20-HETE synthase inhibitor

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.

Description

TECHNICAL FIELD

[0001] The present invention relates to hydroxyformamidinobenzene derivatives inhibiting a synthase of 20-hydroxyeicosatetraenoic acid (20-HETE) biosynthesized from arachidonic acid.

BACKGROUND ART

[0002] Prostaglandins produced by cyclooxygenase and lypoxygenases produced by lipoxygenase have been well known as physiologically active substances synthesized from arachidonic acid. Recently, it has been elucidated that 20-HETE, which is produced from arachidonic acid by the cytochrome P450 family enzymes, functions in various manner in vivo (J. Vascular Research, vol. 32, p.79 (1995)). It has been reported that 20-HETE induces constriction or dilation of important organs such as the kidneys and the cerebral blood vessels, and causes cell proliferation, and it is suggested that 20-HETE plays important physiological roles in vivo, and participates in various kidney diseases, cerebrovascular diseases, or circulatory diseases (J. Vascular Research, vol.32, p.79 (1995); Am. J. Physiol., vol. 277, p. R607 (1999); and the like).

DISCLOSURE OF THE INVENTION

[0003] An object of the present invention is to provide an inhibitor for production of 20-HETE, which participates in constriction or dilation of microvessels in the important organs such as the kidneys and the cerebral blood vessels, or in causing cell proliferation.

[0004] As a result of various studies in order to solve the above problem, the present inventors have found that aromatic compounds having a specific substructure unexpectedly possess the inhibitory activity for 20-HETE synthase, to accomplish the present invention.

[0005] That is, one mode of the present invention corresponds to an inhibitor of 20-hydroxyeicosatetraenoic acid synthase, comprising, as an effective ingredient, a hydroxyformamidine derivative represented by the general formula (1) as follows: 1

[0006] [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 C1-14 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-substituted 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 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 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 to3 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—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 C3-8 cycloalkoxy 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 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—(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 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 R” 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,

[0007] 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.

[0008] In the general formula (1) described above, it is preferable that R1 to R5 be identical or different and represent a hydrogen atom; a hydroxyl group; a carboxyl group; a halogen atom; a C1-14 alkyl group; a C1-14 alkyl group substituted with 1 to 6 halogen atoms; 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 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—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—(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 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].

[0009] In addition, in the inhibitors of 20-hydroxyeicosatetraenoic acid synthase according to the present invention, it is preferable that in the compounds of the general formula (1), the compounds wherein R1, R2, R4, and R5 represent hydrogen atoms, or the pharmaceutically-acceptable salts thereof, be employed as effective ingredients.

[0010] In addition, the other mode of the present invention corresponds to hydroxyformamidine derivatives having a novel chemical structure in the compounds of the general formula (1) described above or a pharmaceutically-acceptable salt thereof.

[0011] That is, the other mode of the present invention corresponds to a hydroxyformamidine derivative represented by the general formula (2) as follows: 2

[0012] (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)aminoalkyl 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 alkoxy C1-6 alkoxy group; a C1-6 alkoxy C1-6 alkoxy C1-6 alkoxy group; a C1-6 hydroxyalkyl group; a C3-8 cycloalkoxy 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—(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 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 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,

[0013] the two groups adjacent to each other of R11 to R55, 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, 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.

[0014] In the compounds of the general formula (2), at least one of R11 to R55 may represent a C5-14 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 in the phenylsulfonyl 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; or a group represented by the formula: —SO2NR8R9 [wherein R8 and R9are 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 R8 and R9, 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,

[0015] the two groups adjacent to each other of R11 to R55, taken together with the benzene ring to which they are bonded, may 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, and the remaining groups of R11 to R55 may be 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.

[0016] In this case, it is preferable that at least one of R11 to R55 represent a C5-14 alkyl group; a C2-6 alkynyl group; a C3-8cycloalkyl 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 carbamoyl group; a carbamoyl 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 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 benzoyl group; 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 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; 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 R8 and R9, 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] and the remaining groups of R11 to R55 be 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.

[0017] On the other hand, in the compounds of the general formula (2), at least one of R11 to R55 may represent 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 C3-8 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 C26 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—(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 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], and the remaining groups of R11 to R55 may be 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.

[0018] In this case, it is preferable that at least one of R11 to R55 represent a group represented by the formula: —O—(CR61R62)m—(CR63R64)n—R77 [wherein R6l , 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 di(C1-6 alkyl) amino group; a di(C1-6 alkyl)amino C1-6 alkoxy group; a piperidyl group; a piperidinyl group substituted with a C1-6 alkyl group; a piperidino group; a piperidino group substituted with a C1-6 alkyl group; a pyridyl group; a pyridinyl group substituted with a C1-6 alkyl group; a pyridinyl group substituted with a C1-6 alkoxy group; a pyridylthio group; a pyrrolidino group; a pyrrolidino group substituted with a C1-6 alkyl group; a pyrrolidon-1-yl group; a pyrrolidinyl group; a pyrrolidinyl group substituted with a C1-6 alkyl group; a pyrrolyl group; a thienyl group; a thiazolyl group; a morpholino 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; or a homopiperidinyl group substituted with a C1-6 alkyl group; m is an integer of 1 to 6; and n is an integer of 0 to 6], 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.

[0019] In addition, in the compounds of the general formula (2), the compounds wherein R11, R221, R44, and R55 represent a hydrogen atom, that is, only R3 at the para position of the hydroxyformamidino group on the benzene ring is a non-hydrogen atom substituent, are preferred.

[0020] It was discovered by the present inventors that the compounds of the general formulae (1) and (2) described above exhibit an inhibiting activity of 20-HETE synthase. Therefore, these compounds are useful as therapeutic agents for kidney diseases, cerebrovascular diseases, or circulatory diseases.

[0021] The terms used in the present invention are defined in the following. In the present invention, “Cx-y” means that the group following the “Cx,y” has the number of x-y of carbon atoms.

[0022] The term “halogen atom” refers to a fluorine, chlorine, bromine, or iodine atom.

[0023] The term “C1-4, C1-6, C1-8, and C1-14 alkyl group” means straight-chain or branched alkyl groups having 1 to 4, 1 to 6, 1 to 8, and 1 to 14 carbon atoms, respectively. For example, as a C1-14 alkyl group, mention may be made of a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, an isopentyl group, a hexyl group, an isohexyl group, a heptyl group, an octyl group, a nonyl group, or a decyl group, or the like.

[0024] The term “C1-14 alkyl group substituted with 1 to 6 halogen atoms” means a straight-chain or branched alkyl group having 1 to 14 carbon atoms, substituted with 1 to 6 halogen atoms. A methyl or ethyl group substituted with 1 to 4 halogen atoms is preferred. As an example thereof, mention may be made of a difluoromethyl group, a dibromomethyl group, a trifluoromethyl group, or a trifluoroethyl group, or the like. Among these groups, a trifluoromethyl group is preferable.

[0025] The term “C2-6 alkenyl” means a straight-chain or branched alkynyl group having a double bond, and 2 to 6 carbon atoms. As an example thereof, mention may be made of an ethenyl group, a propenyl group, or a butenyl group, or the like.

[0026] The term “C2-6 alkynyl group” means a straight-chain or branched alkynyl group having a triple bond, and 2 to 6 carbon atoms. As an example thereof, mention may be made of an ethynyl group, a propynyl group, or a butynyl group, or the like.

[0027] The term “C3-8 cycloalkyl group” means a cyclic alkyl group having 3 to 8 carbon atoms, including, for example, a cyclopropyl group, a cyclopentyl group, or a cyclohexyl group, or the like.

[0028] The term “C3-8 cycloalkyl C1-6 alkyl group” means a group having a combined structure of a C3-8 cycloalkyl group and a C1-6 alkyl group, including, for example, a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, or a cyclohexylmethyl group, or the like.

[0029] The term C1-6 alkoxy group” means a straight-chain or branched alkoxy group having 1 to 6 carbon atoms. As an example thereof, mention may be made of a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a 2,2-dimethylpropoxy group, a butoxy group, a tert-butoxy group, a 3-methylbutoxy group, a 3,3-dimethylbutoxy group, a 3-methylpentoxy group, or a 4-methylpentoxy group, or the like.

[0030] The term “C1-6 alkoxy C1-6 alkyl group” means a group having a combined structure of a C1-6 alkoxy group and a C1-6 alkyl group. As an example thereof, mention may be made of a methoxymethyl group, an ethoxymethyl group, a methoxyethyl group, an ethoxyethyl group, a propoxyethyl group, an isopropoxyethyl group, a butoxyethyl group, or a tert-butoxyethyl group, or the like.

[0031] The term “C3-8 cycloalkoxy group” means a cyclic alkoxy group having 3 to 8 carbon atoms, including, for example, a cyclopropyloxy group, a cyclopentyloxy group, or a cyclohexyloxy group, or the like.

[0032] The term “C2-10 alkanoyl group” means a straight-chain or branched alkanoyl group having 2 to 10 carbon atoms. As an example thereof, mention may be made of an acetyl group, a propionyl group, a butyryl group, an isobutylyl group, or a valeryl group, or the like. Among these groups, an acetyl group is preferable.

[0033] The term “C1-6 hydroxyalkyl” means a C1-6 alkyl group substituted with hydroxyl group(s). As an example thereof, mention may be made of a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, a 3-hydroxypropyl group, a 2,3-dihydroxyethyl group, or the like. Among these groups, a hydroxymethyl group, a 1-hydroxyethyl group, a 2-7hydroxyethyl group, or a 3-hydroxypropyl group is in particular, preferable.

[0034] The term “C2-6 alkanoyloxy C1-6 alkyl group” means a group wherein the hydroxyl group(s) of above C1-6 hydroxyalkyl group is/are substituted with C2-6 alkanoyloxy group(s), including, for example, a 2,3-diacetoxyethyl group. The term “C1-6 hydroxyalkyl group substituted with 1 to 6 halogen atoms” means a C1-6 hydroxyalkyl group substituted with 1 to 6 halogen atoms. As an example thereof, mention may be made of a hydroxyfluoromethyl group, a 1-hydroxy-2-fluoroethyl group, a 2-hydroxy-2-fluoroethyl group, a 3-hydroxy-2-chloropropyl group, a 2,3-dihydroxy-3-bromopropyl group, a 1, 1,1,3,3,3-hexafluoro-2-hydroxypropyl group, or the like. Among these groups, a 1,1,1,3,3,3-hexafluoro-2-hydroxypropyl group is preferable.

