1-ene-1,4-diyl,
but-2-ene-1,4-diyl, 2-methylpropene-1,3-diyl, pent-2-ene-1,5-diyl,
and hex-3-ene-1,6-diyl, which are C.sub.1 to C.sub.6 straight chain
or branched chain alkylene groups.
[0053] Examples of the alkylidene group include, for example,
methylidene, ethylidene, propylidene, isopropylidene, butylidene,
pentylidene, and hexylidene, which are C.sub.1 to C.sub.6 straight
chain or branched chain alkylidene groups.
[0054] Examples of the cycloalkyl group include, for example,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and
cyclooctyl, which are C.sub.3 to C.sub.8 cycloalkyl groups.
[0055] The aforementioned cycloalkyl group may be fused with
benzene ring, naphthalene ring and the like, and examples include,
for example, 1-indanyl, 2-indanyl,
1,2,3,4-tetrahydronaphthalen-1-yl, and
1,2,3,4-tetrahydronaphthalen-2-yl.
[0056] Examples of the cycloalkenyl group include, for example,
2-cyclopropen-1-yl, 2-cyclobuten-1-yl, 2-cyclopenten-1-yl,
3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl,
1-cyclobuten-1-yl, and 1-cyclopenten-1-yl, which are C.sub.3 to
C.sub.6 cycloalkenyl groups.
[0057] The aforementioned cycloalkenyl group may be fused with
benzene ring, naphthalene ring and the like, and examples include,
for example, 1-indanyl, 2-indanyl,
1,2,3,4-tetrahydronaphthalen-1-yl,
1,2,3,4-tetrahydronaphthalen-2-yl, 1-indenyl, and 2-indenyl.
[0058] Examples of the cycloalkanedienyl group include, for
example, 2,4-cyclopentadien-1-yl, 2,4-cyclohexanedien-1-yl, and
2,5-cyclohexanedien-1-yl, which are C.sub.5 to C.sub.6
cycloalkanedienyl groups.
[0059] The aforementioned cycloalkanedienyl group may be fused with
benzene ring, naphthalene ring and the like, and examples include,
for example, 1-indenyl and 2-indenyl.
[0060] Examples of the cycloalkyl-alkyl group include the groups in
which one hydrogen atom of the alkyl group is substituted with a
cycloalkyl group, and include, for example, cyclopropylmethyl,
1-cyclopropylethyl, 2-cyclopropylethyl, 3-cyclopropylpropyl,
4-cyclopropylbutyl, 5-cyclopropylpentyl, 6-cyclopropylhexyl,
cyclobutylmethyl, cyclopentylmethyl, cyclobutylmethyl,
cyclopentylmethyl, cyclohexylmethyl, cyclohexylpropyl,
cyclohexylbutyl, cycloheptylmethyl, cyclooctylmethyl, and
6-cyclooctylhexyl, which are C.sub.4 to C.sub.14 cycloalkyl-alkyl
groups.
[0061] Examples of the cycloalkylene group include, for example,
cyclopropane-1,1-diyl, cyclopropane-1,2-diyl, cyclobutane-1,1-diyl,
cyclobutane-1,2-diyl, cyclobutane-1,3-diyl, cyclopentane-1,1-diyl,
cyclopentane-1,2-diyl, cyclopentane-1,3-diyl, cyclohexane-1,1-diyl,
cyclohexane-1,2-diyl, cyclohexane-1,3-diyl, cyclohexane-1,4-diyl,
cycloheptane-1,1-diyl, cycloheptane-1,2-diyl, cyclooctane-1,1-diyl,
and cyclooctane-1,2-diyl, which are C.sub.3 to C.sub.8
cycloalkylene groups.
[0062] Examples of the cycloalkenylene group include, for example,
2-cyclopropene-1,1-diyl, 2-cyclobutene-1,1-diyl,
2-cyclopentene-1,1-diyl, 3-cyclopentene-1,1-diyl,
2-cyclohexene-1,1-diyl, 2-cyclohexene-1,2-diyl,
2-cyclohexene-1,4-diyl, 3-cyclohexene-1,1-diyl,
1-cyclobutene-1,2-diyl, 1-cyclopentene-1,2-diyl, and
1-cyclohexene-1,2-diyl, which are C.sub.3 to C.sub.6
cycloalkenylene groups.
[0063] Examples of the aryl group include a monocyclic or a fused
polycyclic aromatic hydrocarbon group, and include, for example,
phenyl, 1-naphthyl, 2-naphthyl, anthryl, phenanthryl, and
acenaphthylenyl, which are C.sub.6 to C.sub.14 aryl groups.
[0064] The aforementioned aryl group may be fused with the
aforementioned C.sub.3 to C.sub.8 cycloalkyl group, C.sub.3 to
C.sub.6 cycloalkenyl group, C.sub.5 to C.sub.6 cycloalkanedienyl
group or the like, and examples include, for example, 4-indanyl,
5-indanyl, 1,2,3,4-tetrahydronaphthalen-5-yl,
1,2,3,4-tetrahydronaphthalen-6-yl, 3-acenaphthenyl,
4-acenaphthenyl, inden-4-yl, inden-5-yl, inden-6-yl, inden-7-yl,
4-phenalenyl, 5-phenalenyl, 6-phenalenyl, 7-phenalenyl,
8-phenalenyl, and 9-phenalenyl.
[0065] Examples of the arylene group include, for example,
1,2-phenylene, 1,3-phenylene, 1,4-phenylene, naphthalene-1,2-diyl,
naphthalene-1,3-diyl, naphthalene-1,4-diyl, naphthalene-1,5-diyl,
naphthalene-1,6-diyl, naphthalene-1,7-diyl, naphthalene-1,8-diyl,
naphthalene-2,3-diyl, naphthalene-2,4-diyl, naphthalene-2,5-diyl,
naphthalene-2,6-diyl, naphthalene-2,7-diyl, naphthalene-2,8-diyl,
and anthracene-1,4-diyl, which are C.sub.6 to C.sub.14 arylene
groups.
[0066] Examples of the aralkyl group include the groups in which
one hydrogen atom of the alkyl group is substituted with an aryl
group, and include, for example, benzyl, 1-naphthylmethyl,
2-naphthylmethyl, anthracenylmethyl, phenanthrenylmethyl,
acenaphthylenylmethyl, diphenylmethyl, 1-phenethyl, 2-phenethyl,
1-(1-naphthyl)ethyl, 1-(2-naphthyl)ethyl, 2-(1-naphthyl)ethyl,
2-(2-naphthyl)ethyl, 3-phenylpropyl, 3-(1-naphthyl)propyl,
3-(2-naphthyl)propyl, 4-phenylbutyl, 4-(1-naphthyl)butyl,
4-(2-naphthyl)butyl, 5-phenylpentyl, 5-(1-naphthyl)pentyl,
5-(2-naphthyl)pentyl, 6-phenylhexyl, 6-(1-naphthyl)hexyl, and
6-(2-naphthyl)hexyl, which are C.sub.7 to C.sub.16 aralkyl
groups.
[0067] Examples of the bridged cyclic hydrocarbon group include,
for example, bicyclo[2.1.0]pentyl, bicyclo[2.2.1]heptyl,
bicyclo[2.2.1]octyl, and adamantyl.
[0068] Examples of the spiro cyclic hydrocarbon group include, for
example, spiro[3,4]octyl, and spiro[4,5]deca-1,6-dienyl.
[0069] Examples of the terpene hydrocarbon include, for example,
geranyl, neryl, linalyl, phytyl, menthyl, and bornyl.
[0070] Examples of the halogenated alkyl group include the groups
in which one hydrogen atom of the alkyl group is substituted with a
halogen atom, and include, for example, fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, bromomethyl, dibromomethyl, tribromomethyl,
iodomethyl, diiodomethyl, triiodomethyl, 2,2,2-trifluoroethyl,
pentafluoroethyl, 3,3,3-trifluoropropyl, heptafluoropropyl,
heptafluoroisopropyl, nonafluorobutyl, and perfluorohexyl, which
are C.sub.1 to C.sub.6 straight chain or branched chain halogenated
alkyl groups substituted with 1 to 13 halogen atoms.
[0071] Examples of the heterocyclic group include, for example, a
monocyclic or a fused polycyclic hetero aryl group which comprises
at least one atom of 1 to 3 kinds of hetero atoms selected from
oxygen atom, sulfur atom, nitrogen atom and the like as
ring-constituting atoms (ring forming atoms), and a monocyclic or a
fused polycyclic non-aromatic heterocyclic group which comprises at
least one atom of 1 to 3 kinds of hetero atoms selected from oxygen
atom, sulfur atom, nitrogen atom and the like as ring-constituting
atoms (ring forming atoms).
[0072] Examples of the monocyclic heteroaryl group include, for
example, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1-pyrrolyl,
2-pyrrolyl, 3-pyrrolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl,
3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl,
5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl,
1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl,
1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl,
(1,2,3-oxadiazol)-4-yl, (1,2,3-oxadiazol)-5-yl,
(1,2,4-oxadiazol)-3-yl, (1,2,4-oxadiazol)-5-yl,
(1,2,5-oxadiazol)-3-yl, (1,2,5-oxadiazol)-4-yl,
(1,3,4-oxadiazol)-2-yl, (1,3,4-oxadiazol)-5-yl, furazanyl,
(1,2,3-thiadiazol)-4-yl, (1,2,3-thiadiazol)-5-yl,
(1,2,4-thiadiazol)-3-yl, (1,2,4-thiadiazol)-5-yl,
(1,2,5-thiadiazol)-3-yl, (1,2,5-thiadiazol)-4-yl,
(1,3,4-thiadiazolyl)-2-yl, (1,3,4-thiadiazolyl)-5-yl,
(1H-1,2,3-triazol)-1-yl, (1H-1,2,3-triazol)-4-yl,
(1H-1,2,3-triazol)-5-yl, (2H-1,2,3-triazol)-2-yl,
(2H-1,2,3-triazol)-4-yl, (1H-1,2,4-triazol)-1-yl,
(1H-1,2,4-triazol)-3-yl, (1H-1,2,4-triazol)-5-yl,
(4H-1,2,4-triazol)-3-yl, (4H-1,2,4-triazol)-4-yl,
(1H-tetrazol)-1-yl, (1H-tetrazol)-5-yl, (2H-tetrazol)-2-yl,
(2H-tetrazol)-5-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-pyridazinyl,
4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl,
2-pyrazinyl, (1,2,3-triazin)-4-yl, (1,2,3-triazin)-5-yl,
(1,2,4-triazin)-3-yl, (1,2,4-triazin)-5-yl, (1,2,4-triazin)-6-yl,
(1,3,5-triazin)-2-yl, 1-azepinyl, 2-azepinyl, 3-azepinyl,
4-azepinyl, (1,4-oxazepin)-2-yl, (1,4-oxazepin)-3-yl,
(1,4-oxazepin)-5-yl, (1,4-oxazepin)-6-yl, (1,4-oxazepin)-7-yl,
(1,4-thiazepin)-2-yl, (1,4-thiazepin)-3-yl, (1,4-thiazepin)-5-yl,
(1,4-thiazepin)-6-yl, and (1,4-thiazepin)-7-yl, which are 5 to
7-membered monocyclic heteroaryl groups.
[0073] Examples of the fused polycyclic heteroaryl group include,
for example, 2-benzofuranyl, 3-benzofuranyl, 4-benzofuranyl,
5-benzofuranyl, 6-benzofuranyl, 7-benzofuranyl, 1-isobenzofuranyl,
4-isobenzofuranyl, 5-isobenzofuranyl, 2-benzo[b]thienyl,
3-benzo[b]thienyl, 4-benzo[b]thienyl, 5-benzo[b]thienyl,
6-benzo[b]thienyl, 7-benzo[b]thienyl, 1-benzo[c]thienyl,
4-benzo[c]thien yl, 5-benzo[c]thienyl, 1-indolyl, 1-indolyl,
2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl,
(2H-isoindol)-1-yl, (2H-isoindol)-2-yl, (2H-isoindol)-4-yl,
(2H-isoindol)-5-yl, (1H-indazol)-1-yl, (1H-indazol)-3-yl,
(1H-indazol)-4-yl, (1H-indazol)-5-yl, (1H-indazol)-6-yl,
(1H-indazol)-7-yl, (2H-indazol)-1-yl, (2H-indazol)-2-yl,
(2H-indazol)-4-yl, (2H-indazol)-5-yl, 2-benzoxazolyl,
2-benzoxazolyl, 4-benzoxazolyl, 5-benzoxazolyl, 6-benzoxazolyl,
7-benzoxazolyl, (1,2-benzisoxazol)-3-yl, (1,2-benzisoxazol)-4-yl,
(1,2-benzisoxazol)-5-yl, (1,2-benzisoxazol)-6-yl,
(1,2-benzisoxazol)-7-yl, (2,1-benzisoxazol)-3-yl,
(2,1-benzisoxazol)-4-yl, (2,1-benzisoxazol)-5-yl,
(2,1-benzisoxazol)-6-yl, (2,1-benzisoxazol)-7-yl, 2-benzothiazolyl,
4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl,
7-benzothiazolyl, (1,2-benzisothiazol)-3-yl,
(1,2-benzisothiazol)-4-yl, (1,2-benzisothiazol)-5-yl,
(1,2-benzisothiazol)-6-yl, (1,2-benzisothiazol)-7-yl,
(2,1-benzisothiazol)-3-yl, (2,1-benzisothiazol)-4-yl,
(2,1-benzisothiazol)-5-yl, (2,1-benzisothiazol)-6-yl,
(2,1-benzisothiazol)-7-yl, (1,2,3-benzoxadiazol)-4-yl,
(1,2,3-benzoxadiazol)-5-yl, (1,2,3-benzoxadiazol)-6-yl,
(1,2,3-benzoxadiazol)-7-yl, (2,1,3-benzoxadiazol)-4-yl,
(2,1,3-benzoxadiazol)-5-yl, (1,2,3-benzothiadiazol)-4-yl,
(1,2,3-benzothiadiazol)-5-yl, (1,2,3-benzothiadiazol)-6-yl,
(1,2,3-benzothiadiazol)-7-yl, (2,1,3-benzothiadiazol)-4-yl,
(2,1,3-benzothiadiazol)-5-yl, (1H-benzotriazol)-1-yl,
(1H-benzotriazol)-4-yl, (1H-benzotriazol)-5-yl,
(1H-benzotriazol)-6-yl, (1H-benzotriazol)-7-yl,
(2H-benzotriazol)-2-yl, (2H-benzotriazol)-4-yl,
(2H-benzotriazol)-5-yl, 2-quinolyl, 3-quinolyl, 4-quinolyl,
5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl, 1-isoquinolyl,
3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl,
7-isoquinolyl, 8-isoquinolyl, 3-cinnolinyl, 4-cinnolinyl,
5-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl,
2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl,
7-quinazolinyl, 8-quinazolinyl, 2-quinoxalinyl, 5-quinoxalinyl,
6-quinoxalinyl, 1-phthalazinyl, 5-phthalazinyl, 6-phthalazinyl,
2-naphthyridinyl, 3-naphthyridinyl, 4-naphthyridinyl, 2-purinyl,
6-purinyl, 7-purinyl, 8-purinyl, 2-pteridinyl, 4-pteridinyl,
6-pteridinyl, 7-pteridinyl, 1-carbazolyl, 2-carbazolyl,
3-carbazolyl, 4-carbazolyl, 9-carbazolyl, 2-(.alpha.-carbolinyl),
3-(.alpha.-carbolinyl), 4-(.alpha.-carbolinyl),
5-(.alpha.-carbolinyl), 6-(.alpha.-carbolinyl),
7-(.alpha.-carbolinyl), 8-(.alpha.-carbolinyl),
9-(.alpha.-carbolinyl), 1-(.beta.-carbolinyl),
3-(.beta.-carbolinyl), 4-(.beta.-carbolinyl),
5-(.beta.-carbolinyl), 6-(.beta.-carbolinyl),
7-(.beta.-carbolinyl), 8-(.beta.-carbolinyl),
9-(.beta.-carbolinyl), 1-(.gamma.-carbolinyl),
2-(.gamma.-carbolinyl), 4-(.gamma.-carbolinyl),
5-(.gamma.-carbolinyl), 6-(.gamma.-carbolinyl),
7-(.gamma.-carbolinyl), 8-(.gamma.-carbolinyl),
9-(.gamma.-carbolinyl), 1-acridinyl, 2-acridinyl, 3-acridinyl,
4-acridinyl, 9-acridinyl, 1-phenoxazinyl, 2-phenoxazinyl,
3-phenoxazinyl, 4-phenoxazinyl, 10-phenoxazinyl, 1-phenothiazinyl,
2-phenothiazinyl, 3-phenothiazinyl, 4-phenothiazinyl,
10-phenothiazinyl, 1-phenazinyl, 2-phenazinyl, 1-phenanthridinyl,
2-phenanthridinyl, 3-phenanthridinyl, 4-phenanthridinyl,
6-phenanthridinyl, 7-phenanthridinyl, 8-phenanthridinyl,
9-phenanthridinyl, 10-phenanthridinyl, 2-phenanthrolinyl,
3-phenanthrolinyl, 4-phenanthrolinyl, 5-phenanthrolinyl,
6-phenanthrolinyl, 7-phenanthrolinyl, 8-phenanthrolinyl,
9-phenanthrolinyl, 10-phenanthrolinyl, 1-thianthrenyl,
2-thianthrenyl, 1-indolizinyl, 2-indolizinyl, 3-indolizinyl,
5-indolizinyl, 6-indolizinyl, 7-indolizinyl, 8-indolizinyl,
1-phenoxathiinyl, 2-phenoxathiinyl, 3-phenoxathiinyl,
4-phenoxathiinyl, thieno[2,3-b]furyl, pyrrolo[1,2-b]pyridazinyl,
pyrazolo[1,5-a]pyridyl, imidazo[11,2-a]pyridyl,
imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl,
imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl, and
1,2,4-triazolo[4,3-a]pyridazinyl, which are 8 to 14-membered fused
polycyclic heteroaryl groups.
[0074] Examples of the monocyclic non-aromatic heterocyclic group
include, for example, 1-aziridinyl, 1-azetidinyl, 1-pyrrolidinyl,
2-pyrrolidinyl, 3-pyrrolidinyl, 2-tetrahydrofuryl,
3-tetrahydrofuryl, thiolanyl, 1-imidazolidinyl, 2-imidazolidinyl,
4-imidazolidinyl, 1-pyrazolidinyl, 3-pyrazolidinyl,
4-pyrazolidinyl, 1-(2-pyrrolinyl), 1-(2-imidazolinyl),
2-(2-imidazolinyl), 1-(2-pyrazolinyl), 3-(2-pyrazolinyl),
piperidino, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl,
1-homopiperidinyl, 2-tetrahydropyranyl, morpholino,
(thiomorpholin)-4-yl, 1-piperazinyl, and 1-homopiperazinyl, which
are 3 to 7-membered saturated or unsaturated monocyclic
non-aromatic heterocyclic groups.
[0075] Examples of the fused polycyclic non-aromatic heterocyclic
group include, for example, 2-quinuclidinyl, 2-chromanyl,
3-chromanyl, 4-chromanyl, 5-chromanyl, 6-chromanyl, 7-chromanyl,
8-chromanyl, 1-isochromanyl, 3-isochromanyl, 4-isochromanyl,
5-isochromanyl, 6-isochromanyl, 7-isochromanyl, 8-isochromanyl,
2-thiochromanyl, 3-thiochromanyl, 4-thiochromanyl, 5-thiochromanyl,
6-thiochromanyl, 7-thiochromanyl, 8-thiochromanyl,
1-isothiochromanyl, 3-isothiochromanyl, 4-isothiochromanyl,
5-isothiochromanyl, 6-isothiochromanyl, 7-isothiochromanyl,
8-isothiochromanyl, 1-indolinyl, 2-indolinyl, 3-indolinyl,
4-indolinyl, 5-indolinyl, 6-indolinyl, 7-indolinyl, 1-isoindolinyl,
2-isoindolinyl, 4-isoindolinyl, 5-isoindolinyl, 2-(4H-chromenyl),
3-(4H-chromenyl), 4-(4H-chromenyl), 5-(4H-chromenyl),
6-(4H-chromenyl), 7-(4H-chromenyl), 8-(4H-chromenyl),
1-isochromenyl, 3-isochromenyl, 4-isochromenyl, 5-isochromenyl,
6-isochromenyl, 7-isochromenyl, 8-isochromenyl,
1-(1H-pyrrolidinyl), 2-(1H-pyrrolidinyl), 3-(1H-pyrrolidinyl),
5-(1H-pyrrolidinyl), 6-(1H-pyrrolidinyl), and 7-(1H-pyrrolidinyl),
which are 8 to 10-membered saturated or unsaturated fused
polycyclic non-aromatic heterocyclic groups.
[0076] Among the aforementioned heterocyclic groups, a monocyclic
or a fused polycyclic hetero aryl groups which may have 1 to 3
kinds of hetero atoms selected from oxygen atom, sulfur atom,
nitrogen atom and the like, in addition to the nitrogen atom that
has the bond, as ring-constituting atoms (ring forming atoms), and
a monocyclic or a fused polycyclic non-aromatic heterocyclic groups
which may have 1 to 3 kinds of hetero atoms selected from oxygen
atom, sulfur atom, nitrogen atom and the like, in addition to the
nitrogen atom that has the bond, as ring-constituting atoms (ring
forming atoms) are referred to as "cyclic amino group." Examples
include, for example, 1-pyrrolidinyl, 1-imidazolidinyl,
1-pyrazolidinyl, 1-oxazolidinyl, 1-thiazolidinyl, piperidino,
morpholino, 1-piperazinyl, thiomorpholin-4-yl, 1-homopiperidinyl,
1-homopiperazinyl, 2-pyrrolin-1-yl, 2-imidazolin-1-yl,
2-pyrazolin-1-yl, 1-indolinyl, 2-isoindolinyl,
1,2,3,4-tetrahydroquinolin-1-yl,
1,2,3,4-tetrahydroisoquinolin-2-yl, 1-pyrrolyl, 1-imidazolyl,
1-pyrazolyl, 1-indolyl, 1-indazolyl, and 2-isoindolyl.
[0077] The aforementioned cycloalkyl group, cycloalkenyl group,
cycloalkanedienyl group, aryl group, cycloalkylene group,
cycloalkenylene group, arylene group, bridged cyclic hydrocarbon
group, spiro cyclic hydrocarbon group, and heterocyclic group are
generically referred to as "cyclic group." Furthermore, among said
cyclic groups, particularly, aryl group, arylene group, monocyclic
heteroaryl group, and fused polycyclic heteroaryl group are
generically referred to as "aromatic ring group."
[0078] Examples of the hydrocarbon-oxy group include the groups in
which a hydrogen atom of the hydroxy group is substituted with a
hydrocarbon group, and examples of the hydrocarbon include similar
groups to the aforementioned hydrocarbon groups. Examples of the
hydrocarbon-oxy group include, for example, alkoxy group (alkyl-oxy
group), alkenyl-oxy group, alkynyl-oxy group, cycloalkyl-oxy group,
cycloalkyl-alkyl-oxy group and the like, which are aliphatic
hydrocarbon-oxy groups; aryl-oxy group; aralkyl-oxy group; and
alkylene-dioxy group.
[0079] Examples of the alkoxy (alkyl-oxy group) include, for
example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,
isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy,
2-methylbutoxy, 1-methylbutoxy, neopentyloxy, 1,2-dimethylpropoxy,
1-ethylpropoxy, n-hexyloxy, 4-methylpentyloxy, 3-methylpentyloxy,
2-methylpentyloxy, 1-methylpentyloxy, 3,3-dimethylbutoxy,
2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy,
1,3-dimethylbutoxy, 2,3-dimethylbutoxy, 2-ethylbutoxy,
1-ethylbutoxy, 1-ethyl-1-methylpropoxy, n-heptyloxy, n-octyloxy,
n-nonyloxy, n-decyloxy, n-undecyloxy, n-dodecyloxy, n-tridecyloxy,
n-tetradecyloxy, and n-pentadecyloxy, which are C.sub.1 to C.sub.15
straight chain or branched chain alkoxy groups.
[0080] Examples of the alkenyl-oxy group include, for example,
vinyloxy, (prop-1-en-1-yl)oxy, allyloxy, isopropenyloxy,
(but-1-en-1-yl)oxy, (but-2-en-1-yl)oxy, (but-3-en-1-yl)oxy,
(2-methylprop-2-en-1-yl)oxy, (1-methylprop-2-en-1-yl)oxy,
(pent-1-en-1-yl)oxy, (pent-2-en-1-yl)oxy, (pent-3-en-1-yl)oxy,
(pent-4-en-1-yl)oxy, (3-methylbut-2-en-1-yl)oxy,
(3-methylbut-3-en-1-yl)oxy, (hex-1-en-1-yl)oxy, (hex-2-en-1-yl)oxy,
(hex-3-en-1-yl)oxy, (hex-4-en-1-yl)oxy, (hex-5-en-1-yl)oxy,
(4-methylpent-3-en-1-yl)oxy, (4-methylpent-3-en-1-yl)oxy,
(hept-1-en-1-yl)oxy, (hept-6-en-1-yl)oxy, (oct-1-en-1-yl)oxy,
(oct-7-en-1-yl)oxy, (non-1-en-1-yl)oxy, (non-8-en-1-yl)oxy,
(dec-1-en-1-yl)oxy, (dec-9-en-1-yl)oxy, (undec-1-en-1-yl)oxy,
(undec-10-en-1-yl)oxy, (dodec-1-en-1-yl)oxy, (dodec-11-en-1-yl)oxy,
(tridec-1-en-1-yl)oxy, (tridec-12-en-1-yl)oxy,
(tetradec-1-en-1-yl)oxy, (tetradec-13-en-1-yl)oxy,
(pentadec-1-en-0,1-yl)oxy, and (pentadec-14-en-1-yl)oxy, which are
C.sub.2 to C.sub.15 straight chain or branched chain alkenyl-oxy
groups.
[0081] Examples of the alkynyl-oxy group include, for example,
ethynyloxy, (prop-1-yn-1-yl)oxy, (prop-2-yn-1-yl)oxy,
(but-1-yn-1-yl)oxy, (but-3-yn-1-yl)oxy,
(1-methylprop-2-yn-1-yl)oxy, (pent-1-yn-1-yl)oxy,
(pent-4-yn-1-yl)oxy, (hex-1-yn-1-yl)oxy, (hex-5-yn-1-yl)oxy,
(hept-1-yn-1-yl)oxy, (hept-6-yn-1-yl)oxy, (oct-1-yn-1-yl)oxy,
(oct-7-yn-1-yl)oxy, (non-1-yn-1-yl)oxy, (non-8-yn-1-yl)oxy,
(dec-1-yn-1-yl)oxy, (dec-9-yn-1-yl)oxy, (undec-1-yn-1-yl)oxy,
(undec-10-yn-1-yl)oxy, (dodec-1-yn-1-yl)oxy, (dodec-11-yn-1-yl)oxy,
(tridec-1-yn-1-yl)oxy, (tridec-12-yn-1-yl)oxy,
(tetradec-1-yn-1-yl)oxy, (tetradec-13-yn-1-yl)oxy,
(pentadec-1-yn-1-yl)oxy, and (pentadec-14-yn-1-yl)oxy, which are
C.sub.2 to C.sub.15 straight chain or branched chain alkynyl-oxy
groups.
[0082] Examples of the cycloalkyl-oxy group include, for example,
cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy,
cycloheptyloxy, and cyclooctyloxy, which are C.sub.3 to C.sub.8
cycloalkyl-oxy groups.
[0083] Examples of the cycloalkyl-alkyl-oxy group include, for
example, cyclopropylmethoxy, 1-cyclopropylethoxy,
2-cyclopropylethoxy, 3-cyclopropylpropoxy, 4-cyclopropylbutoxy,
5-cyclopropylpentyloxy, 6-cyclopropylhexyloxy, cyclobutylmethoxy,
cyclopentylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy,
cyclohexylmethoxy, 2-cyclohexylethoxy, 3-cyclohexylpropoxy,
4-cyclohexylbutoxy, cycloheptylmethoxy, cyclooctylmethoxy, and
6-cyclooctylhexyloxy, which are C.sub.4 to C.sub.14
cycloalkyl-alkyl-oxy groups.
[0084] Examples of the aryl-oxy group include, for example,
phenoxy, 1-naphthyloxy, 2-naphthyloxy, anthryloxy, phenanthryloxy,
and acenaphthylenyloxy, which are C.sub.6 to C.sub.14 aryl-oxy
groups.
[0085] Examples of the aralkyl-oxy group include, for example,
benzyloxy, 1-naphthylmethoxy, 2-naphthylmethoxy,
anthracenylmethoxy, phenanthrenylmethoxy, acenaphthylenylmethoxy,
diphenylmethoxy, 1-phenethyloxy, 2-phenethyloxy,
1-(1-naphthyl)ethoxy, 1-(2-naphthyl)ethoxy, 2-(1-naphthyl)ethoxy,
2-(2-naphthyl)ethoxy, 3-phenylpropoxy, 3-(1-naphthyl)propoxy,
3-(2-naphthyl)propoxy, 4-phenylbutoxy, 4-(1-naphthyl)butoxy,
4-(2-naphthyl)butoxy, 5-phenylpentyloxy, 5-(1-naphthyl)pentyloxy,
5-(2-naphthyl)pentyloxy, 6-phenylhexyloxy, 6-(1-naphthyl)hexyloxy,
and 6-(2-naphthyl)hexyloxy, which are C.sub.7 to C.sub.16
aralkyl-oxy groups.
[0086] Examples of the alkylenedioxy group include, for example,
methylenedioxy, ethylenedioxy, 1-methylmethylenedioxy, and
1,1-dimethylmethylenedioxy.
[0087] Examples of the halogenated alkoxy group (halogenated
alkyl-oxy group) include the groups in which a hydrogen atom of the
hydroxy group is substituted with a halogenated alkyl group, and
include, for example, fluoromethoxy, difluoromethoxy,
chloromethoxy, bromomethoxy, iodomethoxy, trifluoromethoxy,
trichloromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy,
3,3,3-trifluoropropoxy, heptafluoropropoxy, heptafluoroisopropoxy,
nonafluorobutoxy, and perfluorohexyloxy, which are C.sub.1 to
C.sub.6 straight chain or branched chain halogenated alkoxy groups
substituted with 1 to 13 halogen atoms.
[0088] Examples of the heterocyclic-oxy group include the groups in
which a hydrogen atom of the hydroxy group is substituted with a
heterocyclic group, and examples of the heterocyclic ring include
similar groups to the aforementioned heterocyclic groups. Examples
of the heterocyclic-oxy group include, for example, a monocyclic
heteroaryl-oxy group, a fused polycyclic heteroaryl-oxy group, a
monocyclic non-aromatic heterocyclic-oxy group, and a fused
polycyclic non-aromatic heterocyclic-oxy group.
[0089] Examples of the monocyclic heteroaryl-oxy group include, for
example, 3-thienyloxy, (isoxazol-3-yl)oxy, (thiazol-4-yl)oxy,
2-pyridyloxy, 3-pyridyloxy, 4-pyridyloxy, and
(pyrimidin-4-yl)oxy.
[0090] Examples of the fused polycyclic heteroaryl-oxy group
include, for example, 5-indolyloxy, (benzimidazol-2-yl)oxy,
2-quinolyloxy, 3-quinolyloxy, and 4-quinolyloxy.
[0091] Examples of the monocyclic non-aromatic heterocyclic-oxy
group include, for example, 3-pyrrolidinyloxy, and
4-piperidinyloxy.
[0092] Examples of the fused polycyclic non-aromatic
heterocyclic-oxy group include, for example, 3-indolynyloxy, and
4-chromanyloxy.
[0093] Examples of the hydrocarbon-sulfanyl group include the
groups in which a hydrogen atom of the sulfanyl group is
substituted with a hydrocarbon group, and examples of the
hydrocarbon include similar groups to the aforementioned
hydrocarbon groups. Examples of the hydrocarbon-sulfanyl groups
include, for example, alkyl-sulfanyl group, alkenyl-sulfanyl group,
alkynyl-sulfanyl group, cycloalkyl-sulfanyl group,
cycloalkyl-alkyl-sulfanyl group and the like, which are aliphatic
hydrocarbon-sulfanyl groups; aryl-sulfanyl group, and
aralkyl-sulfanyl group.
[0094] Examples of the alkyl-sulfanyl group include, for example,
methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl,
n-butylsulfanyl, isobutylsulfanyl, sec-butylsulfanyl,
tert-butylsulfanyl, n-pentylsulfanyl, isopentylsulfanyl,
(2-methylbutyl)sulfanyl, (1-methylbutyl)sulfanyl,
neopentylsulfanyl, (1,2-dimethylpropyl)sulfanyl,
(1-ethylpropyl)sulfanyl, n-hexylsulfanyl, (4-methylpentyl)sulfanyl,
(3-methylpentyl)sulfanyl, (2-methylpentyl)sulfanyl,
(1-methylpentyl)sulfanyl, (3,3-dimethylbutyl)sulfanyl,
(2,2-dimethylbutyl)sulfanyl, (1,1-dimethylbutyl)sulfanyl,
(1,2-dimethylbutyl)sulfanyl, (1,3-dimethylbutyl)sulfanyl,
(2,3-dimethylbutyl)sulfanyl, (2-ethylbutyl)sulfanyl,
(1-ethylbutyl)sulfanyl, (1-ethyl-1-methylpropyl)sulfanyl,
n-heptylsulfanyl, n-octylsulfanyl, n-nonylsulfanyl,
n-decylsulfanyl, n-undecylsulfanyl, n-dodecylsulfanyl,
n-tridecylsulfanyl, n-tetradecylsulfanyl, and n-pentadecylsulfanyl,
which are C.sub.1 to C.sub.15 straight chain or branched chain
alkyl-sulfanyl groups.
[0095] Examples of the alkenyl-sulfanyl group include, for example,
vinylsulfanyl, (prop-1-en-1-yl)sulfanyl, allylsulfanyl,
isopropenylsulfanyl, (but-1-en-1-yl)sulfanyl,
(but-2-en-1-yl)sulfanyl, (but-3-en-1-yl)sulfanyl,
(2-methylprop-2-en-1-yl)sulfanyl, (1-methylprop-2-en-1-yl)sulfanyl,
(pent-1-en-1-yl)sulfanyl, (pent-2-en-1-yl)sulfanyl,
(pent-3-en-1-yl)sulfanyl, (pent-4-en-1-yl)sulfanyl,
(3-methylbut-2-en-1-yl)sulfanyl, (3-methylbut-3-en-1-yl)sulfanyl,
(hex-1-en-1-yl)sulfanyl, (hex-2-en-1-yl)sulfanyl,
(hex-3-en-1-yl)sulfanyl, (hex-4-en-1-yl)sulfanyl,
(hex-5-en-1-yl)sulfanyl, (4-methylpent-3-en-1-yl)sulfanyl,
(4-methylpent-3-en-1-yl)sulfanyl, (hept-1-en-1-yl)sulfanyl,
(hept-6-en-1-yl)sulfanyl, (oct-1-en-1-yl)sulfanyl,
(oct-7-en-1-yl)sulfanyl, (non-1-en-1-yl)sulfanyl,
(non-8-en-1-yl)sulfanyl, (dec-1-en-1-yl)sulfanyl,
(dec-9-en-1-yl)sulfanyl, (undec-1-en-1-yl)sulfanyl,
(undec-10-en-1-yl)sulfanyl, (dodec-1-en-1-yl)sulfanyl,
(dodec-11-en-1-yl)sulfanyl, (tridec-1-en-1-yl)sulfanyl,
(tridec-12-en-1-yl)sulfanyl, (tetradec-1-en-1-yl)sulfanyl,
(tetradec-13-en-1-yl)sulfanyl, (pentadec-1-en-1-yl)sulfanyl, and
(pentadec-14-en-1-yl)sulfanyl, which are C.sub.2 to C.sub.15
straight chain or branched chain alkenyl-sulfanyl groups.
[0096] Examples of the alkynyl-sulfanyl group include, for example,
ethynylsulfanyl, (prop-1-yn-1-yl)sulfanyl,
(prop-2-yn-1-yl)sulfanyl, (but-1-yn-1-yl)sulfanyl,
(but-3-yn-1-yl)sulfanyl, (1-methylprop-2-yn-1-yl)sulfanyl,
(pent-1-yn-1-yl)sulfanyl, (pent-4-yn-1-yl)sulfanyl,
(hex-1-yn-1-yl)sulfanyl, (hex-5-yn-1-yl)sulfanyl,
(hept-1-yn-1-yl)sulfanyl, (hept-6-yn-1-yl)sulfanyl,
(oct-1-yn-1-yl)sulfanyl, (oct-7-yn-1-yl)sulfanyl,
(non-1-yn-1-yl)sulfanyl, (non-8-yn-1-yl)sulfanyl,
(dec-1-yn-1-yl)sulfanyl, (dec-9-yn-1-yl)sulfanyl,
(undec-1-yn-1-yl)sulfanyl, (undec-10-yn-1-yl)sulfanyl,
(dodec-1-yn-1-yl)sulfanyl, (dodec-11-yn-1-yl)sulfanyl,
(tridec-1-yn-1-yl)sulfanyl, (tridec-12-yn-1-yl)sulfanyl,
(tetradec-1-yn-1-yl)sulfanyl, (tetradec-13-yn-1-yl)sulfanyl,
(pentadec-1-yn-1-yl)sulfanyl, and (pentadec-14-yn-1-yl)sulfanyl,
which are C.sub.2 to C.sub.15 straight chain or branched chain
alkynyl-sulfanyl groups.
[0097] Examples of the cycloalkyl-sulfanyl group include, for
example, cyclopropylsulfanyl, cyclobutylsulfanyl,
cyclopentylsulfanyl, cyclohexylsulfanyl, cycloheptylsulfanyl, and
cyclooctylsulfanyl, which are C.sub.3 to C.sub.8
cycloalkyl-sulfanyl groups.
[0098] Examples of the cycloalkyl-alkyl-sulfanyl group include, for
example, (cyclopropylmethyl)sulfanyl, (1-cyclopropylethyl)sulfanyl,
(2-cyclopropylethyl)sulfanyl, (3-cyclopropylpropyl)sulfanyl,
(4-cyclopropylbutyl)sulfanyl, (5-cyclopropylpentyl)sulfanyl,
(6-cyclopropylhexyl)sulfanyl, (cyclobutylmethyl)sulfanyl,
(cyclopentylmethyl)sulfanyl, (cyclobutylmethyl)sulfanyl,
(cyclopentylmethyl)sulfanyl, (cyclohexylmethyl)sulfanyl,
(2-cyclohexylethyl)sulfanyl, (3-cyclohexylpropyl)sulfanyl,
(4-cyclohexylbutyl)sulfanyl, (cycloheptylmethyl)sulfanyl,
(cyclooctylmethyl)sulfanyl, and (6-cyclooctylhexyl)sulfanyl, which
are C.sub.4 to C.sub.14 cycloalkyl-alkyl-sulfanyl groups.
[0099] Examples of the aryl-sulfanyl group include, for example,
phenylsulfanyl, 1-naphthylsulfanyl, 2-naphthylsulfanyl,
anthrylsulfanyl, fenanthrylsulfanyl, and acenaphthylenylsulfanyl,
which are C.sub.6 to C.sub.14 aryl-sulfanyl groups.
[0100] Examples of the aralkyl-sulfanyl group include, for example,
benzylsulfanyl, (1-naphthylmethyl)sulfanyl,
(2-naphthylmethyl)sulfanyl, (anthracenylmethyl)sulfanyl,
(phenanthrenylmethyl)sulfanyl, (acenaphthylenylmethyl)sulfanyl,
(diphenylmethyl)sulfanyl, (1-phenethyl)sulfanyl,
(2-phenethyl)sulfanyl, (1-(1-naphthyl)ethyl)sulfanyl,
(1-(2-naphthyl)ethyl)sulfanyl, (2-(1-naphthyl)ethyl)sulfanyl,
(2-(2-naphthyl)ethyl)sulfanyl, (3-phenylpropyl)sulfanyl,
(3-(1-naphthyl)propyl)sulfanyl, (3-(2-naphthyl)propyl)sulfanyl,
(4-phenylbutyl)sulfanyl, (4-(1-naphthyl)butyl)sulfanyl,
(4-(2-naphthyl)butyl)sulfanyl, (5-phenylpentyl)sulfanyl,
(5-(1-naphthyl)pentyl)sulfanyl, (5-(2-naphthyl)pentyl)sulfanyl,
(6-phenylhexyl)sulfanyl, (6-(1-naphthyl)hexyl)sulfanyl, and
(6-(2-naphthyl)hexyl)sulfanyl, which are C.sub.7 to C.sub.16
aralkyl-sulfanyl groups.
[0101] Examples of the halogenated alkyl-sulfanyl group include the
groups in which a hydrogen atom of the sulfanyl group is
substituted with a halogenated alkyl group, and include, for
example, (fluoromethyl)sulfanyl, (chloromethyl)sulfanyl,
(bromomethyl)sulfanyl, (iodomethyl)sulfanyl,
(difluoromethyl)sulfanyl, (trifluoromethyl)sulfanyl,
(trichloromethyl)sulfanyl, (2,2,2-trifluoroethyl)sulfanyl,
(pentafluoroethyl)sulfanyl, (3,3,3-trifluoropropyl)sulfanyl,
(heptafluoropropyl)sulfanyl, (heptafluoroisopropyl)sulfanyl,
(nonafluorobutyl)sulfanyl, and (perfluorohexyl)sulfanyl, which are
C.sub.1 to C.sub.6 straight chain or branched chain halogenated
alkyl-sulfanyl groups substituted with 1 to 13 halogen atoms.
[0102] Examples of the heterocyclic-sulfanyl group include the
groups in which a hydrogen atom of the sulfanyl group is
substituted with a heterocyclic group, and examples of the
heterocyclic ring include similar groups to the aforementioned
heterocyclic groups. Examples of the heterocyclic-sulfanyl group
include, for example, a monocyclic heteroaryl-sulfanyl group, a
fused polycyclic heteroaryl-sulfanyl group, a monocyclic
non-aromatic heterocyclic-sulfanyl group, and a fused polycyclic
non-aromatic heterocyclic-sulfanyl group.
[0103] Examples of the monocyclic heteroaryl-sulfanyl group
include, for example, (imidazol-2-yl)sulfanyl,
(1,2,4-triazol-2-yl)sulfanyl, (pyridin-2-yl)sulfanyl,
(pyridin-4-yl)sulfanyl, and (pyrimidin-2-yl)sulfanyl.
[0104] Examples of the fused polycyclic heteroaryl-sulfanyl group
include, for example, (benzimidazol-2-yl)sulfanyl,
(quinolin-2-yl)sulfanyl, and (quinolin-4-yl)sulfanyl.
[0105] Examples of the monocyclic non-aromatic
heterocyclic-sulfanyl groups include, for example,
(3-pyrrolidinyl)sulfanyl, and (4-piperidinyl)sulfanyl.
[0106] Examples of the fused polycyclic non-aromatic
heterocyclic-sulfanyl group include, for example,
(3-indolinyl)sulfanyl, and (4-chromanyl)sulfanyl.
[0107] Examples of the acyl group include, for example, formyl
group, glyoxyloyl group, thioformyl group, carbamoyl group,
thiocarbamoyl group, sulfamoyl group, sulfinamoyl group, carboxy
group, sulfo group, phosphono group, and groups represented by the
following formulas: ##STR11## ##STR12## wherein R.sup.a1 and
R.sup.b1 may be the same or different and represent a hydrocarbon
group or a heterocyclic group, or R.sup.a1 and R.sup.b1 combine to
each other, together with the nitrogen atom to which they bind, to
form a cyclic amino group.
[0108] In the definition of the aforementioned acyl group, among
the groups represented by the formula (.omega.-1A), those groups in
which R.sup.a1 is a hydrocarbon group are referred to as
"hydrocarbon-carbonyl group" whose examples include, for example,
acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl,
pivaloyl, lauroyl, myristoyl, palmitoyl, acryloyl, propioloyl,
methacryloyl, crotonoyl, isocrotonoyl, cyclohexylcarbonyl,
cyclohexylmethylcarbonyl, benzoyl, 1-naphthoyl, 2-naphthoyl, and
phenylacetyl, and those groups in which R.sup.a1 is a heterocyclic
group are referred to as "heterocyclic ring-carbonyl group" whose
examples include, for example, 2-thenoyl, 3-furoyl, nicotinoyl, and
isonicotinoyl.
[0109] Among the groups represented by the formula (.omega.-2A),
those groups in which R.sup.a1 is a hydrocarbon group are referred
to as "hydrocarbon-oxy-carbonyl group" whose examples include, for
example, methoxycarbonyl, ethoxycarbonyl, phenoxycarbonyl, and
benzyloxycarbonyl, and those groups in which R.sup.a1 is a
heterocyclic group are referred to as "heterocyclic
ring-oxy-carbonyl group" whose examples include, for example,
3-pyridyloxycarbonyl.
[0110] Among the groups represented by the formula (.omega.-3A),
those groups in which R.sup.a1 is a hydrocarbon group are referred
to as "hydrocarbon-carbonyl-carbonyl group" whose examples include,
for example, pyruvoyl, and those groups in which R.sup.a1 is a
heterocyclic group are referred to as "heterocyclic
ring-carbonyl-carbonyl group."
[0111] Among the groups represented by the formula (.omega.-4A),
those groups in which R.sup.a1 is a hydrocarbon group are referred
to as "hydrocarbon-oxy-carbonyl-carbonyl group" whose examples
include, for example, methoxalyl and ethoxalyl groups, and those
groups in which R.sup.a1 is a heterocyclic group are referred to as
"heterocyclic ring-oxy-carbonyl-carbonyl group."
[0112] Among the groups represented by the formula (.omega.-5A),
those groups in which R.sup.a1 is a hydrocarbon group are referred
to as "hydrocarbon-sulfanyl-carbonyl group," and those groups in
which R.sup.a1 is a heterocyclic group are referred to as
"heterocyclic ring-sulfanyl-carbonyl group."
[0113] Among the groups represented by the formula (.omega.-6A),
those groups in which R.sup.a1 is a hydrocarbon group are referred
to as "hydrocarbon-thiocarbonyl group," and those groups in which
R.sup.a1 is a heterocyclic group are referred to as "heterocyclic
ring-thiocarbonyl group."
[0114] Among the groups represented by the formula (.omega.-7A),
those groups in which R.sup.a1 is a hydrocarbon group are referred
to as "hydrocarbon-oxy-thiocarbonyl group," and those groups in
which R.sup.a1 is a heterocyclic group are referred to as
"heterocyclic ring-oxy-thiocarbonyl group."
[0115] Among the groups represented by the formula (.omega.-8A),
those groups in which R.sup.a1 is a hydrocarbon group are referred
to as "hydrocarbon-sulfanyl-thiocarbonyl group," and those groups
in which R.sup.a1 is a heterocyclic group are referred to as
"heterocyclic ring-sulfanyl-thiocarbonyl group."
[0116] Among the groups represented by the formula (.omega.-9A),
those groups in which R.sup.a1 is a hydrocarbon group are referred
to as referred to as "N-hydrocarbon-carbamoyl, group" whose
examples include, for example, N-methylcarbamoyl group, and those
groups in which R.sup.a1 is a heterocyclic group are referred to as
"N-heterocyclic ring-carbamoyl group."
[0117] Among the groups represented by the formula (.omega.-10A),
those groups in which both R.sup.a1 and R.sup.b1 are hydrocarbon
groups are referred to as "N,N-di(hydrocarbon)-carbamoyl group"
whose examples include, for example, N,N-dimethylcarbamoyl group,
those groups in which both R.sup.a1 and R.sup.b1 are heterocyclic
groups are referred to as "N,N-di(heterocyclic ring)-carbamoyl
group," those groups in which R.sup.a1 is a hydrocarbon group and
R.sup.b1 is a heterocyclic group are referred to as
"N-hydrocarbon-N-heterocyclic ring-substituted carbamoyl group,"
and those groups in which R.sup.a1 and R.sup.b1 combine to each
other, together with the nitrogen atom to which they bind, to form
a cyclic amino group are referred to as "cyclic amino-carbonyl
group" whose examples include, for example,
morpholino-carbonyl.
[0118] Among the groups represented by the formula (.omega.-11A),
those groups in which R.sup.a1 is a hydrocarbon group are referred
to as "N-hydrocarbon-thiocarbamoyl group," and those groups in
which R.sup.a1 is a heterocyclic group are referred to as
"N-heterocyclic ring-thiocarbamoyl group."
[0119] Among the groups represented by the formula (.omega.-12A),
those groups in which both R.sup.a1 and R.sup.b1 are hydrocarbon
groups are referred to as "N,N-di(hydrocarbon)-thiocarbamoyl
group," those groups in which both R.sup.a1 and R.sup.b1 are
heterocyclic groups are referred to as "N,N-di(heterocyclic
ring)-thiocarbamoyl group," those groups in which R.sup.a1 is a
hydrocarbon group and R.sup.b1 is a heterocyclic group are referred
to as "N-hydrocarbon-N-heterocyclic ring-thiocarbamoyl group," and
those groups in which R.sup.a1 and R.sup.b1 combine to each other,
together with the nitrogen atom to which they bind, to form a
cyclic amino group are referred to as "cyclic amino-thiocarbonyl
group."
[0120] Among the groups represented by the formula (.omega.-13A),
those groups in which R.sup.a1 is a hydrocarbon group are referred
to as "N-hydrocarbon-sulfamoyl group," and those groups in which
R.sup.a1 is a heterocyclic group are referred to as "N-heterocyclic
ring-sulfamoyl group."
[0121] Among the groups represented by the formula (.omega.-14A),
those groups in which both R.sup.a1 and R.sup.b1 are hydrocarbon
groups are referred to as "N,N-di(hydrocarbon)-sulfamoyl group"
whose examples include, for example, N,N-dimethylsulfamoyl group,
those groups in which both R.sup.a1 and R.sup.b1 are heterocyclic
groups are referred to as "N,N-di(heterocyclic ring)-sulfamoyl
group," those groups in which R.sup.a1 is a hydrocarbon group and
R.sup.b1 is a heterocyclic group are referred to as
"N-hydrocarbon-N-heterocyclic ring-sulfamoyl group," and those
groups in which R.sup.a1 and R.sup.b1 combine to each other,
together with the nitrogen atom to which they bind, to form a
cyclic amino group are referred to as "cyclic amino-sulfonyl group"
whose examples include, for example 1-pyrrolylsulfonyl.
[0122] Among the groups represented by the formula (.omega.-15A),
those groups in which R.sup.a1 is a hydrocarbon group are referred
to as "N-hydrocarbon-sulfinamoyl group," and those groups in which
R.sup.a1 is a heterocyclic group are referred to as "N-heterocyclic
ring-sulfinamoyl group."
[0123] Among the groups represented by the formula (.omega.-16A),
those groups in which both R.sup.a1 and R.sup.b1 are hydrocarbon
groups are referred to as "N,N-di(hydrocarbon)-sulfinamoyl group,"
those groups in which both R.sup.a1 and R.sup.b1 are heterocyclic
groups are referred to as "N,N-di(heterocyclic ring)-sulfinamoyl
group," those groups in which R.sup.a1 is a hydrocarbon group and
R.sup.b1 is a heterocyclic group are referred to as
"N-hydrocarbon-N-heterocyclic ring-sulfinamoyl group," and those
groups in which R.sup.a1 and R.sup.b1 combine to each other,
together with the nitrogen atom to which they bind, to form a
cyclic amino group are referred to as "cyclic amino-sulfinyl
group."
[0124] Among the groups represented by the formula (.omega.-17A),
those groups in which R.sup.a1 is a hydrocarbon group are referred
to as "hydrocarbon-oxy-sulfonyl group," and those groups in which
R.sup.a1 is a heterocyclic group are referred to as "heterocyclic
ring-oxy-sulfonyl group."
[0125] Among the groups represented by the formula (.omega.-18A),
those groups in which R.sup.a1 is a hydrocarbon group are referred
to as "hydrocarbon-oxy-sulfinyl group," and those groups in which
R.sup.a1 is a heterocyclic group are referred to as "heterocyclic
ring-oxy-sulfinyl group."
[0126] Among the groups represented by the formula (.omega.-19A),
those groups in which both R.sup.a1 and R.sup.b1 are hydrocarbon
groups are referred to as "O,O'-di(hydrocarbon)-phosphono group,"
those groups in which both R.sup.a1 and R.sup.b1 are heterocyclic
groups are referred to as "O,O'-di(heterocyclic ring)-phosphono
group," and those groups in which R.sup.a1 is a hydrocarbon group
and R.sup.b1 is a heterocyclic group are referred to as
"O-hydrocarbon-O'-heterocyclic ring-phosphono group."
[0127] Among the groups represented by the formula (.omega.-20A),
those groups in which R.sup.a1 is a hydrocarbon group are referred
to as "hydrocarbon-sulfonyl group" whose examples include, for
example, methanesulfonyl and benzenesulfonyl, and those groups in
which R.sup.a1 is a heterocyclic group are referred to as
"heterocyclic ring-sulfonyl group."
[0128] Among the groups represented by the formula (.omega.-21A),
those groups in which R.sup.a1 is a hydrocarbon group are referred
to as "hydrocarbon-sulfinyl group" whose examples include, for
example, methylsulfinyl and benzenesulfinyl, and those groups in
which R.sup.a1 is a heterocyclic group are referred to as
"heterocyclic ring-sulfinyl group."
[0129] Examples of the hydrocarbon in the groups represented by the
aforementioned formulas (.omega.-1A) through (.omega.-21A) include
the similar groups to the aforementioned hydrocarbon group.
Examples of the hydrocarbon-carbonyl group represented by the
formula (.omega.-1A) include, for example, an alkyl-carbonyl group,
an alkenyl-carbonyl group, an alkynyl-carbonyl group, a
cycloalkyl-carbonyl group, a cycloalkenyl-carbonyl group, a
cycloalkanedienyl-carbonyl group, a cycloalkyl-alkyl-carbonyl
group, which are aliphatic hydrocarbon-carbonyl groups; an
aryl-carbonyl group; an aralkyl-carbonyl group; a bridged cyclic
hydrocarbon-carbonyl group; a spirocyclic hydrocarbon-carbonyl
group; and a terpene family hydrocarbon-carbonyl group. In the
following, groups represented by the formulas (.omega.-2A) through
(.omega.-21A) are similar to those explained above.
[0130] Examples of the heterocyclic ring in the groups represented
by the aforementioned formulas (.omega.-1A) through (.omega.-21A)
include similar groups to the aforementioned heterocyclic group.
Examples of the heterocyclic ring-carbonyl group represented by the
formula (.omega.-1A) include, for example, a monocyclic
heteroaryl-carbonyl group, a fused polycyclic heteroaryl-carbonyl
group, a monocyclic non-aromatic heterocyclic ring-carbonyl group,
and a fused polycyclic non-aromatic heterocyclic ring-carbonyl
group. In the following, groups represented by the formulas
(.omega.-2A) through (.omega.-21A) are similar to those explained
above.
[0131] Examples of the cyclic amino in the groups represented by
the aforementioned formulas (.omega.-10A) through (.omega.-16A)
include similar groups to the aforementioned cyclic amino
group.
[0132] In the present specification, when a certain functional
group is defined as "which may be substituted," the definition
means that the functional group may sometimes have one or more
substitutents at chemically substitutable positions, unless
otherwise specifically mentioned. Kind of substitutents, number of
substitutents, and the position of substitutents existing in the
functional groups are not particularly limited, and when two or
more substitutents exist, they may be the same or different.
Examples of the substitutent existing in the functional group
include, for example, halogen atoms, oxo group, thioxo group, nitro
group, nitroso group, cyano group, isocyano group, cyanato group,
thiocyanato group, isocyanato group, isothiocyanato group, hydroxy
group, sulfanyl group, carboxy group, sulfanylcarbonyl group, oxalo
group, methooxalo group, thiocarboxy group, dithiocarboxy group,
carbamoyl group, thiocarbamoyl group, sulfo group, sulfamoyl group,
sulfino group, sulfinamoyl group, sulfeno group, sulfenamoyl group,
phosphono group, hydroxyphosphonyl group, hydrocarbon group,
heterocyclic group, hydrocarbon-oxy group, heterocyclic ring-oxy
group, hydrocarbon-sulfanyl group, heterocyclic ring-sulfanyl
group, acyl group, amino group, hydrazino group, hydrazono group,
diazenyl group, ureido group, thioureido group, guanidino group,
carbamoimidoyl group (amidino group), azido group, imino group,
hydroxyamino group, hydroxyimino group, aminooxy group, diazo
group, semicarbazino group, semicarbazono group, allophanyl group,
hydantoyl group, phosphano group, phosphoroso group, phospho group,
boryl group, silyl group, stannyl group, selanyl group, oxido group
and the like.
[0133] When two or more substitutents exist according to the
aforementioned definition of "which may be substituted," said two
or more substitutents may combine to each other, together with
atom(s) to which they bind, to form a ring. For these cyclic
groups, as ring-constituting atoms (ring forming atoms), one to
three kinds of one or more hetero atoms selected from oxygen atom,
sulfur atom, nitrogen atom and the like may be included, and one or
more substitutents may exist on the ring. The ring may be
monocyclic or fused polycyclic, and aromatic or non-aromatic.
[0134] The above substitutents according to the aforementioned
definition of "which may be substituted" may further be substituted
with the aforementioned substitutents at the chemically
substitutable positions on the substitutent. Kind of substitutents,
number of substitutents, and positions of substitutents are not
particularly limited, and when the substitutents are substituted
with two or more substitutents, they may be the same or different.
Examples of the substitutent include, for example, a halogenated
alkyl-carbonyl group whose examples include, for example,
trifluoroacetyl, a halogenated alkyl-sulfonyl group whose examples
include, for example, trifluoromethanesulfonyl, an acyl-oxy group,
an acyl-sulfanyl group, an N-hydrocarbon-amino group, an
N,N-di(hydrocarbon)-amino group, an N-heterocyclic ring-amino
group, an N-hydrocarbon-N-heterocyclic ring-amino group, an
acyl-amino group, and a di(acyl)-amino group. Moreover,
substitution on the aforementioned substitutents may be repeated
multiple orders.
[0135] Examples of the acyl-oxy group include the groups in which
hydrogen atom of hydroxy group is substituted with acyl group, and
include, for example, formyloxy group, glyoxyloyloxy group,
thioformyloxy group, carbamoloxy group, thiocarbamoyloxy group,
sulfamoyloxy group, sulfinamoloxy group, carboxyoxy group,
sulphooxy group, phosphonooxy group, and groups represented by the
following formulas: ##STR13## ##STR14## wherein R.sup.a2 and
R.sup.b2 may be the same or different and represent a hydrocarbon
group or a heterocyclic group, or R.sup.a2 and R.sup.b2 combine to
each other, together with the nitrogen atom to which they bind, to
form a cyclic amino group.
[0136] In the definition of the aforementioned acyl-oxy group,
among the groups represented by the formula (.omega.-1B), those
groups in which R.sup.a2 is a hydrocarbon group are referred to as
"hydrocarbon-carbonyl-oxy group" whose examples include, for
example, acetoxy and benzoyloxy, and those groups in which R.sup.a2
is a heterocyclic group are referred to as "heterocyclic
ring-carbonyl-oxy group."
[0137] Among the groups represented by the formula (.omega.-2B),
those groups in which R.sup.a2 is a hydrocarbon group are referred
to as "hydrocarbon-oxy-carbonyl-oxy group," and those groups in
which R.sup.a2 is a heterocyclic group are referred to as
"heterocyclic ring-oxy-carbonyl-oxy group."
[0138] Among the groups represented by the formula (.omega.-3B),
those groups in which R.sup.a2 is a hydrocarbon group are referred
to as "hydrocarbon-carbonyl-carbonyl-oxy group," and those groups
in which R.sup.a2 is a heterocyclic group are referred to as
"heterocyclic ring-carbonyl-carbonyl-oxy group."
[0139] Among the groups represented by the formula (.omega.-4B),
those groups in which R.sup.a2 is a hydrocarbon group are referred
to as "hydrocarbon-oxy-carbonyl-carbonyl-oxy group," and those
groups in which R.sup.a2 is a heterocyclic group are referred to as
"heterocyclic ring-oxy-carbonyl-carbonyl-oxy group."
[0140] Among the groups represented by the formula (.omega.-5B),
those groups in which R.sup.a2 is a hydrocarbon group are referred
to as "hydrocarbon-sulfanyl-carbonyl-oxy group," and those groups
where R.sup.a2 is a heterocyclic group are referred to as
"heterocyclic ring-sulfanyl-carbonyl-oxy group."
[0141] Among the groups represented by the formula (.omega.-6B),
those groups in which R.sup.a2 is a hydrocarbon group are referred
to as "hydrocarbon-thiocarbonyl-oxy group," and those groups where
R.sup.a2 is a heterocyclic group are referred to as "heterocyclic
ring-thiocarbonyl-oxy group."
[0142] Among the groups represented by the formula (.omega.-7B),
those groups in which R.sup.a2 is a hydrocarbon group are referred
to as "hydrocarbon-oxy-thiocarbonyl-oxy group," and those groups in
which R.sup.a2 is a heterocyclic group are referred to as
"heterocyclic ring-oxy-thiocarbonyl-oxy group."
[0143] Among the groups represented by the formula (.omega.-8B),
those groups in which R.sup.a2 is a hydrocarbon group are referred
to as "hydrocarbon-sulfanyl-thiocarbonyl-oxy group," and those
groups wherein R.sup.a2 is a heterocyclic group are referred to as
"heterocyclic ring-sulfanyl-thiocarbonyl-oxy group."
[0144] Among the groups represented by the formula (.omega.-9B),
those groups in which R.sup.a2 is a hydrocarbon group are referred
to as "N-hydrocarbon-carbamoyl-oxy group," and those groups in
which R.sup.a2 is a heterocyclic group are referred to as
"N-heterocyclic ring-carbamoyl-oxy group."
[0145] Among the groups represented by the formula (.omega.-10B),
those groups in which both R.sup.a2 and R.sup.b2 are hydrocarbon
groups are referred to as "N,N-di(hydrocarbon)-carbamoyl-oxy
group," those groups in which both R.sup.a2 and R.sup.b2 are
heterocyclic groups are referred to as "N,N-di(heterocyclic
ring)-carbamoyl-oxy group," those groups in which R.sup.a2 is a
hydrocarbon group and R.sup.b2 is a heterocyclic group are referred
to as "N-hydrocarbon-N-heterocyclic ring-carbamoyl-oxy group," and
those groups in which R.sup.a2 and R.sup.b2 combine to each other,
together with the nitrogen atom to which they bind, to form a
cyclic amino group are referred to as "cyclicamino-carbonyl-oxy
group."
[0146] Among the groups represented by the formula (.omega.-11B),
those groups in which R.sup.a2 is a hydrocarbon group are referred
to as "N-hydrocarbon-thiocarbamoyl-oxy group," and those groups in
which R.sup.a2 is a heterocyclic group are referred to as
"N-heterocyclic ring-thiocarbamoyl-oxy group."
[0147] Among the groups represented by the formula (.omega.-12B),
those groups in which both R.sup.a2 and R.sup.b2 are hydrocarbon
groups are referred to as "N,N-di(hydrocarbon)-thiocarbamoyl-oxy
group," those groups in which both R.sup.a2 and R.sup.b2 are
heterocyclic groups are referred to as "N,N-di(heterocyclic
ring)-thiocarbamoyl-oxy group," those groups in which R.sup.a2 is a
hydrocarbon group and R.sup.b2 is a heterocyclic group are referred
to as "N-hydrocarbon-N-heterocyclic ring-thiocarbamoyl-oxy group,"
and those groups in which R.sup.a2 and R.sup.b2 combine to each
other, together with the nitrogen atom to which they bind, to form
a cyclic amino group are referred to as
"cyclicamino-thiocarbonyl-oxy group."
[0148] Among the groups represented by the formula (.omega.-13B),
those groups in which R.sup.a2 is a hydrocarbon group are referred
to as "N-hydrocarbon-sulfamoyl-oxy group," and those groups in
which R.sup.a2 is a heterocyclic group are referred to as
"N-heterocyclic ring-sulfamoyl-oxy group."
[0149] Among the groups represented by the formula (.omega.-14B),
those groups in which both R.sup.a2 and R.sup.b2 are hydrocarbon
groups are referred to as "N,N-di(hydrocarbon)-sulfamoyl-oxy
group," those groups in which both R.sup.a2 and R.sup.b2 are
heterocyclic groups are referred to as "N,N-di(heterocyclic
ring)-sulfamoyl-oxy group," those groups in which R.sup.a2 is a
hydrocarbon group and R.sup.b2 is a heterocyclic group are referred
to as "N-hydrocarbon-N-heterocyclic ring-sulfamoyl-oxy group," and
those groups in which R.sup.a2 and R.sup.b2 combine to each other,
together with the nitrogen atom to which they bind, to form a
cyclic amino group are referred to as "cyclic amino-sulfonyl-oxy
group."
[0150] Among the groups represented by the formula (.omega.-15B),
those groups in which R.sup.a2 is a hydrocarbon group are referred
to as "N-hydrocarbon-sulfinamoyl-oxy group," and those groups where
R.sup.a2 is a heterocyclic group are referred to as "N-heterocyclic
ring-sulfinamoyl-oxy group."
[0151] Among the groups represented by the formula (.omega.-16B),
those groups in which both R.sup.a2 and R.sup.b2 are hydrocarbon
groups are referred to as "N,N-di(hydrocarbon)-sulfinamoyl-oxy
group," those groups in which both R.sup.a2 and R.sup.b2 are
heterocyclic groups are referred to as "N,N-di(heterocyclic
ring)-sulfinamoyl-oxy group," those groups in which R.sup.a2 is a
hydrocarbon group and R.sup.b2 is a heterocyclic group are referred
to as "N-hydrocarbon-N-heterocyclic ring-sulfinamoyl-oxy group,"
and those groups in which R.sup.a2 and R.sup.b2 combine to each
other, together with the nitrogen atom to which they bind, to form
a cyclic amino group are referred to as "cyclic amino-sulfinyl-oxy
group."
[0152] Among the groups represented by the formula (.omega.-17B),
those groups in which R.sup.a2 is a hydrocarbon group are referred
to as "hydrocarbon-oxy-sulfonyl-oxy group," and those groups in
which R.sup.a2 is a heterocyclic group are referred to as
"heterocyclic ring-oxy-sulfonyl-oxy group."
[0153] Among the groups represented by the formula (.omega.-18B),
those groups in which R.sup.a2 is a hydrocarbon group are referred
to as "hydrocarbon-oxy-sulfinyl-oxy group," those groups in which
R.sup.a2 is a heterocyclic group are referred to as "heterocyclic
ring-oxy-sulfinyl-oxy group."
[0154] Among the groups represented by the formula (.omega.-19B),
those groups in which both R.sup.a2 and R.sup.b2 are hydrocarbon
groups are referred to as "O,O'-di(hydrocarbon)-phosphono-oxy
group," those groups in which both R.sup.a2 and R.sup.b2 are
heterocyclic groups are referred to as "O,O'-di(heterocyclic
ring)-phosphono-oxy group," and those groups in which R.sup.a2 is a
hydrocarbon group and R.sup.b2 is a heterocyclic group are referred
to as "O-hydrocarbon substituted-O'-heterocyclic ring substituted
phophono-oxy group."
[0155] Among the groups represented by the formula (.omega.-20B),
those groups in which R.sup.a2 is a hydrocarbon group are referred
to as "hydrocarbon-sulfonyl-oxy group," and those groups in which
R.sup.a2 is a heterocyclic group referred to as "heterocyclic
ring-sulfonyl-oxy group."
[0156] Among the groups represented by the formula (.omega.-21B),
those groups in which R.sup.a2 is a hydrocarbon group are referred
to as "hydrocarbon-sulfinyl-oxy group," and those groups in which
R.sup.a2 is a heterocyclic group are referred to as "heterocyclic
ring-sulfinyl-oxy group."
[0157] Examples of the hydrocarbon in the groups represented by the
aforementioned formulas (.omega.-1B) through (.omega.-21B) include
the similar groups to the aforementioned hydrocarbon group.
Examples of the hydrocarbon-carbonyl-oxy group represented by the
formula (.omega.-1B) include, for example, an alkyl-carbonyl-oxy
group, an alkenyl-carbonyl-oxy group, an alkynyl-carbonyl-oxy
group, a cycloalkyl-carbonyl-oxy group, a cycloalkenyl-carbonyl-oxy
group, a cycloalkanedienyl-carbonyl-oxy group, and a
cycloalkyl-alkyl-carbonyl-oxy group, which are aliphatic
hydrocarbon-carbonyl-oxy groups; an aryl-carbonyl-oxy group; an
aralkyl-carbonyl-oxy group; a bridged cyclic
hydrocarbon-carbonyl-oxy group; a spirocyclic
hydrocarbon-carbonyl-oxy group; and a terpene family
hydrocarbon-carbonyl-oxy group. In the following, groups
represented by the formulas (.omega.-2B) through (.omega.-21B) are
similar to those explained above.
[0158] Examples of the heterocyclic ring in the groups represented
by the aforementioned formulas (.omega.-1B) through (.omega.-21B)
include similar groups to the aforementioned heterocyclic group.
Examples of the heterocyclic ring-carbonyl group represented by the
formula (.omega.-1B) include, for example, a monocyclic
heteroaryl-carbonyl group, a fused polycyclic heteroaryl-carbonyl
group, a monocyclic non-aromatic heterocyclic ring-carbonyl group,
and a fused polycyclic non-aromatic heterocyclic ring-carbonyl
group. In the following, groups represented by the formulas
(.omega.-2B) through (.omega.-21B) are similar to those groups
explained above.
[0159] Examples of the cyclic amino in the groups represented by
the aforementioned formulas (.omega.-10B) through (.omega.-16B)
include similar groups to the aforementioned cyclic amino
group.
[0160] The aforementioned acyl-oxy group, hydrocarbon-oxy group,
and heterocyclic-oxy group are generically referred to as
"substituted oxy group." Moreover, these substituted oxy group and
hydroxy group are generically referred to as "hydroxy group which
may be substituted."
[0161] Examples of the acyl-sulfanyl group include the groups in
which hydrogen atom of sulfanyl group is substituted with acyl
group, and include, for example, formylsulfanyl group,
glyoxyloylsulfanyl group, thioformylsulfanyl group, carbamoyloxy
group, thicarbamoyloxy group, sulfamoyloxy group, sulfinamoyloxy
group, carboxyoxy group, sulphooxy group, phosphonooxy group, and
groups represented by the following formulas: ##STR15## ##STR16##
wherein R.sup.a3 and R.sup.b3 may be the same or different and
represent a hydrocarbon group which may be substituted or a
heterocyclic group which may be substituted, or R.sup.a3 and
R.sup.b3 combine to each other, together with the nitrogen atom to
which they bind, to form a cyclic amino group which may be
substituted.
[0162] In the definition of the aforementioned acyl-sulfanyl group,
among the groups represented by the formula (.omega.-1C), those
groups in which R.sup.a3 is a hydrocarbon group are referred to as
"hydrocarbon-carbonyl-sulfanyl group," and those groups in which
R.sup.a3 is a heterocyclic group are referred to as "heterocyclic
ring-carbonyl-sulfanyl group."
[0163] Among the groups represented by the formula (.omega.-2C),
those groups in which R.sup.a3 is a hydrocarbon group are referred
to as "hydrocarbon-oxy-carbonyl-sulfanyl group," and those groups
in which R.sup.a3 is a heterocyclic group are referred to as
"heterocyclic ring-oxy-carbonyl-sulfanyl group."
[0164] Among the groups represented by the formula (.omega.-3C),
those groups in which R.sup.a3 is a hydrocarbon group are referred
to as "hydrocarbon-carbonyl-carbonyl-sulfanyl group," and those
groups in which R.sup.a3 is a heterocyclic group are referred to as
"heterocyclic ring-carbonyl-carbonyl-sulfanyl group."
[0165] Among the groups represented by the formula (.omega.-4C),
those groups in which R.sup.a3 is a hydrocarbon group are referred
to as "hydrocarbon-oxy-carbonyl-carbonyl-sulfanyl group," and those
groups in which R.sup.a3 is a heterocyclic group are referred to as
"heterocyclic ring-oxy-carbonyl-carbonyl-sulfanyl group."
[0166] Among the groups represented by the formula (.omega.-5C),
those groups in which R.sup.a3 is a hydrocarbon group are referred
to as "hydrocarbon-sulfanyl-carbonyl-sulfanyl group," and those
groups in which R.sup.a3 is a heterocyclic group are referred to as
"heterocyclic ring-sulfanyl-carbonyl-sulfanyl group."
[0167] Among the groups represented by the formula (.omega.-6C),
those groups in which R.sup.a3 is a hydrocarbon group are referred
to as "hydrocarbon-thiocarbonyl-sulfanyl group," and those groups
in which R.sup.a3 is a heterocyclic group are referred to as
"heterocyclic ring-thiocarbonyl-sulfanyl group."
[0168] Among the groups represented by the formula (.omega.-7C),
those groups in which R.sup.a3 is a hydrocarbon group are referred
to as "hydrocarbon-oxy-thiocarbonyl-sulfanyl group," and those
groups in which R.sup.a3 is a heterocyclic group are referred to as
"heterocyclic ring-oxy-thiocarbonyl-sulfanyl group."
[0169] Among the groups represented by the formula (.omega.-8C),
those groups in which R.sup.a3 is a hydrocarbon group are referred
to as "hydrocarbon-sulfanyl-thiocarbonyl-sulfanyl group," and those
groups in which R.sup.a3 is a heterocyclic group are referred to as
"heterocyclic ring-sulfanyl-thiocarbonyl-sulfanyl group."
[0170] Among the groups represented by the formula (.omega.-9C),
those groups in which R.sup.a3 is a hydrocarbon group are referred
to as "N-hydrocarbon-carbamoyl-sulfanyl group," and those groups in
which R.sup.a3 is a heterocyclic group are referred to as
"N-heterocyclic ring-carbamoyl-sulfanyl group."
[0171] Among the groups represented by the formula (.omega.-10C),
those groups in which both R.sup.a3 and R.sup.b3 are a hydrocarbon
groups are referred to as "N,N-di(hydrocarbon)-carbamoyl-sulfanyl
group," those groups in which both R.sup.a3 and R.sup.b3 are
heterocyclic groups are referred to as "N,N-di(heterocyclic
ring)-carbamoyl-sulfanyl group," those groups in which R.sup.a3 is
a hydrocarbon group and R.sup.b3 is a heterocyclic group are
referred to as "N-hydrocarbon-N-heterocyclic
ring-carbamoyl-sulfanyl group," and those groups in which R.sup.a3
and R.sup.b3 combine to each other, together with the nitrogen atom
to which they bind, to form a cyclic amino group are referred to as
"cyclicamino-carbonyl-sulfamoyl group."
[0172] Among the groups represented by the formula (.omega.-11C),
those groups in which R.sup.a3 is a hydrocarbon group are referred
to as "N-hydrocarbon-thiocarbamoyl-sulfanyl group," and those
groups in which R.sup.a3 is a heterocyclic group are referred to as
"N-heterocyclic ring-thiocarbamoyl-sulfanyl group."
[0173] Among the groups represented by the formula (.omega.-12C),
those groups in which both R.sup.a3 and R.sup.b3 are hydrocarbon
groups are referred to as
"N,N-di(hydrocarbon)-thiocarbamoyl-sulfanyl group," those groups in
which and R.sup.a3 and R.sup.b3 are heterocyclic groups are
referred to as "N,N-di(heterocyclic ring)-thiocarbamoyl-sulfanyl
group," those groups in which R.sup.a3 is a hydrocarbon group and
R.sup.b3 is a heterocyclic group are referred to as
"N-hydrocarbon-N-heterocyclic ring-thiocarbamoyl-sulfanyl group,"
and those groups in which R.sup.a3 and R.sup.b3 combine to each
other, together with the nitrogen atom to which they bind, to form
a cyclic amino group are referred to as
"cyclicamino-thiocarbonyl-sulfamoyl group."
[0174] Among the groups represented by the formula (.omega.-13C),
those groups in which R.sup.a3 is a hydrocarbon group are referred
to as "N-hydrocarbon-sulfamoyl-sulfanyl group," and those groups in
which R.sup.a3 is a heterocyclic group are referred to as
"N-heterocyclic ring-sulfamoyl-sulfanyl group."
[0175] Among the groups represented by the formula (.omega.-14C),
those groups in which both R.sup.a3 and R.sup.b3 are hydrocarbon
groups are referred to as "N,N-di(hydrocarbon)-sulfamoyl-sulfanyl
group," those groups in which both R.sup.a3 and R.sup.b3 are
heterocyclic groups are referred to as "N,N-di(heterocyclic
ring)-sulfamoyl-sulfinyl group," those groups in which R.sup.a3 is
a hydrocarbon group and R.sup.b3 is a heterocyclic group are
referred to as "N-hydrocarbon-N-heterocyclic
ring-sulfamoyl-sulfanyl group," and those groups in which R.sup.a3
and R.sup.b3 combine to each other, together with the nitrogen atom
to which they bind, to form a cyclic amino group are referred to as
"cyclicamino-sulfonyl-sulfanyl group."
[0176] Among the groups represented by the formula (.omega.-15C),
those groups in which R.sup.a3 is a hydrocarbon group are referred
to as "N-hydrocarbon-sulfinamoyl-sulfanyl group," and those groups
in which R.sup.a3 is a heterocyclic group are referred to as
"N-heterocyclic ring-sulfinamoyl-sulfanyl group."
[0177] Among the groups represented by the formula (.omega.-16C),
those groups in which both R.sup.a3 and R.sup.b3 are hydrocarbon
groups are referred to as "N,N-di(hydrocarbon)-sulfinamoyl-sulfanyl
group," those groups in which both R.sup.a3 and R.sup.b3 are
heterocyclic groups are referred to as "N,N-di(heterocyclic
ring)-sulfinamoyl-sulfanyl group," those groups in which R.sup.a3
is a hydrocarbon group and R.sup.b3 is a heterocyclic group are
referred to as "N-hydrocarbon-N-heterocyclic
ring-sulfinamoyl-sulfanyl group," and those groups in which
R.sup.a3 and R.sup.b3 combine to each other, together with the
nitrogen atom to which they bind, to form a cyclic amino group are
referred to as "cyclicamino-sulfanyl-sulfanyl group."
[0178] Among the groups represented by the formula (.omega.-17C),
those groups in which R.sup.a3 is a hydrocarbon group are referred
to as "hydrocarbon-oxy-sulfonyl-sulfanyl group," and those groups
in which R.sup.a3 is a heterocyclic group are referred to as
"heterocyclic ring-oxy-sulfonyl-sulfanyl group."
[0179] Among the groups represented by the formula (.omega.-18C),
those groups in which R.sup.a3 is a hydrocarbon group are referred
to as "hydrocarbon-oxy-sulfinyl-sulfanyl group," and those groups
in which R.sup.a3 is a heterocyclic group are referred to as
"heterocyclic ring-oxy-sulfinyl-sulfanyl group."
[0180] Among the groups represented by the formula (.omega.-19C),
those groups in which both R.sup.a3 and R.sup.b3 are hydrocarbon
groups are referred to as "O,O'-di(hydrocarbon)-phosphono-sulfanyl
group," those groups in which both R.sup.a3 and R.sup.b3 are
heterocyclic groups are referred to as "O,O'-di(heterocyclic
ring)-phosphono-sulfanyl group," and those groups in which R.sup.a3
is a hydrocarbon group and R.sup.b3 is a heterocyclic group are
referred to as "O-hydrocarbon-O'-heterocyclic
ring-phosphono-sulfanyl group."
