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US 2004/0110830 A1Published application
20-HETE synthase inhibitor
AssigneeTaisho Pharmaceutical Co., Ltd.
InventorsMasakazu Sato, Noriyuki Miyata, Takaaki Ishii, Yuko Kobayashi, Hideaki Amada
Life of this patent
Estimating the term…
Abstract
The present invention relates to an inhibitor for production of 20-hydroxyeicosatetraenoic acid, comprising, as an effective ingredient, specific hydroxyformamidine derivatives or pharmaceutically-acceptable salts thereof. The inhibitors according to the present invention are useful as therapeutic agents for kidney diseases, cerebrovascular diseases, or circulatory diseases. In addition, the present invention also provides novel hydroxyformamidine derivatives or pharmaceutically-acceptable salts thereof.
Claims12
An inhibitor for production of 20-hydroxyeicosatetraenoic acid, comprising, as an effective ingredient, a hydroxyformamidine derivative represented by the formula:
- 465
- wherein R1 to R5 are identical or different and represent a hydrogen atom;
- a hydroxyl group;
- a carboxyl group;
- a halogen atom;
- a C1-14 alkyl group;
- a C1-4 alkyl group substituted with 1 to 6 halogen atoms;
- a C2-6 alkenyl group;
- a C1-6 alkoxy C1-6 alkyl group;
- a C3-8 cycloalkyl C1-6 alkyl group;
- a C2-6 alkynyl group;
- a C3-8 cycloalkyl group;
- a C3-8 cycloalkoxy group;
- a C2-10 alkanoyl group;
- a C1-6 hydroxyalkyl group;
- a C1-6 hydroxyalkyl group substituted with 1 to 6 halogen atoms;
- a C2-6 alkoxycarbonyl group;
- a 3-phenyl-2-propenyloxycarbonyl group;
- a C2-6 alkoxycarbonyl C1-6 alkyl group;
- a di(C1-6 alkyl)amino C2-6 alkoxycarbonyl group;
- a mono- or di(C1-6 alkyl)amino group;
- a C2-10 alkanoylamino group;
- a C2-6 alkanoylamino group substituted with a C1-6 alkyl group;
- a benzoylamino group;
- a carbamoyl group;
- a carbamoyl group mono- or di-substituted with C1-6 alkyl or phenyl groups;
- an N—(N′,N′-di(C1-6 alkyl)amino C1-6 alkyl)carbamoyl group;
- a cyano group;
- a cyano C1-6 alkyl group;
- a nitro group;
- a thiol group;
- a phenoxy group;
- a phenoxy group substituted with 1 to 3 substituents selected from the group consisting of C1-6 alkyl groups, C1-6 alkoxy groups, and halogen atoms;
- a phenylthio group;
- a nitrophenylthio group;
- a C1-6 alkylsulfonyl group;
- a phenylsulfonyl group;
- a C1-6 alkylthio C1-6 alkyl group;
- a phenylsulfonyl C1-6 alkylthio wherein the benzene ring is substituted with 1 to 5 halogen atoms;
- a phenyl group;
- a benzyl group;
- a phenyl group substituted with 1 to 3 substituents selected from the group consisting of cyano groups, halogen atoms, C1-6 alkyl groups, and C1-6 alkoxy groups;
- a biphenyl group;
- an α-cyanobenzyl group;
- an α-cyanobenzyl group substituted with 1 to 5 halogen atoms;
- a benzyl group substituted with a bicyclo[2.2.1]-hept-5-en-2,3-dicarboxyimidyl group;
- a benzoyl group;
- a styryl group;
- a styryl group substituted with 1 to 5 substituents selected from the group consisting of C1-6 alkoxy groups and di(C1-6 alkyl)amino alkyl groups;
- a pyrrolidino group;
- a piperidino group;
- a morpholino group;
- a pyridyl group;
- a pyrimidinyl group;
- a pyrimidinyl group substituted with 1 to 3 substituents selected from the group consisting of C1-6 alkyl groups and C1-6 alkoxy groups;
- a phthalimidoyl group;
- a phthalimidoyl group substituted with 1 to 3 halogen atoms;
- an N-carbazolyl group;
- a dioxopiperidinyl group substituted with 1 to 3C1-6 alkyl groups;
- a phenylsulfonylamino group;
- a phenylsulfonylamino group substituted with 1 to 3 C1-6 alkyl groups;
- a C1-6 alkylaminosulfonyl C1-6 alkyl group;
- a thiadiazolyl group;
- an oxadiazolyl group;