[0035] The term “C2-6 alkoxycarbonyl group” means a group having a combined structure of a straight-chain or branched C1-5 alkoxy group and a carbonyl group. As an example thereof, mention may be made of a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, or a butoxycarbonyl group, or the like, and among these groups, a methoxycarbonyl group or a propoxycarbonyl group is preferable.

[0036] The term “C2-6 alkoxycarbonyl C1-6 alkyl group” means a group having a combined structure of a C2-6 alkoxycarbonyl group and a C1-6 alkoxy group. Therefore, a C1-6 alkoxycarbonyl C1-6 alkyl group may be represented by the general formula: —(CH2)k—COOR14 (wherein k is an integer of 1 to 6; R14 is a C1-6 alkyl group), including, for example, —CH2COOCH3 (a methoxycarbonylmethyl group), —CH2COOCH2CH3 (an ethoxycarbonylmethyl group), —CH2CH2COOCH3 (a methoxycarbonylethyl group), —CH2CH2COOCH2CH3 (an ethoxycarbonylethyl group), or the like. Among these groups, an ethoxycarbonylmethyl group is particularly preferable.

[0037] The term “di(C1-6 alkyl)amino C2-6 alkoxycarbonyl” means a group having a combined structure of an amino group substituted with two C1-6 alkyl groups and a C2-6 alkoxycarbonyl group. As an example thereof, mention may be made of an N,N-diethylaminoethoxycarbonyl group, or an N,N-dibutylaminopropoxycarbonyl group, or the like. In particular, an N,N-diethylaminoethoxycarbonyl group is preferable.

[0038] The term “mono- or di(C1-6 alkyl)amino group” means an amino group substituted with one or two C1-6 alkyl groups. As an example thereof, mention may be made of a methylamino group, an ethylamino group, a dimethylamino group, or a diethylamino group, or the like. Among these groups, a dimethylamino group is preferable.

[0039] The term “C2-10 alkanoylamino group” means an amino group substituted with a C2-10 alkanoyl group, and as an example thereof, an acetylamino group may be given. In addition, as an example of “C2-10 alkanoylamino group substituted with C1-6 alkyl”, mention may be made of an N-acetyl-N-methylamino group.

[0040] As an example of “carbamoyl group mono- or di-substituted with C1-6 alkyl or phenyl groups”, mention may be made of an N-methylcarbamoyl group, a N-butylcarbamoyl group, or an N-phenylcarbamoyl group. As an example of “N—(N′,N′-di(C1-6 alkyl)amino C1-6 alkyl)carbamoyl group”, mention may be made of an N—(N′,N′-diethylaminoethyl)carbamoyl group.

[0041] The term “cyano C1-6 alkyl group” means a group having a combined structure of a cyano group and a C1-6 alkyl group. As an example thereof, mention may be made of a cyanomethyl group, a cyanoethyl group, or a cyanopropyl group. Among these groups, a cyanomethyl group is particularly preferable.

[0042] As an example of “phenoxy group substituted with 1 to 3 substituents selected from the group consisting of nitro groups, thiol groups, phenoxy groups, C1-6 alkyl groups, C1-6 alkoxy groups, and halogen atoms”, mention may be made of a 2-methylphenoxy group, a 3-methylphenoxy group, a 4-methylphenoxy group, a 2-methoxyphenoxy group, a 3-methoxyphenoxy group, a 4-methoxyphenoxy group, a 2-chlorophenoxy group, a 3-chlorophenmoxy group, or a 4-chlorophenoxy group, or the like. Among these groups, a 2-methylphenoxy group, a 4-methylphenoxy group, a 2-methoxyphenoxy group, a 4-methoxyphenoxy group, or a 4-chlorophenoxy group is preferable.

[0043] The term “C1-6 alkylsulfonyl group” means a group having a combined structure of a C1-6 alkyl group and a sulfonyl group (—SO2—). As an example thereof, mention may be made of a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, an isopropylsulfonyl group, a butylsulfonyl group, an isobutylsulfonyl group, a tert-butylsulfonyl group, a pentylsulfonyl group, or an isopentylsulfonyl group, or the like. A methylsulfonyl group is preferable.

[0044] The term “C1-6 alkylthio C1-6 alkyl group” means a group having a combined structure of a C1-6 alkylthio group and a C1-6 alkyl group. As an example thereof, a methylthiomethyl group, or a 2-methylthioethyl group, or the like may be given, and a methylthiomethy group is preferable.

[0045] The term “phenylsulfonyl C1-6 alkylthio wherein the benzene ring is substituted with 1 to 5 halogen atoms” means a group having a combined structure of a substituted phenylsulfonyl group and a C1-6 alkylthio group. As an example thereof, a 4-chlorophenylsulfonylmethylthio group or the like may be given.

[0046] As an example of the “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”, mention may be made of a 4-cyanophenyl group, a 4-chlorophenyl group, a 4-methylphenyl group, or a 4-methoxyphenyl group, or the like. Among these groups, a 4-cyanophenyl group is preferable. As the “α-cyanobenzyl group substituted with 1 to 5 halogen atoms”, for example, an α-cyano-4-chlorobenzyl group or the like may be given.

[0047] As an example of the “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”, mention may be made of a 4-methoxystyryl group, or an 4-N,N-dimethylaminostyryl group, or the like.

[0048] As an example of the “pyrimidinyl group substituted with 1 to 3 substituents selected from the group consisting of C1-6 alkyl groups and C1-6 alkoxy groups”, mention may be made of a 6-methoxypyrimidin-4-yl group, or a 2-methylpyrimidin-4-yl group, or the like.

[0049] As an example of the “phthalimidoyl group substituted with 1 to 3 halogen atoms”, a 5-chloro-N-phthalimidoyl group or the like may be given.

[0050] As an example of the “dioxopiperidinyl group substituted with 1 to 3 C1-6 alkyl groups”, a 2,6-dioxo-3-ethylpiperidin-3-yl group or the like may be given.

[0051] As an example of the “phenylsulfonylamino group substituted with 1 to 3 C1-6 alkyl groups”, a 4-methylphenylsulfonylamino group or the like may be given. As an example of the “C1-6 alkylaminosulfonyl C1-6 alkyl group”, a methylaminosulfonylmethyl group or the like may be given.

[0052] As an example of the “oxadiazolyl group substituted with 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”, mention may be made of a group wherein an oxadiazole ring is substituted with a phenyl group substituted with a tert-butyl group, or a methoxy group, or a bromine atom. More particularly, a 5-(p-tert-butylphenyl)oxadiazolin-2-yl group, a 5-(m-methoxyphenyl)oxadiazolin-2-yl group, or a 5-(5-bromo-3-methoxyphenyl)oxadiazolin-2-yl group, or the like may be given.

[0053] As an example of “pyrazolyl group substituted with 1 to 3 substituents selected from the group consisting of halogen atoms, C1-6 alkyl groups, and trifluoromethyl groups”, a 3-trifluoromethylpyrazolyl group or the like may be given.

[0054] As an example of “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”, mention may be made of a furyl group substituted with a methyl group, or an ethoxycarbonyl group, or the like, and more particularly, a 5-methyl-4-ethoxycarbonyl-2-furyl group or the like.

[0055] As the “thienopyrimidinylthio group substituted with 1 to 3 C1-6 alkyl groups”, a substituted thienopyrimidinylthio group wherein the fused ring is substituted with one methyl or ethyl group is preferable, and more particularly, a group wherein a thiophene ring is substituted with a methyl group is more preferable.

[0056] As the “thienopyridylthio group substituted with 1 to 3 C1-6 alkyl groups”, a substituted thienopyridylthio group wherein the fused ring is substituted with one methyl or ethyl group is preferable, and more particularly, a group wherein a thiophene ring is substituted with a methyl group is more preferable.

[0057] As the “benzothiazolylthio group substituted with 1 to 3 halogen atoms”, a benzothiazolylthio group wherein the fused ring is substituted with one halogen atom is preferable, and more particularly, a group wherein the benzene ring is substituted with a chlorine atom is more preferable.

[0058] As the “isoxazolyl group substituted with 1 to 3 C1-6 alkyl groups”, an isoxazolyl group substituted with one or two methyl or ethyl groups is preferable, and more particularly, a 5-methylisoxazolyl-3-yl group is more preferable.

[0059] As the “thiazolyl group substituted with 1 to 3 C1-6 alkyl groups”, a thiazolyl group substituted with one or two methyl or ethyl groups is preferable.

[0060] As the “pyridyl group substituted with 1 to 3 C1-6 alkyl groups”, a pyridyl group substituted with one or two methyl or ethyl groups, and in particular, a 2-methylpyridin-6-yl group is preferable.

[0061] As the “pyrimidinyl group substituted with 1 to 3 C1-6 alkyl groups”, a pyrimidinyl group substituted with one or two methyl or ethyl groups is preferable, and more particularly, a 2,4-dimethylpyrimidin-6-yl group is more preferable.

[0062] As the “pyrimidinyl group substituted with 1 to 3 C1-6 alkoxy groups”, a pyrimidinyl group substituted with one or two methoxy or ethoxy groups is preferable, and more particularly, a 4-methoxypyrimidin-6-yl group, or a 2,4-dimethylpyrimidin-6-yl group is more preferable.

[0063] As the “pyridazinyl group substituted with 1 to 3 C1-6 alkoxy groups”, a pyridazinyl group substituted with one or two methoxy or ethoxy groups is preferable.

[0064] The term “C2-10 alkenyl group” means a straight-chain or branched alkenyl group having a double bond, and 2 to 10 carbon atoms. As an example thereof, mention may be made of an ethenyl group, a propenyl group, or a butynyl group, or the like, and more particularly, a 1,5-dimethyl-4-hexenyl group, or the like.