[0181] Among the groups represented by the formula (.omega.-20C),
those groups in which R.sup.a3 is a hydrocarbon group are referred
to as "hydrocarbon-sulfonyl-sulfanyl group," and those groups in
which R.sup.a3 is a heterocyclic group are referred to as
"heterocyclic ring-sulfonyl-sulfanyl group."
[0182] Among the groups represented by the formula (.omega.-21C),
those groups in which R.sup.a3 is a hydrocarbon group are referred
to as "hydrocarbon-sulfinyl-sulfanyl group," and those groups in
which R.sup.a3 is a heterocyclic group are referred to as
"heterocyclic ring-sulfinyl-sulfanyl group."
[0183] Examples of the hydrocarbon in the groups represented by the
aforementioned formulas (.omega.-1C) through (.omega.-21C) include
similar groups to the aforementioned hydrocarbon group. Examples of
the hydrocarbon-carbonyl-sulfanyl group represented by the formula
(.omega.-1C) include, for example, an alkyl-carbonyl-sulfanyl
group, an alkenyl-carbonyl-sulfanyl group, an
alkynyl-carbonyl-sulfanyl group, a cycloalkyl-carbonyl-sulfanyl
group, a cycloalkenyl-carbonyl-sulfanyl group, a
cycloalkanedienyl-carbonyl-sulfanyl group, a
cycloalkyl-alkyl-carbonyl-sulfanyl group which are aliphatic
hydrocarbon-carbonyl-sulfanyl groups; an aryl-carbonyl-sulfanyl
group; an aralkyl-carbonyl-sulfanyl group; a bridged cyclic
hydrocarbon-carbonyl-sulfanyl group; a spiro cyclic
hydrocarbon-carbonyl-sulfanyl group; and a terpene family
hydrocarbon-carbonyl-sulfanyl group. In the following, groups
represented by the formulas (.omega.-2C) through (.omega.-21C) are
similar to those explained above.
[0184] Examples of the heterocyclic ring in the groups represented
by the aforementioned formulas (.omega.-C) through (.omega.-21C)
include similar groups to the aforementioned heterocyclic group.
Examples of the heterocyclic ring-carbonyl-sulfanyl group
represented by the formula (.omega.-1C) include, for example, a
monocyclic heteroaryl-carbonyl-sulfanyl group, a fused polycyclic
heteroaryl-carbonyl-sulfanyl group, a monocyclic non-aromatic
heterocyclic ring-carbonyl-sulfanyl group, and a fused polycyclic
non-aromatic heterocyclic ring-carbonyl-sulfanyl group. In the
following, groups represented by the formula (.omega.-2C) through
(.omega.-21C) are similar to those groups explained above.
[0185] Examples of the cyclic amino in the groups represented by
the aforementioned formulas (.omega.-10C) through (.omega.-16C)
include similar groups to the aforementioned cyclic amino
group.
[0186] The aforementioned acyl-sulfanyl group, hydrocarbon-sulfanyl
group, and heterocyclic-sulfanyl group are generically referred to
as "substituted sulfanyl group." Moreover, these substituted
sulfanyl group and sulfanyl group are generically referred to as
"sulfanyl group which may be substituted."
[0187] Examples of the N-hydrocarbon-amino group include the groups
in which one hydrogen atom of amino group is substituted with a
hydrocarbon group, and include, for example, an N-alkyl-amino
group, an N-alkenyl-amino group, an N-alkynyl-amino group, an
N-cycloalkyl-amino group, an N-cycloalkyl-alkyl-amino group, an
N-aryl-amino group, and an N-aralkyl-amino group.
[0188] Examples of the N-alkyl-amino group include, for example,
methylamino, ethylamino, n-propylamino, isopropylamino,
n-butylamino, isobutylamino, sec-butylamino, tert-butylamino,
n-pentylamino, isopentylamino, (2-methylbutyl)amino,
(1-methylbutyl)amino, neopentylamino, (1,2-dimethylpropyl)amino,
(1-ethylpropyl)amino, n-hexylamino, (4-methylpentyl)amino,
(3-methylpentyl)amino, (2-methylpentyl)amino,
(1-methylpentyl)amino, (3,3-dimethylbutyl)amino,
(2,2-dimethylbutyl)amino, (1,1-dimethylbutyl)amino,
(1,2-dimethylbutyl)amino, (1,3-dimethylbutyl)amino,
(2,3-dimethylbutyl)amino, (2-ethylbutyl)amino, (1-ethylbutyl)amino,
(1-ethyl-1-methylpropyl)amino, n-heptylamino, n-octylamino,
n-nonylamino, n-decylamino, n-undecylamino, n-dodecylamino,
n-tridecylamino, n-tetradecylamino, and n-pentadecylamino, which
are C.sub.1 to C.sub.15 straight chain or branched chain N-alkyl
amino groups.
[0189] Examples of the N-alkenyl-amino group include, for example,
vinyl amino, (prop-1-en-1-yl)amino, allylamino, isopropenylamino,
(but-1-en-1-yl)amino, (but-2-en-1-yl)amino, (but-3-en-1-yl)amino,
(2-methylprop-2-en-1-yl)amino, (1-methylprop-2-en-1-yl)amino,
(pent-1-en-1-yl)amino, (pent-2-en-1-yl)amino,
(pent-3-en-1-yl)amino, (pent-4-en-1-yl)amino,
(3-methylbut-2-en-1-yl)amino, (3-methylbut-3-en-1-yl)amino,
(hex-1-en-1-yl)amino, (hex-2-en-1-yl)amino, (hex-3-en-1-yl)amino,
(hex-4-en-1-yl)amino, (hex-5-en-1-yl)amino,
(4-methylpent-3-en-1-yl)amino, (4-methylpent-3-en-1-yl)amino,
(hept-1-en-1-yl)amino, (hept-6-en-1-yl)amino, (oct-1-en-1-yl)amino,
(oct-7-en-1-yl)amino, (non-1-en-1-yl)amino, (non-8-en-1-yl)amino,
(dec-1-en-1-yl)amino, (dec-9-en-1-yl)amino, (undec-1-en-1-yl)amino,
(undec-10-en-1-yl)amino, (dodec-1-en-1-yl)amino,
(dodec-11-en-1-yl)amino, (tridec-1-en-1-yl)amino,
(tridec-12-en-1-yl)amino, (tetradec-1-en-1-yl)amino,
(tetradec-13-en-1-yl)amino, (pentadec-1-en-1-yl)amino, and
(pentadec-14-en-1-yl)amino, which are C.sub.2 to C.sub.15 straight
chain or branched chain N-alkenyl amino groups.
[0190] Examples of the N-alkynyl-amino group include, for example,
ethynylamino, (prop-1-yn-1-yl)amino, (prop-2-yn-1-yl)amino,
(but-1-yn-1-yl)amino, (but-3-yn-1-yl)amino,
(1-methylprop-2-yn-1-yl)amino, (pent-1-yn-1-yl)amino,
(pent-4-yn-1-yl)amino, (hex-1-yn-1-yl)amino, (hex-5-yn-1-yl)amino,
(hept-1-yn-1-yl)amino, (hept-6-yn-1-yl)amino, (oct-1-yn-1-yl)amino,
(oct-7-yn-1-yl)amino, (non-1-yn-1-yl)amino, (non-8-yn-1-yl)amino,
(dec-1-yn-1-yl)amino, (dec-9-yn-1-yl)amino, (undec-1-yn-1-yl)amino,
(undec-10-yn-1-yl)amino, (dodec-1-yn-1-yl)amino,
(dodec-11-yn-1-yl)amino, (tridec-1-yn-1-yl)amino,
(tridec-12-yn-1-yl)amino, (tetradec-1-yn-1-yl)amino,
(tetradec-13-yn-1-yl)amino, (pentadec-1-yn-1-yl)amino, and
(pentadec-14-yn-1-yl)amino, which are C.sub.2 to C.sub.15 straight
chain or branched chain N-alkynyl-amino groups.
[0191] Examples of the N-cycloalkyl-amino group include, for
example, cyclopropylamino, cyclobutylamino, cyclopentylamino,
cyclohexylamino, cycloheptylamino, and cyclooctylamino, which are
C.sub.3 to C.sub.8 N-cycloalkyl-amino groups.
[0192] Examples of the N-cycloalkyl-alkyl-amino group include, for
example, (cyclopropylmethyl)amino, (1-cyclopropylethyl)amino,
(2-cyclopropylethyl)amino, (3-cyclopropylpropyl)amino,
(4-cyclopropylbutyl)amino, (5-cyclopropylpentyl)amino,
(6-cyclopropylhexyl)amino, (cyclobutylmethyl)amino,
(cyclopentylmethyl)amino, (cyclobutylmethyl)amino,
(cyclopentylmethyl)amino, (cyclohexylmethyl)amino,
(2-cyclohexylethyl)amino, (3-cyclohexylpropyl)amino,
(4-cyclohexylbutyl)amino, (cycloheptylmethyl)amino,
(cyclooctylmethyl)amino, and (6-cyclooctylhexyl)amino, which are
C.sub.4 to C.sub.14 N-cycloalkyl-alkyl-amino groups.
[0193] Examples of the N-aryl-amino group include, for example,
phenylamino, 1-naphthylamino, 2-naphtylamino, anthrylamino,
phenanthrylamino, and acenaphthylenylamino, which are C.sub.6 to
C.sub.14 N-mono-arylamino groups.
[0194] Examples of the N-aralkyl-amino group include, for example,
benzylamino, (1-naphthylmethyl)amino, (2-naphthylmethyl)amino,
(anthracenylmethyl)amino, (phenanthrenylmethyl)amino,
(acenaphthylenylmethyl)amino, (diphenylmethyl)amino,
(1-phenethyl)amino, (2-phenethyl)amino, (1-(1-naphthyl)ethyl)amino,
(1-(2-naphthyl)ethyl)amino, (2-(1-naphthyl)ethyl)amino,
(2-(2-naphthyl)ethyl)amino, (3-phenylpropyl)amino,
(3-(1-naphthyl)propyl)amino, (3-(2-naphthyl)propyl)amino,
(4-phenylbutyl)amino, (4-(1-naphthyl)butyl)amino,
(4-(2-naphthyl)butyl)amino, (5-phenylpentyl)amino,
(5-(1-naphthyl)pentyl)amino, (5-(2-naphthyl)pentyl)amino,
(6-phenylhexyl)amino, (6-(1-naphthyl)hexyl)amino, and
(6-(2-naphthyl)hexyl)amino, which are C.sub.7 to C.sub.16
N-aralkyl-amino groups.
[0195] Examples of the N,N-di(hydrocarbon)-amino group include the
groups in which two hydrogen atoms of amino group are substituted
with hydrocarbon groups, and include, for example,
N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino,
N,N-di-n-propylamino, N,N-diisopropylamino, N-allyl-N-methylamino,
N-(prop-2-yn-1-yl)-N-methylamino, N,N-dicyclohexylamino,
N-cyclohexyl-N-methylamino, N-cyclohexylmethylamino-N-methylamino,
N,N-diphenylamino, N-methyl-N-phenylamino, N,N-dibenzylamino, and
N-benzyl-N-methylamino.
[0196] Examples of the N-heterocyclic ring-amino group include the
groups in which one hydrogen atom of amino group is substituted
with a heterocyclic group, and include, for example,
(3-pyrrolizinyl)amino, (4-piperidinyl)amino,
(2-tetrahydropyranyl)amino, (3-indolinyl)amino, (4-chromanyl)amino,
(3-thienyl)amino, (3-pyridyl)amino, (3-quinolyl)amino, and
(5-indolyl)amino.
[0197] Examples of the N-hydrocarbon-N-heterocyclic ring-amino
group include the groups in which two hydrogen atoms of amino group
are substituted with hydrocarbon group and heterocyclic group
respectively, and include, for example,
N-methyl-N-(4-piperidinyl)amino, N-(4-chromanyl)-N-methylamino,
N-methyl-N-(3-thienyl)amino, N-methyl-N-(3-pyridyl)amino,
N-methyl-N-(3-quinolyl)amino.
[0198] Examples of the acyl-amino group include the groups in which
one hydrogen atom of the amino group is substituted with an acyl
group, and include, for example, formylamino group, glyoxyloylamino
group, thioformylamino group, carbamoylamino group,
thiocarbamoylamino group, sulfamoylamino group, sulfinamoylamino
group, carboxyamino group, sulphoamino group, phosphonoamino group,
and groups represented by the following formulas: ##STR17##
##STR18## wherein R.sup.a4 and R.sup.b4 may be the same or
different and represent a hydrocarbon group which may be
substituted or a heterocyclic group which may be substituted, or
R.sup.a4 and R.sup.b4 combine to each other, together with the
nitrogen atom to which they bind, to form a cyclic amino group
which may be substituted.
[0199] In the definition of the aforementioned acyl-amino group,
among the groups represented by the formula (.omega.-1D), those
groups in which R.sup.a4 is a hydrocarbon group are referred to as
"hydrocarbon-carbonyl-amino group," and those groups in which
R.sup.a4 is a heterocyclic group are referred to as "heterocyclic
ring-carbonyl-amino group."
[0200] Among the groups represented by the formula (.omega.-2D),
those groups in which R.sup.a4 is a hydrocarbon group are referred
to as "hydrocarbon-oxy-carbonyl-amino group," and those groups in
which R.sup.a4 is a heterocyclic group are referred to as
"heterocyclic ring-oxy-carbonyl-amino group."
[0201] Among the groups represented by the formula (.omega.-3D),
those groups in which R.sup.a4 is a hydrocarbon group are referred
to as "hydrocarbon-carbonyl-carbonyl-amino group," and those groups
in which R.sup.a4 is a heterocyclic group are referred to as
"heterocyclic ring-carbonyl-carbonyl-amino group."
[0202] Among the groups represented by the formula (.omega.-4D),
those groups in which R.sup.a4 is a hydrocarbon group are referred
to as "hydrocarbon-oxy-carbonyl-carbonyl-amino group," and those
groups in which R.sup.a4 is a heterocyclic group are referred to as
"heterocyclic ring-oxy-carbonyl-carbonyl-amino group."
[0203] Among the groups represented by the formula (.omega.-5D),
those groups in which R.sup.a4 is a hydrocarbon group are referred
to as "hydrocarbon-sulfanyl-carbonyl-amino group," and those groups
in which R.sup.a4 is a heterocyclic group are referred to as
"heterocyclic ring-sulfanyl-carbonyl-amino group."
[0204] Among the groups represented by the formula (.omega.-6D),
those groups in which R.sup.a4 is a hydrocarbon group are referred
to as "hydrocarbon-thiocarbonyl-amino group," and those groups in
which R.sup.a4 is a heterocyclic group are referred to as
"heterocyclic ring-thiocarbonyl-amino group."
[0205] Among the groups represented by the formula (.omega.-7D),
those groups in which R.sup.a4 is a hydrocarbon group are referred
to as "hydrocarbon-oxy-thiocarbonyl-amino group," and those groups
in which R.sup.a4 is a heterocyclic group are referred to as
"heterocyclic ring-oxy-thiocarbonyl-amino group."
[0206] Among the groups represented by the formula (.omega.-8D),
those groups in which R.sup.a4 is a hydrocarbon group are referred
to as "hydrocarbon-sulfanyl-thiocarbonyl-amino group," and those
groups in which R.sup.a4 is a heterocyclic group are referred to as
"heterocyclic ring-sulfanyl-thiocarbonyl-amino group."
[0207] Among the groups represented by the formula (.omega.-9D),
those groups in which R.sup.a4 is a hydrocarbon group are referred
to as "N-hydrocarbon-carbamoyl group," and those groups in which
R.sup.a4 is a heterocyclic group are referred to as "N-heterocyclic
ring-carbamoyl-amino group."
[0208] Among the groups represented by the formula (.omega.-10D),
those groups in which both R.sup.a4 and R.sup.b4 are hydrocarbon
groups are referred to as "N,N-di(hydrocarbon)-carbamoyl-amino
group," those groups in which both R.sup.a4 and R.sup.b4 are
heterocyclic groups are referred to as "N,N-di(heterocyclic
ring)-carbamoyl-amino group," those groups in which R.sup.a4 is a
hydrocarbon group and R.sup.b4 is a heterocyclic group are referred
to as "N-hydrocarbon-N-heterocyclic ring-carbamoyl-amino group,"
and those groups in which R.sup.a4 and R.sup.b4 combine to each
other, together with the nitrogen atom to which they bind, to form
a cyclic amino group are referred to as "cyclic
amino-carbonyl-amino group."
[0209] Among the groups represented by the formula (.omega.-11D),
those groups in which R.sup.a4 is a hydrocarbon group are referred
to as "N-hydrocarbon-thiocarbamoyl-amino group," and those groups
in which R.sup.a4 is a heterocyclic ring group are referred to as
"N-heterocyclic-thiocarbamoyl-amino group."
[0210] Among the groups represented by the formula (.omega.-12D),
those groups in which both R.sup.a4 and R.sup.b4 are hydrocarbon
groups are referred to as "N,N-di(hydrocarbon)-thiocarbamoyl-amino
group," those groups in which both R.sup.a4 and R.sup.b4 are
heterocyclic groups are referred to as "N,N-di(heterocyclic
ring)-thiocarbamoyl-amino group," those groups in which R.sup.a4 is
a hydrocarbon group and R.sup.b4 is a heterocyclic group are
referred to as "N-hydrocarbon-N-heterocyclic
ring-thiocarbamoyl-amino group," and those groups in which R.sup.a4
and R.sup.b4 combine to each other, together with the nitrogen atom
to which they bind, to form a cyclic amino group are referred to as
"cyclic amino-thiocarbonyl-amino group."
[0211] Among the groups represented by the formula (.omega.-13D),
those groups in which R.sup.a4 is a hydrocarbon group are referred
to as "N-hydrocarbon-sulfamoyl-amino group," and those groups in
which R.sup.a4 is a heterocyclic group are referred to as
"N-heterocyclic ring-sulfamoyl-amino group."
[0212] Among the groups represented by the formula (.omega.-14D),
those groups in which both R.sup.a4 and R.sup.b4 are hydrocarbon
groups are referred to as "di(hydrocarbon)-sulfamoyl-amino group,"
those groups in which both R.sup.a4 and R.sup.b4 are heterocyclic
groups are referred to as "N,N-di(heterocyclic
ring)-sulfamoyl-amino group," those groups in which R.sup.a4 is a
hydrocarbon group and R.sup.b4 is a heterocyclic group are referred
to as "N-hydrocarbon-N-heterocyclic ring-sulfamoyl-amino group,"
and those groups in which R.sup.a4 and R.sup.b4 combine to each
other, together with the nitrogen atom to which they bind, to form
a cyclic amino group are referred to as "cyclic
amino-sulfonyl-amino group."
[0213] Among the groups represented by the formula (.omega.-15D),
those groups in which R.sup.a4 is a hydrocarbon group are referred
to as "N-hydrocarbon-sulfinamoyl-amino group," and those groups in
which R.sup.a4 is a heterocyclic group are referred to as
"N-heterocyclic ring-sulfinamoyl-amino group."
[0214] Among the groups represented by the formula (.omega.-16D),
those groups in which both R.sup.a4 and R.sup.b4 are hydrocarbon
groups are referred to as "N,N-di(hydrocarbon)-sulfinamoyl-amino
group," those groups in which both R.sup.a4 and R.sup.b4 are
heterocyclic groups are referred to as "N,N-di(heterocyclic
ring)-sulfinamoyl-amino group," groups in which R.sup.a4 is a
hydrocarbon group and R.sup.b4 is a heterocyclic group are referred
to as "N-hydrocarbon-N-heterocyclic ring-sulfinamoyl-amino group,"
and those groups in which R.sup.a4 and R.sup.b4 combine to each
other, together with the nitrogen atom to which they bind, to form
a cyclic amino group are referred to as "cyclic
amino-sulfinyl-amino group."
[0215] Among the groups represented by the formula (.omega.-17D),
those groups in which R.sup.a4 is a hydrocarbon group are referred
to as "hydrocarbon-oxy-sulfonyl-amino group," and those groups in
which R.sup.a4 is a heterocyclic group are referred to as
"heterocyclic ring-oxy-sulfonyl-amino group."
[0216] Among the groups represented by the formula (.omega.-18D),
those groups in which R.sup.a4 is a hydrocarbon group are referred
to as "hydrocarbon-oxy-sulfinyl-amino group," and those groups in
which R.sup.a4 is a heterocyclic group are referred to as
"heterocyclic ring-oxy-sulfinyl-amino group."
[0217] Among the groups represented by the formula (.omega.-19D),
those groups in which both R.sup.a4 and R.sup.b4 are hydrocarbon
groups are referred to as "O,O'-di(hydrocarbon)-phosphono-amino
group," those groups in which both R.sup.a4 and R.sup.b4 are
heterocyclic groups are referred to as "O,O'-di(heterocyclic
ring)-phosphono-amino group," and those groups in which R.sup.a4 is
a hydrocarbon group and R.sup.b4 is a heterocyclic group are
referred to as "O-hydrocarbon-O'-heterocyclic ring-phosphono-amino
group."
[0218] Among the groups represented by the formula (.omega.-20D),
those groups in which R.sup.a4 is a hydrocarbon group are referred
to as "hydrocarbon-sulfonyl-amino group," and those groups in which
R.sup.a4 is a heterocyclic group are referred to as "heterocyclic
ring-sulfonyl-amino group."
[0219] Among the groups represented by the formula (.omega.-21D),
those groups in which R.sup.a4 is a hydrocarbon group are referred
to as "hydrocarbon-sulfinyl-amino group," and those groups in which
R.sup.a4 is a heterocyclic group are referred to as "heterocyclic
ring-sulfinyl-amino group."
[0220] Examples of the hydrocarbon in the groups represented by the
aforementioned formulas (.omega.-1D) through (.omega.-21D) include
the similar groups to the aforementioned hydrocarbon group.
Examples of the hydrocarbon-carbonyl-amino groups represented by
the formula (.omega.-1D) include, for example, an
alkyl-carbonyl-amino group, an alkenyl-carbonyl-amino group, an
alkynyl-carbonyl-amino group, a cycloalkyl-carbonyl-amino group, a
cycloalkenyl-carbonyl-amino group, a
cycloalkanedienyl-carbonyl-amino group, a
cycloalkyl-alkyl-carbonyl-amino group which are aliphatic
hydrocarbon-carbonyl-amino groups; an aryl-carbonyl-amino group; an
aralkyl-carbonyl-amino group; a bridged cyclic
hydrocarbon-carbonyl-amino group; a spiro cyclic
hydrocarbon-carbonyl-amino group; and a terpene family
hydrocarbon-carbonyl-amino group. In the following, groups
represented by the formulas (.omega.-2D) through (.omega.-21D) are
similar to those explained above.
[0221] Examples of the heterocyclic ring in the groups represented
by the aforementioned formulas (.omega.-2D) through (.omega.-21D)
include similar groups to the aforementioned heterocyclic group.
Examples of the heterocyclic ring-carbonyl-amino group represented
by the formula (.omega.-1D) include, for example, a monocyclic
heteroaryl-carbonyl-amino group, a fused polycyclic
heteroaryl-carbonyl-amino group, a monocyclic non-aromatic
heterocyclic-carbonyl-amino group, and a fused polycyclic
non-aromatic heterocyclic-carbonyl-amino group. In the following,
groups represented by the formulas (.omega.-2D) through
(.omega.-21D) are similar to those groups explained above.
[0222] Examples of the cyclic amino in the groups represented by
the aforementioned formulas (.omega.-10D) through (.omega.-16D)
include similar groups to the aforementioned cyclic amino
group.
[0223] Examples of the di(acyl)-amino group include the groups in
which two hydrogen atoms of amino group are substituted with acyl
groups in the definitions of the aforementioned substitutents
according to "which may be substituted." Examples include, for
example, di(formyl)-amino group, di(glyoxyloyl)-amino group,
di(thioformyl)-amino group, di(carbamoyl)-amino group,
di(thiocarbamoyl)-amino group, di(sulfamoyl)-amino group,
di(sulfinamoyl)-amino group, di(carboxy)-amino group,
di(sulfo)-amino group, di(phosphono)-amino group, and groups
represented by the following formulas ##STR19## ##STR20## wherein
R.sup.a5 and R.sup.b5 may be the same or different and represent
hydrogen atom, a hydrocarbon group which may be substituted or a
heterocyclic group which may be substituted, or R.sup.a5 and
R.sup.b5 combine to each other, together with the nitrogen atom to
which they bind, to form a cyclic amino group which may be
substituted.
[0224] In the definition of aforementioned di(acyl)-amino group,
among the groups represented by the formula (.omega.-1E), those
groups in which R.sup.a5 is a hydrocarbon group are referred to as
"bis(hydrocarbon-carbonyl)-amino group," and those groups in which
R.sup.a5 is a heterocyclic group are referred to as
"bis(heterocyclic ring-carbonyl)-amino group.
[0225] Among the groups represented by the formula (.omega.-2E),
those groups in which R.sup.a5 is a hydrocarbon group are referred
to as "bis(hydrocarbon-oxy-carbonyl)-amino group," and those groups
in which R.sup.a5 is a heterocyclic group are referred to as
"bis(heterocyclic ring-oxy-carbonyl)-amino group."
[0226] Among the groups represented by the formula (.omega.-3E),
those groups in which R.sup.a5 is a hydrocarbon group are referred
to as "bis(hydrocarbon-carbonyl-carbonyl)-amino group," and those
groups in which R.sup.a5 is a heterocyclic group are referred to as
"bis(heterocyclic ring-carbonyl-carbonyl)-amino group."
[0227] Among the groups represented by the formula (.omega.-4E),
those groups in which R.sup.a5 is a hydrocarbon group are referred
to as "bis(hydrocarbon-oxy-carbonyl-carbonyl)-amino group," and
those groups in which R.sup.a5 is a heterocyclic group are referred
to as "bis(heterocyclic ring-oxy-carbonyl-carbonyl)-amino
group."
[0228] Among the groups represented by the formula (.omega.-5E),
those groups in which R.sup.a5 is a hydrocarbon group are referred
to as "bis(hydrocarbon-sulfanyl-carbonyl)-amino group," and those
groups in which R.sup.a5 is a heterocyclic group are referred to as
"bis(heterocyclic ring-sulfanyl-carbonyl)-amino group."
[0229] Among the groups represented by the formula (.omega.-6E),
those groups in which R.sup.a5 is a hydrocarbon group are referred
to as "bis(hydrocarbon-thiocarbonyl)-amino group," and those groups
in which R.sup.a5 is a heterocyclic group are referred to as
"bis(heterocyclic ring-thiocarbonyl)-amino group."
[0230] Among the groups represented by the formula (.omega.-7E),
those groups in which R.sup.a5 is a hydrocarbon group are referred
to as "bis(hydrocarbon-oxy-thiocarbonyl)-amino group," and those
groups in which R.sup.a5 is a heterocyclic group are referred to as
"bis(heterocyclic ring-oxy-thiocarbonyl)-amino group."
[0231] Among the groups represented by the formula (.omega.-8E),
those groups in which R.sup.a5 is a hydrocarbon group are referred
to as "bis(hydrocarbon-sulfanyl-thiocarbonyl)-amino group," and
those groups in which R.sup.a5 is a heterocyclic group are referred
to as "bis(heterocyclic ring-sulfanyl-thiocarbonyl)-amino
group."
[0232] Among the groups represented by the formula (.omega.-9E),
those groups in which R.sup.a5 is a hydrocarbon group are referred
to as "bis(N-hydrocarbon-carbamoyl)-amino group," and those groups
in which R.sup.a5 is a heterocyclic group are referred to as
"bis(N-heterocyclic ring-carbamoyl)-amino group."
[0233] Among the groups represented by the formula (.omega.-1E),
those groups in which both R.sup.a5 and R.sup.b5 are hydrocarbon
groups are referred to as "bis[N,N-di(hydrocarbon)-carbamoyl]-amino
group," those groups in which both R.sup.a5 and R.sup.b5 are
heterocyclic groups are referred to as "bis[N,N-di(heterocyclic
ring)-carbamoyl]-amino group," groups in which R.sup.a5 is a
hydrocarbon group and R.sup.b5 is a heterocyclic group are referred
to as "bis(N-hydrocarbon-N-heterocyclic ring-carbamoyl)-amino
group," and those groups in which R.sup.a5 and R.sup.b5 combine to
each other, together with the nitrogen atom to which they bind, to
form a cyclic amino groups are referred to as "bis(cyclic
amino-carbonyl)amino group."
[0234] Among the groups represented by the formula (.omega.-11E),
those groups in which R.sup.a5 is a hydrocarbon group are referred
to as "bis(N-hydrocarbon-thiocarbamoyl)-amino group," and those
groups in which R.sup.a5 is a heterocyclic group are referred to as
"bis(N-heterocyclic ring-thiocarbamoyl)-amino group.
[0235] Among the groups represented by the formula (.omega.-12E),
those groups in which both R.sup.a5 and R.sup.b5 are hydrocarbon
groups are referred to as
"bis[N,N-di(hydrocarbon)-thiocarbamoyl]-amino group," those groups
in which both R.sup.a5 and R.sup.b5 are heterocyclic groups are
referred to as "bis[N,N-di(heterocyclic ring)-thiocarbamoyl]-amino
group," those groups in which R.sup.a5is a hydrocarbon group and
R.sup.b5 is a heterocyclic group are referred to as
"bis(N-hydrocarbon-N-heterocyclic ring-thiocarbamoyl)-amino group,"
and those groups in which R.sup.a5 and R.sup.b5 combine to each
other, together with the nitrogen atom to which they bind, to form
a cyclic amino group are referred to as "bis(cyclic
amino-thiocarbonyl)-amino group."
[0236] Among the groups represented by the formula (.omega.-13E),
those groups in which R.sup.a5 is a hydrocarbon group are referred
to as "bis(N-hydrocarbon-sulfamoyl)-amino group," and those groups
in which R.sup.a5 is a heterocyclic group are referred to as
"bis(N-heterocyclic ring-sulfamoyl)-amino group."
[0237] Among the groups represented by the formula (.omega.-14E),
those groups in which both R.sup.a5 and R.sup.b5 are hydrocarbon
groups are referred to as "bis[N,N-di(hydrocarbon)-sulfamoyl]-amino
group," those groups in which both R.sup.a5 and R.sup.b5 are
heterocyclic groups are referred to as "bis[N,N-di(heterocyclic
ring)-sulfamoyl]-amino group," those groups in which R.sup.a5 is a
hydrocarbon group and R.sup.b5 is a heterocyclic group are referred
to as "bis(N-hydrocarbon-N-heterocyclic ring-sulfamoyl)-amino
group," and those groups in which R.sup.a5 and R.sup.b5 combine to
each other, together with the nitrogen atom to which they bind, to
form a cyclic amino group are referred to as "bis(cyclic
amino-sulfonyl)amino group."
[0238] Among the groups represented by the formula (.omega.-15E),
those groups in which R.sup.a5 is a hydrocarbon group are referred
to as "bis(N-hydrocarbon-sulfinamoyl)-amino group," and those
groups in which R.sup.a5 is a heterocyclic group are referred to as
"bis(N-heterocyclic ring-sulfinamoyl)-amino group."
[0239] Among the groups represented by the formula (.omega.-16E),
those groups in which R.sup.a5 and R.sup.b5 are hydrocarbon groups
are referred to as "bis[N,N-di(hydrocarbon)-sulfinamoyl]-amino
group," those groups in which R.sup.a5 and R.sup.b5 are
heterocyclic groups are referred to as "bis[N,N-di(heterocyclic
ring)-sulfinamoyl]-amino group," those groups in which R.sup.a5 is
a hydrocarbon group and R.sup.b5 is a heterocyclic group are
referred to as "bis(N-hydrocarbon-N-heterocyclic
ring-sulfinamoyl)-amino group," and those groups in which R.sup.a5
and R.sup.b5 combine to each other, together with the nitrogen atom
to which they bind, to form a cyclic amino group are referred to as
"bis(cyclic amino-sulfinyl)amino group."
[0240] Among the groups represented by the formula (.omega.-17E),
those groups in which R.sup.a5 is a hydrocarbon group are referred
to as "bis(hydrocarbon-oxy-sulfonyl)-amino group," and those groups
in which R.sup.a5 is a heterocyclic group are referred to as
"bis(heterocyclic ring-oxy-sulfonyl)-amino group."
[0241] Among the groups represented by the formula (.omega.-18E),
those groups in which R.sup.a5 is a hydrocarbon group are referred
to as "bis(hydrocarbon-oxy-sulfinyl)-amino group," and those groups
in which R.sup.a5 is a heterocyclic group are referred to as
"bis(heterocyclic ring-oxy-sulfinyl)-amino group."
[0242] Among the groups represented by the formula (.omega.-19E),
those groups in which both R.sup.a5 and R.sup.b5 are hydrocarbon
groups are referred to as
"bis[O,O'-di(hydrocarbon)-phosphono]-amino group," those groups in
which both R.sup.a5 and R.sup.b5 are heterocyclic groups are
referred to as "bis[O,O'-di(heterocyclic ring)-phosphono]-amino
group," and those groups in which R.sup.a5 is a hydrocarbon group
and R.sup.b5 is a heterocyclic group are referred to as
"bis(O-hydrocarbon-O'-heterocyclic ring-phosphono)-amino
group."
[0243] Among the groups represented by the formula (.omega.-20E),
those groups in which R.sup.a5 is a hydrocarbon group are referred
to as "bis(hydrocarbon-sulfonyl)-amino group," and those groups in
which R.sup.a5 is a heterocyclic group are referred to as
"bis(heterocyclic ring-sulfonyl)-amino group."
[0244] Among the groups represented by the formula (.omega.-21E),
those groups in which R.sup.a5 is a hydrocarbon group are referred
to as "bis(hydrocarbon-sulfinyl)-amino group," and those groups in
which R.sup.a5 is a heterocyclic group are referred to as
"bis(heterocyclic ring-sulfinyl)-amino group."
[0245] Examples of the hydrocarbon in the groups represented by the
aforementioned formulas (.omega.-1E) through (.omega.-21E) include
the similar groups to the aforementioned hydrocarbon group.
Examples of the bis(hydrocarbon-carbonyl)-amino groups represented
by the formula (.omega.-1E) include, for example, a
bis(alkyl-carbonyl)-amino group, a bis(alkenyl-carbonyl)-amino
group, a bis(alkynyl-carbonyl)-amino group, a
bis(cycloalkyl-carbonyl)-amino group, a
bis(cycloalkenyl-carbonyl)-amino group, a
bis(cycloalkanedienyl-carbonyl)-amino group, a
bis(cycloalkyl-alkyl-carbonyl)-amino group which are bis(aliphatic
hydrocarbon-carbonyl)-amino groups; a bis(aryl-carbonyl)-amino
group; a bis(aralkyl-carbonyl)-amino group; a bis(bridged cyclic
hydrocarbon-carbonyl)-amino group; a bis(spiro cyclic
hydrocarbon-carbonyl)-amino group; and a bis(terpene family
hydrocarbon-carbonyl)-amino group. In the following, groups
represented by the formulas (.omega.-2E) through (.omega.-21E) are
similar to those explained above.
[0246] Examples of the heterocyclic ring in the groups represented
by the aforementioned formulas (.omega.-1E) through (.omega.-21E)
include similar groups to the aforementioned heterocyclic group.
Examples of the bis(heterocyclic ring-carbonyl)-amino group
represented by the formula (.omega.-1E) include, for example, a
bis(monocyclic heteroaryl-carbonyl)-amino group, a bis(fused
polycyclic heteroaryl-carbonyl)-amino group, a bis(monocyclic
non-aromatic heterocyclic-carbonyl)-amino group, and a bis(fused
polycyclic non-aromatic heterocyclic-carbonyl)-amino group. In the
following, groups represented by the formulas (.omega.-2E) through
(.omega.-21E) are similar to those groups explained above.
[0247] Examples of the cyclic amino in the groups represented by
the aforementioned formulas (.omega.-10E) through (.omega.-16E)
include similar groups to the aforementioned cyclic amino
group.
[0248] The aforementioned acyl-amino group and di(acyl)-amino group
are generically referred to as "acyl substituted amino group."
Furthermore, the aforementioned N-hydrocarbon-amino group,
N,N-di(hydrocarbon)-amino group, N-heterocyclic-amino group,
N-hydrocarbon-N-heterocyclic-amino group, cyclic amino group,
acyl-amino group, and di(acyl)-amino group are generically referred
to as "substituted amino group."
[0249] In the following, compounds represented by the
aforementioned general formula (I) are explained in details.
[0250] "Connecting group whose number of atoms of main chain is 2
to 5" in the definition of X means connecting groups wherein 2 to 5
atoms in a main chain link together between rings Z and E. The
aforementioned "number of atoms of the main chain" is counted so as
to minimize the number of connecting atoms existing between the
rings Z and E, regardless of the presence or absence of hetero
atom(s). For example, the number of atoms of 1,2-cyclopentylene is
counted as 2, the number of atoms of 1,3-cyclopentylene is counted
as 3, the number of atoms of 1,4-phenylene is counted as 4, and the
number of atoms of 2,6-pyridine-diyl is counted as 3.
[0251] The aforementioned "connecting group whose number of atoms
of main chain is 2 to 5" is formed by one functional group selected
from the following group of divalent group .zeta.-1, or formed by
combining 2 to 4 functional groups of 1 to 4 kinds selected from
the following divalent group .zeta.-2. [Divalent group .zeta.-1]
the following formulas: ##STR21## [Divalent group .zeta.-2] the
following formulas: ##STR22## When 2 or more divalent groups
combine, each group may be the same or different.
[0252] The aforementioned "connecting group wherein the number of
atoms of the main chain is 2 to 5," is preferably a group selected
from the following "connecting group .alpha.." [Connecting group
.alpha.] the following formulas: ##STR23## wherein a bond at the
left end binds to ring Z and a bond at the right end binds to
E.
[0253] The group represented by the following formula is most
preferred: ##STR24## wherein the bond at the left end binds to ring
Z and the bond at the right end binds to E.
[0254] Examples of the substitutent, according to "connecting group
which may be substituted" in the definition of "a connecting group
whose number of atoms of the main chain is 2 to 5," include similar
groups to the substitutents in the definition of the aforementioned
"which may be substituted." A C.sub.1 to C.sub.6 alkyl group is
preferred, and a methyl group is more preferred. The substitutent
may combine with a substitutent of the ring E or Z, together with
atoms to which they bind, to form a cyclic group which may be
substituted. Examples include the compounds represented by the
general formula (I) being those represented by the following
formulas: ##STR25##
[0255] In the aforementioned general formula (I), examples of A
include hydrogen atom or acetyl group, and hydrogen atom is
preferred.
[0256] Examples of the "arene" in "an arene which may have one or
more substitutents in addition to the group represented by formula
--O-A wherein A has the same meaning as that defined above and the
group represented by formula --X-E wherein each of X and E has the
same meaning as that defined above" in the definition of ring Z
include a monocyclic or fused heterocyclic aromatic hydrocarbon,
and include, for example, benzene ring, naphthalene ring,
anthracene ring, phenanthrene ring, and acenaphylene ring. C.sub.6
to C.sub.10 arenes such as benzene ring, naphthalene ring and the
like are preferred, benzene ring and naphthalene ring are more
preferred, and benzene ring is most preferred.
[0257] Examples of the substitutent in the definition of "an arene
which may have one or more substitutents in addition to the group
represented by formula --O-A wherein A has the same meaning as that
defined above and the group represented by formula --X-E wherein
each of X and E has the same meaning as that defined above" in the
aforementioned definition of ring Z include similar groups to the
substitutent explained for the definition "which may be
substituted." The position of substitutents existing on the arene
is not particularly limited, and when two or more substitutents
exist, they may be the same or different.
[0258] When "an arene which may have one or more substitutents in
addition to the group represented by formula --O-A wherein A has
the same meaning as that defined above and the group represented by
formula --X-E wherein each of X and E has the same meaning as that
defined above" in the aforementioned definition of ring Z is "a
benzene ring which may have one or more substitutents in addition
to the group represented by formula --O-A wherein A has the same
meaning as that defined above and the group represented by formula
--X-E wherein each of X and E has the same meaning as that defined
above," "a benzene ring which has one to three substitutents in
addition to the group represented by formula --O-A wherein A has
the same meaning as that defined above and the group represented by
formula --X-E wherein each of X and E has the same meaning as that
defined above" is preferred, and "a benzene ring which has one,
substitutent in addition to the group represented by formula --O-A
wherein A has the same meaning as that defined above and the group
represented by formula --X-E wherein each of X and E has the same
meaning as that defined above" is more preferred. Preferred
examples of said substitutents include groups selected from the
following Substituent Group .gamma.-1z. Halogen atom and tert-butyl
group [(1,1-dimethyl)ethyl group] are more preferred, and halogen
atom is most preferred.
[0259] [Substituent Group .gamma.-1z] halogen atom, nitro group,
cyano group, hydroxy group, methoxy group, methyl group, isopropyl
group, tert-butyl group, 1,1,3,3-tetramethylbutyl group,
2-phenylethen-1-yl group, 2,2-dicyanoethen-1-yl group,
2-cyano-2-(methoxycarbonyl)ethen-1-yl group,
2-carboxy-2-cyanoethen-1-yl group, ethynyl group, phenylethynyl
group, (trimethylsilyl)ethynyl group, trifluoromethyl group,
pentafluoroethyl group, phenyl group, 4-(trifluoromethyl)phenyl
group, 4-fluorophenyl group, 2,4-difluorophenyl group, 2-phenethyl
group, 1-hydroxyethyl group, 1-(methoxyimino)ethyl group,
1-[(benzyloxy)imino]ethyl group, 2-thienyl group [thiophen-2-yl
group], 3-thienyl group [thiophen-3-yl group], 1-pyrrolyl group
[pyrrol-1-yl group], 2-methylthiazol-4-yl group,
imidazo[1,2-a]pyridin-2-yl group, 2-pyridyl group [pyridin-2-yl
group], acetyl group, isobutyryl group, piperidinocarbonyl group,
4-benzylpiperidinocarbonyl group, (pyrrol-1-yl)sulfonyl group,
carboxy group, methoxycarbonyl group,
N-[3,5-bis(trifluoromethyl)phenyl]carbamoyl group,
N,N-dimethylcarbamoyl group, sulfamoyl group,
N-[3,5-bis(trifluoromethyl)phenyl]sulfamoyl group,
N,N-dimethylsulfamoyl group, amino group, N,N-dimethylamino group,
acetylamino group, benzoylamino group, methanesulfonylamino group,
benzenesulfonylamino group, 3-phenylureido group,
(3-phenyl)thioureido group, (4-nitrophenyl)diazenyl group, and
{[4-(pyridin-2-yl)sulfamoyl]phenyl}diazenyl group
[0260] When "an arene which may have one or more substitutents in
addition to the group represented by formula --O-A wherein A has
the same meaning as that defined above and the group represented by
formula --X-E wherein each of X and E has the same meaning as that
defined above" in the aforementioned definition of ring Z is "a
benzene ring which may have one or more substitutents in addition
to the group represented by formula --O-A wherein A has the same
meaning as that defined above and the group represented by formula
--X-E wherein each of X and E has the same meaning as that defined
above," it is most preferable that one substitutent exists and
locates on the position of R.sup.z when the following partial
formula (Iz-1) in the general formula containing ring Z ##STR26##
is represented by the following formula (Iz-2). ##STR27## At this
time, said substitutents can be defined as R.sup.z. Preferred
examples of R.sup.z include a group selected from the following
Substituent Group .gamma.-2z. Halogen atom and tert-butyl group are
more preferred, and halogen atom is most preferred. [Substituent
Group .gamma.-2z] halogen atom, nitro group, cyano group, methoxy
group, methyl group, isopropyl group, tert-butyl group,
1,1,3,3-tetramethylbutyl group, 2-phenylethen-1-yl group,
2,2-dicyanoethen-1-yl group, 2-cyano-2-(methoxycarbonyl)ethen-1-yl
group, 2-carboxy-2-cyanoethen-1-yl group, ethynyl group,
phenylethynyl group, (trimethylsilyl)ethynyl group, trifluoromethyl
group, pentafluoroethyl group, phenyl group,
4-(trifluoromethyl)phenyl group, 4-fluorophenyl group,
2,4-difluorophenyl group, 2-phenethyl group, 1-hydroxyethyl group,
1-(methoxyimino)ethyl group, 1-[(benzyloxy)imino]ethyl group,
2-thienyl group, 3-thienyl group, 1-pyrrolyl group,
2-methylthiazol-4-yl group, imidazo[1,2-a]pyridin-2-yl group,
2-pyridyl group, acetyl group, isobutyryl group, piperidinocarbonyl
group, 4-benzylpiperidinocarbonyl group, (pyrrol-1-yl)sulfonyl
group, carboxy group, methoxycarbonyl group,
N-[3,5-bis(trifluoromethyl)phenyl]carbamoyl group,
N,N-dimethylcarbamoyl group, sulfamoyl group,
N-[3,5-bis(trifluoromethyl)phenyl]sulfamoyl group,
N,N-dimethylsulfamoyl group, amino group, N,N-dimethylamino group,
acetylamino group, benzoylamino group, methanesulfonylamino group,
benzenesulfonylamino group, 3-phenylureido group,
(3-phenyl)thioureido group, (4-nitrophenyl)diazenyl group, and
{[4-(pyridin-2-yl)sulfamoyl]phenyl}diazenyl group
[0261] When "an arene which may have one or more substitutents in
addition to the group represented by formula --O-A wherein A has
the same meaning as that defined above and the group represented by
formula --X-E wherein each of X and E has the same meaning as that
defined above" in the aforementioned definition of ring Z is "a
naphthalene ring which may have one or more substitutents in
addition to the group represented by formula --O-A wherein Ahas the
same meaning as that defined above and the group represented by
formula --X-E wherein each of X and E has the same meaning as that
defined above," naphthalene ring is preferred.
[0262] Examples of the "hetero arene" in "a hetero arene which may
have one or more substitutents in addition to the group represented
by formula --O-A wherein A has the same meaning as that defined
above and the group represented by formula --X-E wherein each of X
and E has the same meaning as that defined above" in the
aforementioned definition of ring Z include a monocyclic or a fused
polycyclic aromatic heterocyclic rings containing at least one of 1
to 3 kinds of heteroatoms selected from oxygen atom, sulfur atom
and nitrogen atom and the like as ring-constituting atoms (ring
forming atoms), and include, for example, furan ring, thiophene
ring, pyrrole ring, oxazole ring, isoxazole ring, thiazole ring,
isothiazole ring, imidazole ring, pyrazole ring, 1,2,3-oxadiazole
ring, 1,2,3-thiadiazole ring, 1,2,3-triazole ring, pyridine ring,
pyridazine ring, pyrimidine ring, pyrazine ring, 1,2,3-triazine
ring, 1,2,4-triazine ring, 1H-azepine ring, 1,4-oxepine ring,
1,4-thiazepine ring, benzofuran ring, isobenzofuran ring,
benzo[b]thiophene ring, benzo[c]thiophene ring, indole ring,
2H-isoindole ring, 1H-indazole ring, 2H-indazole ring, benzoxazole
ring, 1,2-benzisoxazole ring, 2,1-benzisoxazole ring, benzothiazole
ring, 1,2-benzisothiazole ring, 2,1-benzisothiazole ring,
1,2,3-benzoxadiazol ring, 2,1,3-benzoxadiazol ring,
1,2,3-benzothiadiazole ring, 2,1,3-benzothiadiazole ring,
1H-benzotriazole ring, 2H-benzotriazole ring, quinoline ring,
isoquinoline ring, cinnoline ring, quinazoline ring, quinoxaline
ring, phthalazine ring, naphthyridine ring, 1H-1,5-benzodiazepine
ring, carbazole ring, .alpha.-carboline ring, .beta.-carboline
ring, .gamma.-carboline ring, acridine ring, phenoxazine ring,
phenothiazine ring, phenazine ring, phenanthridine ring,
phenanthroline ring, thianthrene ring, indolizine ring, and
phenoxathiine ring, which are 5 to 14-membered monocyclic or fused
polycyclic aromatic heterocyclic rings. 5 to 13-membered monocyclic
or fused polycyclic aromatic heterocyclic rings are preferred, and
thiophene ring, pyridine ring, indole ring, quinoxaline ring, and
carbazole ring are more preferred.
[0263] Examples of the substitutent in the definition of "a hetero
arene which may have one or more substitutents in addition to the
group represented by formula --O-A wherein A has the same meaning
as that defined above and the group represented by formula --X-E
wherein each of X and E has the same meaning as that defined above"
in the aforementioned definition of ring Z include similar groups
to the substitutent explained for the aforementioned definition
"which may be substituted." The position of substitutents existing
on the hetero arene is not particularly limited, and when two or
more substitutents exist, they may be the same or different.
[0264] Halogen atoms are preferred as the substitutent in the
definition of "a hetero arene which may have one or more
substitutents in addition to the group represented by formula --O-A
wherein A has the same meaning as that defined above and the group
represented by formula --X-E wherein each of X and E has the same
meaning as that defined above" in the aforementioned definition of
ring Z.
[0265] Examples of the aryl group of "an aryl group which may be
substituted" in the definition of E include similar groups to the
aryl group in the definition of the aforementioned "hydrocarbon
group," and C.sub.6 to C.sub.10 aryl groups such as phenyl group,
1-naphthyl group, 2-naphthyl group and the like are preferred, and
phenyl group is most preferred.
[0266] Examples of the substitutent in the definition of "an aryl
group which may be substituted" in the definition of E include
similar groups to the substitutent explained for the definition
"which may be substituted." The position of substitutents existing
on the aryl group is not particularly limited, and when two or more
substitutents exist, they may be the same or different.
[0267] When "an aryl group which may be substituted" in the
aforementioned definition of E is "a phenyl group which may be
substituted," "a mono-substituted phenyl group," "a di-substituted
phenyl group," and "a phenyl group which has three or more
substitutents" are preferred, and "a di-substituted phenyl group"
is more preferred.
[0268] When "an aryl group which may be substituted" in the
aforementioned definition of E is "a di-substituted phenyl group,"
preferred examples of the group include groups represented by the
following Substituent Group .delta.-1e.
[0269] [Substituent Group .delta.-1e]
3,5-bis(trifluoromethyl)phenyl group, 3,4-propylenedioxyphenyl
group, 3,5-dichlorophenyl group, 2,4-dihydroxyphenyl group,
2,5-dimethoxyphenyl group, 2-chloro-5-(trifluoromethyl)phenyl
group, 3,5-bis[(1,1-dimethyl)ethyl]phenyl group,
2,5-bis(trifluoromethyl)phenyl group,
4-chloro-2-(trifluoromethyl)phenyl group,
2-fluoro-3-(trifluoromethyl)phenyl group,
4-fluoro-3-(trifluoromethyl)phenyl group,
4-chloro-3-(trifluoromethyl)phenyl group,
3-fluoro-5-(trifluoromethyl)phenyl group,
3-bromo-5-(trifluoromethyl)phenyl group,
2-fluoro-5-(trifluoromethyl)phenyl group,
4-nitro-3-(trifluoromethyl)phenyl group,
2-nitro-5-(trifluoromethyl)phenyl group,
4-cyano-3-(trifluoromethyl)phenyl group,
2-methyl-3-(trifluoromethyl)phenyl group,
4-methyl-3-(trifluoromethyl)phenyl group,
2-methyl-5-(trifluoromethyl)phenyl group,
4-methoxy-3-(trifluoromethyl)phenyl group,
3-methoxy-5-(trifluoromethyl)phenyl group,
2-methoxy-5-(trifluoromethyl)phenyl group,
2-methylsulfanyl-5-(trifluoromethyl)phenyl group,
2-(1-pyrrolidinyl)-5-(trifluoromethyl)phenyl group,
2-morpholino-5-(trifluoromethyl)phenyl group,
2-chloro-4-(trifluoromethyl)phenyl group, 2,5-dichlorophenyl group,
3,4-dichlorophenyl group, 3,5-difluorophenyl group,
3,5-dinitrophenyl group, 2,5-bis[(1,1-dimethyl)ethyl]phenyl group,
5-[(1,1-dimethyl)ethyl]-2-methoxyphenyl group, 3,5-dimethylphenyl
group, 4-methoxybiphenyl-3-yl group, 3,5-dimethoxyphenyl group,
3,5-bis(methoxycarbonyl)phenyl group,
2-bromo-5-(trifluoromethyl)phenyl group,
3-methoxycarbonyl-5-(trifluoromethyl)phenyl group,
3-carboxy-5-(trifluoromethyl)phenyl group,
2-(2-naphthyloxy)-5-(trifluoromethyl)phenyl group,
2-(2,4-dichlorophenoxy)-5-(trifluoromethyl)phenyl group,
2-[4-(trifluoromethyl)piperidin-1-yl]-5-(trifluoromethyl)phenyl
group, 2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl group,
2-(2-methoxyphenoxy)-5-(trifluoromethyl)phenyl group,
2-(4-chloro-3,5-dimethylphenoxy)-5-(trifluoromethyl)phenyl group,
2-piperidino-5-(trifluoromethyl)phenyl group,
2-(4-methylphenoxy)-5-(trifluoromethyl)phenyl group,
2-(4-chlorophenoxy)-5-(trifluoromethyl)phenyl group,
3,5-dicarboxyphenyl group, 5-isopropyl-2-methylphenyl group,
2,5-diethoxyphenyl group, 2,5-dimethylphenyl group,
5-chloro-2-cyano group, 5-diethylsulfamoyl-2-methoxyphenyl group,
2-chloro-5-nitrophenyl group, 2-methoxy-5-(phenylcarbamoyl)phenyl
group, 5-acetylamino-2-methoxyphenyl group,
5-methoxy-2-methylphenyl group, 2,5-dibutoxyphenyl group,
2,5-diisopentyloxy group, 5-carbamoyl-2-methoxyphenyl group,
5-[(1,1-dimethyl)propyl]-2-phenoxyphenyl group,
2-hexyloxy-5-methanesulfonyl group,
5-(2,2-dimethylpropionyl)-2-methylphenyl group,
5-methoxy-2-(1-pyrrolyl)phenyl group,
5-chloro-2-(p-toluenesulfonyl)phenyl group,
2-chloro-5-(p-toluenesulfonyl)phenyl group,
2-fluoro-5-methanesulfonyl group, 2-methoxy-5-phenoxy group,
4-methylbiphenyl-3-yl group,
2-methoxy-5-(1-methyl-1-phenylethyl)phenyl group,
5-morpholino-2-nitrophenyl group, 5-fluoro-2-(1-imidazolyl)phenyl
group, 2-butyl-5-nitrophenyl group,
5-[(1,1-dimethyl)]propyl-2-hydroxyphenyl group,
2-methoxy-5-methylphenyl group, 2,5-difluorophenyl group,
4-isopropyl-2-(trifluoromethyl)phenyl group,
2-nitro-4-(trifluoromethyl)phenyl group,
4-bromo-3-(trifluoromethyl)phenyl group,
4-bromo-2-(trifluoromethyl)phenyl group,
2-bromo-4-(trifluoromethyl)phenyl group,
4-fluoro-2-(trifluoromethyl)phenyl group,
4-isopropoxy-2-(trifluoromethyl)phenyl group,
4-cyano-2-(trifluoromethyl)phenyl group, 2,6-diisopropylphenyl
group, 2,6-dimethylphenyl group, 3,4-dimethylphenyl group,
2,4-dichlorophenyl group, 2,3-dimethylphenyl group, indan-5-yl
group, 2,4-dimethylphenyl group, 2,6-dichlorophenyl group,
4-bromo-2-(trifluoromethoxy)phenyl group, 3,4-ethylenedioxyphenyl
group, 3-chloro-4-cyanophenyl group,
3-chloro-4-(trifluoromethoxy)phenyl group, 2-chloro-4-cyanophenyl
group, 2,3-dichlorophenyl group, 4-isopropyl-3-methylphenyl group,
4-[(1,1-dimethyl)propyl]-2-hydroxyphenyl group,
3-chloro-2-cyanophenyl group, 2-cyano-4-methylphenyl group,
2,2-difluoro-1,3-benzodioxol-4-yl group,
2,2,3,3-tetrafluoro-1,4-benzodioxen-5-yl group,
3-chloro-4-(trifluoromethylsulfanyl)phenyl group,
2-nitro-4-(trifluoromethoxy)phenyl group,
2,2-difluoro-1,3-benzodioxol-5-yl group,
2-methyl-4-(trifluoromethoxy)phenyl group, 4-bromo-2-fluorophenyl
group, 2,4-bis(methanesulfonyl)phenyl group,
2,2,3,3-tetrafluoro-1,4-benzodioxen-6-yl group,
2-benzoyl-4-chlorophenyl group, 2-bromo-4-fluorophenyl group,
3,4-dimethoxyphenyl group, 3,4-difluorophenyl group,
3-chloro-4-methoxyphenyl group, 2-chloro-4-nitrophenyl group,
2,4-difluorophenyl group, 2-benzoyl-5-methylphenyl group,
2-bromo-4-(trifluoromethoxy)phenyl group, 3,4-dihexyloxyphenyl
group, 2,4-bis(trifluoromethyl)phenyl group,
4-cyano-2-(trifluoromethoxy)phenyl group,
2-(4-cyanophenoxy)-5-(trifluoromethyl)phenyl group, and
2-(4-methoxyphenoxy)-5-(trifluoromethyl)phenyl group
[0270] When "an aryl group which may be substituted" in the
aforementioned definition of E is "a di-substituted phenyl group,"
"a 2,5-di-substituted phenyl group," and "a 3,5-di-substituted
phenyl group" are preferred.
[0271] When "an aryl group which may be substituted" in the
aforementioned definition of E is "a 2,5-di-substituted phenyl
group," preferred examples of the group include groups represented
by the following Substituent Group .delta.-2e.
[0272] [Substituent Group .delta.-2e] 2,5-dimethoxyphenyl group,
2-chloro-5-(trifluoromethyl)phenyl group,
2,5-bis(trifluoromethyl)phenyl group,
2-fluoro-5-(trifluoromethyl)phenyl group,
2-nitro-5-(trifluoromethyl)phenyl group,
2-methyl-5-(trifluoromethyl)phenyl group,
2-methoxy-5-(trifluoromethyl)phenyl group,
2-methylsulfanyl-5-(trifluoromethyl)phenyl group,
2-(1-pyrrolidinyl)-5-(trifluoromethyl)phenyl group,
2-morpholino-5-(trifluoromethyl)phenyl group, 2,5-dichlorophenyl
group, 2,5-bis[(1,1-dimethyl)ethyl]phenyl group,
5-[(1,1-dimethyl)ethyl]-2-methoxyphenyl group,
4-methoxybiphenyl-3-yl group, 2-bromo-5-(trifluoromethyl)phenyl
group, 2-(2-naphthyloxy)-5-(trifluoromethyl)phenyl group,
2-(2,4-dichlorophenoxy)-5-(trifluoromethyl)phenyl group,
2-[4-(trifluoromethyl)piperidin-1-yl]-5-(trifluoromethyl)phenyl
group, 2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl group,
2-(2-methoxyphenoxy)-5-(trifluoromethyl)phenyl group,
2-(4-chloro-3,5-dimethylphenoxy)-5-(trifluoromethyl)phenyl group,
2-piperidino-5-(trifluoromethyl)phenyl group,
2-(4-methylphenoxy)-5-(trifluoromethyl)phenyl group,
2-(4-chlorophenoxy)-5-(trifluoromethyl)phenyl group,
5-isopropyl-2-methylphenyl group, 2,5-diethoxyphenyl group,
2,5-dimethylphenyl group, 5-chloro-2-cyano group,
5-diethylsulfamoyl-2-methoxyphenyl group, 2-chloro-5-nitrophenyl
group, 2-methoxy-5-(phenylcarbamoyl)phenyl group,
5-acetylamino-2-methoxyphenyl group, 5-methoxy-2-methylphenyl
group, 2,5-dibutoxyphenyl group, 2,5-diisopentyloxy group,
5-carbamoyl-2-methoxyphenyl group,
5-[(1,1-dimethyl)propyl]-2-phenoxyphenyl group,
2-hexyloxy-5-methanesulfonyl group,
5-(2,2-dimethylpropionyl)-2-methylphenyl group,
5-methoxy-2-(1-pyrrolyl)phenyl group,
5-chloro-2-(p-toluenesulfonyl)phenyl group,
2-chloro-5-(p-toluenesulfonyl)phenyl group,
2-fluoro-5-methanesulfonyl group, 2-methoxy-5-phenoxy group,
2-methoxy-5-(1-methyl-1-phenylethyl)phenyl group,
5-morpholino-2-nitrophenyl group, 5-fluoro-2-(1-imidazolyl)phenyl
group, 2-butyl-5-nitrophenyl group,
5-[(1,1-dimethyl)propyl]-2-hydroxyphenyl group,
2-methoxy-5-methylphenyl group, 2,5-difluorophenyl group,
2-benzoyl-5-methylphenyl group,
2-(4-cyanophenoxy)-5-(trifluoromethyl)phenyl group, and
2-(4-methoxyphenoxy)-5-(trifluoromethyl)phenyl group
[0273] When "an aryl group which may be substituted" in the
aforementioned definition of E is "a 2,5-di-substituted phenyl
group," "a 2,5-di-substituted phenyl group wherein at least one of
said substitutents is trifluoromethyl group" is more preferred, a
group selected from the following Substituent Group .delta.-3e is
further preferred, and 2,5-bis(trifluoromethyl)phenyl group is most
preferred.
[0274] [Substituent Group .delta.-3e]
2-chloro-5-(trifluoromethyl)phenyl group,
2,5-bis(trifluoromethyl)phenyl group,
2-fluoro-5-(trifluoromethyl)phenyl group,
2-nitro-5-(trifluoromethyl)phenyl group,
2-methyl-5-(trifluoromethyl)phenyl group,
2-methoxy-5-(trifluoromethyl)phenyl group,
2-methylsulfanyl-5-(trifluoromethyl)phenyl group,
2-(1-pyrrolidinyl)-5-(trifluoromethyl)phenyl group,
2-morpholino-5-(trifluoromethyl)phenyl group,
2-bromo-5-(trifluoromethyl)phenyl group,
2-(2-naphthyloxy)-5-(trifluoromethyl)phenyl group,
2-(2,4-dichlorophenoxy)-5-(trifluoromethyl)phenyl group,
2-[4-(trifluoromethyl)piperidin-1-yl]-5-(trifluoromethyl)phenyl
group, 2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl group,
2-(2-methoxyphenoxy)-5-(trifluoromethyl)phenyl group,
2-(4-chloro-3,5-dimethylphenoxy)-5-(trifluoromethyl)phenyl group,
2-piperidino-5-(trifluoromethyl)phenyl group,
2-(4-methylphenoxy)-5-(trifluoromethyl)phenyl group,
2-(4-chlorophenoxy)-5-(trifluoromethyl)phenyl group,
2-(4-cyanophenoxy)-5-(trifluoromethyl)phenyl group, and
2-(4-methoxyphenoxy)-5-(trifluoromethyl)phenyl group
[0275] When "an aryl group which may be substituted" in the
aforementioned definition of E is "a 3,5-di-substituted phenyl
group," preferred examples of the group include groups represented
by the following Substituent Group .delta.-4e.
[0276] [Substituent Group .delta.-4e]
3,5-bis(trifluoromethyl)phenyl group, 3,5-dichlorophenyl group,
3,5-bis[(1,1-dimethyl)ethyl]phenyl group,
3-fluoro-5-(trifluoromethyl)phenyl group,
3-bromo-5-(trifluoromethyl)phenyl group,
3-methoxy-5-(trifluoromethyl)phenyl group, 3,5-difluorophenyl
group, 3,5-dinitrophenyl group, 3,5-dimethylphenyl group,
3,5-dimethoxyphenyl group, 3,5-bis(methoxycarbonyl)phenyl group,
3-methoxycarbonyl-5-(trifluoromethyl)phenyl group,
3-carboxy-5-(trifluoromethyl)phenyl group, and 3,5-dicarboxyphenyl
group
[0277] When "an aryl group which may be substituted" in the
aforementioned definition of E is "a 3,5-di-substituted phenyl
group," "a 3,5-di-substituted phenyl group wherein at least one of
said substitutents is trifluoromethyl group" is more preferred, a
group selected from the following Substituent Group .delta.-5e is
further preferred, and 3,5-bis(trifluoromethyl)phenyl group is most
preferred.
[0278] [Substituent Group .delta.-5e]
3,5-bis(trifluoromethyl)phenyl group,
3-fluoro-5-(trifluoromethyl)phenyl group,
3-bromo-5-(trifluoromethyl)phenyl group,
3-methoxy-5-(trifluoromethyl)phenyl group,
3-methoxycarbonyl-5-(trifluoromethyl)phenyl group, and
3-carboxy-5-(trifluoromethyl)phenyl group
[0279] When "an aryl group which may be substituted" in the
aforementioned definition of E is "a mono-substituted phenyl
group," preferred examples of the group include groups represented
by the following Substituent Group .delta.-6e.
[0280] [Substituent Group .delta.-6e] 4-methoxyphenyl group,
4-chlorophenyl group, 2-methoxyphenyl group,
2-(trifluoromethyl)phenyl group, 3-(trifluoromethyl)phenyl group,
4-(trifluoromethyl)phenyl group, 3-chlorophenyl group,
biphenyl-3-yl group, 3-acetylphenyl group, 3-(acetylamino)phenyl
group, 3-carbamoylphenyl group, 3-methylcarbomoylphenyl group,
4-methylphenyl group, 3-(trifluoromethoxy)phenyl group,
2-benzylphenyl group, 4-(trifluoromethoxy)phenyl group,
4-[(1,1-dimethyl)ethyl]phenyl group, 3-isopropoxyphenyl group,
4-isopropoxyphenyl group, 4-hexylphenyl group, 3-methylphenyl
group, 4-cyclohexylphenyl group, 4-benzylphenyl group,
2-chlorophenyl group, 2-methylphenyl group, 4-butylphenyl group,
4-benzyloxyphenyl group, 3-benzylphenyl group, 4-hexyloxyphenyl
group, 3-isopropylphenyl group, 4-cyanophenyl group, 3-cyanophenyl
group, 4-(ethoxycarbonylmethyl)phenyl group,
3-(trifluoromethylsulfanyl)phenyl group,
4-(trifluoromethylsulfanyl)phenyl group,
4-(trifluoromethanesulfonyl)phenyl group, 3-ethynylphenyl group,
4-(1-methylpropyl)phenyl group, 3-benzoylphenyl group,
3-methoxyphenyl group, 4-(acetylamino)phenyl group,
4-sulfamoylphenyl group, 4-difluoromethoxy)phenyl group,
3-methylsulfanylphenyl group, 4-methanesulfonylphenyl group,
3-(butylsulfamoyl)phenyl group, 3-benzyloxyphenyl group,
4-(p-toluenesulfonylamino)phenyl group, 4-morpholinophenyl group,
3-[(1,1-dimethyl)ethyl]phenyl group, 3-(5-methylfuran-2-yl)phenyl
group, 3-sulfamoylphenyl group, 3-(trifluoromethanesulfonyl)phenyl
group, 3-hexyloxyphenyl group, 4-acetylphenyl group, biphenyl-2-yl
group, biphenyl-4-yl group,
3-[5-phenyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl group,
3-{5-[(1,1-dimethyl)ethyl]-3-(trifluoromethyl)pyrazol-1-yl}phenyl
group, 4-[3,5-bis(trifluoromethyl)pyrazol-1-yl]phenyl group,
3-[3,5-bis(trifluoromethyl)pyrazol-1-yl]phenyl group, and
4-[5-phenyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl group
[0281] When "an aryl group which may be substituted" in the
aforementioned definition of E is "a phenyl group which has three
or more substitutents," preferred examples of the group include
groups represented by the following Substituent Group
.delta.-7e.
[0282] [Substituent Group .delta.-7e]
3,5-bis(trifluoromethyl)-2-bromophenyl group, 3,4,5-trichlorophenyl
group, 3,5-dichloro-4-hydroxyphenyl group, pentafluorophenyl group,
3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl group,
3,5-bis(trifluoromethyl)-2-methylphenyl group,
2,6-dichloro-4-(trifluoromethyl)phenyl group,
2,4-dimethoxy-5-(trifluoromethyl)phenyl group,
2,4-difluoro-5-(trifluoromethyl)phenyl group,
4-chloro-2-(4-chlorobenzenesulfonyl)-5-(trifluoromethyl)phenyl
group, 5-chloro-2-nitro-4-(trifluoromethyl)phenyl group,
2,3-difluoro-4-(trifluoromethyl)phenyl group,
2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl group,
2,4,6-trimethylphenyl group, 2-cyano-4,5-dimethoxyphenyl group,
2,4-dichloro-5-isopropoxyphenyl group, 2,3,5-trifluorophenyl group,
2,4,5-trichlorophenyl group, and 5-ethoxy-4-fluoro-2-nitrophenyl
group
[0283] When "an aryl group which may be substituted" in the
aforementioned definition of E is "a naphthyl group which may be
substituted," preferred examples of the group include 1-naphthyl
group, 4-methoxynaphthalen-2-yl group, and
4-hydroxy-3-methylnaphthalen-1-yl group.
[0284] Examples of the "heteroaryl group" in "a heteroaryl group
which may be substituted" in the definition of E include similar
groups to the "monocyclic heteroaryl group" and "fused polycyclic
heteroaryl group" in the definition of the aforementioned
"heterocyclic group." A 5 to 13-membered heteroaryl group is
preferred, and preferred examples of the group include thienyl
group, pyrazolyl group, oxazolyl group, 1,3,4-thiadiazolyl group,
pyridyl group, pyrimidinyl group, indolyl group, quinolyl group,
carbazolyl group, thiazolyl group, and pyrazinyl group.
[0285] A 5-membered heteroaryl group is more preferred as the
"heteroaryl group" in a heteroaryl group which may be substituted"
in the definition of E. Thienyl group, pyrazolyl group, oxazolyl
group, 1,3,4-thiadiazolyl group, and thiazolyl group are further
preferred, and thiazolyl group is most preferred.
[0286] Examples of the substitutent in the definition of "a
heteroaryl group which may be substituted" in the aforementioned
definition of E include similar groups to the substitutent
explained for the definition "which may be substituted." The
position of substitutents existing on the heteroaryl group is not
particularly limited, and when two or more substitutents exist,
they may be the same or different.
[0287] When "a heteroaryl group which may be substituted" in the
aforementioned definition of E is "a thiazolyl group which may be
substituted," "a thiazol-2-yl group which may be substituted." "A
mono-substituted thiazol-2-yl group" and "a di-substituted
thiazol-2-yl group" are more preferred, and "a di-substituted
thiazol-2-yl group" is further preferred.
[0288] When "a heteroaryl group which may be substituted" in the
aforementioned definition of E is "a di-substituted thiazol-2-yl
group," a group selected from the following Substituent Group
.delta.-8e is preferred, and
4-[(1,1-dimethyl)ethyl]-5-[(2,2-dimethyl)propionyl]thiazol-2-yl
group is most preferred.
[0289] [Substituent Group .delta.-8e]
5-bromo-4-[(1,1-dimethyl)ethyl]thiazol-2-yl group,
5-bromo-4-(trifluoromethyl)thiazol-2-yl group,
5-cyano-4-[(1,1-dimethyl)ethyl]thiazol-2-yl group,
5-methylthiazol-2-yl group, 4,5-dimethylthiazol-2-yl group,
5-methyl-4-phenylthiazol-2-yl group,
5-(4-fluorophenyl)-4-methylthiazol-2-yl group,
4-methyl-5-[3-(trifluoromethyl)phenyl]thiazol-2-yl group,
4-[(1,1-dimethyl)ethyl]-5-ethylthiazol-2-yl group,
4-ethyl-5-phenylthiazol-2-yl group,
4-isopropyl-5-phenylthiazol-2-yl group,
4-butyl-5-phenylthiazol-2-yl group,
4-[(1,1-dimethyl)ethyl]-5-[(2,2-dimethyl)propionyl]thiazol-2-yl
group, 4-[(1,1-dimethyl)ethyl]-5-(ethoxycarbonyl)thiazol-2-yl
group, 4-[(1,1-dimethyl)ethyl]-5-piperidinothiazol-2-yl group,
4-[(1,1-dimethyl)ethyl]-5-morpholinothiazol-2-yl group,
4-[(1,1-dimethyl)ethyl]-5-(4-methylpiperazin-1-yl)thiazol-2-yl
group,
4-[(1,1-dimethyl)ethyl]-5-(4-phenylpiperazin-1-yl)thiazol-2-yl
group, 5-carboxymethyl-4-phenylthiazol-2-yl group,
4,5-diphenylthiazol-2-yl group, 4-benzyl-5-phenylthiazol-2-yl
group, 5-phenyl-4-(trifluoromethyl)thiazol-2-yl group,
5-acetyl-4-phenylthiazol-2-yl group, 5-benzoyl-4-phenylthiazol-2-yl
group, 5-ethoxycarbonyl-4-phenylthiazol-2-yl group,
5-ethoxycarbonyl-4-(pentafluorophenyl)thiazol-2-yl group,
5-methylcarbamoyl-4-phenylthiazol-2-yl group,
5-ethylcarbamoyl-4-phenylthiazol-2-yl group,
5-isopropylcarbamoyl-4-phenylthiazol-2-yl group,
5-(2-phenylethyl)carbamoyl-4-phenylthiazol-2-yl group,
5-ethoxycarbonyl-4-(trifluoromethyl)thiazol-2-yl group,
5-carboxy-4-[(1,1-dimethyl)ethyl]thiazol-2-yl group,
5-(ethoxycarbonyl)methyl-4-phenylthiazol-2-yl group,
5-carboxy-4-phenylthiazol-2-yl group, and
5-propylcarbamoyl-4-phenylthiazol-2-yl group.
[0290] When "a heteroaryl group which may be substituted" in the
aforementioned definition of E is "a mono-substituted thiazol-2-yl
group," preferred examples of the group include groups represented
by the following Substituent Group .delta.-9e.
[0291] [Substituent Group .delta.-9e]
4-[(1,1-dimethyl)ethyl]thiazol-2-yl group, 4-phenylthiazol-2-yl
group, 4-[3,5-bis(trifluoromethyl)phenyl]thiazol-2-yl group,
4-(2,4-dichlorophenyl)thiazol-2-yl group,
4-(3,4-dichlorophenyl)thiazol-2-yl group,
4-[4-(trifluoromethyl)phenyl]thiazol-2-yl group,
4-(2,5-difluorophenyl)thiazol-2-yl group,
4-(4-methoxyphenyl)thiazol-2-yl group,
4-[3-(trifluoromethyl)phenyl]thiazol-2-yl group, and
4-(pentafluorophenyl)thiazol-2-yl group
[0292] The compounds represented by the aforementioned general
formula (I-1) are explained in details.
[0293] Examples of the substitutent in the definition of
"2-hydroxyphenyl group which may be substituted in the 5-position"
and "2-acetoxyphenyl group which may be substituted in the
5-position" in the definition of Z.sup.1 include similar groups to
the substitutent explained for the definition "which may be
substituted."
[0294] "2-Hydroxyphenyl group which is substituted in the
5-position" is preferred as the "2-hydroxyphenyl group which may be
substituted in the 5-position" in the definition of Z.sup.1.
[0295] Preferred examples of the substitutent in the definition of
"2-hydroxyphenyl group which may be substituted in the 5-position"
and "2-hydroxyphenyl group which is substituted in the 5-position"
in the definition of Z.sup.1 include a group selected from the
following Substituent Group .gamma..sup.1-1z. A halogen atom and
tert-butyl group are more preferred, and a halogen atom is most
preferred.
[0296] [Substituent Group .gamma..sup.1-1z] a halogen atom, nitro
group, cyano group, methoxy group, methyl group, isopropyl group,
tert-butyl group, 1,1,3,3-tetramethylbutyl group,
2-phenylethen-1-yl group, 2,2-dicyanoethen-1-yl group,
2-cyano-2-(methoxycarbonyl)ethen-1-yl group,
2-carboxy-2-cyanoethen-1-yl group, ethynyl group, phenylethynyl
group, (trimethylsilyl)ethynyl group, trifluoromethyl group,
pentafluoroethyl group, phenyl group, 4-(trifluoromethyl)phenyl
group, 4-fluorophenyl group, 2,4-difluorophenyl group, 2-phenethyl
group, 1-hydroxyethyl group, 1-(methoxyimino)ethyl group,
1-[(benzyloxy)imino]ethyl group, 2-thienyl group, 3-thienyl group,
1-pyrrolyl group, 2-methylthiazol-4-yl group,
imidazo[1,2-a]pyridin-2-yl group, 2-pyridyl group, acetyl group,
isobutyryl group, piperidinocarbonyl group,
4-benzylpiperidinocarbonyl group, (pyrrol-1-yl)sulfonyl group,
carboxy group, methoxycarbonyl group,
N-[3,5-bis(trifluoromethyl)phenyl]carbamoyl group,
N,N-dimethylcarbamoyl group, sulfamoyl group,
N-[3,5-bis(trifluoromethyl)phenyl]sulfamoyl group,
N,N-dimethylsulfamoyl group, amino group, N,N-dimethylamino group,
acetylamino group, benzoylamino group, methanesulfonylamino group,
benzenesulfonylamino group, 3-phenylureido group,
(3-phenyl)thioureido group, (4-nitrophenyl)diazenyl group, and
{[4-(pyridin-2-yl)sulfamoyl]phenyl}diazenyl group
[0297] "2-Acetoxyphenyl group which is substituted in the
5-position" is preferred as the "2-acetoxyphenyl group which may be
substituted in the 5-position" in the definition of Z.sup.1.
[0298] A halogen atom is preferred as the substitutent in the
definition of "2-acetoxyphenyl group which may be substituted in
the 5-position" and "2-acetoxyphenyl group which is substituted in
the 5-position" in the definition of Z.sup.1.
[0299] The definition "which may be substituted" in the definition
of "a phenyl group which may be substituted" in the definition of
E.sup.1 has the same meaning as "which may be substituted."
[0300] Examples of the substitutent in the definition of "a phenyl
group which may be substituted" in the definition of E.sup.1
include similar groups to the substitutents explained for the
definition "which may be substituted." A position of a substitutent
existing on the phenyl group is not particularly limited, and when
two or more substitutents exist, they may be the same or
different.
[0301] Preferred examples of "a phenyl group which may be
substituted" in the definition of E.sup.1 include
3,5-bis(trifluoromethyl)phenyl group,
2,5-bis(trifluoromethyl)phenyl group, a phenyl group which has
three or more substitutents wherein at least one of said
substitutents is trifluoromethyl group, and a di-substituted phenyl
group wherein at least one of said substitutents is trifluoromethyl
group, (provided that a 2,5-di-substituted phenyl group and a
3,5-di-substituted phenyl group are excluded as said di-substituted
phenyl group.) 3,5-Bis(trifluoromethyl)phenyl group and
2,5-bis(trifluoromethyl)phenyl group are more preferred.
[0302] When "a phenyl group which may be substituted" in the
definition of E.sup.1 is "a phenyl group which has three or more
substitutents wherein at least one of said substitutents is
trifluoromethyl group," preferred examples of the group include
groups represented by the following Substituent Group
.delta..sup.1-1e.