- an oxadiazolyl group substituted with a substituted phenyl group wherein the substituents in the substituted phenyl group are 1 to 3 substituents selected from the group consisting of halogen atoms, C1-6 alkyl groups, and C1-6 alkoxy groups;
- a pyrrolidinyl group;
- a pyrazolyl group;
- a pyrazolyl group substituted with 1 to 3 substituents selected from the group consisting of halogen atoms, C1-6 alkyl groups, and trifluoromethyl groups;
- a furyl group;
- a furyl group substituted with 1 to 3 substituents selected from the group consisting of halogen atoms, C1-6 alkyl groups, and C2-6 alkoxycarbonyl groups;
- a thienopyrimidinylthio group;
- a thienopyrimidinylthio group substituted with 1 to 3 C1-6 alkyl groups;
- a thienopyridylthio group;
- a thienopyridylthio group substituted with 1 to 3 C1-6 alkyl groups;
- a benzothiazolylthio group;
- a benzothiazolylthio group substituted with 1 to 3 halogen atoms;
- a group represented by the formula:
- —Y—(CR61R62)m—(CR63R64)n—R7 [wherein Y represents an oxygen or sulfur atom;
- R61, R62, R63, and R64 are identical or different and represent a hydrogen atom, a halogen atom, a C1-4 alkyl group, or a trifluoromethyl group;
- R7 represents a hydrogen atom;
- a halogen atom;
- a C1-14 alkyl group;
- a C3-8 cycloalkyl group;
- a C2-10 alkenyl group;
- a C2-6 alkynyl group;
- a phenyl group;
- a phenyl group substituted with 1 to 3 substituents selected from the group consisting of nitro groups, cyano groups, C1-6 alkyl groups, C1-6 alkoxy groups, C1-6 alkylthio groups, phenyl groups, phenoxy groups, phenethyl groups, C2-6 alkoxycarbonyl groups, and halogen atoms;
- a cyano group;
- a carboxyl group;
- a C1-6 alkoxy group;
- a C1-6 hydroxyalkyl group;
- a C3-8 cycloalkoxy group;
- a C1-6 alkoxy C1-6 alkoxy group;
- a C1-6 alkoxy C1-6 alkoxy C1-6 alkoxy group;
- a C1-6 alkylthio group;
- a C2-6 alkanoyloxy group;
- a C2-6 alkanoyloxy C1-6 alkyl group;
- a phenoxy group;
- a phenylthio group;
- an N—(C1-6 alkyl)toluidino group;
- a pyrrolidino group;
- a piperidino group;
- a morpholino group;
- a pyridyl group;
- a pyridyl group substituted with a C1-6 alkyl group;
- a piperidino group substituted with a C1-6 alkyl group;
- a pyridyl group substituted with a C1-6 alkoxy group;
- a pyrrolidino group substituted with a C1-6 alkyl group;
- a morpholino group substituted with a C1-6 alkyl group;
- a morpholinyl group;
- a morpholinyl group substituted with a C1-6 alkyl group;
- a homomorpholinyl group;
- a thiomorpholino group;
- a thiomorpholino group substituted with a C1-6 alkyl group;
- a thiomorpholinyl group;
- a thiomorpholinyl group substituted with a C1-6 alkyl group;
- a piperadinyl group;
- a piperadin-1-yl group substituted with a C1-6 alkyl group at the 4-position;
- a homopiperidinyl group;
- a homopiperidinyl group substituted with a C1-6 alkyl group;
- a pyridylthio group;
- a quinolyl group;
- a furyl group;
- an oxetanyl group;
- an oxolanyl group;
- a dioxolanyl group;
- a dioxolanyl group substituted with a C1-6 alkyl group;
- an oxanyl group;
- a dioxanyl group;
- a dioxanyl group substituted with a C1-6 alkyl group;
- a benzodioxanyl group;
- a pyrrolidon-1-yl group;
- a pyrrolidinyl group;
- an N—(C16 alkyl)pyrrolidinyl group;
- a piperidinyl group;
- an N—(C1-6 alkyl)piperidinyl group;
- a pyrrolyl group;
- a thienyl group;
- a thiazolyl group;
- a thiazolyl group substituted with 1 to 3 C1-6 alkyl groups;
- a 2,6-purindion-7-yl group substituted with C1-6 alkyl group(s);
- a furfuryl group;
- a di(C1-6 alkyl)amino group;
- a C2-6 alkoxycarbonyl group;
- or a di(C1-6 alkyl)amino C1-6 alkoxy group;
- m is an integer of 1 to 6;
- and n is an integer of 0 to 6];
- or a group represented by the formula:
- —SO2NR8R9 [wherein R8and R9 are identical or different and represent a hydrogen atom, a C1-10 alkyl group, a C2-6 alkanoyl group, an isoxazolyl group, an isoxazolyl group substituted with 1 to 3 C1-6 alkyl groups, a thiadiazolyl group, a thiadiazolyl group substituted with 1 to 3C1-6 alkyl groups, a thiazolyl group, a thiazolyl group substituted with 1 to 3 C1-6 alkyl groups, a pyridyl group, a pyridyl group substituted with 1 to 3 C1-6 alkyl groups, a pyrimidinyl group, a pyrimidinyl group substituted with 1 to 3 C1-6 alkyl groups, a pyrimidinyl group substituted with 1 to 3 C1-6 alkoxy groups, a pyridazinyl group, a pyridazinyl group substituted with 1 to 3 C1-6 alkoxy groups, an indazolyl group, or a carbamoyl group mono- or di-substituted with C1-6 alkyl groups, or alternatively, taken together with the nitrogen atom to which they are bonded, form a 3,5-dioxopiperadino group, a pyrrolidinyl group, a piperidino group, or a morpholino group], or alternatively, the two groups adjacent to each other of R1 to R5, taken together with the benzene ring to which they are bonded, form a phthalimide ring;
- a phthalimide ring substituted with a C1-6 alkyl group;
- an indole ring;
- an indane ring;
- an indazole ring;
- a benzotriazole ring;
- an S,S-dioxobenzothiophene ring;
- a 2,3-dihydroimidazo[2,1-b]benzothiazole ring;
- a dibenzofuran ring;
- a dibenzofuran ring substituted with a C1-6 alkoxy group;
- a fluorene ring;
- a fluorene ring substituted with a halogen atom;
- a pyrene ring;
- a carbostyryl ring;
- a carbostyryl ring substituted with a C1-6 alkyl group;
- a naphthalene ring;
- a naphthalene ring substituted with 1 to 3 substituents selected from the group consisting of cyano groups, halogen atoms, nitro groups, and C1-6 alkyl groups;
- a 1,2,3,4-tetrahydronaphthalene ring;
- a quinoline ring;
- a quinoline ring substituted with a C1-6 alkyl group;
- an isoquinoline ring;
- a 2-oxo-α-chromene ring;
- a 2-oxo-α-chromene ring substituted with 1 to 3 substituents selected from the group consisting of C1-6 alkyl groups, C1-6 alkoxy groups, and C1-6 alkoxy C1-6 alkyl groups;
- a cinnolin ring;
- a cinnolin ring substituted with a C1-6 alkyl group;
- a phthalazindione ring;
- a benzothiazol ring;
- a benzothiazol ring substituted with a C1-6 alkyl group;
- a benzodioxorane ring;
- or a benzobutyrolactone ring, or a pharmaceutically-acceptable salt thereof.
175 more elements
A hydroxyformamidine derivative represented by the formula:
- 466
- wherein at least one of R11 to R55 represents a C5-14 alkyl group;
- a C2-6 alkenyl group;
- a C3-8 cycloalkyl C1-6 alkyl group;
- a C2-6 alkynyl group;
- a C3-8 cycloalkyl group;
- a C3-8 cycloalkoxy group;
- a C2-10 alkanoyl group;
- a C1-6 hydroxyalkyl group;
- a C1-6 hydroxyalkyl group substituted with 1 to 6 halogen atoms;
- a C2-6 alkoxycarbonyl group;
- a 3-phenyl-2-propenyloxycarbonyl group;
- a C2-6 alkoxycarbonyl C1-6 alkyl group;
- a di(C1-6 alkyl)amino C2-6 alkoxycarbonyl group;
- a mono- or di(C1-6 alkyl)amino group;
- a C2-10 alkanoylamino group;
- a C2-6 alkanoylamino group substituted with a C1-6 alkyl group;
- a benzoylamino group;
- a carbamoyl group;
- a carbamoyl group mono- or di-substituted with C1-6 alkyl or phenyl groups;
- an N—(N′,N′-di(C1-6 alkyl)amino C1-6 alkyl) carbamoyl group;
- a cyano group;
- a cyano C1-6 alkyl group;
- a C1-6 alkylsulfonyl group;
- a phenylsulfonyl group;
- a C1-6 alkylthio C1-6 alkyl group;
- a phenylsulfonyl C1-6 alkylthio group wherein the benzene ring is substituted with 1 to 5 halogen atoms;
- a phenyl group;
- a benzyl group;
- a phenyl group substituted with 1 to 3 substituents selected from the group consisting of cyano groups, halogen atoms, C1-6 alkyl groups, and C1-6 alkoxy groups;