[0065] The term “C1-6 alkylthio group” means a straight-chain or branched alkylthio group having 1 to 6 carbon atoms. As an example thereof, mention may be made of a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, an isobutylthio group, a tert-butylthio group, a pentylthio group, or an isopentylthio group, or the like, and a methylthio group is particularly preferable.

[0066] The term “C2-6 alkanoyloxy group” means a group having a combined structure of a C2-6 alkanoyl group and an oxy group (—O—). As an example thereof, mention may be made of an acetyloxy group, a propionyloxy group, a butyryloxy group, an isobutyryloxy group, or a valeryloxy group, or the like.

[0067] As an example of “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”, mention may be made of a 4-chlorophenyl group, a 4-fluorophenyl group, a 2,5-difluorophenyl group, a 2,5-dichlorophenyl group, an o-phenethylphenyl group, a 4-methylthiophenyl group, a m-phenoxyphenyl group, a 4-methylphenyl group, a 3-methylphenyl group, a 2-methylphenyl group, a 2-methoxyphenyl group, a 3-methoxyphenyl group, a 4-methoxyphenyl group, a 2,3-dimethoxyphenyl group, a 2,4-dimethoxyphenyl group, a 4-methoxycarbonylphenyl group, a p-phenylphenyl group, or a m-cyanophenyl group, or the like.

[0068] The term “C1-6 alkoxy C1-6 alkoxy group” means a group having a combined structure of a C1-6 alkoxy group and a C1-6 alkoxy group. As an example thereof, mention may be made of a methoxymethoxy group, a methoxyethoxy group, an ethoxyethoxy group, or a methoxypropoxy group, or the like.

[0069] Examples of the “C1-6 alkoxy C1-6 alkoxy C1-6 alkoxy group” include CH3OCH2CH2OCH2CH2O— and the like.

[0070] Examples of the “di(C1-6 alkyl)amino group” include —N(CH3)2, —N(CH2CH3)2, —N(CH2CH2CH3)2, and the like.

[0071] Examples of the “di(C1-6 alkyl)amino C1-6 alkoxy group” include  OCH2N(CH3)2, —OCH2CH2N(CH3)2, —OCH2CH2N(CH2CH3)2, and the like.

[0072] The term “N—(C1-6 alkyl)toluidino group” means a group having a structure wherein a toluidino group (CH3—C6H4—NH—) is substituted with a C1-6 alkyl group and preferably is substituted with a methyl or ethyl group. In particular, an N-ethyl-m-toluidino group is preferable.

[0073] The “furyl group” includes a 2-furyl or 3-furyl group.

[0074] The “oxetanyl group” has a structure of a saturated 4-membered ring having one oxygen atom as a hetero atom, and includes a 2-oxetanyl group, or a 3-oxetanyl group.

[0075] The “oxolanyl group” has a structure of a saturated 5-membered ring having one oxygen atom as a hetero atom, and includes a 2-oxolanyl group, or a 3-oxolanyl group.

[0076] The “dioxolanyl group” refers to a mono-valent group derived by eliminating hydrogen atom from a saturated 5-membered ring having two oxygen atoms as hetero atoms (dioxolane), preferably from a 1,3-dioxolane ring. In the dioxolanyl group, the ring thereof may be substituted with C1-6 alkyl group(s). As an example thereof, a 2,2-dimethyl-1,3-dioxolan-4-yl group or the like may be given.

[0077] The “oxanyl group” has a structure of a saturated 6-membered ring having one oxygen atom as a hetero atom, and includes a 2-oxanyl, a 3-oxanyl group, or a 4-oxanyl group.

[0078] The “dioxanyl group” refers to a mono-valent group derived by eliminating hydrogen atom from a saturated 6-membered ring having two oxygen atoms as hetero atoms (dioxane), preferably from a 1,3-dioxane ring. In the dioxanyl group, the ring thereof may be substituted with C1-6 alkyl group(s). As an example thereof, a 5,5-dimethyl-1,3-dioxan-2-yl group or the like may be given.

[0079] The “benzodioxanyl group” refers to a mono-valent group derived by eliminating hydrogen atom from a benzodioxane ring, preferably a 1,4-benzodioxane ring. As an example thereof, a 1,4-benzodioxan-2-yl group or the like may be given.

[0080] The “piperidinyl group” includes a 2-piperidinyl, a 3-piperidinyl group, or a 4-piperidinyl group. In addition, in the piperidinyl group, the nitrogen atom present therein may be substituted with a C1-6 alkyl group, and an N-methyl-piperidinyl group is preferred.

[0081] The “piperidino group” refers to a mono-valent group derived by eliminating a hydrogen atom present on the nitrogen atom of piperidine.

[0082] The “pyridyl group” includes a 2-pyridyl group, a 3-pyridyl group, or a 4-pyridyl group. In the pyridyl group, the ring thereof maybe substituted with a C1-6 alkyl group, preferably a methyl group. As an example thereof, a 6-methyl-2-pyridyl group may be given.

[0083] The “pyridylthio group” has a combined structure of a pyridyl group and one thio group, and includes a pyridin-2-ylthio group, a pyridin-3-ylthio group, or a pyridin-4-ylthio group, and a pyridin-2-yl group is preferable.

[0084] The “pyrrolidino group” refers to a mono-valent group derived by eliminating a hydrogen atom present on the nitrogen atom of pyrrolidine.

[0085] The “pyrrolidon-1-yl group” includes a 2-pyrrolidon-1-yl or 3-pyrrolidon-1-yl group.

[0086] The “pyrrolidinyl group” includes a 2-pyrrolidinyl group or 3-pyrrolidinyl group. In the pyrrolidinyl group, the nitrogen atom present thereon may be substituted with a C1-6 alkyl group. As an example thereof, an N-methyl-2-pyrrolidinyl group or the like may be given.

[0087] The “quinolyl” includes a 2-quinolyl group, a 3-quinolyl group, a 4-quinolyl group, a 5-quinolyl group, a 6-quinolyl group, a 7-quinolyl group, or a 8-quinolyl group, and a 2-quinolyl group is preferable.

[0088] The “pyrrolyl group” includes a 1-pyrrolyl group, a 2-pyrrolyl group, or a 3-pyrrolyl group, and a 1-pyrrolyl group (N-pyrrolyl group) is preferable.

[0089] The “thienyl group” includes a2-thienyl group, or a 3-thienyl group.

[0090] The “thiazolyl group” includes a 2-thiazolyl group, a 4-thiazolyl group, or a 5-thiazolyl group. In addition, in the thiazolyl group, the ring thereof may be substituted with a C1-6 alkyl group. As an example thereof, a 4-methyl-5-thiazolyl group or the like may be given.

[0091] The “morpholino group” refers to a mono-valent group derived by eliminating a hydrogen atom present on the nitrogen atom of morpholine.

[0092] The “furfuryl group” means a 2-furfuryl group.

[0093] The “2,6-purindion-7-yl group” refers to a mono-valent group derived from 2,6-purindione wherein oxo groups (═O) are bonded to the carbon atoms at the 2-position and the 6-position of the purine ring and a group derived by eliminating the hydrogen atom present on the nitrogen atom at the 7-position. For the “2,6-purindion-7-yl substituted with C1-6 alkyl group(s)”, it is preferable that one or two nitrogen atoms on the group be substituted with a C1-6 alkyl group, and in particular, a methyl group. As an example thereof, a 1,3-dimethyl-2,6-purindion-7-yl group or the like may be given.

[0094] Any two groups of R1 to R5 adjacent to each other in the general formula (1), taken together with the benzene ring to which they are bonded, may form the ring structures described above. In these rings, the following rings may be specially mentioned.

[0095] As the “phthalimide ring substituted with a C1-6 alkyl group”, a ring substituted with a methyl or ethyl group is preferable, and more particularly, for example, a ring substituted with a methyl group such as an N-methyl-phthalimide ring is more preferable.

[0096] As the “dibenzofuran ring substituted with a C1-6alkoxy group”, a ring substituted with a methoxy or ethoxy group is preferable, and particularly, a ring substituted with a methoxy group is more preferable.

[0097] As the “fluorene ring substituted with a halogen atom”, a ring substituted with a chlorine or bromine atom is preferred, and furthermore, a ring substituted with a bromine atom is more preferable.

[0098] As the “carbostyryl ring substituted with a C1-6 alkyl group”, a ring substituted with a methyl or ethyl group is preferable and furthermore, a ring substituted with a methyl group is more preferable.

[0099] As the “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 ring substituted with 1 to 3 cyano groups, halogen atoms, nitro groups, methyl groups or ethyl groups is preferable, and particularly, a ring substituted with a cyano group, a bromine or chlorine atom, a nitro group or a methyl group is more preferable.

[0100] As the “quinoline ring substituted with a C1-6 alkyl group”, a ring substituted with a methyl or ethyl group is preferred, and in particular, a quinoline ring substituted with a methyl group is more preferable.

[0101] As the “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 ring substituted with a methyl group, an ethyl group, a methoxy group, an ethoxy group, a methoxymethyl group, a methoxyethyl group, an ethoxymethyl group, or an ethoxyethyl group is preferred, and in particular, a ring substituted with a methyl or methoxymethyl group is more preferable.

[0102] As the “cinnolin ring substituted with a C1-6 alkyl group”, a ring substituted with a methyl or ethyl group is preferred, and in particular, a ring substituted with a methyl group is more preferable.

[0103] As the “benzothiazol ring substituted with a C1-6 alkyl group”, the ring substituted with a methyl or ethyl group is preferred and furthermore, a ring substituted with a methyl group is more preferable.