[0303] [Substituent Group .delta..sup.1-1e]
3,5-bis(trifluoromethyl)-2-bromophenyl group,
3,5-bis(trifluoromethyl)-2-methylphenyl group,
2,6-dichloro-4-(trifluoromethyl)phenyl group,
2,4-dimethoxy-5-(trifluoromethyl)phenyl group,
2,4-difluoro-5-(trifluoromethyl)phenyl group,
4-chloro-2-(4-chlorobenzenesulfonyl)-5-(trifluoromethyl)phenyl
group, 5-chloro-2-nitro-4-(trifluoromethyl)phenyl group,
2,3-difluoro-4-(trifluoromethyl)phenyl group, and
2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl group
[0304] When "a phenyl group which may be substituted" in the
definition of E.sup.1 is "a di-substituted phenyl group wherein at
least one of said substitutents is trifluoromethyl group, (provided
that a 2,5-di-substituted phenyl group and a 3,5-di-substituted
phenyl group are excluded from said di-substituted phenyl group)"
preferred examples of the group include groups represented by the
following Substituent Group .gamma..sup.1-2e.
[0305] [Substituent Group .gamma..sup.1-2e]
4-chloro-2-(trifluoromethyl)phenyl group,
2-fluoro-3-(trifluoromethyl)phenyl group,
4-fluoro-3-(trifluoromethyl)phenyl group,
4-chloro-3-(trifluoromethyl)phenyl group,
4-nitro-3-(trifluoromethyl)phenyl group,
4-cyano-3-(trifluoromethyl)phenyl group,
2-methyl-3-(trifluoromethyl)phenyl group,
4-methyl-3-(trifluoromethyl)phenyl group,
4-methoxy-3-(trifluoromethyl)phenyl group,
2-chloro-4-(trifluoromethyl)phenyl group,
4-isopropyl-2-(trifluoromethyl)phenyl group,
2-nitro-4-(trifluoromethyl)phenyl group,
4-bromo-3-(trifluoromethyl)phenyl group,
4-bromo-2-(trifluoromethyl)phenyl group,
2-bromo-4-(trifluoromethyl)phenyl group,
4-fluoro-2-(trifluoromethyl)phenyl group,
4-isopropoxy-2-(trifluoromethyl)phenyl group,
4-cyano-2-(trifluoromethyl)phenyl group, and
2,4-bis(trifluoromethyl)phenyl group
[0306] Compounds represented by the aforementioned general formula
(I-2) are explained in details.
[0307] Examples of the substitutent in the definition of
"2-hydroxyphenyl group which may be substituted in the 5-position"
and "2-acetoxyphenyl group which may be substituted in the
5-position" in the definition of Z.sup.2 include similar groups to
the substitutent explained for the definition "which may be
substituted."
[0308] "2-Hydroxyphenyl group which is substituted in the
5-position" is preferred as the "2-hydroxyphenyl group which may be
substituted in the 5-position" in the definition of Z.sup.2.
[0309] A halogen atom, nitro group, methyl group, and methoxy group
are preferred as the substitutent in the definition of
"2-hydroxyphenyl group which may be substituted in the 5-position"
and "2-hydroxyphenyl group which is substituted in the 5-position"
in the definition of Z.sup.2, and a halogen atom is most
preferred.
[0310] "2-Acetoxyphenyl group which is substituted in the
5-position" is preferred as the "2-acetoxyphenyl group which may be
substituted in the 5-position" in the definition of Z.sup.2.
[0311] A halogen atom is preferred as the substitutent in the
definition of "2-acetoxyphenyl group which may be substituted in
the 5-position" and "2-acetoxyphenyl group which is substituted in
the 5-position" in the definition of Z.sup.2.
[0312] Examples of the substitutent in the definition of "a
2,5-di-substituted phenyl group wherein one of said substitutents
is trifluoromethyl group" and "a 3,5-di-substituted phenyl group
wherein one of said substitutents is trifluoromethyl group" in the
definition of E.sup.2 include similar groups to the substitutent
explained for the definition "which may be substituted."
[0313] A group selected from the following Substituent Group
.gamma..sup.2-1e is preferred as a 2,5-di-substituted phenyl group
wherein one of said substitutents is trifluoromethyl group" in the
definition of E.sup.2.
[0314] [Substituent Group .delta..sup.2-1e]
2-chloro-5-(trifluoromethyl)phenyl group,
2,5-bis(trifluoromethyl)phenyl group,
2-fluoro-5-(trifluoromethyl)phenyl group,
2-nitro-5-(trifluoromethyl)phenyl group,
2-methyl-5-(trifluoromethyl)phenyl group,
2-methoxy-5-(trifluoromethyl)phenyl group,
2-methylsulfanyl-5-(trifluoromethyl)phenyl group,
2-(1-pyrrolidinyl)-5-(trifluoromethyl)phenyl group,
2-morpholino-5-(trifluoromethyl)phenyl group,
2-bromo-5-(trifluoromethyl)phenyl group,
2-(2-naphthyloxy)-5-(trifluoromethyl)phenyl group,
2-(2,4-dichlorophenoxy)-5-(trifluoromethyl)phenyl group,
2-[4-(trifluoromethyl)piperidin-1-yl]-5-(trifluoromethyl)phenyl
group, 2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl group,
2-(2-methoxyphenoxy)-5-(trifluoromethyl)phenyl group,
2-(4-chloro-3,5-dimethylphenoxy)-5-(trifluoromethyl)phenyl group,
2-piperidino-5-(trifluoromethyl)phenyl group,
2-(4-methylphenoxy)-5-(trifluoromethyl)phenyl group,
2-(4-chlorophenoxy)-5-(trifluoromethyl)phenyl group,
2-(4-cyanophenoxy)-5-(trifluoromethyl)phenyl group, and
2-(4-methoxyphenoxy)-5-(trifluoromethyl)phenyl group
[0315] A group selected from the following Substituent Group
.delta..sup.2-2e is preferred as "a 3,5-di-substituted phenyl group
wherein one of said substitutents is trifluoromethyl group" in the
definition of E.sup.2.
[0316] [Substituent Group .delta.2-2e]
3,5-bis(trifluoromethyl)phenyl group,
3-fluoro-5-(trifluoromethyl)phenyl group,
3-bromo-5-(trifluoromethyl)phenyl group,
3-methoxy-5-(trifluoromethyl)phenyl group,
3-methoxycarbonyl-5-(trifluoromethyl)phenyl group, and
3-carboxy-5-(trifluoromethyl)phenyl group
[0317] Compounds represented by the aforementioned general formula
(I-3) are explained in details.
[0318] Examples of the substitutent in the definition of
"2-hydroxyphenyl group which may be substituted in the 5-position"
and "2-acetoxyphenyl group which may be substituted in the
5-position" in the definition of Z.sup.3 include similar groups to
the substitutent explained for the definition "which may be
substituted."
[0319] "2-Hydroxyphenyl group which is substituted in the
5-position" is preferred as the "2-hydroxyphenyl group which may be
substituted in the 5-position" in the definition of Z.sup.3.
[0320] A halogen atom, nitro group, methyl group and methoxy group
are preferred as the substitutent in the definition of
"2-hydroxyphenyl group which may be substituted in the 5-position"
and "2-hydroxyphenyl group which is substituted in the 5-position"
in the definition of Z.sup.3, and a halogen atom is most
preferred.
[0321] "2-Acetoxyphenyl group which is substituted in the
5-position" is preferred as the "2-acetoxyphenyl group which may be
substituted in the 5-position" in the definition of Z.sup.3.
[0322] A halogen atom is preferred as the substitutent in the
definition of "2-acetoxyphenyl group which may be substituted in
the 5-position" and "2-acetoxyphenyl group which is substituted in
the 5-position" in the definition of Z.sup.3.
[0323] Examples of the substitutent in the definition of "a
hydrocarbon group which may be substituted" in the definition of
R.sup.3e2 and R.sup.3e3 and "a C.sub.2 to C.sub.6 hydrocarbon group
which may be substituted" in the definition of R.sup.3e5 include
similar groups to the substitutent explained for the definition
"which may be substituted."
[0324] Examples of the "hydrocarbon group" in the definition of "a
hydrocarbon group which may be substituted" in the definition of
R.sup.3e2 and R.sup.3e3 and "a C.sub.2 to C.sub.6 hydrocarbon group
which may be substituted" in the definition of R.sup.3e5 include
similar groups to the "hydrocarbon group" in the aforementioned
definition.
[0325] Examples of the "hydroxy group which may be substituted" in
the definition of R.sup.3e2 and R.sup.3e3 include similar groups to
the "hydroxy group which may be substituted" explained for the
definition "which may be substituted."
[0326] As E.sup.3, 3,5-bis[(1,1-dimethyl)ethyl]phenyl group,
2,5-bis[(1,1-dimethyl)ethyl]phenyl group,
5-[(1,1-dimethyl)ethyl]-2-methoxyphenyl group,
4-methoxybiphenyl-3-yl group,
5-[(1,1-dimethyl)propyl]-2-phenoxyphenyl group,
4-methylbiphenyl-3-yl group and
5-[(1,1-dimethyl)propyl]-2-hydroxyphenyl group are preferred, and
3,5-bis[(1,1-dimethyl)ethyl]phenyl group is more preferred.
[0327] Compounds represented by the aforementioned general formula
(I-4) are explained in details.
[0328] Examples of the substitutent in the definition of
"2-hydroxyphenyl group which may be substituted in the 5-position"
and "2-acetoxyphenyl group which may be substituted in the
5-position" in the definition of Z.sup.4 include similar groups to
the substitutent explained for the definition "which may be
substituted."
[0329] "2-Hydroxyphenyl group which is substituted in the
5-position" is preferred as the "2-hydroxyphenyl group which may be
substituted in the 5-position" in the definition of Z.sup.4.
[0330] A halogen atom, phenyl group, 4-fluorophenyl group,
2,4-difluorophenyl group, 4-(trifluoromethyl)phenyl group,
1-pyrrolyl group and 2-thienyl group are preferred as the
substitutent in the definition of "2-hydroxyphenyl group which may
be substituted in the 5-position" and "2-hydroxyphenyl group which
is substituted in the 5-position" in the definition of Z.sup.4, and
a halogen atom is most preferred.
[0331] "2-Acetoxyphenyl group which is substituted in the
5-position" is preferred as the "2-acetoxyphenyl group which may be
substituted in the 5-position" in the definition of Z.sup.4.
[0332] A halogen atom is preferred as the substitutent in the
definition of "2-acetoxyphenyl group which may be substituted in
the 5-position" and "2-acetoxyphenyl group which is substituted in
the 5-position" in the definition of Z.sup.4.
[0333] Examples of the substitutent in the definition of "a
hydrocarbon group which may be substituted" in the definition of
R.sup.4e4, and "an acyl group which may be substituted" and "a
heterocyclic group which may be substituted" in the definition of
R.sup.4e5 include similar groups to the substitutent explained for
the definition "which may be substituted."
[0334] Examples of the "hydrocarbon group" in the definition of "a
hydrocarbon group which may be substituted" in the definition of
R.sup.4e4 include similar groups to the "hydrocarbon group" in the
aforementioned definition.
[0335] Examples of the "acyl group" in the definition of "an acyl
group which may be substituted" in the definition of R.sup.4e5
include similar groups to the "acyl group" in the aforementioned
definition.
[0336] Examples of the "heterocyclic group" in the definition of "a
heterocyclic group which may be substituted" in the definition of
R.sup.4e5 include similar groups to the "heterocyclic group" in the
aforementioned definition.
[0337] A group selected from the following Substituent Group
.delta..sup.4-1e is preferred as E.sup.4, and
4-[(1,1-dimethyl)ethyl]-5-[(2,2-dimethyl)propionyl]thiazol-2-yl
group is most preferred.
[0338] [Substituent Group .delta..sup.4-1e]
5-bromo-4-[(1,1-dimethyl)ethyl]thiazol-2-yl group,
5-bromo-4-(trifluoromethyl)thiazol-2-yl group,
5-cyano-4-[(1,1-dimethyl)ethyl]thiazol-2-yl group,
5-methylthiazol-2-yl group,
4-[(1,1-dimethyl)ethyl]-5-[(2,2-dimethyl)propionyl]thiazol-2-yl
group, 4-[(1,1-dimethyl)ethyl]-5-(ethoxycarbonyl)thiazol-2-yl
group, 4-[(1,1-dimethyl)ethyl]-5-piperidinothiazol-2-yl group,
4-[(1,1-dimethyl)ethyl]-5-morpholinothiazol-2-yl group,
4-[(1,1-dimethyl)ethyl]-5-(4-methylpiperazin-1-yl)thiazol-2-yl
group,
4-[(1,1-dimethyl)ethyl]-5-(4-phenylpiperazin-1-yl)thiazol-2-yl
group, 5-carboxymethyl-4-phenylthiazol-2-yl group,
5-acetyl-4-phenylthiazol-2-yl group, 5-benzoyl-4-phenylthiazol-2-yl
group, 5-ethoxycarbonyl-4-phenylthiazol-2-yl group,
5-ethoxycarbonyl-4-(pentafluorophenyl)thiazol-2-yl group,
5-methylcarbamoyl-4-phenylthiazol-2-yl group,
5-ethylcarbamoyl-4-phenylthiazol-2-yl group,
5-isopropylcarbamoyl-4-phenylthiazol-2-yl group,
5-(2-phenylethyl)carbamoyl-4-phenylthiazol-2-yl group,
5-ethoxycarbonyl-4-(trifluoromethyl)thiazol-2-yl group,
5-carboxy-4-[(1,1-dimethyl)ethyl]thiazol-2-yl group,
5-carboxy-4-phenylthiazol-2-yl group, and
5-propylcarbamoyl-4-phenylthiazol-2-yl group.
[0339] Among the compound represented by the general formulas (I),
(I-1), (I-2), (I-3) and (I-4), preferred compounds are those other
than "substituted benzoic acid derivatives represented by the
following general formula (X-1) and/or compounds represented by the
following Compound Group .phi.-1.". ##STR28## wherein R.sup.1001
represents the following general formula (X-2): ##STR29## or the
following general formula (X-3): ##STR30## wherein each of
R.sup.1003, R.sup.1004 and R.sup.1006 independently represents
hydrogen atom, an alkyl group having from 1 to 6 carbons or an
alkoxy group having from 1 to 6 carbons, each of R.sup.1009 and
R.sup.1010 independently represents hydrogen atom, an alkyl group
having from 1 to 6 carbons, or an acyl group having from 2 to 11
carbons; R.sup.1002 represents hydrogen atom, a lower alkyl group
having from 1 to 6 carbons, which may be substituted, an aryl group
having from 6 to 12 carbons, which may be substituted, a heteroaryl
group having from 4 to 11 carbons, which may be substituted, an
aralkyl group having from 7 to 14 carbons, which may be
substituted, a heteroarylalkyl group having from 5 to 13 carbons,
which may be substituted, or an acyl group having from 2 to 11
carbons; X.sup.1001 represents carboxy group which may be
esterified or amidated. [Compound Group .phi.-1] ##STR31##
[0340] Each compound defined by the aforementioned general formulas
(I-1), (I-2), (I-3), and (I-4), or a pharmacologically acceptable
salt thereof, or a hydrate thereof or a solvate thereof is novel.
Uses of the compound according to the aforementioned chemical
substance invention are not particularly limited.
[0341] The compounds represented by the aforementioned general
formulas (I), (I-1), (I-2), (I-3) and (I-4) may form salts.
Examples of pharmacologically acceptable salts include, when acidic
groups exist, metal salts such as lithium salt, sodium salt,
potassium salt, magnesium salt, calcium salts, or ammonium salts
such as ammonium salt, methylammonium salt, dimethylammonium salt,
trimethylammonium salt, dicyclohexylammonium salt, and when basic
groups exist, mineral acid salts such as hydrochloride, oxalate,
hydrosulfate, nitrate, phosphate, or organic acid salts such as
methane sulfonate, benzene sulfonate, para-toluene sulfonate,
acetate, propionate, tartrate, fumarate, maleate, malate, oxalate,
succinate, citrate, benzoate, mandelate, cinnamate, lactate. Salts
may sometimes be formed with amino acids such as glycine. As active
ingredients of the medicament of the present invention,
pharmacologically acceptable salts may also be suitably used.
[0342] The compounds or salts thereof represented by the
aforementioned general formulas (I), (I-1), (I-2), (I-3) and (I-4)
may exist as hydrates or solvates. As active ingredients of the
medicament of the present invention, any of the aforementioned
substances may be used. Furthermore, the compounds represented by
the aforementioned general formulas (I), (I-1), (I-2), (I-3) and
(I-4) may sometimes have one or more asymmetric carbons, and may
exist as steric isomers such as optically active substance and
diastereomer. As active ingredients of the medicament of the
present invention, pure forms of stereoisomers, arbitrary mixture
of enantiomers or diastereomers, and racemates may be used.
[0343] Furthermore, when the compounds represented by the general
formulas (I), (I-1), (I-2), (I-3) and (I-4) has, for example,
2-hydroxypyridine form, the compounds may exist as 2-pyridone form
which is a tautomer. As active ingredients of the medicament of the
present invention, pure forms of tautomers or a mixture thereof may
be used. When the compounds represented by the general formulas
(I), (I-1), (I-2), (I-3) and (I-4) have olefinic double bonds, the
configuration may be in either E or Z, and as active ingredients of
the medicament of the present invention, geometrical isomer in
either of the configurations or a mixture thereof may be used.
[0344] Examples of the compounds included in the general formulas
(I), (I-1), (I-2), (I-3) and (I-4) as active ingredients of the
medicaments of the present invention are shown below. However, the
active ingredients of the medicaments of the present invention are
not limited to the compound set out below.
[0345] The abbreviations used in the following tables have the
following meanings.
[0346] Me: methyl group, Et: ethyl group. TABLE-US-00001 ##STR32##
Compound Number ##STR33## X E 1 ##STR34## ##STR35## ##STR36## 2
##STR37## ##STR38## ##STR39## 3 ##STR40## ##STR41## 4 ##STR42##
##STR43## ##STR44## 5 ##STR45## ##STR46## ##STR47## 6 ##STR48##
##STR49## ##STR50## 7 ##STR51## ##STR52## ##STR53## 8 ##STR54##
##STR55## ##STR56## 9 ##STR57## ##STR58## ##STR59## 10 ##STR60##
##STR61## ##STR62## 11 ##STR63## ##STR64## ##STR65## 12 ##STR66##
##STR67## ##STR68## 13 ##STR69## ##STR70## ##STR71## 14 ##STR72##
##STR73## ##STR74## 15 ##STR75## ##STR76## ##STR77## 16 ##STR78##
##STR79## ##STR80## 17 ##STR81## ##STR82## ##STR83## Compound
Number ##STR84## E 18 ##STR85## ##STR86## 19 ##STR87## ##STR88## 20
##STR89## ##STR90## 21 ##STR91## ##STR92## 22 ##STR93## ##STR94##
23 ##STR95## ##STR96## 24 ##STR97## ##STR98## 25 ##STR99##
##STR100## 26 ##STR101## ##STR102## 27 ##STR103## ##STR104## 28
##STR105## ##STR106## 29 ##STR107## ##STR108## 30 ##STR109##
##STR110## 31 ##STR111## ##STR112## 32 ##STR113## ##STR114## 33
##STR115## ##STR116## 34 ##STR117## ##STR118## 35 ##STR119##
##STR120## 36 ##STR121## ##STR122## 37 ##STR123## ##STR124## 38
##STR125## ##STR126## 39 ##STR127## ##STR128## 40 ##STR129##
##STR130## 41 ##STR131## ##STR132## 42 ##STR133## ##STR134## 43
##STR135## ##STR136## 44 ##STR137## ##STR138## 45 ##STR139##
##STR140## 46 ##STR141## ##STR142## 47 ##STR143## ##STR144## 48
##STR145## ##STR146## 49 ##STR147## ##STR148## 50 ##STR149##
##STR150## 51 ##STR151## ##STR152## 52 ##STR153## ##STR154## 53
##STR155## ##STR156## 54 ##STR157## ##STR158## 55 ##STR159##
##STR160## 56 ##STR161## ##STR162## 57 ##STR163## ##STR164## 58
##STR165## ##STR166## 59 ##STR167## ##STR168## 60 ##STR169##
##STR170## 61 ##STR171## ##STR172## 62 ##STR173## ##STR174## 63
##STR175## ##STR176## 64 ##STR177## ##STR178## 65 ##STR179##
##STR180## 66 ##STR181## ##STR182## 67 ##STR183## ##STR184## 68
##STR185## ##STR186## 69 ##STR187## ##STR188## 70 ##STR189##
##STR190## 71 ##STR191## ##STR192## 72 ##STR193## ##STR194## 73
##STR195## ##STR196## 74 ##STR197## ##STR198## 75 ##STR199##
##STR200## 76 ##STR201## ##STR202## 77 ##STR203## ##STR204## 78
##STR205## ##STR206## 79 ##STR207## ##STR208## 80 ##STR209##
##STR210## 81 ##STR211## ##STR212## 82 ##STR213## ##STR214## 83
##STR215## ##STR216## 84 ##STR217## ##STR218## 85 ##STR219##
##STR220## 86 ##STR221## ##STR222## 87 ##STR223## ##STR224## 88
##STR225## ##STR226## 89 ##STR227## ##STR228## 90 ##STR229##
##STR230## 91 ##STR231## ##STR232## 92 ##STR233## ##STR234## 93
##STR235## ##STR236## 94 ##STR237## ##STR238## 95 ##STR239##
##STR240## 96 ##STR241## ##STR242## 97 ##STR243## ##STR244## 98
##STR245## ##STR246## 99 ##STR247## ##STR248## 100 ##STR249##
##STR250## 101 ##STR251## ##STR252## 102 ##STR253## ##STR254## 103
##STR255## ##STR256## 104 ##STR257## ##STR258## 105 ##STR259##
##STR260## 106 ##STR261## ##STR262## 107 ##STR263## ##STR264## 108
##STR265## ##STR266## 109 ##STR267## ##STR268## 110 ##STR269##
##STR270## 111 ##STR271## ##STR272## 112 ##STR273## ##STR274## 113
##STR275## ##STR276## 114 ##STR277## ##STR278## 115 ##STR279##
##STR280## 116 ##STR281## ##STR282##
117 ##STR283## ##STR284## 118 ##STR285## ##STR286## 119 ##STR287##
##STR288## 120 ##STR289## ##STR290## 121 ##STR291## ##STR292## 122
##STR293## ##STR294## 123 ##STR295## ##STR296## 124 ##STR297##
##STR298## 125 ##STR299## ##STR300## 126 ##STR301## ##STR302## 127
##STR303## ##STR304## 128 ##STR305## ##STR306## 129 ##STR307##
##STR308## 130 ##STR309## ##STR310## 131 ##STR311## ##STR312## 132
##STR313## ##STR314## 133 ##STR315## ##STR316## 134 ##STR317##
##STR318## 135 ##STR319## ##STR320## 136 ##STR321## ##STR322## 137
##STR323## ##STR324## 138 ##STR325## ##STR326## 139 ##STR327##
##STR328## 140 ##STR329## ##STR330## 141 ##STR331## ##STR332## 142
##STR333## ##STR334## 143 ##STR335## ##STR336## 144 ##STR337##
##STR338## 145 ##STR339## ##STR340## 146 ##STR341## ##STR342## 147
##STR343## ##STR344## 148 ##STR345## ##STR346## 149 ##STR347##
##STR348## 150 ##STR349## ##STR350## 151 ##STR351## ##STR352## 152
##STR353## ##STR354## 153 ##STR355## ##STR356## 154 ##STR357##
##STR358## 155 ##STR359## ##STR360## 156 ##STR361## ##STR362## 157
##STR363## ##STR364## 158 ##STR365## ##STR366## 159 ##STR367##
##STR368## 160 ##STR369## ##STR370## 161 ##STR371## ##STR372## 162
##STR373## ##STR374## 163 ##STR375## ##STR376## 164 ##STR377##
##STR378## 165 ##STR379## ##STR380## 166 ##STR381## ##STR382## 167
##STR383## ##STR384## 168 ##STR385## ##STR386## 169 ##STR387##
##STR388## 170 ##STR389## ##STR390## 171 ##STR391## ##STR392## 172
##STR393## ##STR394## 173 ##STR395## ##STR396## 174 ##STR397##
##STR398## 175 ##STR399## ##STR400## 176 ##STR401## ##STR402## 177
##STR403## ##STR404## 178 ##STR405## ##STR406## 179 ##STR407##
##STR408## 180 ##STR409## ##STR410## 181 ##STR411## ##STR412## 182
##STR413## ##STR414## 183 ##STR415## ##STR416## 184 ##STR417##
##STR418## 185 ##STR419## ##STR420## 186 ##STR421## ##STR422## 187
##STR423## ##STR424## 188 ##STR425## ##STR426## 189 ##STR427##
##STR428## 190 ##STR429## ##STR430## 191 ##STR431## ##STR432## 192
##STR433## ##STR434## 193 ##STR435## ##STR436## 194 ##STR437##
##STR438## 195 ##STR439## ##STR440## 196 ##STR441## ##STR442## 197
##STR443## ##STR444## 198 ##STR445## ##STR446## 199 ##STR447##
##STR448## 200 ##STR449## ##STR450## 201 ##STR451## ##STR452## 202
##STR453## ##STR454## 203 ##STR455## ##STR456## 204 ##STR457##
##STR458## 205 ##STR459## ##STR460## 206 ##STR461## ##STR462## 207
##STR463## ##STR464## 208 ##STR465## ##STR466## 209 ##STR467##
##STR468## 210 ##STR469## ##STR470## 211 ##STR471## ##STR472## 212
##STR473## ##STR474## 213 ##STR475## ##STR476## 214 ##STR477##
##STR478## 215 ##STR479## ##STR480## 216 ##STR481## ##STR482## 217
##STR483## ##STR484## 218 ##STR485## ##STR486## 219 ##STR487##
##STR488## 220 ##STR489## ##STR490## 221 ##STR491## ##STR492## 222
##STR493## ##STR494## 223 ##STR495## ##STR496## ##STR497## Compound
Number ##STR498## X E 301 ##STR499## ##STR500## ##STR501## 302
##STR502## ##STR503## ##STR504## 303 ##STR505## ##STR506##
##STR507## 304 ##STR508## ##STR509## ##STR510## 305 ##STR511##
##STR512## ##STR513## 306 ##STR514## ##STR515## ##STR516## 307
##STR517## ##STR518## ##STR519## 308 ##STR520## ##STR521## 309
##STR522## ##STR523## ##STR524## 310 ##STR525## ##STR526##
##STR527## 311 ##STR528## ##STR529## 312 ##STR530## ##STR531##
##STR532## 313 ##STR533## ##STR534## ##STR535##
314 ##STR536## ##STR537## ##STR538## 315 ##STR539## ##STR540##
##STR541## 316 ##STR542## ##STR543## ##STR544## 317 ##STR545##
##STR546## ##STR547## 318 ##STR548## ##STR549## ##STR550## 319
##STR551## ##STR552## ##STR553## 320 ##STR554## ##STR555## 321
##STR556## ##STR557## ##STR558## ##STR559## Compound Number
##STR560## E 322 ##STR561## ##STR562## 323 ##STR563## ##STR564##
324 ##STR565## ##STR566## 325 ##STR567## ##STR568## 326 ##STR569##
##STR570## 327 ##STR571## ##STR572## 328 ##STR573## ##STR574## 329
##STR575## ##STR576## 330 ##STR577## ##STR578## 331 ##STR579##
##STR580## 332 ##STR581## ##STR582## 333 ##STR583## ##STR584## 334
##STR585## ##STR586## 335 ##STR587## ##STR588## 336 ##STR589##
##STR590## 337 ##STR591## ##STR592## 338 ##STR593## ##STR594## 339
##STR595## ##STR596## 340 ##STR597## ##STR598## 341 ##STR599##
##STR600## 342 ##STR601## ##STR602## 343 ##STR603## ##STR604## 344
##STR605## ##STR606## 345 ##STR607## ##STR608## 346 ##STR609##
##STR610## 347 ##STR611## ##STR612## 348 ##STR613## ##STR614## 349
##STR615## ##STR616## 350 ##STR617## ##STR618## 351 ##STR619##
##STR620## 352 ##STR621## ##STR622## 353 ##STR623## ##STR624## 354
##STR625## ##STR626## 355 ##STR627## ##STR628## 356 ##STR629##
##STR630## 357 ##STR631## ##STR632## 358 ##STR633## ##STR634## 359
##STR635## ##STR636## 360 ##STR637## ##STR638## 361 ##STR639##
##STR640## 362 ##STR641## ##STR642## 363 ##STR643## ##STR644## 364
##STR645## ##STR646## 365 ##STR647## ##STR648## 366 ##STR649##
##STR650## 367 ##STR651## ##STR652## 368 ##STR653## ##STR654## 369
##STR655## ##STR656## 370 ##STR657## ##STR658## 371 ##STR659##
##STR660## 372 ##STR661## ##STR662## 373 ##STR663## ##STR664## 374
##STR665## ##STR666## 375 ##STR667## ##STR668## 376 ##STR669##
##STR670## 377 ##STR671## ##STR672## 378 ##STR673## ##STR674## 379
##STR675## ##STR676## 380 ##STR677## ##STR678## 381 ##STR679##
##STR680## 382 ##STR681## ##STR682## 383 ##STR683## ##STR684## 384
##STR685## ##STR686## 385 ##STR687## ##STR688## 386 ##STR689##
##STR690## 387 ##STR691## ##STR692## 388 ##STR693## ##STR694## 389
##STR695## ##STR696## 390 ##STR697## ##STR698## 391 ##STR699##
##STR700## 392 ##STR701## ##STR702## 393 ##STR703## ##STR704## 394
##STR705## ##STR706## 395 ##STR707## ##STR708## 396 ##STR709##
##STR710## 397 ##STR711## ##STR712## 398 ##STR713## ##STR714## 399
##STR715## ##STR716## 400 ##STR717## ##STR718## 401 ##STR719##
##STR720## 402 ##STR721## ##STR722## 403 ##STR723## ##STR724## 404
##STR725## ##STR726## 405 ##STR727## ##STR728## 406 ##STR729##
##STR730## 407 ##STR731## ##STR732## 408 ##STR733## ##STR734## 409
##STR735## ##STR736## 410 ##STR737## ##STR738## 411 ##STR739##
##STR740## 412 ##STR741## ##STR742## 413 ##STR743## ##STR744## 414
##STR745## ##STR746## 415 ##STR747## ##STR748## 416 ##STR749##
##STR750## 417 ##STR751## ##STR752## 418 ##STR753## ##STR754## 419
##STR755## ##STR756## 420 ##STR757## ##STR758## 421 ##STR759##
##STR760## 422 ##STR761## ##STR762## 423 ##STR763## ##STR764## 424
##STR765## ##STR766## 425 ##STR767## ##STR768## 426 ##STR769##
##STR770## 427 ##STR771## ##STR772## 428 ##STR773## ##STR774## 429
##STR775## ##STR776## 430 ##STR777## ##STR778## 431 ##STR779##
##STR780## 432 ##STR781## ##STR782## 433 ##STR783## ##STR784## 434
##STR785## ##STR786##
435 ##STR787## ##STR788## 436 ##STR789## ##STR790## 437 ##STR791##
##STR792## 438 ##STR793## ##STR794## 439 ##STR795## ##STR796## 440
##STR797## ##STR798## 441 ##STR799## ##STR800## 442 ##STR801##
##STR802## 443 ##STR803## ##STR804## 444 ##STR805## ##STR806## 445
##STR807## ##STR808## 446 ##STR809## ##STR810## 447 ##STR811##
##STR812## 448 ##STR813## ##STR814## 449 ##STR815## ##STR816## 450
##STR817## ##STR818## 451 ##STR819## ##STR820## 452 ##STR821##
##STR822## 453 ##STR823## ##STR824## 454 ##STR825## ##STR826## 455
##STR827## ##STR828## 456 ##STR829## ##STR830## 457 ##STR831##
##STR832## 458 ##STR833## ##STR834## 459 ##STR835## ##STR836## 460
##STR837## ##STR838## 461 ##STR839## ##STR840## 462 ##STR841##
##STR842## 463 ##STR843## ##STR844## 464 ##STR845## ##STR846## 465
##STR847## ##STR848## 466 ##STR849## ##STR850## 467 ##STR851##
##STR852## 468 ##STR853## ##STR854## 469 ##STR855## ##STR856## 470
##STR857## ##STR858## 471 ##STR859## ##STR860## 472 ##STR861##
##STR862## 473 ##STR863## ##STR864## 474 ##STR865## ##STR866## 475
##STR867## ##STR868## 476 ##STR869## ##STR870## 477 ##STR871##
##STR872## 478 ##STR873## ##STR874## 479 ##STR875## ##STR876## 480
##STR877## ##STR878## 481 ##STR879## ##STR880## 482 ##STR881##
##STR882## 483 ##STR883## ##STR884## 484 ##STR885## ##STR886## 485
##STR887## ##STR888## 486 ##STR889## ##STR890## 487 ##STR891##
##STR892## 488 ##STR893## ##STR894## 489 ##STR895## ##STR896## 490
##STR897## ##STR898## 491 ##STR899## ##STR900## 492 ##STR901##
##STR902## 493 ##STR903## ##STR904## 494 ##STR905## ##STR906## 495
##STR907## ##STR908## 496 ##STR909## ##STR910## 497 ##STR911##
##STR912## 498 ##STR913## ##STR914## 499 ##STR915## ##STR916## 500
##STR917## ##STR918## 501 ##STR919## ##STR920## 502 ##STR921##
##STR922## 503 ##STR923## ##STR924## 504 ##STR925## ##STR926## 505
##STR927## ##STR928## 506 ##STR929## ##STR930## 507 ##STR931##
##STR932## 508 ##STR933## ##STR934## 509 ##STR935## ##STR936## 510
##STR937## ##STR938## 511 ##STR939## ##STR940## 512 ##STR941##
##STR942## 513 ##STR943## ##STR944## 514 ##STR945## ##STR946## 515
##STR947## ##STR948## 516 ##STR949## ##STR950## 517 ##STR951##
##STR952## 518 ##STR953## ##STR954## 519 ##STR955## ##STR956## 520
##STR957## ##STR958## 521 ##STR959## ##STR960## 522 ##STR961##
##STR962## 523 ##STR963## ##STR964## 524 ##STR965## ##STR966## 525
##STR967## ##STR968## 526 ##STR969## ##STR970## 527 ##STR971##
##STR972## 528 ##STR973## ##STR974## 529 ##STR975## ##STR976## 530
##STR977## ##STR978## 531 ##STR979## ##STR980## 532 ##STR981##
##STR982## 533 ##STR983## ##STR984## 534 ##STR985## ##STR986## 535
##STR987## ##STR988## 536 ##STR989## ##STR990## 537 ##STR991##
##STR992## 538 ##STR993## ##STR994## 539 ##STR995## ##STR996## 540
##STR997## ##STR998## 541 ##STR999## ##STR1000## 542 ##STR1001##
##STR1002## 543 ##STR1003## ##STR1004## 544 ##STR1005## ##STR1006##
545 ##STR1007## ##STR1008## 546 ##STR1009## ##STR1010## 547
##STR1011## ##STR1012## 548 ##STR1013## ##STR1014## 549 ##STR1015##
##STR1016## 550 ##STR1017## ##STR1018## 551 ##STR1019## ##STR1020##
552 ##STR1021## ##STR1022## ##STR1023## Compound Number ##STR1024##
X E 553 ##STR1025## ##STR1026## ##STR1027## 554 ##STR1028##
##STR1029## ##STR1030## 555 ##STR1031## ##STR1032## ##STR1033##
[0347] Methods for preparation of the compounds represented by the
general formulas (I), (I-1), (I-2), (I-3) and (I-4) are not
particularly limited. Reference to methods described in the
pamphlet of International Publication WO02/49632 is useful.
[0348] The compounds represented by the general formulas (I),
(I-1), (I-2), (I-3) and (I-4) can be prepared, for example, by
methods shown bellow.
<Method 1>
[0349] The compounds represented by the general formula (I),
wherein X is --CONH --(the hydrogen atom on the nitrogen may be
substituted) and the compounds represented by the general formulas
(I-1), (I-2), (I-3) and (I-4) can be prepared, for example, by a
method described in the reaction scheme 1. ##STR1034## wherein each
of A, ring Z, and E has the same meaning as that defined in the
general formula (I), A.sup.101 represents a hydrogen atom or
protecting groups of hydroxy group (preferably, an alkyl group such
as methyl group and the like; an aralkyl group such as benzyl group
and the like; an acetyl group, an alkoxyalkyl group such as
methoxymethyl group and the like; a substituted silyl group such as
trimethylsilyl group or the like), each of R and R.sup.101
represents a hydrogen atom, a C.sub.1 to C.sub.6 alkyl group or the
like, E.sup.101 represents E or precursor of E in the definition of
the general formula (I), G represents a hydroxy group, halogen
atoms (preferably, a chlorine atom), a hydrocarbon-oxy group
(preferably, an aryl-oxy group which may be substituted by halogen
atom), an acyl-oxy group, an imido-oxy group or the like. (First
Step)
[0350] The amide (3) can be prepared by dehydrocondensation of the
carboxylic acid derivative (1) and the amine (2). This reaction is
carried out at a reaction temperature of from 0.degree. C. to
180.degree. C., without solvent or in an aprotic solvent, in the
presence of an acid halogenating agent or a dehydrocondensing
agent, and in the presence or absence of a base.
[0351] As the halogenating agent, examples include, for example,
thionyl chloride, thionyl bromide, sulfuryl chloride, phosphorus
oxychloride, phosphorus trichloride, phosphorus pentachloride or
the like. When A.sup.101 is hydrogen atom, phosphorus trichloride
is preferable, and when A.sup.101 is acetyl group or the like,
phosphorus oxychloride is preferable. As the dehydrocondensing
agent, examples include, for example,
N,N'-dicyclohexylcarbodiimide,
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride,
diphenylphosphorylazide or the like. As the base, examples include
inorganic bases such as sodium carbonate, potassium carbonate,
sodium hydrogencarbonate or the like, or organic bases such as
pyridine, triethylamine, N,N'-diethylaniline or the like. As the
aprotic solvent, examples include dichloromethane, dichloroethane,
chloroform, tetrahydrofuran, 1,4-dioxane, benzene, toluene,
monochlorobenzene, o-dichlorobenzene, N,N'-dimethylformamide,
N-methylpyrrolidone or the like, when the reaction is carried out
in the presence of the acid halogenating agent, particularly,
toluene, monochlorobenzene, o-dichlorobenzene are preferable.
[0352] A target compound can also be prepared, for example, by a
method or similar method described in Journal of Medicinal
Chemistry, (USA), 1998, Vol. 41, No. 16, p. 2939-2945, in which the
acid chloride is prepared and isolated beforehand from carboxylic
acid, then the result is made to react with an amine having
E.sup.101.
[0353] When G is hydroxy group, the reaction condition described in
Archiv der Pharmazie, (Germany), 1998, Vol. 331, No. 1, p. 3-6 can
be used as a preferred reaction condition.
[0354] Kinds of carboxylic acid derivative (1) and amine (2) are
not particularly limited, and new compounds synthesized by
referring to well-known preparation method described in the
literature or commercially available reagents can be used for the
aforementioned reaction.
(Second Step)
[0355] When the amide (3) has a protecting group and/or has a
favorable substitutent for functional group modification, for
example, an amino group and a protected amino group or its
precursor; a carboxy group and a protected carboxy group or its
precursor; a hydroxy group and a protected hydroxy group or its
precursor, the final target compound (4) can be prepared by a
reaction for deprotection and/or functional group modification in
this step. Various well-known methods can be used for the reaction.
For the reaction of deprotection and functional group modification,
for example, methods described in "Protective Groups in Organic
Syntheses", (USA), Theodra W. Green, Peter G. M. Wuts, Eds., Third
edition, April in 1999, John Wiley & Sons, and "Handbook of
Reagents for Organic Synthesis", (USA), 4 Volumes, June in 1999,
John Wiley & Sons can be used, and for the reaction of
functional group modification, for example, methods described in
"Palladium Reagents in Organic Syntheses", (USA), Richard F. Heck,
1985, Academic Press, and "Palladium Reagents and Catalysts:
Innovations in Organic Synthesis", (USA), J. Tsuji, 1999, John
Wiley & Sons, or the like can be used.
[0356] The aforementioned methods are applicable by appropriately
combining raw materials even for the compounds wherein X is other
connecting group, for example, --SO.sub.2NH--, --NHCO--,
--NHSO.sub.2--, --CONHCH.sub.2--, --CONHCH.sub.2CH.sub.2--,
--CONHCH.sub.2CONH--, --CONHNHCO--, --CONHNHCH.sub.2--, --COO--,
--CONHNH --; wherein the hydrogen atom on said connecting group may
be substituted.
[0357] In the general formula (I), when X is the formula:
--CONHCH.sub.2-- wherein the hydrogen atom on said connecting group
may be substituted, the target compound can be prepared by using an
amine represented by the formula: H.sub.2N--CH.sub.2-E.sup.101,
wherein E.sup.101 has the same meaning as that defined above,
instead of the amine (2).
[0358] In the general formula (I), when X is the formula:
--CONHCH.sub.2CH.sub.2-- wherein the hydrogen atom on said
connecting group may be substituted, the target compound can be
prepared by using an amine represented by the formula:
H.sub.2N--CH.sub.2 CH.sub.2-E.sup.101, wherein E.sup.101 has the
same meaning as that defined above, instead of the amine (2).
[0359] In the general formula (I), when X is the formula:
--SO.sub.2NH--, the target compound can be prepared by using a
sulfonyl chloride represented by the formula: A.sup.101-O-(ring
Z)-SO.sub.2Cl, wherein each of A.sup.101 and ring Z has the same
meaning as that defined above, instead of the carboxylic acid
derivative (1).
[0360] In the general formula (I), when X is the formula: --NHCO--,
the target compound can be prepared by using an amine represented
by the formula: A.sup.101-O-(ring Z)-NH.sub.2, wherein each of
A.sup.101 and ring Z has the same meaning as that defined above,
and a carboxylic acid represented by the formula: E.sup.101-COOH,
wherein -E.sup.101 has the same meaning as that defined above, or a
carboxylic acid chloride represented by the formula:
E.sup.101-COCl, wherein -E.sup.101 has the same meaning as that
defined above.
[0361] In the general formula (I), when X is the formula:
--NHSO.sub.2--, wherein said connecting group may be substituted,
the target compound can be prepared by using an amine represented
by the formula: HO-(ring Z)-NH.sub.2, wherein ring Z has the same
meaning as that defined above, and a sulfonyl chloride represented
by the formula: E.sup.101-SO.sub.2Cl, wherein E.sup.101 has the
same meaning as that defined above.
[0362] In the general formula (I), when X is the formula:
--CONHNHCO--, the target compound can be prepared by using a
hydrazide represented by the formula: HO-(ring Z)-CONHNH.sub.2,
wherein ring Z has the same meaning as that defined above, and a
carboxylic acid chloride represented by the formula:
E.sup.101-COCl, wherein -E.sup.101 has the same meaning as that
defined above.
[0363] In the general formula (I), when X is the formula: --COO--,
the target compound can be prepared by using a phenol derivative
represented by the formula: HO-E.sup.101, wherein -E.sup.101 has
the same meaning as that defined above, instead of the amine
(2).
[0364] In the general formula (I), when X is the formula:
--CONHNH--, the target compound can be prepared by using a
hydrazine represented by the formula: H.sub.2N --NH -E.sup.101,
wherein E.sup.101 has the same meaning as that defined above,
instead of the amine (2).
[0365] In the general formula (I), when X is the formula:
--CONHCH.sub.2CONH--, the target compound can be prepared by using
an amine represented by the formula: H.sub.2N
--CH.sub.2CONH-E.sup.101, wherein E.sup.101 has the same meaning as
that defined above, instead of the amine (2).
[0366] The amine represented by the formula:
H.sub.2N--CH.sub.2CONH-E.sup.101, can be prepared, for example, by
condensation of the amine (2) and a N-protected amino acid (for
example, N-(tert-butoxycarbonyl)glycine), according to the
aforementioned method 1, followed by a deprotection reaction.
[0367] In the general formula (I), when X is the following formula:
##STR1035## wherein said connecting group may be substituted, the
target compound can be prepared by using an amine represented by
the following formula: ##STR1036## wherein ring Z has the same
meaning as that defined above, and a carboxylic acid represented by
the formula: E.sup.101-COOH, wherein E.sup.101 has the same meaning
as that defined above, or a carboxylic acid chloride represented by
the formula: E.sup.101-COCl, wherein E.sup.101 has the same meaning
as that defined above.
[0368] The amine represented by the following formula: ##STR1037##
can be prepared, for example, by a method described in the reaction
scheme 1-2. ##STR1038## wherein ring Z has the same meaning as that
defined above.
[0369] The bromoacetophenone (20) can be prepared by bromination of
the acetophenone (19).
[0370] This reaction is carried out at a reaction temperature of
from 0.degree. C. to 100.degree. C. in a solvent, in the presence
of a brominating agent.
[0371] As the brominating agent, for example,
phenyltrimethylammonium tribromide can preferably be used.
[0372] As the reaction solvent, any solvent can be used as long as
it does not inhibit the reaction, for example, ethers such as
tetrahydrofuran can be used.
[0373] The amine (21) can be prepared by reacting the
bromoacetophenone (20) with thiourea.
[0374] This reaction is carried out at a reaction temperature of
from 0.degree. C. to 120.degree. C. in a solvent.
[0375] As the reaction solvent, any solvent can be used as long as
it does not inhibit the reaction, for example, alcohols such as
ethanol can be used.
<Method 2>
[0376] The compounds represented by the general formula (I),
wherein X is --CH.sub.2NH -- can be prepared, for example, by a
method described in the reaction scheme 2. ##STR1039## wherein each
of A, ring Z, and E has the same meaning as that defined in the
general formula (I).
[0377] The imine derivative of the formula (7) can be prepared by
dehydrocondensation of the aldehyde (5) and the amine (6). This
reaction is carried out at a reaction temperature of from 0.degree.
C. to 100.degree. C. in a solvent, in the presence or absence of a
dehydrating agent. As the dehydrating agent, examples include
anhydrous magnesium sulfate, molecular sieves or the like. As the
solvent, examples include inert solvent, and tetrahydrofuran,
1,4-dioxane, methanol, ethanol or the like are preferable.
[0378] The aforementioned methods are applicable by appropriately
combining raw materials even for the compounds wherein X is other
connecting group, for example, --CONHN.dbd.CH--, --CH.dbd.NNHCO--,
--CHNNH--; wherein the hydrogen atom on said connecting group may
be substituted.
[0379] In the general formula (I), when X is the formula:
--CONHN.dbd.CH--, the target compound can be prepared by using a
hydrazide represented by the formula: HO-(ring Z)-CONHNH.sub.2,
wherein ring Z has the same meaning as that defined above, and an
aldehyde represented by the formula: E-CHO, wherein E has the same
meaning as that defined above.
[0380] In the general formula (I), when X is the formula:
--CH.dbd.NNHCO--, the target compound can be prepared by using an
aldehyde represented by the formula: HO-(ring Z)-CHO, wherein ring
Z has the same meaning as that defined above, and a hydrazide
represented by the formula: E-CONHNH.sub.2, wherein E has the same
meaning as that defined above.
[0381] In the general formula (I), when X is the formula:
--CH.dbd.NNH--, the target compound can be prepared by using an
aldehyde represented by the formula: HO-(ring Z)-CHO, wherein ring
Z has the same meaning as that defined above, and a hydrazine
represented by the formula: E-NHNH.sub.2, wherein E has the same
meaning as that defined above.
[0382] The target compound (8) can be prepared by reduction of the
imine derivative (7). This reaction is carried out at a reaction
temperature of from 0.degree. C. to 100.degree. C. in a solvent, in
the presence of a reducing agent. As the reducing agent, examples
include sodium borohydride, lithium borohydride or the like. As the
solvent, examples include inert solvent, and tetrahydrofuran,
1,4-dioxane, methanol, ethanol or the like are preferable. This
reaction can also be carried out by a method of catalytic
hydrogenation. As the catalyst, examples include palladium carbon,
platinum carbon, palladium hydroxide, palladium black or the like.
As solvent, examples include inert solvent, and tetrahydrofuran,
1,4-dioxane, methanol, ethanol or the like are preferable. The
reaction is carried out at a reaction temperature of from 0.degree.
C. to 200.degree. C., and the hydrogen pressure may be an ordinary
pressure or a positive pressure.
<Method 3>
[0383] The compounds represented by the general formula (I),
wherein X is --CH.dbd.CH-- (the hydrogen atom on said connecting
group may be substituted), can be prepared, for example, by methods
described in the reaction scheme 3-1 or the reaction scheme 3-2.
##STR1040## wherein each of ring Z and E has the same meaning as
that defined in the general formula (I), W.sup.301 represents
O,O'-di-hydrocarbon-phosphono group or triarylphosphonium group
[0384] The target compound (11) can be prepared by
dehydrocondensation of the aldehyde (9-1) and the phosphorus
compound (10-1). This reaction is carried out in a solvent at a
reaction temperature of from 0.degree. C. to the boiling point of
the solvent, in the presence of a base. As the base, examples
include inorganic base such as sodium carbonate, potassium
carbonate, sodium hydrogencarbonate or the like, or organic base
such as pyridine, triethylamine, N,N-diethylaniline or the like. As
the solvent, examples include inert solvent, and tetrahydrofuran,
1,4-dioxane, methanol, ethanol, water or the like are preferable.
##STR1041## wherein each of ring Z and E has the same meaning as
that defined in the general formula (I), W.sup.302 represents
halogen atoms (preferably, iodine atom and bromine atom),
(trifluoromethanesulfonyl)oxy group and the like.
[0385] The target compound (11) can be prepared by reacting the
halogenated compound (9-2) with the styrene compound (10-2) in the
presence of a transition-metal complex catalyst. This reaction is
carried out in a solvent at a reaction temperature of from
0.degree. C. to the boiling point of the solvent, in the presence
or absence of a ligand and/or a base. As the transition-metal
complex catalyst, examples include palladium catalyst such as
palladium acetate and dichlorobis(triphenylphosphine)palladium. As
the ligand, examples include phosphine ligand such as
triphenylphosphine. As the base, examples include inorganic base
such as sodium carbonate, potassium carbonate, and sodium hydrogen
carbonate, or organic base such as pyridine, triethylamine, and
N,N-diethylaniline. As the solvent, examples include inert
solvents, and N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane
or the like are preferable.
<Method 4>
[0386] The compounds represented by the general formula (I),
wherein X is --COCH .dbd.CH-- and --COCH.sub.2CH.sub.2-- (the
hydrogen atom on said connecting group may be substituted), can be
prepared, for example, by a method described in the reaction scheme
4. ##STR1042## wherein each of rings Z and E has the same meaning
as that defined in the general formula (I).
[0387] The target compound enone (14) can be prepared by
dehydrocondensation of the ketone (12) and the aldehyde (13). This
reaction is carried out in a solvent at a reaction temperature of
from 0.degree. C. to the boiling point of the solvent, in the
presence of a base. As the base, examples include inorganic base
such as sodium hydroxide, potassium hydroxide, sodium carbonate,
potassium carbonate, sodium hydrogencarbonate or the like, or
organic base such as pyridine, triethylamine, N,N-diethylaniline or
the like. Examples include inert solvent, and tetrahydrofuran,
1,4-dioxane, methanol, ethanol, water or the like are
preferable.
[0388] Next, the target compound (15) can be prepared by reduction
of the enone (14). This reaction is carried out at a reaction
temperature of from 0.degree. C. to 100.degree. in solvent, in the
presence of a reducing agent. As the reducing agent, examples
include sodium borohydride, lithium borohydride or the like. As the
solvent, examples include inert solvent, and tetrahydrofuran,
1,4-dioxane, methanol, ethanol or the like are preferable.
Moreover, this reaction is carried out by a method of catalytic
hydrogenation also. As the catalyst, examples include palladium
carbon, platinum carbon, palladium hydroxide, palladium black or
the like. As solvent, examples include inert solvent, and
tetrahydrofuran, 1,4-dioxane, methanol, ethanol or the like are
preferable. The reaction is carried out at a reaction temperature
of from 0.degree. C. to 200.degree. C., and the hydrogen pressure
is at normal pressure or applied pressure.
<Method 5>
[0389] The compounds represented by the general formula (I),
wherein X is --NHCONH-- (the hydrogen atom on said connecting group
may be substituted), can be prepared, for example, by a method
described in the reaction scheme 5. ##STR1043## wherein each of
ring Z and E has the same meaning as that defined in the general
formula (I).
[0390] First, the target compound urea (18) can be prepared by
reacting the amine
[0391] (16) with the isocyanate (17). This reaction is carried out
in a solvent at a reaction temperature of from 0.degree. C. to the
boiling point of the solvent, in the presence or absence of a base.
As the base, examples include inorganic base such as sodium
hydroxide, potassium hydroxide, sodium carbonate, potassium
carbonate, sodium hydrogencarbonate or the like, or organic base
such as pyridine, triethylamine, N,N-diethylaniline or the like.
Examples include inert solvent, and tetrahydrofuran, 1,4-dioxane,
methanol, ethanol, water or the like are preferable.
<Method 6>
[0392] The compounds represented by the general formula (I),
wherein X is the formula: --CONHNHCH.sub.2-- (the hydrogen atom on
said connecting group may be substituted), can be prepared, for
example, by a method described in the reaction scheme 6.
##STR1044## wherein each of ring Z and E has the same meaning as
that defined above, and V represents a leaving group such as
halogen atom.
[0393] The target compound hydrazide (24) can be prepared by
reacting the hydrazide (22) with the benzyl derivative (23).
[0394] This reaction is carried out at a reaction temperature of
from 0.degree. C. to 180.degree. C. in a solvent, in the presence
or absence of a base.
[0395] As the base, for example, organic base such as pyridine,
triethylamine or the like can preferably be used.
[0396] As the reaction solvent, any solvent can be used as long as
it does not inhibit the reaction, for example, halogenated solvent
such as dichloromethane; ethers such as tetrahydrofuran; and
hydrocarbon solvent such as toluene can be used.
<Method 7>
[0397] The compounds represented by the general formula (I),
wherein X is the formula: ##STR1045## can be prepared, for example,
by a method described in the reaction scheme 7. ##STR1046## wherein
each of ring Z and E has the same meaning as that defined
above.
[0398] The target compound
5-(benzylidene)-3-benzylthiazolidin-2,4-dione derivative (26) can
be prepared by reacting the aldehyde (9-1) with the
3-benzylthiazolidin-2,4-dione derivative (25).
[0399] This reaction is carried out at a reaction temperature of
from 0.degree. C. to 180.degree. C. in a solvent, in the presence
of a catalyst. As the catalyst, for example, a mixture of
piperidine/acetic acid can preferably be used. As the reaction
solvent, any solvent can be used as long as it does not inhibit the
reaction, for example, hydrocarbon solvent such as toluene can be
used.
[0400] The 3-benzylthiazolidine-2,4-dione derivative represented by
the following formula: ##STR1047## wherein E has the same meaning
as that defined above, can be prepared, for example, by a method
described in the reaction scheme 7-1. ##STR1048## wherein each of E
and V has the same meaning as that defined above.
[0401] The target compound 3-benzylthiazolidine-2,4-dione
derivative (28) can be prepared by reacting thiazolidine-2,4-dione
(30) with the benzyl derivative (23).
[0402] This reaction is carried out at a reaction temperature of
from 0.degree. C. to 180.degree. C. in a solvent, in the presence
of a base. As the base, for example, inorganic base such as sodium
hydroxide, potassium carbonate or the like, or organic base such as
pyridine, triethylamine or the like can preferably be used.
[0403] As the reaction solvent, any solvent can be used as long as
it does not inhibit the reaction, for example, water; alcohols such
as ethanol or the like; halogenated solvent such as dichloromethane
or the like; ethers such as tetrahydrofuran or the like; or amides
such as N,N-dimethylformamide or the like can be used.
[0404] The compounds represented by the general formulas (I),
(I-1), (I-2), (I-3) and (I-4) prepared by the aforementioned
methods can be isolated and purified by methods widely known by
those skilled in the art, for example, extraction, precipitation,
fractional chromatography, fractional crystallization, suspension
and washing, and recrystallization. Furthermore, each of the
pharmaceutically acceptable salt of the compound of the present
invention, the hydrate thereof and the solvate thereof can be
prepared by methods widely known by those skilled in the art.
[0405] In the examples of the specification, preparation methods of
typical compounds included in the general formulas (I), (I-1),
(I-2), (I-3) and (I-4) are explained in details. Therefore, those
skilled in the art can prepare any compound fall within the general
formulas (I), (I-1), (I-2), (I-3) and (I-4) by referring to the
explanations of the aforementioned general preparation methods and
those of specific preparation methods of the examples, by choosing
appropriate reaction raw materials, reaction reagents, and reaction
conditions, and by adding appropriate modification and alteration
of these methods, if necessary.
[0406] The compounds represented by the general formulas (I),
(I-1), (I-2), (I-3), and (I-4) have antiallergic action, and
accordingly, they are useful as active ingredients of the
medicaments for the preventive and/or therapeutic treatment of
allergic diseases. The aforementioned medicaments have inhibitory
activity against the proliferation of mast cells, inhibitory
activity against the production of IgE from activated B cells, and
inhibitory activity against the degranulation from activated mast
cells. Therefore, they can be suitably used as a suppressant
against allergic reaction expression. More specifically, the
medicaments of the present invention are useful for the preventive
and/or therapeutic treatment of the following diseases wherein
allergic reaction is believed to be involved, for example, allergic
diseases such as contact dermatitis, a topic dermatitis, eczema,
pruritus, pollinosis, asthma, bronchitis, urticaria, vasculitis,
rhinitis, gastrointestinal symptoms, diarrhea, interstitial
pneumonia, arthritis, ophthalmia, conjunctivitis, neuritis, otitis
media, granulomatosis, encephalomyelitis, cystitis, laryngitis,
peliosis, food allergy, insect allergy, drug allergy, metal
allergy, anaphylactic shock and the like, and/or endometriosis
and/or hysteromyoma.
[0407] Furthermore, in endometriosis, it is known that an adhesion
of the uterus with its peripheral tissue frequently occurs due to
an abnormal proliferation of endometrial tissue outside the uterus.
It is known that this is caused by an inflammatory reaction by
allergy and the like, and a phenomenon called as "remodeling"
including fibrosis and hyperplasia of tissue as typical examples
occurs (Frontiers in Bioscience, (USA), 2002, Vol. 7, the April 1
issue, p.e 91-115). As for the fibrosis of tissue, it is widely
known that one of the causes is a production of a large amount of
collagen, which is triggered by infiltration of effector cells and
activation of proliferation of fibroblast by inflammation. This
remodeling phenomenon is considered to be occurred on the basis of
a mechanism common in the remodeling of cardiac muscle after
myocardial infarction, the remodeling of a vessel by
arteriosclerosis, the remodeling of bronchus by bronchial asthma or
the like, as well as in the adhesion of a tissue in endometriosis.
Accordingly, an inhibitor against the proliferation or activation
of a fibroblast is considered to be useful as a therapeutic drug
not only for endometriosis but for diseases in which fibrosis or
remodeling of a tissue is believed to be involved, for example,
myocardial infarction, arteriosclerosis, asthma, nephritis,
interstitial pneumonia, pulmonary fibrosis, hepatic cirrhosis and
the like.
[0408] The compounds of the present invention was found to inhibit
cell proliferation of HT-1080, which is a fibrosarcoma cell having
properties similar to those of fibroblast and collagen
productivity, under proliferative stimulation by PDGF
(platelet-derived growth factor). Therefore, they are considered to
be useful as a therapeutic drug and/or a preventive drug for
diseases in which fibrosis or remodeling of tissue is involved.
[0409] As the active ingredient of the medicament on the present
invention, one or more kinds of substances selected from the group
consisting of the compound represented by the general formulas (I),
(I-1), (I-2), (I-3) and (I-4) and a pharmacologically acceptable
salt thereof, and a hydrate thereof and a solvate thereof may be
used. The aforementioned substance, per se, may be administered as
the medicament of the present invention, however, preferably, the
medicament of the present invention is provided in the form of a
pharmaceutical composition comprising the aforementioned substance
which is an active ingredient together with one or more
pharmacologically acceptable pharmaceutical additives. In the
aforementioned pharmaceutical compositions, a ratio of the active
ingredient to the pharmaceutical additives is 1 weight % to 90
weight %.
[0410] The pharmaceutical compositions of the present invention may
be administered as pharmaceutical compositions for oral
administration, for example, granules, subtilized granules,
powders, hard capsules, soft capsules, syrup, emulsion, suspension,
or solution, or may be administered as pharmaceutical compositions
for parenteral administration, for example, injections for
intravenous administration, intramuscular administration, or
subcutaneous administration, drip infusions, suppositories,
percutaneous absorbent, transmucosal absorption preparations, nasal
drops, ear drops, instillation, and inhalants. Preparations made as
pharmaceutical compositions in a form of powder may be dissolved
when necessary and used as injections or drip infusions.
[0411] For preparation of pharmaceutical compositions, solid or
liquid pharmaceutical additives may be used. Pharmaceutical
additives may either be organic or inorganic. When an oral solid
preparation is prepared, an excipient is added to the active
ingredient, and further binders, disintegrator, lubricant,
colorant, corrigent are added, if necessary, to manufacture
preparations in the forms of tablets, coating tablets, granules,
powders, capsules and the like by ordinary procedures. Examples of
the excipient include lactose, sucrose, saccharose, glucose, corn
starch, starch, talc, sorbit, crystal cellulose, dextrin, kaolin,
calcium carbonate, and silicon dioxide. Examples of the binder
include, for example, polyvinyl alcohol, polyvinyl ether, ethyl
cellulose, methyl cellulose, gum Arabic, tragacanth, gelatine,
shellac, hydroxypropyl cellulose, hydroxypropyl methyl cellulose,
calcium citrate, dextrin, and pectin. Examples of the lubricant
include, for example, magnesium stearate, talc, polyethylene
glycol, silica, and hydrogenated vegetable oil. As the coloring
agent, any material can be used which are approved to be added to
ordinary pharmaceuticals. As the corrigent, cocoa powder, menthol,
aromatic acid, peppermint oil, d-borneol, cinnamon powder and the
like can be used. These tables and granules may be applied with
sugarcoating, gelatin coating, or an appropriate coating, if
necessary. Preservatives, antioxidant and the like may be added, if
required.
[0412] For liquid preparations for oral administration such as
emulsions, syrups, suspensions, and solutions, ordinary used
inactive diluents, for example, water or vegetable oil may be used.
For these preparations, besides inactive diluents, adjuvants such
as wetting agents, suspending aids, sweating agents, flavoring
agents, coloring agents or preservatives may be blended. After a
liquid preparation is manufactured, the preparation may be filled
in capsules made of a absorbable substance such as gelatin.
Examples of solvents or suspending agents used for the preparations
of parenteral administration such as injections or suppositories
include, for example, water, propylene glycol, polyethylene glycol,
benzyl alcohol, ethyl oleate, and lecithin. Examples of base
materials used for preparation of suppositories include, for
example, cacao butter, emulsified cacao butter, lauric fat, and
witepsol. Methods for preparation of the aforementioned
preparations are not limited, and any method ordinarily used in the
art may be used.
[0413] When the composition are prepared in the form of injections,
carriers such as, for example, diluents including water, ethanol,
macrogol, propylene glycol, citric acid, acetic acid, phosphoric
acid, lactic acid, sodium lactate, sulfuric acid and sodium
hydroxide, pH modifiers and buffer solutions including sodium
citrate, sodium acetate and sodium phosphate, stabilizers such as
sodium pyrosulfite, ethylenediaminetetraacetic acid, thioglycolic
acid and thiolactate may be used. For the preparation, a sufficient
amount of a salt, glucose, mannitol or glycerin may be blended in
the preparation to manufacture an isotonic solution, and an
ordinary solubilizer, a soothing agent, or a topical anesthetic may
be used.
[0414] When the preparation in the form of an ointment such as a
paste, a cream, and a gel is manufactured, an ordinarily used base
material, a stabilizer, a wetting agent, and a preservative may be
blended, if necessary, and may be prepared by mixing the components
by a common method. As the base material, for example, white
petrolatum, polyethylene, paraffin, glycerin, cellulose
derivatives, polyethylene glycol, silicon, and bentonite may be
used. As the preservative, paraoxy methyl benzoate, paraoxy ethyl
benzoate, paraoxy propyl benzoate and the like may be used. When
the preparation in the form of a patch is manufactured, the
aforementioned ointment, cream gel, or paste and the like may be
applied by a common method to an ordinary support. As the support,
fabric made of cotton, span rayon, and synthetic fibers or nonwoven
fabric, and a film or a foam sheet such as made of soft vinyl
chloride, polyethylene, and polyurethane and the like may be
preferably used.
[0415] A dose of the medicament of the present invention is not
particularly limited. For oral administration, a dose may generally
be 0.01 to 5,000 mg per day for an adult as the weight of the
compound of the present invention. It is preferred to increase or
decrease the above dose appropriately depending on the age,
pathological conditions, and symptoms of a patient. The above dose
may be administered once a day or 2 to 3 times a day as divided
portions with appropriate intervals, or intermittent administration
for every several days may be applied. When the medicament is used
as an injection, the dose may be 0.001 to 100 mg per day for an
adult as the weight of the compound of the present invention.
EXAMPLES
[0416] The present invention will be explained more specifically
with reference to the following examples. However the scope of the
present invention is not limited to the following examples. The
compound number in the following examples correspond to those in
the table shown above. And the commercially available compounds,
which were purchased and used for the examinations, are contained
in these examples. As for such compounds, the suppliers of the
reagents and the catalog code numbers are shown.
Example 1
Preparation of the Compound of Compound No. 1
[0417] Under argon atmosphere,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (it is
abbreviated as WSC.HCl hereafter; 192 mg, 1 mmol) was added to a
mixture of 5-bromosalicylic acid (217 mg, 1 mmol),
3,5-bis(trifluoromethyl)benzylamine (243 mg, 1 mmol),
4-dimethylaminopyridine (12 mg, 0.1 mmol) and tetrahydrofuran (10
mL), and the mixture was stirred at room temperature for 1 hour.
The reaction mixture was poured into diluted hydrochloric acid and
extracted with ethyl acetate. After the organic layer was washed
with water and brine, dried over anhydrous magnesium sulfate, the
residue obtained by evaporation under reduced pressure was purified
by chromatography on silica gel (n-hexane:ethyl acetate=4:1) to
give the title compound (244.8 mg, 55.4%) as a white solid.
[0418] .sup.1H-NMR(DMSO-d.sub.6):.delta. 4.69(2H, d, J=5.7 Hz),
6.93(1H, d, J=8.7 Hz), 7.56(1H, dd, J=8.7, 2.4 Hz), 8.02(1H, d,
J=2.4 Hz), 8.06(3H, s), 9.41(1H, t, J=5.7 Hz), 12.13(1H, s).
Example 2
Preparation of the Compound of Compound No. 2
(1) 2-Acetoxy-N-(2-phenethyl)benzamide
[0419] O-Acetylsalicyloyl chloride (0.20 g, 1.00 mmol) was
dissolved in benzene (8 mL). Phenethylamine (0.12 g, 1.00 mmol) and
pyridine (0.3 mL) were added, and the mixture was stirred at room
temperature for 2 hours. The reaction mixture was poured into
diluted hydrochloric acid and extracted with ethyl acetate. After
the organic layer was washed with water and brine, dried over
anhydrous sodium sulfate, the residue obtained by evaporation under
reduced pressure was purified by chromatography on silica gel
(n-hexane:ethyl acetate=2:1.fwdarw.1:1) to give the title compound
(155.5 mg, 54.9%) as a white crystal.
[0420] .sup.1H-NMR(CDCl.sub.3):.delta. 2.09(3H, s), 2.92(2H, t,
J=6.8 Hz), 3.71(2H, q, J=6.8 Hz), 6.32(1H, brs), 7.07(1H, dd,
J=8.4, 1.2 Hz), 7.23-7.35(6H, m), 7.44(1H, ddd, J=8.0, 7.6, 1.6
Hz), 7.73(1H, dd, J=7.6, 1.6 Hz).
[0421] When the preparation method described in Example 2(1) is
referred in the following examples, organic bases such as pyridine,
triethylamine or the like were used as the base. As the reaction
solvent, solvents such as dichloromethane, tetrahydrofuran, benzene
or the like were used alone or as a mixture.
(2) 2-Hydroxy-N-(2-phenethyl)benzamide
[0422] Methanol (5 mL) and 2N sodium hydroxide (0.1 mL) were added
to 2-acetoxy-N-(2-phenethyl)benzamide (155.5 mg), and the mixture
was stirred at room temperature for 30 minutes. The reaction
mixture was poured into diluted hydrochloric acid and extracted
with ethyl acetate. After the organic layer was washed with water
and brine, dried over anhydrous sodium sulfate, the residue
obtained by evaporation under reduced pressure was crystallized
(dichloromethane/hexane) to give the title compound (106.9 mg,
80.7%) as a white solid.
[0423] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.86(2H, t, J=7.6 Hz),
3.52(1H, q, J=7.6 Hz), 6.84-6.88(2H, m), 7.18-7.31(5H, m), 7.37(1H,
ddd, J=8.4, 7.2, 1.6 Hz), 7.80(1H, dd, J=8.4, 1.6 Hz), 8.84(1H, s),
12.51(1H, s).
[0424] When the method described in Example 2(2) is referred in the
following examples, inorganic bases such as sodium hydroxide,
potassium carbonate or the like were used as the base. As the
reaction solvent, solvents such as water, methanol, ethanol,
tetrahydrofuran or the like were used alone or as a mixture.
(3) 5-Bromo-2-hydroxy-N-(2-phenethyl)benzamide (Compound No. 2)
[0425] Carbon tetrachloride (5 mL), iron powder (0.03 g) and
bromine (25 .mu.l, 0.48 mmol) were added to
2-hydroxy-N-(2-phenethyl)benzamide (79.6 mg, 0.33 mmol), and the
mixture was stirred at room temperature for 1 hour. The reaction
mixture was poured into aqueous sodium hydrogen sulfite and
extracted with ethyl acetate. After the organic layer was washed
with brine, dried over anhydrous sodium sulfate, the residue
obtained by evaporation under reduced pressure was purified by
chromatography on silica gel (n-hexane:ethyl acetate=5:1) to give
the title compound (62 mg, 58.7%) as a white powder.
[0426] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.85(2H, t, J=7.6 Hz),
3.52(1H, q, J=7.6 Hz), 6.87(1H, d, J=8.8 Hz), 7.18-7.31(5H, m),
7.52(1H, dd, J=8.8, 2.4 Hz), 8.01(1H, d, J=2.4 Hz), 8.90(1H, s),
12.51(1H, s).
Example 3
Preparation of the Compound of Compound No. 3
[0427] WSC.HCl (96 mg, 0.5 mmol) was added to a solution of
5-bromosalicylic acid (109 mg, 0.5 mmol),
2-amino-5-(morpholino)carbonylindane (141 mg, 0.5 mmol) and
triethylamine (70 .mu.L, 0.5 mmol) in dichloromethane (5 mL), and
the mixture was stirred at 40.degree. C. for 1.5 hours. After
cooling, the reaction mixture was diluted with ethyl acetate,
washed successively with 2N hydrochloric acid, water, and brine,
dried over anhydrous magnesium sulfate, concentrated, and the
residue was purified by column chromatography on silica gel
(dichloromethane:methanol=19:1) to give the title compound (26 mg,
11.9%) as a white crystal.
[0428] .sup.1H-NMR(CDCl.sub.3):.delta. 2.66(1H, dd, J=16.2, 7.2
Hz), 2.82(1H, dd, J=16.2, 7.2 Hz), 3.16-3.25(2H, m), 3.43-3.86(8H,
m), 4.79-4.92(1H, m), 6.88(1H, d, J=8.7 Hz), 7.14-7.15(3H, m),
7.46(1H, dd, J=8.7, 2.4 Hz), 7.74(1H, d, J=7.8 Hz), 7.84(1H, d,
J=2.4 Hz).
[2-Amino-5-(morpholino)carbonylindane: Refer to "Chemical and
Pharmaceutical Bulletin", 2000, Vol. 48, p. 131.]
Example 4
The Compound of Compound No. 4
[0429] This compound is a commercially available compound.
Supplier: Apin Chemicals.
Catalog code number: N 0100D.
Example 5
The Compound of Compound No. 5
[0430] This compound is a commercially available compound.
Supplier: Specs.
Catalog code number: AI-233/31581024.
Example 6
The Compound of Compound No. 6
[0431] This compound is a commercially available compound.
Supplier: Maybridge.
Catalog code number: RJC 00106.
Example 7
The Compound of Compound No. 7
[0432] This compound is a commercially available compound.
Supplier: Maybridge.
Catalog code number: BTB 13230.
Example 8
The Compound of Compound No. 8
[0433] This compound is a commercially available compound.
Supplier: Maybridge.
Catalog code number: BTB 114482.
Example 9
Preparation of the Compound of Compound No. 9
[0434] 5-Chlorosalicylaldehyde (313 mg, 2 mmol) and
4-chlorobenzyltriphenylphosphonium chloride (847 mg, 2 mmol) were
dissolved in N,N-dimethylfomamide (20 mL). Potassium carbonate
(1.382 g, 10 mmol) dissolved in water (10 mL) was added, and the
mixture was refluxed for 5 hours. After cooling, the reaction
mixture was poured into 2N hydrochloric acid and extracted with
ethyl acetate. After the organic layer was washed with water and
brine, dried over anhydrous magnesium sulfate, the residue obtained
by evaporation under reduced pressure was purified by
chromatography on silica gel (n-hexane:ethyl acetate=3:1) to give
the title compound (44.6 mg, 8.4%) as a light gray solid.
[0435] .sup.1H-NMR(CDCl.sub.3):.delta. 5.04(1H, s), 6.74(1H, d,
J=9.0 Hz), 7.05(1H, d, J=16.5 Hz), 7.10(1H, dd, J=8.4, 2.4 Hz),
7.26(1H, d, J=16.5 Hz), 7.33(2H, d, J=8.4 Hz), 7.45(2H, d, J=8.4
Hz), 7.49(1H, d, J=2.4 Hz).
Example 10
Preparation of the Compound of Compound No. 10
(1) 5-Bromo-N-(3,5-dichlorophenyl)-2-methoxybenzenesulfonamide
[0436] 5-Bromo-2-methoxybenzenesulfonyl chloride (857 mg, 3 mmol)
was dissolved in dichloromethane (6 mL). A solution of
3,5-dichloroaniline (510 mg, 3.15 mmol) and pyridine (261 mg, 3.3
mmol) in dichloromethane (2 mL) was added dropwise under ice
cooling and argon atmosphere, and the mixture was stirred at room
temperature for 6 hours. After the reaction mixture was diluted
with dichloromethane, washed successively with 2N hydrochloric
acid, water, and brine, dried over anhydrous magnesium sulfate, the
solvent was evaporated under reduced pressure. The obtained residue
was crystallized from n-hexane-ethyl acetate to give
5-bromo-2-methoxy-N-(3,5-dichloro)benzenesulfonamide (900 mg,
73.0%) as a white crystal.
[0437] .sup.1H-NMR(DMSO-d.sub.6):.delta. 4.03(3H, s), 6.92(1H, d,
J=9.0 Hz), 7.01(2H, d, J=1.8 Hz), 7.07-7.08(1H, m), 7.24(1H, brs),
7.63(1H, dd, J=8.7, 2.4 Hz), 7.99(1H, d, J=2.4 Hz).
(2) 5-Bromo-N-(3,5-dichlorophenyl)-2-hydroxybenzenesulfonamide
(Compound No. 10)
[0438] A mixture of the white crystal of
5-Bromo-N-(3,5-dichlorophenyl)-2-methoxybenzenesulfonamide (206 mg,
0.5 mmol), lithium iodide (134 mg, 1 mmol) and 2,4,6-collidine (5
mL) was refluxed for 30 minutes under argon atmosphere. After
cooling to room temperature, the reaction mixture was poured into
2N hydrochloric acid and extracted with ethyl acetate. After the
ethyl acetate layer was washed successively with water and brine,
dried over anhydrous magnesium sulfate, the solvent was evaporated
under reduced pressure. The obtained residue was crystallized from
n-hexane-ethyl acetate to give the title compound (90 mg, 45.3%) as
a white crystal.
[0439] mp 158-159.degree. C.
[0440] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.92(1H, d, J=8.7 Hz),
7.11(2H, d, J=2.1 Hz), 7.21-7.22(1H, m), 7.62(1H, dd, J=8.7, 2.7
Hz), 7.80(1H, d, J=2.4 Hz), 10.70(1H, br), 11.37(1H, br).
Example 11
Preparation of the Compound of Compound No. 11
[0441] 2-Aminophenol (120 mg, 1.1 mmol) was dissolved in
dichloromethane (5 mL). A solution of
3,5-bis(trifluoromethyl)benzoyl chloride (300 mg, 1.1 mmol) in
dichloromethane (3 mL) and pyridine (0.5 mL) was added dropwise
under ice cooling and argon atmosphere, and the mixture was stirred
at room temperature for 1 hour. The reaction mixture was poured
into 2N hydrochloric acid and extracted with ethyl acetate. After
the ethyl acetate layer was washed successively with water and
brine, dried over anhydrous magnesium sulfate, the solvent was
evaporated under reduced pressure. The obtained residue was
dissolved in ethanol (5 mL). 2N Sodium hydroxide (0.1 mL, 0.2 mmol)
was added dropwise, and the mixture was stirred at room temperature
for 30 minutes. The reaction mixture was poured into 2N
hydrochloric acid and extracted with ethyl acetate. After the ethyl
acetate layer was washed successively with water and brine, dried
over anhydrous sodium sulfate, the solvent was evaporated under
reduced pressure. The obtained residue was purified by column
chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give
the title compound (288 mg, 73.6%) as a light pink crystal.
[0442] mp 183.degree. C. (dec.).
[0443] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.83(1H, td, J=8.0, 1.2
Hz), 6.93(1H, dd, J=8.0, 1.2 Hz), 7.08(1H, td, J=8.0, 1.6 Hz),
7.50(1H, d, J=8.0 Hz), 8.35(2H, s), 9.61(1H, s), 10.15(1H, s).
Example 12
Preparation of the Compound of Compound No. 12
[0444] 2-Amino-4-chlorophenol (316 mg, 2.2 mmol) and triethylamine
(243 mg, 2.4 mmol) were dissolved in dichloromethane (8 mL). A
solution of 3,5-dichlorobenzoyl chloride (419 mg, 2 mmol) in
dichloromethane (2 mL) was added dropwise under ice cooling and
argon atmosphere, and the mixture was stirred at room temperature
for 15 hours. After the reaction mixture was diluted with ethyl
acetate, washed successively with water and brine, dried over
anhydrous magnesium sulfate, the solvent was evaporated under
reduced pressure. The obtained residue was purified by column
chromatography on silica gel (n-hexane:ethyl acetate=3:1) to give a
light brown solid. The solid was suspended and washed with
n-hexane-ethyl acetate under heating at reflux to give the title
compound (205 mg, 32.4%) as a white crystal.
[0445] mp 251-252.degree. C.
[0446] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.93(1H, d, J=9.0 Hz),
7.11(1H, dd, J=8.7, 2.7 Hz), 7.67(2H, d, J=2.7 Hz), 7.86-7.87(1H,
m), 7.97(1H, d, J=1.8 Hz), 9.85(1H, s), 10.03(1H, s).
Example 13
Preparation of the Compound of Compound No. 13
[0447] 2-Amino-4-chlorophenol (287 mg, 2 mmol) and
3,5-dichlorobenzenesulfonyl chloride (540 mg, 2.2 mmol) were
dissolved in dichloromethane (4 mL). Pyridine (1 mL) was added
dropwise under ice cooling and argon atmosphere, and the mixture
was stirred at room temperature for 1 hour. The reaction mixture
was poured into 2N hydrochloric acid and extracted with ethyl
acetate. After the ethyl acetate layer was washed successively with
water and brine, dried over anhydrous magnesium sulfate, the
solvent was evaporated under reduced pressure. The obtained residue
was purified by column chromatography on silica gel (n-hexane:ethyl
acetate=3:1.fwdarw.1:1) to give a reddish brown solid. The solid
was crystallized from n-hexane-ethyl acetate to give the title
compound (445 mg, 63.1%) as a slight dark brown crystal.
