US2008090779A1PendingUtilityA1
Antiallergic agents
Assignee: INST MED MOLECULAR DESIGN INCPriority: Jun 6, 2002Filed: Dec 7, 2007Published: Apr 17, 2008
Est. expiryJun 6, 2022(expired)· nominal 20-yr term from priority
A61P 9/00A61P 9/10A61P 7/00A61P 35/00A61P 37/08A61P 43/00A61P 27/02A61P 25/28A61P 29/00A61P 27/16A61P 27/14A61P 25/00A61K 31/165A61K 31/381A61P 13/10A61K 31/5375A61K 31/421A61P 15/00A61K 31/616A61K 31/498A61K 31/422A61K 31/609A61K 31/47A61K 31/40A61P 17/04A61K 31/4035A61K 31/055A61K 31/403A61K 31/4453A61K 31/167A61P 1/12A61P 17/00A61K 31/445A61P 11/00A61K 31/18A61K 31/137A61K 31/427A61P 11/02A61K 31/15A61K 31/357A61P 11/06A61K 31/404A61K 31/455A61K 31/606A61P 1/04A61K 31/63C07C 235/64A61P 19/02C07D 295/192A61K 31/426
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Claims
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: 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 hetero aryl group which may be substituted, ring Z represents an arene which may have one or more substituents 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 substituents 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.
Claims
exact text as granted — not AI-modified1 . A medicament composition for the therapeutic treatment of allergic diseases and/or endometriosis and/or hysteromyoma in a mammal, which comprises 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) and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof:
wherein X represents a group represented by the following formula
wherein the bond at the left end binds to ring Z and the bond at the right end binds to E,
A represents a hydrogen atom or an acetyl group,
E represents a 3,5-di-substituted phenyl group wherein at least one of the substituents is a trifluoromethyl group,
ring Z represents a benzene ring which may have one or more substituents 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 substituents 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 substituents 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 substituents 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 substituents 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 substituents 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 substituents 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 substituents 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 substituents 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 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,
provided that the following compounds are excluded:
N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide,
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide,
N-[3,5-bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide,
N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide
N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-nitrobenzamide,
N-[3,5-bis(trifluoromethyl)phenyl]-3,5-dibromo-2-hydroxybenzamide,
N-[3,5-bis(trifluoromethyl)phenyl]-3,5-dichloro-2-hydroxybenzamide,
N-[3,5-bis(trifluoromethyl)phenyl]-4-(trifluoromethyl)-2-hydroxybenzamide,
5-chloro-N-[5-chloro-3-(trifluoromethyl)phenyl]-2-hydroxybenzamide, and
N-[5-chloro-3-(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide.
2 . The medicament composition according to claim 1 , for inhibiting production of IgE, and/or inhibiting degranulation from an activated mast cell, and/or inhibiting proliferation of a mast cell in a mammal, which comprises an effective amount of a substance according to claim 1 .
3 . A compound represented by the general formula (I-1) or a salt thereof, or a hydrate thereof or a solvate thereof:
wherein
Z 1 represents a 2-hydroxyphenyl group which may be substituted with a substituent 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 substituents 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 substituents 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 substituents 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 substituents 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 substituents 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 substituents 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 substituents 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 substituents 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 substituent 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 substituents 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 substituents selected from the group consisting of
an aryl group,
cyano group,
an alkyl-oxy-carbonyl group, and
carboxy group;
an alkynyl group which may be substituted with one or more substituents 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 substituents 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 substituents 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 substituents 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 substituents 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 substituents selected from the group consisting of
a nitro group, and
a 6-membered heteroaryl-sulfamoyl group
in the 5-position, E 1 represents a 3,5-bis(trifluoromethyl)phenyl group,
provided that the following compounds are excluded:
N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide,
N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide,
N-[3,5-bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide,
N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide, and
N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-nitrobenzamide.
4 . A compound represented by the general formula (I-2) or a salt thereof, or a hydrate thereof or a solvate thereof:
wherein Z 2 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 2 represents a 3,5-di-substituted phenyl group wherein one of said substituents is a trifluoromethyl group, provided that the following compounds are excluded:
5-chloro-N-[5-chloro-3-(trifluoromethyl)phenyl]-2-hydroxybenzamide, and
N-[5-chloro-3-(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide.