[0104] In addition, in the present invention, the term “pharmaceutically-acceptable salt”refers to a salt with an alkali metal, an alkali earth metal, ammonium, an alkylammonium, or the like, as well as, a salt with a mineral acid or an organic acid. As an example thereof, mention may be made of sodium salts, potassium salts, calcium salts, ammonium salts, aluminum salts, triethylammonium salts, acetates, propionates, butyrates, formates, trifluoroacetates, maleates, tartarates, citrates, stearates, succinates, ethylsuccinates, lactobionates, gluconates, glucoheptonates, benzoates, methanesulfonates, ethanesulfonates, 2-hydroxyethanesulfonates, benzenesulfonates, para-toluenesulfonates, laurylsulfates, malates, aspartates, glutamates, adipates, salts with cysteine, salts with N-acetylcysteines, hydrochlorides, hydrobromides, phosphates, sulfates, hydroiodides, nicotinates, oxalates, picrates, thiocyanates, undecanates, salts with polymeric acrylic acid, salts with carboxyvinyl polymers, or the like.

[0105] The compounds represented by the general formula (1) of the present invention may be prepared by or according to the methods described in Japanese Patent Application, Toku-Kai-Sho 61-165360 (which is incorporated herein by reference.)

[0106] For example, the compounds of the present invention may be synthesized by reacting aniline derivatives substituted with R1 to R5 described below 3

[0107] with orthoformates such as trimethyl orthoformate, triethyl orthoformate, or the like in the presence or absence of a catalytic amount of an organic acid such as acetic acid, a mineral acid such as hydrochloric acid, or a salt of a mineral acid and an amine such as pyridine hydrochloride, for 2 to 72 hours at a temperature preferably in the range of room temperature to 150° C., and more preferably in the range of 70 to 100° C. to obtain an intermediate, and subsequently treating the intermediate, after isolation or in the state as produced, with hydroxylamine in a solvent such as ethanol.

[0108] The aniline derivatives described above may be prepared, for example, by the following method. Herein, in order to simplify the explanation, the aniline derivatives wherein R1, R2, R4, and R5 are hydrogen atoms and R3is a group represented by the formula: —Y—(CR61R62)m—(CR63R64”)n—R7, are employed.

[0109] At first, a compound represented by the formula (a): 4

[0110] (wherein X represents a halogen atom) and a compound, for example, represented by the following formula (b):

R7(CR63R64)m—(CR61R62)mYH   (b)

[0111] (wherein R7, Y, R61, R62, m, R63, R64, and n have the same meanings as described above) are reacted in the presence of a base to obtain a compound represented by the following formula (c). 5

[0112] Subsequently, the compound represented by the formula (c) described above is derived to an aniline derivative represented by the following formula (d) by means of a general method for reducing an aromatic nitro group to an aromatic amino group. 6

[0113] The inhibitors for production of 20-HETE according to the present invention comprise compounds represented by the general formula (1) or the pharmaceutically-acceptable salts thereof as active ingredients, and effectively inhibit the production of 20-HETE.

[0114] In addition, the inhibitors for production of 20-HETE of the present invention are useful as medicines, and in particular, therapeutic agents for kidney diseases, cerebrovascular diseases, or circulatory diseases.

[0115] The dose of the medicines (including therapeutic agents for kidney diseases, cerebrovascular diseases, or circulatory diseases), as well as the inhibitors for production of 20-HETE according to the present invention, is preferably in a range of 1 to 2000 mg per day as the compounds represented by the general formula (1) or the pharmaceutically-acceptable salts thereof, in the case of an adult human subject to be treated. They may be administered in a single dose or divided into several doses per day. The doses may vary depending on the usage, as well as, the age, weight, and conditions of each individual patient, and the like.

[0116] The medicines (therapeutic agents for kidney diseases, cerebrovascular diseases, or circulatory diseases) as well as, the inhibitors for production of 20-HETE according to the present invention may be administered orally or parenterally, in the form of tablets, capsules, granules, powders, troches, ointments, creams, emulsions, suspensions, suppositories, injectable solutions, or the like, each of which may be produced according to the conventional formulation methods (for example, methods defined in the 12th revision of Japanese Pharmacopeia). These preparation forms may be selected depending on the conditions and ages of the patients, as well as the purpose of the treatment. Upon manufacturing preparations in various formulations, conventional fillers (for example, crystalline cellulose, starch, lactose, mannitol, or the like), binders (for example, hydroxypropylcellulose, polyvinylpyrrolidone, or the like), lubricants (for example, magnesium stearate, talc, or the like), disintegrants (for example, carboxymethylcellulose calcium, or the like), and the like, may be employed.

BEST MODES FOR CARRYING OUR THE INVENTION

[0117] In the following, the present invention is illustrated in detail by the following examples. However, it should be understood that the present invention is not limited to the examples described below.

EXAMPLE 1

Synthesis of N-(4-butyl-2-methylphenyl)-N′-hydroxy-formamidine

[0118] 4-Butyl-2-methylaniline (129.18 g) and ethyl orthoformate (234.66 g) were stirred for 11 hours at 100° C. Subsequently, the excess of the ethyl orthoformate was removed. The obtained crude product was dissolved in methanol (200 ml). To a methanol solution (500 ml) of hydroxylamine hydrochloride (65.59 g), a methanol solution (350 ml) of sodium methoxide (51.02 g) was added dropwise at 0° C. to neutralize. The precipitated sodium chloride was filtered off. The filtrate was added dropwise to the methanol solution of the crude product, and subsequently, the mixture was stirred for 15 hours at room temperature. The methanol was removed. The obtained residue was dissolved in 800 ml of chloroform, and subsequently, washed with water and saturated brine. The organic layer was dried over an hydrous magnesium sulfate and then the solvent was removed. The obtained residue was washed with hexane to yield 63.66 g of crude crystals of the target compound. One portion of the crude crystals (35.47 g) was recrystallized from hexane:ethyl acetate (1:4) to yield 29.85 g of the target compound as a colorless powder (Compound 1 in Table 1 described below).

[0119] Melting point: 131.5-134.0° C.

EXAMPLE 2

Synthesis of N-(4-tert-butylphenyl)-N′-hydroxy-formamidine

[0120] 4-tert-Butylaniline (3.9 g) and ethyl orthoformate (7.9 g) were stirred for 6.5 hours at 100° C. Subsequently, the excess of the ethyl orthoformate was removed. The obtained crude product was dissolved in methanol (10 ml). To a methanol solution (20 ml) of hydroxylamine hydrochloride (2.1 g), a methanol solution (15 ml) of sodium methoxide (1.6 g) was added dropwise at 0° C. to neutralize. The precipitated sodium chloride was filtered off. The filtrate was added dropwise to the methanol solution of the crude product, and subsequently, the mixture was stirred for 1.5 hours at room temperature. The methanol was removed. The obtained residue was dissolved in 50 ml of chloroform, and subsequently, washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to yield 1.65 g of the target compound (Compound 2 in Table 1 described below).

[0121] Melting point: 113.5-114.5° C.

EXAMPLE 3

Synthesis of N-(4-methoxycarbonylphenyl)-N′-hydroxyformamidine

[0122] A mixture of 4-aminobenzoic acid methyl ester (1.98 g) and ethyl orthoformate (4.07 g) was stirred for 16 hours at 100° C. Subsequently, the excess of the ethyl orthoformate was removed. To the obtained residue, a methanol solution (16 ml) of hydroxylamine prepared from hydroxylamine hydrochloride (1.50 g) and sodium methoxide (1.10 g) was added, and the mixture was stirred for 6 hours at room temperature. The solvent was removed and subsequently, to the residue, chloroform was added. Subsequently, it was washed successively with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed. The residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate), and subsequently, by recrystallized from chloroform—methanol to yield the target compound (Compound 123 in Table 1 described below) (0.32 g) as a colorless powder.

[0123] Melting point: 167.0-167.5° C.

EXAMPLE 4

Synthesis of N-(2-aminosulfonylphenyl)-N′-hydroxyformamidine

[0124] A mixture of 2-aminobenzsulfonamide (3.0 g), ethyl orthoformate (5.15 g), and ethyl acetate (20 ml) was stirred for 5 hours at 100° C. Subsequently, the excess of the ethyl orthoformate was removed. To a methanol solution (30 ml) of the residue, a methanol solution (40 ml) of hydroxylamine prepared from hydroxylamine hydrochloride (1.50 g) and sodium methoxide (1.10 g) was added, and the mixture was stirred for 2 days at room temperature. The solvent was removed and subsequently, to the residue, chloroform was added, and washed successively with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to yield the target compound (Compound 236 in Table 1 described below) (0.73 g) as a colorless powder.

[0125] Melting point: 130.5-131.5° C.

EXAMPLE 5

Synthesis of N-[4-(pyridin-2-ylmethoxy) phenyl]-N′-hydroxyformamidine

[0126] A mixture of 4-(pyridin-2-ylmethoxy)aniline (1.715 g) and ethyl orthoformate (2.613 g) was stirred for 14 hours at 100° C. Subsequently, the excess of the ethyl orthoformate was removed. To a methanol solution (20 ml) of the residue, a 1M methanol solution (10 ml) of hydroxylamine was added, and the mixture was stirred for 2.5 days at room temperature. The solvent was removed and subsequently, to the residue, chloroform was added. Subsequently, it was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed. The obtained residue was purified by recrystallization from ethyl acetate to yield the target compound (Compound 345 in Table 1 described below) (0.524 g) as a colorless powder.

[0127] Melting point: 159.5-161.0° C.

EXAMPLE 6

Synthesis of N-[4-(benzylthio)phenyl]-N′-hydroxyformamidine

[0128] A mixture of 4-(benzylthio) aniline (1.18 g) and ethyl orthoformate (1.78 g) was stirred for 12 hours at 100° C. Subsequently, the excess of the ethyl orthoformate was removed. To a methanol solution (20 ml) of the residue, a 1M methanol solution (10 ml) of hydroxylamine was added, and the mixture was stirred for 2.5 days at room temperature. The solvent was removed and subsequently, to the residue, chloroform was added. Subsequently, it was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed. The obtained residue was recrystallized from ethyl acetate to yield the target compound (Compound 441 in Table 1 described below) (0.43 g) as a colorless powder.

[0129] Melting point: 166° C.

EXAMPLE 7

[0130] The compounds shown in Table 1 described below were obtained by carrying out the similar procedures as those of Production Example 1. The compounds obtained in Production Examples 1 to 6, together with the other compounds are also shown in Table 1.