[0448] mp 190-191.degree. C.
[0449] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.68(1H, d, J=9.0 Hz),
7.08(1H, dd, J=8.7, 2.7 Hz), 7.17(1H, d, J=2.4 Hz), 7.70(2H, d,
J=1.8 Hz), 7.95-7.96(1H, m), 10.00(1H, s), 10.06(1H, s).
Example 14
Preparation of the Compound of Compound No. 14
(1) 4-Bromo-2-[(3,5-diphenylimino)methyl]phenol
[0450] A mixture of 5-bromosalicylaldehyde (1.01 g, 5 mmol),
3,5-dichloroaniline (810 mg, 5 mmol) and ethanol (25 mL) was
refluxed for 1 hour under argon atmosphere. After the reaction
mixture was cooled to room temperature, the separated crystal was
filtered to give the title compound (1.52 g, 88.2%) as an orange
crystal.
[0451] mp 161-163.degree. C.
[0452] .sup.1H-NMR(CDCl.sub.3):.delta. 6.94(1H, d, J=9.0 Hz),
7.16(2H, d, J=1.8 Hz), 7.30-7.31(1H, m), 7.47-7.53(2H, m), 8.51(1H,
s).
(2) N-[(5-Bromo-2-hydroxyphenyl)methyl]-3,5-dichloroaniline
(Compound No. 14)
[0453] 4-Bromo-2-[(3,5-diphenylimino)methyl]phenol (1.04 g, 3 mmol)
was dissolved in tetrahydrofuran (12 mL) and ethanol (6 mL). Sodium
borohydride (113 mg, 3 mmol) was added under ice cooling and argon
atmosphere, and the mixture was stirred at room temperature for 12
hours. Acetone (10 mL) was added to the reaction mixture. Water was
added to the residue obtained by concentration under reduced
pressure, and it was extracted with dichloromethane. After the
dichloromethane layer was washed successively with water and brine,
dried over anhydrous magnesium sulfate, the solvent was evaporated
under reduced pressure. The obtained residue was purified by column
chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give a
light yellow viscous material. This was crystallized by n-hexane to
give the title compound (971 mg, 93.3%) as a white crystal.
[0454] mp 125-126.degree. C.
[0455] .sup.1H-NMR(CDCl.sub.3):.delta. 4.31(2H, s), 6.64(2H, d,
J=1.8 Hz), 6.74-6.77(1H, m), 6.84-6.85(1H, m), 7.30-7.34(2H,
m).
Example 15
The Compound of Compound No. 15
[0456] This compound is a commercially available compound.
Supplier: Sigma-Aldrich.
Catalog code number: S3203-5.
Example 16
Preparation of the Compound of Compound No. 16
[0457] A mixture of 5-chlorosalicylic acid (173 mg, 1 mmol),
3,5-bis(trifluoromethyl)-N-methylaniline (243 mg, 1 mmol),
phosphorus trichloride (44 .mu.l, 0.5 mmol) and monochlorobenzene
(5 mL) was refluxed for 3 hours under argon atmosphere. After the
reaction mixture was cooled to room temperature, n-hexane (50 mL)
was added, and the separated crude crystal was filtered and
dissolved in ethyl acetate (50 mL). After the ethyl acetate
solution was washed successively with water and brine, dried over
anhydrous sodium sulfate, the solvent was evaporated under reduced
pressure. The obtained residue was purified by column
chromatography on silica gel (n-hexane:ethyl acetate=2:1) to give
the title compound (75 mg, 18.9%) as a white crystal.
[0458] .sup.1H-NMR(CDCl.sub.3):.delta. 3.57(3H, s), 6.59(1H, d,
J=2.4 Hz), 6.94(1H, d, J=9.0 Hz), 7.21(1H, dd, J=9.0, 2.7 Hz),
7.58(2H, s), 7.80(1H, s), 10.00(1H, brs).
[0459] When the method described in Example 16 is referred in the
following examples, phosphorus trichloride was used as the acid
halogenating agent. As the reaction solvent, solvents such as
monochlorobenzene, toluene or the like were used.
Example 17
Preparation of the Compound of Compound No. 17
[0460] Using 5-bromosalicylic acid and
7-trifluoromethyl-1,2,3,4-tetrahydroquinoline as the raw materials,
the same operation as the Example 16 gave the title compound.
[0461] Yield: 42.0%.
[0462] .sup.1H-NMR(CDCl.sub.3):.delta. 2.08(2H, m), 2.92(2H, t,
J=6.6 Hz), 3.95(2H, t, J=6.6 Hz), 6.91-6.94(2H, m), 7.14(1H, s),
7.32-7.35(2H, m), 7.40(1H, dd, J=8.7, 2.4 Hz), 10.06(1H, s).
Example 18
Preparation of the Compound of Compound No. 18
[0463] Using 2-hydroxynaphthalene-1-carboxylic acid and
3,5-dichloroaniline as the raw materials, the same operation as the
Example 16 gave the title compound.
[0464] Yield: 51.2%.
[0465] mp 246-248.degree. C.
[0466] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.26(1H, d, J=9.3 Hz),
7.31-7.37(2H, m), 7.44-7.50(1H, m), 7.65-7.68(1H, m), 7.85-7.90(4H,
m), 10.23(1H, s), 10.74(1H, s).
Example 19
Preparation of the Compound of Compound No. 19
[0467] Using 3-hydroxynaphthalene-2-carboxylic acid and
3,5-dichloroaniline as the raw materials, the same operation as the
Example 16 gave the title compound.
[0468] Yield: 44.3%.
[0469] mp 254-255.degree. C.
[0470] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.34-7.39(3H, m),
7.49-7.54(1H, m), 7.76-7.79(1H, m), 7.89(2H, d, J=1.8 Hz), 7.92(1H,
m), 8.39(1H, s), 10.75(1H, s), 11.01(1H, s).
Example 20
The Compound of Compound No. 20
[0471] This compound is a commercially available compound.
Supplier: Sigma-Aldrich.
Catalog code number: S01361-8.
Example 21
Preparation of the Compound of Compound No. 21
[0472] Using 1-hydroxynaphthalene-2-carboxylic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0473] Yield: 65.5%.
[0474] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.51(1H, d, J=9.0 Hz),
7.60(1H, td, J=7.8, 0.9 Hz), 7.70(1H, td, J=7.8, 0.9 Hz), 7.89(1H,
s), 7.93(1H, d, J=8.4 Hz), 8.09(1H, d, J=9.0 Hz), 8.33(1H, d, J=8.7
Hz), 8.51(2H, s), 10.92(1H, s), 13.36(1H, s).
Example 22
The Compound of Compound No. 22
[0475] This compound is a commercially available compound.
Supplier: Sigma-Aldrich.
Catalog code number: S58026-0.
Example 23
The Compound of Compound No. 23
[0476] This compound is a commercially available compound.
Supplier: Sigma-Aldrich.
Catalog code number: S63263-5.
Example 24
Preparation of the Compound of Compound No. 24
[0477] 5-Chloro-2-hydroxynicotinic acid (174 mg, 1 mmol),
3,5-bis(trifluoromethyl)aniline (275 mg, 1.2 mmol) and pyridine
(316 mg, 4 mmol) were dissolved in tetrahydrofuran (20 mL) and
dichloromethane (10 mL). Phosphorus oxychloride (0.112 ml, 1.2
mmol) was added, and the mixture was stirred at room temperature
for 2 hours. The reaction mixture was poured into ethyl acetate
(100 mL) and 0.2N hydrochloric acid (100 mL), filtered through
celite after stirring for 30 minutes, and the water layer of the
filtrate was extracted with ethyl acetate. After the combined ethyl
acetate layer was washed successively with water and brine, dried
over anhydrous magnesium sulfate, the solvent was evaporated under
reduced pressure. The residue was purified by column chromatography
on silica gel (n-hexane:ethyl acetate=2:1.fwdarw.1:1) to give a
light yellow solid. This was suspended and washed with ethanol
under heating at reflux to give the title compound (183 mg, 47.6%)
as a white crystal.
[0478] mp>270.degree. C.
[0479] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.83(1H, s), 8.15(1H, d,
J=3.3 Hz), 8.36(1H, d, J=3.0 Hz), 8.40(2H, s), 12.43(1H, s).
[0480] When the preparation method described in Example 24 is
referred in the following examples, phosphorus oxychloride was used
as the acid halogenating agent. Pyridine was used as the base. As
the reaction solvent, solvents such as dichloromethane,
tetrahydrofuran or the like were used alone or as a mixture.
Example 25
Preparation of the Compound of Compound No. 25
[0481] Using 5-chloro-2-hydroxynicotinic acid and
2-chloro-5-(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 24 gave the title compound.
[0482] Yield: 42.9%.
[0483] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.52(1H, dd, J=8.4, 2.1
Hz), 7.81(1H, d, J=8.4 Hz), 8.16(1H, s), 8.39(1H, d, J=2.7 Hz),
8.96(1H, d, J=2.1 Hz), 12.76(1H, s), 13.23(1H, s).
Example 26
Preparation of the Compound of Compound No. 26
[0484] Using 5-chloro-2-hydroxynicotinic acid and
3,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the same
operation as the Example 24 gave the title compound.
[0485] Yield: 59.1%.
[0486] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.29(18H, s), 7.18(1H, t,
J=1.8 Hz), 7.52(2H.d, J=1.8 Hz), 8.07(1H, d, J=2.4 Hz), 8.35(1H, d,
J=3.3 Hz), 11.92(1H, s), 13.10(1H, s).
Example 27
Preparation of the Compound of Compound No. 27
[0487] Using 3-hydroxypyridine-2-carboxylic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 24 gave the title compound.
[0488] Yield: 45.0%.
[0489] .sup.1H-NMR(CDCl.sub.3):.delta. 7.40(1H, dd, J=8.4, 1.8 Hz),
7.46(1H, dd, J=8.4, 4.2 Hz), 7.68(1H, s), 8.16(1H, dd, J=4.2, 1.2
Hz), 8.25(2H, s), 10.24(1H, s), 11.42(1H, s).
Example 28
Preparation of the Compound of Compound No. 28
[0490] Under argon atmosphere,
3,5-bis(trifluoromethyl)phenylisocyanate (255 mg, 1.0 mmol) was
dissolved in tetrahydrofuran (5 mL). A solution of
6-chloro-oxindole (184 mg, 1.1 mmol) in tetrahydrofuran (5 ml) and
triethylamine (0.3 mL) were added, and the mixture was stirred at
room temperature for 4 hours. The reaction mixture was poured into
diluted hydrochloric acid and extracted with ethyl acetate. After
the organic layer was washed with water and brine, dried over
anhydrous magnesium sulfate, the residue obtained by evaporation
under reduced pressure was purified by chromatography on silica gel
(n-hexane:ethyl acetate=4:1) to give the title compound (172.2 mg,
40.7%) as a pink solid.
[0491] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.97(2H, s), 7.29(1H, dd,
J=8.1, 2.1 Hz), 7.41(1H, d, J=8.1 Hz), 7.88(1H, s), 8.04(1H, d,
J=2.1 Hz), 8.38(2H, s), 10.93(1H, s).
Example 29
Preparation of the Compound of Compound No. 29
[0492] Using 3-hydroxyquinoxaline-2-carboxylic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0493] Yield: 2.7%.
[0494] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.40-7.45(2H, m), 7.69(1H,
td, J=8.4, 1.5 Hz), 7.90-7.93(2H, m), 8.41(2H, s), 11.64(1H, s),
13.02(1H, s).
Example 30
The Compound of Compound No. 30
[0495] This compound is a commercially available compound.
Supplier: Sigma-Aldrich.
Catalog code number: S83846-2.
Example 31
The Compound of Compound No. 31
[0496] This compound is a commercially available compound.
Supplier: Maybridge.
Catalog code number: RDR 01818.
Example 32
Preparation of the Compound of Compound No. 32
[0497] Using 5-chlorosalicylic acid and 1-naphthylamine as the raw
materials, the same operation as the Example 16 gave the title
compound.
[0498] Yield: 65.0%.
[0499] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.09(1H, d, J=8.7 Hz),
7.51-7.61(4H, m), 7.85(1H, d, J=8.4 Hz), 7.96(1H, d, J=7.5 Hz),
7.99-8.05(2H, m), 8.13(1H, d, J=2.7 Hz), 10.88(1H, s), 12:31(1H,
s).
Example 33
Preparation of the Compound of Compound No. 33
[0500] Using 5-chlorosalicylic acid and 4-methoxy-2-naphthylamine
as the raw materials, the same operation as the Example 16 gave the
title compound.
[0501] Yield: 84.3%.
[0502] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.99(3H, s), 7.05(1H, d,
J=9.0 Hz), 7.30(1H, d, J=1.5 Hz), 7.39-7.45(1H, m), 7.48-7.54(2H,
m), 7.83(1H, d, J=7.8 Hz), 8.00(1H, s), 8.02(1H, d, J=2.4 Hz),
8.09(1H, d, J=7.8 Hz), 10.54(1H, s), 11.88(1H, s).
Example 34
Preparation of the Compound of Compound No. 34
(1) 2-Acetoxy-5-chlorobenzoic acid
[0503] Concentrated sulfuric acid (0.08 mL) was added slowly to a
mixture of 5-chlorosalicylic acid (13.35 g, 77 mmol) and acetic
anhydride (20 mL). After the reaction mixture was solidified, it
was poured into ice water and extracted with ethyl acetate. The
organic layer was washed with water and brine, and dried over
anhydrous sodium sulfate. The residue obtained by evaporation of
the solvent under reduced pressure was washed with n-hexane under
suspension to give the title compound (15.44 g, 93.0%) as a white
crystal.
[0504] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.25(3H, s), 7.27(1H, d,
J=8.7 Hz), 7.72(1H, dd, J=8.7, 2.7 Hz), 7.89(1H, d, J=2.7 Hz),
13.47(1H, s).
(2) 2-Acetoxy-5-chloro-N-(1-methoxynaphthalen-3-yl)benzamide
(Compound No. 34)
[0505] Using 2-acetoxy-5-chlorobenzoic acid and
4-methoxy-2-naphthylamine as the raw materials, the same operation
as the Example 24 gave the title compound.
[0506] Yield: 39.9%, red solid.
[0507] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.23(3H, s), 3.96(3H, s),
7.23(1H, d, J=1.2 Hz), 7.34(1H, d, J=8.7 Hz), 7.40(1H, dt, J=8.1,
1.2 Hz), 7.50(1H, dt, J=8.1, 1.5 Hz), 7.67(1H, dd, J=8.7, 2.7 Hz),
7.81(1H, d, J=8.7 Hz), 7.82(1H, d, J=3.0 Hz), 8.02(1H, s), 8.08(1H,
d, J=8.7 Hz), 10.58(1H, s).
Example 35
Preparation of the Compound of Compound No. 35
[0508] Using 5-chlorosalicylic acid and
2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid ethyl
ester as the raw materials, the same operation as the Example 16
gave the title compound.
[0509] Yield: 49.6%.
[0510] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.32(3H, t, J=7.2 Hz),
1.74(4H, br), 2.63(2H, br), 2.75(2H, br), 4.30(2H, q, J=7.2 Hz),
7.05(1H, d, J=9.0 Hz), 7.50(1H, dd, J=8.7, 3.0 Hz), 7.92(1H, d,
J=3.0 Hz), 12.23(1H, s), 13.07(1H, s).
Example 36
Preparation of the Compound of Compound No. 36
[0511] Using 5-bromosalicylic acid and 3-amino-5-phenylpyrazole as
the raw materials, the same operation as the Example 16 gave the
title compound.
[0512] Yield: 9.2%.
[0513] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.98(1H, d, J=8.8 Hz),
7.01(1H, s), 7.35(1H, t, J=7.6 Hz), 7.46(2H, t, J=7.6 Hz), 7.58(1H,
dd, J=8.8, 2.8 Hz), 7.74-7.76(2H, m), 8.19(1H, s), 10.86(1H, s),
12.09(1H, s), 13.00(1H, brs).
Example 37
Preparation of the Compound of Compound No. 37
(1) 2-Amino-4,5-diethyloxazole
[0514] Propioin (1.03 g, 8.87 mmol) was dissolved in ethanol (15
mL). Cyanamide (0.75 g, 17.7 mmol) and sodium ethoxide (1.21 g,
17.7 mmol) were added, and the mixture was stirred at room
temperature for 3.5 hours. The reaction mixture was poured into
water and extracted with ethyl acetate. After the organic layer was
washed with water and brine, dried over anhydrous sodium sulfate,
the residue obtained by evaporation under reduced pressure was
purified by chromatography on silica gel
(dichloromethane:methanol=9:1) to give the title compound (369.2
mg, 29.7%) as an yellow amorphous.
[0515] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.04(3H, t, J=7.5 Hz),
1.06(3H, t, J=7.5 Hz), 2.20(2H, q, J=7.5 Hz), 2.43(2H, q, J=7.5
Hz), 6.15(2H, s).
(2) 2-Acetoxy-5-bromo-N-(4,5-diethyloxazol-2-yl)benzamide
[0516] Using 2-acetoxy-5-bromobenzoic acid and
2-amino-4,5-diethyloxazole as the raw materials, the same operation
as the Example 24 gave the title compound.
[0517] Yield: 22.0%.
[0518] .sup.1H-NMR(CDCl.sub.3):.delta. 1.22(3H, t, J=7.5 Hz),
1.23(3H, t, J=7.5 Hz), 2.38(3H, s), 2.48(2H, q, J=7.5 Hz), 2.57(2H,
q, J=7.5 Hz), 6.96(1H, d, J=8.7 Hz), 7.58(1H, dd, J=8.7, 2.7 Hz),
8.32(1H, s), 11.40(1H, br).
[0519] [2-Acetoxy-5-bromosalicylic acid: It was obtained, using
5-bromosalicylic acid and acetic anhydride as the raw materials, by
the same operation as the Example 34(1) with reference to "European
Journal of Medicinal Chemistry", 1996, Vol. 31, p. 861-874.]
(3) 5-Bromo-N-(4,5-diethyloxazol-2-yl)-2-hydroxybenzamide (Compound
No. 37)
[0520] Using 2-acetoxy-5-bromo-N-(4,5-diethyloxazol-2-yl)benzamide
as the raw material, the same operation as the Example 2(2) gave
the title compound.
[0521] Yield: 70.2%.
[0522] .sup.1H-NMR(CDCl.sub.3).delta. :1.25(3H, t, J=7.5 Hz),
1.26(3H, t, J=7.5 Hz), 2.52(2H, q, J=7.5 Hz), 2.60(2H, q, J=7.5
Hz), 6.84(1H, d, J=8.7 Hz), 7.43(1H, dd, J=8.7, 3.0 Hz), 8.17(1H,
d, J=3.0 Hz), 11.35(1H, br), 12.83(1H, br).
Example 38
Preparation of the Compound of Compound No. 38
[0523] Using 5-bromosalicylic acid and 2-amino-4,5-diphenyloxazole
as the raw materials, the same operation as the Example 16 gave the
title compound.
[0524] Yield: 32.6%.
[0525] mp 188-189.degree. C.
[0526] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.98(1H, d, J=8.7 Hz),
7.40-7.49(6H, m), 7.53-7.56(2H, m), 7.59-7.63(3H, m), 8.01(1H, d,
J=2.4 Hz), 11.80(2H, brs).
[2-Amino-4,5-diphenyloxazole: Refer to "Zhournal Organicheskoi
Khimii: Russian Journal of Organic Chemistry", (Russia), 1980, Vol.
16, p. 2185.]
Example 39
Preparation of the Compound of Compound No. 39
(1) 2-Amino-4,5-bis(furan-2-yl)oxazole
[0527] Furoin (0.50 g, 2.60 mmol) was dissolved in ethanol (15 mL).
Cyanamide (218.8 mg, 5.20 mmol) and sodium ethoxide (530.8 mg, 7.80
mmol) were added, and the mixture was stirred at room temperature
for 2 hours. The reaction mixture was poured into water and
extracted with ethyl acetate. After the organic layer was washed
with water and brine, dried over anhydrous sodium sulfate, the
residue obtained by evaporation under reduced pressure was purified
by chromatography on silica gel (hexane:ethyl
acetate=1:1.fwdarw.1:2) to give the title compound (175.0 mg,
31.1%) as a dark brown crystal.
[0528] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.59(1H, dd, J=3.3, 2.1
Hz), 6.62(1H, dd, J=3.3, 2.1 Hz), 6.73(1H, dd, J=3.3, 0.6 Hz),
6.80(1H, dd, J=3.3, 0.9 Hz), 7.05(2H, s), 7.75-7.76(2H, m).
(2) 5-Bromo-N-[4,5-bis(furan-2-yl)oxazol-2-yl]-2-hydroxybenzamide
(Compound No. 39)
[0529] Using 5-bromosalicylic acid and
2-amino-4,5-bis(furan-2-yl)oxazole as the raw materials, the same
operation as the Example 16 gave the title compound.
[0530] Yield: 12.9%.
[0531] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.65(1H, dd, J=3.6, 1.8
Hz), 6.68(1H, dd, J=3.6, 1.8 Hz), 6.75(1H, d, J=8, 7 Hz), 6.92(1H,
dd, J=3.6, 0.9 Hz), 6.93(1H, d, J=3.3 Hz), 7.37(1H, dd, J=8.7, 2.7
Hz), 7.80(1H, dd, J=1.8, 0.9 Hz), 7.84(1H, dd, J=1.8, 0.9 Hz),
7.92(1H, d, J=3.0 Hz), 14.88(2H, br).
Example 40
Preparation of the Compound of Compound No. 40
(1)
2-Acetoxy-N-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)benzamide
[0532] Using O-acetylsalicyloyl chloride and
2-amino-5-(trifluoromethyl)-1,3,4-thiadiazole as the raw materials,
the same operation as the Example 2(1) gave the title compound.
[0533] Yield: 51.1%.
[0534] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.23(3H, s), 7.32(1H, dd,
J=8.0, 1.2 Hz), 7.45(1H, td, J=7.6, 1.2 Hz), 7.69(1H, td, J=8.0,
2.0 Hz), 7.87(1H, dd, J=8.0, 2.0 Hz), 13.75(1H, brs).
(2) 2-Hydroxy-N-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)benzamide
(Compound No. 40)
[0535] Using
2-acetoxy-N-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)benzamide as
the raw material, the same operation as the Example 2(2) gave the
title compound.
[0536] Yield: 92.9%.
[0537] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.00(1H, td, J=8.0, 0.8
Hz), 7.06(1H, d, J=8.4 Hz), 7.51(1H, ddd, J=8.4, 7.6, 2.0 Hz),
7.92(1H, dd, J=8.0, 1.6 Hz), 12.16(1H, br).
Example 41
Preparation of the Compound of Compound No. 41
[0538] Using 5-bromosalicylic acid and
2-amino-5-trifluoromethyl-1,3,4-thiadiazole as the raw materials,
the same operation as the Example 16 gave the title compound.
[0539] Yield: 80.2%.
[0540] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.01(1H, d, J=9.0 Hz),
7.63(1H, dd, J=8.7, 2.7 Hz), 7.97(1H, d, J=2.4 Hz).
Example 42
Preparation of the Compound of Compound No. 42
[0541] Using 5-chlorosalicylic acid and 5-amino-2-chloropyridine as
the raw materials, the same operation as the Example 16 gave the
title compound.
[0542] Yield: 12.2%.
[0543] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.04(1H, d, J=9.0 Hz),
7.49(1H, dd, J=9.0, 3.0 Hz), 7.54(1H, d, J=8.4 Hz), 7.88(1H, d,
J=2.7 Hz), 8.21(1H, dd, J=8.7, 2.7 Hz), 8.74(1H, d, J=2.7 Hz),
10.62(1H, s), 11.57(1H, s).
Example 43
Preparation of the Compound of Compound No. 43
[0544] Using 5-chlorosalicylic acid and
2-amino-6-chloro-4-methoxypyrimidine as the raw materials, the same
operation as the Example 16 gave the title compound.
[0545] Yield: 2.2%, white solid.
[0546] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.86(3H, s), 6.85(1H, s),
7.01(1H, d, J=9.0 Hz), 7.47(1H, dd, J=9.0, 3.0 Hz), 7.81(1H, d,
J=3.0 Hz), 11.08(1H, s), 11.65(1H, s).
Example 44
Preparation of the Compound of Compound No. 44
[0547] Using 2-acetoxy-5-chlorobenzoic acid and 5-aminoindole as
the raw materials, the same operation as the Example 24 gave the
title compound.
[0548] Yield: 13.3%.
[0549] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.20(3H, s), 6.41(1H, t,
J=2.1 Hz), 7.27-7.36(4H, m), 7.63(1H, dd, J=8.7, 2.7 Hz), 7.74(1H,
d, J=2.7 Hz), 7.93(1H, s), 10.21(1H, s), 11.04(1H, s).
Example 45
The Compound of Compound No. 45
[0550] This compound is a commercially available compound.
Supplier: Peakdale.
Catalog code number: PFC-0448.
Example 46
Preparation of the Compound of Compound No. 46
[0551] Using 5-chlorosalicylic acid and 3-aminoquinoline as the raw
materials, the same operation as the Example 16 gave the title
compound.
[0552] Yield: 4.3%.
[0553] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.07(1H, d, J=8.7 Hz),
7.51(1H, dd, J=9.0, 3.0 Hz), 7.61(1H, dt, J=7.8, 1.2 Hz), 7.70(1H,
dt, J=7.8, 1.5 Hz), 7.98(2H, d, J=3.0 Hz), 8.01(1H, s), 8.82(1H, d,
J=2.4 Hz), 10.80(1H, s), 11.74(1H, s).
Example 47
Preparation of the Compound of Compound No. 47
[0554] Using 5-chlorosalicylic acid and 3-amino-9-ethylcarbazole as
the raw materials, the same operation as the Example 16 gave the
title compound.
[0555] Yield: 64.6%.
[0556] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.33(3H, t, J=7.0 Hz),
4.46(2H, q, J=7.0 Hz), 7.04(1H, d, J=9.0 Hz), 7.21(1H, t, J=7.3
Hz), 7.45-7.52(2H, m), 7.64-7.65(2H, m), 7.70(1H, d, J=8.4, 1.9
Hz), 8.11-8.15(2H, m), 8.49(1H, d, J=1.9 Hz), 10.55(1H, s),
12.22(1H, s).
Example 48
Preparation of the Compound of Compound No. 95
[0557] Using O-acetylsalicyloyl chloride and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 2(1) gave the title compound.
[0558] Yield: 84.2%.
[0559] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.36(3H, s), 7.19(1H, dd,
J=8.0, 1.2 Hz), 7.39(1H, td, J=7.6, 1.2 Hz), 7.57(1H, ddd, J=8.0,
7.6, 1.6 Hz), 7.65(1H, s), 7.83(1H, dd, J=8.0, 1.6 Hz), 8.11(2H,
s), 8.31(1H, s).
Example 49
Preparation of the Compound of Compound No. 48
[0560] Using 2-acetoxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide
(Compound No. 95) as the raw material, the same operation as the
Example 2(2) gave the title compound.
[0561] Yield: 45.1%.
[0562] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.96-7.02(2H, m), 7.45(1H,
ddd, J=8.0, 7.2, 1.6 Hz), 7.81(1H, s), 7.87(1H, dd, J=8.0, 1.6 Hz),
8.46(2H, s), 10.80(1H, s), 11.26(1H, s).
Example 50
Preparation of the Compound of Compound No. 49
[0563] Using 5-fluorosalicylic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0564] Yield: 58.7%.
[0565] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.04(1H, ddd, J=9.0, 4.5,
1.2 Hz), 7.30-7.37(1H, m), 7.66(1H, ddd, J=9.0, 3.3, 1.2 Hz),
7.84(1H, s), 8.46(2H, s), 10.85(1H, s), 11.21(1H, brs).
Example 51
Preparation of the Compound of Compound No. 50
[0566] Using 5-chlorosalicylic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0567] Yield: 85.5%.
[0568] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.05(1H, d, J=8.7 Hz),
7.49(1H, dd, J=8.7, 2.7 Hz), 7.85(1H, s), 7.87(1H, d, J=2.7 Hz),
8.45(2H, s), 10.85(1H, s), 11.39(1H, s).
Example 52
Preparation of the Compound of Compound No. 51
[0569] Using 5-bromosalicylic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0570] Yield: 88.5%.
[0571] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.98(1H, d, J=8.8 Hz),
7.59(1H, dd, J=8.8, 2.8 Hz), 7.83(1H, s), 7.98(1H, d, J=2.8 Hz),
8.43(2H, s), 10.82(1H, s), 11.37(1H, s).
[0572] This compound was obtained also by the following preparation
method.
[0573] Iron powder (30 mg, 0.54 mmol) and bromine (0.02 mL, 0.39
mmol) were added to a solution of
2-acetoxy-N-[3,5-bis(trifluoromethyl)]benzamide (Compound No. 95;
100 mg, 0.25 mmol) in carbon tetrachloride (8 mL), and the mixture
was stirred at 50.degree. C. for 4 hours. After the reaction
mixture was cooled to room temperature, it was poured into aqueous
NaHSO.sub.4 and extracted with ethyl acetate. The ethyl acetate
layer was washed with water and brine, and dried over anhydrous
sodium sulfate. The residue obtained by evaporation of the solvent
under reduced pressure was purified by column chromatography on
silica gel (n-hexane:ethyl acetate=4:1) to give the title compound
(600 mg, 54.9%) as a white solid.
Example 53
Preparation of the Compound of Compound No. 52
[0574] Using 5-iodosalicylic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0575] Yield: 62.2%.
[0576] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.86(1H, d, J=8.4 Hz),
7.74(1H, dd, J=8.7, 2.4 Hz), 7.84(1H, s), 8.13(1H, d, J=2.1 Hz),
8.84(2H, s), 10.82(1H, s), 11.41(1H, s).
Example 54
Preparation of the Compound of Compound No. 53
[0577] Using 5-nitrosalicylic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0578] Yield: 57.2%.
[0579] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.18(1H, d, J=9.0 Hz),
7.86(1H, s), 8.31(1H, dd, J=9.0, 3.0 Hz), 8.45(2H, s), 8.70(1H, d,
J=3.0 Hz), 11.12(1H, s).
Example 55
Preparation of the Compound of Compound No. 54
(1) 2-Benzyloxy-5-formylbenzoic acid benzyl ester
[0580] A mixture of 5-formylsalicylic acid (4.98 g, 30 mmol),
benzyl bromide (15.39 g, 90 mmol), potassium carbonate (16.59 g,
120 mmol), and methyl ethyl ketone (350 mL) was refluxed for 8
hours. After cooling, the solvent was evaporated under reduced
pressure. 2N Hydrochloric acid was added to the residue, and the
mixture was extracted with ethyl acetate. The layer was washed with
water and brine, and dried over anhydrous magnesium sulfate. The
residue obtained by evaporation of the solvent under reduced
pressure was purified by column chromatography on silica gel
(n-hexane:ethyl acetate=3:1), suspended and washed with isopropyl
ether under heating at reflux to give the title compound (5.98 g,
57.5%) as a white solid.
[0581] .sup.1H-NMR(CDCl.sub.3):d 5.27(2H, s), 5.37(2H, s), 7.15(1H,
d, J=9.0 Hz), 7.26-7.46(10H, m), 7.99(1H, dd, J=9.0, 2.4 Hz),
8.36(1H, d, J=2.4 Hz), 9.91(1H, s).
(2) 2-Benzyloxy-5-cyanobenzoic acid benzyl ester
[0582] A mixture of 2-benzyloxy-5-formylbenzoic acid benzyl ester
(693 mg, 2 mmol), hydroxylamine hydrochloride (167 mg, 2.4 mmol),
and N-methylpyrrolidone (3 mL) was stirred at 1150 for 4 hours.
After the reaction mixture was cooled, 2N hydrochloric acid (5 mL)
and water (30 mL) were added and the mixture was extracted with
ethyl acetate. The organic layer was washed with 2N aqueous sodium
hydroxide, water, and brine, and dried over anhydrous magnesium
sulfate. The residue obtained by evaporation of the solvent under
reduced pressure was suspended and washed with isopropyl ether
under heating at reflux to give the title compound (527 mg, 76.7%)
as a white solid.
[0583] .sup.1H-NMR(CDCl.sub.3):d 5.23(2H, s), 5.35(2H, s), 7.08(1H,
d, J=8.7 Hz), 7.33-7.43(10H, m), 7.70(1H, dd, J=8.7, 2.4 Hz),
8.13(1H, d, J=2.4 Hz).
(3) 5-Cyanosalicylic acid
[0584] Ethanol (10 mL) and tetrahydrofuran (10 mL) were added to
2-benzyloxy-5-cyanobenzoic acid benzyl ester (446 mg, 1.3 mmol) and
5% palladium on carbon (45 mg), and the mixture was hydrogenated at
room temperature for 2 hours. After the insoluble matter was
filtered off, the solvent was evaporated under reduced pressure to
give the title compound (212 mg, 100.0%) as a white solid.
[0585] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.02(1H, d, J=8.7 Hz),
7.82(1H, dd, J=8.7, 2.4 Hz), 8.12(1H, d, J=2.1 Hz).
(4) N-[3,5-Bis(trifluoromethyl)phenyl]-5-cyano-2-hydroxybenzamide
(Compound No. 54)
[0586] Using 5-cyanosalicylic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0587] Yield: 16.6%.
[0588] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.15(1H, d, J=8.7 Hz),
7.85(1H, s), 7.86(1H, dd, J=8.7, 2.1 Hz), 8.22(1H, d, J=2.4 Hz),
8.43(2H, s), 10.93(1H, s), 12.00(1H, brs).
Example 56
Preparation of the Compound of Compound No. 55
[0589] Using 5-methylsalicylic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0590] Yield: 54.9%.
[0591] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.92(1H, d, J=8.7 Hz),
7.28(1H, dd, J=8.7, 1.8 Hz), 7.71(1H, d, J=1.8 Hz), 7.82(1H, s),
8.47(2H, s), 10.80(1H, s), 11.14(1H, s).
Example 57
Preparation of the Compound of Compound No. 56
(1) 5-[(1,1-Dimethyl)ethyl]salicylic acid
[0592] Sulfamic acid (1.76 g, 18.1 mmol) and sodium
dihydrogenphosphate (7.33 g, 47 mmol) were added to a solution of
5-[(1,1-dimethyl)ethyl]-2-hydroxybenzaldehyde (2.15 g, 12.1 mmol)
in 1,4-dioxane (100 mL) and water (40 mL). A solution of sodium
chlorite (1.76 g, 15.5 mmol) in water (10 mL) was added to the
mixture under ice cooling, and it was stirred for 1 hour. Then,
sodium sulfite (1.80 g, 14.3 mmol) was added to the mixture, and it
was stirred for 30 minutes. Concentrated hydrochloric acid was
added to the reaction mixture, and pH was adjusted to 1. The
residue obtained by evaporation of 1,4-dioxane under reduced
pressure was extracted with ethyl acetate. The organic layer was
washed with water and brine, and dried over anhydrous magnesium
sulfate. The residue obtained by evaporation of the solvent under
reduced pressure was washed with n-hexane under suspension to give
the title compound (1.81 g, 77.4%) as a white powder.
[0593] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.26(9H, s), 6.90(1H, d,
J=9.0 Hz), 7.58(1H, dd, J=8.7, 2.4 Hz), 7.75(1H, d, J=2.4 Hz),
11.07(1H, brs).
(2)
N-[3,5-Bis(trifluoromethyl)phenyl]-5-[(1,1-dimethyl)ethyl]-2-hydroxybe-
nzamide (Compound No. 56).
[0594] Using 5-[(1,1-dimethyl)ethyl]salicylic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0595] Yield: 53.8%.
[0596] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.30(9H, s), 6.96(1H, d,
J=8.7 Hz), 7.50(1H, dd, J=8.7, 2.4 Hz), 7.82(1H, d, J=2.4 Hz),
7.83(1H, s), 8.46(2H, s), 10.80(1H, s) 11.12(1H, s).
Example 58
Preparation of the Compound of Compound No. 78
(1) 5-Acetyl-2-benzyloxybenzoic acid methyl ester
[0597] A mixture of 5-acetylsalicylic acid methyl ester (13.59 g,
70 mmol), benzyl bromide (17.96 g, 105 mmol), potassium carbonate
(19.35 g, 140 mmol) and methyl ethyl ketone (350 mL) was refluxed
for 8 hours. After cooling, the solvent was evaporated under
reduced pressure. 2N Hydrochloric acid was added to the residue,
and it was extracted with ethyl acetate. After the ethyl acetate
layer was washed with water and brine, dried over anhydrous
magnesium sulfate and concentrated, the residue was recrystallized
from isopropyl ether to give the title compound (14.20 g, 71.4%) as
a white solid.
[0598] .sup.1H-NMR(CDCl.sub.3):.delta. 2.58(3H, s), 3.93(3H, s),
5.27(2H, s), 7.07(1H, d, J=8.7 Hz), 7.26-7.43(3H, m), 7.47-7.50(2H,
m), 8.07(1H, dd, J=8.7, 2.4 Hz), 8.44(1H, d, J=2.4 Hz).
(2) 5-Acetyl-2-benzyloxybenzoic acid
[0599] 5-Acetyl-2-benzyloxybenzoic acid methyl ester (5.69 g, 20
mmol) was dissolved in a mixed solvent of methanol (20 mL) and
tetrahydrofuran (20 mL). 2N Sodium hydroxide (11 mL) was added
dropwise, and the mixture was stirred for 8 hours. The solvent was
evaporated under reduced pressure. 2N Hydrochloric acid was added
to the residue, and it was extracted with dichloromethane. After
the dichloromethane layer was washed with water and brine, dried
over anhydrous magnesium sulfate and concentrated, the residue was
washed with isopropyl ether to give the title compound (4.92 g,
91.0%) as a white solid.
[0600] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.55(3H, s), 5.32(2H, s),
7.30-7.43(4H, m), 7.49-7.52(2H, m), 8.09(1H, dd, J=9.0, 2.7 Hz),
8.22(1H, d, J=2.4 Hz).
(3)
5-Acetyl-2-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide
[0601] Using 5-acetyl-2-benzyloxybenzoic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 24 gave the title compound.
[0602] Yield: 63.1%.
[0603] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.57(3H, s), 7.11(1H, d,
J=8.7 Hz), 7.86(1H, s), 8.05(1H, dd, J=8.4, 2.1 Hz), 8.44(1H, d,
J=2.1 Hz), 8.47(2H, s), 10.96(1H, s), 11.97(1H, brs).
(4) 5-Acetyl-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide
(Compound No. 78)
[0604] Ethanol (6 mL) and tetrahydrofuran (72 mL) were added to
5-acetyl-2-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide
(602 mg, 1.25 mmol) and 5% palladium on carbon (60 mg), and the
mixture was hydrogenated at room temperature for 30 minutes. After
the insoluble matter was filtered off, the solvent was evaporated
under reduced pressure and the residue was recrystallized from
n-hexane-ethyl acetate to give the title compound (230 mg, 47.0%)
as a white solid.
[0605] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.59(3H, s), 5.35(2H, s),
7.32-7.36(3H, m), 7.43(1H, d, J=8.7 Hz), 7.52-7.55(2H, m), 7.82(1H,
s), 8.16(1H, dd, J=8.7, 2.4 Hz), 8.25(1H, d, J=2.4 Hz), 8.31(2H,
s), 10.89(1H, s).
Example 59
Preparation of the Compound of Compound No. 57
[0606]
5-Acetyl-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide
(Compound No. 78; 50.5 mg, 0.13 mmol) was suspended in ethanol (2
mL). Sodium borohydride (23.6 mg, 0.62 mmol) was added, and the
mixture was stirred at room temperature for 12 hours. The reaction
mixture was poured into diluted hydrochloric acid and extracted
with ethyl acetate. After the organic layer was washed with water
and brine, dried over anhydrous sodium sulfate, the residue
obtained by evaporation under reduced pressure was washed with
isopropyl ether/n-hexane under suspension to give the title
compound (39.7 mg, 78.3%) as a white powder.
[0607] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.34(3H, d, J=6.3 Hz),
4.71(1H, q, J=6.3 Hz), 5.18(1H, brs), 6.97(1H, d, J=8.4 Hz),
7.44(1H, dd, J=8.4, 2.1 Hz), 7.84(1H, s), 7.86(1H, d, J=2.1 Hz),
8.48(2H, s), 10.85(1H, s), 11.32(1H, s).
Example 60
Preparation of the Compound of Compound No. 58
[0608]
5-Acetyl-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide
(Compound No. 78; 100.0 mg, 0.26 mmol) was dissolved in ethanol (3
mL). Pyridine (45 .mu.l, 0.56 mmol) and O-methylhydroxylamine
hydrochloride (25.8 mg, 0.31 mmol) were added, and the mixture was
refluxed for 1 hour. After cooling, the reaction mixture was poured
into diluted hydrochloric acid and extracted with ethyl acetate.
After the organic layer was washed with water and brine, dried over
anhydrous sodium sulfate, the residue obtained by evaporation under
reduced pressure was purified by chromatography on silica gel
(hexane:ethyl acetate=4:1) to give the title compound (102.1 mg,
95.3%) as a white crystal.
[0609] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.19(3H, s), 3.91(3H, s),
7.05(1H, d, J=8.7 Hz), 7.77(1H, dd, J=8.7, 2.4 Hz), 7.85(1H, s),
8.09(1H, d, J=2.4 Hz), 8.47(2H, s), 10.87(1H, s), 11.48(1H, s).
Example 61
Preparation of the Compound of Compound No. 59
[0610] Using
5-acetyl-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide
(Compound No. 78) and O-benzylhydroxylamine hydrochloride as the
raw materials, the same operation as the Example 60 gave the title
compound.
[0611] Yield: 79.9%.
[0612] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.24(3H, s), 5.20(2H, s),
7.04(1H, d, J=8.7 Hz), 7.29-7.47(5H, m), 7.76(1H, dd, J=8.7, 2.4
Hz), 7.85(1H, s), 8.07(1H, d, J=2.1 Hz), 8.46(2H, s), 10.87(1H, s),
11.47(1H, s).
Example 62
Preparation of the Compound of Compound No. 60
(1) 5-(2,2-Dicyanoethen-1-yl)-2-hydroxybenzoic acid
[0613] Malononitrile (132 mg, 2 mmol) was dissolved in ethanol (6
mL), and 5-formylsalicylic acid (332 mg, 2 mmol) was added. After
cooling with ice bath, benzylamine (0.1 mL) was added and the
mixture was stirred at room temperature for 2 hours. The separated
yellow crystal was filtered and recrystallized (ethanol) to give
the title compound (139.9 mg, 32.7%) as a light yellow solid.
[0614] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.12(1H, d, J=8.7 Hz),
8.09(1H, dd, J=8.7, 2.4 Hz), 8.41(1H, s), 8.50(1H, d, J=2.4
Hz).
(2)
N-[3,5-Bis(trifluoromethyl)phenyl]-5-(2,2-dicyanoethen-1-yl)-2-hydroxy-
benzamide (Compound No. 60).
[0615] Using 5-(2,2-dicyanoethen-1-yl)-2-hydroxybenzoic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0616] Yield: 9.1%.
[0617] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.13(1H, d, J=9.0 Hz),
7.83(1H, s), 8.04(1H, dd, J=9.0, 2.4 Hz), 8.36(1H, s), 8.38(1H, d,
J=2.4 Hz), 8.43(2H, s), 11.43(1H, s).
Example 63
Preparation of the Compound of Compound No. 62
(1) 5-[(2-Cyano-2-methoxycarbonyl)ethen-1-yl]-2-hydroxybenzoic
acid
[0618] Triethylamine (0.2 ml) was added to a mixture of
5-formylsalicylic acid (332 mg, 2 mmol). Cyanoacetic acid methyl
ester (198 mg, 2 mmol) and acetic acid (6 mL), and the mixture was
refluxed for 5 hours. After cooling, the reaction mixture was
poured into water, and the separated crystal was filtered and
recrystallized (n-hexane) to give the title compound (327.7 mg,
66.3%) as a light yellow solid.
[0619] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.85(3H, s), 7.15(1H, d,
J=8.7 Hz), 8.20(1H, dd, J=8.7, 2.4 Hz), 8.37(1H, s), 8.66(1H, d,
J=2.4 Hz).
(2)
3-({N-[3,5-Bis(trifluoromethyl)phenyl]carbamoyl}-4-hydroxyphenyl)-2-cy-
anoacrylic acid methyl ester (Compound No. 62).
[0620] Using
5-[(2-cyano-2-methoxycarbonyl)ethen-1-yl]-2-hydroxybenzoic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0621] Yield: 66.3%.
[0622] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.85(3H, s), 7.19(1H, d,
J=9.0 Hz), 7.85(1H, s), 8.20(1H, dd, J=8.7, 2.1 Hz), 8.33(1H, s),
8.45(2H, s), 8.50(1H, d, J=2.1 Hz), 11.00(1H, s), 11.03(1H, s).
Example 64
Preparation of the Compound of Compound No. 61
[0623]
3-({N-[3,5-Bis(trifluoromethyl)phenyl]carbamoyl}-4-hydroxyphenyl)--
2-cyanoacrylic acid methyl ester (Compound No. 62; 50 mg, 0.11
mmol) was dissolved in ethanol (5 mL). 2N Sodium hydroxide (0.11
ml, 0.22 mmol) was added, and the mixture was stirred at room
temperature for 3 hours. The reaction mixture was poured into
diluted hydrochloric acid and extracted with ethyl acetate. After
the organic layer was washed with brine, dried over anhydrous
magnesium sulfate, the residue obtained by evaporation under
reduced pressure was recrystallized (ethyl acetate) to give the
title compound (13.5 mg, 30.4%) as a light yellow solid.
[0624] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.12(1H, d, J=8.4 Hz),
7.84(1H, s), 7.94(1H, dd, J=8.4, 2.1 Hz), 8.38(1H, d, J=2.1 Hz),
8.45(2H, s), 9.87(1H, s), 11.41(1H, s).
Example 65
Preparation of the Compound of Compound No. 63
[0625] A mixture of
N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide
(Compound No. 52; 475 mg, 1 mmol), styrene (130 mg, 1.25 mmol),
palladium acetate (4.5 mg, 0.02 mmol), tris(ortho-tolyl)phosphine
(12.2 mg, 0.04 mmol), diisopropylamine (388 mg, 3 mmol) and
N,N-dimethylformamide (2 mL) was refluxed for 8 hours. After
cooling, water was added to the reaction mixture, and it was
extracted with ethyl acetate. After the ethyl acetate layer was
washed with water and brine, dried over anhydrous magnesium sulfate
and concentrated, the residue was purified by column chromatography
on silica gel (n-hexane:isopropyl ether=2:1.fwdarw.1:1) to give the
title compound (173 mg, 38.3%) as a pale yellow solid.
[0626] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.04(1H, d, J=8.4 Hz),
7.20-7.29(3H, m), 7.38(2H, t, J=7.5 Hz), 7.59(2H, d, J=7.5 Hz),
7.72(1H, dd, J=8.4, 2.1 Hz), 7.86(1H, s), 8.07(1H, d, J=2.1 Hz),
8.49(2H, s), 10.89(1H, s), 11.33(1H, brs).
Example 66
Preparation of the Compound of Compound No. 66
[0627] N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide
(Compound No. 52; 950 mg, 2 mmol) and trimethylsilylacetylene (246
mg, 2.5 mmol) were dissolved in triethylamine (2 mL) and
N,N-dimethylformamide (4 mL).
[0628] Tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol) and
cuprous iodide (4 mg, 0.02 mmol) were added under argon atmosphere,
and the mixture was stirred at 40.degree. C. for 2 hours. After
cooling to room temperature, the reaction mixture was poured into
ethyl acetate (100 mL) and 1N citric acid (100 mL), stirred, and
filtered through celite. After the ethyl acetate layer was washed
successively with water and brine, dried over anhydrous magnesium
sulfate, the solvent was evaporated under reduced pressure. The
obtained residue was purified by column chromatography on silica
gel (n-hexane:ethyl acetate=19:1) to give a light orange solid.
This was crystallized by n-hexane to give the title compound (286
mg, 32.1%) as a white crystal.
[0629] .sup.1H-NMR(DMSO-d.sub.6):.delta. 0.23(9H, s), 7.00(1H, d,
J=8.7 Hz), 7.54(1H, dd, J=8.7, 2.4 Hz), 7.85(1H, s), 7.98(1H, d,
J=2.1 Hz), 8.46(2H, s), 10.86(1H, s), 11.69(1H, s).
Example 67
Preparation of the Compound of Compound No. 64
[0630]
N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-[(trimethylsilyl)et-
hynyl]-benzamide (Compound No. 66; 233 mg, 0.5 mmol) was dissolved
in methanol (1 mL). 2N Sodium hydroxide (1 mL) was added, and the
mixture was stirred at room temperature for 1 hour. The reaction
mixture was poured into 2N hydrochloric acid and extracted with
ethyl acetate. After the ethyl acetate layer was washed
successively with water and brine, dried over anhydrous magnesium
sulfate, the solvent was evaporated under reduced pressure. The
obtained residue was crystallized from ethanol-water to give the
title compound (67 mg, 35.9%) as a light gray crystal.
[0631] .sup.1H-NMR(DMSO-d.sub.6):.delta. 4.11(1H, s), 7.02(1H, d,
J=8.4 Hz), 7.55(1H, dd, J=8.4, 2.1 Hz), 7.85(1H, s), 7.98(1H, d,
J=2.1 Hz), 8.46(2H, s), 8.46(2H, s), 10.86(1H, s), 11.62(1H,
s).
Example 68
Preparation of the Compound of Compound No. 65
[0632] Using
N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide
(Compound No. 52) and phenylacetylene as the raw materials, the
same operation as the Example 66 gave the title compound.
[0633] Yield: 40.8%.
[0634] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.06(1H, d, J=8.4 Hz),
7.42-7.46(3H, m), 7.53-7.57(2H, m), 7.64(1H, dd, J=8.7, 2.1 Hz),
7.86(1H, s), 8.06(1H, d, J=2.1 Hz), 8.48(2H, s), 10.94(1H, s),
11.64(1H, brs).
Example 69
Preparation of the Compound of Compound No. 67
[0635] N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide
(Compound No. 52; 200 mg, 0.42 mmol) was dissolved in
1,2-dimethoxyethane (3 mL). Tetrakis(triphenylphosphine)palladium
(16 mg, 0.0014 mmol) was added under argon atmosphere, and the
mixture was stirred at room temperature for 5 minutes. Then
dihydroxyphenylborane (57 mg, 0.47 mmol) and 1M sodium carbonate
(1.3 mL) were added and the mixture was refluxed for 2 hours. After
cooling to room temperature, the reaction mixture was poured into
diluted hydrochloric acid and extracted with ethyl acetate. After
the ethyl acetate layer was washed successively with water and
brine, dried over anhydrous sodium sulfate, the solvent was
evaporated under reduced pressure. The obtained residue was
purified by column chromatography on silica gel (n-hexane:ethyl
acetate=6:1.fwdarw.3:1) to give the title compound (109 mg, 61.1%)
as a white crystal.
[0636] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.12(1H, d, J=8.7 Hz),
7.33-7.38(1H, m), 7.48(2H, t, J=7.5 Hz), 7.67-7.70(2H, m), 7.79(1H,
dd, J=8.4, 2.4 Hz), 7.87(1H, s), 8.17(1H, d, J=2.4 Hz), 8.49(2H,
s), 10.92(1H, s), 11.41(1H, s).
Example 70
Preparation of the Compound of Compound No. 68
[0637] Using
N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-(phenylethynyl)benzamide
(Compound No. 65) as the raw material, the same operation as the
Example 58(4) gave the title compound.
[0638] Yield: 86.2%.
[0639] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.88(4H, s), 6.93(1H, d,
J=8.1 Hz), 7.15-7.34(6H, m), 7.76(1H, d, J=2.4 Hz), 7.84(1H, s),
8.47(2H, s), 10.79(1H, s), 11.15(1H, s).
Example 71
Preparation of the Compound of Compound No. 69
[0640] Using 2-hydroxy-5-(trifluoromethyl)benzoic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0641] Yield: 44.7%.
[0642] .sup.1H-NMR(CDCl.sub.3):.delta. 7.17(1H, d, J=9.0 Hz)
7.72-7.75(2H, m), 7.86(1H, s), 8.17(2H, s), 8.35(1H, s) 11.88(1H,
s).
[2-Hydroxy-5-(trifluoromethyl)benzoic acid: Refer to "Chemical and
Pharmaceutical Bulletin", 1996, Vol. 44, p. 734.]
Example 72
Preparation of the Compound of Compound No. 70
[0643] Using 2-hydroxy-5-(pentafluoroethyl)benzoic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0644] .sup.1H-NMR(CDCl.sub.3):.delta. 7.19(1H, d, J=9.0 Hz)
7.70(1H, dd, J=8.7, 2.1 Hz), 7.81(1H, d, J=2.1 Hz), 8.17(2H, s),
8.37(1H, s), 11.92(1H, s).
[2-Hydroxy-5-(pentafluoromethyl)benzoic acid: Refer to "Chemical
and Pharmaceutical Bulletin", 1996, Vol. 44, p. 734.]
Example 73
Preparation of the Compound of Compound No. 71
[0645] Using 2-hydroxy-5-(pyrrol-1-yl)benzoic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0646] Yield: 57.8%.
[0647] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.27(2H, dd, J=2.4, 1.8
Hz), 7.10(1H, d, J=9.0 Hz), 7.29(2H, dd, J=2.4, 1.8 Hz), 7.66(1H,
dd, J=9.0, 2.7 Hz), 7.86(1H, s), 7.98(1H, d, J=2.4 Hz), 8.47(2H,
s), 10.89(1H, s), 11.24(1H, s).
Example 74
Preparation of the Compound of Compound No. 72
[0648] Using
N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide
(Compound No. 52) and 2-thiopheneboronic acid as the raw materials,
the same operation as the Example 69 gave the title compound.
[0649] Yield: 44.4%.
[0650] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.08(1H, d, J=8.4 Hz),
7.14(1H, dd, J=5.4, 3.6 Hz), 7.45(1H, dd, J=3.6, 1.2 Hz), 7.51(1H,
dd, J=5.1, 0.9 Hz), 7.75(1H, dd, J=8.4, 2.4 Hz), 7.59(1H, s),
8.08(1H, d, J=2.4 Hz), 8.48(2H, s), 10.91(1H, s), 11.38(1H, s).
Example 75
Preparation of the Compound of Compound No. 73
[0651] Using
N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide
(Compound No. 52) and 3-thiopheneboronic acid as the raw materials,
the same operation as the Example 69 gave the title compound.
[0652] Yield: 38.7%.
[0653] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.06(1H, d, J=8.7 Hz),
7.57(1H, dd, J=4.8, 1.5 Hz), 7.66(1H, dd, J=4.8, 3.0 Hz),
7.81-7.84(2H, m), 7.86(1H, s), 8.18(1H, d, J=2.1 Hz), 8.49(2H, s),
10.90(1H, s), 11.33(1H, s).
Example 76
Preparation of the Compound of Compound No. 74
(1)
2-Benzyloxy-5-(2-bromoacetyl)-N-[3,5-bis(trifluoromethyl)phenyl]benzam-
ide
[0654]
5-Acetyl-2-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide
(compound of Example 58(3); 4.81 g, 10 mmol) was dissolved in
tetrahydrofuran (30 ml). Phenyltrimethylammonium tribromide (3.75
g, 10 mmol) was added, and the mixture was stirred at room
temperature for 12 hours. The reaction mixture was poured into
water and extracted with ethyl acetate. After the organic layer was
washed with aqueous sodium hydrogen sulfite, water and brine, dried
over anhydrous magnesium sulfate, the residue obtained by
evaporation under reduced pressure was purified by chromatography
on silica gel (n-hexane:ethyl acetate=4:1), and recrystallized
(ethyl acetate/n-hexane) to give the title compound (2.39 g, 42.7%)
as a white solid.
[0655] .sup.1H-NMR(DMSO-d.sub.6):.delta. 4.91(2H, s), 5.36(2H, s),
7.32-7.35(3H, m), 7.47(1H, d, J=9.0 Hz), 7.52-7.56(2H, m), 7.82(1H,
s), 8.21(1H, dd, J=8.7, 2.4 Hz), 8.29(1H, d, J=2.4 Hz), 8.31(2H,
s), 10.91(1H, s).
(2)
2-Benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]-5-(2-methylthiazol-4-yl-
)benzamide
[0656] A mixture of
2-benzyloxy-5-(2-bromoacetyl)-N-[3,5-bis(trifluoromethyl)phenyl]benzamide
(280 mg, 0.5 mmol), thioacetamide (41 mg, 0.55 mmol), sodium
hydrogen carbonate (50 mg, 0.6 mmol) and ethanol (15 mL) was
refluxed for 1 hour. The reaction mixture was poured into water,
neutralized by sodium hydrogen carbonate, and extracted with ethyl
acetate. After the organic layer was washed with water and brine,
dried over anhydrous magnesium sulfate, the residue obtained by
evaporation under reduced pressure was purified by chromatography
on silica gel (hexane:ethyl acetate=4:1) to give the title compound
(181 mg, 67.5%) as a white solid.
[0657] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.72(3H, s), 5.29(2H, s),
7.33-7.36(3H, m), 7.40(1H, d, J=9.0 Hz), 7.54-7.57(2H, m), 7.81(1H,
s), 7.94(1H, s), 8.12(1H, dd, J=8.7, 2.1 Hz), 8.27(1H, d, J=2.1
Hz), 8.31(2H, s), 10.86(1H, s).
(3)
N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-(2-methylthiazol-4-yl)b-
enzamide (Compound No. 74).
[0658]
2-Benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]-5-(2-methylthiazol--
4-yl)benzamide (160 mg, 0.3 mmol) and 10% Pd--C(240 mg) were
dissolved in ethanol (10 ml) and stirred for 3.5 hours under
hydrogen atmosphere. The reaction mixture was filtered and the
filtrate was evaporated under reduced pressure to give the title
compound (103.4 mg, 79.2%) as a white solid.
[0659] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.72(3H, s), 7.08(1H, d,
J=8.7 Hz), 7.83(1H, s), 7.85(1H, s), 8.01(1H, dd, J=8.7, 2.4 Hz),
8.42(1H, d, J=2.1 Hz), 8.50(2H, s), 10.96(1H, s), 11.40(1H, s).
Example 77
Preparation of the Compound of Compound No. 75
[0660] A mixture of
2-benzyloxy-5-(2-bromoacetyl)-N-[3,5-bis(trifluoromethyl)-phenyl]benzamid-
e (compound of Example 58(3); 280 mg, 0.5 mmol), 2-aminopyridine
(51.8 mg, 0.55 mmol), sodium hydrogen carbonate (50 mg, 0.6 mmol)
and ethanol (10 mL) was refluxed for 2 hours. After cooling, the
reaction mixture was poured into aqueous sodium hydrogen carbonate
and extracted with ethyl acetate. After the organic layer was
washed with water and brine, dried over anhydrous magnesium
sulfate, the residue obtained by evaporation under reduced pressure
was purified by chromatography on silica gel (n-hexane:ethyl
acetate=1:2) to give a white solid (130.3 mg, 45.9%). Then, a
mixture of this solid (108 mg, 0.19 mmol), 10% Pd--C(11 mg),
ethanol (8 mL) and ethyl acetate (8 mL) was stirred for 7 hours
under hydrogen atmosphere. The reaction mixture was filtered and
the residue obtained by evaporation of the filtrate under reduced
pressure was purified by chromatography on silica gel
(n-hexane:ethyl acetate=1:3) to give the title compound (18.3 mg,
20.2%) as a white solid.
[0661] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.90(1H, dt, J=6.6, 0.9
Hz), 7.10(1H, d, J=8.7 Hz), 7.25(1H, m), 7.57(1H, d, J=9.0 Hz),
7.86(1H, s), 8.04(1H, dd, J=8.7, 2.1 Hz), 8.35(1H, s),
8.48-8.56(4H, m), 11.00(1H, s), 11.41(1H, s).
Example 78
Preparation of the Compound of Compound No. 76
(1)
N-[3,5-Bis(trifluoromethyl)phenyl]-5-iodo-2-methoxymethoxybenzamide
[0662] A mixture of
N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide
(Compound No. 52; 4.75 g, 10 mmol), chloromethyl methyl ether (1.14
ml, 15 mmol), potassium carbonate (2.76 g, 20 mmol) and acetone (50
mL) was refluxed for 8 hours. The reaction mixture was poured into
diluted hydrochloric acid and extracted with ethyl acetate. After
the organic layer was washed with water and brine, dried over
anhydrous magnesium sulfate, the residue obtained by evaporation
under reduced pressure was purified by chromatography on silica gel
(n-hexane:ethyl acetate=3:1), and recrystallized (n-hexane/ethyl
acetate) to give the title compound (3.96 g, 76.3%) as a white
solid.
[0663] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.38(3H, s), 5.28(2H, s),
7.12(1H, d, J=9.0 Hz), 7.81(1H, s), 7.82(1H, dd, J=8.7, 2.4 Hz),
7.88(1H, d, J=2.4 Hz), 8.40(2H, s), 10.87(1H, s).
(2)
N-[3,5-Bis(trifluoromethyl)phenyl]-2-methoxymethoxy-5-(pyridin-2-yl)be-
nzamide
[0664]
N-[3,5-Bis(trifluoromethyl)phenyl]-5-iodo-2-methoxymethoxybenzamid-
e (0.20 g, 0.39 mmol) was dissolved in N,N-dimethylformamide (8
ml). Tri-n-butyl(2-pyridyl)tin (0.13 ml, 0.41 mmol) and
dichlorobis(triphenylphosphine)palladium (32.1 mg, 0.05 mmol) were
added, and the mixture was stirred at 100.degree. C. for 1.5 hours.
After cooling, the reaction mixture was poured into water and
extracted with ethyl acetate. After the organic layer was washed
with water and brine, dried over anhydrous sodium sulfate, the
residue obtained by evaporation under reduced pressure was purified
by chromatography on silica gel (n-hexane:ethyl
acetate=2:1.fwdarw.1:1) to give the title compound (37.9 mg, 20.8%)
as a white powder.
[0665] .sup.1H-NMR(CDCl.sub.3):.delta. 3.64(3H, s), 5.53(2H, s),
7.23-7.28(1H, m), 7.36(1H, d, J=8.7 Hz), 7.65(1H, s), 7.77-7.84(2H,
m), 8.20(2H, s), 8.31(1H, dd, J=8.7, 2.4 Hz), 8.68-8.70(1H, m),
8.83(1H, d, J=2.4 Hz), 10.12(1H, s).
(3)
N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-(pyridin-2-yl)benzamide
(Compound No. 76).
[0666] Methanol (3 ml) and concentrated hydrochloric acid (0.5 ml)
were added to
N-[3,5-bis(trifluoromethyl)phenyl]-2-methoxymethoxy-5-(pyridin-2-
-yl)benzamide (37.9 mg, 0.08 mmol), and the mixture was refluxed
for 2 hours. After cooling, the reaction mixture was poured into
saturated aqueous sodium hydrogen carbonate and extracted with
ethyl acetate. After the organic layer was washed with water and
brine, dried over anhydrous sodium sulfate, the residue obtained by
evaporation under reduced pressure was purified by chromatography
on silica gel (n-hexane:ethyl acetate=2:1) to give the title
compound (16.2 mg, 47.2%) as a white powder.
[0667] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.13(1H, d, J=8.4 Hz),
7.33(1H, ddd, J=7.5, 6.3, 1.2 Hz), 7.86-7.91(2H, m), 7.97(1H, d,
J=7.8 Hz), 8.20(1H, dd, J=8.7, 2.1 Hz), 8.50(2H, s), 8.59(1H, d,
J=2.4 Hz), 8.64-8.66(1H, m), 10.97(1H, s), 11.53(1H, s).
Example 79
Preparation of the Compound of Compound No. 77
[0668] Using 5-methoxysalicylic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0669] Yield: 56.8%.
[0670] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.77(3H, s), 6.97(1H, d,
J=9.0 Hz), 7.10(1H, dd, J=9.0, 3.0 Hz), 7.43(1H, d, J=3.0 Hz),
7.84(1H, s), 8.47(2H, s), 10.84(1H, s), 10.91(1H, s).
Example 80
Preparation of the Compound of Compound No. 79
(1) 5-Acetyl-2-methoxybenzoic acid methyl ester
[0671] A mixture of 5-acetylsalicylic acid methyl ester (5.00 g,
25.7 mmol), sodium carbonate (7.10 g, 51.4 mmol) and
N,N-dimethylformamide (25 mL) was cooled with ice bath. Methyl
iodide (2.5 mL, 40.1 mmol) was added, and the mixture was stirred
at room temperature for 3 hours. The reaction mixture was poured
into water, neutralized by hydrochloric acid, and extracted with
ethyl acetate. After the organic layer was washed with water and
brine, dried over anhydrous sodium sulfate, the residue obtained by
evaporation under reduced pressure was washed under suspension
(isopropyl ether/n-hexane) to give the title compound (5.17 g,
96.5%) as a white crystal.
[0672] .sup.1H-NMR(CDCl.sub.3):.delta. 2.59(3H, s), 3.92(3H, s),
3.99(3H, s), 7.04(1H, d, J=8.7 Hz), 8.12(1H, dd, J=8.7, 2.4 Hz),
8.41(1H, d, J=2.4 Hz).
(2) 5-Isobutyryl-2-methoxybenzoic acid methyl ester
[0673] A mixture of 5-acetyl-2-methoxybenzoic acid methyl ester
(0.50 g, 2.40 mmol), potassium tert-butoxide (0.81 g, 7.22 mmol)
and tetrahydrofuran (10 mL) was cooled with ice bath. Methyl iodide
(0.5 mL, 8.03 mmol) was added, and the mixture was stirred at room
temperature for 1 hour. The reaction mixture was poured into water,
neutralized by hydrochloric acid, and extracted with ethyl acetate.
After the organic layer was washed with water and brine, dried over
anhydrous sodium sulfate, the residue obtained by evaporation under
reduced pressure was purified by chromatography on silica gel
(n-hexane:ethyl acetate=3:1.fwdarw.2:1) to give the title compound
(143.1 mg, 25.2%) as a light yellow oil.
[0674] .sup.1H-NMR(CDCl.sub.3):.delta. 1.22(6H, d, J=6.9 Hz),
3.52(1H, m), 3.92(3H, s), 3.98(3H, s), 7.05(1H, d, J=8.7 Hz),
8.13(1H, dd, J=8.7, 2.4 Hz), 8.42(1H, d, J=2.4 Hz).
(3) 5-Isobutyryl-2-methoxybenzoic acid
[0675] 5-Isobutyryl-2-methoxybenzoic acid methyl ester (143.1 mg,
0.60 mmol) was dissolved in methanol (5 mL). 2N Aqueous sodium
hydroxide (1 ml) was added, and the mixture was refluxed for 1
hour. After cooling, the reaction mixture was poured into 2N
hydrochloric acid and extracted with ethyl acetate. The organic
layer was washed with water and brine, dried over anhydrous sodium
sulfate, and evaporated under reduced pressure to give the title
compound (134 mg, yield: quantitative) as a white crystal.
[0676] .sup.1H-NMR(CDCl.sub.3):.delta. 1.22(6H, d, J=6.9 Hz),
3.59(1H, m), 4.15(3H, s), 7.16(1H, d, J=8.7 Hz), 8.24(1H, dd,
J=8.7, 2.4 Hz), 8.73(1H, d, J=2.1 Hz).
(4)
5-Isobutyryl-N-[3,5-bis(trifluoromethyl)phenyl]-2-methoxybenzamide
[0677] Using 5-isobutyryl-2-methoxybenzoic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0678] Yield: 61.4%.
[0679] .sup.1H-NMR(CDCl.sub.3):.delta. 1.23(6H, d, J=6.9 Hz),
3.64(1H, m), 4.20(3H, s), 7.18(1H, d, J=8.7 Hz), 7.65(1H, s),
8.19(2H, s), 8.22(1H, dd, J=8.7, 2.1 Hz), 8.88(1H, d, J=2.1 Hz),
9.98(1H, s).
(5)
N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-isobutyrylbenzamide
(Compound No. 79).
[0680] A mixture of
5-isobutyryl-N-[3,5-bis(trifluoromethyl)phenyl]-2-methoxybenzamide
(143.4 mg, 0.33 mmol), 2,4,6-collidine (3 ml) and lithium iodide
(53.1 mg, 0.40 mmol) was refluxed for 1 hour. After cooling, the
reaction mixture was poured into 2N hydrochloric acid and extracted
with ethyl acetate. After the organic layer was washed with brine,
dried over anhydrous sodium sulfate, the residue obtained by
evaporation under reduced pressure was purified by chromatography
on silica gel (n-hexane:ethyl acetate=3:1) and crystallized (ethyl
acetate/isopropyl ether) to give the title compound (90.3 mg,
65.3%) as a white crystal.
[0681] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.12(6H, d, J=6.9 Hz),
3.66(1H, m), 7.12(1H, d, J=8.4 Hz), 7.85(1H, s), 8.07(1H, dd,
J=8.4, 2.4 Hz), 8.45(1H, d, J=2.4 Hz), 8.47(2H, s), 10.93(1H, s),
11.95(1H, brs).
Example 81
Preparation of the Compound of Compound No. 81
[0682] Using 4-hydroxyisophthalic acid 1-methyl ester and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0683] Yield: 91.5%.
[0684] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.85(3H, s), 7.12(1H, d,
J=8.4 Hz), 7.86(1H, s), 8.02(1H, dd, J=8.7, 2.4 Hz), 8.46-8.47(3H,
m), 10.96(1H, s), 12.03(1H, brs).
[4-Hydroxyisophthalic acid 1-methyl ester: Refer to "Journal of the
Chemical Society", (England), 1956, p. 3099-3107.]
Example 82
Preparation of the Compound of Compound No. 80
[0685] N-[3,5-Bis(trifluoromethyl)phenyl]-4-hydroxyisophthalamic
acid methyl ester (Compound No. 81; 2.85 g, 7 mmol) was suspended
in a mixed solvent of methanol (14 mL) and tetrahydrofuran (14 mL).
2N Aqueous sodium hydroxide (14 mL) was added, and the mixture was
refluxed for 2 hours. After cooling, 2N hydrochloric acid (20 ml)
was added to the reaction mixture and the separated solid was
filtered, washed with water, dried to give the title compound (2.68
g, 97.4%) as a white crystal.
[0686] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.10(1H, d, J=8.7 Hz),
7.82(1H, s), 7.86(1H, s), 8.01(1H, dd, J=8.7, 2.4 Hz), 8.47(2H, s),
8.48(1H, d, J=2.4 Hz), 10.97(1H, s), 11.98(1H, brs).
[0687] When the method described in Example 82 is referred in the
following examples, inorganic bases such as sodium hydroxide,
potassium carbonate or the like were used as the base. As the
reaction solvent, solvents such as water, methanol, ethanol,
tetrahydrofuran or the like were used alone or as a mixture.
Example 83
Preparation of the Compound of Compound No. 82
[0688] Using 4-hydroxyisophthalic acid (182 mg, 1 mmol),
3,5-bis(trifluoromethyl)-aniline (687 mg, 3 mmol), phosphorus
trichloride (87 .mu.l; 1 mmol) and toluene (10 mL), the same
operation as the Example 16 gave the title compound (151 mg, 25.0%)
as a white crystal.
[0689] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.18(1H, d, J=8.7 Hz),
7.82(1H, s), 7.86(1H, s), 8.11(1H, dd, J=8.7, 2.4 Hz), 8.50(2H, s),
8.54(2H, s), 8.56(1H, d, J=2.4 Hz), 10.79(1H, s), 10.99(1H, s),
11.84(1H, brs).
Example 84
Preparation of the Compound of Compound No. 83
(1) 4-Benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]isophthalamic
acid methyl ester
[0690] Sodium hydride (60%; 1.04 g, 26 mmol) was washed with
n-hexane, and suspended in N,N-dimethylformamide (100 mL). A
solution of
N-[3,5-bis(trifluoromethyl)phenyl]-4-hydroxyisophthalamic acid
methyl ester (Compound No. 81; 8.15 g, 20 mmol) in
N,N-dimethylformamide (100 mL) was added dropwise under cooling
with ice bath. After the addition was finished, the mixture was
stirred at room temperature for 1 hour. A solution of benzyl
bromide (4.45 g, 26 mmol) in N,N-dimethylformamide (10 mL) was
added, and the mixture was stirred at 60.degree. C. for 3 hours.
After cooling, the reaction mixture was poured into ice and water,
and extracted with ethyl acetate. After the organic layer was
washed with water and brine, dried over anhydrous magnesium
sulfate, the residue obtained by evaporation under reduced pressure
was recrystallized (ethyl acetate/n-hexane) to give the title
compound (5.38 g, 54.1%) as a white solid.
[0691] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.87(3H, s), 5.33(2H, s),
7.33-7.36(3H, m), 7.46(1H, d, J=8.7 Hz), 7.53-7.56(2H, m), 7.82(1H,
s), 8.15(1H, dd, J=8.7, 2.1 Hz), 8.25(1H, d, J=2.1 Hz) 8.28(2H, s),
10.87(1H, s).
(2) 4-Benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]isophthalamic
acid
[0692] Using
4-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]isophthalamic acid
methyl ester as the raw material, the same operation as the Example
82 gave the title compound.
[0693] Yield: 79.7%.
[0694] .sup.1H-NMR(DMSO-d.sub.6):.delta. 5.32(2H, s), 7.32-7.34(3H,
m), 7.43(1H, d, J=8.7 Hz), 7.52-7.56(2H, m), 7.81(1H, s), 8.12(1H,
dd, J=8.7, 2.1 Hz), 8.22(1H, d, J=2.1 Hz), 8.28(2H, s), 10.85(1H,
s), 13.81(1H, brs).
(3)
4-Benzyloxy-N.sup.3-[3,5-bis(trifluoromethyl)phenyl]-N.sup.1,N.sup.1-d-
imethylisophthalamide
[0695] WSC.HCl (95 mg, 0.50 mmol) was added to a solution of
4-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]isophthalamic acid
(242 mg, 0.50 mmol), dimethylamine hydrochloride (41 mg, 0.50 mmol)
and triethylamine (51 mg, 0.50 mmol) in tetrahydrofuran (5 mL)
under ice cooling, and the mixture was stirred at room temperature
for 3 hours. The reaction mixture was poured into water and
extracted with ethyl acetate. After the organic layer was washed
with diluted hydrochloric acid, water and brine, dried over
anhydrous magnesium sulfate, the residue obtained by evaporation of
the solvent under reduced pressure was purified by chromatography
on silica gel (hexane:ethyl acetate=1:4) to give the title compound
(165 mg, 64.9%) as a white solid.
[0696] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.99(6H, s) 5.29(2H, s),
7.32-7.38(4H, m), 7.52-7.56(2H, m), 7.64(1H, dd, J=8.7, 2.1 Hz),
7.73(1H, d, J=2.1 Hz), 7.80(1H, s), 8.28(2H, s), 10.83(1H, s).
[0697] When the method described in Example 84(3) is referred in
the following examples, organic bases such as pyridine,
triethylamine or the like were used as the base. As the reaction
solvent, solvents such as dichloromethane, tetrahydrofuran or the
like were used alone or as a mixture.
(4)
N.sup.3-[3,5-bis(trifluoromethyl)phenyl]-4-hydroxy-N.sup.1,N.sup.1-dim-
ethylisophthalamide (Compound No. 83).
[0698] A solution of
4-benzyloxy-N.sup.3-[3,5-bis(trifluoromethyl)phenyl]-N.sup.1,N.sup.1-dime-
thyl-isophthalamide (141 mg, 0.28 mmol) and 5% Pd--C(14 mg) in a
mixed solvent of ethanol (5 ml) and ethyl acetate (5 ml) was
stirred at room temperature for 1 hour under hydrogen atmosphere.
The reaction mixture was filtered and the filtrate was evaporated
under reduced pressure to give the title compound (106 mg, 91.2%)
as a white solid.
[0699] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.98(6H, s), 7.02(1H, d,
J=8.7 Hz), 7.52(1H, dd, J=8.7, 2.1 Hz), 7.84(1H, s), 7.95(1H, d,
J=2.1 Hz), 8.46(2H, s), 11.10(1H, brs), 11.63(1H, brs).
Example 85
Preparation of the Compound of Compound No. 84
(1)
2-Benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]-5-(piperidine-1-carbony-
l)-benzamide
[0700] Using
4-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]isophthalamic acid
(compound of Example 84(2)) and piperidine as the raw materials,
the same operation as the Example 84(3) gave the title
compound.
[0701] Yield: 56.4%.
[0702] .sup.1H-NMR(CDCl.sub.3):.delta. 1.53-1.70(6H, m), 3.44(2H,
brs), 3.70(2H, brs), 5.26(2H, s), 7.24(1H, d, J=8.7 Hz), 7.26(1H,
s), 7.52-7.58(5H, m), 7.66(2H, s), 7.74(1H, dd, J=8.7, 2.4 Hz),
8.37(1H, d, J=2.1 Hz), 10.27(1H, s).
(2)
N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-(piperidine-1-carbonyl)-
benzamide (Compound No. 84).
[0703] Using
2-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]-5-(piperidine-1-carbonyl)b-
enzamide as the raw material, the same operation as the Example
84(4) gave the title compound.
[0704] Yield: 96.3%, white solid.
[0705] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.51(4H, brs),
1.60-1.65(2H, m), 3.47(4H, brs), 7.04(1H, d, J=8.4 Hz), 7.48(1H,
dd, J=8.4, 2.1 Hz), 7.85(1H, s), 7.92(1H, d, J=2.1 Hz), 8.46(2H,
s), 10.99(1H, s), 11.64(1H, brs).
Example 86
Preparation of the Compound of Compound No. 85
(1)
2-Benzyloxy-5-(4-benzylpiperidine-1-carbonyl)-N-[3,5-bis(trifluorometh-
yl)phenyl]-benzamide
[0706] Using
4-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]isophthalamic acid
(compound of Example 84(2)) and 4-benzylpiperidine as the raw
materials, the same operation as the Example 84(3) gave the title
compound.
[0707] Yield: 76.7%.
[0708] .sup.1H-NMR(CD.sub.3OD):.delta. 1.18-1.38(2H, m), 1.67(1H,
brs), 1.74(1H, brs), 1.84-1.93(1H, m), 2.60(2H, d, J=7.2 Hz),
2.83(1H, brs), 3.10(1H, brs), 3.78(1H, brs), 4.59(1H, brs),
5.34(2H, s), 7.15-7.18(3H, m), 7.24-7.28(2H, m), 7.40-7.46(4H, m),
7.57-7.63(3H, m), 7.65(1H, dd, J=8.7, 2.4 Hz), 7.96(2H, s),
8.05(1H, d, J=2.1 Hz).
(2)
N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-(4-benzylpiperidine-1-c-
arbonyl)-benzamide (Compound No. 85).
[0709] Using
2-benzyloxy-5-(4-benzylpiperidine-1-carbonyl)-N-[3,5-bis(trifluoromethyl)-
phenyl]-benzamide as the raw material, the same operation as the
Example 84(4) gave the title compound.
[0710] Yield: 54.3%, white solid.