- a biphenyl group;
- an α-cyanobenzyl group;
- an α-cyanobenzyl group substituted with 1 to 5 halogen atoms;
- a benzyl group substituted with a bicyclo[2.2.1]-hept-5-en-2,3-dicarboxyimidyl group;
- a benzoyl group;
- a styryl group;
- a styryl group substituted with 1 to 5 substituents selected from the group consisting of C1-6 alkoxy groups and di(C1-6 alkyl)amino alkyl groups;
- a pyrrolidino group;
- a piperidino group;
- a morpholino group;
- a pyridyl group;
- a pyrimidinyl group;
- a pyrimidinyl group substituted with 1 to 3 substituents selected from the group consisting of C1-6 alkyl groups and C1-6 alkoxy groups;
- a phthalimidoyl group;
- a phthalimidoyl group substituted with 1 to 3 halogen atoms;
- an N-carbazolyl group;
- a dioxopiperidinyl group substituted with 1 to 3 C1-6 alkyl groups;
- a phenylsulfonylamino group;
- a phenylsulfonylamino group substituted with 1 to 3 C1-6 alkyl groups;
- a C1-6 alkylaminosulfonyl C1-6 alkyl group;
- a thiadiazolyl group;
- an oxadiazolyl group;
- an oxadiazolyl group substituted with a substituted phenyl group wherein the substituents in the substituted phenyl group are 1 to 3 substituents selected from the group consisting of halogen atoms, C1-6 alkyl groups, and C1-6 alkoxy groups;
- a pyrrolidinyl group;
- a pyrazolyl group;
- a pyrazolyl group substituted with 1 to 3 substituents selected from the group consisting of halogen atoms, C1-6 alkyl groups, and trifluoromethyl groups;
- a furyl group;
- a furyl group substituted with 1 to 3 substituents selected from the group consisting of halogen atoms, C1-6 alkyl groups, and C2-6 alkoxycarbonyl groups;
- a thienopyrimidinylthio group;
- a thienopyrimidinylthio group substituted with 1 to 3 C1-6 alkyl groups;
- a thienopyridylthio group;
- a thienopyridylthio group substituted with 1 to 3 C1-6 alkyl groups;
- a benzothiazolylthio group;
- a benzothiazolylthio group substituted with 1 to 3 halogen atoms;
- a group represented by the formula:
- —Y—(CR61R62)m—(CR63R64 )n—R77 [wherein Y represents an oxygen or sulfur atom;
- R61, R62, R63, and R64 are identical or different and represent a hydrogen atom, a halogen atom, a C1-4 alkyl group, or a trifluoromethyl group;
- R77 represents a halogen atom;
- a C4-14 alkyl group;
- a C3-8 cycloalkyl group;
- a C2-10 alkenyl group;
- a C2-6 alkynyl group;
- a phenyl group;
- a phenyl group substituted with 1 to 3 substituents selected from the group consisting of nitro groups, cyano groups, C1-6 alkyl groups, C1-6 alkoxy groups, C1-6 alkylthio groups, phenyl groups, phenoxy groups, phenethyl groups, C2-6 alkoxycarbonyl groups, and halogen atoms;
- a cyano group;
- a carboxyl group;
- a C1-6 alkoxy group;
- a C1-6 hydroxyalkyl group;
- a C3-8cycloalkoxy group;
- a C1-6 alkoxy C1-6 alkoxy group;
- a C1-6 alkoxy C1-6 alkoxy C1-6 alkoxy group;
- a C1-6 alkylthio group;
- a C2-6 alkanoyloxy group;
- a phenoxy group;
- a phenylthio group;
- an N—(C1-6 alkyl) toluidino group;
- a pyrrolidino group;
- a piperidino group;
- a morpholino group;
- a pyridyl group;
- a pyridyl group substituted with a C1-6 alkyl group;
- a piperidino group substituted with a C1-6 alkyl group;
- a pyridyl group substituted with a C1-6 alkoxy group;
- a pyrrolidino group substituted with a C1-6 alkyl group;
- a morpholino group substituted with a C1-6 alkyl group;
- a morpholinyl group;
- a morpholinyl group substituted with a C1-6 alkyl group;
- a homomorpholinyl group;
- a thiomorpholino group;
- a thiomorpholino group substituted with a C1-6 alkyl group;
- a thiomorpholinyl group;
- a thiomorpholinyl group substituted with a C1-6 alkyl group;
- a piperadinyl group;