5 . The compound according to claim 4 or a salt thereof, or a hydrate thereof or a solvate thereof, wherein Z 2 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.
6 . A method for at least one of prophylactic and therapeutic treatment of allergic diseases and/or endometriosis and/or hysteromyoma in a mammal, which comprises administering 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) and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof:
wherein X represents a group represented by the following formula
wherein the bond at the left end binds to ring Z and the bond at the right end binds to E,
A represents a hydrogen atom or an acetyl group,
E represents a 3,5-di-substituted phenyl group wherein at least one of said substituents is a trifluoromethyl group,
ring Z represents a benzene ring which may have one or more substituents 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 substituents 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 substituents 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 substituents 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 substituents 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 substituents 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 substituents 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 substituents 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 substituents 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, 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, to a mammal.
7 . The method according to claim 6 , wherein E is a 3,5-di-substituted phenyl group wherein at least one of said substituents is trifluoromethyl group,
the following partial formula (Iz-1) in the general formula containing ring Z
is represented by the following formula (Iz-2):
wherein R z represents
a hydrogen atom;
a halogen atom;
a nitro group;
a cyano group;
an alkoxy group;
an alkyl group which may be substituted with one or more substituents 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 substituents 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 substituents 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 substituents 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 substituents 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 substituents 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 substituents 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; or
a diazenyl group which may be substituted with one or more aryl groups wherein said aryl groups may be substituted with one or more substituents selected from the group consisting of
a nitro group, and
a 6-membered heteroaryl-sulfamoyl group.
8 . The method according to claim 7 , wherein A is hydrogen atom,
E is a 3,5-di-substituted phenyl group wherein at least one of said substituents is trifluoromethyl group, R z is a group selected from Substituent Groupγ-2z, wherein Substituent Groupγ-2z comprises 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, a 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, 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.
9 . The method according to claim 8 , wherein A is a hydrogen atom,
R z is a halogen atom, E is a group selected from Substituent Groupδ-5e, wherein Substituent Groupδ-5e comprises a 3,5-bis(trifluoromethyl)phenyl group, a 3-fluoro-5-(trifluoromethyl)phenyl group, a 3-bromo-5-(trifluoromethyl)phenyl group, a 3-methoxy-5-(trifluoromethyl)phenyl group, a 3-methoxycarbonyl-5-(trifluoromethyl)phenyl group, and a 3-carboxy-5-(trifluoromethyl)phenyl group
10 . The method according to claim 9 , wherein
R z is a chlorine atom, E is a 3,5-bis(trifluoromethyl)phenyl group.
11 . The method according to claim 6 , wherein
E is a 3,5-bis(trifluoromethyl)phenyl group.
12 . The medicament composition according to claim 1 , wherein the allergic disease is selected from the group consisting of contact dermatitis, atopic 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.
13 . The compound according to claim 3 or a salt thereof, or a hydrate thereof or a solvate thereof, wherein E 1 is a 3,5-bis(trifluoromethyl)phenyl group,
Z 1 is a 2-hydroxyphenyl group substituted with a substituent selected from Substituent Groupγ 1 -1z in the 5-position, wherein Substituent Groupγ 1 -1z comprises 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, a 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, 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.
14 . The compound according to claim 5 or a salt thereof, or a hydrate thereof or a solvate thereof, wherein Z 2 is a 2-hydroxyphenyl group which is substituted with a halogen atom in the 5-position,
E 2 is a 3-fluoro-5-(trifluoromethyl)phenyl group, a 3-bromo-5-(trifluoromethyl)phenyl group, a 3-methoxy-5-(trifluoromethyl)phenyl group, a 3-methoxycarbonyl-5-(trifluoromethyl)phenyl group or a 3-carboxy-5-(trifluoromethyl)phenyl group.
15 . A method of inhibiting production of IgE, and/or inhibiting degranulation from an activated mast cell, and/or inhibiting proliferation of a mast cell in a mammal, which comprises the step of administering an effective amount of a substance according to claim 6 to a mammal.
16 . The method according to claim 6 , wherein the mammal is a human.
17 . The method according to claim 6 , wherein the allergic disease is selected from the group consisting of contact dermatitis, atopic 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.
18 . The medicament according to claim 1 , wherein the mammal is a human.
19 . The medicament according to claim 2 , wherein the mammal is a human.Join the waitlist — get patent alerts
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