[0711] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.08-1.22(2H, m),
1.59-1.62(2H, m), 1.77-1.80(1H, m), 2.50-2.55(2H, m), 2.87(2H,
brs), 3.75(1H, br), 4.39(1H, br), 7.06(1H, d, J=8.4 Hz),
7.17-7.20(3H, m), 7.28(2H, t, J=7.2 Hz), 7.49(1H, dd, J=8.4, 2.1
Hz), 7.84(1H, s), 7.93(1H, d, J=2.1 Hz), 8.47(2H, s), 10.89(1H, s),
11.65(1H, s).
Example 87
Preparation of the Compound of Compound No. 86
(1) 2-Methoxy-5-sulfamoylbenzoic acid
[0712] Methyl 2-methoxy-5-sulfamoylbenzoate (4.91 g, 20 mmol) was
dissolved in methanol (30 mL). 2N Aqueous sodium hydroxide (30 mL,
60 mmol) was added, and the mixture was stirred at room temperature
for 1 hour. The reaction mixture was poured into 2N hydrochloric
acid, and the separated solid was filtered to give the title
compound (4.55 g, 98.3%) as a white solid.
[0713] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.89(3H, s), 7.30(1H, d,
J=8.7 Hz), 7.32(2H, s), 7.92(1H, dd, J=8.7, 2.7 Hz), 8.09(1H, d,
J=2.7 Hz), 13.03(1H, br).
(2)
N-[3,5-Bis(trifluoromethyl)phenyl]-2-methoxy-5-sulfamoylbenzamide
[0714] Using 2-methoxy-5-sulfamoylbenzoic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 24 gave the title compound.
[0715] Yield: 24.2%.
[0716] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.97(3H, s), 7.38(2H, s),
7.39(1H, d, J=8.7 Hz), 7.85(1H, s), 7.96(1H, dd, J=8.7, 2.4 Hz),
8.06(1H, d, J=2.4 Hz), 8.43(2H, s), 10.87(1H, s).
(3)
N-[3,5-Bis(trifluoromethyl)phenyl]-5-dimethylsulfamoyl-2-methoxybenzam-
ide
[0717] A suspension of
N-[3,5-bis(trifluoromethyl)phenyl]-2-methoxy-5-sulfamoylbenzamide
(442 mg, 1.0 mmol), methyl iodide (710 mg, 5.0 mmol) and sodium
carbonate (415 mg, 3.0 mmol) in acetonitrile (10 mL) was refluxed
for 3 hours. After cooling to room temperature, the reaction
mixture was poured into water and extracted with ethyl acetate.
After the organic layer was washed with water and brine, dried over
anhydrous magnesium sulfate, the residue obtained by evaporation of
the solvent under reduced pressure was recrystallized from a mixed
solvent of n-hexane and ethyl acetate (2:1) to give the title
compound (207 mg, 44.1%) as a white solid.
[0718] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.62(6H, s), 3.99(3H, s),
7.45(1H, d, J=9.0 Hz), 7.85(1H, s), 7.91(1H, dd, J=8.7, 2.4 Hz),
7.95(1H, d, J=2.4 Hz) 8.43(2H, s), 10.90(1H, s).
(4)
N-[3,5-Bis(trifluoromethyl)phenyl]-5-dimethylsulfamoyl-2-hydroxybenzam-
ide (Compound No. 86).
[0719] Using
N-[3,5-bis(trifluoromethyl)phenyl]-5-dimethylsulfamoyl-2-methoxybenzamide
as the raw material, the same operation as the Example 80(5) gave
the title compound.
[0720] Yield: 45.5%.
[0721] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.61(6H, s), 7.20(1H, d,
J=8.7 Hz), 7.77(1H, dd, J=8.7, 2.1 Hz), 7.86(1H, s), 8.14(1H, d,
J=2.1 Hz) 8.45(2H, s), 11.16(1H, s), 12.15(1H, br).
Example 88
Preparation of the Compound of Compound No. 87
(1)
N-[3,5-Bis(trifluoromethyl)phenyl]-2-methoxy-5-(pyrrole-1-sulfonyl)ben-
zamide
[0722] A mixture of
N-[3,5-bis(trifluoromethyl)phenyl]-2-methoxy-5-sulfamoyl-benzamide
(compound of Example 87(2); 442 mg, 1 mmol),
2,5-dimethoxytetrahydrofuran (159 mg, 1.2 mmol) and acetic acid (5
mL) was refluxed for 2 hours. After cooling, the reaction mixture
was poured into water and extracted with ethyl acetate. After the
organic layer was washed with water, saturated aqueous sodium
hydrogen carbonate and brine, dried over anhydrous magnesium
sulfate, the residue obtained by evaporation of the solvent under
reduced pressure was purified by chromatography on silica gel
(n-hexane:ethyl acetate=3:2) to give the title compound (436.5 mg,
88.6%) as a white solid.
[0723] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.96(3H, s), 6.36(2H, dd,
J=2.4, 2.1 Hz), 7.37(2H, dd, J=2.4, 2.1 Hz), 7.42(1H, d, J=9.0 Hz),
7.85(1H, s), 8.80(1H, dd, J=9.0, 2.4 Hz) 8.18(1H, d, J=2.7 Hz),
8.38(2H, s), 10.92(1H, s).
(2)
N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-(pyrrole-1-sulfonyl)ben-
zamide (Compound No. 87).
[0724] Using
N-[3,5-bis(trifluoromethyl)phenyl]-2-methoxy-5-(pyrrole-1-sulfonyl)benzam-
ide as the raw material, the same operation as the Example 80(5)
gave the title compound.
[0725] Yield: 79.4%.
[0726] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.36(2H, dd, J=2.4, 2.1
Hz), 7.18(1H, d, J=9.0 Hz), 7.34(2H, dd, J=2.4, 2.1 Hz), 7.86(1H,
s), 7.99(1H, dd, J=9.0, 2.7 Hz) 8.31(1H, d, J=2.7 Hz), 8.42(2H, s),
10.98(1H, s).
Example 89
Preparation of the Compound of Compound No. 88
[0727] Using
N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-nitrobenzamide
(Compound No. 53) as the raw material, the same operation as the
Example 84(4) gave the title compound.
[0728] Yield: 98.0%.
[0729] .sup.1H-NMR(DMSO-d.sub.6):.delta. 4.79(2H, brs), 6.76(1H, d,
J=2.1 Hz), 6.76(1H, s), 7.09(1H, dd, J=2.1, 1.2 Hz), 7.80(1H, s),
8.45(2H, s), 10.30(1H, br), 10.84(1H, s).
Example 90
Preparation of the Compound of Compound No. 89
[0730] Using 5-dimethylaminosalicylic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0731] Yield: 28.8%.
[0732] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.85(6H, s), 6.92(1H, d,
J=9.0 Hz), 7.01(1H, dd, J=8.7, 3.0 Hz), 7.22(1H, d, J=3.0 Hz),
7.84(1H, s), 8.47(2H, s), 10.62(1H, s), 10.83(1H, s).
Example 91
Preparation of the Compound of Compound No. 90
[0733] Under argon atmosphere, a mixture of
5-amino-N-[3,5-bis(trifluoromethyl)-phenyl]-2-hydroxybenzamide
(Compound No. 88; 364 mg, 1 mmol), pyridine (95 mg, 1.2 mmol) and
tetrahydrofuran (10 mL) was cooled on ice. Benzoyl chloride (155
mg, 1.1 mmol) was added, and the mixture was stirred for 1 hour.
The reaction mixture was poured into water and extracted with ethyl
acetate. After the organic layer was washed with water and brine,
dried over anhydrous magnesium sulfate, the residue obtained by
evaporation under reduced pressure was purified by chromatography
on silica gel (n-hexane:ethyl acetate=4:1) to give the title
compound (121 mg, 25.7%) as a white solid.
[0734] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.04(1H, d, J=8.7 Hz),
7.51-7.62(3H, m), 7.81(1H, dd, J=8.7, 2.4 Hz), 7.83(1H, s),
7.98(2H, d, J=7.2 Hz), 8.22(1H, d, J=2.4 Hz), 8.49(2H, s),
10.27(1H, s), 10.89(1H, s), 11.07(1H, 8).
Example 92
Preparation of the Compound of Compound No. 91
[0735]
5-Amino-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide
(Compound No. 88; 100.2 mg, 0.28 mmol) was dissolved in
acetonitrile (4 ml). 4-Dimethylaminopyridine (3 mg) and
phenylisocyanate (30 .mu.l, 0.28 mmol) were added, and the mixture
was stirred at 60.degree. C. for 5 minutes. The reaction mixture
was concentrated and the residue was purified by chromatography on
silica gel (n-hexane:ethyl acetate=1:1) to give the title compound
(54.8 mg, 41.2%) as a light brown solid.
[0736] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.93-6.98(1H, m), 6.97(1H,
d, J=9.3 Hz), 7.27(2H, t, J=7.8 Hz), 7.34-7.46(2H, m), 7.50(1H, dd,
J=9.0, 2.4 Hz), 7.83(1H, s), 7.88(1H, s), 8.47(2H, s), 8.56(1H, s),
8.63(1H, s), 10.87(1H, s), 10.89(1H, s).
Example 93
Preparation of the Compound of Compound No. 92
[0737] Using
5-amino-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide
(Compound No. 88) and phenylisothiocyanate as the raw materials,
the same operation as the Example 92 gave the title compound.
[0738] Yield: 66.3%.
[0739] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.00(1H, d, J=8.4 Hz),
7.13(1H, tt, J=7.5, 1.2 Hz), 7.34(2H, t, J=7.8 Hz), 7.45-7.51(3H,
m), 7.84(1H, s), 7.87(1H, d, J=2.7 Hz), 8.47(2H, s), 9.65(1H, s),
9.74(1H, s), 10.84(1H, s), 11.32(1H, s).
Example 94
Preparation of the Compound of Compound No. 93
[0740] Using 5-[(4-nitrophenyl)diazenyl]salicylic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0741] Yield: 11.3%.
[0742] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.23(1H, d, J=9.0 Hz),
7.87(1H, s), 8.06(2H, d, J=9.0 Hz), 8.10(1H, dd, J=9.0, 2.4 Hz),
8.44(2H, d, J=9.0 Hz), 8.50(2H, s), 8.53(1H, d, J=2.4 Hz),
11.13(1H, s), 12.14(1H, br).
Example 95
Preparation of the Compound of Compound No. 94
[0743] Using
5-({[(4-pyridin-2-yl)sulfamoyl]phenyl}diazenyl)salicylic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0744] Yield: 7.9%.
[0745] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.87(1H, t, J=6.0 Hz),
7.22(1H, d, J=8.7 Hz), 7.21-7.23(1H, m), 7.77(1H, t, J=8.4 Hz),
7.87(1H, s), 7.95-7.98(3H, m), 8.03-8.07(4H, m), 8.47(1H, d, J=2.4
Hz), 8.49(2H, s), 11.14(1H, s), 12.03(1H, br).
Example 96
Preparation of the Compound of Compound No. 96
[0746]
N-[3,5-Bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide
(Compound No. 50; 1.51 g, 3 mmol) and pyridine (285 mg, 3.6 mmol)
were dissolved in tetrahydrofuran (6 mL). Acetyl chloride (234 mg,
3.3 mmol) was added dropwise under ice cooling, and the mixture was
stirred at room temperature for 1 hour. The solvent was evaporated
under reduced pressure. 2 N hydrochloric acid was added to the
residue, and it was extracted with ethyl acetate. After the ethyl
acetate layer was washed with water and brine, dried over anhydrous
magnesium sulfate and concentrated, the residue was recrystallized
from n-hexane/ethyl acetate to give the title compound (1.06 g,
83.0%) as a white solid.
[0747] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.22(3H, s), 7.35(1H, d,
J=9.0 Hz), 7.71(1H, dd, J=8.7, 2.7 Hz), 7.85(1H, s), 7.88(1H, d,
J=2.7 Hz), 8.37(2H, s), 11.05(1H, brs).
[0748] When the method described in Example 96 is referred in the
following examples, organic bases such as pyridine, triethylamine
or the like were used as the base. As the reaction solvent,
solvents such as dichloromethane, tetrahydrofuran, benzene or the
like were used alone or as a mixture.
Example 97
Preparation of the Compound of Compound No. 97
(1) 4-Acetylamino-5-chloro-2-methoxybenzoic acid
[0749] Using 4-acetylamino-5-chloro-2-methoxybenzoic acid methyl
ester as the raw material, the same operation as the Example 82
gave the title compound.
[0750] Yield: 88.0%.
[0751] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.16(3H, s), 3.78(3H, s),
7.72(1H, s), 7.77(1H, s), 9.57(1H, s), 12.74(1H, s).
(2)
4-Acetylamino-N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-methoxyben-
zamide
[0752] Using 4-acetylamino-5-chloro-2-methoxybenzoic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 24 gave the title compound.
[0753] Yield: 23.8%.
[0754] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.17(3H, s), 3.89(3H, s),
7.77-7.82(3H, m), 8.45-8.49(2H, m), 9.66(1H, s), 10.68(1H, s).
(3)
4-Acetylamino-N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxyben-
zamide (Compound No. 97).
[0755] Using
4-acetylamino-N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-methoxybenzam-
ide as the raw material, the same operation as the Example 80(5)
gave the title compound.
[0756] Yield: 72.8%.
[0757] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.17(3H, s), 7.75(1H, s),
7.82(1H, s), 7.95(1H, s), 8.44(2H, s), 9.45(1H, s), 11.16(1H, brs),
11.63(1H, brs).
Example 98
Preparation of the Compound of Compound No. 98
[0758] Using 4-chlorosalicylic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0759] Yield: 55.8%.
[0760] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.05-7.08(2H, m),
7.84-7.87(2H, m), 8.45(2H, s), 10.84(1H, s) 11.64(1H, brs).
Example 99
Preparation of the Compound of Compound No. 99
[0761] Using 5-chlorosalicylic acid and
3,5-bis(trifluoromethyl)-2-bromoaniline as the raw materials, the
same operation as the Example 16 gave the title compound.
[0762] Yield: 14.5%.
[0763] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.11(1H, d, J=9.0 Hz),
7.53(1H, dd, J=9.0, 2.7 Hz), 7.91(1H, d, J=1.8 Hz), 7.98(1H, d,
J=2.7 Hz), 9.03(1H, d, J=1.8 Hz), 11.26(1H, brs).
Example 100
Preparation of the Compound of Compound No. 100
[0764] Using 5-chlorosalicylic acid and
2,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0765] Yield: 3.6%.
[0766] .sup.1H-NMR(CDCl.sub.3):.delta. 7.03(1H, d, J=8.7 Hz),
7.43-7.48(2H, m), 6.61(1H, d, J=8.1 Hz), 7.85(1H, d, J=8.4 Hz),
8.36(1H, br s), 8.60(1H, s), 11.31(1H, s).
Example 101
Preparation of the Compound of Compound No. 101
[0767] Using 5-bromosalicylic acid and
2,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0768] Yield: 24.0%.
[0769] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.03(1H, d, J=8.7 Hz),
7.65(1H, dd, J=8.7, 2.7 Hz), 7.76(1H, d, J=8.4 Hz), 8.03(1H, d,
J=8.1 Hz) 8.11(1H, d, J=2.7 Hz), 8.74(1H, s), 11.02(1H, s),
12.34(1H, s).
Example 102
Preparation of the Compound of Compound No. 102
[0770] Using 5-methylsalicylic acid and
2,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0771] Yield: 1.5%.
[0772] .sup.1H-NMR(CDCl.sub.3):.delta. 2.36(3H, s), 6.97(1H, d,
J=8.4 Hz), 7.23(1H, s), 7.32(1H, dd, J=8.4, 1.5 Hz), 7.57(1H, d,
J=8.4 Hz), 7.83(1H, d, J=8.4 Hz), 8.46(1H, s), 8.69(1H, s),
11.19(1H, s).
Example 103
Preparation of the Compound of Compound No. 103
[0773] Using
N-[2,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide
(Compound No. 100) and acetyl chloride as the raw materials, the
same operation as the Example 96 gave the title compound.
[0774] Yield: 6.6%.
[0775] .sup.1H-NMR(CDCl.sub.3):.delta. 2.35(3H, s), 7.17(1H, d,
J=8.7 Hz), 7.54(1H, dd, J=8.7, 2.4 Hz), 7.55(1H, d, J=8.1 Hz),
7.80(1H, d, J=8.1 Hz), 7.95(1H, d, J=2.4 Hz), 8.60(1H, s), 8.73(1H,
s).
Example 104
Preparation of the Compound of Compound No. 104
[0776] Using 5-chlorosalicylic acid and 2-(trifluoromethyl)aniline
as the raw materials, the same operation as the Example 16 gave the
title compound.
[0777] Yield: 58.0%.
[0778] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.07(1H, d, J=8.7 Hz),
7.42(1H, t, J=7.5 Hz), 7.52(1H, dd, J=8.7, 2.7 Hz), 7.74(1H, t,
J=8.1 Hz), 7.77(1H, t, J=8.1 Hz), 7.99(1H, d, J=2.7 Hz), 8.18(1H,
d, J=8.1 Hz), 10.76(1H, s), 12.22(1H, s).
Example 105
Preparation of the Compound of Compound No. 105
[0779] Using 5-chlorosalicylic acid and
4-chloro-2-(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0780] Yield: 21.5%.
[0781] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.07(1H, d, J=8.7 Hz),
7.52(1H, dd, J=8.7, 2.7 Hz), 7.80-7.85(2H, m), 7.97(1H, d, J=2.7
Hz), 8.26(1H, d, J=8.4 Hz), 10.80(1H, s), 12.26(1H, s).
Example 106
Preparation of the Compound of Compound No. 106
[0782] Using 5-bromosalicylic acid and 3-(trifluoromethyl)aniline
as the raw materials, the same operation as the Example 16 gave the
title compound.
[0783] Yield: 50.3%.
[0784] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.98(1H, d, J=8.7 Hz),
7.48-7.52(1H, m), 7.59(1H, dd, J=8.7, 2.7 Hz), 7.62(1H, t, J=8.1
Hz), 7.92-7.96(1H, m), 8.02(1H, d, J=2.4 Hz), 8.20(1H, s),
10.64(1H, s), 11.60(1H, s).
Example 107
Preparation of the Compound of Compound No. 107
[0785] Using 5-chlorosalicylic acid and
2-fluoro-3-(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0786] Yield: 71.7%, white solid.
[0787] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.07(1H, d, J=9.0 Hz),
7.46(1H, t, J=7.8 Hz), 7.52(1H, dd, J=9.0, 2.7 Hz), 7.58(1H, t,
J=7.2 Hz), 7.96(1H, d, J=2.7 Hz), 8.49(1H, t, J=7.2 Hz), 10.82(1H,
s), 12.13(1H, brs).
Example 108
Preparation of the Compound of Compound No. 108
[0788] Using 5-chlorosalicylic acid and
4-fluoro-3-(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0789] Yield: 72.1%, white solid.
[0790] .sup.1H-NMR(DMSO-d.sub.6):7.03(1H, d, J=9.0 Hz), 7.48(1H,
dd, J=8.7, 2.7 Hz), 7.56(1H, d, J=9.9 Hz), 7.90(1H, d, J=2.7 Hz),
7.99-8.03(1H, m), 8.21(1H, dd, J=6.6, 2.4 Hz), 10.63(1H, s),
11.58(1H, s).
Example 109
Preparation of the Compound of Compound No. 109
[0791] Using 5-bromosalicylic acid and
4-chloro-3-(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0792] Yield: 37.4%.
[0793] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.98(1H, d, J=8.7 Hz),
7.59(1H, dd, J=8.7, 2.4 Hz), 7.73(1H, d, J=8.7 Hz), 7.98(1H, d,
J=2.4 Hz), 8.00(1H, dd, J=8.7, 2.4 Hz), 8.31(1H, d, J=2.4 Hz),
10.68(1H, s), 11.52(1H, brs).
Example 110
Preparation of the Compound of Compound No. 110
[0794] Using 5-chlorosalicylic acid and
3-fluoro-5-(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0795] Yield: 62.0%.
[0796] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.04(1H, d, J=8.7 Hz),
7.42(1H, d, J=8.4 Hz), 7.48(1H, dd, J=9.0, 3.0 Hz), 7.85(1H, d,
J=2.4 Hz), 7.94(1H, dd, J=11.4, 2.1 Hz), 7.99(1H, s), 10.73(1H, s),
11.46(1H, s).
Example 111
Preparation of the Compound of Compound No. 111
[0797] Using 5-bromosalicylic acid and
3-bromo-5-(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0798] Yield: 73.3%.
[0799] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.99(1H, d, J=9.0 Hz),
7.60(1H, dd, J=9.0, 2.4 Hz), 7.72(1H, s), 7.97(1H, d, J=2.7 Hz),
8.16(1H, s), 8.28(1H, s), 10.69(1H, s), 11.45(1H, s).
Example 112
Preparation of the Compound of Compound No. 112
[0800] Using 5-chlorosalicylic acid and
2-fluoro-5-(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0801] Yield: 77.9%.
[0802] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.07(1H, d, J=9.0 Hz),
7.52(1H, dd, J=9.0, 2.7 Hz), 7.58-7.61(2H, m), 7.95(1H, d, J=2.7
Hz), 8.71(1H, d, J=7.5 Hz), 10.90(1H, s), 12.23(1H, s).
Example 113
Preparation of the Compound of Compound No. 113
[0803] Using 5-chlorosalicylic acid and
2-chloro-5-(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0804] Yield: 49.1%.
[0805] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.09(1H, d, J=9.0 Hz),
7.53(1H, dd, J=9.0, 3.0 Hz), 7.55(1H, dd, J=8.4, 2.7 Hz), 7.83(1H,
d, J=8.4 Hz), 7.98(1H, d, J=3.0 Hz), 8.88(1H, d, J=2.7 Hz),
11.14(1H, s), 12.39(1H, s).
Example 114
Preparation of the Compound of Compound No. 114
[0806] Using 5-bromosalicylic acid and
2-chloro-5-(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0807] Yield: 34.2%.
[0808] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.04(1H, d, J=8.7 Hz),
7.56(1H, ddd, J=8.1, 2.4, 1.2 Hz), 7.64(1H, dd, J=8.7, 2.7 Hz),
7.83(1H, dd, J=8.1, 1.2 Hz), 8.11(1H, d, J=2.7 Hz), 8.87(1H, d,
J=2.4 Hz), 11.12(1H, s), 12.42(1H, s).
Example 115
Preparation of the Compound of Compound No. 115
[0809] Using 5-chlorosalicylic acid and
4-nitro-3-(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0810] Yield: 44.8%.
[0811] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.04(1H, d, J=9.0 Hz),
7.49(1H, dd, J=9.0, 2.7 Hz), 7.81(1H, d, J=2.7 Hz), 8.23-8.24(2H,
m), 8.43(1H, d, J=1.2 Hz), 11.02(1H, s), 11.30(1H, br).
Example 116
Preparation of the Compound of Compound No. 116
[0812] Using 5-chlorosalicylic acid and
2-nitro-5-(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0813] Yield: 8.1%.
[0814] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.08(1H, d, J=9.0 Hz),
7.53(1H, dd, J=8.7, 2.7 Hz), 7.73(1H, dd, J=8.4, 1.8 Hz), 7.95(1H,
d, J=3.0 Hz), 8.36(1H, d, J=8.7 Hz), 9.01(1H, d, J=1.8 Hz),
12.04(1H, s), 12.20(1H, s).
Example 117
Preparation of the Compound of Compound No. 117
[0815] Using 5-bromosalicylic acid and
4-cyano-3-(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0816] Yield: 49.7%.
[0817] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.99(1H, d, J=8.7 Hz),
7.60(1H, dd, J=8.7, 2.4 Hz), 7.92(1H, d, J=2.7 Hz), 8.16(2H, s),
8.42(1H, s), 10.93(1H, s), 11.36(1H, s).
Example 118
Preparation of the Compound of Compound No. 118
[0818] Using 5-chlorosalicylic acid and
2-methyl-3-(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0819] Yield: 14.5%.
[0820] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.36(3H, d, J=1.2 Hz),
7.05(1H, d, J=8.7 Hz), 7.46(1H, t, J=8.1 Hz), 7.50(1H, dd, J=8.7,
2.7 Hz), 7.60(1H, d, J=7.2 Hz), 7.99(1H, d, J=7.2 Hz), 8.00(1H, d,
J=2.4 Hz), 10.43(1H, s), 12.08(1H, s).
Example 119
Preparation of the Compound of Compound No. 119
[0821] Using 5-chlorosalicylic acid and
4-methyl-3-(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0822] Yield: 80.2%.
[0823] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.01(1H, d, J=8.7 Hz),
7.44(1H, d, J=8.4 Hz), 7.47(1H, dd, J=9.0, 2.7 Hz), 7.84(1H, dd,
J=8.4, 2.1 Hz), 7.92(1H, d, J=2.7 Hz), 8.13(1H, d, J=2.1 Hz),
10.65(1H, s), 11.68(1H, br).
Example 120
Preparation of the Compound of Compound No. 120
[0824] Using 5-chlorosalicylic acid and
2-methyl-5-(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0825] Yield: 73.3%.
[0826] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.39(3H, s), 7.07(1H, d,
J=8.7 Hz), 7.44-7.54(3H, m), 7.99(1H, d, J=3.0 Hz), 8.43(1H, s),
10.52(1H, s), 12.17(1H, brs).
Example 121
Preparation of the Compound of Compound No. 121
[0827] Using 5-chlorosalicylic acid and
4-methoxy-3-(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0828] Yield: 79.1%.
[0829] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.89(3H, s), 7.02(1H, d,
J=9.0 Hz), 7.30(1H, d, J=9.0 Hz), 7.48(1H, dd, J=9.0, 3.0 Hz),
7.92(1H, dd, J=9.0, 2.4 Hz), 7.96(1H, d, J=2.7 Hz), 8.04(1H, d,
J=2.4 Hz), 10.47(1H, s), 11.78(1H, s).
Example 122
Preparation of the Compound of Compound No. 122
[0830] Using 5-bromosalicylic acid and
3-methoxy-5-(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0831] Yield: 58.8%.
[0832] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.85(3H, s), 6.98(1H, d,
J=8.7 Hz), 7.03(1H, s), 7.57-7.61(2H, m), 7.77(1H, s), 8.00(1H, d,
J=2.4 Hz), 10.57(1H, s), 11.56(1H, s).
Example 123
Preparation of the Compound of Compound No. 123
[0833] Using 5-bromosalicylic acid and
2-methoxy-5-(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0834] Yield: 71.3%.
[0835] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.99(3H, s), 7.03(1H, d,
J=9.0 Hz), 7.30(1H, d, J=8.7 Hz), 7.47-7.51(1H, m), 7.61(1H, dd,
J=9.0, 2.4 Hz), 8.10(1H, d, J=2.4 Hz), 8.82(1H, d, J=2.1 Hz)
11.03(1H, s), 12.19(1H, s).
Example 124
Preparation of the Compound of Compound No. 124
[0836] Using 5-chlorosalicylic acid and
2-methoxy-5-(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0837] Yield: 83.4%.
[0838] .sup.1H-NMR(DMSO-d.sub.6):.delta. 4.00(3H, s), 7.08(1H, d,
J=9.0 Hz), 7.30(1H, d, J=8.7 Hz), 7.47-7.52(2H, m), 7.97(1H, d,
J=2.7 Hz), 8.83(1H, d, J=2.4 Hz), 11.05(1H, s), 12.17(1H, s).
Example 125
Preparation of the Compound of Compound No. 125
[0839] Using 5-chlorosalicylic acid and
2-methylsulfanyl-5-(trifluoromethyl)aniline as the raw materials,
the same operation as the Example 16 gave the title compound.
[0840] Yield: 79.2%.
[0841] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.57(3H, s), 7.07(1H, d,
J=8.7 Hz), 7.52(1H, dd, J=8.7, 2.4 Hz), 7.55(1H, dd, J=8.4, 1.5
Hz), 7.63(1H, d, J=8.1 Hz), 8.00(1H, d, J=2.4 Hz), 8.48(1H, d,
J=1.5 Hz), 10.79(1H, s), 12.26(1H, s).
Example 126
Preparation of the Compound of Compound No. 126
[0842] Using 5-bromosalicylic acid and
2-(1-pyrrolidinyl)-5-(trifluoromethyl)aniline as the raw materials,
the same operation as the Example 16 gave the title compound.
[0843] Yield: 44.5%.
[0844] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.86-1.91(4H, m),
3.20-3.26(4H, m), 6.99(1H, d, J=8.7 Hz), 7.07(1H, d, J=8.7 Hz),
7.43(1H, dd, J=8.7, 2.1 Hz), 7.62(1H, dd, J=8.7, 2.4 Hz), 7.94(1H,
d, J=2.1 Hz), 8.17(1H, d, J=2.4 Hz), 10.54(1H, s), 12.21(1H,
s).
Example 127
Preparation of the Compound of Compound No. 127
[0845] Using 5-bromosalicylic acid and
2-morpholino-5-(trifluoromethyl)aniline as the raw materials, the
same operation as the Example 16 gave the title compound.
[0846] Yield: 65.9%.
[0847] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.90(4H, dd, J=4.5, 4.2
Hz), 3.84(4H, dd, J=4.8, 4.2 Hz), 7.09(1H, d, J=8.4 Hz), 7.48(2H,
s), 7.61(1H, dd, J=8.4, 2.7 Hz), 8.13(1H, d, J=2.7 Hz), 8.90(1H,
s), 11.21(1H, s), 12.04(1H, s).
Example 128
Preparation of the Compound of Compound No. 128
[0848] Using 5-chlorosalicylic acid and 4-(trifluoromethyl)aniline
as the raw materials, the same operation as the Example 16 gave the
title compound.
[0849] Yield: 75.0%, white solid
[0850] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.04(1H, d, J=9.0 Hz),
7.48(1H, dd, J=8.7, 2.7 Hz), 7.74(2H, d, J=8.7 Hz), 7.90(1H, d,
J=2.7 Hz), 7.95(2H, d, J=9.0 Hz), 10.65(1H, s), 11.59(1H, s).
Example 129
Preparation of the Compound of Compound No. 129
[0851] Using 5-bromosalicylic acid and
2-chloro-4-(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0852] Yield: 34.9%.
[0853] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.04(1H, d, J=8.7 Hz),
7.64(1H, dd, J=8.7, 2.7 Hz), 7.79(1H, dd, J=9.0, 2.1 Hz), 7.99(1H,
d, J=2.1 Hz), 8.11(1H, d, J=2.4 Hz), 8.73(1H, d, J=9.0 Hz),
11.15(1H, s), 12.42(1H, s).
Example 130
Preparation of the Compound of Compound No. 130
[0854] Using
5-chloro-N-[2-chloro-5-(trifluoromethyl)phenyl]-2-hydroxybenzamide
(Compound No. 113) and acetyl chloride as the raw materials, the
same operation as the Example 96 gave the title compound.
[0855] Yield: 34.0%.
[0856] .sup.1H-NMR(CDCl.sub.3):.delta. 2.39(3H, s), 7.16(1H, d,
J=8.7 Hz), 7.37(1H, ddd, J=8.7, 2.4, 0.6 Hz), 7.51-7.56(2H, m),
7.97(1H, d, J=3.0 Hz), 8.85(1H, s), 8.94(1H, d, J=1.8 Hz).
Example 131
Preparation of the Compound of Compound No. 131
[0857] Using 5-nitrosalicylic acid and
2-chloro-5-(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0858] Yield: 31.1%.
[0859] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.98(1H, d, J=9.3 Hz),
7.52(1H, dd, J=8.4, 2.1 Hz), 7.81(1H, d, J=8.4 Hz), 8.21(1H, dd,
J=9.0, 3.3 Hz), 8.82(1H, d, J=3.0 Hz), 8.93(1H, d, J=2.4 Hz),
12.18(1H, s).
Example 132
Preparation of the Compound of Compound No. 132
[0860] Using 5-methylsalicylic acid and
2-chloro-5-(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0861] Yield: 15.8%.
[0862] .sup.1H-NMR(CDCl.sub.3):.delta. 2.36(3H, s), 6.95(1H, d,
J=8.1 Hz), 7.26-7.31(2H, m), 7.37(1H, dd, J=8.4, 1.8 Hz), 7.56(1H,
d, J=8.4 Hz), 8.65(1H, br s), 8.80(1H, d, J=1.8 Hz), 11.33(1H, br
s).
Example 133
Preparation of the Compound of Compound No. 133
[0863] Using 5-methoxysalicylic acid and
2-chloro-5-(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0864] Yield: 56.4%.
[0865] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.77(3H, s), 6.91(1H, d,
J=9.0 Hz), 7.07(1H, dd, J=8.7, 3.0 Hz), 7.20(1H, t, J=1.8 Hz),
7.52-7.54(3H, m), 10.33(1H, s), 11.44(1H, s).
Example 134
Preparation of the Compound of Compound No. 134
[0866] Using 5-methylsalicylic acid and
4-chloro-3-(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0867] Yield: 70.4%.
[0868] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.29(3H, s), 6.91(1H, d,
J=8.3 Hz), 7.27(1H, ddd, J=8.3, 2.2, 0.6 Hz), 7.71(1H, d, J=2.2
Hz), 7.72(1H, d, J=8.5 Hz), 8.02(1H, dd, J=8.5, 2.5 Hz), 8.33(1H,
d, J=2.5 Hz), 10.64(1H, s), 11.25(1H, s).
Example 135
Preparation of the Compound of Compound No. 135
[0869] Using 5-methylsalicylic acid and
4-methyl-3-(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0870] Yield: 63.7%.
[0871] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.29(3H, s), 2.42(3H, s),
6.89(1H, d, J=8.4 Hz), 7.26(1H, ddd, J=8.4, 2.1, 0.6 Hz), 7.44(1H,
d, J=8.1 Hz), 7.75(1H, d, J=2.1 Hz), 7.86(1H, dd, J=8.4, 1.8 Hz),
8.13(1H.d, J=2.1 Hz), 10.50(1H, s), 11.42(1H, s).
Example 136
Preparation of the Compound of Compound No. 136
[0872] Using 5-methylsalicylic acid and
2-methyl-5-(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0873] Yield: 14.2%, white solid.
[0874] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.29(3H, s), 2.38(3H, s),
6.94(1H, d, J=8.4 Hz), 7.27(1H, ddd, J=8.4, 2.4, 0.6 Hz), 7.44(1H,
dd, J=8.1, 1.5 Hz), 7.52(1H, d, J=7.8 Hz), 7.84(1H, d, J=2.4 Hz),
8.46(1H, d, J=1.5 Hz), 10.55(1H, s), 11.72(1H, s).
Example 137
Preparation of the Compound of Compound No. 137
[0875] Using 5-methylsalicylic acid and
4-methoxy-3-(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0876] Yield: 65.1%, slightly yellow solid.
[0877] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.35(3H, s), 3.89(3H, s),
6.88(1H, d, J=8.4 Hz), 7.26(1H, dd, J=8.1, 1.8 Hz), 7.30(1H, d,
J=8.4 Hz), 7.77(1H, d, J=2.1 Hz), 7.92(1H, dd, J=9.0, 2.7 Hz),
8.04(1H, d, J=2.7 Hz), 10.42(1H, s), 11.54(1H, s).
Example 138
Preparation of the Compound of Compound No. 138
[0878] Using 5-methylsalicylic acid and
2-methoxy-5-(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0879] Yield: 77.9%.
[0880] .sup.1H-NMR(CDCl.sub.3):.delta. 2.35(3H, s), 4.02(3H, s),
6.93(1H, d, J=9.0 Hz), 6.98(1H, d, J=8.4 Hz), 7.25-7.28(2H, m),
7.36(1H, ddd, J=8.4, 2.1, 0.9 Hz), 8.65(1H, br s), 8.73(1H, d,
J=2.1 Hz), 11.69(1H, s).
Example 139
Preparation of the Compound of Compound No. 139
[0881] Using 5-bromosalicylic acid and aniline as the raw
materials, the same operation as the Example 16 gave the title
compound.
[0882] Yield: 68.8%.
[0883] mp 229-230.degree. C.
[0884] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.96(1H, d, J=9.0 Hz),
7.12-7.18(1H, m), 7.35-7.41(2H, m), 7.58(1H, dd, J=8.7, 2.7 Hz),
7.67-7.71(2H, m), 8.08(1H, d, J=2.7 Hz), 10.43(1H, s), 11.87(1H,
s).
Example 140
Preparation of the Compound of Compound No. 140
[0885] Using 5-bromosalicylic acid and 3-chloroaniline as the raw
materials, the same operation as the Example 16 gave the title
compound.
[0886] Yield: 63.1%.
[0887] mp 231-232.degree. C.
[0888] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.97(1H, d, J=8.7 Hz),
7.19-7.22(1H, m), 7.38-7.43(1H, m), 7.57-7.63(2H, m), 7.91-7.92(1H,
m), 8.01(1H, d, J=2.7 Hz), 10.49(1H, s), 11.64(1H, s).
Example 141
The Compound of Compound No. 141
[0889] This compound is a commercially available compound.
Supplier: Tokyo Kasei.
Catalog code number: B0897.
Example 142
Preparation of the Compound of Compound No. 142
[0890] Using 5-chlorosalicylic acid and 2,5-dichloroaniline as the
raw materials, the same operation as the Example 16 gave the title
compound.
[0891] Yield: 10.8%.
[0892] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.08(1H, d, J=9.0 Hz),
7.24-7.28(1H, m), 7.50-7.54(1H, m), 7.61(1H, dd, J=9.0, 3.0 Hz),
7.97(1H, d, J=2.7 Hz), 8.58(1H, d, J=2.4 Hz), 11.02(1H, s),
12.35(1H, brs).
Example 143
Preparation of the Compound of Compound No. 143
[0893] Using 5-bromosalicylic acid and 3,4-dichloroaniline as the
raw materials, the same operation as the Example 16 gave the title
compound.
[0894] Yield: 58.2%.
[0895] mp 249-251.degree. C.
[0896] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.97(1H, d, J=8.7 Hz),
7.57-7.70(3H, m), 7.98(1H, d, J=2.7 Hz), 8.10(1H, d, J=2.4 Hz),
10.54(1H, s), 11.55(1H, s).
Example 144
Preparation of the Compound of Compound No. 144
[0897] Using 5-bromosalicylic acid and 3,5-difluoroaniline as the
raw materials, the same operation as the Example 16 gave the title
compound.
[0898] Yield: 36.3%.
[0899] mp 259-261.degree. C.
[0900] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.96-7.04(2H, m),
7.45-7.54(2H, m), 7.58(1H, dd, J=8.7, 2.7 Hz), 7.94(1H, d, J=2.7
Hz), 10.60(1H, s) 11.48(1H, s).
Example 145
Preparation of the Compound of Compound No. 172
[0901] Using O-acetylsalicyloyl chloride and 3,5-dichloroaniline as
the raw materials, the same operation as the Example 2(1) gave the
title compound.
[0902] Yield: 73.5%.
[0903] mp 167-168.degree. C.
[0904] .sup.1H-NMR(CDCl.sub.3):.delta. 2.35(3H, s), 7.14-7.18(2H,
m), 7.35-7.40(1H, m), 7.52-7.57(3H, m), 7.81(1H, dd, J=7.8, 1.8
Hz), 8.05(1H, brs).
Example 146
Preparation of the Compound of Compound No. 145
[0905] Using 2-acetoxy-N-(3,5-dichlorophenyl)benzamide (Compound
No. 172) as the raw material, the same operation as the Example
2(2) gave the title compound.
[0906] Yield: 60.3%.
[0907] mp 218-219.degree. C.
[0908] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.95-7.02(2H, m),
7.35-7.36(1H, m), 7.42-7.47(1H, m), 7.83-7.87(3H, m), 10.54(1H, s),
11.35(1H, s).
Example 147
Preparation of the Compound of Compound No. 146
[0909] Using 5-fluorosalicylic acid and 3,5-dichloroaniline as the
raw materials, the same operation as the Example 16 gave the title
compound.
[0910] Yield: 33.3%.
[0911] mp 258-260.degree. C.
[0912] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.00-7.05(1H, m),
7.28-7.37(2H, m), 7.63(1H, dd, J=9.3, 3.3 Hz), 7.84(2H, d, J=2.1
Hz), 10.56(1H, s), 11.23(1H, s).
Example 148
Preparation of the Compound of Compound No. 147
[0913] Using 5-chlorosalicylic acid and 3,5-dichloroaniline as the
raw materials, the same operation as the Example 16 gave the title
compound.
[0914] Yield: 41.2%.
[0915] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.03(1H, d, J=9.0 Hz),
7.36-7.37(1H, m), 7.48(1H, dd, J=8.7, 2.7 Hz), 7.83-7.84(3H, m),
10.56(1H, s), 11.44(1H, s).
Example 149
Preparation of the Compound of Compound No. 148
[0916] Using 5-bromosalicylic acid and 3,5-dichloroaniline as the
raw materials, the same operation as the Example 16 gave the title
compound.
[0917] Yield: 61.6%.
[0918] mp 243-244.degree. C.
[0919] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.98(1H, d, J=8.7 Hz),
7.36-7.37(1H, m), 7.59(1H, dd, J=9.0, 2.4 Hz), 7.83(2H, d, J=1.8
Hz), 7.95(1H, d, J=2.4 Hz), 10.56(1H, s), 11.46(1H, s).
Example 150
Preparation of the Compound of Compound No. 149
[0920] Using 5-iodosalicylic acid and 3,5-dichloroaniline as the
raw materials, the same operation as the Example 16 gave the title
compound.
[0921] Yield: 65.4%.
[0922] mp 244-245.degree. C.
[0923] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.84(1H, d, J=9.0 Hz),
7.35-7.37(1H, m), 7.72(1H, dd, J=9.0, 2.1 Hz), 7.83(2H, d, J=1.8
Hz), 8.09(1H, d, J=2.1 Hz), 10.55(1H, s), 11.45(1H, s).
Example 151
Preparation of the Compound of Compound No. 150
[0924] Using 3,5-dibromosalicylic acid and 3,5-dichloroaniline as
the raw materials, the same operation as the Example 16 gave the
title compound.
[0925] Yield: 44.2%.
[0926] mp 181-182.degree. C.
[0927] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.42-7.43(1H, m), 7.80(2H,
d, J=1.8 Hz), 8.03(1H, d, J=2.1 Hz), 8.17(1H, d, J=2.1 Hz),
10.82(1H, s).
Example 152
Preparation of the Compound of Compound No. 151
[0928] Using 4-chlorosalicylic acid and 3,5-dichloroaniline as the
raw materials, the same operation as the Example 16 gave the title
compound.
[0929] Yield: 57.2%.
[0930] mp 255-256.degree. C.
[0931] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.03-7.06(2H, m),
7.34-7.36(1H, m), 7.82-7.85(3H,m), 10.51(1H, s), 11.70(1H,
brs).
Example 153
Preparation of the Compound of Compound No. 152
[0932] Using 5-nitrosalicylic acid and 3,5-dichloroaniline as the
raw materials, the same operation as the Example 16 gave the title
compound.
[0933] Yield: 83.1%.
[0934] mp 232-233.degree. C.
[0935] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.16(1H, d, J=9.6 Hz),
7.37-7.39(1H, m), 7.84(1H, d, J=2.1 Hz), 8.29(1H, dd, J=9.0, 3.0
Hz), 8.65(1H, d, J=3.0 Hz), 10.83(1H, s).
Example 154
Preparation of the Compound of Compound No. 153
[0936] Using 5-methylsalicylic acid and 3,5-dichloroaniline as the
raw materials, the same operation as the Example 16 gave the title
compound.
[0937] Yield: 71.0%.
[0938] mp 216-217.degree. C.
[0939] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.28(3H, s), 6.90(1H, d,
J=8.4 Hz), 7.26(1H, dd, J=8.7, 1.8 Hz), 7.34-7.36(1H, m), 7.67(1H,
d, J=1.5 Hz), 7.85(2H, d, J=1.8 Hz), 10.52(1H, s), 11.15(1H,
s).
Example 155
Preparation of the Compound of Compound No. 154
[0940] Using 5-methoxysalicylic acid and 3,5-dichloroaniline as the
raw materials, the same operation as the Example 16 gave the title
compound.
[0941] Yield: 29.8%.
[0942] mp 230-232.degree. C.
[0943] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.76(3H, s), 6.95(1H, d,
J=8.7 Hz), 7.08(1H, dd, J=9.0, 3.0 Hz), 7.35-7.36(1H, m), 7.40(1H,
d, J=3.0 Hz), 7.85(2H, d, J=1.5 Hz), 10.55(1H, s), 10.95(1H,
s).
Example 156
Preparation of the Compound of Compound No. 155
[0944] Using 5-bromosalicylic acid and 3,4,5-trichloroaniline as
the raw materials, the same operation as the Example 16 gave the
title compound.
[0945] Yield: 78.6%.
[0946] mp 297-299.degree. C.
[0947] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.98(1H, d, J=9.0 Hz),
7.58(1H, dd, J=8.4, 2.4 Hz), 7.95(1H, d, J=2.4 Hz), 8.03(1H, s),
10.58(1H, s), 11.49(1H, s).
Example 157
Preparation of the Compound of Compound No. 156
[0948] Using 5-bromosalicylic acid and
3,5-dichloro-4-hydroxyaniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0949] Yield: 22.5%.
[0950] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.96(1H, d, J=8.7 Hz),
7.58(1H, dd, J=8.7, 2.4 Hz), 7.76(2H, s), 8.01(1H, d, J=2.4 Hz),
10.03(1H, s), 10.36(1H, s), 11.67(1H, brs).
Example 158
Preparation of the Compound of Compound No. 157
[0951] Using 5-chlorosalicylic acid and
2,3,4,5,6-pentafluoroaniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0952] Yield: 58.6%.
[0953] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.07(1H, d, J=8.7 Hz),
7.53(1H, dd, J=8.7, 2.7 Hz), 7.91(1H, d, J=2.7 Hz), 10.38(1H, brs),
11.74(1H, brs).
Example 159
Preparation of the Compound of Compound No. 158
[0954] Using 5-bromosalicylic acid and 3,5-dinitroaniline as the
raw materials, the same operation as the Example 16 gave the title
compound.
[0955] Yield: 32.2%.
[0956] mp 258-260.degree. C.
[0957] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.98-7.02(1H, m),
7.59-7.63(1H, m), 7.96-7.97(1H, m), 8.56-8.58(1H, m), 9.03-9.05(2H,
m), 11.04(1H, s), 11.39(1H, brs).
Example 160
Preparation of the Compound of Compound No. 159
[0958] Using 5-chlorosalicylic acid and
2,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0959] Yield: 75.7%.
[0960] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.27(9H, s), 1.33(9H, s),
7.04(1H, d, J=9.0 Hz), 7.26(1H, dd, J=8.4, 2.1 Hz), 7.35-7.38(2H,
m), 7.49(1H, dd, J=8.7, 2.7 Hz), 8.07(1H, d, J=2.4 Hz), 10.22(1H,
s), 12.38(1H, br s).
Example 161
Preparation of the Compound of Compound No. 160
[0961] Using 5-chlorosalicylic acid and
5-[(1,1-dimethyl)ethyl]-2-methoxyaniline as the raw materials, the
same operation as the Example 16 gave the title compound.
[0962] Yield: 89.5%.
[0963] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.28(9H, s), 3.33(3H, s),
7.01(1H, d, J=8.7 Hz), 7.05(1H, d, J=9.0 Hz), 7.11(1H, dd, J=8.7,
2.4 Hz), 7.47(1H, dd, J=9.0, 3.0 Hz), 7.99(1H, d, J=3.0 Hz),
8.49(1H, d, J=2.4 Hz), 10.78(1H, s), 12.03(1H, s).
Example 162
Preparation of the Compound of Compound No. 161
[0964] Using 5-bromosalicylic acid and 3,5-dimethylaniline as the
raw materials, the same operation as the Example 16 gave the title
compound.
[0965] Yield: 58.1%.
[0966] mp 188-190.degree. C.
[0967] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.28(6H, s), 6.80(1H, s),
6.96(1H, d, J=8.7 Hz), 7.33(2H, s), 7.58(1H, dd, J=9.0, 2.4 Hz),
8.10(1H, d, J=2.4 Hz), 10.29(1H, s), 11.93(1H, brs).
Example 163
Preparation of the Compound of Compound No. 162
[0968] Using 5-chlorosalicylic acid and
3,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0969] Yield: 34.1%.
[0970] .sup.1H-NMR(CDCl.sub.3):.delta. 1.26(18H, s), 6.99(1H, d,
J=8.7 Hz), 7.29(1H, t, J=1.8 Hz), 7.39(11 dd, J=9.0, 2.4 Hz),
7.41(2H, d, J=1.5 Hz), 7.51(1H, d, J=2.1 Hz), 7.81(1H, br s),
12.01(1H, s).
Example 164
Preparation of the Compound of Compound No. 163
[0971] Using 5-bromosalicylic acid and
3,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0972] Yield: 45.2%.
[0973] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.30(18H, s), 6.95(1H, d,
J=8.7 Hz), 7.20(1H, t, J=1.5 Hz), 7.56(2H, d, J=1.5 Hz), 7.58(1H,
dd, J=8.7, 2.4 Hz), 8.12(1H, d, J=2.7 Hz), 10.39(1H, s), 11.98(1H,
s).
Example 165
Preparation of the Compound of Compound No. 164
[0974] Using 5-chlorosalicylic acid and
2-amino-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene as the
raw materials, the same operation as the Example 16 gave the title
compound.
[0975] Yield: 77.5%.
[0976] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.23(6H, s), 1.24(6H, s),
1.64(4H, s), 2.19(3H, s), 7.13(1H, d, J=9.0 Hz), 7.20(1H, s),
7.49(1H, dd, J=8.7, 2.7 Hz), 7.67(1H, s), 8.04(1H, d, J=2.7 Hz),
10.23(1H, s), 12.26(1H, s).
Example 166
Preparation of the Compound of Compound No. 165
[0977] Using 5-chlorosalicylic acid and 3-aminobiphenyl as the raw
materials, the same operation as the Example 16 gave the title
compound.
[0978] Yield: 75.6%.
[0979] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.04(1H, d, J=8.7 Hz),
7.35-7.44(1H, m), 7.45-7.54(5H, m), 7.65-7.68(2H, m), 7.72(1H, dt,
J=7.2, 2.1 Hz). 7.99(1H, d, J=3.0 Hz), 8.03(1H, m), 10.50(1H, s),
11.83(1H, brs).
Example 167
Preparation of the Compound of Compound No. 166
[0980] Using 5-chlorosalicylic acid and 3-amino-4-methoxybiphenyl
as the raw materials, the same operation as the Example 16 gave the
title compound.
[0981] Yield: 37.0%.
[0982] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.95(3H, s), 7.08(1H, d,
J=8.7 Hz), 7.20(1H, d, J=8.4 Hz), 7.34(1H, t, J=7.2 Hz),
7.40-7.50(4H, m), 7.62(1H, d, J=8.7 Hz), 8.00(1H, d, J=3.0 Hz),
8.77(1H, d, J=2.1 Hz), 10.92(1H, s), 12.09(1H, s).
Example 168
Preparation of the Compound of Compound No. 167
[0983] Using 5-bromosalicylic acid and 2,5-dimethoxyaniline as the
raw materials, the same operation as the Example 16 gave the title
compound.
[0984] Yield: 39.7%.
[0985] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.72(3H, s), 3.84(3H, s),
6.66(1H, ddd, J=9.0, 3.0, 0.6 Hz), 6.99-7.03(2H, m), 7.58(1H, ddd,
J=9.0, 2.7, 0.6 Hz), 8.10(1H, dd, J=2.4, 0.6 Hz), 8.12(1H, d, J=3.0
Hz), 10.87(1H, s), 12.08(1H, s).
Example 169
Preparation of the Compound of Compound No. 168
[0986] Using 5-bromosalicylic acid and 3,5-dimethoxyaniline as the
raw materials, the same operation as the Example 16 gave the title
compound.
[0987] Yield: 40.3%.
[0988] mp 207-209.degree. C.
[0989] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.75(6H, s), 6.30-6.32(1H,
m), 6.94-6.97(3H, m), 7.57(1H, dd, J=8.7, 2.4 Hz), 8.04(1H, d,
J=2.4 Hz), 10.32(1H, s), 11.78(1H, s).
Example 170
Preparation of the Compound of Compound No. 169
[0990] Using 5-chlorosalicylic acid and 3-acetylaniline as the raw
materials, the same operation as the Example 16 gave the title
compound.
[0991] Yield: 80.0%.
[0992] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.60(3H, s), 7.03(1H, d,
J=9.0 Hz), 7.49(1H, dd, J=9.0, 3.0 Hz), 7.54(1H, t, J=8.1 Hz),
7.76(1H, dq, J=7.8, 0.9 Hz), 7.96-8.00(2H, m), 8.30(1H, t, J=1.8
Hz), 10.56(1H, s), 11.75(1H, s).
Example 171
Preparation of the Compound of Compound No. 170
[0993] Using 5-bromosalicylic acid and 5-aminoisophthalic acid
dimethyl ester as the raw materials, the same operation as the
Example 16 gave the title compound.
[0994] Yield: 74.1%.
[0995] mp 254-256.degree. C.
[0996] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.92(6H, s), 6.97(1H, d,
J=9.0 Hz), 7.60(1H, dd, J=9.0, 2.4 Hz), 8.06(1H, d, J=2.4 Hz),
8.24-8.25(1H, m), 8.62(2H, m), 10.71(1H, s), 11.57(1H, s).
Example 172
The Compound of Compound No. 171
[0997] This compound is a commercially available compound.
Supplier: Maybridge.
Catalog code number: RDR 01434
Example 173
Preparation of the Compound of Compound No. 173
[0998] Using 5-methylsalicylic acid and
2,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[0999] Yield: 61.1%.
[1000] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.27(9H, s), 1.33(9H, s),
2.28(3H, s), 6.89(1H, d, J=8.1 Hz), 7.24(1H, d, J=2.1 Hz), 7.27(1H,
d, J=2.1 Hz), 7.32(1H, d, J=2.4 Hz), 7.37(1H, d, J=8.4 Hz),
7.88(1H, d, J=1.5 Hz), 10.15(1H, s), 11.98(1H, br s).
Example 174
Preparation of the Compound of Compound No. 174
[1001] Using
N-{3,5-bis[(1,1-dimethyl)ethyl]phenyl}-5-chloro-2-hydroxybenzamide
(Compound No. 162) and acetyl chloride as the raw materials, the
same operation as the Example 96 gave the title compound.
[1002] Yield: 66.1%.
[1003] .sup.1H-NMR(CDCl.sub.3):.delta. 1.34(18H, s), 2.36(3H, s),
7.12(1H, d, J=8.4 Hz), 7.25(1H, d, J=1.5 Hz), 7.44(2H, d, J=1.2
Hz), 7.47(1H, dd, J=8.7, 2.7 Hz), 7.87(1H, d, J=2.4 Hz), 7.98(1H,
s).
Example 175
Preparation of the Compound of Compound No. 175
[1004] Using 5-nitrosalicylic acid and
3,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1005] Yield: 46.7%.
[1006] .sup.1H-NMR(CDCl.sub.3):.delta. 1.37(18H, s), 7.13(1H, d,
J=9.3 Hz), 7.32(1H, t, J=1.8 Hz), 7.46(2H, d, J=1.8 Hz), 8.07(1H,
s), 8.33(1H, dd, J=9.3, 2.1 Hz), 8.59(1H, d, J=2.4 Hz), 13.14(1H,
s).
Example 176
Preparation of the Compound of Compound No. 176
[1007] Using 5-methylsalicylic acid and
3,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1008] Yield: 16.3%.
[1009] .sup.1H-NMR(CDCl.sub.3):.delta. 1.35(18H, s), 2.35(3H, s),
6.94(1H, d, H=8.4 Hz), 7.23-7.28(2H, m), 7.31(1H, s), 7.42(1H, d,
J=1.8 Hz), 7.88(1H, s), 11.86(1H, s).
Example 177
Preparation of the Compound of Compound No. 177
[1010] Using 5-methoxysalicylic acid and
3,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1011] Yield: 12.7%.
[1012] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.30(18H, s), 3.77(3H, s),
6.91(1H, d, J=9.0 Hz), 7.07(1H, dd, J=8.7, 3.0 Hz), 7.19-7.20(1H,
m), 7.52-7.54(3H, m), 10.33(1H, s), 11.44(1H, s).
Example 178
Preparation of the Compound of Compound No. 178
[1013] Using
5-chloro-N-{5-[(1,1-dimethyl)ethyl]-2-methoxyphenyl}-2-hydroxybenzamide
(Compound No. 160) and acetyl chloride as the raw materials, the
same operation as the Example 96 gave the title compound.
[1014] Yield: 87.5%.
[1015] .sup.1H-NMR(CDCl.sub.3):.delta. 1.35(9H, s), 2.37(3H, s),
3.91(3H, s), 6.86(1H, d, J=8.7 Hz), 7.12(1H, dd, J=8.7, 2.4 Hz),
7.13(1H, d, J=9.0 Hz), 7.47(1H, dd, J=9.0, 2.4 Hz), 8.02(1H, d,
J=2.7 Hz), 8.66(1H, d, J=2.4 Hz), 8.93(1H, s).
Example 179
Preparation of the Compound of Compound No. 179
[1016] Using 5-methylsalicylic acid and
5-[(1,1-dimethyl)ethyl]-2-methoxyaniline as the raw materials, the
same operation as the Example 16 gave the title compound.
[1017] Yield: 84.7%.
[1018] .sup.1H-NMR(CDCl.sub.3):.delta. 1.35(9H, s), 2.34(3H, s),
3.93(3H, s), 6.86(1H, d, J=8.7 Hz), 6.93(1H, d, J=8.4 Hz), 7.12(1H,
dd, J=8.7, 2.4 Hz), 7.24(1H, dd, J=8.4, 1.8 Hz), 7.27(1H, br s),
8.48(1H, d, J=2.4 Hz), 8.61(1H, brs), 11.95(1H, s).
Example 180
Preparation of the Compound of Compound No. 179
[1019] Using 5-bromosalicylic acid and 2-aminothiazole as the raw
materials, the same operation as the Example 16 gave the title
compound.
[1020] Yield: 12.0%.
[1021] mp 212.degree. C. (dec.).
[1022] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.94(1H, brd, J=8.0 Hz),
7.25(1H, brd, J=3.2 Hz), 7.56(2H, m), 8.05(1H, d, J=2.8 Hz).
Example 181
Preparation of the Compound of Compound No. 186
(1) 2-Amino-4-[(1,1-dimethyl)ethyl]thiazole
[1023] A mixture of 1-bromo-3,3-dimethyl-2-butanone (5.03 g, 28.1
mmol), thiourea (2.35 g, 30.9 mmol) and ethanol (30 mL) was
refluxed for 1.5 hours. After cooling, the reaction mixture was
poured into saturated aqueous sodium hydrogen carbonate and
extracted with ethyl acetate. After the organic layer was washed
with water and brine, dried over anhydrous sodium sulfate, the
residue obtained by evaporation under reduced pressure was purified
by chromatography on silica gel (n-hexane:ethyl
acetate=2:1.fwdarw.1:1) to give the title compound (3.99 g, 90.9%)
as an yellowish white powder.
[1024] .sup.1H-NMR(CDCl.sub.3):.delta. 1.26(9H, s), 4.96(2H, brs),
6.09(1H, s).
[1025] When the method described in Example 181(1) is referred in
the following examples, solvents such as ethanol or the like were
used as the reaction solvent.
(2)
2-Acetoxy-5-bromo-N-{4-[(1,1-dimethyl)ethyl]thiazol-2-yl)benzamide
[1026] Using 2-acetoxy-5-bromobenzoic acid and
2-amino-4-[(1,1-dimethyl)ethyl]thiazole as the raw materials, the
same operation as the Example 24 gave the title compound.
[1027] Yield: 59.4%.
[1028] .sup.1H-NMR(CDCl.sub.3):.delta. 1.31(9H, s), 2.44(3H, s),
6.60(1H, s), 7.13(1H, d, J=8.4 Hz), 7.68(1H, dd, J=8.7, 2.4 Hz),
8.17(1H, d, J=2.4 Hz), 9.72(1H, brs).
(3)
5-Bromo-N-{4-[(1,1-dimethyl)ethyl}thiazol-2-yl]-2-hydroxybenzamide
(Compound No. 186).
[1029]
2-Acetoxy-5-bromo-N-{4-[(1,1-dimethyl)ethyl]thiazol-2-yl}benzamide
(100.1 mg, 0.25 mmol) was dissolved in tetrahydrofuran (3 mL). 2N
Sodium hydroxide (0.2 ml) was added, and the mixture was stirred at
room temperature for 20 minutes. The reaction mixture was poured
into diluted hydrochloric acid and extracted with ethyl acetate.
After the organic layer was washed with brine, dried over anhydrous
sodium sulfate, the residue obtained by evaporation under reduced
pressure was crystallized (isopropyl ether/n-hexane) to give the
title compound (70.1 mg, 78.9%) as a white powder.
[1030] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.30(9H, s), 6.80(1H,
brs), 6.95(1H, brs), 7.57(1H, brs), 8.06(1H, d, J=2.4 Hz),
11.82(1H, brs), 13.27(1H, brs).
Example 182
Preparation of the Compound of Compound No. 181
(1)
2-Acetoxy-5-bromo-N-{5-bromo-4-[(1,1-dimethyl)ethyl]thiazol-2-yl}benza-
mide
[1031]
2-Acetoxy-5-bromo-N-(4-[(1,1-dimethyl)ethyl]thiazol-2-yl}benzamide
(compound of Example 181(2); 0.20 g, 0.50 mmol) was dissolved in
acetonitrile (10 mL). N-Bromosuccinimide (97.9 mg, 0.55 mmol) was
added, and the mixture was stirred at room temperature for 1 hour.
The reaction mixture was concentrated under reduced pressure, and
the obtained residue was purified by chromatography on silica gel
(n-hexane:ethyl acetate=3:1) to give the title compound as a crude
product.
(2)
5-Bromo-N-{5-bromo-4-[(1,1-dimethyl)ethyl}thiazol-2-yl]-2-hydroxybenza-
mide (Compound No. 181).
[1032] Using
2-acetoxy-5-bromo-N-{5-bromo-4-[(1,1-dimethyl)ethyl]thiazol-2-yl}benzamid-
e as the raw material, the same operation as the Example 2(2) gave
the title compound.
[1033] Yield: 90.9% (2 steps).
[1034] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.42(9H, s), 6.99(1H, d,
J=8.7 Hz), 7.61(1H, dd, J=8.7, 2.7 Hz), 8.02(1H, d, J=2.4 Hz),
11.79(1H, brs), 12.00(1H, brs).
Example 183
Preparation of the Compound of Compound No. 182
[1035] Using 5-bromosalicylic acid and
2-amino-5-bromo-4-(trifluoromethyl)thiazole as the raw materials,
the same operation as the Example 16 gave the title compound.
[1036] Yield: 22.4%.
[1037] mp 215.degree. C. (dec.).
[1038] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.00(1H, d, J=8.8 Hz),
7.61(1H, dd, J=8.8, 2.8 Hz), 7.97(1H, d, J=2.4 Hz).
[2-Amino-5-bromo-4-(trifluoromethyl)thiazole: Refer to "Journal of
Heterocyclic Chemistry", (USA), 1991, Vol. 28, p. 1017.]
Example 184
Preparation of the Compound of Compound No. 183
(1) .alpha.-Bromo-pivaloylacetonitrile
[1039] Pivaloylacetonitrile (1.00 g, 7.99 mmol) was dissolved in
carbon tetrachloride (15 mL). N-Bromosuccinimide (1.42 g, 7.99
mmol) was added, and the mixture was refluxed for 15 minutes. After
cooling, the insoluble matter was filtered off, and the residue
obtained by evaporation of the filtrate under reduced pressure was
purified by chromatography on silica gel (n-hexane:ethyl
acetate=4:1) to give the title compound (1.43 g, 87.9%) as an
yellowish brown oil.
[1040] .sup.1H-NMR(CDCl.sub.3):.delta. 1.33(9H, s), 5.10(1H,
s).
[1041] When the method described in Example 184(1) is referred in
the following examples, N-bromosuccinimide was used as the
brominating agent. As the reaction solvent, solvents such as carbon
tetrachloride or the like were used.
(2) 2-Amino-5-cyano-4-[(1,1-dimethyl)ethyl]thiazole
[1042] Using .alpha.-bromo-pivaloylacetonitrile and thiourea as the
raw materials, the same operation as the Example 181(1) gave the
title compound.
[1043] Yield: 66.3%.
[1044] .sup.1H-NMR(CDCl.sub.3):.delta. 1.41(9H, s), 5.32(2H,
s).
(3)
5-Chloro-N-{5-cyano-4-[(1,1-dimethyl)ethyl}thiazol-2-yl]-2-hydroxybenz-
amide (Compound No. 183).
[1045] Using 5-chlorosalicylic acid and
2-amino-5-cyano-4-[(1,1-dimethyl)-ethyl]thiazole as the raw
materials, the same operation as the Example 16 gave the title
compound.
[1046] Yield: 63.4%.
[1047] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.43(9H, s), 7.06(1H, d,
J=8.7 Hz), 7.51(1H, dd, J=8.7, 3.0 Hz), 7.85(1H, d, J=2.7 Hz),
12.31(2H, br).
Example 185
Preparation of the Compound of Compound No. 184
[1048] Using 5-bromosalicylic acid and
2-amino-5-cyano-4-[(1,1-dimethyl)-ethyl]thiazole (compound of
Example 184(2)) as the raw materials, the same operation as the
Example 16 gave the title compound.
[1049] Yield: 61.3%.
[1050] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.43(9H, s), 7.00(1H, d,
J=8.7 Hz), 7.62(1H, dd, J=8.7, 2.7 Hz), 7.97(1H, d, J=2.7 Hz),
11.75(1H, br), 12.43(1H, br).
Example 186
Preparation of the Compound of Compound No. 185
[1051] Using 5-bromosalicylic acid and 2-amino-5-methylthiazole as
the raw materials, the same operation as the Example 16 gave the
title compound.
[1052] Yield: 12.9%.
[1053] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.33(3H, s), 6.91(1H, d,
J=7.6 Hz), 7.26(1H, s), 7.54(1H, d, J=9.6 Hz), 8.03(1H, d, J=2.8
Hz).
Example 187
Preparation of the Compound of Compound No. 187
[1054] Using 5-bromosalicylic acid and 2-amino-4,5-dimethylthiazole
as the raw materials, the same operation as the Example 16 gave the
title compound.
[1055] Yield: 14.4%.
[1056] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.18(3H, s), 2.22(3H, s),
6.89(1H, d, J=8.8 Hz), 7.51(1H, d, J=6.8 Hz), 8.02(1H, d, J=2.8
Hz), 13.23(1H, brs).
Example 188
Preparation of the Compound of Compound No. 188
[1057] Using 5-bromosalicylic acid and
2-amino-5-methyl-4-phenylthiazole as the raw materials, the same
operation as the Example 16 gave the title compound.
[1058] Yield: 27.7%.
[1059] mp 243-244.degree. C.
[1060] .sup.1H-NMR(CD.sub.3OD):.delta. 2.47(3H, s), 6.92(1H, d,
J=8.7 Hz), 7.36-7.41(1H, m), 7.44-7.50(2H, m), 7.53(1H, dd, J=9.0,
2.7 Hz), 7.57-7.61(2H, m), 8.16(1H, d, J=2.7 Hz).
[2-Amino-5-methyl-4-phenylthiazole: Refer to "Yakugaku Zasshi:
Journal of The Pharmaceutical Society of Japan", 1961, Vol. 81, p.
1456.]
Example 189
Preparation of the Compound of Compound No. 189
[1061] Using (4-fluorophenyl)acetone as the raw material, the same
operation as the Examples 184(1)-(3) gave the title compound.
[1062] Yield: 28.8% (3 steps).
(1) .alpha.-Bromo-(4-fluorophenyl)acetone
[1063] .sup.1H-NMR(CDCl.sub.3):.delta. 2.33(3H, s), 5.41(1H, s),
7.07(2H, t, J=8.7 Hz), 7.43(2H, dd, J=8.7, 5.1 Hz).
(2) 2-Amino-4-methyl-5-(4-fluorophenyl)thiazole
[1064] .sup.1H-NMR(CDCl.sub.3):.delta. 2.27(3H, s), 4.88(2H, s),
7.07(2H, t, J=8.7 Hz), 7.32(2H, dd, J=8.7, 5.4 Hz).
(3)
5-Bromo-N-[4-methyl-5-(4-fluorophenyl)thiazol-2-yl]-2-hydroxybenzamide
(Compound No. 189).
[1065] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.36(3H, s), 6.95(1H, d,
J=8.4 Hz), 7.33(2H, t, J=8.7 Hz), 7.52-7.59(3H, m), 8.06(1H, d,
J=3.0 Hz), 12.01-13.65(2H, br).
Example 190
Preparation of the Compound of Compound No. 190
[1066] Using 3-(trifluoromethyl)phenylacetone as the raw material,
the same operation as the Examples 184(1)-(3) gave the title
compound.
[1067] Yield: 39.8% (3 steps).
(1) .alpha.-Bromo-3-(trifluoromethyl)phenylacetone
[1068] .sup.1H-NMR(CDCl.sub.3):.delta. 2.38(3H, s), 5.43(1H, s),
7.52(1H, t, J=7.8 Hz), 7.61-7.66(2H, m), 7.69-7.70(1H, m).
(2) 2-Amino-4-methyl-5-[3-(trifluoromethyl)phenyl]thiazole
[1069] .sup.1H-NMR(CDCl.sub.3):.delta. 2.32(3H, s), 4.95(2H, s),
7.46-7.56(3H, m), 7.59-7.61(1H, m).
(3)
5-Bromo-N-{4-methyl-5-[3-(trifluoromethyl)phenyl]thiazol-2-yl}-2-hydro-
xy-benzamide (Compound No. 190).
[1070] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.40(3H, s), 6.97(1H, d,
J=8.7 Hz), 7.59(1H, dd, J=8.7, 2.4 Hz), 7.71-7.84(4H, m), (2H, m),
8.06(1H, d, J=2.4 Hz), 12.09(1H, br), 12.91-13.63(1H, br).
Example 191
Preparation of the Compound of Compound No. 191
[1071] Using 2,2-dimethyl-3-hexanone as the raw material, the same
operation as the Examples 184(1)-(3) gave the title compound.
[1072] Yield: 17.0% (3 steps).
(2) 2-Amino-4-[(1,1-dimethyl)ethyl]-5-ethylthiazole
[1073] .sup.1H-NMR(CDCl.sub.3):.delta. 1.21(3H, t, J=7.5 Hz),
1.32(9H, s), 2.79(2H, q, J=7.5 Hz), 4.63(2H, brs).
(3)
5-Bromo-N-{4-[(1,1-dimethyl)ethyl]-5-ethylthiazol-2-yl}-2-hydroxybenza-
mide (Compound No. 191).
[1074] .sup.1H-NMR(CDCl.sub.3):.delta. 1.32(3H, t, J=7.5 Hz),
1.41(9H, s), 2.88(2H, q, J=7.5 Hz), 6.84(1H, d, J=9.0 Hz), 7.44(1H,
dd, J=8.7, 2.4 Hz), 8.05(1H, d, J=2.7 Hz), 11.46(2H, br).
Example 192
Preparation of the Compound of Compound No. 192
[1075] Using 5-bromosalicylic acid and
2-amino-4-ethyl-5-phenylthiazole as the raw materials, the same
operation as the Example 16 gave the title compound.
[1076] Yield: 17.4%.
[1077] mp 224-225.degree. C.
[1078] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.24(3H, t, J=7.6 Hz),
2.70(2H, q, J=7.6 Hz), 6.95(1H, brd, J=7.6 Hz), 7.39-7.42(1H, m),
7.45-7.51(4H, m), 7.56(1H, brd, J=8.0 Hz), 8.06(1H, d, J=2.8 Hz),
11.98(1H, brs).
Example 193
Preparation of the Compound of Compound No. 193
[1079] Using benzyl isopropyl ketone as the raw material, the same
operation as the Examples 184(1)-(3) gave the title compound.
[1080] Yield: 4.4% (3 steps).
(2) 2-Amino-4-isopropyl-5-phenylthiazole
[1081] .sup.1H-NMR(CDCl.sub.3):.delta. 1.23(6H, d, J=6.6 Hz),
3.05(1H, m), 4.94(2H, s), 7.28-7.41(5H, m).
(3) 5-Bromo-N-(4-isopropyl-5-phenylthiazol-2-yl)-2-hydroxybenzamide
(Compound No. 193)
[1082] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.26(6H, d, J=6.0 Hz),
3.15(1H, m), 6.98(1H, brs), 7.43-7.53(5H, m), 7.59(1H, brs),
8.08(1H, d, J=2.7 Hz), 11.90(1H, brd), 13.33(1H, brd).
Example 194
Preparation of the Compound of Compound No. 194
[1083] Using 1-phenyl-2-hexanone as the raw material, the same
operation as the Examples 184(1)-(3) gave the title compound.
[1084] Yield: 52.6% (3 steps).
(1) .alpha.-Bromo-1-phenyl-2-hexanone
[1085] .sup.1H-NMR(CDCl.sub.3):.delta. 0.85(3H, t, J=7.2 Hz),
1.19-1.32(2H, m), 1.50-1.60(2H, m), 2.59(2H, td, J=7.5, 3.9 Hz),
5.44(1H, s), 7.34-7.45(5H, m).
(2) 2-Amino-4-butyl-5-phenylthiazole
[1086] .sup.1H-NMR(CDCl.sub.3):.delta. 0.89(3H, t, J=7.5 Hz),
1.28-1.41(2H, m), 1.61-1.71(2H, m), 2.56-2.61(2H, m), 4.87(2H, s),
7.25-7.40(5H, m).
(3) 5-Bromo-N-(4-butyl-5-phenylthiazol-2-yl)-2-hydroxybenzamide
(Compound No. 194)
[1087] .sup.1H-NMR(DMSO-d.sub.6):.delta. 0.85(3H, t, J=7.2 Hz),
1.23-1.35(2H, m), 1.59-1.69(2H, m), 2.70(2H, t, J=7.2 Hz), 6.96(1H,
d, J=6.9 Hz), 7.39-7.59(6H, m), 8.07(1H, d, J=2.4 Hz), 11.93(1H,
br), 13.18-13.59(1H, br).
Example 195
Preparation of the Compound of Compound No. 195
(1) 4-Bromo-2,2,6,6-tetramethyl-3,5-heptanedione
[.alpha.-Bromo-dipivaloylmethane]
[1088] 2,2,6,6-Tetramethyl-3,5-heptanedione (dipivaloylmethane;
1.00 g, 5.42 mmol) was dissolved in carbon tetrachloride (10 mL).
N-Bromosuccinimide (965.8 mg, 5.42 mmol) was added, and the mixture
was refluxed for 2 hours. After cooling, the insoluble matter was
filtered off, and the filtrate was evaporated under reduced
pressure to give the title compound (1.42 g, quant.) as a white
crystal.
[1089] .sup.1H-NMR(CDCl.sub.3):.delta. 1.27(18H, s), 5.67(1H,
s).
[1090] When the method described in Example 195(1) is referred in
the following examples, N-bromosuccinimide was used as the
brominating agent. As the reaction solvent, solvents such as carbon
tetrachloride or the like were used.
(2)
2-Amino-4-[(1,1-dimethyl)ethyl]-5-[(2,2-dimethyl)propionyl]thiazole
[1091] A mixture of 4-bromo-2,2,6,6-tetramethyl-3,5-heptanedione
(.alpha.-bromo-dipivaloylmethane; 1.42 g, 5.40 mmol), thiourea
(451.8 mg, 5.94 mmol) and ethanol (15 mL) was refluxed for 2 hours.
After cooling, the reaction mixture was poured into saturated
aqueous sodium hydrogen carbonate and extracted with ethyl acetate.
After the organic layer was washed with water and brine, dried over
anhydrous sodium sulfate, the residue obtained by evaporation under
reduced pressure was crystallized (dichloromethane/hexane) to give
the title compound (1.23 g, 94.5%) as a white crystal.
[1092] .sup.1H-NMR(CDCl.sub.3):.delta. 1.26(9H, s), 1.29(9H, s),
5.03(2H, s).
(3)
5-Chloro-N-{4-[(1,1-dimethyl)ethyl]-5-[(2,2-dimethyl)propionyl]thiazol-
-2-yl}-2-hydroxybenzamide (Compound No. 195).
[1093] A mixture of 5-chlorosalicylic acid (143.6 mg, 0.83 mmol),
2-amino-4-[(1,1-dimethyl)ethyl]-5-[(2,2-dimethyl)propionyl]thiazole
(200.0 mg, 0.83 mmol), phosphorus trichloride (40 .mu.l, 0.46 mmol)
and chlorobenzene (4 mL) was refluxed for 3 hours. The residue
obtained by concentration of the reaction mixture under reduced
pressure was purified by chromatography on silica gel
(n-hexane:ethyl acetate=3:1) to give the title compound (159.1 mg,
48.4%) as a white powder.
[1094] .sup.1H-NMR(CDCl.sub.3):.delta. 1.33(9H, s), 1.35(9H, s),
6.99(1H, d, J=8.7 Hz), 7.43(1H, dd, J=9.0, 2.7 Hz), 7.70(1H, d,
J=2.7 Hz), 10.52(2H, br).
[1095] When the method described in Example 195(3) is referred in
the following examples, phosphorus trichloride was used as the acid
halogenating agent. As the reaction solvent, solvents such as
monochlorobenzene, toluene or the like were used.
Example 196
Preparation of the Compound of Compound No. 196
[1096] Using 5-bromosalicylic acid and
2-amino-4-[(1,1-dimethyl)ethyl]-5-[(2,2-dimethyl)propionyl]thiazole
(compound of Example 195(2)) as the raw materials, the same
operation as the Example 195(3) gave the title compound.
[1097] Yield: 23.8%.
[1098] .sup.1H-NMR(CDCl.sub.3):.delta. 1.33(9H, s), 1.35(9H, s),
6.94(1H, d, J=8, 7 Hz), 7.55(1H, dd, J=8.7, 2.1 Hz), 7.85(1H, d,
J=2.1 Hz), 10.51(2H, br).
Example 197
Preparation of the Compound of Compound No. 197
[1099] Using pivaloylacetic acid ethyl ester as the raw material,
the same operation as the Examples 195(1)-(3) gave the title
compound.
[1100] Yield: 45.7% (3 steps).
(1) .alpha.-Bromo-pivaloylacetic acid ethyl ester
[1101] .sup.1H-NMR(CDCl.sub.3):.delta. 1.28(9H, s), 1.29(3H, t,
J=7.2 Hz), 4.26(2H, q, J=7.2 Hz), 5.24(1H, s).
(2) 2-Amino-4-[(1,1-dimethyl)ethyl]thiazole-5-carboxylic acid ethyl
ester
[1102] .sup.1H-NMR(CDCl.sub.3):.delta. 1.32(3H, t, J=7.2 Hz),
1.43(9H, s), 4.24(2H, q, J=7.2 Hz), 5.18(2H, s).
(3)
2-(5-Bromo-2-hydroxybenzoyl)amino-4-[(1,11-dimethyl)ethyl]thiazole-5-c-
arboxylic acid ethyl ester (Compound No. 197).
[1103] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.30(3H, t, J=7.2 Hz),
1.44(9H, s), 4.27(2H, q, J=6.9 Hz), 7.00(1H, d, J=8.7 Hz), 7.63(1H,
dd, J=8.7, 2.7 Hz), 8.02(1H, d, J=2.4 Hz), 11.80(1H, br), 12.12(1H,
br).