[0131] The Rf values in Table 1 corresponds to the Rf values in the case of development with a mixture of ethyl acetate:hexane (1:2) (no mark) or in the case of development with a mixture of chloroform:methanol (9:1) (marked as *), employing thin layer chromatography Silica gel 60 F254, produced by Merck, or NH-TLC plates, produced by Fuji Silysia Chemical Ltd. In addition, the term “posi” or “nega” denotes data of the cation peak (M+H) or the anion peak (M−H), observed in a positive mode or a negative mode upon measurement of mass spectrum by means of the ESI method.

TABLE 1
										Inhibition
			M + H	M + H	M − H	M − H	Rf	TLC	Developing	rate	IC50
Comp.	Chemical Structure	mp.	(ESI)	(APCI)	(ESI)	(APCI)	value	*	solvent	(1 μM)	(nM)
Comp. 1	7	131.5-134.0	207	207		205	0.56	SiO2(NH)	EtOAc:MeOH=95:5	100.5	3.5
Comp. 2	8	113.5-114.5	193		191		0.13	SiO2	Hexane:AcOEt=2:1	97.0	7.8
Comp. 3	9	84.5-85.5	193		191		0.22	SiO2	Hexane:AcOEt=2:1	98.9
Comp. 4	10	101.0-102.5			191		0.15	SiO2	Hexane:AcOEt=2:1	107.6	3
Comp. 5	11	153.0-154.0	219		217		0.13	SiO2	Hexane:AcOEt=2:1	99.9	3.8
Comp. 6	12	119.5-120.5	223		221		0.20	SiO2	Hexane:AcOEt=2:1	99.9
Comp. 7	13	122.5-124.0	207		205		0.14	SiO2	Hexane:AcOEt=2:1	110.5	12.1
Comp. 8	14	141.0-142.0	193		191		0.21	SiO2	Hexane:AcOEt=2:1	99.9
Comp. 9	15	108.0-110.0	221		219		0.15	SiO2	Hexane:AcOEt=2:1	99.9	4.9
Comp. 10	16	143.5-144.5			151		0.12	SiO2	Hexane:AcOEt=2:1	89.5	669.0
Comp. 11	17	151.0-152.5	185		183		0.18	SiO2	Hexane:AcOEt=2:1	92.7	297.1
Comp. 12	18	139.5-140.5	155				0.08	SiO2	Hexane:AcOEt=2:1	77.1	1415.5
Comp. 13	19	116.0-118.0	165		163		0.12	SiO2	Hexane:AcOEt=2:1	95.9	117.9
Comp. 14	20	151.0-153.0			183		0.19	SiO2	Hexane:AcOEt=2:1	91.7	162.8
Comp. 15	21	155.5-156.0	171		169		0.10	SiO2	Hexane:AcOEt=2:1	92.9	287.7
Comp. 16	22	141.0-142.0	165		163		0.12	SiO2	Hexane:AcOEt=2:1	97.6	6.6
Comp. 17	23	136.5-139.0	181		179		0.15	SiO2	Hexane:AcOEt=2:1	85.3
Comp. 18	24	139.0-140.0	167		165		0.06	SiO2	Hexane:AcOEt=2:1	94.6	45.2
Comp. 19	25	144.0-145.0	181		179		0.08	SiO2	Hexane:AcOEt=2:1	88.0	337.6
Comp. 20	26	149.0-150.0	181		179		0.07	SiO2	Hexane:AcOEt=2:1	97.5	227.6
Comp. 21	27	115.5-116.5	165		163		0.14	SiO2	Hexane:AcOEt=2:1	81.1
Comp. 22	28	139.0-141.0					0.16	SiO2	Hexane:AcOEt=2:1	95.7
Comp. 23	29	110.0-111.5	171		169		0.12	SiO2	Hexane:AcOEt=2:1	82.8	475.8
Comp. 24	30	119.0-120.5	205				0.10	SiO2	Hexane:AcOEt=2:1	89.2	519.7
Comp. 25	31	142.5-144.5	189		187		0.15	SiO2	Hexane:AcOEt=2:1	87.0
Comp. 26	32	155.0-156.5	201		199		0.18	SiO2	Hexane:AcOEt=2:1	86.0	203.7
Comp. 27	33	140.5-142.0	205		203		0.10	SiO2	Hexane:AcOEt=2:1	103.3	1.7
Comp. 28	34	119.0-120.5	235		233		0.15	SiO2	Hexane:AcOEt=2:1	92.5	4.7
Comp. 29	35	93.0-94.5	179		177		0.13	SiO2	Hexane:AcOEt=2:1	93.6
Comp. 30	36	143.0-143.5	179		177		0.12	SiO2	Hexane:AcOEt=2:1	103.3	2.4
Comp. 31	37	131.0-132.0	179				0.12	SiO2	Hexane:AcOEt=2:1	97.8	6.6
Comp. 32	38	114.0-115.0	179				0.16	SiO2	Hexane:AcOEt=2:1	87.2
Comp. 33	39	171.0			291		0.23	SiO2	Hexane:AcOEt=2:1	91.9
Comp. 34	40	163.0-163.5	293		291		0.17	SiO2	Hexane:AcOEt=2:1	90.6	79.7
Comp. 35	41	161.0					0.17	SiO2	Hexane:AcOEt=2:1	95.4	86.5
Comp. 36	42	163.0-164.0	215		213		0.10	SiO2	Hexane:AcOEt=2:1	98.3	136.5
Comp. 37	43	167.0-167.5	195		193		0.06	SiO2	Hexane:AcOEt=2:1	92.7
Comp. 38	44	151.0-152.5	185		183		0.13	SiO2	Hexane:AcOEt=2:1	89.8	79.8
Comp. 39	45	110.0-113.0	221		219		0.10	SiO2	Hexane:AcOEt=2:1	99.0	22
Comp. 40	46	160.0-161.0	205		203		0.16	SiO2	Hexane:AcOEt=2:1	98.2
Comp. 41	47	161.0-161.5	229		227		0.13	SiO2	Hexane:AcOEt=2:1	96.6	49.0
Comp. 42	48	144.0-145.0					0.44	SiO2	CHCl3:MeOH=9:1	99.9
Comp. 43	49	123.0-124.0	169		167		0.30	SiO2	CHCl3:MeOH=9:1		168.1
Comp. 44	50	145.0-146.0	223		221		0.32	SiO2	CHCl3:MeOH=9:1		8.1
Comp. 45	51	163.5-164.5	243				0.45	SiO2	CHCl3:MeOH=9:1	53.5
Comp. 46	52	100.5-102.0	205		203		0.24	SiO2	CHCl3:MeOH=9:1	48.5	355.3
Comp. 47	53	166.0-166.5	277		275		0.37	SiO2	CHCl3:MeOH=9:1	94.8	6.5
Comp. 48	54	155.0-156.0	335				0.52	SiO2	CHCl3:MeOH=9:1
Comp. 49	55	122.5-124.0			271		0.44	SiO2	CHCl3:MeOH=9:1	46.7
Comp. 50	56	155.5-156.5	173		171		0.34	SiO2	CHCl3:MeOH=9:1		25.5
Comp. 51	57	157.0-158.0	229		227		0.42	SiO2	CHCl3:MeOH=9:1	50.2	21.8
Comp. 52	58	145.0-146.0	181				0.43	SiO2	CHCl3:MeOH=9:1
Comp. 53	59	159.0-160.0	271				0.66	SiO2	CHCl3:MeOH=9:1
Comp. 54	60	162.5-163.5					0.43	SiO2	CHCl3:MeOH=9:1
Comp. 55	61	130.5-132.0	277		275		0.5	SiO2	CHCl3:MeOH=9:1	31.3
Comp. 56	62	144.0-145.5	190		188		0.42	SiO2	CHCl3:MeOH=9:1	50.6
Comp. 57	63		193		191		0.22	SiO2	Hexane:AcOEt=2:1	59.1
Comp. 58	64	146.5-148.0	257		255		0.21	SiO2	Hexane:AcOEt=2:1	99.9	7.1
Comp. 59	65		167		165		0.13	SiO2	Hexane:AcOEt=2:1	49.0
Comp. 60	66		181		179		0.15	SiO2	Hexane:AcOEt=2:1
Comp. 61	67				163		0.17	SiO2	Hexane:AcOEt=2:1
Comp. 62	68		151				0.12	SiO2	Hexane:AcOEt=2:1	69.5
Comp. 63	69		165		163		0.15	SiO2	Hexane:AcOEt=2:1	49.3
Comp. 64	70				163		0.13	SiO2	Hexane:AcOEt=2:1
Comp. 65	71		167		165		0.08	SiO2	Hexane:AcOEt=2:1	59.3
Comp. 66	72		181		179		0.10	SiO2	Hexane:AcOEt=2:1	41.2
Comp. 67	73		185		183		0.15	SiO2	Hexane:AcOEt=2:1	48.4
Comp. 68	74		205		203		0.15	SiO2	Hexane:AcOEt=2:1
Comp. 69	75		189		187		0.15	SiO2	Hexane:AcOEt=2:1	58.7
Comp. 70	76		249		247		0.15	SiO2	Hexane:AcOEt=2:1	32.9
Comp. 71	77		179		177		0.18	SiO2	Hexane:AcOEt=2:1	42.5
Comp. 72	78	168.0-169.0	179				0.12	SiO2	Hexane:AcOEt=2:1	99.2
Comp. 73	79		297		295		0.18	SiO2	Hexane:AcOEt=2:1	99.9
Comp. 74	80		243		241		0.11	SiO2	Hexane:AcOEt=2:1	43.7
Comp. 75	81		215		213		0.16	SiO2	Hexane:AcOEt=2:1	46.9
Comp. 76	82				195		0.06	SiO2	Hexane:AcOEt=2:1	35.1
Comp. 77	83				281		0.17	SiO2	Hexane:AcOEt=2:1	49.0