- a piperadin-1-yl group substituted with a C1-6 alkyl group at the 4-position;
- a homopiperidinyl group;
- a homopiperidinyl group substituted with a C1-6 alkyl group;
- a pyridylthio group;
- a quinolyl group;
- a furyl group;
- an oxetanyl group;
- an oxolanyl group;
- a dioxolanyl group;
- a dioxolanyl group substituted with a C1-6 alkyl group;
- an oxanyl group;
- a dioxanyl group;
- a dioxanyl group substituted with a C1-6 alkyl group;
- a benzodioxanyl group;
- a pyrrolidon-1-yl group;
- a pyrrolidinyl group;
- an N—(C1-6 alkyl)pyrrolidinyl group;
- a piperidinyl group;
- an N—(C1-6 alkyl)piperidinyl group;
- a pyrrolyl group;
- a thienyl group;
- a thiazolyl group;
- a thiazolyl group substituted with 1 to 3 C1-6 alkyl groups;
- a 2,6-purindion-7-yl group substituted with at least one C1-6 alkyl group;
- a furfuryl group;
- a di(C1-6 alkyl)amino group;
- a C2-6 alkoxycarbonyl group;
- or a di(C1-6 alkyl)amino C1-6 alkoxy group;
- m is an integer of 1 to 6;
- and n is an integer of 0 to 6];
- or a group represented by the formula:
- —SO2NR8R9 [wherein R8 and R9 are identical or different and represent a hydrogen atom, a C1-10 alkyl group, a C2-6 alkanoyl group, an isoxazolyl group, an isoxazolyl group substituted with 1 to 3 C1-6 alkyl groups, a thiadiazolyl group, a thiadiazolyl group substituted with 1 to 3 C1-6 alkyl groups, a thiazolyl group, a thiazolyl group substituted with 1 to 3 C1-6 alkyl groups, a pyridyl group, a pyridyl group substituted with 1 to 3 C1-6 alkyl groups, a pyrimidinyl group, a pyrimidinyl group substituted with 1 to 3 C1-6 alkyl groups, a pyrimidinyl group substituted with 1 to 3 C1-6 alkoxy groups, a pyridazinyl group, a pyridazinyl group substituted with 1 to 3 C1-6 alkoxy groups, an indazolyl group, or a carbamoyl group mono- or di-substituted with C1-6 alkyl groups, or alternatively, taken together with the nitrogen atom to which they are bonded, form a 3,5-dioxopiperadino group, a pyrrolidinyl group, a piperidino group, or a morpholino group], or alternatively,
- the two groups adjacent to each other of R11 to R5 5, taken together with the benzene ring to which they are bonded, form a phthalimide ring;
- a phthalimide ring substituted with a C1-6 alkyl group;
- an indole ring;
- an indane ring;
- an indazole ring;
- a benzotriazole ring;
- an S,S-dioxobenzothiophene ring;
- a 2,3-dihydroimidazo[2,1-b]benzothiazole ring;
- a dibenzofuran ring;
- a dibenzofuran ring substituted with a C1-6 alkoxy group;
- a fluorene ring;
- a fluorene ring substituted with a halogen atom;
- a pyrene ring;
- a carbostyryl ring;
- a carbostyryl ring substituted with a C1-6 alkyl group;
- a naphthalene ring;
- a naphthalene ring substituted with 1 to 3 substituents selected from the group consisting of cyano groups, halogen atoms, nitro groups, and C1-6 alkyl groups;
- a 1,2,3,4-tetrahydronaphthalene ring;
- a quinoline ring;
- a quinoline ring substituted with a C1-6 alkyl group;
- an isoquinoline ring;
- a 2-oxo-α-chromene ring;
- a 2-oxo-α-chromene ring substituted with 1 to 3 substituents selected from the group consisting of C1-6 alkyl groups, C1-6 alkoxy groups, and C1-6 alkoxy C1-6 alkyl groups;
- a cinnolin ring;
- a cinnolin ring substituted with a C1-6 alkyl group;
- a phthalazindione ring;
- a benzothiazol ring;
- a benzothiazol ring substituted with a C1-6 alkyl group;
- a benzodioxorane ring;
- and a benzobutyrolactone ring, and the remaining groups of R11 to R55 are identical or different and represent a hydrogen atom, a C1-4 alkyl group, a C1-4 alkoxy group, a trifluoromethyl group, a nitro group, or a halogen atom, or a pharmaceutically-acceptable salt thereof.
162 more elements
Dependencies are inferred from the claim text.