Example 198
Preparation of the Compound of Compound No. 198
(1) 2-Amino-5-bromo-4-[(1,1-dimethyl)ethyl]thiazole
[1104] 2-Amino-4-[(1,1-dimethyl)ethyl]thiazole (compound of Example
181(1); 0.87 g, 5.6 mmol) was dissolved in carbon tetrachloride (9
mL). N-Bromosuccinimide (1.00 g, 5.6 mmol) was added, and the
mixture was stirred at room temperature for 1 hour. Hexane was
added to the reaction mixture. The insoluble matter was filtered
off, and the residue obtained by evaporation of the filtrate under
reduced pressure was purified by chromatography on silica gel
(hexane:ethyl acetate=2:1) to give the title compound (1.23 g,
93.7%) as an yellowish gray powder.
[1105] .sup.1H-NMR(CDCl.sub.3):.delta. 1.39(9H, s), 4.81(2H,
brs).
(2) 2-Amino-4-[(1,1-dimethyl)ethyl]-5-piperidinothiazole
[1106] A mixture of 2-amino-5-bromo-4-[(1,1-dimethyl)ethyl]thiazole
(0.10 g, 0.42 mmol), piperidine (0.1 mL), potassium carbonate (0.20
g) and acetonitrile (4 mL) was refluxed for 3 hours. The reaction
mixture was poured into water and extracted with ethyl acetate.
After the organic layer was washed with water and brine, dried over
anhydrous sodium sulfate, the residue obtained by evaporation under
reduced pressure was purified by chromatography on silica gel
(n-hexane:ethyl acetate=2:1) to give the title compound (80.7 mg,
79.3%) as an yellow crystal.
[1107] .sup.1H-NMR(CDCl.sub.3):.delta. 1.32(9H, s), 1.64(4H, t,
J=5.7 Hz), 1.71-1.77(2H, m), 2.35(2H, brs), 2.99(2H, brs), 4.68(2H,
s).
[1108] When the preparation method described in Example 198(2) is
referred in the following examples, bases such as potassium
carbonate or the like were used as the base. As the reaction
solvent, solvents such as acetonitrile or the like were used.
(3)
2-Acetoxy-5-bromo-N-{4-[(1,1-dimethyl)ethyl]-5-piperidinothiazol-2-yl}-
benzamide
[1109] Under argon atmosphere, phosphorus oxychloride (46 .mu.l,
0.50 mmol) was added to a mixture of 2-acetoxy-5-bromobenzoic acid
(90.3 mg, 0.35 mmol),
2-amino-4-[(1,1-dimethyl)ethyl]-5-piperidinothiazole (80.7 mg, 0.34
mmol), pyridine (0.1 mL) and tetrahydrofuran (3 mL), and the
mixture was stirred at room temperature for 2 hours. The reaction
mixture was poured into 2N hydrochloric acid and extracted with
ethyl acetate. After the organic layer was washed with water and
brine, dried over anhydrous sodium sulfate, the residue obtained by
evaporation under reduced pressure was purified by chromatography
on silica gel (n-hexane:ethyl acetate=3:1) to give the title
compound (84.3 mg) as a crude product.
[1110] When the preparation method described in Example 198(3) is
referred in the following examples, phosphorus oxychloride was used
as the acid halogenating agent. As the reaction base, pyridine was
used. As the reaction solvent, solvents such as dichloromethane,
tetrahydrofuran or the like were used.
(4)-5-Bromo-N-{4-[(1,1-dimethyl)ethyl]-5-piperidinothiazol-2-yl}-2-hydroxy-
benzamide (Compound No. 198).
[1111]
2-Acetoxy-5-bromo-N-{4-[(1,1-dimethyl)ethyl]-5-piperidinothiazol-2-
-yl}-benzamide (crude product, 84.3 mg) was dissolved in ethanol (3
mL). 2N Aqueous sodium hydroxide (0.1 mL) was added, and the
mixture was stirred at room temperature for 1 hour. The reaction
mixture was poured into 2N hydrochloric acid and extracted with
ethyl acetate. After the organic layer was washed with water and
brine, dried over anhydrous sodium sulfate, the residue obtained by
evaporation under reduced pressure was purified by chromatography
on silica gel (n-hexane:ethyl acetate=4:1) to give the title
compound (54.1 mg, 36.3%; 2 steps) as a white powder.
[1112] .sup.1H-NMR(CDCl.sub.3):.delta. 1.41(9H, s), 1.56(2H, brs),
1.67-1.74(4H, m), 2.79(4H, brs), 6.85(1H, d, J=9.0 Hz), 7.45(1H,
dd, J=9.0, 2.4 Hz), 8.06(1H, d, J=2.4 Hz), 11.70(2H, br).
[1113] When the preparation method described in Example 198(4) is
referred in the following examples, inorganic bases such as sodium
hydroxide, potassium carbonate or the like were used as the base.
As the reaction solvent, solvents such as water, methanol, ethanol,
tetrahydrofuran or the like were used alone or as a mixture.
Example 199
Preparation of the Compound of Compound No. 199
[1114] Using 2-amino-5-bromo-4-[(1,1-dimethyl)ethyl]thiazole
(compound of Example 198(1)) and morpholine as the raw materials,
the same operation as the Examples 198(2)-(4) gave the title
compound.
[1115] Yield: 17.1%.
(2) 2-Amino-4-[(1,1-dimethyl)ethyl]-5-morpholinothiazole
[1116] .sup.1H-NMR(CDCl.sub.3):.delta. 1.33(9H, s), 2.76(4H, brs),
3.79(4H, brs), 4.66(2H, s).
(3)
2-Acetoxy-5-bromo-N-{4-[(1,1-dimethyl)ethyl]-5-morpholinothiazol-2-yl}-
benzamide
[1117] The product was used for the next reaction as a crude
product.
(4)
5-Bromo-N-{4-[(1,1-dimethyl)ethyl]-5-morpholinothiazol-2-yl}-2-hydroxy-
benzamide (Compound No. 199).
[1118] .sup.1H-NMR(CDCl.sub.3):.delta. 1.24(9H, s), 2.89(4H, dd,
J=4.8, 4.2 Hz), 3.83(4H, dd, J=4.5, 4.2 Hz), 6.89(1H, d, J=9.0 Hz),
7.49(1H, dd, J=9.0, 2.4 Hz), 7.98(1H, d, J=2.1 Hz), 11.20(2H,
br).
Example 200
Preparation of the Compound of Compound No. 200
[1119] Using 2-amino-5-bromo-4-[(1,1-dimethyl)ethyl]thiazole
(compound of Example 198(1)) and 4-methylpiperazine as the raw
materials, the same operation as the Examples 198(2)-(4) gave the
title compound.
[1120] Yield: 6.9%.
(2)
2-Amino-4-[(1,1-dimethyl)ethyl]-5-(4-methylpiperazin-1-yl)thiazole
[1121] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.25(9H, s), 2.12(2H,
brs), 2.19(3H, s), 2.57(2H, brs), 2.72(4H, brs), 6.51(2H, s).
(3)
2-Acetoxy-N-{4-[(1,1-dimethyl)ethyl]-5-(4-methylpiperazin-1-yl)thiazol-
-2-yl}-benzamide
[1122] The product was used for the next reaction as a crude
product.
(4)
5-Bromo-N-{4-[(1,1-dimethyl)ethyl]-5-(4-methylpiperazin-1-yl)thiazol-2-
-yl}-2-hydroxybenzamide (Compound No. 200).
[1123] .sup.1H-NMR(CD.sub.3OD):.delta. 1.41(9H, s), 2.55(3H, s),
2.87(4H, brs), 3.03(4H, brs), 6.88(1H, d, J=8.7 Hz), 7.49(1H, dd,
J=8.7, 2.7 Hz), 8.11(1H, d, J=2.7 Hz).
Example 201
Preparation of the Compound of Compound No. 201
[1124] Using 2-amino-5-bromo-4-[(1,1-dimethyl)ethyl]thiazole
(compound of Example 198(1)) and 4-phenylpiperazine as the raw
materials, the same operation as the Examples 198(2)-(4) gave the
title compound.
[1125] Yield: 6.9%.
(2)
2-Amino-4-[(1,1-dimethyl)ethyl]-5-(4-phenylpiperazin-1-yl)thiazole
[1126] .sup.1H-NMR(CDCl.sub.3):.delta. 1.34(9H, s), 2.80(2H, brs),
3.03(4H, brs), 3.55(2H, brs), 4.69(2H, s), 6.88(1H, tt, J=7.2, 1.2
Hz), 6.95(2H, dd, J=9.0, 1.2 Hz), 7.28(2H, dd, J=8.7, 7.2 Hz).
(3)
2-Acetoxy-5-bromo-N-{4-[(1,1-dimethyl)ethyl]-5-(4-phenylpiperazin-1-yl-
)thiazol-2-yl}benzamide
[1127] The product was used for the next reaction as a crude
product.
(4)
5-Bromo-N-{4-[(1,1-dimethyl)ethyl]-5-(4-phenylpiperazin-1-yl)thiazol-2-
-yl}-2-hydroxybenzamide (Compound No. 201).
[1128] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.39(9H, s), 2.97(4H, s),
3.30(4H, s), 6.82(1H, t, J=7.5 Hz), 6.97(2H, brs), 6.99(2H, t,
J=7.5 Hz), 7.58(1H, brs), 8.05(1H, d, J=2.4 Hz), 11.69(1H, brs),
11.82(1H, brs).
Example 202
Preparation of the Compound of Compound No. 202
[1129] Using 5-bromosalicylic acid and 2-amino-4-phenylthiazole as
the raw materials, the same operation as the Example 195(3) gave
the title compound.
[1130] Yield: 16.0%.
[1131] mp 239.degree. C. (dec.).
[1132] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.02(1H, d, J=8.4 Hz),
7.34(1H, t, J=7.6 Hz), 7.44(2H, t, J=7.6 Hz), 7.62(1H, dd, J=8.4,
2.8 Hz), 7.67(1H, s), 7.92(2H, d, J=7.2 Hz), 8.08(1H, d, J=2.8 Hz),
11.88(1H, brs), 12.05(1H, brs).
Example 203
Preparation of the Compound of Compound No. 203
(1)
{2-[(5-Bromo-2-hydroxybenzoyl)amino]-4-phenylthiazol-5-yl}acetic
acid methyl ester
[1133] Using 5-bromosalicylic acid and
2-amino-4-phenylthiazole-5-acetic acid methyl ester as the raw
materials, the same operation as the Example 195(3) gave the title
compound.
[1134] Yield: 32.1%.
[1135] mp 288.5-229.5.degree. C.
[1136] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.66(3H, s), 3.95(2H, s),
6.99(1H, d, J=8.0 Hz), 7.42(1H, d, J=6.0 Hz), 7.48(2H, brt, J=7.6
Hz), 7.56-7.61(3H, m), 8.07(1H, d, J=2.4 Hz), 11.85(1H, brs),
11.98(1H, brs).
(2)
{2-[(5-Bromo-2-hydroxybenzoyl)amino]-4-phenylthiazol-5-yl}acetic
acid (Compound No. 203).
[1137]
{2-[(5-Bromo-2-hydroxybenzoyl)amino]-4-phenylthiazol-5-yl}acetic
acid methyl ester (75 mg, 0.17 mmol) was dissolved in methanol (5
mL). 2N Sodium hydroxide (0.5 mL, 1 mmol) was added, and the
mixture was stirred at room temperature for 12 hours. The reaction
mixture was poured into 2N hydrochloric acid and extracted with
ethyl acetate. After the ethyl acetate layer was washed
successively with water and brine, dried over anhydrous sodium
sulfate, the solvent was evaporated under reduced pressure. The
obtained residue was suspended and washed with n-hexane-ethyl
acetate under heating at reflux to give the title compound (56 mg,
77.3%) as a light yellow white crystal.
[1138] mp 284-286.degree. C.
[1139] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.84(2H, s), 6.98(1H, d,
J=8.8 Hz), 7.42(1H, d, J=6.8 Hz), 7.49(2H, t, J=7.6 Hz),
7.58-7.61(3H, m), 8.07(1H, d, J=2.8 Hz), 12.25(H, brs).
Example 204
Preparation of the Compound of Compound No. 204
[1140] Using 5-bromosalicylic acid and 2-amino-4,5-diphenylthiazole
as the raw materials, the same operation as the Example 195(3) gave
the title compound.
[1141] Yield: 25.9%.
[1142] mp 262-263.degree. C.
[1143] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.02(1H, d, J=8.1 Hz),
7.34-7.47(10H, m), 7.63(1H, d, J=6.9 Hz), 8.08(1H, d, J=2.4 Hz),
11.88(1H, brs), 12.08(1H, brs).
[2-Amino-4,5-diphenylthiazole: Refer to "Nihon Kagaku Zasshi",
1962, Vol. 83, p. 209.]
Example 205
Preparation of the Compound of Compound No. 205
[1144] Using 5-bromosalicylic acid and
2-amino-4-benzyl-5-phenylthiazole as the raw materials, the same
operation as the Example 195(3) gave the title compound.
[1145] Yield: 28.1%.
[1146] mp 198-200.degree. C.
[1147] .sup.1H-NMR(DMSO-d.sub.6):.delta. 4.08(2H, s), 6.95(1H, d,
J=8.8 Hz), 7.15-7.22(3H, m), 7.30(2H, t, J=7.6 Hz), 7.38-7.43(1H,
m), 7.47(4H, d, J=4.4 Hz), 7.57(1H, brd, J=8.8 Hz), 8.05(1H, d,
J=2.4 Hz), 11.98(1H, brs).
[2-Amino-4-benzyl-5-phenylthiazole: Refer to "Chemical and
Pharmaceutical Bulletin", 1962, Vol. 10, p. 376.]
Example 206
Preparation of the Compound of Compound No. 206
[1148] Using 5-bromosalicylic acid and
2-amino-5-phenyl-4-(trifluoromethyl)thiazole as the raw materials,
the same operation as the Example 195(3) gave the title
compound.
[1149] Yield: 33.2%.
[1150] mp 250.degree. C. (dec.).
[1151] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.02(1H, d, J=8.8 Hz),
7.51(5H, s), 7.63(1H, dd, J=8.8, 2.4 Hz), 8.02(1H, d, J=2.8 Hz),
12.38(1H, brs).
Example 207
Preparation of the Compound of Compound No. 207
[1152] Using 1-phenyl-1,3-butanedione as the raw material, the same
operation as the Examples 195(1)-(3) gave the title compound.
[1153] Yield: 8.9% (3 steps).
(1) .alpha.-Bromo-1-phenyl-1,3-butanedione
[1154] .sup.1H-NMR(CDCl.sub.3):.delta. 2.46(3H, s), 5.62(1H, s),
7.48-7.54(2H, m), 7.64(1H, tt, J=7.5, 2.1 Hz), 7.97-8.01(2H,
m).
(2) 2-Amino-5-acetyl-4-phenylthiazole
[1155] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.18(3H, s), 7.50-7.55(2H,
m), 7.59-7.68(3H, m), 8.69(2H, brs).
(3) 5-Bromo-N-(5-acetyl-4-phenylthiazol-2-yl)-2-hydroxybenzamide
(Compound No. 207)
[1156] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.44(3H, s), 6.99(1H, d,
J=9.0 Hz), 7.55-7.71(4H, m), 7.76-7.80(2H, m), 8.01(1H, d, J=2.4
Hz), 12.36(2H, br).
Example 208
Preparation of the Compound of Compound No. 208
[1157] Using 1,3-diphenyl-1,3-propanedione as the raw material, the
same operation as the Examples 195(1)-(3) gave the title
compound.
[1158] Yield: 49.7%.
(1) .alpha.-Bromo-1,3-diphenyl-1,3-propanedione
[1159] .sup.1H-NMR(CDCl.sub.3):.delta. 6.55(1H, s), 7.45-7.50(4H,
m), 7.61(2H, tt, J=7.2, 2.1 Hz), 7.98-8.01(4H, m).
(2) 2-Amino-5-benzoyl-4-phenylthiazole
[1160] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.04-7.18(5H, m),
7.22-7.32(3H, m), 7.35-7.38(2H, m), 8.02(2H, s).
(3) 5-Bromo-N-(5-benzoyl-4-phenylthiazol-2-yl)-2-hydroxybenzamide
(Compound No. 208)
[1161] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.03(1H, d, J=8.7 Hz),
7.17-7.30(5H, m), 7.39-7.47(3H, m), 7.57-7.60(2H, m), 7.64(1H, dd,
J=8.7, 2.7 Hz), 8.05(1H, d, J=2.4 Hz), 11.82(1H, brs), 12.35(1H,
brs).
Example 209
Preparation of the Compound of Compound No. 210
[1162] Using 5-chlorosalicylic acid and
2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as the raw
materials, the same operation as the Example 195(3) gave the title
compound.
[1163] Yield: 69.4%.
[1164] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.22(3H, t, J=7.5 Hz),
4.21(2H, q, J=7.5 Hz), 7.07(1H, d, J=8.7 Hz), 7.43-7.47(3H, m),
7.53(1H, dd, J=8.7, 2.4 Hz), 7.70-7.74(2H, m), 7.92(1H, d, J=3.0
Hz), 11.88(1H, br), 12.29(1H, brs).
Example 210
Preparation of the Compound of Compound No. 209
[1165] Using 5-bromosalicylic acid and
2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as the raw
materials, the same operation as the Example 195(3) gave the title
compound.
[1166] Yield: 28.6%.
[1167] mp 197-199.degree. C.
[1168] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.21(3H, t, J=6.8 Hz),
4.20(2H, q, J=6.8 Hz), 7.01(1H, d, J=8.8 Hz), 7.43-7.48(3H, m),
7.63(1H, dd, J=8.8, 2.4 Hz), 7.70-7.72(2H, m), 8.04(1H, d, J=2.4
Hz), 12.33(1H, brs).
Example 211
Preparation of the Compound of Compound No. 211
[1169] Using pentafluorobenzoylacetic acid ethyl ester as the raw
material, the same operation as the Examples 195(1)-(3) gave the
title compound.
[1170] Yield: 40.0% (3 steps).
(1) .alpha.-Bromo-pentafluorobenzoylacetic acid ethyl ester
[1171] It was used for the next reaction as a crude product.
(2) 2-Amino-4-(pentafluorophenyl)thiazole-5-carboxylic acid ethyl
ester
[1172] .sup.1H-NMR(CDCl.sub.1): .delta. 1.23(3H, t, J=7.2 Hz),
4.21(2H, q, J=7.2 Hz), 5.41(2H, s).
(3) Ethyl
2-(5-bromo-2-hydroxybenzoyl)amino-4-(pentafluorophenyl)thiazole--
5-carboxylate (Compound No. 211).
[1173] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.20(3H, t, J=7.2 Hz),
2.51(2H, q, J=7.2 Hz), 7.02(1H, d, J=8.7 Hz), 7.64(1H, dd, J=8.7,
2.7 Hz), 7.90(1H, d, J=3.0 Hz), 11.92(1H, br), 12.58(1H, br).
Example 212
Preparation of the Compound of Compound No. 212
(1) 2-(5-Bromo-2-hydroxybenzoyl)amino-4-phenylthiazole-5-carboxylic
acid
[1174] Using
2-(5-bromo-2-hydroxybenzoyl)amino-4-phenylthiazole-5-carboxylic
acid ethyl ester (compound No. 209) as the raw material, the same
operation as the Example 82 gave the title compound.
[1175] Yield: 67.0%.
[1176] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.00(1H, d, J=8.8 Hz),
7.42-7.44(3H, m), 7.62(1H, dd, J=8.8, 2.4 Hz), 7.70-7.72(2H, m),
8.04(1H, d, J=2.4 Hz), 12.31(1H, brs), 12.99(1H, brs).
(2)
[2-(5-Bromo-2-hydroxybenzoyl)amino-4-phenylthiazol-5-yl]-N-methylcarbo-
xamide (Compound No. 212).
[1177] A mixture of
2-(5-bromo-2-hydroxybenzoyl)amino-4-phenylthiazole-5-carboxylic
acid (0.20 g, 0.48 mmol), methylamine 40% methanol solution (0.2
ml), 1-hydroxybenzotriazole hydrate (96.7 mg, 0.72 mmol), WSC.HCl
(137.2 mg, 0.72 mmol) and tetrahydrofuran (15 mL) was stirred at
room temperature for 18 hours. The reaction mixture was poured into
2N hydrochloric acid and extracted with ethyl acetate. After the
organic layer was washed with water and brine, dried over anhydrous
sodium sulfate, the residue obtained by evaporation under reduced
pressure was purified by chromatography on silica gel
(n-hexane:ethyl acetate=1:2), and crystallized
(dichloromethane/n-hexane) to give the title compound (87.9 mg,
42.6%) as a white powder.
[1178] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.70(3H, d, J=4.5 Hz),
7.02(1H, d, J=9.0 Hz), 7.40-7.48(3H, m), 7.63(1H, dd, J=9.0, 2.4
Hz), 7.68-7.71(2H, m), 8.06(1H, d, J=2.4 Hz), 8.16(1H, t, J=4.5
Hz), 11.88(1H, br), 12.15(1H, brs).
[1179] When the method described in Example 212(2) is referred in
the following examples, WSC.HCl and 1-hydroxybenzotriazole hydrate
were used as the dehydrocondensating agent. As the reaction
solvent, solvents such as tetrahydrofuran or the like were
used.
Example 213
Preparation of the Compound of Compound No. 213
[1180] Using
2-(5-bromo-2-hydroxybenzoyl)amino-4-phenylthiazole-5-carboxylic
acid (compound of Example 212(1)) and 70% aqueous ethylamine
solution as the raw materials, the same operation as the Example
212(2) gave the title compound.
[1181] Yield: 62.5%.
[1182] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.05(3H, t, J=6.9 Hz),
3.15-3.24(2H, m), 7.02(1H, d, J=8.7 Hz), 7.40-7.47(3H, m), 7.63(1H,
dd, J=8.7, 3.0 Hz), 7.69-7.72(2H, m), 8.06(1H, d, J=2.4 Hz),
8.20(1H, t, J=5.4 Hz), 11.84(1H, br), 12.14(1H, brs).
Example 214
Preparation of the Compound of Compound No. 214
[1183] Using
2-(5-bromo-2-hydroxybenzoyl)amino-4-phenylthiazole-5-carboxylic
acid (compound of Example 212(1)) and isopropylamine as the raw
materials, the same operation as the Example 212(2) gave the title
compound.
[1184] Yield: 23.9%.
[1185] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.07(6H, d, J=6.3 Hz),
4.02(1H, m), 7.02(1H, d, J=9.0 Hz), 7.40-7.52(3H, m), 7.64(1H, dd,
J=8.7, 2.7 Hz), 7.69-7.73(2H, m), 8.06(1H, d, J=2.7 Hz), 11.89(1H,
br), 12.14(1H, brs).
Example 215
Preparation of the Compound of Compound No. 215
[1186] Using
2-(5-bromo-2-hydroxybenzoyl)amino-4-phenylthiazole-5-carboxylic
acid (compound of Example 212(1)) and 2-phenethylamine as the raw
materials, the same operation as the Example 212(2) gave the title
compound.
[1187] Yield: 62.2%.
[1188] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.78(2H, t, J=7.5 Hz),
3.43(2H, q, J=7.5 Hz), 7.02(1H, d, J=9.0 Hz), 7.19-7.24(3H, m),
7.27-7.33(2H, m), 7.39-7.41(3H, m), 7.61-7.65(3H, m), 8.06(1H, d,
J=2.4 Hz), 8.25(1H, t, J=6.0 Hz), 11.85(1H, brs), 12.15(1H,
brs).
Example 216
Preparation of the Compound of Compound No. 216
[1189] Using 5-bromosalicylic acid and
2-amino-4-(trifluoromethyl)thiazole-5-carboxylic acid ethyl ester
as the raw materials, the same operation as the Example 195(3) gave
the title compound.
[1190] Yield: 88.7%.
[1191] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.32(3H, t, J=7.2 Hz),
4.33(2H, q, J=7.2 Hz), 7.01(1H, d, J=8.7 Hz), 7.63(1H, dd, J=8.7,
2.7 Hz), 7.98(1H, d, J=2.4 Hz), 12.64(1H, br).
Example 217
Preparation of the Compound of Compound No. 217
[1192] Using
5-chloro-N-{4-[(1,1-dimethyl)ethyl]-5-[(2,2-dimethyl)propionyl}thiazol-2--
yl]-2-hydroxybenzamide (compound No. 195) and acetyl chloride as
the raw materials, the same operation as the Example 96 gave the
title compound.
[1193] Yield: 65.3%.
[1194] .sup.1H-NMR(CDCl.sub.3):.delta. 1.32(9H, s), 1.33(9H,s),
2.46(3H, s), 7.22(1H, d, J=8.4 Hz), 7.56(1H, dd, J=8.7, 2.4 Hz),
8.05(1H, d, J=2.7 Hz), 9.82(1H, brs).
Example 218
Preparation of the Compound of Compound No. 218
[1195] Using 4-hydroxybiphenyl-3-carboxylic acid and
2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as the raw
materials, the same operation as the Example 195(3) gave the title
compound.
[1196] Yield: 61.7%.
[1197] mp 207-208.degree. C.
[1198] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.23(3H, t, J=7.2 Hz),
4.22(2H, q, J=7.2 Hz), 7.16(1H, d, J=8.7 Hz), 7.36(1H, t, J=7.5
Hz), 7.45-7.50(5H, m), 7.69-7.76(4H, m), 7.85(1H, dd, J=8.7, 2.4
Hz), 8.31(1H, d, J=2.4 Hz), 11.73(1H, brs), 12.60(1H, brs).
[4-Hydroxybiphenyl-3-carboxylic acid: Refer to "Tetrahedron", 1997,
Vol. 53, p. 11437.]
Example 219
Preparation of the Compound of Compound No. 219
[1199] Using (4'-fluoro-4-hydroxybiphenyl)-3-carboxylic acid and
2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as the raw
materials, the same operation as the Example 195(3) gave the title
compound.
[1200] Yield: 62.7%.
[1201] mp 237-238.degree. C.
[1202] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.22(3H, t, J=7.2 Hz),
4.21(2H, q, J=7.2 Hz), 7.13(1H, d, J=8.4 Hz), 7.28(2H, t, J=8.8
Hz), 7.44-7.45(3H, m), 7.71-7.75(4H, m), 7.81(1H, dd, J=8.8, 2.4
Hz), 8.27(1H, d, J=2.4 Hz), 11.67(1H, brs), 12.58(1H, brs).
[(4'-Fluoro-4-hydroxybiphenyl)-3-carboxylic acid: Refer to
"Tetrahedron", 1997, Vol. 53, p. 11437.]
Example 220
Preparation of the Compound of Compound No. 220
[1203] Using (2',4'-difluoro-4-hydroxybiphenyl)-3-carboxylic acid
and 2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as the
raw materials, the same operation as the Example 195(3) gave the
title compound.
[1204] Yield: 45.6%.
[1205] mp 206-207.degree. C.
[1206] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.22(3H, t, J=7.2 Hz),
4.22(2H, q, J=7, 2 Hz), 7.17(1H, d, J=9.0 Hz), 7.21(1H, td, J=8.7,
2.4 Hz), 7.38(1H, ddd, J=11.7, 9.3, 2.4 Hz), 7.44-7.46(3H, m),
7.60-7.75(4H, m), 8.13-8.14(1H, m), 11.86(1H, brs), 12.46(1H,
brs).
Example 221
Preparation of the Compound of Compound No. 221
(1) [4-Hydroxy-4'-(trifluoromethyl)biphenyl]-3-carboxylic acid
[1207] A mixture of 5-bromosalicylic acid (500 mg, 2.30 mmol),
dihydroxy-4-(trifluoromethyl)phenylborane (488 mg, 2.57 mmol),
palladium acetate (10 mg, 0.040 mmol) and 1M sodium carbonate (7
mL) was stirred at 80.degree. C. for 1 hour. The reaction mixture
was poured into 2N hydrochloric acid and extracted with ethyl
acetate. After the ethyl acetate layer was washed successively with
water and brine, dried over anhydrous sodium sulfate, the solvent
was evaporated under reduced pressure. According to the fixed
procedure, the obtained residue was methyl-esterified by
trimethylsilyldiazomethane and methanol, and purified by column
chromatography on silica gel (n-hexane:ethyl acetate=5:1) to give a
colourless liquid (563 mg). This liquid was dissolved in methanol
(10 mL). 2N Sodium hydroxide (3 mL) was added, and the mixture was
stirred at 60.degree. C. for 1 hour. After the reaction mixture was
cooled to room temperature, it was poured into 2N hydrochloric acid
and extracted with ethyl acetate. After the ethyl acetate layer was
washed successively with water and saturated brine, dried over
anhydrous magnesium sulfate, the solvent was evaporated under
reduced pressure. The obtained residue was suspended and washed
with n-hexane-dichloromethane under heating at reflux to give the
title compound (458 mg, 70.4%) as a white crystal.
[1208] mp 185.degree. C. (dec).
[1209] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.09(1H, d, J=8.8 Hz),
7.77(2H, d, J=8.0 Hz), 7.85(2H, d, J=8.0 Hz), 7.90(1H, dd, J=8.8,
2.0 Hz), 8.10(1H, d, J=2.4 Hz), 11.80(1H, brs).
(2)
2-{[4-Hydroxy-4'-(trifluoromethyl)biphenyl]-3-carbonyl}amino-4-phenylt-
hiazole-5-carboxylic acid ethyl ester (Compound No. 221).
[1210] Using [4-hydroxy-4'-(trifluoromethyl)biphenyl]-3-carboxylic
acid and 2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as
the raw materials, the same operation as the Example 195(3) gave
the title compound.
[1211] Yield: 41.7%.
[1212] mp 236-237.degree. C.
[1213] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.22(3H, t, J=7.2 Hz),
4.21(2H, q, J=7.2 Hz), 7.18(1H, d, J=8.8 Hz), 7.44-7.45(3H, m),
7.72-7.74(2H, m), 7.81(2H, d, J=8.4 Hz), 7.91(1H, dd, J=8.8, 2.4
Hz), 7.93(2H, d, J=8.4 Hz), 8.36(1H, d, J=2.4 Hz), 11.78(1H, brs),
12.62(1H, brs).
Example 222
Preparation of the Compound of Compound No. 222
[1214] Using 2-hydroxy-5-(1-pyrrolyl)benzoic acid and
2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as the raw
materials, the same operation as the Example 195(3) gave the title
compound.
[1215] Yield: 55.0%.
[1216] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.22(3H, t, J=7.2 Hz),
4.22(2H, q, J=7.2 Hz), 6.26(2H, t, J=2.1 Hz), 7.13(1H, d, J=8.7
Hz), 7.32(2H, t, J=2.1 Hz), 7.43-7.47(3H, m), 7.70-7.75(3H, m),
8.09(1H, d, J=2.7 Hz), 11.58(1H, brs), 12.55(1H, brs).
Example 223
Preparation of the Compound of Compound No. 223
(1) 2-Hydroxy-5-(2-thienyl)benzoic acid
[1217] 5-Bromosalicylic acid (500 mg, 2.30 mmol) was dissolved in
1,2-dimethoxyethane (5 mL). Tetrakis(triphenylphosphine)palladium
(80 mg, 0.07 mmol) was added under argon atmosphere, and the
mixture was stirred at room temperature for 10 minutes. Then
dihydroxy-2-thienylborane (324 mg, 2.53 mmol) and 1M sodium
carbonate (7 mL) were added, and the mixture was refluxed for 2
hours. After the reaction mixture was cooled to room temperature,
it was poured into 2N hydrochloric acid and extracted with ethyl
acetate. After the ethyl acetate layer was washed successively with
water and brine, dried over anhydrous sodium sulfate, the solvent
was evaporated under reduced pressure. According to the fixed
procedure, the obtained residue was methyl-esterified by
trimethylsilyldiazomethane and methanol, and purified by column
chromatography on silica gel (n-hexane:ethyl acetate=5:1) to give
an yellow liquid (277 mg). This was dissolved in methanol (5 mL).
2N Sodium hydroxide (1.5 mL) was added, and the mixture was stirred
at 60.degree. C. for 1 hour. After the reaction mixture was cooled
to room temperature, it was poured into 2N hydrochloric acid and
extracted with ethyl acetate. After the ethyl acetate layer was
washed successively with water and brine, dried over anhydrous
magnesium sulfate, the residue obtained by evaporation of the
solvent under reduced pressure was crystallized from
n-hexane-dichloromethane to give the title compound (58 mg, 11.5%)
as a white crystal.
[1218] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.95(1H, d, J=8.8 Hz),
7.09(1H, dd, J=4.8, 3.6 Hz), 7.37(1H, dd, J=4.0, 1.2 Hz), 7.45(1H,
dd, J=5.2, 1.2 Hz), 7.74(1H, dd, J=8.8, 2.8 Hz), 7.96(1H, d, J=2.8
Hz).
(2)
2-[2-Hydroxy-5-(2-thienyl)benzoyl]amino-4-phenylthiazole-5-carboxylic
acid ethyl ester (Compound No. 223).
[1219] Using 2-hydroxy-5-(2-thienyl)benzoic acid and
2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as the raw
materials, the same operation as the Example 195(3) gave the title
compound.
[1220] Yield: 58.2%.
[1221] mp 213-214.degree. C.
[1222] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.22(3H, t, J=7.2 Hz),
4.21(2H, q, J=7.2 Hz), 7.10(1H, d, J=9.2 Hz), 7.12(1H, dd, J=4.8,
3.6 Hz), 7.44-7.46(4H, m), 7.50(1H, dd, J=4.8, 1.2 Hz),
7.71-7.74(2H, m), 7.79(1H, dd, J=8.8, 2.4 Hz), 8.21(1H, d, J=2.4
Hz), 11.78(1H, brs), 12.44(1H, brs).
Example 301
Preparation of the Compound of Compound No. 0301
(1) 5-Chloro-2-methoxy-.beta.-phenylstyrene
[1223] Palladium acetate (21 mg, 7 mol %) was added to a solution
of 2-bromo-4-chloroanisole (300 mg, 1.4 mmol), styrene (211 mg, 2
mmol), triethylamine (13 .mu.L, 0.1 mmol) and triphenylphosphine
(50 mg, 1.9 mmol) in acetonitrile (6 mL), and the mixture was
refluxed for 8 hours under argon atmosphere. After the reaction
mixture was cooled to room temperature, the solvent was
concentrated under reduced pressure and the obtained residue was
diluted with ethyl acetate (15 mL). After the solution was washed
successively with 2N hydrochloric acid, water and brine, dried over
anhydrous sodium sulfate, the residue obtained by evaporation of
the solvent under reduced pressure was purified by column
chromatography on silica gel (n-hexane:ethyl acetate=10:1) to give
the title compound (118 mg, 35.6%) as a white powder.
[1224] .sup.1H-NMR(CDCl.sub.3):.delta. 3.85(3H, s), 6.80(1H, d,
J=8.8 Hz), 7.08(1H, d, J=16.8 Hz), 7.17(1H, dd, J=8.8, 2.5 Hz),
7.20-7.42(4H, m), 7.51-7.55(3H, m).
(2) 4-Chloro-2-styrylphenol (Compound No. 301)
[1225] Under argon atmosphere, 1 mol/L boron
tribromide/dichloromethane solution (0.5 mL, 0.5 mmol) was added to
a solution of 5-chloro-2-methoxy-.beta.-phenylstyrene (80 mg, 0.3
mmol) in dichloromethane (2 mL) at room temperature, and the
mixture was stirred for 12 hours. The reaction mixture was diluted
with ethyl acetate (15 mL), and after it was washed successively
with water and brine, dried over anhydrous sodium sulfate, the
residue obtained by evaporation of the solvent under reduced
pressure was purified by column chromatography on silica gel
(n-hexane:ethyl acetate=3:1) to give the title compound (34.2 mg,
45.4%) as a white powder.
[1226] .sup.1H-NMR(CDCl.sub.3):.delta. 4.95(1H, brs), 6.74(1H, d,
J=8.7 Hz), 7.09(1H, dd, =8.7, 2.4 Hz), 7.10(1H, d, J=16.2 Hz),
7.28-7.39(4H, m), 7.49-7.54(3H, m).
Example 302
Preparation of the Compound of Compound No. 302
(1)
(S)-2-Amino-3-phenyl-N-[3,5-bis(trifluoromethyl)phenyl]propionamide
[1227] A mixture of 3,5-bis(trifluoromethyl)aniline (0.20 g, 0.87
mmol), N-(tert-butoxycarbonyl)-L-phenylalanine (254.8 mg, 0.96
mmol), phosphorus trichloride (40 .mu.L, 0.46 mmol) and toluene (4
mL) was stirred at 80.degree. C. for 1.5 hours under argon
atmosphere. After the reaction mixture was cooled to room
temperature, it was poured into aqueous sodium hydrogen carbonate
and extracted with ethyl acetate. After the ethyl acetate layer was
washed with brine, dried over anhydrous sodium sulfate, the residue
obtained by evaporation of the solvent under reduced pressure was
crystallized by isopropyl ether/n-hexane to give the title compound
(333.7 mg, 92.9%) as an yellow white powder.
[1228] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.13(1H, dd, J=13.8, 8.1
Hz), 3.29(1H, dd, J=13.8, 6.0 Hz), 4.37(1H, s), 7.25-7.38(5H, m),
7.86(1H, s), 8.30(2H, s), 8.48(3H, s), 11.95(1H, s).
[1229] When the method described in Example 302(1) is referred in
the following examples, phosphorus trichloride was used as the acid
halogenating agent. As the reaction solvent, solvents such as
toluene, monochlorobenzene or the like were used.
(2)
(S)-2-Acetoxy-5-chloro-N-(2-phenyl-1-{[3,5-bis(trifluoromethyl)phenyl]-
carbamoyl}-ethyl)benzamide
[1230] WSC.HCl (184 mg, 0.96 mmol) was added to a solution of
2-acetoxy-5-chlorobenzoic acid (104 mg, 0.48 mmol),
(S)-2-amino-3-phenyl-N-[3,5-bis(trifluoromethyl)phenyl]propionamide
(0.20 g, 0.48 mmol) and 1-hydroxybenzotriazole (71.4 mg, 0.53 mmol)
in N,N-dimethylformamide (4 mL), and the mixture was stirred at
room temperature for 3 hours. The reaction mixture was poured into
diluted hydrochloric acid and extracted with ethyl acetate. After
the ethyl acetate layer was washed successively with water and
brine, dried over anhydrous sodium sulfate, the residue obtained by
evaporation of the solvent under reduced pressure was purified by
column chromatography on silica gel (n-hexane:ethyl
acetate=3:1.fwdarw.2:1) to give the title compound (141.4 mg,
51.4%) as a white crystal.
[1231] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.05(3H, s), 3.04(1H, dd,
J=13.8, 9.9 Hz), 3.19(1H, dd, J=13.8, 4.8 Hz), 4.73-4.81(1H, m),
7.22-7.35(6H, m), 7.54(1H, d, J=2.4 Hz), 7.60(1H, dd, J=8.7, 2.4
Hz), 7.81(1H, s), 8.27(2H, s), 8.91(1H, d, J=7.8 Hz), 10.81(1H,
s).
[1232] When the method described in Example 302(2) is referred in
the following examples, WSC.HCl and 1-hydroxybenzotriazole hydrate
were used as the dehydrocondensating agent. As the reaction
solvent, solvents such as N,N-dimethylformamide or the like were
used.
(3)
(S)-5-Chloro-2-hydroxy-N-(2-phenyl-1-{[3,5-bis(trifluoromethyl)phenyl]-
carbamoyl}-ethyl)benzamide (Compound No. 302).
[1233] 5N Aqueous sodium hydroxide (0.2 mL) was added to a solution
of
(S)-2-acetoxy-5-chloro-N-(2-phenyl-1-{[3,5-bis(trifluoromethyl)phenyl]car-
bamoyl}-ethyl)benzamide (141.4 mg, 0.25 mmol) in a mixed solvent of
methanol/tetrahydrofuran (2 mL+2 mL), and the mixture was stirred
at room temperature for 20 minutes. The reaction mixture was poured
into diluted hydrochloric acid and extracted with ethyl acetate.
After the ethyl acetate layer was washed successively with water
and brine, dried over anhydrous sodium sulfate, the residue
obtained by evaporation of the solvent under reduced pressure was
crystallized by ethyl acetate/isopropyl ether/n-hexane to give the
title compound (74.4 mg, 56.8%) as a white powder.
[1234] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.13(1H, dd, J=13.8, 9.0
Hz), 3.26(1H, dd, J=14.1, 4.8 Hz), 4.85-4.92(1H, m), 6.95(1H, d,
J=8.7 Hz), 7.19-7.23(1H, m), 7.26-7.31(4H, m), 7.45(1H, dd, J=8.7,
2.4 Hz), 7.81(1H, s), 7.97(1H, d, J=2.4 Hz), 8.26(2H, s), 9.12(1H,
d, J=7.2 Hz), 10.89(1H, s), 12.01(1H, s).
[1235] When the method described in Example 302(3) is referred in
the following examples, inorganic bases such as sodium hydroxide,
potassium carbonate or the like were used as the base. As the
reaction solvent, solvents such as water, methanol, ethanol,
tetrahydrofuran or the like were used alone or as a mixture.
Example 303
Preparation of the Compound of Compound No. 303
(1)
[1-({[3,5-Bis(trifluoromethyl)phenyl]amino}carbonyl)methyl]carbamic
acid 1,1-dimethyl ester
[1236] Under argon atmosphere, N-(tert-butoxycarbonyl)glycine
(183.5 mg, 1.05 mmol) and triethylamine (0.25 mL, 1.79 mmol) were
added to a solution of 3,5-bis(trifluoromethyl)aniline (0.20 g,
0.87 mmol) in tetrahydrofuran (4 mL), and after cooling with ice
bath, phosphorus oxychloride (96 .mu.L, 1.05 mmol) was added and
the mixture was stirred at room temperature for 5 hours. The
reaction mixture was poured into water and extracted with ethyl
acetate. After the ethyl acetate layer was washed successively with
water and brine, dried over anhydrous sodium sulfate, the residue
obtained by evaporation of the solvent under reduced pressure was
purified by column chromatography on silica gel (n-hexane:ethyl
acetate=2:1.fwdarw.3:2) to give the title compound (101.9 mg,
30.3%) as a white crystal.
[1237] .sup.1H-NMR(CDCl.sub.3):.delta. 1.49(9H, s), 3.99(2H, d,
J=6.0 Hz), 5.37(1H, t, J=6.0 Hz), 7.57(1H, s), 8.00(2H, s),
9.06(1H, brs).
(2) 2-Amino-N-[3,5-bis(trifluoromethyl)phenyl]acetamide
hydrochloride
[1238] 4N Hydrochloric acid/ethyl acetate solution (1 mL) was added
to
[1-({[3,5-bis(trifluoromethyl)phenyl]amino}carbonyl)methyl]carbamic
acid 1,1-dimethyl ester (101.9 mg, 0.26 mmol), and the mixture was
stirred at room temperature for 1 hour. n-Hexane (15 mL) was added
to the reaction mixture and the separated white solid was filtered
to give the title compound (80.8 mg, 96.4%) as a white powder.
[1239] .sup.1H-NMR(CD.sub.3OD):.delta. 3.89(2H, s), 7.71(1H, s),
8.22(2H, s).
(3)
2-Acetoxy-5-chloro-N-({[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-meth-
yl)benzamide
[1240] WSC.HCl (95.9 mg, 0.5 mmol) was added to a solution of
2-acetoxy-5-chlorobenzoic acid (59.1 mg, 0.28 mmol),
2-amino-N-[3,5-bis(trifluoromethyl)phenyl]acetamide hydrochloride
(80.8 mg, 0.25 mmol) and 1-hydroxybenzotriazole (37.2 mg, 0.28
mmol) in N,N-dimethylformamide (3 mL), and the mixture was stirred
at room temperature for 3 hours. The reaction mixture was poured
into diluted hydrochloric acid and extracted with ethyl acetate.
After the ethyl acetate layer was washed with brine, dried over
anhydrous sodium sulfate, the residue obtained by evaporation of
the solvent under reduced pressure was purified by column
chromatography on silica gel (n-hexane:ethyl acetate=3:21:1) to
give the title compound (83.7 mg, 69.3%) as a white crystal.
[1241] .sup.1H-NMR(CDCl.sub.3):.delta. 2.40(3H, s), 4.40(2H, d,
J=5.4 Hz), 7.17(1H, d.J=8.4 Hz), 7.40(1H, t, J=5.4 Hz), 7.53(1H,
dd, J=8.4, 2.4 Hz), 7.62(1H, s), 7.82(1H, d, J=2.4 Hz), 8.19(2H,
s), 9.20(1H, s).
(4)
5-Chloro-2-hydroxy-N-({[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-meth-
yl)benzamide (Compound No. 303).
[1242] 5N Aqueous sodium hydroxide (0.1 mL) was added to a solution
of
2-acetoxy-5-chloro-N-({[3,5-bis(trifluoromethyl)phenyl]carbamoyl}methyl)b-
enzamide (83.7 mg, 0.17 mmol) in methanol/tetrahydrofuran (2 mL+1
mL), and the mixture was stirred at room temperature for 20
minutes. The reaction mixture was poured into diluted hydrochloric
acid and extracted with ethyl acetate. After the ethyl acetate
layer was washed with water and brine, dried over anhydrous sodium
sulfate, the residue obtained by evaporation of the solvent under
reduced pressure was purified by column chromatography on silica
gel (n-hexane:ethyl acetate=2:1) and washed with n-hexane under
suspension to give the title compound (47.7 mg, 63.7%) as a white
crystal.
[1243] .sup.1H-NMR(DMSO-d.sub.6):.delta. 4.18(2H, d, J=5.4 Hz),
7.00(1H, d, J=9.0 Hz), 7.47(1H, dd, J=9.0, 2.7 Hz), 7.80(1H, s),
7.96(1H, d, J=2.7 Hz), 8.27(2H, s), 9.25(1H, t, J=5.4 Hz),
10.78(1H, s), 12.14(1H, s).
Example 304
Preparation of the Compound of Compound No. 304
(1) 5-Chlorosalicylhydrazide
[1244] A mixture of 5-chloro-2-hydroxybenzoic acid methyl ester
(0.50 g, 2.7 mmol), hydrazine monohydrate (0.3 mL, 6.2 mmol) and
ethanol (5 mL) was refluxed for 6 hours. After the reaction mixture
was cooled to room temperature, n-hexane was added and the
separated crystal was filtered to give the title compound (395.9
mg, 79.2%) as a white crystal.
[1245] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.90(1H, d, J=8.7 Hz),
7.38(1H, dd, J=8.7, 2.7 Hz), 7.85(1H, d, J=8.7 Hz), 10.23(brs).
(2) 5-Chlorosalicylic acid
[3,5-bis(trifluoromethyl)benzylidene]hydrazide (Compound No.
304).
[1246] A mixture of 5-chlorosalicylhydrazide (213.9 mg, 1.2 mmol),
3,5-bis(trifluoromethyl)benzaldehyde (190 .mu.L, 1.2 mmol),
concentrated sulfuric acid (3 drops) and ethanol (5 mL) was
refluxed for 30 minutes.
[1247] 3,5-Bis(trifluoromethyl)benzaldehyde (100 .mu.L, 0.61 mmol)
was added and the mixture was refluxed for further 1 hour. After
the reaction mixture was cooled to room temperature, it was poured
into water and extracted with ethyl acetate. After the ethyl
acetate layer was washed with brine, dried over sodium sulfate, the
residue obtained by evaporation of the solvent under reduced
pressure was purified by column chromatography on silica gel
(n-hexane:ethyl acetate=3:1.fwdarw.2:1) and washed with n-hexane
under suspension to give the title compound (362.6 mg, 76.8%) as a
white powder.
[1248] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.03(1H, d, J=9.0 Hz),
7.49(1H, dd, J=9.0, 2.7 Hz), 7.86(1H, d, J=3.0 Hz), 8.20(1H, s),
8.40(2H, s), 8.59(1H, s), 11.65(1H, s), 12.14(1H, s).
Example 305
Preparation of the Compound of Compound No. 305
(1)
(S)-2-Amino-4-methyl-N-[3,5-bis(trifluoromethyl)phenyl]pentanamide
[1249] Using N-(tert-butoxycarbonyl)-L-leucine and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 302(1) gave the title compound.
[1250] Yield: 25.2%.
[1251] .sup.1H-NMR(CDCl.sub.3):.delta. 0.98(3H, d, J=6.3 Hz),
1.01(3H, d, J=6.3 Hz), 1.39-1.48(1H, m), 1.74-1.89(2H, m), 3.55(1H,
dd, J=9.9, 3.6 Hz), 7.58(1H, s), 8.12(2H, s), 10.01(1H, s).
(2)
(S)-5-Chloro-2-hydroxy-N-(3-methyl-1-{[3,5-bis(trifluoromethyl)phenyl]-
carbamoyl}-butyl)benzamide (Compound No. 305).
[1252] Using 2-acetoxy-5-chlorobenzoic acid and
(S)-2-amino-4-methyl-N-[3,5-bis-(trifluoromethyl)phenyl]pentanamide
as the raw materials, the same operation as the Example 302(2)-(3)
gave the title compound.
[1253] Yield: 24.8% (2 steps).
[1254] .sup.1H-NMR(DMSO-d.sub.6):.delta. 0.95(3H, d, J=5.7 Hz),
0.97(3H, d, J=6.0 Hz), 1.65-1.84(3H, m), 4.65-4.72(1H, m), 6.98(1H,
d, J=9.0 Hz), 7.47(1H, dd, J=8.7, 2.4 Hz), 7.79(1H, s), 8.06(1H, d,
J=2.7 Hz), 8.32(2H, s), 9.03(1H, d, J=8.1 Hz), 10.85(1H, s),
12.20(1H, s).
Example 306
Preparation of the Compound of Compound No. 306
[1255] Using 5-chlorosalicylaldehyde and
3,5-bis(trifluoromethyl)benzhydrazide as the raw materials, the
same operation as the Example 304(2) gave the title compound.
[1256] Yield: 24.7%.
[1257] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.97(1H, d, J=8.7 Hz),
7.34(1H, dd, J=9.0, 2.7 Hz), 7.73(1H, d, J=2.4 Hz), 8.41(1H, s),
8.59(2H, s), 8.67(1H, s), 11.07(1H, s), 12.45(1H, s).
Example 307
Preparation of the Compound of Compound No. 307
[1258] Using 5-chlorosalicylic acid and
3,5-bis(trifluoromethyl)phenethylamine as the raw materials, the
same operation as the Example 16 gave the title compound.
[1259] Yield: 30.2%.
[1260] .sup.1H-NMR(CDCl.sub.3):.delta. 3.10(2H, t, J=6.9 Hz),
3.71-3.77(2H, m), 6.34(1H, brs), 6.95(1H, d, J=8.7 Hz), 7.23(1H, d,
J=2.7 Hz), 7.36(1H, dd, J=8.7, 2.4 Hz), 7.70(2H, s), 7.80(1H, s),
12.06(1H, s).
Example 308
Preparation of the Compound of Compound No. 308
[1261] A mixture of 3-hydroxyphthalic anhydride (100 mg, 0.6 mmol),
3,5-bis(trifluoromethyl)aniline (168 mg, 0.7 mmol) and acetic acid
(5 mL) was refluxed for 6 hours under argon atmosphere. After the
reaction mixture was cooled to room temperature, acetic acid was
evaporated under reduced pressure and the obtained residue was
dissolved in ethyl acetate (15 mL). After the ethyl acetate
solution was washed successively with water and brine, dried over
anhydrous sodium sulfate, the residue obtained by evaporation of
the solvent under reduced pressure was purified by column
chromatography on silica gel (n-hexane:ethyl acetate=3:1) to give
the title compound (100 mg, 43.7%) as a white powder.
[1262] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.31(1H, d, J=8.1 Hz),
7.42(1H, d, J=7.5 Hz), 7.72(1H, dd, J=8.1, 7.5 Hz), 8.21(1H, s),
8.24(2H, s), 11.28(1H, s).
Example 309
Preparation of the Compound of Compound No. 309
[1263] 3,5-Bis(trifluoromethyl)phenylisocyanate (180 .mu.L, 1.04
mmol) was added to a solution of 2-amino-4-chlorophenol (143.6 mg,
1 mmol) in a mixed solvent of tetrahydrofuran/toluene (0.5 mL+4.5
mL), and the mixture was stirred at 100.degree. C. for 1 hour.
After the reaction mixture was cooled to room temperature, the
residue obtained by evaporation of the solvent under reduced
pressure was purified by column chromatography on silica gel
(n-hexane:ethyl acetate=1:1) and crystallized by isopropyl
ether/n-hexane to give the title compound (288.5 mg, 72.4%) as a
light yellowish brown powder.
[1264] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.84-6.91(2H, m), 7.67(1H,
s), 8.06(2H, s), 8.14(1H, d, J=2.1 Hz), 8.45(1H, s), 10.10(1H, s),
10.44(1H, s).
Example 310
Preparation of the Compound of Compound No. 310
(1)
5-Chloro-2-methoxy-.beta.-[3,5-bis(trifluoromethyl)phenyl]styrene
[1265] A solution of sodium nitrite (57 mg, 0.8 mmol) in water (1
mL) was added to a solution of 2-amino-4-chloroanisole (131 mg, 0.8
mmol) in 48% hydrogen tetrafluoroborate (0.3 mL) under ice cooling
and argon atmosphere. After the mixture was stirred at 0.degree. C.
for 1 hour, a solution of 3,5-bis(trifluoromethyl)styrene (100 mg,
0.4 mmol) in methanol (3 mL) was added and the mixture was stirred
at 50.degree. C. for 1 hour. After the reaction mixture was cooled
to room temperature, the residue obtained by evaporation of the
solvent under reduced pressure was diluted with ethyl acetate.
After the solution was washed successively with 2N hydrochloric
acid, water and brine, dried over anhydrous sodium sulfate, the
residue obtained by evaporation of the solvent under reduced
pressure was purified by column chromatography on silica gel
(n-hexane:ethyl acetate=5:1) to give the title compound (52.8 mg,
33.3%) as a white powder.
[1266] .sup.1H-NMR(CDCl.sub.3):.delta. 3.85(3H, s), 6.80(1H, d,
J=8.8 Hz), 7.08(1H, d, J=16.8 Hz), 7.17(1H, dd, J=8.8, 2.5 Hz),
7.20-7.42(4H, m), 7.51-7.55(3H, m).
(2) 4-Chloro-2-[3,5-bis(trifluoromethyl)styryl]phenol (Compound No.
310)
[1267] Using
5-chloro-2-methoxy-.beta.-[3,5-bis(trifluoromethyl)phenyl]styrene
as the raw material, the same operation as the Example 301(2) gave
the title compound.
[1268] Yield: 18.1%.
[1269] .sup.1H-NMR(CDCl.sub.3):.delta. 5.16(1H brs), 6.76(1H,
d,J=8.4 Hz), 7.15(1H, dd, J=8.4, 2.7 Hz), 7.19(1H, d, J=16.5 Hz),
7.45(1H, d, J=15.5 Hz), 7.53(1H, d, J=2.4 Hz), 7.76(1H, s),
7.93(2H, s):
Example 311
Preparation of the Compound of Compound No. 311
[1270] Using 5-chlorosalicylic acid and 2-aminoindane as the raw
materials, the same operation as the Example 16 gave the title
compound.
[1271] Yield: 45.3%.
[1272] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.98(2H, dd, J=16.2, 5.7
Hz), 3.29(2H, dd, J=16.2, 7.5 Hz), 4.69-4.79(1H, m), 6.93(1H, d,
J=8.7 Hz), 7.16-7.20(2H, m), 7.23-7.28(2H, m), 7.43(1H, dd, J=8.7,
2.4 Hz), 8.02(1H, d, J=2.4 Hz), 9.03(1H, d, J=6.9 Hz), 12.66(1H,
s).
Example 312
Preparation of the Compound of Compound No. 312
(1)
4-Chloro-2-({[3,5-bis(trifluoromethyl)phenyl]imino}methyl)phenol
[1273] Using 5-chlorosalicylaldehyde and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 14(1) gave the title compound.
[1274] Yield: 76.6%.
[1275] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.04(1H, d, J=9.0 Hz),
7.50(1H, dd, J=9.0, 2.7 Hz), 7.80(1H, d, J=2.7 Hz), 8.01(1H, s),
8.12(2H, s), 9.03(1H, s), 12.09(1H, brs).
(2)
N-[(5-Chloro-2-hydroxyphenyl)methyl]-3,5-bis(trifluoromethyl)aniline
(Compound No. 312).
[1276] Using
4-chloro-2-({[3,5-bis(trifluoromethyl)phenyl]imino}methyl)phenol as
the raw material, the same operation as the Example 14(2) gave the
title compound.
[1277] Yield: 78.1%.
[1278] .sup.1H-NMR(CDCl.sub.3):.delta. 4.40(3H, s), 6.27(1H, s),
6.80(1H, d, J=8.4 Hz), 7.11(2H, s), 7.17-7.20(2H, m), 7.30(1H,
s).
Example 313
Preparation of the Compound of Compound No. 313
[1279] WSC.HCl (138 mg, 0.7 mmol) was added to a solution of
N-[(5-chloro-2-hydroxyphenyl)methyl]-3,5-bis(trifluoromethyl)aniline
(Compound No. 312; 88.8 mg, 0.24 mmol) and acetic acid (43 mg, 0.7
mmol) in dichloromethane (2 mL) under argon atmosphere, and the
mixture was stirred at room temperature for 12 hours. After the
reaction mixture was diluted with ethyl acetate, washed
successively with water and brine, dried over anhydrous sodium
sulfate, the residue obtained by evaporation of the solvent under
reduced pressure was purified by column chromatography on silica
gel (n-hexane:ethyl acetate=3:1) to give the title compound (69 mg,
70.4%) as a white powder.
[1280] .sup.1H-NMR(CDCl.sub.1): .delta. 1.92(3H, s), 4.73(2H, s),
6.54(1H, d, J=2.4 Hz), 6.95(1H, d, J=8.4 Hz), 7.22(1H, dd, J=8.7,
2.4 Hz), 7.53(2H, s), 7.99(1H, s), 9.21(1H, s).
Example 314
Preparation of the Compound of Compound No. 314
[1281] 3,5-Bis(trifluoromethyl)benzoyl chloride (100 .mu.L, 0.55
mmol) was added to a solution of 5-chlorosalicylhydrazide (compound
of Example 304(1); 0.1 g, 0.53 mmol) in pyridine (3 mL) and the
mixture was stirred at room temperature for 6 hours. The reaction
mixture was poured into 2N hydrochloric acid and extracted with
ethyl acetate. After the ethyl acetate layer was washed with brine
and dried over anhydrous sodium sulfate, the residue obtained by
evaporation of the solvent under reduced pressure was washed with
ethyl acetate/isopropyl ether/n-hexane under suspension to give the
title compound (169 mg, 74.7%) as a white powder.
[1282] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.04(1H, d, J=9.0 Hz),
7.51(1H, dd, J=8.7, 2.4 Hz), 7.92(1H, d, J=2.4 Hz), 8.43(1H, s),
8.57(2H, s), 10.79(1H, s), 11.37(1H, s), 11.81(1H, s).
Example 315
Preparation of the Compound of Compound No. 315
[1283] A mixture of 5-chlorosalicylhydrazide (compound of Example
304(1); 0.10 g, 0.53 mmol), 3,5-bis(trifluoromethyl)benzyl bromide
(120 .mu.L, 0.65 mmol), triethylamine (0.2 mL, 1.43 mmol) and
toluene (4 mL) was stirred at 100.degree. C. for 2 hours. After the
reaction mixture was cooled to room temperature, it was poured into
diluted hydrochloric acid and extracted with ethyl acetate. After
the ethyl acetate layer was washed with brine and dried over
anhydrous sodium sulfate, the residue obtained by evaporation of
the solvent under reduced pressure was purified by column
chromatography on silica gel (n-hexane:ethyl acetate=3:1) and
crystallized by n-hexane to give the title compound (45.6 mg,
20.9%) as a white powder.
[1284] .sup.1H-NMR(CDCl.sub.3):.delta. 4.22(2H, d, J=4.8 Hz),
5.13(1H, q, J=4.8 Hz), 6.96(1H, d, J=8.7 Hz), 7.23(1H, d, J=2.4
Hz), 7.37(1H, dd, J=9.0, 2.4 Hz), 7.69(1H, d, J=4.8 Hz), 7.85(1H,
s), 7.88(2H, s), 11.54(1H, s).
Example 316
Preparation of the Compound of Compound No. 316
[1285] A mixture of 5-chlorosalicylic acid (172.6 mg, 1 mmol),
3,5-bis(trifluoromethyl)phenol (152 .mu.L, 1 mmol), phosphorus
oxychloride (40 .mu.L, 0.43 mmol) and xylene (3 mL) was stirred at
140.degree. C. for 2 hours. After the reaction mixture was cooled
to room temperature, it was poured into water and extracted with
ethyl acetate. After the ethyl acetate layer was washed with brine
and dried over anhydrous sodium sulfate, the residue obtained by
evaporation of the solvent under reduced pressure was purified by
column chromatography on silica gel (n-hexane:ethyl
acetate=10:1.fwdarw.5:1) to give the title compound (53.6 mg,
13.9%) as a white crystal.
[1286] .sup.1H-NMR(CDCl.sub.3):.delta. 7.04(1H, d, J=9.0 Hz),
7.54(1H, dd, J=9.0, 2.7 Hz), 7.75(2H, s), 7.86(1H, s), 8.02(1H, d,
J=2.7 Hz), 10.09(1H, s).
Example 317
Preparation of the Compound of Compound No. 317
[1287] WSC.HCl (30.9 mg, 0.2 mmol) was added to a solution of
5-chlorosalicylic acid (35 mg, 0.2 mmol) and
3,5-bis(trifluoromethyl)phenylhydrazine (50 mg, 0.2 mmol) in
dichloromethane (2 mL) under argon atmosphere, and the mixture was
stirred at room temperature for 1 hour. After the reaction mixture
was diluted with ethyl acetate, washed successively with water and
brine, dried over anhydrous sodium sulfate, the residue obtained by
evaporation of the solvent under reduced pressure was purified by
column chromatography on silica gel (n-hexane:ethyl acetate=3:1) to
give the title compound (56.3 mg, 69.6%) as a white powder.
[1288] .sup.1H-NMR(CDCl.sub.3):.delta. 6.61(1H, d, J=2.7 Hz),
6.99(1H, d, J=8.7 Hz), 7.28(2H, s), 7.41-7.45(2H, m), 7.62(1H, d,
J=2.4 Hz), 8.53(1H, brs), 11.11(1H, s).
Example 318
Preparation of the Compound of Compound No. 318
(1) 2-Bromo-1-(5-chloro-2-hydroxyphenyl)ethanone
[1289] Phenyltrimethylammonium tribromide (0.44 g, 1.17 mmol) was
added to a solution of 5'-chloro-2'-hydroxyacetophenone (0.20 g,
1.17 mmol) in tetrahydrofuran (6 mL) and the mixture was stirred at
room temperature for 8 hours. The reaction mixture was poured into
water and extracted with ethyl acetate. After the ethyl acetate
layer was washed with brine and dried over anhydrous sodium
sulfate, the residue obtained by evaporation of the solvent under
reduced pressure was purified by column chromatography on silica
gel (n-hexane:ethyl acetate=5:1) to give the title compound (220.7
mg, 75.6%) as an yellow oil.
[1290] .sup.1H-NMR(CDCl.sub.3):.delta. 4.41(2H, s), 7.00(1H, d,
J=9.3 Hz), 7.47(1H, dd, J=8.7, 2.4 Hz), 7.71(1H, d, J=2.7 Hz),
11.63(1H, s).
(2) 2-(2-Aminothiazol-4-yl)-4-chlorophenol
[1291] A mixture of 2-bromo-1-(5-chloro-2-hydroxyphenyl)ethanone
(156.9 mg, 0.63 mmol), thiourea (47.9 mg, 0.63 mmol) and ethanol (3
mL) was refluxed for 2 hours. After the reaction mixture was cooled
to room temperature, it was poured into saturated sodium hydrogen
carbonate solution and extracted with ethyl acetate. After the
ethyl acetate layer was washed with brine and dried over anhydrous
sodium sulfate, the residue obtained by evaporation of the solvent
under reduced pressure was purified by column chromatography on
silica gel (n-hexane:ethyl acetate=2:1) to give the title compound
(98.6 mg, 64.5%) as a light yellowish white powder.
[1292] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.85(1H, d, J=8.7 Hz),
7.14(1H, dd, J=8.7, 3.0 Hz), 7.25(1H, s), 7.48(2H, s), 7.79(1H, d,
J=3.0 Hz), 11.95(1H, s).
(3)
N-[4-(5-Chloro-2-hydroxymethyl)thiazol-2-yl]-[3,5-bis(trifluoromethyl)-
phenyl]-benzamide (Compound No. 318).
[1293] Phosphorus trichloride (36 .mu.L, 0.41 mmol) was added to a
mixture of 2-(2-aminothiazol-4-yl)-4-chlorophenol (98.6 mg, 0.41
mmol), 3,5-bis(trifluoromethyl)benzoid acid (104.9 mg, 0.41 mmol),
chlorobenzene (3 mL) and N-methyl-2-pyrrolidinone (3 mL), and the
mixture was refluxed for 3 hours. After the reaction mixture was
cooled to room temperature, it was poured into water and extracted
with ethyl acetate. After the ethyl acetate layer was washed with
brine and dried over anhydrous sodium sulfate, the residue obtained
by evaporation of the solvent under reduced pressure was purified
by column chromatography on silica gel (n-hexane:ethyl
acetate=4:1.fwdarw.2:1) and washed with isopropyl ether/n-hexane
under suspension to give the title compound (19.6 mg, 10.3%) as a
white powder.
[1294] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.98(1H, d, J=8.4 Hz),
7.21(1H, dd, J=8.7, 2.7 Hz), 7.95(1H, s), 8.08(1H, d, J=2.7 Hz),
8.45(1H, s), 8.77(2H, s), 10.90(1H, s), 13.15(1H, s).
Example 319
Preparation of the Compound of Compound No. 319
(1) 3-[3,5-Bis(trifluoromethyl)benzyl]thiazolidine-2,4-dione
[1295] 5N Aqueous sodium hydroxide (0.5 mL) was added to a mixture
of 2,4-thiazolidinedione (198.7 mg, 1.69 mmol),
3,5-bis(trifluoromethyl)benzyl bromide (0.50 g, 1.63 mmol) and
ethanol (5 mL), and the mixture was refluxed for 4 hours. After the
reaction mixture was cooled to room temperature, it was poured into
water and extracted with ethyl acetate. After the ethyl acetate
layer was washed with brine and dried over anhydrous sodium
sulfate, the residue obtained by evaporation of the solvent under
reduced pressure was purified by column chromatography on silica
gel (n-hexane:ethyl acetate=3:1.fwdarw.2:1) to give the title
compound (405.6 mg, 72.5%) as a white crystal.
[1296] .sup.1H-NMR(CDCl.sub.3):.delta. 4.01(2H, s), 4.87(2H, s),
7.84(1H, s), 7.86(2H, s).
(2)
5-(5-Chloro-2-hydroxybenzylidene)-3-[3,5-bis(trifluoromethyl)benzyl]th-
iazolidine-2,4-dione (Compound No. 319).
[1297] A mixture of
3-[3,5-bis(trifluoromethyl)benzyl]thiazolidine-2,4-dione (0.20 g,
0.58 mmol), piperidine (3 drops), acetic acid (3 drops) and toluene
(5 mL) was stirred at room temperature for 10 minutes, then
5-chlorosalicylaldehyde (92.3 mg, 0.59 mmol) was added and the
mixture was refluxed for 1 hour. After the reaction mixture was
cooled to room temperature, it was poured into water and extracted
with ethyl acetate. After the ethyl acetate layer was washed with
brine and dried over anhydrous sodium sulfate, the residue obtained
by evaporation of the solvent under reduced pressure was purified
by column chromatography on silica gel (n-hexane:ethyl
acetate=2:1.fwdarw.3:2) to give the title compound (173.2 mg,
62.0%) as a light yellow powder.
[1298] .sup.1H-NMR(DMSO-d.sub.6):.delta. 5.03(2H, s), 7.00(1H, d,
J=9.0 Hz), 7.33(1H, d, J=2.4 Hz), 7.38(1H, dd, J=8.7, 2.7 Hz),
8.03(1H, s), 8.05(2H, s), 8.07(1H, s), 10.95(1H, s).
Example 320
Preparation of the Compound of Compound No. 320
[1299] A mixture of 3-hydroxyphthalic anhydride (33.5 mg, 0.2
mmol), 3,5-bis(trifluoromethyl)benzyl amine (62 mg, 0.2 mmol) and
chlorobenzene (5 mL) was refluxed for 3 hours under argon
atmosphere. After the reaction mixture was cooled to room
temperature, the solvent was evaporated under reduced pressure and
the obtained residue was crystallized from n-hexane/ethyl acetate
to give the title compound (68.5 mg, 85.2%) as a white crystal.
[1300] .sup.1H-NMR(CDCl.sub.3):.delta. 4.90(2H, s), 7.19(1H, dd,
J=8.4, 0.6 Hz), 7.41(1H, dd, J=7.2, 0.6 Hz), 7.61(1H, dd, J=8.4,
7.2 Hz), 7.75(1H, brs), 7.82(1H, brs), 7.86(2H, s).
Example 321
Preparation of the Compound of Compound No. 321
[1301] A mixture of 5-chlorosalicylaldehyde (150 mg, 1 mmol),
3,5-bis(trifluoromethyl)phenylhydrazine (200 mg, 0.9 mmol) and
methanol (5 mL) was refluxed for 1 hour under argon atmosphere.
After the reaction mixture was cooled to room temperature, methanol
was evaporated under reduced pressure and the obtained residue was
crystallized from n-hexane/ethyl acetate to give the title compound
(224 mg, 66.6%) as a white powder.
[1302] .sup.1H-NMR(CDCl.sub.3):.delta. 6.97(1H, d, J=8.7 Hz),
7.17(1H,d,J=2.4 Hz), 7.24(1H, dd, J=9.0, 2.7 Hz), 7.35(2H, s),
7.41(1H, s), 7.82(1H, s), 7.87(1H, s), 10.29(1H, s).
Example 322
Preparation of the Compound of Compound No. 322
[1303] Using 6-hydroxysalicylic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1304] Yield: 86.9%.
[1305] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.36(2H,d,J=8.4 Hz),
7.13(1H,t,J=8.4 Hz), 7.79(1H, s), 8.38(2H, s), 11.40(2H,brs),
11.96(1H, brs).
Example 323
Preparation of the Compound of Compound No. 323
[1306] Using 4-methylsalicylic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1307] Yield: 42.9%.
[1308] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.32(3H, s) 6.82(1H, d,
J=6.6 Hz) 6.84(1H, s) 7.83(1H, s) 7.84(1H, d, J=8.5 Hz) 8.47(2H, s)
10.76(1H, s) 11.44(1H, s).
Example 324
Preparation of the Compound of Compound No. 324
[1309] Using 5-bromo-4-hydroxysalicylic acid and
3,5-bis(trifluoromethyl)aniline as the raw material, the same
operation as the Example 16 gave the title compound.
[1310] Yield: 82.4%.
[1311] .sup.1H-NMR(CDCl.sub.3):.delta. 5.89(1H, s) 6.70(1H, s)
7.69(2H, s) 7.95(1H, s) 8.12(2H, s) 11.62(1H, s).
Example 325
Preparation of the Compound of Compound No. 325
[1312] Using 4-hydroxysalicylic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1313] Yield: 29.9%.
[1314] .sup.1H-NMR(DMSO-de): .delta. 6.37(1H, d, J=2.5 Hz),
6.42(1H, dd, J=8.8, 2.5 Hz), 7.81(1H, s), 7.86(1H, d, J=8.5 Hz),
8.44(2H, s), 10.31(1H, s), 10.60(1H, s), 11.77(1H, s).
Example 326
Preparation of the Compound of Compound No. 326
[1315] Using 3,5-dichlorosalicylic-acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1316] Yield: 44.8%.
[1317] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.85(1H, d, J=2.5 Hz),
7.91(1H, s), 8.01(1H, d, J=2.5 Hz), 8.42(2H, s), 11.10(1H, s).
Example 327
Preparation of the Compound of Compound No. 327
[1318] Using 3-hydroxysalicylic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1319] Yield: 22.7%.
[1320] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.81(1H, t, J=8.0 Hz),
7.01(1H, dd, J=8.0, 1.5 Hz), 7.35(1H, dd, J=8.0, 1.5 Hz), 7.84(1H,
s), 8.46(2H, s), 9.56(1H, s), 10.79(1H, s), 10.90(1H, brs).
Example 328
Preparation of the Compound of Compound No. 328
[1321] Using 3-methylsalicylic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1322] Yield: 54.9%.
[1323] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.22(3H, s), 6.94(1H, t,
J=7.4 Hz), 7.42(1H, d, J=7.4 Hz), 7.84-7.85(2H, m), 8.47(2H, s),
10.87(1H, s), 11.87(1H, s).
Example 329
Preparation of the Compound of Compound No. 329
[1324] Using 3-methoxysalicylic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1325] Yield: 34.6%.
[1326] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.85(3H, s), 6.94(1H, t,
J=8.0 Hz), 7.20(1H, dd, J=8.0, 1.4 Hz), 7.44(1H, dd, J=8.0, 1.4
Hz), 7.84(1H, s), 8.45(2H, s), 10.82(1H, s), 10.94(1H, brs).
Example 330
Preparation of the Compound of Compound No. 330
[1327] Using 5-[(1,1,3,3-tetramethyl)butyl]salicylic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1328] Yield: 64.2%.
[1329] .sup.1H-NMR(DMSO-d.sub.6):.delta. 0.70(9H, s), 1.35(6H, s),
1.72(2H, s), 6.95(1H, d, J=8.4 Hz), 7.50(1H, dd, J=8.0, 2.1 Hz),
7.83(1H, s), 7.84(1H, d, J=2.1 Hz), 8.46(1H, s), 10.77(1H, s),
11.20(1H, s).
Example 331
Preparation of the Compound of Compound No. 331
[1330] Using 3,5,6-trichlorosalicylic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1331] Yield: 26.2%.
[1332] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.88(1H, s), 7.93(1H, s),
8.33(2H, s), 10.88(1H, s), 11.36(1H, s).
Example 332
Preparation of the Compound of Compound No. 332
[1333] Using 3,5-bis[(1,1-dimethyl)ethyl]salicylic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1334] Yield: 65.0%.
[1335] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.34(9H, s), 1.40(9H, s),
7.49(1H, d, J=2.2 Hz), 7.82(1H, d, J=2.2 Hz), 7.91(1H, s), 8.40(2H,
s), 10.82(1H, s), 12.44(1H, s).
Example 333
Preparation of the Compound of Compound No. 333
[1336] Using 6-fluorosalicylic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1337] Yield: 35.9%.
[1338] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.73-6.82(2H, m), 7.32(1H,
ddd, J=1.4, 8.5, 15.3 Hz), 7.83(1H, s), 8.39(2H, s), 10.50(1H, d,
J=1.4 Hz), 11.11(1H, s).
Example 334
Preparation of the Compound of Compound No. 334
[1339] Using 3-chlorosalicylic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1340] Yield: 61.3%.
[1341] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.05(1H, dd, J=7.6, 8.0
Hz), 7.69(1H, dd, J=1.4, 13.3 Hz), 7.90(1H, s), 7.93(1H, dd, J=1.4,
8.0 Hz), 8.44(2H, s), 11.01(1H, s), 11.92(1H, br.s).
Example 335
Preparation of the Compound of Compound No. 335
[1342] Using 4-methoxysalicylic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1343] Yield: 14.2%.
[1344] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.81(3H, s), 6.54(1H, d,
J=2.5 Hz), 6.61(1H, dd, J=2.5, 8.8 Hz), 7.83(1H, s), 7.95(1H, d,
J=8.8 Hz), 8.45(2H, s), 10.69(1H, s), 11.89(1H, s).
Example 336
Preparation of the Compound of Compound No. 336
[1345] Using 6-methoxysalicylic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1346] Yield: 63.1%.
[1347] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.24(3H, s), 6.03(1H, d,
J=8.0 Hz), 6.05(1H, d, J=8.5 Hz), 6.71(1H, dd, J=8.2, 8.5 Hz),
7.25(1H, s), 7.88(2H, s), 9.67(1H, s), 10.31(1H, s)
Example 337
Preparation of the Compound of Compound No. 337
[1348] Using
5-amino-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide
(Compound No. 88) and methanesulfonyl chloride as the raw
materials, the same operation as the Example 91 gave the title
compound.
[1349] Yield: 22.6%.
[1350] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.93(3H, s), 7.02(1H, d,
J=8.4 Hz), 7.31(1H, dd, J=8.4, 2.7 Hz), 7.68(1H, d, J=2.7 Hz),
7.83(1H, s), 8.46(2H, s), 9.48(1H, s), 10.85(1H, s), 11.15(1H,
s).
Example 338
Preparation of the Compound of Compound No. 338
[1351] Using
5-amino-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide
(Compound No. 88) and benzenesulfonyl chloride as the raw
materials, the same operation as the Example 91 gave the title
compound.
[1352] Yield: 45.3%.
[1353] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.89(1H, d, J=8.7 Hz),
7.10(1H, dd, J=8.7, 2.7 Hz), 7.51-7.64(4H, m), 7.68-7.71(2H, m),
7.81(1H, s), 8.42(2H, s), 10.03(1H, s), 10.87(1H, s), 11.13(1H,
brs).
Example 339
Preparation of the Compound of Compound No. 339
[1354] Using
5-amino-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide
(Compound No. 88) and acetyl chloride as the raw materials, the
same operation as the Example 91 gave the title compound.
[1355] Yield: 44.8%.
[1356] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.02(3H, s), 6.97(1H, d,
J=8.7 Hz), 7.61(1H, dd, J=8.7, 2.7 Hz), 7.82(1H, s), 7.99(1H, d,
J=2.7 Hz), 8.46(2H, s), 9.90(1H, s), 10.85(1H, s), 10.94(1H,
s).
Example 340
Preparation of the Compound of Compound No. 340
[1357] Using
N-[3,5-bis(trifluoromethyl)phenyl]-2-methoxy-5-sulfamoyl-benzamide
(compound of Example 87(2)) as the raw material, the same operation
as the Example 80(5) gave the title compound.
[1358] Yield: 59.9%.
[1359] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.17(1H, d, J=8.7 Hz),
7.31(2H, s), 7.85(1H, s), 7.86(1H, dd, J=8.4, 2.4 Hz), 8.26(1H, d,
J=2.7 Hz), 8.47(2H, s), 10.95(1H, s), 11.90(1H, s).
Example 341
Preparation of the Compound of Compound No. 341
[1360] Using 3-hydroxynaphthalene-2-carboxylic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1361] Yield: 46.9%.
[1362] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.36-7.41(2H, m),
7.50-7.55(1H, m), 7.79(1H, d, J=8.2 Hz), 7.85(1H, d, J=0.6 Hz),
7.96(1H, d, J=8.0 Hz), 8.51(2H, s), 10.98(1H, s), 11.05(1H, s).
Example 342
Preparation of the Compound of Compound No. 342
[1363] Using 2-hydroxynaphthalene-1-carboxylic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1364] Yield: 30.2%.
[1365] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.27(1H, d, J=8.8 Hz),
7.32-7.38(1H, m), 7.45-7.50(1H, m), 7.72(1H, d, J=8.5 Hz),
7.82-7.93(3H, m), 8.50(1H, s), 10.28(1H, s), 11.07(1H, brs).