Comp. 78	84		197		195		0.03	SiO2	Hexane:AcOEt=2:1	36.3
Comp. 79	85		155		153		0.15	SiO2	Hexane:AcOEt=2:1	35.3
Comp. 80	86		239		237		0.32	SiO2	Hexane:AcOEt=2:1	37.2
Comp. 81	87		205		203		0.14	SiO2	Hexane:AcOEt=2:1	51.3
Comp. 82	88	133.5-134.5	215		213		0.12	SiO2	Hexane:AcOEt=2:1	70.9
Comp. 83	89		249				0.46	SiO2	CHCl3:MeOH=9:1
Comp. 84	90		221		219		0.27	SiO2	CHCl3:MeOH=9:1
Comp. 85	91		229		227		0.37	SiO2	CHCl3:MeOH=9:1
Comp. 86	92		185		183		0.29	SiO2	CHCl3:MeOH=9:1	58.7
Comp. 87	93		187				0.22	SiO2	CHCl3:MeOH=9:1
Comp. 88	94		231		229		0.31	SiO2	CHCl3:MeOH=9:1
Comp. 89	95		210		208		0.32	SiO2	CHCl3:MeOH=9:1
Comp. 90	96		235				0.33	SiO2	CHCl3:MeOH=9:1	36.5
Comp. 91	97		263				0.27	SiO2	CHCl3:MeOH=9:1	36.6
Comp. 92	98		230		228		0.51	SiO2	CHCl3:MeOH=9:1
Comp. 93	99						0.21	SiO2	CHCl3:MeOH=9:1
Comp. 94	100		226		224		0.29	SiO2	CHCl3:MeOH=9:1	41.2
Comp. 95	101		210		208		0.32	SiO2	CHCl3:MeOH=9:1	44.5
Comp. 96	102		335				0.40	SiO2	CHCl3:MeOH=9:1
Comp. 97	103		239		237		0.32	SiO2	CHCl3:MeOH=9:1
Comp. 98	104		185				0.21	SiO2	CHCl3:MeOH=9:1	43.9
Comp. 99	105		197		195		0.29	SiO2	CHCl3:MeOH=9:1	40.8
Comp. 100	106		370		368		0.38	SiO2	CHCl3:MeOH=9:1	44.3
Comp. 101	107		201		199		0.24	SiO2	CHCl3:MeOH=9:1	52.4
Comp. 102	108		375		373		0.41	SiO2	CHCl3:MeOH=9:1	44.4
Comp. 103	109	143.0-146.0	227		225		0.21	SiO2	CHCl3:MeOH=9:1
Comp. 104	110		181				0.39	SiO2	CHCl3:MeOH=9:1	31.9
Comp. 105	111		303		301		0.12	SiO2	CHCl3:MeOH=9:1	46.7
Comp. 106	112		165		163		0.25	SiO2	CHCl3:MeOH=9:1
Comp. 107	113		196		194		0.37	SiO2	CHCl3:MeOH=9:1
Comp. 108	114		231				0.39	SiO2	CHCl3:MeOH=9:1	36.4
Comp. 109	115		196		194		0.13	SiO2	CHCl3:MeOH=9:1
Comp. 110	116						0.13	SiO2	CHCl3:MeOH=9:1
Comp. 111	117		191				0.37	SiO2	CHCl3:MeOH=9:1
Comp. 112	118				160		0.24	SiO2	CHCl3:MeOH=9:1	37.4
Comp. 113	119		196		194		0.08	SiO2	CHCl3:MeOH=9:1
Comp. 114	120				223		0.21	SiO2	CHCl3:MeOH=9:1
Comp. 115	121		239		237		0.4	SiO2	CHCl3:MeOH=9:1
Comp. 116	122		197		195		0.37	SiO2	CHCl3:MeOH=9:1
Comp. 117	123		249		247		0.39	SiO2	CHCl3:MeOH=9:1	71.6
Comp. 118	124		225		223		0.41	SiO2	CHCl3:MeOH=9:1
Comp. 119	125		249				0.27	SiO2	CHCl3:MeOH=9:1
Comp. 120	126		173		171		0.37	SiO2	CHCl3:MeOH=9:1
Comp. 121	127	166.5-167.0			237		0.29	SiO2	EtOAc:hexane=1:2	72.0
Comp. 122	128	106.0-107.5	223		221		0.05	SiO2	EtOAc:hexane=1:2	94.7	28.9
Comp. 123	129	167.0-167.5		195	193		0.47	SiO2(NH)	EtOAc:MeOH=95:5	92.7
Comp. 124	130	100.0-102.0			227		0.12	SiO2	EtOAc:hexane=1:2	92.2	354.5
Comp. 125	131	138.0-139.5 (dec.)								67.6
Comp. 126	132	172.5-173.0 (dec.)								34.9
Comp. 127	133	137.5-138.5		209		207	0.53	SiO2(NH)	EtOAc:MeOH=95:5
Comp. 128	134	143.0-145.0	263				0.26	SiO2	CHCl3:MeOH=9:1	102.0	7.0
Comp. 129	135	183.0-183.5		253	251		0.50	SiO2(NH)	EtOAc:MeOH=95:5
Comp. 130	136	155.0-156.0	243		241		0.10	SiO2	EtOAc:hexane=1:2	116.5	6.9
Comp. 131	137	144.0-145.5	229		227		0.09	SiO2	EtOAc:hexane=1:2	89.2	26
Comp. 132	138	122.0-123.5								117.6	3.9
Comp. 133	139	116.5-117.5								48.6	720
Comp. 134	140	154.0-154.5								57.4	3625
Comp. 135	141		137		135		0.10	SiO2	EtOAc:hexane=1:2	49.3
Comp. 136	142		243		2441		0.17	SiO2	EtOAc:hexane=1:2
Comp. 137	143		229		227		0.15	SiO2	EtOAc:hexane=1:2
Comp. 138	144		297		295		0.11	SiO2	EtOAc:hexane=1:2	44.0
Comp. 139	145		179		177		0.13	SiO2	EtOAc:hexane=1:2	69.7
Comp. 140	146			194	192		0.23	SiO2(NH)	AcOEt:EtOH=90:10
Comp. 141	147			194	192		0.06	SiO2	CHCl3:MeOH=95:5
Comp. 142	148				219		0.22	SiO2	AcOEt:EtOH=90:10
Comp. 143	149			196	194		0.25	SiO2	CHCl3:MeOH=95:5	37.3
Comp. 144	150			215	213		0.13	SiO2	CHCl3:MeOH=95:5
Comp. 145	151				213		0.11	SiO2	CHCl3:MeOH=95:5
Comp. 146	152			235	233		0.25	SiO2(NH)	AcOEt
Comp. 147	153			273	271		0.26	SiO2(NH)	AcOEt
Comp. 148	154			327	325		0.32	SiO2(NH)	AcOEt
Comp. 149	155			265	263		0.34	SiO2(NH)	AcOEt	36.5
Comp. 150	156			262	260		0.15	SiO2(NH)	AcOEt	34.1
Comp. 151	157			203	201		0.20	SiO2(NH)	AcOEt	108.2
Comp. 152	158			255	253		0.28	SiO2(NH)	AcOEt
Comp. 153	159			203	201		0.29	SiO2(NH)	AcOEt	39.4
Comp. 154	160			237	235		0.24	SiO2(NH)	AcOEt
Comp. 155	161			246	244		0.23	SiO2(NH)	AcOEt
Comp. 156	162			327	325		0.32	SiO2(NH)	AcOEt	39.4
Comp. 157	163			277	275		0.28	SiO2(NH)	AcOEt	121.4
Comp. 158	164			195	193		0.24	SiO2(NH)	AcOEt
Comp. 159	165			209	207		0.26	SiO2(NH)	AcOEt
Comp. 160	166			181	179		0.21	SiO2(NH)	EtOAc:MeOH=95:5
Comp. 161	167	156.0-157.0		169		167	0.51	SiO2(NH)	EtOAc:MeOH=95:5	88.6	13.4
Comp. 162	168			183	181		0.49	SiO2(NH)	EtOAc:MeOH=95:5	62.6
Comp. 163	169			207		205	0.61	SiO2(NH)	EtOAc:MeOH=95:5	40.0
Comp. 164	170			186		184	0.55	SiO2(NH)	EtOAc:MeOH=95:5	86.7
Comp. 165	171			169			0.54	SiO2(NH)	EtOAc:MeOH=95:5	105.7
Comp. 166	172			200			0.56	SiO2(NH)	EtOAc:MeOH=95:5
Comp. 167	173			221		219	0.58	SiO2(NH)	EtOAc:MeOH=95:5
Comp. 168	174			228	226		0.57	SiO2(NH)	EtOAc:MeOH=95:5	61.9
Comp. 169	175			272	270		0.57	SiO2(NH)	EtOAc:MeOH=95:5	104.1
Comp. 170	176			186		184	0.50	SiO2(NH)	EtOAc:MeOH=95:5	99.8
Comp. 171	177			181			0.23	SiO2(NH)	EtOAc:MeOH=95:5	54.1
Comp. 172	178			181			0.21	SiO2(NH)	EtOAc:MeOH=95:5
Comp. 173	179			181		179	0.30	SiO2(NH)	EtOAc:MeOH=95:5
Comp. 174	180			202			0.22	SiO2(NH)	EtOAc:MeOH=95:5	62.4
Comp. 175	181			193		191	0.56	SiO2(NH)	EtOAc:MeOH=95:5	69.9
Comp. 176	182			230		228	0.51	SiO2(NH)	EtOAc:MeOH=95:5	67.0
Comp. 177	183			244	242		0.53	SiO2(NH)	EtOAc:MeOH=95:5	85.4
Comp. 178	184	121.0-122.5		193		191	0.52	SiO2(NH)	EtOAc:MeOH=95:5	91.4	9.0
Comp. 179	185			179		177	0.54	SiO2(NH)	EtOAc:MeOH=95:5	63.5
Comp. 180	186			206	204		0.59	SiO2(NH)	EtOAc:MeOH=95:5
Comp. 181	187				227		0.54	SiO2(NH)	EtOAc:MeOH=95:5
Comp. 182	188			216	214		0.56	SiO2(NH)	EtOAc:MeOH=95:5	90.2