Example 343
Preparation of the Compound of Compound No. 343
(1) 4-Bromo-3-hydroxythiophene-2-carboxylic acid
[1366] A mixture of 4-bromothiophene-2-carboxylic acid methyl ester
(500 mg, 2.1 mmol), sodium hydroxide (261 mg, 6.3 mmol) in a mixed
solvent of methanol/water (2.5 mL+2.5 mL) was refluxed for 2 hours.
After the reaction mixture was cooled to room temperature, 2N
hydrochloric acid was added to adjust pH to 1, and it was diluted
with ethyl acetate. After the ethyl acetate layer was washed
successively with water and brine, dried over anhydrous sodium
sulfate, the solvent was evaporated under reduced pressure to give
the title compound (326 mg, 69.4%) as a red brown powder.
[1367] .sup.1H-NMR(CDCl.sub.3):.delta. 4.05(1H, brs), 7.40(1H,
s).
(2)
4-Bromo-3-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]thiophene-2-carbox-
amide (Compound No. 343).
[1368] Using 4-bromo-3-hydroxythiophene-2-carboxylic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1369] Yield: 82.4%.
[1370] .sup.1H-NMR(CDCl.sub.3):.delta. 7.42(1H, s), 7.67(1H, brs),
7.78(1H, brs), 8.11(2H, s), 9.91(1H, brs).
Example 344
Preparation of the Compound of Compound No. 344
[1371] Using 3,5-bis(trifluoromethyl)phenylisocyanate and oxindole
as the raw materials, the same operation as the Example 28 gave the
title compound.
[1372] Yield: 44.8%.
[1373] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.98(2H, s), 7.22(1H, td,
J=7.8, 1.2 Hz), 7.33-7.40(2H, m), 7.87(1H, s), 8.02(1H, d, J=7.8
Hz), 8.38(2H, s), 11.00(1H, s).
Example 345
Preparation of the Compound of Compound No. 345
[1374] Using 3,5-bis(trifluoromethyl)phenylisocyanate and
5-chlorooxindole as the raw materials, the same operation as the
Example 28 gave the title compound.
[1375] Yield: 31.1%.
[1376] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.99(2H, s), 7.41(1H, dd,
J=8.7, 2.4 Hz), 7.47(1H, d, J=2.1 Hz), 7.87(1H, s), 8.01(1H, d,
J=8.4 Hz), 8.38(2H, s), 10.93(1H, s).
Example 346
Preparation of the Compound of Compound No. 346
[1377] Using 5-chlorosalicylic acid and
3-bromo-5-(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1378] Yield: 37.1%.
[1379] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.03(1H, d, J=9.3 Hz),
7.48(1H, dd, J=8.7, 2.4 Hz), 7.72(1H, s), 7.84(1H, d, J=2.7 Hz),
8.16(1H, s), 8.28(1H, s), 10.69(1H, s), 11.42(1H, s).
Example 347
Preparation of the Compound of Compound No. 347
[1380] Using 5-chlorosalicylic acid and
3-methoxy-5-(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1381] Yield: 68.0%.
[1382] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.85(3H, s), 7.02(1H, s),
7.03(1H, d, J=8.7 Hz), 7.48(1H, dd, J=8.7, 2.7 Hz), 7.61(1H, s),
7.77(1H, s), 7.88(1H, d, J=2.7 Hz), 10.57(1H, s), 11.53(1H, s).
Example 348
Preparation of the Compound of Compound No. 348
[1383] Using 5-chlorosalicylic acid and
2-morpholino-5-(trifluoromethyl)aniline as the raw materials, the
same operation as the Example 16 gave the title compound.
[1384] Yield: 64.8%.
[1385] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.90(4H, m), 3.84(4H, m),
7.15(1H, d, J=9.0 Hz), 7.48(2H, s), 7.50(1H, dd, J=9.0, 2.7 Hz),
8.00(1H, d, J=2.7 Hz), 8.91(1H, s), 11.24(1H, s), 12.05(1H
Example 349
Preparation of the Compound of Compound No. 349
[1386] Using 5-chlorosalicylic acid and
2-bromo-5-(trifluoromethyl)aniline as the raw material, the same
operation as the Example 16 gave the title compound.
[1387] Yield: 59.2%.
[1388] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.10(1H, d, J=8.7 Hz),
7.48(1H, dd, J=8.4, 2.1 Hz), 7.53(1H, dd, J=8.7, 3.0 Hz),
7.97-7.99(2H, m), 8.81(1H, d, J=2.1 Hz), 11.03(1H, s), 12.38(1H,
s).
Example 350
Preparation of the Compound of Compound No. 350
[1389] Using 5-chlorosalicylic acid and
3-amino-5-(trifluoromethyl)benzoic acid methyl ester as the raw
materials, the same operation as the Example 16 gave the title
compound.
[1390] Yield: 67.0%.
[1391] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.91(3H, s), 7.02(1H, d,
J=9.3 Hz), 7.43(1H, dd, J=9.0, 2.4 Hz), 7.57(1H, d, J=2.4 Hz),
8.13(1H, s), 8.23(1H, s), 8.29(1H, s), 8.36(1H, s), 11.52(1H,
s).
Example 351
Preparation of the Compound of Compound No. 351
[1392] 2N Aqueous sodium hydroxide (0.6 mL) was added to a mixture
of
5-chloro-2-hydroxy-N-[3-methoxycarbonyl-5-(trifluoromethyl)phenyl]benzami-
de (Compound No. 350; 105 mg, 0.281 mmol) and methanol (2.5 mL),
and the mixture was stirred at room temperature for 3 hours. Water
was added to the reaction mixture and it was washed with ethyl
acetate. After the water layer was acidified by addition of diluted
hydrochloric acid, it was extracted with ethyl acetate. After the
ethyl acetate layer was washed successively with water and brine,
dried over anhydrous sodium sulfate, the residue obtained by
evaporation of the solvent under reduced pressure was crystallized
by isopropyl ether to give the title compound (100 mg, 99.0%) as a
white solid.
[1393] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.04(1H, d, J=9.0 Hz),
7.49(1H, dd, J=8.7, 2.7 Hz), 7.91(1H, d, J=2.7 Hz), 7.93(1H, s),
8.43(1H, s), 8.59(1H, s), 10.78(1H, s), 11.48(1H, s).
Example 352
Preparation of the Compound of Compound No. 352
[1394] Using 5-chlorosalicylic acid and
2-(2-naphthyloxy)-5-(trifluoromethyl)aniline as the raw materials,
the same operation as the Example 16 gave the title compound.
[1395] Yield: 89.6%.
[1396] .sup.1H-NMR(CDCl.sub.3):.delta. 6.94(1H, d, J=9.6 Hz),
6.98(1H, d, J=9.2 Hz), 7.25-7.41(4H, m), 7.48-7.57(3H, m), 7.81(1H,
d, J=6.9 Hz), 7.88(1H, d, J=6.9 Hz), 7.95(1H, d, J=8.9 Hz),
8.72(1H, s), 8.83(1H, d, J=2.0 Hz), 11.70(1H, s).
Example 353
Preparation of the Compound of Compound No. 353
[1397] Using 5-chlorosalicylic acid and
2-(2,4-dichlorophenoxy)-5-(trifluoromethyl)aniline as the raw
materials, the same operation as the Example 16 gave the title
compound.
[1398] Yield: 4.7%.
[1399] .sup.1H-NMR(CDCl.sub.3):.delta. 6.78(1H, d, J=8.9 Hz),
7.02(1H, d, J=8.6 Hz), 7.16(1H, d, J=8.6 Hz), 7.33-7.38(3H, m),
7.42(1H, dd, J=8.6, 2.6 Hz), 7.49(1H, d, J=2.6 Hz) 7.58(1H, d,
J=2.3 Hz), 8.66(1H, brs), 8.82(1H, d, J=2.0 Hz), 11.65(1H, s).
Example 354
Preparation of the Compound of Compound No. 354
[1400] Using 5-chlorosalicylic acid and
2-[(4-trifluoromethyl)piperidino]-5-(trifluoromethyl)aniline as the
raw materials, the same operation as the Example 16 gave the title
compound.
[1401] Yield: 60.5%.
[1402] .sup.1H-NMR(CDCl.sub.3):.delta. 1.85-2.05(2H, m), 2.15(2H,
d, J=10.9 Hz), 2.28(1H, m), 2.82(2H, t, J=11.0 Hz), 3.16(2H, d,
J=12.2 Hz), 7.02(1H, d, J=8.9 Hz), 7.31(1H, d, J=8.3 Hz), 7.42(2H,
m), 7.50(1H, d, J=2.6 Hz), 8.75(1H, s), 9.60(1H, s), 11.94(1H,
s)
Example 355
Preparation of the Compound of Compound No. 355
[1403] Using 5-chlorosalicylic acid and
2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)-aniline as the raw
materials, the same operation as the Example 16 gave the title
compound.
[1404] Yield: 94.5%.
[1405] .sup.1H-NMR(CDCl.sub.3):.delta. 4.58(2H, q, J=7.9 Hz),
6.99-7.05(2H, m), 7.41-7.50(3H, m), 8.63(1H, brs), 8.79(1H, d,
J=2.0 Hz), 11.59(1H, s).
Example 356
Preparation of the Compound of Compound No. 356
[1406] Using 5-chlorosalicylic acid and
2-(2-methoxyphenoxy)-5-(trifluoromethyl)aniline as the raw
materials, the same operation as the Example 16 gave the title
compound.
[1407] Yield: 80.6%.
[1408] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.74(3H, s), 6.70(1H, d,
J=8.4 Hz), 7.02(1H, d, J=8.7 Hz), 7.07(1H, dd, J=1.5, 7.8 Hz),
7.24-7.39(4H, m), 7.49(1H, dd, J=3.0, 8.7 Hz), 8.00(1H, d, J=3.0
Hz), 8.92(1H, d, J=2.1 Hz), 11.36(1H, s), 12.18(1H, s).
Example 357
Preparation of the Compound of Compound No. 357
[1409] Using 5-chlorosalicylic acid and
2-(4-chloro-3,5-dimethylphenoxy)-5-(trifluoromethyl)aniline as the
raw materials, the same operation as the Example 16 gave the title
compound.
[1410] Yield: 91.5%.
[1411] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.34(6H, s), 7.03(1H, d,
J=8.8 Hz), 7.05(1H, d, J=8.1 Hz), 7.11(2H, s), 7.43-7.47(1H, m),
7.48(1H, dd, J=2.9, 8.8 Hz), 7.97(1H, d, J=2.6 Hz), 8.94(1H, d,
J=2.2 Hz), 11.25(1H, s), 12.12(1H, s).
Example 358
Preparation of the Compound of Compound No. 358
[1412] Using 5-chlorosalicylic acid and
2-piperidino-5-(trifluoromethyl)aniline as the raw materials, the
same operation as the Example 16 gave the title compound.
[1413] Yield: 73.7%.
[1414] .sup.1H-NMR(CDCl.sub.3):.delta. 1.68-1.72(2H, m),
1.80-1.88(4H, m), 2.89(4H, t, J=5.2 Hz), 7.01(1H, d, J=8.7 Hz),
7.31(1H, d, J=8.4 Hz), 7.39-7.43(2H, m), 7.55(1H, d, J=2.4 Hz),
8.73(1H, d, J=1.8 Hz), 9.71(1H, s), 12.05(1H, s)
Example 359
Preparation of the Compound of Compound No. 359
[1415] Using 5-chlorosalicylic acid and
2-(4-methylphenoxy)-5-(trifluoromethyl)-aniline as the raw
materials, the same operation as the Example 16 gave the title
compound.
[1416] Yield: 67.3%.
[1417] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.33(3H, s), 6.93(1H, d,
J=8.8 Hz), 7.03(1H, dd, J=0.5, 8.8 Hz), 7.12(2H, d, J=8.2 Hz),
7.29(2H, d, J=8.5 Hz), 7.43(1H, dd, J=2.0, 8.6 Hz), 7.48(1H, ddd,
J=0.8, 2.7, 8.8 Hz), 7.98(1H, dd, J=0.8, 2.7 Hz), 8.94(1H, d, J=2.2
Hz), 11.29(1H, s), 12.15(1H, s).
Example 360
Preparation of the Compound of Compound No. 360
[1418] Using 5-chlorosalicylic acid and
2-(4-chlorophenoxy)-5-(trifluoromethyl)-aniline as the raw
materials, the same operation as the Example 16 gave the title
compound.
[1419] Yield: 74.5%.
[1420] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.01(1H, d, J=8.8 Hz),
7.06(1H, d, J=8.5 Hz), 7.22(1H, d, J=8.5 Hz), 7.43-7.48(2H, m),
7.50(2H, d, J=8.2 Hz), 7.94(1H, dd, J=0.5, 2.7 Hz), 8.92(1H, d,
J=2.2 Hz), 11.20(1H, s), 12.10(1H, s).
Example 361
Preparation of the Compound of Compound No. 361
[1421] Using
5-bromo-2-hydroxy-N-[3,5-bis(methoxycarbonyl)phenyl]benzamide
(Compound No. 170) as the raw material, the same operation as the
Example 351 gave the title compound.
[1422] Yield: 89.0%.
[1423] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.98(1H, d, J=8.7 Hz),
7.60(1H, dd, J=8.7, 2.4 Hz), 7.24(1H, dd, J=8.7, 2.7 Hz), 8.08(1H,
d, J=2.7 Hz), 8.24(1H, t, J=1.5 Hz), 8.57(2H, d, J=1.2 Hz),
10.67(1H, s), 11.64(1H, s).
Example 362
Preparation of the Compound of Compound No. 362
[1424] Using 5-chlorosalicylic acid and
2-methyl-5-[(1-methyl)ethyl]aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1425] Yield: 19.1%.
[1426] .sup.1H-NMR(CDCl.sub.3):.delta. 1.26(6H, d, J=6.9 Hz),
2.30(3H, s), 2.87-2.96(1H, m), 7.00(1H, d, J=8.7 Hz), 7.08(1H, dd,
J=7.8, 1.8 Hz), 7.20(1H, d, J=7.8 Hz), 7.40(1H, dd, J=8.7, 2.4 Hz),
7.49(1H, d, J=2.7 Hz), 7.50(1H, s), 7.71(1H, s), 11.99(1H, s).
Example 363
Preparation of the Compound of Compound No. 363
[1427] Using 5-chlorosalicylic acid and 2,5-diethoxyaniline as the
raw materials, the same operation as the Example 16 gave the title
compound.
[1428] Yield: 59.2%.
[1429] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.32(3H, t, J=6.9 Hz),
1.41(3H, t, J=6.9 Hz), 3.97(2H, q, J=6.9 Hz), 4.06(2H, q, J=6.9
Hz), 6.61(1H, dd, J=9.0, 3.0 Hz), 6.98(1H, d, J=8.7 Hz), 7.10(1H,
d, J=8.7 Hz), 7.48(1H, dd, J=8.7, 2.7 Hz), 7.97(1H, d, J=2.7 Hz),
8.16(1H, d, J=3.0 Hz), 10.96(1H, s), 11.91(1H, s).
Example 364
Preparation of the Compound of Compound No. 364
[1430] Using 5-chlorosalicylic acid and 2,5-dimethylaniline as the
raw materials, the same operation as the Example 16 gave the title
compound.
[1431] Yield: 90.5%.
[1432] .sup.1H-NMR(CDCl.sub.3):.delta. 2.28(3H, s), 2.35(3H, s),
6.99(1H, d, J=8.8 Hz), 7.02(1H, brs), 7.15(1H, d, J=7.7 Hz),
7.40(1H, dd, J=8.8, 2.5 Hz), 7.45(1H, brs), 7.49(1H, d, J=2.5 Hz)
7.70(1H, br), 11.96(1H, brs).
Example 365
Preparation of the Compound of Compound No. 365
[1433] Using 5-chlorosalicylic acid and 5-chloro-2-cyanoaniline as
the raw materials, the same operation as the Example 16 gave the
title compound.
[1434] Yield: 90.0%.
[1435] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.09(1H, d, J=9.0 Hz),
7.53(1H, dd, J=8.7, 3.0 Hz), 7.82(1H, dd, J=8.7, 2.4 Hz), 7.95(1H,
d, J=3.0 Hz), 8.07(1H, d, J=2.4 Hz), 8.36(1H, d, J=9.0 Hz),
11.11(1H, s), 12.36(1H, s).
Example 366
Preparation of the Compound of Compound No. 366
[1436] Using 5-chlorosalicylic acid and
5-(N,N-diethylsulfamoyl)-2-methoxyaniline as the raw materials, the
same operation as the Example 16 gave the title compound.
[1437] Yield: 44.8%.
[1438] .sup.1H-NMR(CDCl.sub.3):.delta. 1.17(6H, t, J=7.3 Hz),
3.29(4H, q, J=7.3 Hz), 4.05(3H, s), 7.00(2H, dd, J=2.3, 8.9 Hz),
7.41(1H, dd, J=2.3, 8.9 Hz), 7.48(1H, d, J=2.6 Hz), 7.65(1H, dd,
J=2.3, 8.6 Hz), 8.56(1H, br.s), 8.84(1H, d, J=2.3 Hz), 11.82(1H,
s).
Example 367
Preparation of the Compound of Compound No. 367
[1439] Using 5-chlorosalicylic acid and 2-chloro-5-nitroaniline as
the raw materials, the same operation as the Example 16 gave the
title compound.
[1440] Yield: 73.3%.
[1441] .sup.1H-NMR(CD.sub.3OD):.delta. 6.98(1H, d, J=8.6 Hz),
7.43(1H, dd, J=2.6, 8.6 Hz), 7.74(1H, d, J=8.9 Hz), 7.99(1H, dd,
J=3.0, 8.9 Hz), 8.08(1H, d, J=2.6 Hz), 9.51(1H, d, J=2.6 Hz).
Example 368
Preparation of the Compound of Compound No. 368
[1442] Using 5-chlorosalicylic acid and
5-(N-phenylcarbamoyl)-2-methoxyaniline as the raw material, the
same operation as the Example 16 gave the title compound.
[1443] Yield: 40.3%.
[1444] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.99(3H, s), 7.09(2H, dd,
J=6.6, 6.9 Hz), 7.24(1H, d, J=8.6 Hz), 7.35(2H, dd, 6.9, 7.3 Hz),
7.49(1H, d, J=2.3, 8.9 Hz), 7.77(3H, d, J=8.6 Hz), 8.00(1H, s),
8.97(1H, s), 10.17(1H, s), 10.91(1H, s), 12.11(1H, s).
Example 369
Preparation of the Compound of Compound No. 369
[1445] Using 5-chlorosalicylic acid and 2,5-dimethoxyaniline as the
raw materials, the same operation as the Example 16 gave the title
compound.
[1446] Yield: 73.9%.
[1447] .sup.1H-NMR(CDCl.sub.3):.delta. 3.82(3H, s), 3.93(3H, s),
6.66(1H, dd, J=3.0, 8.9 Hz), 6.86(1H, d, J=8.9 Hz), 6.98(1H, d,
J=8.9 Hz), 7.39(1H, dd, J=2.6, 8.9 Hz), 7.47(1H, d, J=2.6 Hz),
8.08(1H, d, J=3.0 Hz), 8.60(1H, br.s), 12.03(1H, s).
Example 370
Preparation of the Compound of Compound No. 370
[1448] Using 5-chlorosalicylic acid and
5-acetylamino-2-methoxyaniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1449] Yield: 16.9%.
[1450] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.01(3H, s), 3.85(3H, s),
7.03(2H, t, J=9.6 Hz), 7.49(2H, dd, J=8.9, 9.2 Hz), 7.96(1H, s),
8.51(1H, s), 9.87(1H, s), 10.82(1H, s), 12.03(1H, d, J=4.0 Hz).
Example 371
Preparation of the Compound of Compound No. 371
[1451] Using 5-chlorosalicylic acid and 5-methoxy-2-methylaniline
as the raw materials, the same operation as the Example 16 gave the
title compound.
[1452] Yield: 100%.
[1453] .sup.1H-NMR(CDCl.sub.3):.delta. 2.29(3H, s), 3.82(3H, s),
6.75(1H, dd, J=2.6, 8.2 Hz), 7.00(1H, d, J=8.9 Hz), 7.16(1H, d,
J=8.6 Hz), 7.38(1H, d, 2.3 Hz), 7.41(1H, dd, J=2.3, 8.9 Hz),
7.48(1H, d, J=2.3 Hz), 7.70(1H, br.s), 11.92(1H, s).
Example 372
Preparation of the Compound of Compound No. 372
[1454] Using 5-chlorosalicylic acid and 2,5-dibutoxyaniline as the
raw materials, the same operation as the Example 16 gave the title
compound.
[1455] Yield: 73.9%.
[1456] .sup.1H-NMR(CDCl.sub.3):.delta. 0.98(3H, t, J=7.2 Hz),
1.05(3H, t, J=7.2 Hz), 1.44-1.65(4H, m), 1.72-1.79(2H, m),
1.81-1.91(2H, m), 3.97(2H, t, J=6.3 Hz), 4.07(2H, t, J=6.3 Hz),
6.64(1H, dd, J=9.0, 3.0 Hz), 6.85(1H, d, J=9.3 Hz), 6.99(1H, d,
J=9.0 Hz), 7.39(1H, dd, J=8.7, 2.4 Hz), 7.44(1H, d, J=2.7 Hz),
8.08(1H, d, J=3.0 Hz), 8.76(1H, s), 12.08(1H, s).
Example 373
Preparation of the Compound of Compound No. 373
[1457] Using 5-chlorosalicylic acid and 2,5-diisopentyloxyaniline
as the raw materials, the same operation as the Example 16 gave the
title compound.
[1458] Yield: 59.7%.
[1459] .sup.1H-NMR(CDCl.sub.3):.delta. 0.97(6H, d, J=6.6 Hz),
1.03(6H, d, 6.6 Hz), 1.64-1.98(6H, m), 3.99(2H, t, J=6.6 Hz),
4.09(2H, t, J=6.3 Hz), 6.63(1H, dd, J=8.7, 3.0 Hz), 6.85(1H, d,
J=8.7 Hz), 6.98(1H, d, J=8.7 Hz), 7.38(1H, dd, J=9.0, 2.4 Hz),
7.43(1H, d, J=2.7 Hz), 8.09(1H, d, J=3.0 Hz), 8.75(1H, s),
12.08(1H, s).
Example 374
Preparation of the Compound of Compound No. 374
[1460] Using 5-chlorosalicylic acid and
5-carbamoyl-2-methoxyaniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1461] Yield: 31.2%.
[1462] .sup.1H-NMR(CD.sub.3OD):.delta. 4.86(3H, s), 6.93(1H, d,
J=7.6 Hz), 7.18(1H, d, J=8.6 Hz), 7.35(1H, dd, J=3.0, 7.6 Hz),
7.47(1H, dd, J=2.0, 8.6 Hz), 8.00(1H, d, J=3.0 Hz), 8.80(1H, d,
J=2.0 Hz).
Example 375
Preparation of the Compound of Compound No. 375
[1463] Using 5-chlorosalicylic acid and
5-[(1,1-dimethyl)propyl]-2-phenoxyaniline as the raw materials, the
same operation as the Example 16 gave the title compound.
[1464] Yield: 65.2%.
[1465] .sup.1H-NMR(CDCl.sub.3):.delta. 0.69(3H, t, J=7.6 Hz),
1.29(6H, s), 1.64(2H, q, J=7.6 Hz), 6.91(1H, dd, J=1.7, 7.6 Hz),
6.96(1H, d, J=8.9 Hz), 7.03(2H, d, J=8.9 Hz), 7.10(1H, dt, J=1.7,
7.6 Hz), 7.16(1H, dt, J=1.7, 7.6 Hz), 7.40-7.31(4H, m), 8.42(1H,
dd, J=2.0, 7.9 Hz), 8.53(1H, br.s) 11.94(1H, s).
Example 376
Preparation of the Compound of Compound No. 376
[1466] Using 5-chlorosalicylic acid and
2-hexyloxy-5-(methylsulfonyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1467] Yield: 33.0%.
[1468] .sup.1H-NMR(CDCl.sub.3):.delta. 0.92(3H, t, J=6.9 Hz),
1.40-1.59(6H, m), 1.90-2.01(2H, m), 3.09(3H, s), 4.22(2H, t, J=6.3
Hz), 7.01(1H, d, J=8.9 Hz), 7.06(1H, d, J=8.6 Hz), 7.40-7.43(2H,
m), 7.73(1H, dd, J=8.6, 2.3 Hz), 8.74(1H, brs), 8.99(1H, d, J=2.3
Hz), 11.76(1H, s).
Example 377
Preparation of the Compound of Compound No. 377
[1469] Using 5-chlorosalicylic acid and
3'-amino-2,2,4'-trimethylpropiophenone as the raw materials, the
same operation as the Example 16 gave the title compound.
[1470] Yield: 44.8%.
[1471] .sup.1H-NMR(CDCl.sub.3):.delta. 1.38(9H, s), 2.38(3H, s),
7.01(1H, d, J=8.9 Hz), 7.31(1H, d, J=7.9 Hz), 7.42(1H, dd, J=8.9,
2.6 Hz), 7.53(1H, d, J=2.6 Hz), 7.57(1H, dd, J=7.9, 2.0 Hz),
7.83(1H, brs), 8.11(1H, d, J=2.0 Hz), 11.82(1H, s).
Example 378
Preparation of the Compound of Compound No. 378
[1472] Using 5-chlorosalicylic acid and
5-methoxy-2-(1-pyrrolyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1473] Yield: 53.4%.
[1474] .sup.1H-NMR(CDCl.sub.1): .delta. 2.46(3H, s), 6.51-6.52(2H,
m), 6.82-6.85(3H, m), 6.93(1H d, J=8.9 Hz), 7.06(1H, d, J=7.9 Hz),
7.30(1H, d, J=7.9 Hz), 7.32(1H, dd, J=2.3, 8.9 Hz), 7.61(1H, s),
8.29(1H, s), 11.86(1H, br.s).
Example 379
Preparation of the Compound of Compound No. 379
[1475] Using 5-chlorosalicylic acid and 5-chloro-2-tosylaniline as
the raw materials, the same operation as the Example 16 gave the
title compound.
[1476] Yield: 8.0%.
[1477] .sup.1H-NMR(CDCl.sub.3):.delta. 2.38(3H, s), 7.02(1H, d,
J=8.9 Hz), 7.25-7.31(3H, m), 7.46(1H, dd, J=2.6, 8.9 Hz), 7.68(2H,
d, J=8.6 Hz), 7.74(1H, d, J=2.3 Hz), 7.96(1H, d, J=8.6 Hz),
8.56(1H, d, J=2.0 Hz), 10.75(1H, s), 11.70(1H, s).
Example 380
Preparation of the Compound of Compound No. 380
[1478] Using 5-chlorosalicylic acid and 2-chloro-5-tosylaniline as
the raw materials, the same operation as the Example 16 gave the
title compound.
[1479] Yield: 43.5%.
[1480] .sup.1H-NMR(CDCl.sub.3):.delta. 2.38(3H, s), 7.02(1H, d,
J=8.9 Hz), 7.27(1H, d, J=7.9 Hz), 7.29(1H, dd, J=2.0, 6.6 Hz),
7.46(1H, dd, J=2.3, 8.9 Hz), 7.68(2H, d, J=8.6 Hz), 7.73(2H, d,
J=2.3 Hz), 7.97(1H, d, J=8.6 Hz), 8.56(1H, d, J=2.0 Hz), 10.73(1H,
s), 11.71(1H, s).
Example 381
Preparation of the Compound of Compound No. 381
[1481] Using 5-chlorosalicylic acid and
2-fluoro-5-(methylsulfonyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1482] Yield: 28.8%.
[1483] .sup.1H-NMR(CDCl.sub.3):.delta. 3.12(3H, s), 7.03(1H, d,
J=8.9 Hz), 7.38(1H, dd, J=8.6, 10.2 Hz), 7.45(1H, dd, J=2.3, 8.9
Hz), 7.53(1H, d, J=2.3 Hz), 7.80(1H, ddd, J=2.3, 4.6, 8.6 Hz),
8.25(1H, s), 8.98(1H, dd, J=2.3, 7.7 Hz), 11.33(1H, br.s).
Example 382
Preparation of the Compound of Compound No. 382
[1484] Using 5-chlorosalicylic acid and 2-methoxy-5-phenoxyaniline
as the raw materials, the same operation as the Example 16 gave the
title compound.
[1485] Yield: 77.0%.
[1486] .sup.1H-NMR(CDCl.sub.3):.delta. 3.98(3H, s), 6.80(1H, d,
J=8.8 Hz), 6.90(1H, d, J=8.8 Hz), 6.95-7.00(3H, m), 7.04-7.09(1H,
m), 7.29-7.35(2H, m), 7.38(1H, dd, J=8.8, 2.6 Hz), 7.47(1H, d,
J=2.6 Hz), 8.19(1H, d, J=2.9 Hz), 8.61(1H, brs), 11.92(1H, s).
Example 383
Preparation of the Compound of Compound No. 383
[1487] Using 5-chlorosalicylic acid and 3-amino-4-methylbiphenyl as
the raw materials, the same operation as the Example 16 gave the
title compound.
[1488] Yield: 47.7%.
[1489] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.33(3H, s), 7.06(1H, d,
J=8.7 Hz), 7.43-7.52(4H, m), 7.64-7.67(2H, m), 8.04(1H, d, J=2.7
Hz), 8.19(1H, d, J=1.5 Hz), 10.40(1H, s), 12.22(1H, s).
Example 384
Preparation of the Compound of Compound No. 384
[1490] Using 5-chlorosalicylic acid and
5-(.alpha.,.alpha.-dimethylbenzyl)-2-methoxyaniline as the raw
materials, the same operation as the Example 16 gave the title
compound.
[1491] Yield: 89.0%.
[1492] .sup.1H-NMR(CDCl.sub.3):.delta. 1.72(6H, s), 3.93(3H, s),
6.83(1H, d, J=8.8 Hz), 6.93(1H, dd, J=2.6, 8.8 Hz), 6.96(1H, d,
J=9.2 Hz), 7.15-7.20(1H, m), 7.25-7.28(4H, m), 7.36(1H, dd, J=2.6,
8.8 Hz), 7.46(1H, d, J=2.6 Hz), 8.35(1H, d, J=2.6 Hz), 8.51(1H, s),
12.04(1H, s).
Example 385
Preparation of the Compound of Compound No. 385
[1493] Using 5-chlorosalicylic acid and 5-morpholino-2-nitroaniline
as the raw materials, the same operation as the Example 16 gave the
title compound.
[1494] Yield: 4.1%.
[1495] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.46-3.52(4H, m),
3.85-3.94(4H, m), 7.03(1H, d, J=8.8 Hz),
[1496] 7.47(1H, dd, J=2.9, 8.8 Hz), 7.80(1H, dd, J=2.6, 8.8 Hz),
7.82(1H, d, J=2.6 Hz), 7.88(1H, d, J=8.8 Hz), 8.20(1H, d, J=2.2
Hz), 10.70(1H, s), 11.43(1H, s)
Example 386
Preparation of the Compound of Compound No. 386
[1497] Using 5-chlorosalicylic acid and
5-fluoro-2-(1-imidazolyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1498] Yield: 33.8%.
[1499] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.99(1H, d, J=8.8 Hz),
7.12-7.19(2H, m), 7.42-7.51(3H, m), 7.89(1H, d, J=2.8 Hz), 7.93(1H,
d, J=1.1 Hz), 8.34(1H, dd, J=11.4, 2.8 Hz), 10.39(1H, s), 11.76(1H,
brs).
Example 387
Preparation of the Compound of Compound No. 387
[1500] Using 5-chlorosalicylic acid and 2-butyl-5-nitroaniline as
the raw materials, the same operation as the Example 16 gave the
title compound.
[1501] Yield: 15.3%.
[1502] .sup.1H-NMR(CDCl.sub.3):.delta. 0.99(3H, t, J=7.3 Hz),
1.39-1.51(2H, m), 1.59-1.73(2H, m), 2.71-2.79(2H, m), 7.03(1H, d,
J=8.9 Hz), 7.41-7.49(3H, m), 7.92(1H, s), 8.07(1H, dd, J=2.3, 8.4
Hz), 8.75(1H, d, J=2.4 Hz), 11.51(1H, s).
Example 388
Preparation of the Compound of Compound No. 388
[1503] Using 5-chlorosalicylic acid and
5-[(1,1-dimethyl)propyl]-2-hydroxyaniline as the raw materials, the
same operation as the Example 16 gave the title compound.
[1504] Yield: 36.0%.
[1505] .sup.1H-NMR(CDCl.sub.3):.delta. 0.70(3H, t, J=7.4 Hz),
1.28(6H, s), 1.63(2H, q, J=7.4 Hz), 6.97(1H, d, J=6.3 Hz), 7.00(1H,
d, J=6.6 Hz), 7.08(1H, s), 7.14(1H, dd, J=2.5, 8.6 Hz), 7.36(1H, d,
J=2.2 Hz), 7.42(1H, dd, J=2.5, 8.8 Hz), 7.57(1H, d, J=2.5 Hz),
8.28(1H, s), 11.44(1H, s).
Example 389
Preparation of the Compound of Compound No. 389
[1506] Using 5-chlorosalicylic acid and 2-methoxy-5-methylaniline
as the raw materials, the same operation as the Example 16 gave the
title compound.
[1507] Yield: 74.2%.
[1508] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.27(3H, s), 3.85(3H, s),
6.90(1H, dd, J=9.0, 2.4 Hz), 6.98(1H, d, J=9.0 Hz), 7.05(1H, d,
J=9.0 Hz), 7.47(1H, dd, J=9.0, 3.0 Hz), 7.97(1H, d, J=3.0 Hz),
8.24(1H, d, J=2.4 Hz), 10.79(1H, s), 12.03(1H, s).
Example 390
Preparation of the Compound of Compound No. 390
[1509] Using 5-chlorosalicylic acid and 2,5-difluoroaniline as the
raw materials, the same operation as the Example 16 gave the title
compound.
[1510] Yield: 81.5%.
[1511] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.98-7.07(1H, m), 7.07(1H,
d, J=9.0 Hz), 7.37-7.49(1H, m), 7.52(1H, dd, J=8.7, 3.0 Hz),
7.95(1H, d, J=2.7 Hz), 8.15-8.22(1H, m), 10.83(1H, s), 12.25(1H,
s).
Example 391
Preparation of the Compound of Compound No. 391
[1512] Using 5-chlorosalicylic acid and 3,5-difluoroaniline as the
raw materials, the same operation as the Example 16 gave the title
compound.
[1513] Yield: 82.0%.
[1514] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.00(1H, tt, J=9.3, 2.1),
7.03(1H, d, J=9.0 Hz), 7.47(1H, dd, J=7.5, 2.7 Hz), 7.49(1H, d,
J=2.7 Hz), 7.51(1H, d, J=2.1 Hz), 7.82(1H, d, J=3.0 Hz), 10.63(1H,
s), 11.43(1H, brs).
Example 392
Preparation of the Compound of Compound No. 392
[1515] Using
2-(5-bromo-2-hydroxybenzoyl)amino-4-[(1,1-dimethyl)ethyl]thiazole-5-carbo-
xylic acid ethyl ester (Compound No. 197) as the raw material, the
same operation as the Example 82 gave the title compound.
[1516] Yield: 85.6%.
[1517] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.44(9H, s), 7.00(1H, d,
J=9.0 Hz), 7.62(1H, dd, J=9.0, 2.7 Hz), 8.02(1H, d, J=2.4 Hz),
11.83(1H, brs), 12.04(1H, brs), 12.98(1H, brs).
Example 393
Preparation of the Compound of Compound No. 393
[1518] Using 5-bromosalicylic acid and
2-amino-4-phenylthiazole-5-acetic acid methyl ester as the raw
materials, the same operation as the Example 195(3) gave the title
compound. (This compound is the compound of Example 203(1).)
[1519] Yield: 32.1%.
[1520] mp 288.5-229.5.degree. C.
[1521] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.66(3H, s), 3.95(2H, s),
6.99(1H, d, J=8.0 Hz), 7.42(1H, d, J=6.0 Hz), 7.48(2H, brt, J=7.6
Hz), 7.56-7.61(3H, m), 8.07(1H, d, J=2.4 Hz), 11.85(1H, brs),
11.98(1H, brs).
Example 394
Preparation of the Compound of Compound No. 394
[1522] Using
2-(5-bromo-2-hydroxybenzoyl)amino-4-phenylthiazole-5-carboxylic
acid ethyl ester (Compound No. 209) as the raw material, the same
operation as the Example 82 gave the title compound. (This compound
is the compound of Example 212(1).)
[1523] Yield: 67.0%.
[1524] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.00(1H, d, J=8.8 Hz),
7.42-7.44(3H, m), 7.62(1H, dd, J=8.8, 2.4 Hz), 7.70-7.72(2H, m),
8.04(1H, d, J=2.4 Hz), 12.31(1H, brs), 12.99(1H, brs).
Example 395
Preparation of the Compound of Compound No. 395
(1) 2-Amino-4-[3,5-bis(trifluoromethyl)phenyl]thiazole
[1525] Phenyltrimethylammonium tribromide (753 mg, 2 mmol) was
added to a solution of 3',5'-bis(trifluoromethyl)acetophenone (0.51
g, 2.0 mmol) in tetrahydrofuran (5 mL) and the mixture was stirred
at room temperature for 5 hours. The reaction mixture was poured
into water and extracted with ethyl acetate. After the ethyl
acetate layer was washed with brine, dried over anhydrous sodium
sulfate, ethanol (5 mL) and thiourea (152 mg, 2 mmol) were added to
the residue obtained by evaporation of the solvent under reduced
pressure, and the mixture was refluxed for 30 minutes. After the
reaction mixture was cooled to room temperature, it was poured into
saturated aqueous sodium hydrogen carbonate and extracted with
ethyl acetate. After the ethyl acetate layer was washed with brine
and dried over anhydrous sodium sulfate, the residue obtained by
evaporation of the solvent under reduced pressure was purified by
column chromatography on silica gel (n-hexane:ethyl acetate=2:1)
and washed with n-hexane under suspension to give the title
compound (520.1 mg, 83.3%) as a light yellow white crystal.
[1526] .sup.1H-NMR(CDCl.sub.3):.delta. 5.03(2H, s), 6.93(1H, s),
7.77(1H, s), 8.23(2H, s).
(2)
5-Chloro-2-hydroxy-N-{4-[3,5-bis(trifluoromethyl)phenyl]thiazol-2-yl}b-
enzamide (Compound No. 395).
[1527] A mixture of 5-chlorosalicylic acid (172.6 mg, 1 mmol),
2-amino-4-[3,5-bis(trifluoromethyl)phenyl]thiazole (312.2 mg, 1
mmol), phosphorus trichloride (44 .mu.L, 0.5 mmol) and
monochlorobenzene (5 mL) was refluxed for 4 hours. After the
reaction mixture was cooled to room temperature, it was poured into
water and extracted with ethyl acetate. After the ethyl acetate
layer was washed with brine, dried over anhydrous sodium sulfate,
the residue obtained by evaporation of the solvent under reduced
pressure was purified by column chromatography on silica gel
(n-hexane:ethyl acetate=3:1.fwdarw.2:1) to give the title compound
(109.8 mg, 23.5%) as a pale yellow white powder.
[1528] .sup.1H-NMR(DMSO-de): .delta. 7.08(1H, d, J=8.7 Hz),
7.53(1H, dd, J=9.0, 3.0 Hz), 7.94(1H, d, J=3.0 Hz), 8.07(1H, s),
8.29(1H, s), 8.60(2H, s), 11.77(1H, s), 12.23(1H, s).
Example 396
Preparation of the Compound of Compound No. 396
[1529] Using 5-chlorosalicylic acid and 3-aminopyridine as the raw
materials, the same operation as the Example 16 gave the title
compound.
[1530] Yield: 23.2%.
[1531] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.02(1H, d, J=9.3 Hz),
7.42(1H, ddd, J=9.0, 4.8, 0.6 Hz), 7.47(1H, dd, J=8.7, 5.7 Hz),
7.92(1H, d, J=2.7 Hz), 8.15(1H, ddd, J=8.4, 2.4, 1.5 Hz), 8.35(1H,
dd, J=7.8, 1.5 Hz), 8.86(1H, d, J=2.4 Hz), 10.70(1H, s).
Example 397
Preparation of the Compound of Compound No. 397
[1532] Using 5-chlorosalicylic acid and 2-amino-6-bromopyridine as
the raw materials, the same operation as the Example 16 gave the
title compound.
[1533] Yield: 12.3%.
[1534] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.07(1H, d, J=8.7 Hz),
7.42(1H, d, J=7.8 Hz), 7.51(1H, dd, J=8.7, 2.7 Hz), 7.82(1H, t,
J=7.5 Hz), 7.94(1H, d, J=3.0 Hz), 8.24(1H, d, J=7.8 Hz), 10.95(1H,
s), 11.97(1H, s).
Example 398
Preparation of the Compound of Compound No. 398
(1) 2-Acetoxy-5-chloro-N-(pyridazin-2-yl)benzamide
[1535] Using 2-acetoxy-5-chlorobenzoic acid and 2-aminopyridazine
as the raw materials, the same operation as the Example 198(3) gave
the title compound.
[1536] Yield: 19.7%.
[1537] .sup.1H-NMR(CDCl.sub.3):.delta. 2.42(3H, s), 7.19(1H, d,
J=8.7 Hz), 7.54(1H, dd, J=8.7, 2.7 Hz), 8.01(1H, d, J=2.4 Hz),
8.28(1H, dd, J=2.4, 1.8 Hz), 8.42(1H, d, J=2.4 Hz), 9.09(1H, s),
9.66(1H, d, J=1.8 Hz).
(2) 5-Chloro-2-hydroxy-N-(pyridazin-2-yl)benzamide (Compound No.
398)
[1538] Using 2-acetoxy-5-chloro-N-(pyridazin-2-yl)benzamide as the
raw material, the same operation as the Example 2(2) gave the title
compound.
[1539] Yield: 72.6%.
[1540] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.09(1H, d, J=9.0 Hz),
7.52(1H, dd, J=8.7, 2.7 Hz), 7.96(1H, d, J=2.7 Hz), 8.44-8.47(2H,
m), 9.49(1H, s), 10.99(1H, s), 12.04(1H, s).
Example 399
Preparation of the Compound of Compound No. 399
[1541] Using 5-bromosalicylic acid and 2-amino-5-bromopyrimidine as
the raw materials, the same operation as the Example 16 gave the
title compound.
[1542] Yield: 10.3%.
[1543] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.98(1H, d, J=8.8 Hz),
7.59(1H, dd, J=8.8, 2.4 Hz), 8.00(1H, d, J=2.8 Hz), 8.86(2H, s),
11.09(1H, s), 11.79(1H, s).
Example 400
Preparation of the Compound of Compound No. 400
[1544] Using
2-(5-bromo-2-hydroxybenzoyl)amino-4-phenylthiazole-5-carboxylic
acid (Compound No. 394) and propylamine as the raw materials, the
same operation as the Example 212(2) gave the title compound.
[1545] Yield: 23.1%.
[1546] .sup.1H-NMR(DMSO-d.sub.6):.delta. 0.82(3H, t, J=7.5 Hz),
1.39-1.51(2H, m), 3.13(2H, q, J=6.6 Hz), 7.02(1H, d, J=9.0 Hz),
7.40-7.48(3H, m), 7.63(1H, dd, J=8.7, 2.7 Hz), 7.68-7.72(2H, m),
8.06(1H, d, J=2.7 Hz), 8.18(1H, t, J=5.7 Hz), 11.87(1H, brs),
12.14(1H, brs).
Example 401
Preparation of the Compound of Compound No. 401
[1547] Using 5-chlorosalicylic acid and
2-methyl-3,5-bis(trifluoromethyl)aniline as the raw materials, the
same operation as the Example 16 gave the title compound.
[1548] Yield: 15.0%.
[1549] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.49(3H, s), 7.07(1H, d,
J=8.7 Hz), 7.52(1H, dd, J=8.7, 2.8 Hz), 7.84(1H, s), 7.97(1H, d,
J=2.8 Hz), 8.60(1H, s), 10.69(1H, brs), 12.07(1H, brs).
Example 402
Preparation of the Compound of Compound No. 402
[1550] Using 5-chlorosalicylic acid and
4-chloro-3-(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1551] Yield: 66.5%.
[1552] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.03(1H, d, J=8.7 Hz),
7.48(1H, dd, J=8.7, 2.7 Hz), 7.73(1H, d, J=8.7 Hz), 7.86(1H, d,
J=2.4 Hz), 8.00(1H, dd, J=8.7, 2.4 Hz), 8.32(1H, d, J=2.4 Hz),
10.69(1H, s), 11.49(1H, s).
Example 403
Preparation of the Compound of Compound No. 403
[1553] Using 5-chlorosalicylic acid and
4-isopropyl-2-(trifluoromethyl)aniline as the raw materials, the
same operation as the Example 16 gave the title compound.
[1554] Yield: 33.4%.
[1555] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.24(6H, d, J=6.6 Hz),
2.97-3.06(1H, m), 7.06(1H, d, J=8.7 Hz), 7.51(1H, dd, J=8.7, 2.7
Hz), 7.61(1H, s), 7.62(1H, d, J=7.5 Hz), 7.98(1H, d, J=2.7 Hz),
8.03(1H, d, J=8.1 Hz), 10.67(1H, s), 12.21(1H, s).
Example 404
Preparation of the Compound of Compound No. 404
[1556] Using 5-chlorosalicylic acid and 3-(trifluoromethyl)aniline
as the raw materials, the same operation as the Example 16 gave the
title compound.
[1557] Yield: 68.5%.
[1558] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.03(1H, d, J=8.6 Hz),
7.46-7.51(2H, m), 7.62(1H, t, J=7.9 Hz), 7.90(1H, d, J=3.0 Hz),
7.94(1H, d, J=9.2 Hz), 8.21(1H, s), 10.64(1H, s), 11.58(1H,
brs).
Example 405
Preparation of the Compound of Compound No. 405
[1559] Using 5-chlorosalicylic acid and
2-nitro-4-(trifluoromethyl)aniline as the raw materials the same
operation as the Example 16 gave the title compound.
[1560] Yield: 18.7%.
[1561] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.08(1H, d, J=9.0 Hz),
7.54(1H, dd, J=8.7, 2.7 Hz), 7.94(1H, d, J=2.7 Hz), 8.17(1H, dd,
J=9.0, 2.4 Hz), 8.46(1H, d, J=1.8 Hz), 8.88(1H, d, J=9.0 Hz),
12.19(1H, s), 12.25(1H, s).
Example 406
Preparation of the Compound of Compound No. 406
[1562] Using 5-chlorosalicylic acid and
2,6-dichloro-4-(trifluoromethyl)aniline as the raw materials, the
same operation as the Example 16 gave the title compound.
[1563] Yield: 22.1%.
[1564] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.07(1H; d, J=8.7 Hz),
7.55(1H, dd, J=8.7, 2.7 Hz), 7.99(1H, d, J=2.4 Hz), 8.10(2H, s),
10.62(1H, s), 11.88(1H, s).
Example 407
Preparation of the Compound of Compound No. 407
[1565] Using 5-chlorosalicylic acid and
4-cyano-3-(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1566] Yield: 55.8%.
[1567] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.04(1H, d, J=8.7 Hz),
7.49(1H, dd, J=8.7, 2.7 Hz), 7.80(1H, d, J=2.7 Hz), 8.17(2H, s),
8.43(1H, s), 10.94(1H, s), 11.34(1H, s).
Example 408
Preparation of the Compound of Compound No. 408
[1568] Using 5-chlorosalicylic acid and
4-bromo-3-(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1569] Yield: 81.2%.
[1570] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.03(1H, d, J=8.7 Hz),
7.48(1H, dd, J=9.0, 2.7 Hz), 7.85-7.94(3H, m), 8.31(1H, d, J=1.8
Hz), 10.67(1H, s), 11.48(1H, s).
Example 409
Preparation of the Compound of Compound No. 409
[1571] Using 5-chlorosalicylic acid and
4-bromo-2-(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1572] Yield: 41.8%.
[1573] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.07(1H, d, J=8.7 Hz),
7.52(1H, dd, J=9.0, 2.7 Hz), 7.93-7.97(3H, m), 8.21(1H, d, J=9.3
Hz), 10.81(1H, s), 12.28(1H, s).
Example 410
Preparation of the Compound of Compound No. 410
[1574] Using 5-chlorosalicylic acid and
2-bromo-4-(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1575] Yield: 17.6%.
[1576] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.10(1H, d, J=9.0 Hz),
7.53(1H, dd, J=8.7, 3.0 Hz), 7.82(1H, dd, J=9.0, 1.8 Hz), 7.98(1H,
d, J=3.0 Hz), 8.11(1H, d, J=1.5 Hz), 8.67(1H, d, J=8.7 Hz),
11.05(1H, s), 12.40(1H, s).
Example 411
Preparation of the Compound of Compound No. 411
[1577] Using 5-chlorosalicylic acid and
4-fluoro-2-(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1578] Yield: 36.0%.
[1579] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.06(1H, d, J=9.0 Hz),
7.52(1H, dd, J=8.7, 2.7 Hz), 7.63(1H, td, J=8.7, 3.3 Hz), 7.71(1H,
dd, J=8.7, 3.0 Hz), 7.97(1H, d, J=2.7 Hz), 8.11(1H, dd, J=8.7, 5.1
Hz), 10.67(1H, s), 12.20(1H, s).
Example 412
Preparation of the Compound of Compound No. 412
[1580] Using 5-chlorosalicylic acid and
4-isopropyloxy-2-(trifluoromethyl)aniline as the raw materials, the
same operation as the Example 16 gave the title compound.
[1581] Yield: 39.2%.
[1582] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.29(6H, d, J=5.7 Hz),
4.67-4.79(1H, m), 7.04(1H, d, J=9.0 Hz), 7.22(1H, d, J=2.7 Hz),
7.30(1H, dd, J=8.7, 2.7 Hz), 7.51(1H, dd, J=8.7, 2.4 Hz), 7.86(1H,
d, J=9.0 Hz), 7.99(1H, d, J=3.0 Hz), 10.50(1H, s), 12.18(1H,
s).
Example 413
Preparation of the Compound of Compound No. 413
[1583] Using 5-chlorosalicylic acid and
2,4-dimethoxy-5-(trifluoromethyl)aniline as the raw materials, the
same operation as the Example 16 gave the title compound.
[1584] Yield: 19.0%.
[1585] .sup.1H-NMR(CDCl.sub.3):.delta. 3.93(3H, s), 4.03(3H, s),
6.70(1H, s), 6.98(1H, d, J=8.9 Hz), 7.39(1H, dd, J=8.9, 2.6 Hz),
7.45(1H, d, J=2.6 Hz), 8.29(1H, brs), 8.54(1H, s), 11.92(1H,
s).
Example 414
Preparation of the Compound of Compound No. 414
[1586] Using 5-chlorosalicylic acid and
2,4-difluoro-5-(trifluoromethyl)aniline as the raw materials, the
same operation as the Example 16 gave the title compound.
[1587] Yield: 66.0%.
[1588] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.06(1H, d, J=8.8 Hz),
7.51(1H, dd, J=8.8, 2.8 Hz), 7.82(1H, t, J=10.7 Hz), 7.94(1H, d,
J=2.8 Hz), 8.64(1H, d, J=8.0 Hz), 10.78(1H, s), 12.37(1H, brs).
Example 415
Preparation of the Compound of Compound No. 415
[1589] Using 5-chlorosalicylic acid and
4-cyano-2-(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1590] Yield: 24.8%.
[1591] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.06(1H, d, J=8.8 Hz),
7.52(1H, dd, J=2.8, 8.8 Hz), 7.94(1H, d, J=2.8 Hz), 8.17(1H, dd,
J=1.8, 8.9 Hz), 8.31(1H, d, J=2.1 Hz), 8.63(1H, d, J=8.9 Hz),
11.16(1H, s), 12.45(1H, br.s).
Example 416
Preparation of the Compound of Compound No. 416
[1592] Using 5-chlorosalicylic acid and
4-chloro-2-(4-chlorobenzenesulfonyl)-5-(trifluoromethyl)aniline as
the raw materials, the same operation as the Example 16 gave the
title compound.
[1593] Yield: 8.5%.
[1594] .sup.1H-NMR(CDCl.sub.3):.delta. 6.98(1H, d, J=8.9 Hz),
7.13(1H, d, J=2.6 Hz), 7.22(2H, d, J=8.6 Hz), 7.34(2H, d, J=8.6
Hz), 7.40(1H, dd, J=2.3, 8.9 Hz), 7.66(1H, s), 8.71(1H, s),
8.80(1H, s), 11.42(1H, s).
Example 417
Preparation of the Compound of Compound No. 417
[1595] Using 5-chlorosalicylic acid and
5-chloro-2-nitro-4-(trifluoromethyl)aniline as the raw materials,
the same operation as the Example 16 gave the title compound.
[1596] Yield: 22.8%.
[1597] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.08(1H, d, J=8.8 Hz),
7.55(1H, dd, J=8.8, 2.8 Hz), 7.93(1H, d, J=2.8 Hz), 8.52(1H, s),
9.13(1H, s), 12.38(1H, brs), 12.45(1H, s).
Example 418
Preparation of the Compound of Compound No. 418
[1598] Using 5-chlorosalicylic acid and
2,3-difluoro-4-(trifluoromethyl)aniline as the raw materials, the
same operation as the Example 16 gave the title compound.
[1599] Yield: 21.8%.
[1600] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.07(1H, d, J=8.8 Hz),
7.53(1H, dd, J=2.9, 8.8 Hz), 7.66(1H, dt, J=1.8, 7.7 Hz), 7.93(1H,
d, J=2.6 Hz), 8.35(1H, t, J=7.7 Hz), 11.02(1H, d, J=1.5 Hz),
12.32(1H, s).
Example 419
Preparation of the Compound of Compound No. 419
[1601] Using 5-chlorosalicylic acid and
4,4'-diamino-2,2'-bis(trifluoromethyl)biphenyl as the raw
materials, the same operation as the Example 16 gave the title
compound.
[1602] Yield: 35.9%.
[1603] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.05(2H, d, J=8.8 Hz),
7.39(2H, d, J=8.5 Hz), 7.49-7.51(2H, m), 7.91(2H, d, J=2.5 Hz),
7.99(2H, dd, J=2.0, 8.5 Hz), 8.31(2H, d, J=1.9 Hz), 10.71(2H, s),
11.54(2H, s).
Example 420
Preparation of the Compound of Compound No. 420
[1604] Using 5-chlorosalicylic acid and
2,3,5,6-tetrafluoro-4-(trifluoromethyl)aniline as the raw
materials, the same operation as the Example 16 gave the title
compound.
[1605] Yield: 42.5%.
[1606] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.08(1H, d, J=8.8 Hz),
7.53(1H, dd, J=2.9, 8.8 Hz), 7.89(1H, d, J=2.6 Hz), 10.65(1H,
br.s), 11.76(1H, br.s).
Example 421
Preparation of the Compound of Compound No. 421
[1607] Using 5-chlorosalicylic acid and 3'-aminoacetanilide as the
raw materials, the same operation as the Example 16 gave the title
compound.
[1608] Yield: 22.4%.
[1609] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.05(3H, s), 7.01(1H, d,
J=8.7 Hz), 7.24-7.39(3H, m), 7.47(1H, dd, J=9.0, 3.0 Hz), 7.97(1H,
d, J=3.0 Hz), 8.03(1H, s), 10.01(1H, s), 10.41(1H, s), 11.87(1H,
s).
Example 422
Preparation of the Compound of Compound No. 422
(1) 2-Acetoxy-5-chloro-N-(3-carbamoylphenyl)benzamide
[1610] Using 2-acetoxy-5-chlorobenzoic acid and 3-aminobenzamide as
the raw materials, the same operation as the Example 24 gave the
title compound.
[1611] Yield: 15.8%.
[1612] .sup.1H-NMR(CDCl.sub.3):.delta. 2.33(3H, s), 5.89(1H, brs),
6.31(1H, brs), 7.14(1H, d, J=9.0 Hz), 7.42-7.49(2H, m),
7.55-7.58(1H, m), 7.80(1H, d, J=2.7 Hz), 7.93(1H, d, J=8.1 Hz),
8.07(1H, s), 8.71(1H, s).
(2) 5-Chloro-2-hydroxy-N-(3-carbamoylphenyl)benzamide (Compound No.
422)
[1613] Using 2-acetoxy-5-chloro-N-(3-carbamoylphenyl)benzamide as
the raw material, the same operation as the Example 2(2) gave the
title compound.
[1614] Yield: 76.0%.
[1615] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.03(1H, d, J=8.7 Hz),
7.40(1H, brs), 7.45(1H, t, J=7.5 Hz), 7.48(1H, dd, J=8.7, 2.4 Hz),
7.62-7.65(1H, m), 7.86-7.89(1H, m), 7.98-7.99(2H, m), 8.15(1H, t,
J=1.8 Hz), 10.51(1H, s), 11.85(1H, s).
Example 423
Preparation of the Compound of Compound No. 423
[1616] Using 5-chlorosalicylic acid and 3-amino-N-methylbenzamide
as the raw materials, the same operation as the Example 16 gave the
title compound.
[1617] Yield: 19.3%.
[1618] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.79(3H, d, J=4.5 Hz),
7.03(1H, d, J=9.0 Hz), 7.43-7.51(2H, m), 7.59(1H, dt, J=8.1, 1.5
Hz), 7.87(1H, ddd, J=8.1, 2.1, 0.9 Hz), 7.99(1H, d, J=2.4 Hz),
8.15(1H, t, J=1.8 Hz), 8.46(1H, d, J=4.2 Hz), 10.52(1H, s),
11.84(1H, s).
Example 424
Preparation of the Compound of Compound No. 424
[1619] Using 5-chlorosalicylic acid and 2,6-diisopropylaniline as
the raw materials, the same operation as the Example 16 gave the
title compound.
[1620] Yield: 52.5%.
[1621] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.14(12H, s),
2.96-3.13(2H, m), 7.16(1H, d, J=8.7 Hz), 7.23(1H, d, J=7.5 Hz),
7.33(1H, dd, J=8.4, 6.6 Hz), 7.52(1H, dd, J=8.7, 2.4 Hz), 8.11(1H,
d, J=2.4 Hz), 10.09(1H, s), 12.40(1H, s).
Example 425
Preparation of the Compound of Compound No. 425
[1622] Using 5-chlorosalicylic acid and 4-methylaniline as the raw
materials, the same operation as the Example 16 gave the title
compound.
[1623] Yield: 58.6%.
[1624] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.29(3H, s), 7.01(1H, d,
J=8.7 Hz), 7.18(1H, d, J=8.1 Hz), 7.47(1H, dd, J=8.7, 2.7 Hz),
7.58(1H, d, J=8.4 Hz), 7.98(1H, d, J=2.7 Hz), 10.35(1H, s),
11.94(1H, s).
Example 426
Preparation of the Compound of Compound No. 426
[1625] Using 5-chlorosalicylic acid and 2,6-dimethylaniline as the
raw materials, the same operation as the Example 16 gave the title
compound.
[1626] Yield: 59.6%.
[1627] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.19(6H, s), 7.01(1H, d,
J=9.0 Hz), 7.15-7.16(2H, m), 7.50(1H, dd, J=9.0, 2.7 Hz), 8.07(1H,
d, J=2.7 Hz), 10.03(1H, s), 10.10(1H, s), 12.29(1H, s).
Example 427
Preparation of the Compound of Compound No. 427
[1628] Using 5-chlorosalicylic acid and 3,4-dimethylaniline as the
raw materials, the same operation as the Example 16 gave the title
compound.
[1629] Yield: 68.3%.
[1630] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.20(3H, s), 2.23(3H, s),
7.01(1H, d, J=9.0 Hz), 7.13(1H, d, J=8.4 Hz), 7.40-7.47(2H, m),
7.47(1H, dd, J=9.0, 2.7 Hz), 7.99(1H, d, J=2.7 Hz), 10.29(1H, s),
11.97(1H, brs).
Example 428
Preparation of the Compound of Compound No. 428
[1631] Using 5-chlorosalicylic acid and 2,4,6-trimethylaniline as
the raw materials, the same operation as the Example 16 gave the
title compound.
[1632] Yield: 61.0%.
[1633] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.14(6H, s), 2.26(3H, s),
6.95(2H, s), 7.00(1H, d, J=9.3 Hz), 7.48(1H, dd, J=8.7, 2.7 Hz),
8.09(1H, d, J=2.4 Hz), 10.03(1H, s), 12.37(1H, s).
Example 429
Preparation of the Compound of Compound No. 429
[1634] Using 5-chlorosalicylic acid and 3-(trifluoromethoxy)aniline
as the raw materials, the same operation as the Example 16 gave the
title compound.
[1635] Yield: 41.4%.
[1636] .sup.1H-NMR(CDCl.sub.3):.delta. 7.00(1H, d, J=9.0 Hz),
7.09(1H, d, J=7.5 Hz), 7.40-7.48(3H, m), 7.51(1H, d, J=2.4 Hz),
7.64(1H, s), 7.94(1H, s), 11.66(1H, s).
Example 430
Preparation of the Compound of Compound No. 430
[1637] Using 5-chlorosalicylic acid and 2-benzylaniline as the raw
materials, the same operation as the Example 16 gave the title
compound.
[1638] Yield: 93.3%.
[1639] .sup.1H-NMR(CDCl.sub.3):.delta. 4.08(2H, s), 6.56(1H, d,
J=2.5 Hz), 6.92(1H, d, J=8.8 Hz), 7.20-7.46(9H, m), 7.53(1H, brs),
7.85(1H, d, J=8.0 Hz), 12.01(1H, brs).
Example 431
Preparation of the Compound of Compound No. 431
[1640] Using 5-chlorosalicylic acid and 4-(trifluoromethoxy)aniline
as the raw materials, the same operation as the Example 16 gave the
title compound.
[1641] Yield: 20.4%.
[1642] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.03(1H, d, J=9.3 Hz),
7.39(2H, d, J=9.0 Hz), 7.48(1H, dd, J=9.0, 2.7 Hz), 7.83(2H, d,
J=9.3 Hz), 7.92(1H, d, J=2.7 Hz), 10.54(1H, s), 11.78(1H, s).
Example 432
Preparation of the Compound of Compound No. 432
[1643] Using 5-chlorosalicylic acid and 2,4-dichloroaniline as the
raw materials, the same operation as the Example 16 gave the title
compound.
[1644] Yield: 60.0%.
[1645] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.08(1H, d, J=8.7 Hz),
7.48-7.54(2H, m), 7.75(1H, d, J=2.1 Hz), 7.98(1H, d, J=2.7 Hz),
8.44(1H, d, J=8.7 Hz), 10.93(1H, s), 12.31(1H, s).
Example 433
Preparation of the Compound of Compound No. 433
[1646] Using 5-chlorosalicylic acid and 4-(tert-butyl)aniline as
the raw materials, the same operation as the Example 16 gave the
title compound.
[1647] Yield: 69.0%.
[1648] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.29(9H, s), 7.01(1H, d,
J=8.7 Hz), 7.39(2H, d, J=8.4 Hz), 7.47(1H, dd, J=8.7, 2.7 Hz),
7.61(2H, d, J=8.4 Hz), 7.99(1H, d, J=2.4 Hz), 10.37(1H, s),
11.96(1H, s).
Example 434
Preparation of the Compound of Compound No. 434
[1649] Using 5-chlorosalicylic acid and 2,3-dimethylaniline as the
raw materials, the same operation as the Example 16 gave the title
compound.
[1650] Yield: 79.6%.
[1651] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.14(3H, s), 2.29(3H, s),
7.03(1H, d, J=9.0 Hz), 7.06-7.15(2H, m), 7.46-7.51(2H, m), 8.05(1H,
d, J=3.0 Hz), 10.32(1H, s), 12.28(1H, s).
Example 435
Preparation of the Compound of Compound No. 435
[1652] Using 5-chlorosalicylic acid and 5-aminoindane as the raw
materials, the same operation as the Example 16 gave the title
compound.
[1653] Yield: 80.7%.
[1654] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.98-2.08(2H, m),
2.81-2.89(4H, m), 7.01(1H, d, J=8.8 Hz), 7.21(1H, d, J=8.0, Hz),
7.42(1H, dd, J=8.0, 1.9 Hz), 7.48(1H, dd, J=8.8, 2.8 Hz), 7.60(1H,
s), 7.99(1H, d, J=2.8, Hz), 10.34(1H, s), 12.00(1H, brs).
Example 436
Preparation of the Compound of Compound No. 436
[1655] Using 5-chlorosalicylic acid and 2,4-dimethylaniline as the
raw materials, the same operation as the Example 16 gave the title
compound.
[1656] Yield: 37.1%.
[1657] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.23(3H, s), 2.28(3H, s),
7.03(2H, d, J=8.7 Hz), 7.10(1H, s), 7.49(1H, dd, J=9.0, 2.7 Hz),
7.63(1H, d, J=8.1 Hz), 8.03(1H, d, J=2.4 Hz), 10.24(1H, s),
12.25(1H, s).
Example 437
Preparation of the Compound of Compound No. 437
[1658] Using 5-chlorosalicylic acid and 3-isopropyloxyaniline as
the raw materials, the same operation as the Example 16 gave the
title compound.
[1659] Yield: 21.5%.
[1660] .sup.1H-NMR(CDCl.sub.3):.delta. 1.36(6H, d, J=6.0 Hz),
4.52-4.64(1H, m), 6.75(1H, ddd, J=8.4, 2.4, 0.9 Hz), 6.99(1H, d,
J=8.7 Hz), 7.03(1H, ddd, J=8.1, 2.1, 0.9 Hz), 7.25-7.31(3H, m),
7.39(1H, dd, J=8.7, 2.4 Hz), 7.49(1H d, J=2.4 Hz), 7.81(1H, s).
Example 438
Preparation of the Compound of Compound No. 438
[1661] Using 5-chlorosalicylic acid and 2,6-dichloroaniline as the
raw materials, the same operation as the Example 16 gave the title
compound.
[1662] Yield: 10.3%.
[1663] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.05(1H, d, J=8.7 Hz),
7.43(1H, dd, J=8.7, 7.8 Hz), 7.54(1H, dd, J=9.0, 2.7 Hz), 7.62(1H,
d, J=8.1 Hz), 8.05(1H, d, J=2.4 Hz), 10.52(1H, s), 12.01(1H,
s).
Example 439
Preparation of the Compound of Compound No. 439
[1664] Using 5-chlorosalicylic acid and 4-isopropyloxyaniline as
the raw materials, the same operation as the Example 16 gave the
title compound.
[1665] Yield: 76.8%.
[1666] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.26(6H, d, J=6.3 Hz),
4.52-4.64(1H, m), 6.93(2H, dt, J=9.0, 2.1 Hz), 7.46(1H, dd, J=9.0,
2.7 Hz), 7.58(2H, dt, J=9.0, 2.1 Hz), 7.99(1H, d, J=3.0 Hz),
10.36(1H, s), 11.83(1H, brs).
Example 440
Preparation of the Compound of Compound No. 440
[1667] Using 5-chlorosalicylic acid and
4-bromo-2-(trifluoromethoxy)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1668] Yield: 59.2%.
[1669] .sup.1H-NMR(CDCl.sub.3):.delta. 7.01(1H, d, J=9.3 Hz),
7.42-7.52(4H, m), 8.23(1H, s), 8.31(1H, d, J=9.3 Hz), 11.35(1H,
s).
Example 441
Preparation of the Compound of Compound No. 441
[1670] Using 5-chlorosalicylic acid and 4-butylaniline as the raw
materials, the same operation as the Example 16 gave the title
compound.
[1671] Yield: 77.6%
[1672] .sup.1H-NMR(CDCl.sub.3):.delta. 0.89(3H, t, J=6.9 Hz),
1.27-1.36(6H, m), 1.56-1.64(2H, m), 2.61(2H, t, J=7.8 Hz), 6.99(1H,
d, J=9.0 Hz), 7.21(2H, d, J=8.7 Hz), 7.39(1H, dd, J=9.0, 2.7 Hz),
7.44-7.49(3H, m), 7.80(1H, s), 11.96(1H, s).
Example 442
Preparation of the Compound of Compound No. 442
[1673] Using 5-chlorosalicylic acid and 3-methylaniline as the raw
materials, the same operation as the Example 16 gave the title
compound.
[1674] Yield: 88.3%.
[1675] .sup.1H-NMR(CDCl.sub.3):.delta. 2.38(3H, s), 6.98(1H, d,
J=8.8 Hz), 7.03(1H, d, J=7.4 Hz), 7.25-7.40(4H, m), 7.48(1H, d,
J=2.2 Hz), 7.83(1H, brs), 11.92(1H, brs).
Example 443
Preparation of the Compound of Compound No. 443
[1676] Using 5-chlorosalicylic acid and 4-cyclohexylaniline as the
raw materials, the same operation as the Example 16 gave the title
compound.
[1677] Yield: 90.6%.
[1678] .sup.1H-NMR(CDCl.sub.3):.delta. 1.15-1.47(5H, m),
1.56-1.87(5H, m), 2.40-2.53(2H, m), 7.01(1H, d, J=8.8 Hz), 7.21(2H,
d, J=8.5 Hz), 7.47(1H, dd, J=8.8, 2.7 Hz), 7.60(2H, d, J=8.5H),
8.00(1H, d, J=2.7 Hz), 10.36(1H, s), 11.98(1H, brs).
Example 444
Preparation of the Compound of Compound No. 444
[1679] Using 5-chlorosalicylic acid and 4-benzylaniline as the raw
materials, the same operation as the Example 16 gave the title
compound.
[1680] Yield: 90.3%.
[1681] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.93(2H, s), 7.01(1H, d,
J=9.0 Hz), 7.16-7.32(7H, m), 7.57(1H, dd, J=9.0, 2.7 Hz), 7.61(2H,
d, J=8.4 Hz), 7.96(1H, d, J=2.4 Hz), 10.37(1H, s).
Example 445
Preparation of the Compound of Compound No. 445
[1682] Using 5-chlorosalicylic acid and
2-amino-4,5-dimethoxybenzonitrile as the raw materials, the same
operation as the Example 16 gave the title compound.
[1683] Yield: 52.8%.
[1684] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.81(3H, s), 3.86(3H, s),
7.08(1H, d, J=8.7 Hz), 7.40(1H, s), 7.52(1H, dd, J=8.7, 2.7 Hz),
7.89(1H, s), 7.99(1H, d, J=3.0 Hz), 10.93(1H, s), 12.31(1H, s).
Example 446
Preparation of the Compound of Compound No. 446
[1685] Using 5-chlorosalicylic acid and 6-amino-1,4-benzodioxane as
the raw materials, the same operation as the Example 16 gave the
title compound.
[1686] Yield: 79.7%.
[1687] .sup.1H-NMR(DMSO-d.sub.6):.delta. 4.25(4H, s), 6.86(1H, d,
J=8.8 Hz), 7.00(1H, d, J=8.8 Hz), 7.12(1H, dd, J=8.8, 2.5 Hz),
7.33(1H, d, J=2.5 Hz), 7.46(1H, dd, J=8.8, 2.5 Hz), 7.97(1H, d,
J=2.5 Hz), 10.27(1H, s), 11.96(1H, s).
Example 447
Preparation of the Compound of Compound No. 447
[1688] Using 5-chlorosalicylic acid and
2,4-dichloro-5-(isopropyloxy)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1689] Yield: 76.1%.
[1690] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.35(6H, d, J=6.0 Hz),
4.58-4.66(1H, m), 7.07(1H, d, J=9.0 Hz), 7.51(1H, dd, J=8.7, 3.0
Hz), 7.68(1H, s), 7.98(1H, d, J=3.0 Hz), 8.35(1H, s), 10.94(1H, s),
12.34(1H, s).
Example 448
Preparation of the Compound of Compound No. 448
[1691] Using 5-chlorosalicylic acid and
4-amino-2-chlorobenzonitrile as the raw materials, the same
operation as the Example 16 gave the title compound.
[1692] Yield: 57.9%.
[1693] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.04(1H, d, J=9.0 Hz),
7.48(1H, dd, J=8.7, 2.7 Hz), 7.78(1H, d, J=2.7 Hz), 7.82(1H, dd,
J=9.0, 2.1 Hz), 7.97(1H, d, J=8.7 Hz), 8.19(1H, d, J=2.1 Hz),
10.79(1H, s), 11.38(1H, s).
Example 449
Preparation of the Compound of Compound No. 449
[1694] Using 5-chlorosalicylic acid and
3-chloro-4-(trifluoromethoxy)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1695] Yield: 50.6%.
[1696] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.03(1H, d, J=8.7 Hz),
7.48(1H, dd, J=8.7, 2.7 Hz), 7.60(1H, dd, J=9.0, 1.5 Hz), 7.76(1H,
dd, J=9.0, 2.4 Hz), 7.85(1H, d, J=3.0 Hz), 8.13(1H, d, J=2.4 Hz),
10.61(1H, s), 11.51(1H, s).
Example 450
Preparation of the Compound of Compound No. 450
[1697] Using 5-chlorosalicylic acid and
4-amino-3-methylbenzonitrile as the raw materials, the same
operation as the Example 16 gave the title compound.
[1698] Yield: 80.6%.
[1699] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.36(3H, s), 7.06(1H, d,
J=8.7 Hz), 7.49(1H, dd, J=8.7, 2.4 Hz), 7.71(1H, dd, J=8.4, 1.8
Hz), 7.77(1H, s), 7.95(1H, d, J=3.0 Hz), 8.40(1H, d, J=8.4 Hz),
10.76(1H, s), 12.31(1H, brs).
Example 451
Preparation of the Compound of Compound No. 451
[1700] Using 5-chlorosalicylic acid and 2,3-dichloroaniline as the
raw materials, the same operation as the Example 16 gave the title
compound.
[1701] Yield: 37.1%.
[1702] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.08(1H, d, J=9.0 Hz),
7.40-7.48(2H, m), 7.52(1H, dd, J=9.0, 2.7 Hz), 7.98(1H, d, J=2.7
Hz), 8.40(1H, dd, J=7.2, 2.4 Hz), 11.00(1H, s), 12.32(1H, s).
Example 452
Preparation of the Compound of Compound No. 452
[1703] Using 5-chlorosalicylic acid and 2-chloroaniline as the raw
materials, the same operation as the Example 16 gave the title
compound.
[1704] Yield: 67.3%.
[1705] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.08(1H, d, J=8.7 Hz),
7.20(1H, td, J=8.1, 1.8 Hz), 7.40(1H, td, J=8.4, 1.8 Hz), 7.52(1H,
dd, J=8.7, 2.7 Hz), 7.57(1H, dd, J=8.4, 1.8 Hz), 8.00(1H, d, J=2.7
Hz), 8.40(1H, dd, J=8.4, 1.8 Hz), 10.89(1H, s), 12.27(1H, s).
Example 453
Preparation of the Compound of Compound No. 453
[1706] Using 5-chlorosalicylic acid and 4-isopropyl-3-methylaniline
as the raw materials, the same operation as the Example 16 gave the
title compound.
[1707] Yield: 21.6%.
[1708] .sup.1H-NMR(CDCl.sub.3):.delta. 1.23(6H, d, J=6.9 Hz),
2.36(3H, s), 3.12(1H, m), 6.89(1H, d, J=9.0 Hz), 7.15-7.40(5H, m),
7.48(1H, d, J=2.1 Hz), 7.83(1H, brs).
Example 454
Preparation of the Compound of Compound No. 454
[1709] Using 5-chlorosalicylic acid and
2-amino-5-[(1,1-dimethyl)propyl]phenol as the raw materials, the
same operation as the Example 16 gave the title compound.
[1710] Yield: 24.9%.
[1711] .sup.1H-NMR(CDCl.sub.3):.delta. 0.69(3H, t, J=7.5 Hz),
1.28(6H, s), 1.63(2H, q, J=7.5 Hz), 6.98(1H, d, J=8.7 Hz), 7.01(1H,
d, J=9.0 Hz), 7.06(1H, s), 7.15(1H, dd, =8.4, 2.4 Hz), 7.35(1H, d,
J=2.1 Hz), 7.42(1H, dd, J=8.7, 2.4 Hz), 7.56(1H, d, J=2.4 Hz),
8.26(1H, s), 11.44(1H, s).
Example 455
Preparation of the Compound of Compound No. 455
[1712] Using 5-chlorosalicylic acid and 2-methylaniline as the raw
materials, the same operation as the Example 16 gave the title
compound.
[1713] Yield: 64.7%.
[1714] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.28(3H, s), 7.05(1H, d,
J=8.7 Hz), 7.13(1H, td, J=7.5, 1.5 Hz), 7.22-7.30(2H, m), 7.50(1H,
dd, J=9.0, 2.7 Hz), 7.83(1H, d, J=7.8 Hz), 8.03(1H, d, J=3.0 Hz),
10.32(1H, s), 12.22(1H, s).
Example 456
Preparation of the Compound of Compound No. 456
[1715] Using 5-chlorosalicylic acid and 4-butylaniline as the raw
materials, the same operation as the Example 16 gave the title
compound.
[1716] Yield: 82.1%.
[1717] .sup.1H-NMR(DMSO-d.sub.6):.delta. 0.90(3H, t, J=7.2 Hz),
1.24-1.36(2H, m), 1.50-1.60(2H, m), 2.56(2H, t, J=7.2 Hz), 7.01(1H,
d, J=8.7 Hz), 7.19(2H, d, J=8.7 Hz), 7.47(1H, dd, J=8.7, 2.4 Hz),
7.59(2H, d, J=8.4 Hz), 7.98(1H, d, J=2.7 Hz), 10.36(1H, s),
11.94(1H, s).
Example 457
Preparation of the Compound of Compound No. 457
[1718] Using 5-chlorosalicylic acid and
2-amino-6-chlorobenzonitrile as the raw materials, the same
operation as the Example 16 gave the title compound.
[1719] Yield: 12.7%.
[1720] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.09(1H, d, J=8.7 Hz),
7.52(1H, d, J=8.1 Hz), 7.53(1H, dd, J=9.0, 3.0 Hz), 7.76(1H, t,
J=8.7 Hz), 7.95(1H, d, J=3.0 Hz), 8.34(1H, d, J=8.4 Hz), 11.17(1H,
s), 12.39(1H, s).
Example 458
Preparation of the Compound of Compound No. 458
[1721] Using 5-chlorosalicylic acid and
2-amino-5-methylbenzonitrile as the raw materials, the same
operation as the Example 16 gave the title compound.
[1722] Yield: 9.0%.
[1723] .sup.1H-NMR(CDCl.sub.3):.delta. 2.48(3H, s), 7.01(1H, d,
J=9.0 Hz), 7.10(1H, dd, J=8.0, 0.9 Hz), 7.44(1H, d, J=9.0, 2.4 Hz),
7.56(1H, d, J=8.1 Hz), 7.62(1H, d, J=2.4 Hz), 8.22(1H, s), 8.54(1H,
brs), 11.25(1H, brs).
Example 459
Preparation of the Compound of Compound No. 459
[1724] Using 5-chlorosalicylic acid and 4-benzyloxyaniline as the
raw materials, the same operation as the Example 16 gave the title
compound.
[1725] Yield: 26.8%.
[1726] .sup.1H-NMR(DMSO-d.sub.6):.delta. 5.11(2H, s), 6.99-7.05(3H,
m), 7.33-7.49(6H, m), 7.60(2H, d, J=9.0 Hz), 7.99(1H, d, J=2.7 Hz),
10.33(1H, s), 12.02(1H, s).
Example 460
Preparation of the Compound of Compound No. 460
[1727] Using 5-chlorosalicylic acid and
4-amino-2,2-difluorobenzo[1,3]dioxole as the raw materials, the
same operation as the Example 16 gave the title compound.
[1728] Yield: 66.9%.
[1729] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.05(1H, d, J=8.8 Hz),
7.31-7.32(2H, m), 7.51(1H, dd, J=8.8, 2.8 Hz), 7.70(1H, dd, J=5.6,
3.8 Hz), 7.96(1H, d, J=2.8 Hz), 10.59(1H, s), 12.05(1H, brs).
Example 461
Preparation of the Compound of Compound No. 461
[1730] Using 5-chlorosalicylic acid and
5-amino-2,2,3,3-tetrafluoro-2,3-dihydrobenzo[1,4]dioxene as the raw
materials, the same operation as the Example 16 gave the title
compound.
[1731] Yield: 67.9%.
[1732] .sup.1H-NMR(CDCl.sub.3):.delta. 6.99-7.03(2H, m),
7.21-7.27(2H, m), 7.45(1H, dd, J=8.9, 2.5 Hz), 7.52(1H, d, J=2.5
Hz), 8.13(1H, s), 11.44(1H, s).
Example 462
Preparation of the Compound of Compound No. 462
[1733] Using 5-chlorosalicylic acid and
3-chloro-4-(trifluoromethyl)sulfanylaniline as the raw materials,
the same operation as the Example 16 gave the title compound.
[1734] Yield: 52.3%.
[1735] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.03(1H, d, J=8.8 Hz),
7.47(1H, dd, J=2.9, 8.8 Hz), 7.80(1H, dd, J=2.6, 8.8 Hz), 7.82(1H,
d, J=2.6 Hz), 7.88(1H, d, J=8.8 Hz), 8.20(1H, d, J=2.2 Hz),
10.70(1H, s), 11.43(1H, s).
Example 463
Preparation of the Compound of Compound No. 463
[1736] Using 5-chlorosalicylic acid and
2-nitro-4-(trifluoromethoxy)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1737] Yield: 68.4%.
[1738] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.07(1H, d, J=8.8 Hz),
7.52(1H, dd, J=2.6, 8.8 Hz), 7.85-7.89(1H, m), 7.93(1H, d, J=2.6
Hz), 8.17(1H, d, J=2.9 Hz), 8.67(1H, d, J=9.5 Hz), 11.92(1H, s),
12.14(1H, s).
Example 464
Preparation of the Compound of Compound No. 464
[1739] Using 5-chlorosalicylic acid and
5-amino-2,2-difluorobenzo[1,3]dioxole as the raw materials, the
same operation as the Example 16 gave the title compound.
[1740] Yield: 75.8%.
[1741] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.02(1H, d, J=8.8 Hz),
7.42-7.43(2H, m), 7.48(1H, dd, J=8.8, 2.5 Hz), 7.90(1H, d, J=2.5
Hz), 10.54(1H, s), 11.69(1H, s).
Example 465
Preparation of the Compound of Compound No. 465
[1742] Using 5-chlorosalicylic acid and 3-benzylaniline as the raw
materials, the same operation as the Example 16 gave the title
compound.
[1743] Yield: 66.4%.
[1744] .sup.1H-NMR(CDCl.sub.3):.delta. 3.99(2H, s), 6.97(1H, d,
J=9.1 Hz), 7.06(1H, d, J=7.4 Hz), 7.18-7.48(8H, m), 7.37(1H, dd,
J=9.1, 2.5 Hz), 7.45(1H, d, J=2.5 Hz), 7.80(1H, brs), 11.88(1H,
s).
Example 466
Preparation of the Compound of Compound No. 466
[1745] Using 5-chlorosalicylic acid and
2-nitro-4-(trifluoromethoxy)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1746] Yield: 40.9%.
[1747] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.33(3H, s), 7.05(1H, d,
J=8.8 Hz), 7.25(1H, dd, J=1.8, 8.8 Hz), 7.33(1H, d, J=1.8 Hz),
7.49(1H, dd, J=2.9, 8.8 Hz), 7.97-8.00(2H, m), 10.37(1H, s),
12.15(1H, s).
Example 467
Preparation of the Compound of Compound No. 467
[1748] Using 5-chlorosalicylic acid and 2,3,5-trifluoroaniline as
the raw materials, the same operation as the Example 16 gave the
title compound.
[1749] Yield: 54.2%.
[1750] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.06(1H, d, J=8.8 Hz),
7.28-7.37(1H, m), 7.51(1H, dd, J=2.6, 8.8 Hz), 7.92(1H, d, J=2.6
Hz), 7.98-8.04(1H, m), 10.93(1H, s), 12.27(1H, br.s)
Example 468
Preparation of the Compound of Compound No. 468
[1751] Using 5-chlorosalicylic acid and 4'-aminobenzo-15-crown-5 as
the raw materials, the same operation as the Example 16 gave the
title compound.
[1752] Yield: 45.1%.
[1753] .sup.1H-NMR(CDCl.sub.3):.delta. 3.74-3.77(8H, m),
3.90-3.92(4H, m), 4.10-4.15(4H, m), 6.83(1H, d, J=8.5 Hz),
6.96-6.99(2H, m), 7.24(1H, d, J=2.5 Hz), 7.36(1H, dd, J=2.5, 8.8
Hz), 7.53(1H, s), 8.06(1H, br.s), 11.92(1H, s).
Example 469
Preparation of the Compound of Compound No. 469
[1754] Using 5-chlorosalicylic acid and 4-bromo-2-fluoroaniline as
the raw materials, the same operation as the Example 16 gave the
title compound.
[1755] Yield: 45.1%.
[1756] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.05(1H, d, J=8.8 Hz),
7.43-7.53(2H, m), 7.64-7.71(1H, m), 7.94(1H, d, J=1.5 Hz), 8.20(1H,
dd, J=8.4, 8.8 Hz), 10.70(1H, s), 12.16(1H, s).
Example 470
Preparation of the Compound of Compound No. 470
[1757] Using 5-chlorosalicylic acid and
2,4-bis(methanesulfonyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1758] Yield: 7.2%.
[1759] .sup.1H-NMR(CDCl.sub.3):.delta. 3.13(3H, s), 3.21(3H, s),
7.04(1H, d, J=8.9 Hz), 7.48(1H, dd, J=2.2, 8.9 Hz), 7.62(1H, d,
J=2.2 Hz), 8.24(1H, dd, J=2.4, 9.0 Hz), 8.56(1H, d, J=2.4 Hz),
8.91(1H, d, J=8.9 Hz), 10.96(1H, s), 11.57(1H, s).
Example 471
Preparation of the Compound of Compound No. 471
[1760] A mixture of 5-chlorosalicylic acid (87 mg, 0.5 mmol),
2,2-bis(3-amino-4-methylphenyl)-1,1,1,3,3,3-hexafluoropropane (363
mg, 1 mmol), phosphorus trichloride (44 .mu.L, 0.5 mmol) and
toluene (4 mL) was refluxed for 4 hours. After the reaction mixture
was cooled to room temperature, it was purified by column
chromatography on silica gel (n-hexane:ethyl acetate=5:1) to give
the white title compound (16 mg, 4.9%). (The compound of Compound
No. 529 described in the following Example 529 was obtained as a
by-product.)
[1761] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.34(6H, s), 7.04(4H, d,
J=8.8 Hz), 7.39(2H, d, J=8.4 Hz), 7.48(2H, dd, J=2.9, 8.8 Hz),
7.96(2H, d, J=2.9 Hz), 8.19(2H, s), 10.44(2H, s), 12.17(2H, s).
Example 472
Preparation of the Compound of Compound No. 472
[1762] Using 5-chlorosalicylic acid and
6-amino-2,2,3,3-tetrafluoro-2,3-dihydrobenzo-[1,4]dioxene as the
raw materials, the same operation as the Example 16 gave the title
compound.
[1763] Yield: 10.1%.
[1764] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.03(1H, d, J=8.8 Hz),
7.48(1H, dd, J=9.0, 2.7 Hz), 7.50(1H, d, J=9.0 Hz), 7.59(1H, dd,
J=8.8, 2.2 Hz), 7.86(1H, d, J=2.7 Hz), 7.92(1H, d, J=2.2 Hz),
10.59(1H, s), 11.55(1H, s).
Example 473
Preparation of the Compound of Compound No. 473
[1765] Using 5-chlorosalicylic acid and
2-amino-5-chlorobenzophenone as the raw materials, the same
operation as the Example 16 gave the title compound.
[1766] Yield: 27.6%.
[1767] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.96(1H, d, J=8.7 Hz),
7.43(1H, dd, J=8.7, 3.0 Hz), 7.49-7.56(3H, m), 7.64-7.75(5H, m),
8.21(1H, d, J=9.3 Hz), 11.21(1H, s), 11.83(1H, s).
Example 474
Preparation of the Compound of Compound No. 474
[1768] Using 5-chlorosalicylic acid and 2-bromo-4-fluoroaniline as
the raw materials, the same operation as the Example 16 gave the
title compound.
[1769] Yield: 77.1%.
[1770] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.07(1H, d, J=9.0 Hz),
7.31-7.38(1H, m), 7.51(1H, dd, J=9.0, 3.0 Hz), 7.72(1H, d, J=8.1,
3.0 Hz), 8.00(1H, d, J=3.0 Hz), 8.23(1H, dd, J=9.3, 5.4 Hz),
10.70(1H, s), 12.24(1H, s).
Example 475
Preparation of the Compound of Compound No. 475
[1771] Using 5-chlorosalicylic acid and 4-hexyloxyaniline as the
raw materials, the same operation as the Example 16 gave the title
compound.
[1772] Yield: 74.8%.
[1773] .sup.1H-NMR(DMSO-d.sub.6):.delta. 0.88(3H, t, J=6.6 Hz),
1.28-1.46(6H, m), 2.49-2.52(2H, m), 3.95(2H, t, J=6.6 Hz),
6.91-6.96(2H, m), 7.00(1H, d, J=8.8 Hz), 7.46(1H, dd, J=8.8, 2.9
Hz), 7.55-7.61(2H, m), 8.00(1H, d, J=2.9 Hz), 10.31(1H, s),
12.03(1H, s).
Example 476
Preparation of the Compound of Compound No. 476
[1774] Using 5-chlorosalicylic acid and
2,2-bis(3-aminophenyl)-1,1,1,3,3,3-hexafluoropropane as the raw
materials, the same operation as the Example 16 gave the title
compound.
[1775] Yield: 64.5%.
[1776] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.99(2H, d, J=8.8 Hz),
7.11(2H, d, J=8.0 Hz), 7.45(2H, dd, J=8.8, 2.6 Hz), 7.50(2H, t,
J=8.4 Hz), 7.86(2H, d, J=2, 6 Hz), 7.88-7.91(4H, m), 10.53(2H, s),
11.56(2H, s).
Example 477
Preparation of the Compound of Compound No. 477
[1777] Using 5-chlorosalicylic acid and 2,4,5-trichloroaniline as
the raw materials, the same operation as the Example 16 gave the
title compound.
[1778] Yield: 38.9%.
[1779] .sup.1H-NMR(CDCl.sub.3):.delta. 7.02(1H, d, J=8.6 Hz),
7.46(1H, d, J=8.6 Hz), 7.49(1H, s), 7.57(1H, s), 8.41(1H, br.s),
8.63(1H, s), 11.42(1H, s).
Example 478
Preparation of the Compound of Compound No. 478
[1780] Using 5-chlorosalicylic acid and 3-isopropylaniline as the
raw materials, the same operation as the Example 16 gave the title
compound.
[1781] Yield: 55.3%.
[1782] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.22(6H, d, 6.9 Hz),
2.76-2.94(1H, m), 7.01(1H, d, J=8.6 Hz), 7.04(1H, d, J=7.9 Hz),
7.29(1H, t, J=7.9 Hz), 7.47(1H, dd, J=8.6, 2.6 Hz), 7.54(1H, d,
J=7.9 Hz), 7.57(1H, s), 7.98(1H, d, J=2.6 Hz), 10.37(1H, s),
11.90(1H, brs).
Example 479
Preparation of the Compound of Compound No. 479
[1783] Using 5-chlorosalicylic acid and 4-aminobenzonitrile as the
raw materials, the same operation as the Example 16 gave the title
compound.
[1784] Yield: 45.6%.
[1785] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.03(1H, d, J=8.6 Hz),
7.47(1H, dd, J=8.6, 2.6 Hz), 7.83(1H, d, J=2.6 Hz), 7.84(2H, d,
J=8.9 Hz), 7.92(2H, d, J=8.9 Hz), 10.71(1H, s), 11.59(1H, brs).
Example 480
Preparation of the Compound of Compound No. 480
[1786] Using 5-chlorosalicylic acid and 3-aminobenzonitrile as the
raw materials, the same operation as the Example 16 gave the title
compound.
[1787] Yield: 97.1%.
[1788] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.03(1H, d, J=8.7 Hz),
7.48(1H, dd, J=9.0, 2.7 Hz), 7.56-7.63(2H, m), 7.88(1H, d, J=2.7
Hz), 7.95-8.02(1H, m), 8.20-8.21(1H, m), 10.62(1H, s), 11.57(1H,
s).
Example 481
Preparation of the Compound of Compound No. 481
[1789] Using 5-chlorosalicylic acid and 3,4-dimethoxyaniline as the
raw materials, the same operation as the Example 16 gave the title
compound.
[1790] Yield: 73.3%.
[1791] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.75(3H, s), 3.76(3H, s),
6.95(1H, d, J=8.7 Hz), 7.01(1H, d, J=9.0 Hz), 7.24(1H, dd, J=8.7,
2.7 Hz), 7.38(1H, d, J=2.1 Hz), 7.47(1H, dd, J=8.7, 2.7 Hz),
8.00(1H, d, J=2.4 Hz), 10.30(1H, s), 12.01(1H, s).
Example 482
Preparation of the Compound of Compound No. 482
[1792] Using 5-chlorosalicylic acid and 4-aminophenylacetic acid
ethyl ester as the raw materials, the same operation as the Example
16 gave the title compound.
[1793] Yield: 66.1%.
[1794] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.19(3H, t, J=7.5 Hz),
3.64(2H, s), 4.08(2H, q, J=7.2 Hz), 7.01(1H, d, J=8.7 Hz), 7.26(2H,
d, J=8.7 Hz), 7.47(1H, dd, J=8.7, 3.0 Hz), 7.64(1H, d, J=8.4 Hz),
7.96(1H, d, J=2.4 Hz), 10.40(1H, s), 11.87(1H, s).
Example 483
Preparation of the Compound of Compound No. 483
[1795] Using 5-chlorosalicylic acid and
3-[(trifluoromethyl)sulfanyl]aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1796] Yield: 67.1%.
[1797] .sup.1H-NMR(CDCl.sub.3):.delta. 7.01(1H, d, J=8.9 Hz),
7.42(1H, dd, J=8.9, 2.3 Hz), 7.47-7.53(2H, m), 7.51(1H, d, J=2.3
Hz), 7.76(1H, dt, J=7.6 Hz, 2.0 Hz), 7.88(1H, brs), 7.92(1H, s),
11.64(1H, s).
Example 484
Preparation of the Compound of Compound No. 484
[1798] Using 5-chlorosalicylic acid and
4-[(trifluoromethyl)sulfanyl]aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1799] Yield: 63.2%.
[1800] .sup.1H-NMR(CDCl.sub.3):.delta. 7.01(1H, d, J=8.9 Hz),
7.43(1H, dd, J=8.9, 2.3 Hz), 7.50(1H, d, J=2.3 Hz), 7.70(4H, s),
7.90(1H, brs), 11.60(1H, s).
Example 485
Preparation of the Compound of Compound No. 485
[1801] Using 5-chlorosalicylic acid and
4-(trifluoromethanesulfonyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1802] Yield: 38.7%.
[1803] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.04(1H, d, J=8.6 Hz),
7.49(1H, dd, J=8.6, 2.6 Hz), 7.80(1H, d, J=2.6 Hz), 8.12(2H, d,
J=9.4 Hz), 8.17(2H, d, J=9.4 Hz), 8.16(1H, s), 10.95(1H, s),
11.37(1H, brs).
Example 486
Preparation of the Compound of Compound No. 486
[1804] Using 5-chlorosalicylic acid and 3,4-difluoroaniline as the
raw materials, the same operation as the Example 16 gave the title
compound.
[1805] Yield: 75.4%.
[1806] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.02(1H, d, J=8.9 Hz),
7.39-7.51(3H, m), 7.85-7.93(2H, m), 10.51, (1H, s), 11.60(1H,
s).
Example 487
Preparation of the Compound of Compound No. 487
[1807] Using 5-chlorosalicylic acid and 3-ethynylaniline as the raw
materials, the same operation as the Example 16 gave the title
compound.
[1808] Yield: 35.8%.
[1809] .sup.1H-NMR(DMSO-d.sub.6):.delta. 4.22(1H, s), 7.02(1H, d,
J=8.6 Hz), 7.25(1H, d, J=7.6 Hz), 7.39(1H, t, J=7.6 Hz), 7.47(1H,
dd, J=8.6, 2.6 Hz), 7.70(1H, d, J=7.6 Hz), 7.89(1H, s), 7.91(1H, d,
J=2.6 Hz), 10.46(1H, s), 11.69(1H, brs).
Example 488
Preparation of the Compound of Compound No. 488
[1810] Using 5-chlorosalicylic acid and 4-(sec-butyl)aniline as the
raw materials, the same operation as the Example 16 gave the title
compound.
[1811] Yield: 40.1%.
[1812] .sup.1H-NMR(DMSO-d.sub.6):.delta. 0.77(3H, t, 7.4 Hz),
1.19(3H, d, 6.9 Hz), 1.50-1.61(2H, m), 2.52-2.62(1H, m), 7.01(1H,
d, J=8.9 Hz), 7.20(2H, d, J=8.6 Hz), 7.47(1H, dd, J=8.9, 2.6 Hz),
7.60(2H, d, J=8.6 Hz), 7.98(1H, d, J=2.6 Hz), 10.36(1H, s),
11.94(1H, brs).
Example 489
Preparation of the Compound of Compound No. 489
[1813] Using 5-chlorosalicylic acid and 3-chloro-4-methoxyaniline
as the raw materials, the same operation as the Example 16 gave the
title compound.
[1814] Yield: 75.7%.
[1815] .sup.1H-NMR(CDCl.sub.3):.delta. 6.98(2H, t, J=9.2 Hz),
7.38-7.44(2H, m), 7.47(1H, d, J=2.6 Hz), 7.66(1H, d, J=2.6 Hz),
7.73(1H, br.s), 11.81(1H, s).
Example 490
Preparation of the Compound of Compound No. 490
[1816] Using 5-chlorosalicylic acid and 3-aminobenzophenone as the
raw materials, the same operation as the Example 16 gave the title
compound.
[1817] Yield: 34.3%.
[1818] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.02(1H, d, J=8.6 Hz),
7.48(1H, dd, J=9.1, 2.6 Hz), 7.52-7.62(4H, m), 7.68-7.79(3H, m),
7.93(1H, d, J=2.6 Hz), 8.02(1H, d, J=7.9 Hz), 8.16(1H, s),
10.60(1H, s), 11.68(1H, brs).
Example 491
Preparation of the Compound of Compound No. 491
[1819] Using 5-chlorosalicylic acid and 3-methoxyaniline as the raw
materials, the same operation as the Example 16 gave the title
compound.
[1820] Yield: 23.5%.
[1821] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.76(3H, s), 6.69-6.75(1H,
m), 7.01(1H, d, J=8.6 Hz), 7.25-7.28(2H, m), 7.39(1H, s), 7.47(1H,
dd, J=8.6, 2.6 Hz), 7.94(1H, d, J=2.6 Hz), 10.39(1H, s), 11.81(1H,
brs).
Example 492
Preparation of the Compound of Compound No. 492
[1822] Using 5-chlorosalicylic acid and 4'-aminoacetanilide as the
raw materials, the same operation as the Example 16 gave the title
compound.
[1823] Yield: 36.2%.
[1824] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.50(3H, s), 7.01(1H, d,
J=8.6 Hz), 7.47(1H, dd, J=8.6, 2.6 Hz), 7.57(2H, d, J=9.1 Hz),
7.61(2H, d, J=9.1 Hz), 7.98(1H, d, J=2.6 Hz), 9.95(1H, s),
10.38(1H, s), 11.99(1H, brs).
Example 493
Preparation of the Compound of Compound No. 493
[1825] Using 5-chlorosalicylic acid and sulfanilamide as the raw
materials, the same operation as the Example 16 gave the title
compound.
[1826] Yield: 25.7%.
[1827] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.03(1H, d, J=8.9 Hz),
7.31(2H, s), 7.47(1H, dd, J=8.9, 2.3 Hz), 7.81(2H, d, J=8.9 Hz),
7.89(2H, d, J=8.9 Hz), 7.89(1H, d, J=2.3 Hz), 10.70(1H, s),
11.55(1H, brs).
Example 494
Preparation of the Compound of Compound No. 494
[1828] Using 5-chlorosalicylic acid and
2-(4-aminophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol as the raw
materials, the same operation as the Example 16 gave the title
compound. (The compound was obtained by separation from the mixture
with the compound of Compound No. 498 described in the following
Example 498.)
[1829] Yield: 11.7%.
[1830] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.02(1H, d, J=8.6 Hz),
7.47(1H, dd, J=8.6, 2.6 Hz), 7.68(2H, d, J=8.7 Hz), 7.85(2H, d,
J=8.7 Hz), 7.91(1H, d, J=2.6 Hz), 8.69(1H, s), 10.62(1H, s).
Example 495
Preparation of the Compound of Compound No. 495
[1831] Using 5-chlorosalicylic acid and 2-chloro-4-nitroaniline as
the raw materials, the same operation as the Example 16 gave the
title compound.
[1832] Yield: 39.6%.
[1833] .sup.1H-NMR(CDCl.sub.3):.delta. 7.04(1H, d, J=8.9 Hz),
7.47(1H, dd, J=2.3, 8.9 Hz), 7.54(1H, d, J=2.3 Hz), 8.25(1H, dd,
J=2.6, 8.9 Hz), 8.39(1H, d, J=2.3 Hz), 8.73(1H, d, J=9.2 Hz),
8.76(1H, br.s), 11.22(1H, s).
Example 496
Preparation of the Compound of Compound No. 496
[1834] Using 5-chlorosalicylic acid and 2,4-difluoroaniline as the
raw materials, the same operation as the Example 16 gave the title
compound.
[1835] Yield: 67.8%.
[1836] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.05(1H, dd, J=1.7, 8.9
Hz), 7.15(1H, dt, J=1.7, 9.2 Hz), 7.41(1H, ddd, J=2.3, 8.9, 9.2
Hz), 7.51(1H, dt, J=2.3, 8.9 Hz), 7.98(1H, d, J=2.3 Hz), 8.11(1H,
dd, J=8.9, 15.1 Hz), 10.59(1H, s), 12.13(1H, s).
Example 497
Preparation of the Compound of Compound No. 497
[1837] Using 5-chlorosalicylic acid and 4-(difluoromethoxy)aniline
as the raw materials, the same operation as the Example 16 gave the
title compound.
[1838] Yield: 85.9%.
[1839] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.01(1H, d, J=8.6 Hz),
7.19(1H, t, J=74.2 Hz), 7.20(2H, d, J=8.6 Hz), 7.47(1H, dd, J=8.6,
2.6 Hz), 7.74(2H, d, J=8.9 Hz), 7.94(1H, d, J=2.6 Hz), 10.47(1H,
s), 11.80(1H, brs).
Example 498
Preparation of the Compound of Compound No. 498
[1840] This compound was obtained by separation from the mixture
with the compound of Compound No. 494 described in the
aforementioned Example 494.
[1841] Yield: 11.6%.
[1842] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.02(1H, d, J=8.6 Hz),
7.46(1H, dd, J=8.6, 2.3 Hz), 7.83(2H, d, J=8.1 Hz), 7.88(1H, d,
J=2.3 Hz), 7.95(2H, d, J=8.1 Hz), 10.71(1H, s).
Example 499
Preparation of the Compound of Compound No. 499
[1843] Using 5-chlorosalicylic acid and 3-(methylsulfanyl)aniline
as the raw materials, the same operation as the Example 16 gave the
title compound.
[1844] Yield: 67.2%.
[1845] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.49(3H, s), 7.00-7.05(1H,
m), 7.01(1H, d, J=8.9 Hz), 7.31(1H, t, J=7.9 Hz), 7.46(1H, dd,
J=8.9, 2.6 Hz), 7.44-7.49(1H, m), 7.68(1H, d, J=1.7 Hz), 7.93(1H,
d, J=2.6 Hz), 10.47(1H, s).
Example 500
Preparation of the Compound of Compound No. 500
[1846] Using 5-chlorosalicylic acid and 4-methanesulfonylaniline as
the raw materials, the same operation as the Example 16 gave the
title compound.
[1847] Yield: 28.6%.
[1848] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.20(3H, s), 7.03(1H, d,
J=8.3 Hz), 7.48(1H, dd, J=8.3, 2.6 Hz), 7.87(1H, d, J=2.6 Hz),
7.92(2H, d, J=8.9 Hz), 7.98(2H, d, J=8.9 Hz), 10.75(1H, s),
11.45(1H, brs).
Example 501
Preparation of the Compound of Compound No. 501
[1849] Using 5-chlorosalicylic acid and
2-amino-4-methylbenzophenone as the raw materials, the same
operation as the Example 16 gave the title compound.
[1850] Yield: 8.7%.
[1851] .sup.1H-NMR(CDCl.sub.3):.delta. 2.50(3H, s), 6.98(1H, d,
J=8.3 Hz), 6.99(1H, d, J=7.3 Hz), 7.39(1H, dd, J=2.0, 8.6 Hz),
7.48-7.64(4H, m), 7.72(2H, d, J=7.6 Hz), 7.83(1H, d, J=2.3 Hz),
8.57(1H, s), 12.18(1H, s), 12.34(1H, br.s).
Example 502
Preparation of the Compound of Compound No. 502
[1852] Using 5-chlorosalicylic acid and
3-amino-N-butylbenzenesulfonamide as the raw materials, the same
operation as the Example 16 gave the title compound.
[1853] Yield: 46.7%.
[1854] .sup.1H-NMR(DMSO-d.sub.6):.delta. 0.80(3H, t, J=7.3 Hz),
1.17-1.41(4H, m), 2.73-2.80(2H, m), 7.03(1H, d, J=8.9 Hz), 7.48(1H,
dd, J=8.9, 2.0 Hz), 7.53-7.64(2H, m), 7.87-7.92(1H, m), 7.92(1H, d,
J=2.0 Hz), 8.27(1H, s), 10.62(1H, s), 11.63(1H, s).
Example 503
Preparation of the Compound of Compound No. 503
[1855] Using 5-chlorosalicylic acid and 3-(benzyloxy)aniline as the
raw materials, the same operation as the Example 16 gave the title
compound.
[1856] Yield: 68.5%.
[1857] .sup.1H-NMR(DMSO-d.sub.6):.delta. 5.11(2H, s), 6.79-6.83(1H,
m), 7.01(1H, d, J=8.9 Hz), 7.27-7.49(9H, m), 7.93(1H, d, J=3.0 Hz),
10.40(1H, s), 11.79(1H, brs).
Example 504
Preparation of the Compound of Compound No. 504
[1858] Using 5-chlorosalicylic acid and
N-(4-aminophenyl)-4-methylbenzenesulfonamide as the raw materials,
the same operation as the Example 16 gave the title compound.
[1859] Yield: 40.6%.
[1860] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.33(3H, s), 6.99(1H, d,
J=8.6 Hz), 7.07(2H, d, J=8.6 Hz), 7.34(2H, d, J=8.3 Hz), 7.45(1H,
dd, J=8.6, 2.1 Hz), 7.53(2H, d, J=8.6 Hz), 7.63(2H, d, J=8.3 Hz),
7.90(1H, d, J=2.1 Hz), 10.14(1H, s), 10.33(1H, s), 11.81(1H,
brs).
Example 505
Preparation of the Compound of Compound No. 505
[1861] Using 5-chlorosalicylic acid and 4-(morpholino)aniline as
the raw materials, the same operation as the Example 16 gave the
title compound.
[1862] Yield: 29.8%.
[1863] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.09(4H, t, J=4.6 Hz),
3.74(4H, t, J=4.6 Hz), 6.94-7.01(3H, m), 7.46(1H, dd, J=8.9, 2.6
Hz), 7.55(2H, d, J=8.9 Hz), 8.01(1H, d, J=2.6 Hz), 10.29(1H, s),
12.10(1H, brs).
Example 506
Preparation of the Compound of Compound No. 506
[1864] Using 5-chlorosalicylic acid and 3-(tert-butyl)aniline as
the raw materials, the same operation as the Example 16 gave the
title compound.
[1865] Yield: 76.1%.
[1866] .sup.1H-NMR(CDCl.sub.3):.delta. 1.35(9H, s), 6.99(1H, d,
J=8.9 Hz), 7.24-7.28(1H, m), 7.32-7.35(1H, m), 7.40(1H, dd, J=8.9,
2.3 Hz), 7.46-7.50(2H, m), 7.51(1H, d, J=2.3 Hz), 7.81(1H, brs),
11.94(1H, s).
Example 507
Preparation of the Compound of Compound No. 507
[1867] Using 5-chlorosalicylic acid and
3-(5-methylfuran-2-yl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1868] Yield: 61.1%.
[1869] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.36(3H, s), 6.22-6.23(1H,
m), 6.81(1H, d, J=3.0 Hz), 7.02(1H, d, J=8.9 Hz), 7.36-7.51(3H, m),
7.58-7.61(1H, m), 7.99-8.01(2H, m), 10.49(1H, s), 11.85(1H,
brs).
Example 508
Preparation of the Compound of Compound No. 508
[1870] Using 5-chlorosalicylic acid and 3-(1-hydroxyethyl)aniline
as the raw materials, the same operation as the Example 16 gave the
title compound.
[1871] Yield: 37.6%.
[1872] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.80(3H, d, J=6.6 Hz),
5.33(1H, q, J=6.6 Hz), 7.01(1H, d, J=8.9 Hz), 7.25(1H, d, J=7.9
Hz), 7.38(1H, t, J=7.9 Hz), 7.47(1H, dd, J=8.9, 2.3 Hz), 7.65(1H,
d, J=7.9 Hz), 7.85(1H, s), 7.96(1H, d, J=2.3 Hz), 10.48(1H, s),
11.80(1H, brs).
Example 509
Preparation of the Compound of Compound No. 509
[1873] Using 5-chlorosalicylic acid and 3-aminobenzenesulfonamide
as the raw materials, the same operation as the Example 16 gave the
title compound.
[1874] Yield: 18.7%.
[1875] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.03(1H, d, J=8.9 Hz),
7.41(2H, s), 7.48(1H, dd, J=8.9, 2.6 Hz), 7.54-7.62(2H, m),
7.84-7.88(1H, m), 7.93(1H, d, J=2.6 Hz), 8.30(1H, s), 10.64(1H, s),
11.68(1H, brs).
Example 510
Preparation of the Compound of Compound No. 510
[1876] Using 5-chlorosalicylic acid and
3-(trifluoromethanesulfonyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1877] Yield: 62.6%.
[1878] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.03(1H, d, J=8.6 Hz),
7.48(1H, dd, J=8.6, 2.6 Hz), 7.82-7.88(3H, m), 8.23-8.26(1H, m),
8.67(1H, s), 10.88(1H, s), 11.45(1H, brs).
Example 511
Preparation of the Compound of Compound No. 511
[1879] Using 5-chlorosalicylic acid and
2-bromo-4-(trifluoromethoxy)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1880] Yield: 17.1%.
[1881] .sup.1H-NMR(CDCl.sub.3):.delta. 7.02(1H, d, J=8.9 Hz),
7.26-7.31(1H, m), 7.44(1H, dd, J=8.9, 2.6 Hz), 7.53(2H, d, J=2.6
Hz), 8.41(1H, brs), 8.42(1H, d, J=8.9 Hz), 11.57(1H, s).
Example 512
Preparation of the Compound of Compound No. 512
[1882] Using 5-chlorosalicylic acid and 3,4-(dihexyloxy)aniline as
the raw materials, the same operation as the Example 16 gave the
title compound.
[1883] Yield: 60.5%.
[1884] .sup.1H-NMR(CDCl.sub.3):.delta. 0.91(6H, t, J=6.3 Hz),
1.34-1.61(12H, m), 1.76-1.89(4H, m), 3.97-4.04(4H, m), 6.88(1H, d,
J=8.9 Hz), 6.97-7.00(2H, m), 7.22(1H, d, J=2.6 Hz), 7.38(1H, dd,
J=8.9, 2.6 Hz), 7.47(1H, d, J=2.6 Hz), 7.73(1H, s), 11.97(1H,
s).
Example 513
Preparation of the Compound of Compound No. 513
[1885] Using 5-chlorosalicylic acid and 3,4-dichloroaniline as the
raw materials, the same operation as the Example 16 gave the title
compound.
[1886] Yield: 16.4%.
[1887] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.03(1H, d, J=8.7 Hz),
77.47(1H, dd, J=8.7, 2.7 Hz), 7.61-7.70(2H, m), 7.86(1H, d, J=2.7
Hz), 8.11(1H, d, J=2.1 Hz), 10.56(1H, s), 11.53(1H, s).
Example 514
Preparation of the Compound of Compound No. 514
[1888] Using 5-chlorosalicylic acid and 3-hexyloxyaniline as the
raw materials, the same operation as the Example 16 gave the title
compound.
[1889] Yield: 88.2%.
[1890] .sup.1H-NMR(DMSO-d.sub.6):.delta. 0.89(3H, t, J=7.0 Hz),
1.28-1.47(6H, m), 1.67-1.76(2H, m), 3.95(2H, t, J=6.6 Hz),
6.69-6.73(1H, m), 7.01(1H, d, J=8.8 Hz), 7.21-7.28(2H, m),
7.39-7.40(1H, m), 7.67(1H, dd, J=8.8, 2.6 Hz), 7.94(1H, d, J=2.6
Hz), 10.34(1H, s), 11.80(1H, s).
Example 515
Preparation of the Compound of Compound No. 515
[1891] Using 5-chlorosalicylic acid and
5-ethoxy-4-fluoro-2-nitroaniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1892] Yield: 20.2%.
[1893] .sup.1H-NMR(DMSO-d.sub.6):.delta. 1.43(3H, t, J=7.0 Hz),
4.27(2H, q, J=7.0 Hz), 7.07(1H, d, J=8.8 Hz), 7.52(1H, dd, J=8.8,
2.9 Hz), 7.95(1H, d, J=2.9 Hz), 8.15(1H, d, J=11.4 Hz), 8.57(1H, d,
J=8.4 Hz), 12.16(1H, s), 12.26(1H, s).
Example 516
Preparation of the Compound of Compound No. 516
[1894] Using 5-chlorosalicylic acid and
4-hydroxy-3-methyl-1-naphthylamine as the raw materials, the same
operation as the Example 16 gave the title compound.
[1895] Yield: 5.9%.
[1896] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.38(3H, s), 7.03(1H, d,
J=9.3 Hz), 7.43(2H, s), 7.46(1H, d, J=2.4 Hz), 7.50-7.54(2H, m),
7.67(1H, d, J=2.1 Hz), 7.78(1H, dd, J=6.0, 2.7 Hz), 8.03(1H, brs),
8.18(1H, dd, J=6.0, 3.6 Hz), 11.98(1H, brs).
Example 517
Preparation of the Compound of Compound No. 517
[1897] This compound is a known compound.
Reference which describes the preparation method: the pamphlet of
International Publication WO99/65449.
Example 518
Preparation of the Compound of Compound No. 518
[1898] This compound is a known compound.
Reference which describes the preparation method: the pamphlet of
International Publication WO99/65449.
Example 519
Preparation of the Compound of Compound No. 519
[1899] This compound is a known compound.
Reference which describes the preparation method: the pamphlet of
International Publication WO99/65449.
Example 520
Preparation of the Compound of Compound No. 520
[1900] This compound is a known compound.
Reference which describes the preparation method: the pamphlet of
International Publication WO99/65449.
Example 521
Preparation of the Compound of Compound No. 521
[1901] This compound is a known compound.
Reference which describes the preparation method: the pamphlet of
International Publication WO99/65449.
Example 522
Preparation of the Compound of Compound No. 522
[1902] This compound is a known compound.
Reference which describes the preparation method: the pamphlet of
International Publication WO99/65449.
Example 523
Preparation of the Compound of Compound No. 523
[1903] This compound is a known compound.
Reference which describes the preparation method: the pamphlet of
International Publication WO99/65449.
Example 524
Preparation of the Compound of Compound No. 524
[1904] Using 5-chlorosalicylic acid and 4-aminobiphenyl as the raw
materials, the same operation as the Example 16 gave the title
compound.
[1905] Yield: 52.4%.
[1906] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.03(1H, d, J=8.7 Hz),
7.33-7.38(1H, m), 7.44-7.51(3H, m), 7.67-7.72(4H, m), 7.82(2H, d,
J=8.7 Hz), 7.98(1H, d, J=2.4 Hz), 10.49(1H, s), 11.84(1H, s).
Example 525
Preparation of the Compound of Compound No. 525
[1907] A mixture of 5-sulfosalicylic acid (218 mg, 1 mmol),
3,5-bis(trifluoromethyl)aniline (229 mg, 1 mmol), phosphorus
trichloride (88 .mu.L, 1 mmol) and o-xylene (5 mL) was refluxed for
3 hours. After the reaction mixture was cooled to room temperature,
it was purified by column chromatography on silica gel
(n-hexane:ethyl acetate=3:1) to give the title compound (29 mg,
9.2%) as a white solid.
[1908] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.15(1H, d, J=8.8 Hz),
7.65(2H, s), 7.73(1H, s), 7.81(1H, s), 7.82(1H, dd, J=8.7, 2.5 Hz),
8.23(1H, d, J=2.5 Hz), 8.38(2H, s), 10.87(1H, s), 11.15(1H,
brs).
Example 526
Preparation of the Compound of Compound No. 526
[1909] Using 5-chlorosalicylic acid and
2,4-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1910] Yield: 6.9%.
[1911] .sup.1H-NMR(CDCl.sub.3):.delta. 7.03(1H, dd, J=8.7, 0.6 Hz),
7.43-7.48(2H, m), 7.91(1H, d, J=9.0 Hz), 7.96(1H, s), 8.42(1H, s),
8.49(1H, d, J=8.7 Hz), 11.26(1H, s).
Example 527
Preparation of the compound of Compound No. 527
[1912] Using 3-phenylsalicylic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1913] Yield: 64.6%.
[1914] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.12(1H, t, J=8.1 Hz),
7.37(1H, tt, J=7.5, 1.5 Hz), 7.43-7.48(2H, m), 7.56-7.60(3H, m),
7.91(1H, s), 8.07, (1H, dd, J=8.1, 1.5 Hz), 8.48(2H, s), 11.00(1H,
s), 12.16(1H, s).
Example 528
Preparation of the Compound of Compound No. 528
[1915] Using 4-fluorosalicylic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1916] Yield: 65.7%.
[1917] .sup.1H-NMR(DMSO-d.sub.6):.delta. 6.81-6.90(2H, m), 7.84(1H,
s), 7.93-7.98(1H, m), 8.45(2H, s), 10.78(1H, s), 11.81(1H, s).
Example 529
Preparation of the Compound of Compound No. 529
[1918] This compound was obtained by separation from the mixture
with the compound of Compound No. 471 described in the
aforementioned Example 471.
[1919] Yield: 9.4%.
[1920] .sup.1H-NMR(CD.sub.3OD):.delta. 2.16(3H, s), 2.34(3H, s),
6.69(1H, d, J=8.2 Hz), 6.76(1H, brs) 6.95(1H, d, J=8.8 Hz),
7.02(1H, d, J=8.0 Hz), 7.15(1H, d, J=8.2 Hz), 7.29(1H, d, J=8.2
Hz), 7.37(1H, dd, J=8.8, 2.6 Hz), 7.97(1H, d, J=2.6 Hz), 7.98(1H,
s).
Example 530
Preparation of the Compound of Compound No. 530
[1921] Using 5-chlorosalicylic acid and
4-amino-3-(trifluoromethoxy)benzonitrile as the raw materials, the
same operation as the Example 16 gave the title compound.
[1922] Yield: 75.2%.
[1923] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.13(1H, d, J=8.8 Hz),
7.54(1H, dd, J=8.8, 2.6 Hz), 7.94(1H, dd, J=8.4, 1.6 Hz), 7.95(1H,
d, J=2.6 Hz), 8.15(1H, t, J=1.5 Hz), 8.75(1H, d, J=8.8 Hz),
11.25(1H, s), 12.45(1H, s).
Example 531
Preparation of the Compound of Compound No. 531
[1924] Using 5-chlorosalicylic acid and
4-[2-amino-4-(trifluoromethyl)phenoxy]benzonitrile as the raw
materials, the same operation as the Example 16 gave the title
compound.
[1925] Yield: 11.6%.
[1926] .sup.1H-NMR(CD.sub.3OD):.delta. 6.88(1H, d, J=8.6 Hz),
7.19(2H, d, J=8.9 Hz), 7.24(1H, d, J=8.6 Hz), 7.33(1H, dd, J=8.8,
2.8 Hz), 7.46(1H, dd, J=8.9, 1.9 Hz), 7.76(2H, d, J=8.9 Hz),
7.98(1H, d, J=2.7 Hz), 8.96(1H, s).
Example 532
Preparation of the Compound of Compound No. 532
[1927] Using 5-chlorosalicylic acid and
3-amino-4-(4-methoxyphenoxy)-benzotrifluoride as the raw materials,
the same operation as the Example 16 gave the title compound.
[1928] Yield: 88.1%.
[1929] .sup.1H-NMR(CDCl.sub.3):.delta. 3.85(3H, s) 6.81(1H, d,
J=8.5 Hz), 6.97-7.02(3H, m), 7.08(2H, d, J=8.8 Hz), 7.30(1H, m),
7.40(1H, dd, J=8.8, 1.9 Hz), 7.45(1H, d, J=2.2 Hz), 8.70(1H, s),
8.78(1H, d, J=1.6 Hz), 11.76(1H, s).
Example 533
Preparation of the Compound of Compound No. 533
[1930] Using salicylic acid and 2,5-bis(trifluoromethyl)aniline as
the raw materials, the same operation as the Example 16 gave the
title compound.
[1931] Yield: 47.8%.
[1932] .sup.1H-NMR(CD.sub.3OD):.delta. 7.00-7.06(2H, m), 7.48(1H,
dt, J=1.5, 7.5 Hz), 7.74(1H, d, J=8.4 Hz), 8.01-8.08(2H, m),
8.79(1H, s), 11.09(1H, s), 12.03(1H, s).
Example 534
Preparation of the Compound of Compound No. 534
(1) 2-Amino-4-(2,4-dichlorophenyl)thiazole
[1933] Using 2',4'-dichloroacetophenone and thiourea as the raw
materials, the same operation as the Example 395(1) gave the title
compound.
[1934] Yield: 97.1%.
[1935] .sup.1H-NMR(CDCl.sub.3):.delta. 5.01(2H, s), 7.09(1H, s),
7.28(1H, dd, J=8.4, 2.1 Hz), 7.45(1H, d, J=2.1 Hz), 7.82(1H, d,
J=8.4 Hz).
(2)
5-Chloro-2-hydroxy-N-[4-(2,4-dichlorophenyl)thiazol-2-yl]benzamide
(Compound No. 534)
[1936] Using 5-chlorosalicylic acid and
2-amino-4-(2,4-dichlorophenyl)thiazole as the raw materials, the
same operation as the Example 16 gave the title compound.
[1937] Yield: 8.0%.
[1938] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.08(1H, d, J=8.7 Hz),
7.50-7.55(2H, m), 7.72-7.76(2H, m), 7.91(1H, d, J=8.4 Hz), 7.95(1H,
d, J=2.4 Hz), 11.87(1H, brs), 12.09(1H, brs).
Example 535
Preparation of the Compound of Compound No. 535
[1939] Using 3-isopropylsalicylic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[1940] Yield: 99.2%.
[1941] .sup.1H-NMR(CDCl.sub.3):.delta. 1.26(6H, d, J=6.9 Hz),
3.44(1H, Hept, J=6.9 Hz), 6.92(1H, t, J=7.8 Hz), 7.38(1H, dd,
J=8.1, 1.2 Hz), 7.44(1H, d, J=7.5 Hz), 7.69(1H, s), 8.13(3H, s),
11.88(1H, s).
Example 536
Preparation of the Compound of Compound No. 536
[1942] Bromine (14.4 .mu.L, 0.28 mmol) and iron powder (1.7 mg,
0.03 mmol) were added to a solution of
N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-3-isopropylbenzamide
(Compound No. 535; 100 mg, 0.26 mmol) in carbon tetrachloride (5
mL) under argon atmosphere, and the mixture was stirred at room
temperature for 2 hours. The reaction mixture was diluted with
ethyl acetate. The ethyl acetate layer was washed with water and
brine, and dried over anhydrous magnesium sulfate. The residue
obtained by evaporation of the solvent under reduced pressure was
crystallized from n-hexane/ethyl acetate to give the title compound
(110 mg, 91.5%) as a white solid.
[1943] .sup.1H-NMR(CDCl.sub.3):.delta. 1.25(6H, d, J=6.9 Hz),
3.39(1H, Hept, J=6.9 Hz), 7.49-7.51(2H, m), 7.71(1H, brs),
8.11-8.14(3H, m), 11.81(1H, brs).
Example 537
Preparation of the Compound of Compound No. 537
[1944] N-Bromosuccinimide (88.2 mg, 0.50 mmol) was added to a
solution of
N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-3-methylbenzamide
(Compound No. 328; 150 mg, 0.41 mmol) in a mixed solvent of
methanol/water (3:1; 5 mL), and the mixture was stirred at room
temperature for 10 minutes. The reaction mixture was diluted with
ethyl acetate. The ethyl acetate layer was washed with 10% aqueous
sodium thiosulfate, water and brine, and dried over anhydrous
magnesium sulfate. The residue obtained by evaporation under
reduced pressure was purified by column chromatography on silica
gel (n-hexane:ethyl acetate=5:1) to give the title compound (167
mg, 91.5%) as a white powder.
[1945] .sup.1H-NMR(CDCl.sub.3):.delta. 2.28(3H, s), 7.47(1H, s),
7.50(1H, d, J=2.4 Hz), 7.71(1H, s), 8.08(1H, brs), 8.13(2H, s),
11.71(1H, s).
Example 538
Preparation of the Compound of Compound No. 538
(1) 1-(3-Nitrophenyl)-5-phenyl-3-(trifluoromethyl)pyrazole
[1946] A mixture of 4,4,4-trifluoro-1-phenyl-1,3-butanedione (432.3
mg, 2 mmol), 3-nitrophenylhydrazine hydrochloride (379.2 mg, 2
mmol), concentrated hydrochloric acid (0.2 mL) and ethanol (8 mL)
was reflued for 2 hours. After the reaction mixture was cooled to
room temperature, it was poured into water and extracted with ethyl
acetate. The ethyl acetate layer was washed with water and brine,
and dried over anhydrous sodium sulfate. The residue obtained by
evaporation under reduced pressure was purified by column
chromatography on silica gel (n-hexane:ethyl
acetate=4:1.fwdarw.3:1) to give the title compound (631.5 mg,
94.7%) as a light yellowish white powder.
[1947] .sup.1H-NMR(CDCl.sub.3):.delta. 6.80(1H, s), 7.23-7.26(2H,
m), 7.35-7.45(3H, m), 7.54(1H, t, J=8.4 Hz), 7.63(1H, ddd, J=8.1,
1.8, 1.2 Hz), 8.19-8.25(2H, m).
(2) 1-(3-Aminophenyl)-5-phenyl-3-(trifluoromethyl)pyrazole
[1948] Acetic acid (3 mL) and ethanol (2 mL) were added to
1-(3-nitrophenyl)-5-phenyl-3-(trifluoromethyl)pyrazole (0.59 g,
1.77 mmol) and 5% palladium on carbon (0.06 g), and the mixture was
hydrogenated at room temperature for 2 hours under hydrogen
atmosphere. After the insoluble matter was filtered off, the
residue obtained by evaporation under reduced pressure was purified
by column chromatography on silica gel (n-hexane:ethyl acetate=2:1)
to give the title compound (491.1 mg, 91.4%) as a white solid.
[1949] .sup.1H-NMR(CDCl.sub.3):.delta. 3.78(2H, s), 6.54(1H, ddd,
J=7.8, 1.8, 0.6 Hz), 6.65(1H, ddd, J=8.4, 2.4, 0.9 Hz),
6.73-6.75(2H, m), 7.07(1H, t, J=8.1 Hz), 7.24-7.36(5H, m).
(3)
5-Chloro-2-hydroxy-N-{3-[5-phenyl-3-(trifluoromethyl)pyrazol-1-yl]phen-
yl}-benzamide (Compound No. 538).
[1950] Using 5-chlorosalicylic acid and
1-(3-aminophenyl)-5-phenyl-3-(trifluoromethyl)pyrazole as the raw
materials, the same operation as the Example 16 gave the title
compound.
[1951] Yield: 74.4%.
[1952] .sup.1H-NMR(CDCl.sub.3):.delta. 6.77(1H, s), 6.97-7.03(2H,
m), 7.27-7.45(8H, m), 7.65(1H, ddd, J=8.4, 2.1, 0.9 Hz), 7.74(1H,
t, J=2.1 Hz), 7.93(1H, s), 11.63(1H, s).
Example 539
Preparation of the Compound of Compound No. 539
(1)
5-(tert-Butyl)-1-(4-nitrophenyl)-3-(trifluoromethyl)pyrazole
[1953] Using 1,1,1-trifluoro-5,5-dimethyl-2,4-hexanedione and
4-nitrophenylhydrazine hydrochloride as the raw materials, the same
operation as the Example 538(1) gave the title compound.
[1954] Yield: 94.7%.
[1955] .sup.1H-NMR(CDCl.sub.3):.delta. 1.23(9H, s), 6.51(1H, s),
7.62(2H, d, J=9.0 Hz), 8.37(2H, d, J=9.0 Hz).
(2)
1-(4-Aminophenyl)-5-(tert-butyl)-3-(trifluoromethyl)pyrazole
[1956] Using
5-(tert-butyl)-1-(4-nitrophenyl)-3-(trifluoromethyl)pyrazole as the
raw material, the same operation as the Example 538(2) gave the
title compound.
[1957] Yield: 98.9%.
[1958] .sup.1H-NMR(CDCl.sub.3):.delta. 1.20(9H, s), 4.00(2H, br),
6.40(1H, s), 6.69(2H, d, J=8.7 Hz), 7.14(2H, d, J=9.0 Hz).
(3)
N-{4-[5-(tert-butyl)-3-(trifluoromethyl)pyrazol-1-yl]phenyl}-5-chloro--
2-hydroxy-benzamide (Compound No. 539).
[1959] Using 5-chlorosalicylic acid and
1-(5-aminophenyl)-5-(tert-butyl)-3-(trifluoromethyl)pyrazole as the
raw materials, the same operation as the Example 16 gave the title
compound.
[1960] Yield: 57.6%.
[1961] .sup.1H-NMR(CDCl.sub.3):.delta. 1.23(9H, s), 6.47(1H, s),
7.00(1H, d, J=9.0 Hz), 7.40-7.44(3H, m), 7.57(1H, d, J=2.4 Hz),
7.72(2H, d, J=8.7 Hz), 8.15(1H, s), 11.58(1H, s).
Example 540
Preparation of the Compound of Compound No. 540
[1962] Using
N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-3-phenylbenzamide
(Compound No. 527), the same operation as the Example 537 gave the
title compound.
[1963] Yield: 67.5%.
[1964] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.36-7.50(3H, m),
7.55-7.59(2H, m), 7.71(1H, d, J=2.1 Hz), 7.93(1H, brs), 8.28(1H, d,
J=2.1 Hz), 8.45(2H, s), 11.06(1H, brs), 12.16(1H, brs).
Example 541
Preparation of the Compound of Compound No. 541
(1) 2-Amino-4-(3,4-dichlorophenyl)thiazole
[1965] Using 3',4'-dichloroacetophenone and thiourea as the raw
materials, the same operation as the Example 395(1) gave the title
compound.
[1966] Yield: 77.8%.
[1967] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.17(2H, s), 7.24(1H, s),
7.62(1H, d, J=8.4 Hz), 7.78(1H, dd, J=8.7, 2.7 Hz), 8.22(1H, d,
J=2.4 Hz).
(2)
5-Chloro-2-hydroxy-N-[4-(3,4-dichlorophenyl)thiazol-2-yl]benzamide
(Compound No. 541)
[1968] Using 5-chlorosalicylic acid and
2-amino-4-(3,4-dichlorophenyl)thiazole as the raw materials, the
same operation as the Example 16 gave the title compound.
[1969] Yield: 15.1%.
[1970] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.08(1H, d, J=8.7 Hz),
7.52(1H, dd, J=8.7, 2.7 Hz), 7.71(1H, d, J=8.4 Hz), 7.91(1H, d,
J=1.8 Hz), 7.94(1H, s), 8.18(1H, d, J=1.5 Hz), 12.09(2H, bs).
Example 542
Preparation of the Compound of Compound No. 542
(1) 2-Amino-4-[4-(trifluoromethyl)phenyl]thiazole
[1971] Using 4'-(trifluoromethyl)acetophenone and thiourea as the
raw materials, the same operation as the Example 395(1) gave the
title compound.
[1972] Yield: 77.5%.
[1973] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.18(2H, s), 7.26(1H, s),
7.72(2H, d, J=8.4 Hz), 8.00(2H, d, J=8.1 Hz).
(2)
5-Chloro-2-hydroxy-N-{4-[4-(trifluoromethyl)phenyl]thiazol-2-yl}benzam-
ide (Compound No. 542).
[1974] Using 5-chlorosalicylic acid and
2-amino-4-[4-(trifluoromethyl)phenyl]thiazole as the raw materials,
the same operation as the Example 16 gave the title compound.
[1975] Yield: 16.0%.
[1976] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.09(1H, d, J=9.0 Hz),
7.53(1H, dd, J=8.7, 2.7 Hz), 7.81(2H, d, J=8.4 Hz), 7.96(1H, d,
J=2.4 Hz), 7.98(1H, s), 8.16(2H, d, J=8.1 Hz), 11.91(1H, bs),
12.13(1H, bs).
Example 543
Preparation of the Compound of Compound No. 543
(1)
2-Acetoxy-N-{4-[3,5-bis(trifluoromethyl)pyrazol-1-yl]phenyl}-5-chlorob-
enzamide
[1977] Using 2-acetoxy-5-chlorobenzoic acid and
1-(4-aminophenyl)-3,5-bis(trifluoromethyl)pyrazole as the raw
materials, the same operation as the Example 24 gave the title
compound.
[1978] Yield: 77.8%.
[1979] .sup.1H-NMR(CDCl.sub.3):.delta. 2.36(3H, s), 7.78(1H, s),
7.14(1H, d, J=8.7 Hz), 7.48-7.51(3H, m), 7.77(2H, d, J=9.0 Hz),
7.83(1H, d, J=2.7 Hz), 8.25(1H, s).
[1-(4-Aminophenyl)-3,5-bis(trifluoromethyl)pyrazole: Refer to
"Journal of Medicinal Chemistry", 2000, Vol. 43, No. 16, p.
2975-2981.]
(2)
N-{4-[3,5-Bis(trifluoromethyl)pyrazol-1-yl]phenyl}-5-chloro-2-hydroxyb-
enzamide (Compound No. 543).
[1980] Using
2-acetoxy-N-{4-[3,5-bis(trifluoromethyl)pyrazol-1-yl]phenyl}-5-chlorobenz-
amide as the raw material, the same operation as the Example 2(2)
gave the title compound.
[1981] Yield: 73.1%.
[1982] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.04(1H, d, J=8.7 Hz),
7.48(1H, dd, J=8.7, 2.7 Hz), 7.63(2H, d, J=8.7 Hz), 7.84(1H, s),
7.89(1H, d, J=3.0 Hz), 7.94(2H, d, J=9.0 Hz), 10.65(1H, s),
11.58(1H, s).
Example 544
Preparation of the Compound of Compound No. 544
(1) 3,5-Bis(trifluoromethyl)-1-(3-nitrophenyl)pyrazole
[1983] Using hexafluoroacetylacetone and 3-nitrophenylhydrazine
hydrochloride as the raw materials, the same operation as the
Example 538(1) gave the title compound.
[1984] Yield: 94.0%.
[1985] .sup.1H-NMR(CDCl.sub.3):.delta. 7.16(1H, s), 7.77(1H, dd,
J=8.7, 0.8.1 Hz), 7.88-7.91(1H, m), 8.42-8.45(2H, m).
(2) 1-(3-Aminophenyl)-3,5-bis(trifluoromethyl)pyrazole
[1986] Using 3,5-bis(trifluoromethyl)-1-(3-nitrophenyl)pyrazole as
the raw material, the same operation as the Example 538(2) gave the
title compound.
[1987] Yield: 73.1%.
[1988] .sup.1H-NMR(CDCl.sub.3):.delta. 3.89(2H, s), 6.77-6.87(3H,
m), 7.04(1H, s), 7.26(1H, t, J=8.7 Hz).
(3)
2-Acetoxy-N-{3-[3,5-bis(trifluoromethyl)pyrazol-1-yl]phenyl}-5-chlorob-
enzamide
[1989] Using 2-acetoxy-5-chlorobenzoic acid and
1-(3-aminophenyl)-3,5-bis(trifluoromethyl)pyrazole as the raw
materials, the same operation as the Example 24 gave the title
compound.
[1990] Yield: 84.4%.
[1991] .sup.1H-NMR(CDCl.sub.3):.delta. 2.33(3H, s), 7.09(1H, s),
7.11(1H, d, J=9.0 Hz), 7.30(1H, d, J=7.8 Hz), 7.45-7.52(2H, m),
7.67(1H, d, J=8.4 Hz), 7.78(1H, d, J=2.4 Hz), 7.95(1H, s), 8.29(1H,
s).
(4)
N-{3-[3,5-Bis(trifluoromethyl)pyrazol-1-yl]phenyl}-5-chloro-2-hydroxyb-
enzamide (Compound No. 544).
[1992] Using
2-acetoxy-N-{3-[3,5-bis(trifluoromethyl)pyrazol-1-yl]phenyl}-5-chlorobenz-
amide as the raw material, the same operation as the Example 2(2)
gave the title compound.
[1993] Yield: 69.9%.
[1994] .sup.1H-NMR(CDCl.sub.3):.delta. 7.01(1H, d, J=8.7 Hz),
7.10(1H, s), 7.34-7.37(1H, m), 7.42(1H, dd, J=8.7, 2.4 Hz),
7.50(1H, d, J=2.4 Hz), 7.56(1H, t, J=8.1 Hz), 7.69-7.73(1H, m),
7.95-7.98(2H, m), 11.57(1H, s).
Example 545
Preparation of the Compound of Compound No. 545
(1) Methyl 2-methoxy-4-phenylbenzoate
[1995] Dichlorobis(triphenylphosphine)palladium (29 mg, 0.04 mmol)
was added to a solution of methyl 4-chloro-2-methoxybenzoate (904
mg, 4.5 mmol), phenylboronic acid (500 mg, 4.1 mmol) and cesium
carbonate (2.7 g, 8.2 mmol) in N,N-dimethylformamide (15 mL) under
argon atmosphere, and the mixture was stirred at 120.degree. C. for
8 hours. After the reaction mixture was cooled to room temperature,
it was diluted with ethyl acetate. The ethyl acetate layer was
washed successively with water and brine, and dried over anhydrous
sodium sulfate. The residue obtained by evaporation of the solvent
under reduced pressure was purified by column chromatography on
silica gel (n-hexane:ethyl acetate=10:1) to give the title compound
(410 mg, 41.2%) as a colourless oil.
[1996] .sup.1H-NMR(CDCl.sub.3):.delta. 3.91(3H, s), 3.98(3H, s),
7.17(1H, d, J=1.5 Hz), 7.20(1H, dd, J=8.1, 1.5 Hz), 7.31-7.50(3H,
m), 7.59-7.63(2H, m), 7.89(1H, d, J=8.1 Hz).
(2) 2-Methoxy-4-phenylbenzoic acid
[1997] 2N Aqueous sodium hydroxide (5 mL) was added to a solution
of methyl 2-methoxy-4-phenylbenzoate (410 mg, 1.69 mmol) in
methanol (5 mL), and the mixture was refluxed for 1 hour. After the
reaction mixture was cooled to room temperature, the solvent was
evaporated under reduced pressure. 2N hydrochloric acid was added
to the obtained residue and the separated crystal was filtered to
give the title compound (371 mg, 96.0%) as a crude product.
[1998] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.93(3H, s), 7.29(1H, dd,
J=8.1, 1.5 Hz), 7.34(1H, d, J=1.5 Hz), 7.40-7.53(3H, m),
7.73-7.77(3H, m), 12.60(1H, s).
(3)
N-[3,5-Bis(trifluoromethyl)phenyl]-2-methoxy-4-phenylbenzamide
[1999] Using 2-methoxy-4-phenylbenzoic acid and
3,5-bis(trifluoromethyl)aniline as the raw materials, the same
operation as the Example 16 gave the title compound.
[2000] Yield: 97.5%.
[2001] .sup.1H-NMR(CDCl.sub.3):.delta. 4.19(3H, s), 7.25(1H, m),
7.38-7.53(4H, m), 7.62-7.65(3H, m), 8.12(2H, s), 8.35(1H, d, J=8.1
Hz), 10.15(1H, brs).
(4) N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-4-phenylbenzamide
(Compound No. 545)
[2002] 1M Boron tribromide-dichloromethane solution (0.71 mL, 0.71
mmol) was added to a solution of
N-[3,5-bis(trifluoromethyl)phenyl]-2-methoxy-4-phenylbenzamide (100
mg, 0.24 mmol) in dichloromethane (5 mL), and the mixture was
stirred at room temperature for 1 hour. The reaction mixture was
diluted with ethyl acetate, washed with water and brine, and dried
over anhydrous magnesium sulfate. The residue obtained by
evaporation of the solvent under reduced pressure was purified by
column chromatography on silica gel (n-hexane:ethyl acetate=5:1) to
give the title compound (69.3 mg, 71.6%) as a white powder.
[2003] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.20(1H, dd, J=8.4.1.8
Hz), 7.30(1H, d, J=1.8 Hz), 7.39-7.51(3H, m), 7.60-7.64(3H, m),
7.70(1H, brs), 8.15(2H, s), 8.19(1H, brs), 11.59(1H, s).
Example 546
Preparation of the Compound of Compound No. 546
(1) 2-Amino-4-(2,5-difluorophenyl)thiazole
[2004] Using 2',5'-difluoroacetophenone and thiourea as the raw
materials, the same operation as the Example 395(1) gave the title
compound.
[2005] Yield: 77.8%.
[2006] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.45(1H, d, J=2.7 Hz),
7.11-7.17(1H, m), 7.19(2H, s), 7.28-7.36(1H, m), 7.65-7.71(1H,
m).
(2)
5-Chloro-2-hydroxy-N-[4-(2,5-difluorophenyl)thiazol-2-yl]benzamide
(Compound No. 546)
[2007] Using 5-chlorosalicylic acid and
2-amino-4-(2,5-difluorophenyl)thiazole as the raw materials, the
same operation as the Example 16 gave the title compound.
[2008] Yield: 36.5%.
[2009] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.09(1H, d, J=8.7 Hz),
7.22-7.30(1H, m), 7.37(1H, m), 7.53(1H, dd, J=8.7, 3.0 Hz),
7.72(1H, d, J=2.4 Hz), 7.77-7.84(1H, m), 7.94(1H, d, J=3.0 Hz),
11.89(1H, bs), 12.12(1H, bs).
Example 547
Preparation of the Compound of Compound No. 547
(1) 2-Acetoxy-4-chlorobenzoic acid
[2010] Using 4-chlorosalicylic acid, concentrated sulfuric acid and
acetic anhydride as the raw materials, the same operation as the
Example 34(1) gave the title compound.
[2011] Yield: 88.1%.
[2012] .sup.1H-NMR(DMSO-d.sub.6):.delta. 2.25(3H, s), 7.42(1H, d,
J=1.8 Hz), 7.48(1H, dd, J=8.4, 2.4 Hz), 7.94(1H, d, J=8.1 Hz),
13.31(1H, s).
(2)
2-Acetoxy-N-{4-[3,5-bis(trifluoromethyl)pyrazol-1-yl]phenyl}-4-chlorob-
enzamide
[2013] Using 2-acetoxy-4-chlorobenzoic acid and
1-(4-aminophenyl)-3,5-bis(trifluoromethyl)pyrazole as the raw
materials, the same operation as the Example 24 gave the title
compound.
[2014] Yield: 74.0%.
[2015] .sup.1H-NMR(CDCl.sub.3):.delta. 2.37(3H, s), 7.08(1H, s),
7.23(1H, d, J=1.8 Hz), 7.37(1H, dd, J=8.1, 2.1 Hz), 7.50(2H, d,
J=8.7 Hz), 7.77(2H, d, J=8.7 Hz), 7.82(1H, d, J=8.1 Hz), 8.23(1H,
s).
(3)
N-{4-[3,5-Bis(trifluoromethyl)pyrazol-1-yl]-phenyl}-4-chloro-2-hydroxy-
benzamide (Compound No. 547).
[2016] Using
2-acetoxy-N-(4-[3,5-bis(trifluoromethyl)pyrazol-1-yl]phenyl)-4-chlorobenz-
amide as the raw material, the same operation as the Example 2(2)
gave the title compound.
[2017] Yield: 56.6%.
[2018] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.03-7.06(2H, m), 7.61(2H,
d, J=8.7 Hz), 7.81(1H, s), 7.89-7.95(3H, m), 10.62(1H, s),
11.82(1H, s).
Example 548
Preparation of the Compound of Compound No. 548
(1) 1-(4-Nitrophenyl)-5-phenyl-3-(trifluoromethyl)pyrazole
[2019] Using 4,4,4-trifluoro-1-phenyl-1,3-butanedione and
4-nitrophenylhydrazine hydrochloride as the raw materials, the same
operation as the Example 538(1) gave the title compound.
[2020] Yield: 95.2%.
[2021] .sup.1H-NMR(CDCl.sub.3):.delta. 6.80(1H, s), 7.22-7.26(2H,
m), 7.37-7.45(3H, m), 7.51(2H, d, J=9.3 Hz), 8.22(2H, d, J=9.0
Hz).
(2) 1-(4-Aminophenyl)-5-phenyl-3-(trifluoromethyl)pyrazole
[2022] Using 1-(4-nitrophenyl)-5-phenyl-3-(trifluoromethyl)pyrazole
as the raw material, the same operation as the Example 538(2) gave
the title compound.
[2023] Yield: 73.0%.
[2024] .sup.1H-NMR(CDCl.sub.3):.delta. 3.80(2H, s), 6.62(2H, d,
J=8.7 Hz), 6.72(1H, s), 7.08(2H, d, J=8.7 Hz), 7.22-7.26(2H, m),
7.30-7.33(3H, m).
(3)
5-Chloro-2-hydroxy-N-{4-[5-phenyl-3-(trifluoromethyl)pyrazol-1-yl]-phe-
nyl}-benzamide (Compound No. 548).
[2025] Using 5-chlorosalicylic acid and
1-(4-aminophenyl)-5-phenyl-3-(trifluoromethyl)pyrazole as the raw
materials, the same operation as the Example 16 gave the title
compound.
[2026] Yield: 73.2%.
[2027] .sup.1H-NMR(CDCl.sub.3):.delta. 7.02(1H, d, J=8.7 Hz),
7.21(1H, s), 7.30-7.42(7H, m), 7.47(1H, dd, J=8.7, 2.7 Hz),
7.79(2H, d, J=8.7 Hz), 7.89(1H, d, J=2.7 Hz), 10.56(1H, s),
11.61(1H, s).
Example 549
Preparation of the Compound of Compound No. 549
(1) 2-Amino-4-(4-methoxyphenyl)thiazole
[2028] Using 4'-methoxyacetophenone and thiourea as the raw
materials, the same operation as the Example 395(1) gave the title
compound.
[2029] Yield: 85.2%.
[2030] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.76(3H, s), 6.82(1H, s),
6.92(2H, d, J=9.0 Hz), 7.01(2H, s), 7.72(2H, d, J=8.7 Hz).
(2) 5-Chloro-2-hydroxy-N-[4-(4-methoxyphenyl)thiazol-2-yl]benzamide
(Compound No. 549)
[2031] Using 5-chlorosalicylic acid and
2-amino-4-(4-methoxyphenyl)thiazole as the raw materials, the same
operation as the Example 16 gave the title compound.
[2032] Yield: 16.4%.
[2033] .sup.1H-NMR(DMSO-d.sub.6):.delta. 3.80(3H, s), 7.01(2H, d,
J=9.0 Hz), 7.07(1H, d, J=8.7 Hz), 7.50-7.55(2H, m), 7.86(2H, d,
J=9.0 Hz), 7.96(1H, d, J=2.7 Hz), 11.90(1H, bs), 12.04(1H, bs).
Example 550
Preparation of the Compound of Compound No. 550
(1) 2-Amino-4-[3-(trifluoromethyl)phenyl]thiazole
[2034] Using 3'-(trifluoromethyl)acetophenone and thiourea as the
raw materials, the same operation as the Example 395(1) gave the
title compound.
[2035] Yield: 94.1%.
[2036] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.19(2H, s), 7.27(1H, s),
7.61(2H, dd, J=3.9, 1.5 Hz), 8.07-8.13(2H, m).
(2)
5-Chloro-2-hydroxy-N-{4-[3-(trifluoromethyl)phenyl]thiazol-2-yl}benzam-
ide (Compound No. 550).
[2037] Using 5-chlorosalicylic acid and
2-amino-4-[3-(trifluoromethyl)phenyl]thiazole as the raw materials,
the same operation as the Example 16 gave the title compound.
[2038] Yield: 31.0%.
[2039] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.13(1H, d, J=8.7 Hz),
7.53(1H, dd, J=9.0, 2.7 Hz), 7.70(1H, d, J=2.4 Hz), 7.71(1H, d,
J=1.2 Hz), 7.95(1H, d, J=2.7 Hz), 8.00(1H, s), 8.24-8.27(2H, m),
12.16(2H, bs).
Example 551
Preparation of the Compound of Compound No. 551
(1) 2-Amino-4-(2,3,4,5,6-pentafluorophenyl)thiazole
[2040] Using 2',3',4',5',6'-pentafluoroacetophenone and thiourea as
the raw materials, the same operation as the Example 395(1) gave
the title compound.
[2041] Yield: 86.7%.
[2042] .sup.1H-NMR(CDCl.sub.3):.delta. 5.19(2H, s), 6.83(1H,
s).
(2)
5-Chloro-2-hydroxy-N-[4-(2,3,4,5,6-pentafluorophenyl)thiazol-2-yl]benz-
amide (Compound No. 551).
[2043] Using 5-chlorosalicylic acid and
2-amino-4-(2,3,4,5,6-pentafluorophenyl)-thiazole as the raw
materials, the same operation as the Example 16 gave the title
compound.
[2044] Yield: 23.8%.
[2045] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.08(1H, d, J=8.7 Hz),
7.53(1H, dd, J=8.7, 2.7 Hz), 7.73(1H, s), 7.93(1H, d, J=2.7 Hz),
11.85(1H, bs), 12.15(1H, bs).
Example 552
Preparation of the Compound of Compound No. 552
[2046] Iron (3 mg, 0.05 mmol) and bromine (129 .mu.l, 2.5 mmol)
were added to a solution of
2-hydroxy-N-[2,5-bis(trifluoromethyl)phenyl]benzamide (Compound No.
533; 175 mg, 0.5 mmol) in carbon tetrachloride (5 mL), and the
mixture was stirred at 50.degree. C. for 12 hours. After the
reaction mixture was cooled to room temperature, it was washed with
saturated aqueous sodium hydrogen carbonate, water and brine, and
dried over anhydrous magnesium sulfate. The residue obtained by
evaporation of the solvent under reduced pressure was purified by
column chromatography on silica gel (n-hexane:ethyl acetate=2:1) to
give the title compound (184.2 mg, 72.7%) as a white crystal.
[2047] .sup.1H-NMR(DMSO-d.sub.6):.delta. 7.92-7.98(1H, m), 8.06(1H,
d, J=2.1 Hz), 8.09(1H, d, J=8.4 Hz), 8.22(1H, d, J=2.1 Hz),
8.27-8.32(1H, m), 11.31(1H, s).
Example 553
Preparation of the Compound of Compound No. 553
[2048] Using 2,3-dihydroxybenzaldehyde and
3-[3,5-bis(trifluoromethyl)benzyl]-thiazolidine-2,4-dione (compound
of Example 319(1)) as the raw materials, the same operation as the
Example 319(2) gave the title compound.
[2049] Yield: 88.5%.
[2050] .sup.1H-NMR(DMSO-d.sub.6):.delta. 5.02(2H, s), 6.88(1H, d,
J=7.8 Hz), 7.00-7.04(2H, m), 7.79(1H, s), 8.03(2H, s), 8.07(1H, s),
9.49(1H, s), 9.91(1H, s).
Example 554
Preparation of the Compound of Compound No. 554
[2051] A mixture of 5-chlorosalicylaldehyde (157 mg, 1 mmol),
2-amino-4-tert-amylphenyl phenyl ether (255 mg, 1 mmol) and ethanol
(2 mL) was stirred at room temperature for 18 hours. The residue
obtained by evaporation of the solvent under reduced pressure was
purified by column chromatography on silica gel (n-hexane:ethyl
acetate=100:1) to give the title compound (57 mg, 14.4%) as a white
solid.
[2052] .sup.1H-NMR(CDCl.sub.3):.delta. 0.66(3H, t, J=7.5 Hz),
1.26(6H, s), 1.61(2H, q, J=7.5 Hz), 6.88-6.94(3H, m), 7.04(1H, dd,
J=8.0, 1.6 Hz), 7.15-7.32(7H, m), 8.61(1H, s), 13.20(1H, s).
Example 555
Preparation of the Compound of Compound No. 555
[2053] A mixture of
4-chloro-2-({[2-phenoxy-5-(tert-amyl)phenyl]imino}-methyl)phenol
(Compound No. 554; 13 mg, 0.03 mmol), sodium borohydride (1.2 mg,
0.03 mmol) and methanol (1 mL) was stirred at room temperature for
5 minutes. The residue obtained by evaporation of the solvent under
reduced pressure was purified by thin layer chromatography on
silica gel (n-hexane:ethyl acetate=5:1) to give the title compound
(13 mg, 100%) as a colourless oil.
[2054] .sup.1H-NMR(CDCl.sub.3):.delta. 0.69(3H, t, J=7.6 Hz),
1.28(6H, s), 1.63(2H, q, J=7.6 Hz), 4.41(2H, s), 6.78(1H, m),
6.93-6.83(5H, m), 7.03(1H, m), 7.15(2H, m), 7.28(3H, m).
Test Example 1
Proliferation Inhibitory Test of Mast Cell under stimulation by SCF
and IL-3
[2055] Bone marrow-derived cultured mast cells (10.sup.5 cells/ml)
of NC/Nga mouse were cultured with rmIL-3(100 U/ml) and SCF (100
ng/ml) in the presence or absence of a test drug in
.alpha.-Modified Eagle's Medium containing 10% of bovine fetal
serum without phenol red, and then stained with trypan blue, and
the number of living cells was counted. The results are shown in
the following table. TABLE-US-00002 Culture Time Compound
Concentration Number of Cell (.times.10.sup.5/ml) Number (.mu.M) 0
hr 24 hr 48 hr 72 hr -- 0 1.0 1.3 1.7 2.6 50 1 1.0 0.86 0.84 1.16 5
1.0 0.7 0.52 0.22
Test Example 2
Degranulation Inhibitory Test of Mast Cell
[2056] Anti DNP IgE was added to mouse bone marrow-derived cultured
mast cells (BMCMC) which were treated beforehand with anti DNP IgE
for 4 days for expression of IgE receptor. The cells were cultured
for 3 days, and treated for 1 hour with or without the addition of
a test substance. Then, the medium was changed to .alpha.-Modified
Eagle's Medium containing 10% of bovine fetal serum without phenol
red. After cultivation for 60 minutes with rmIL-3(100 U/ml) and
DNP-BSA (50 ng/ml) in the presence or absence of the test
substance, the concentrations of .beta.-hexosaminidase in the
culture medium and in the cells were determined, and the progress
of degranulation was measured from a ratio of the amounts. The
inhibitory ratio of the degranulation by the drug was calculated
when degranulation in the absence of the test substance was taken
as 100%, and degranulation in the presence of anti DNP-IgE only and
in the absence of the test substance was taken as 0%. The results
are shown in the following table. TABLE-US-00003 Inhibitory Ration
of Degranulation(%) Compound Number at 10 .mu.M Drug Concentration
50 >99 56 92 63 62 73 91 100 83 101 90 113 93 114 88 122 91 163
88 195 72
Test Example 3
IgE Production Inhibitory Test of Spleen B Cell
[2057] B cell isolated from mouse spleen were cultured with 200
U/ml of rmIL-4 and 100 n/ml of soluble mCD40 ligand in the presence
or absence of a test drug in PRMI 1640 medium containing 10% of
bovine fetal serum for 9 days, and the amount of IgE in the culture
medium was measured by ELISA method. The results are shown in the
following table. TABLE-US-00004 Concentration(.mu.M) Amount of
IgE(ng/ml) Compound Number 0 0.1 1.0 -- 45.6 -- -- 50 -- 24 ND ND =
not detected
Test Example 4
Immediate Type Allergy Reaction Inhibitory Test (Ear swelling
test)
[2058] To NC/Nga mouse sensitized by an intravenous administration
of anti DNP-IgE, a diluent with a test compound for the drug
administered group or that without a test drug for the control
group was intraperitoneally administered. Two hours after the
administration, picryl chloride dissolved in olive oil was applied
to auricle to induce immediate allergy, and then swelling of the
auricle was measured with passage of time for comparison of the
drug administered group and the control group. The results of
Compound 50 (dose: 15 mg/kg) are shown in FIG. 1.
Test Example 5
Dermatitis Inhibitory Test by atopic dermatitis model using NC/Nga
Mouse
[2059] To the conventional NC/Nga mouse with the onset of severe
dermatitis, an ointment containing 1% of a test substance for the
drug treated group or a base material of the ointment for the
control group was applied once a day, and clinical symptoms were
recorded as scores with passage of day. Furthermore, the amounts of
IgE in blood before and after the test were measured by ELISA. The
results for Compound 50 are shown in FIG. 2.
Test Example 6
Proliferation Inhibitory Test of Fibrosarcoma (HT-1080) under PDGF
Stimulation
[2060] HT-1080 cells were cultured for 2 hours in EMEM medium
containing 1% of FBS and NEAA in the presence or absence of a test
substance. PDGF was added and the cells were cultured for 48 hours,
and the proliferation of the cells was measured by MTT assay. The
results are shown in the following table. TABLE-US-00005 Inhibitory
Ratio of Proliferation(%) Compound Drug Concentration Number 500 nM
250 nM 50 96.6 65.4 51 97.6 62.4 67 70.9 38.5 73 84.9 52.0 63 77.9
48.3 114 95.7 48.8 163 80.8 16.9 71 83.1 57.9 56 96.9 37.5 98 59.4
26.4 196 80.2 47.3 122 51.1 32.9 195 81.7 44.7 199 24.2 26.2 201
76.2 60.3 532 91.8 42.2 552 19.4 24.0 101 80.0 53.2
INDUSTRIAL APPLICABILITY
[2061] The medicaments of the present invention are useful for the
preventive and/or therapeutic treatment of allergic diseases and/or
endometriosis and/or hysteromyoma.
* * * * *