Comp. 183	189			209	207		0.50	SiO2(NH)	EtOAc:MeOH=95:5	92.0
Comp. 184	190			255	253		0.48	SiO2(NH)	EtOAc:MeOH=95:5
Comp. 185	191			180	178		0.36	SiO2(NH)	EtOAc:MeOH=95:5
Comp. 186	192			197	195		0.29	SiO2(NH)	EtOAc:MeOH=95:5
Comp. 187	193			195	193		0.50	SiO2(NH)	EtOAc:MeOH=95:5
Comp. 188	194			223	221		0.50	SiO2(NH)	EtOAc:MeOH=95:5	59.1
Comp. 189	195			237	235		0.50	SiO2(NH)	EtOAc:MeOH=95:5	116.8
Comp. 190	196			225	223		0.51	SiO2(NH)	EtOAc:MeOH=95:5	44.9
Comp. 191	197			269	267		0.50	SiO2(NH)	EtOAc:MeOH=95:5
Comp. 192	198			230	228		0.56	SiO2(NH)	EtOAc:MeOH=95:5
Comp. 193	199			209		207	0.52	SiO2(NH)	EtOAc:MeOH=95:5
Comp. 194	200			197		195	0.44	SiO2(NH)	EtOAc:MeOH=95:5	67.5
Comp. 195	201			197			0.51	SiO2(NH)	EtOAc:MeOH=95:5
Comp. 196	202					220	0.52	SiO2(NH)	EtOAc:MeOH=95:5	46.9
Comp. 197	203			190	188		0.57	SiO2(NH)	EtOAc:MeOH=95:5
Comp. 198	204			197			0.50	SiO2(NH)	EtOAc:MeOH=95:5	81.8
Comp. 199	205			209	207		0.50	SiO2(NH)	EtOAc:MeOH=95:5	85.6
Comp. 200	206			274	272		0.50	SiO2(NH)	EtOAc:MeOH=95:5	53.3
Comp. 201	207			321	319		0.50	SiO2(NH)	EtOAc:MeOH=95:5	70.1
Comp. 202	208			244	242		0.53	SiO2(NH)	EtOAc:MeOH=95:5	31.6
Comp. 203	209			217		215	0.45	SiO2(NH)	EtOAc:MeOH=95:5	51.1
Comp. 204	210			181		179	0.30	SiO2(NH)	EtOAc:MeOH=95:5
Comp. 205	211			167		165	0.25	SiO2(NH)	EtOAc:MeOH=95:5
Comp. 206	212			217			0.49	SiO2(NH)	EtOAc:MeOH=95:5
Comp. 207	213	138.0-140.0		181		179	0.29	SiO2(NH)	EtOAc:MeOH=95:5	90.7	11.6
Comp. 208	214			253	251		0.53	SiO2(NH)	EtOAc:MeOH=95:5
Comp. 209	215	169.5-170.0		167	165		0.27	SiO2(NH)	EtOAc:MeOH=95:5	102.2	151.6
Comp. 210	216			313	311		0.58	SiO2(NH)	EtOAc:MeOH=95:5	78
Comp. 211	217		183		181		0.35	SiO2	CHCl3:MeOH=9:1
Comp. 212	218		251		249		0.35	SiO2	CHCl3:MeOH=9:1
Comp. 213	219		279				0.15	SiO2	CHCl3:MeOH=9:1
Comp. 214	220		181		179		0.12	SiO2	CHCl3:MeOH=9:1	31.9
Comp. 215	221				225		0.25	SiO2	CHCl3:MeOH=9:1	36.1
Comp. 216	222				167		0.31	SiO2	CHCl3:MeOH=9:1
Comp. 217	223		253				0.4	SiO2	CHCl3:MeOH=9:1
Comp. 218	224		194				0.08	SiO2	CHCl3:MeOH=9:1
Comp. 219	225		221		219		0.38	SiO2	CHCl3:MeOH=9:1
Comp. 220	226		176		174		0.28	SiO2	CHCl3:MeOH=9:1
Comp. 221	227		193		191		0.35	SiO2	CHCl3:MeOH=9:1
Comp. 222	228				225		0.29	SiO2	CHCl3:MeOH=9:1
Comp. 223	229		290		288		0.34	SiO2	CHCl3:MeOH=9:1	52.2
Comp. 224	230		237		235		0.31	SiO2	CHCl3:MeOH=9:1	47.1
Comp. 225	231		343		341		0.05	SiO2	CHCl3:MeOH=9:1
Comp. 226	232		277		275		0.37	SiO2	CHCl3:MeOH=9:1
Comp. 227	233	139.0-141.0	191		189		0.31	SiO2	AcOEt	117.8	39.7
Comp. 228	234				267		0.15	SiO2	EtOAc:hexane=1:2	72.0
Comp. 229	235	194.0-195.0	238		236		0.34	SiO2	CHCl3:MeOH=9:1	99.3	16.0
Comp. 230	236	165.0-165.5	181		179		0.07	SiO2	EtOAc:hexane=1:2
Comp. 231	237	168.5-169.0	191		189		0.16	SiO2	EtOAc:hexane=1:2	92.9	196.5
Comp. 232	238	154.0-155.0								86.0	6.6
Comp. 233	239	118.0-119.5	227		225		0.10	SiO2	EtOAc:hexane=1:2	87.5	51.9
Comp. 234	240	111.0-113.0	213		211		0.15	SiO2	EtOAc:hexane=1:2	74.1
Comp. 235	241	167.5-168.0			263		0.13	SiO2	EtOAc:hexane=1:2	77.8	5915.9
Comp. 236	242	130.5-131.5
Comp. 237	243	197.5-198.0			237		0.17	SiO2	EtOAc:hexane=1:2	96.6	26.2
Comp. 238	244	142.5-144.0	177		175		0.12	SiO2	EtOAc:hexane=1:2	101.6	30.0
Comp. 239	245	182.5-183.0									4078
Comp. 240	246		227		225		0.15	SiO2	EtOAc:hexane=1:2
Comp. 241	247		243				0.15	SiO2	EtOAc:hexane=1:2
Comp. 242	248		187		185		0.13	SiO2	EtOAc:hexane=1:2	50.6
Comp. 243	249		213		211		0.11	SiO2	EtOAc:hexane=1:2
Comp. 244	250			330	328	328	0.49	SiO2	CHCl3:MeOH=95:5	32.7
Comp. 245	251			276	274	274	0.38	SiO2(NH)	AcOEt:EtOH=90:10	55.4
Comp. 246	252			220	218	218	0.22	SiO2	CHCl3:MeOH=95:5
Comp. 247	253			193	191	191	0.15	SiO2	CHCl3:MeOH=95:5
Comp. 248	254			206	204		0.64	SiO2	AcOEt:EtOH=90:10
Comp. 249	255			206	204		0.6	SiO2	AcOEt:EtOH=90:10
Comp. 250	256			306	304	304	0.3	SiO2(NH)	AcOEt:EtOH=90:10
Comp. 251	257			302	300	300	0.3	SiO2	CHCl3:MeOH=95:5
Comp. 252	258				295		0.24	SiO2	CHCl3:MeOH=95:5
Comp. 253	259			216	214	214	0.27	SiO2(NH)	AcOEt:EtOH=90:10
Comp. 254	260				233		0.56	SiO2(NH)	AcOEt:EtOH=90:10
Comp. 255	261			354	352	352	0.57	SiO2	AcOEt:EtOH=90:10
Comp. 256	262				321		0.28	SiO2	CHCl3:MeOH=95:5
Comp. 257	263			388	386	386	0.15	SiO2	CHCl3:MeOH=95:5
Comp. 258	264			225	223	223	0.08	SiO2	CHCl3:MeOH=95:5
Comp. 259	265			244	242		0.33	SiO2(NH)	AcOEt:EtOH=90:10	52.8
Comp. 260	266			177	175	175	0.21	SiO2	CHCl3:MeOH=95:5
Comp. 261	267			178	176	176	0.04	SiO2	CHCl3:MeOH=95:5
Comp. 262	268			176		174	0.03	SiO2	CHCl3:MeOH=95:5
Comp. 263	269			389	387	387	0.26	SiO2	CHCl3:MeOH=95:5
Comp. 264	270			311	309	309	0.25	SiO2	CHCl3:MeOH=95:5
Comp. 265	271			295		293	0.19	SiO2	CHCl3:MeOH=95:5
Comp. 266	272			317	315		0.24	SiO2	CHCl3:MeOH=95:5
Comp. 267	273				334		0.31	SiO2	CHCl3:MeOH=95:5
Comp. 268	274			299	297	297	0.05	SiO2	CHCl3:MeOH=95:5
Comp. 269	275			219	217	217	0.17	SiO2	CHCl3:MeOH=95:5
Comp. 270	276			322	320	320	0.05	SiO2	CHCl3:MeOH=95:5
Comp. 271	277			288	286	286	0.37	SiO2(NH)	AcOEt
Comp. 272	278			274	272	272	0.33	SiO2(NH)	AcOEt
Comp. 273	279	165.0-167.0		271	269	269	0.20	SiO2(NH)	AcOEt	89.2	96.8
Comp. 274	280			303	301	301	0.16	SiO2(NH)	AcOEt	94.5
Comp. 275	281			261	259	259	0.16	SiO2(NH)	AcOEt
Comp. 276	282	207.0-207.5		304	302	302	0.16	SiO2(NH)	AcOEt	71.8	55.9
Comp. 277	283			257	255	255	0.22	SiO2(NH)	AcOEt	76.4
Comp. 278	284			256	254		0.15	SiO2(NH)	AcOEt	65.3
Comp. 279	285			334	332	332	0.21	SiO2(NH)	AcOEt	42.8
Comp. 280	286			337	335	335	0.21	SiO2(NH)	AcOEt
Comp. 281	287			350	348	348	0.21	SiO2(NH)	AcOEt	50.9
Comp. 282	288			282		280	0.17	SiO2(NH)	AcOEt	122.9
Comp. 283	289			252	250	250	0.16	SiO2(NH)	AcOEt	62.6
Comp. 284	290			286	284	284	0.16	SiO2(NH)	AcOEt
Comp. 285	291			302	300	300	0.16	SiO2(NH)	AcOEt
Comp. 286	292			289	287	287	0.16	SiO2(NH)	AcOEt
Comp. 287	293			289	287	287	0.17	SiO2(NH)	AcOEt
Comp. 288	294			208	206	206	0.14	SiO2(NH)	AcOEt
Comp. 289	295			221	210	219	219	0.13	SiO2(NH)	AcOEt
Comp. 290	296			212	210	210	0.42	SiO2(NH)	EtOAc:MeOH=95:5
Comp. 291	297			222	220		0.48	SiO2(NH)	EtOAc:MeOH=95:5
Comp. 292	298			188	186	186	0.36	SiO2(NH)	EtOAc:MeOH=95:5
Comp. 293	299			220	218	218	0.59	SiO2(NH)	EtOAc:MeOH=95:5
Comp. 294	300	162.0-162.5		220		218	0.47	SiO2(NH)	EtOAc:MeOH=95:5	103.2	4.9
Comp. 295	301			202		200	0.37	SiO2(NH)	EtOAc:MeOH=95:5	73.8
Comp. 296	302			229		227	0.41	SiO2(NH)	EtOAc:MeOH=95:5
Comp. 297	303			188		186	0.35	SiO2(NH)	EtOAc:MeOH=95:5	71.1
Comp. 298	304			203		201	0.33	SiO2(NH)	EtOAc:MeOH=95:5
Comp. 299	305			232	230	230	0.40	SiO2(NH)	EtOAc:MeOH=95:5
Comp. 300	306	182.0-182.5		222		220	0.44	SiO2(NH)	EtOAc:MeOH=95:5	96.3	5.7
Comp. 301	307			208		206	0.36	SiO2(NH)	EtOAc:MeOH=95:5	62.1
Comp. 302	308	177.5-178.0		257		255	0.47	SiO2(NH)	EtOAc:MeOH=95:5	96.5	1.9
Comp. 303	309			249	247	247	0.35	SiO2(NH)	EtOAc:MeOH=95:5
Comp. 304	310			205	203		0.33	SiO2(NH)	EtOAc:MeOH=95:5	68.5
Comp. 305	311			245		243	0.14	SiO2(NH)	EtOAc:MeOH=95:5
Comp. 306	312				216		0.10	SiO2	CHCl3:MeOH=9:1
Comp. 307	313		201				0.40	SiO2	CHCl3:MeOH=9:1
Comp. 308	314		332		330		0.08	SiO2	CHCl3:MeOH=9:1
Comp. 309	315		194				0.17	SiO2	CHCl3:MeOH=9:1
Comp. 310	316		316		314		0.25	SiO2	CHCl3:MeOH=9:1
Comp. 311	317		344		342		0.25	SiO2	CHCl3:MeOH=9:1
Comp. 312	318		315				0.15	SiO2	CHCl3:MeOH=9:1
Comp. 313	319		286		284		0.25	SiO2	CHCl3:MeOH=9:1
Comp. 314	320		290				0.38	SiO2	CHCl3:MeOH=9:1
Comp. 315	321		371		369		0.48	SiO2	CHCl3:MeOH=9:1	50.7
Comp. 316	322	144.0-146.0	195		193		0.09	SiO2	Hexane:AcOEt=2:1	97.9	24.0
Comp. 317	323	132.0-133.0		195			0.51	SiO2(NH)	EtOAc:MeOH=95:5	93.8	3.5
Comp. 318	324	136.5-137.5	209		207		0.09	SiO2	Hexane:AcOEt=2:1		9.9
Comp. 319	325	126.0-137.5	223		221		0.13	SiO2	Hexane:AcOEt=2:1	99.9	3.8
Comp. 320	326	125.0-126.0	237		235		0.11	SiO2	Hexane:AcOEt=2:1	92.5	1.3
Comp. 321	327	121-122.5	251		249		0.36	SiO2(NH)	AcOEt	99.9	3.7
Comp. 322	328		265		263		0.36	SiO2(NH)	AcOEt	117.5
Comp. 323	329	128.0-130.0	279		277		0.12	SiO2	Hexane:AcOEt=2:1		25.9
Comp. 324	330	148.5-149.5	223		221		0.22	SiO2	AcOEt	99	3.7
Comp. 325	331	123.0-125.0	237		235		0.23	SiO2	AcOEt	106	2.6
Comp. 326	332		237		235		0.35	SiO2(NH)	AcOEt	110.8
Comp. 327	333			237	235		0.35	SiO2(NH)	AcOEt	110.1
Comp. 328	334		233		221		0.33	SiO2(NH)	AcOEt	121.4
Comp. 329	335	127.0-128.0		221	219		0.33	SiO2(NH)	AcOEt	121.1	0.7
Comp. 330	336	122.0-124.0	207		205		0.33	SiO2(NH)	AcOEt	118.8	2.4
Comp. 331	337	139.0-139.5		219	217		0.31	SiO2(NH)	AcOEt	118.8	3.2
Comp. 332	338	169.5-170.0	233		231		0.31	SiO2(NH)	AcOEt	110.6	2.1
Comp. 333	339	171.5-172.0	205		203		0.3	SiO2(NH)	AcOEt	119.3	2.2
Comp. 334	340	125.0-126.0	221				0.23	SiO2	AcOEt	105	3.2
Comp. 335	341	139.0-141.0	205				0.23	SiO2	AcOEt	110	1.4
Comp. 336	342	142.5-146.0	207		205		0.31	SiO2(NH)	AcOEt	117.6	3.2
Comp. 337	343	135.0-136.5	219		217		0.31	SiO2(NH)	AcOEt	119.4	2.1
Comp. 338	344	100.0-102.0	221			219	0.33	SiO2(NH)	AcOEt	119.8	0.9
Comp. 339	345	113.5-114.5	250		248		0.11	SiO2	AcOEt	88	124.2
Comp. 340	346	157.5-158								97.4	3.0
Comp. 341	347	129.5-133	263		261		0.23	SiO2	AcOEt	104	1.2
Comp. 342	348	174.5-175.5								98.5	5.3
Comp. 343	349	166.5-167.0								84.5	3.3
Comp. 344	350	180-180.5	244				0.12	SiO2	AcOEt	107	37.5
Comp. 345	351	159.5-161	244				0.14	SiO2	AcOEt	107	37.5
Comp. 346	352	104.0-107.0								106.2	8.9
Comp. 347	353	80.5-81.5	255		253		0.18	SiO2	AcOEt	105	3.7
Comp. 348	354	128.5-129.5	267		265		0.21	SiO2	AcOEt	103	3.4
Comp. 349	355	152.5-153.0	271		269		0.21	SiO2	AcOEt	100	1.6
Comp. 350	356	168.0-168.5	249				0.19	SiO2	AcOEt	91	1.4
Comp. 351	357		252		250		0.18	SiO2	AcOEt	89
Comp. 352	358	158.5-159.5	233				0.2	SiO2	AcOEt	97	4.6
Comp. 353	359	158.0-160.0	278		276		0.14	SiO2	AcOEt	105	3.7
Comp. 354	360	113.0-114.0	239		237		0.23	SiO2	AcOEt	106	3.0
Comp. 355	361	141.0-142.0	266		264		0.14	SiO2	AcOEt	107	5.9
Comp. 356	362	141.0-142.5	207				0.23	SiO2	AcOEt	102	2.6
Comp. 357	363		264		262		0.16	SiO2	AcOEt	98
Comp. 358	364	138.0-139.5	272		270		0.14	SiO2	AcOEt	103	3.1
Comp. 359	365	132.5-134.5	290		288		0.2	SiO2	AcOEt	102	1.4
Comp. 360	366		279		277		0.22	SiO2	AcOEt
Comp. 361	367	104.0-106.0	241		239		0.22	SiO2	AcOEt	106	2.1
Comp. 362	368	156.0-157.0	244				0.11	SiO2	AcOEt	106	2.1
Comp. 363	369	154.0-155.0	272		270		0.11	SiO2	AcOEt	105	0.78
Comp. 364	370	136.5-137.5	295		293		0.21	SiO2	AcOEt	104	2.0
Comp. 365	371	143.5-145.0	287		285		0.19	SiO2	AcOEt	105	1.4
Comp. 366	372	188.0-189.0	272				0.09	SiO2	AcOEt	105	1.2
Comp. 367	373	165.0-166.0	249				0.18	SiO2	AcOEt	103	2.1
Comp. 368	374	165.5-166.0	233				0.19	SiO2	AcOEt	96	2.5
Comp. 369	375	146.5-149.0	258				0.16	SiO2	AcOEt	105	3.1
Comp. 370	376		263	263	261	261	0.33	SiO2(NH)	AcOEt	113.7
Comp. 371	377	93.0-94.0	239	239	237	237	0.31	SiO2(NH)	AcOEt	110.4	0.9
Comp. 372	378			271	269	269	0.31	SiO2(NH)	AcOEt	100.5
Comp. 373	379	97.0-99.0		253	251	251	0.31	SiO2(NH)	AcOEt	115.3	0.8
Comp. 374	380		331	331	329	329	0.3	SiO2(NH)	AcOEt	119.1
Comp. 375	381			301	299	299	0.3	SiO2(NH)	AcOEt	117.7
Comp. 376	382			336	333	334	0.3	SiO2(NH)	AcOEt	114.9
Comp. 377	383			336	334	334	0.3	SiO2(NH)	AcOEt	107.4
Comp. 378	384			295	293	293	0.3	SiO2(NH)	AcOEt	102.4
Comp. 379	385			287	285	285	0.27	SiO2(NH)	AcOEt	105.4
Comp. 380	386			291	289	289	0.26	SiO2(NH)	AcOEt	118.9
Comp. 381	387			285	283	283	0.27	SiO2(NH)	AcOEt	116.0
Comp. 382	388	153.0-153.5		273			0.26	SiO2(NH)	AcOEt	122.5	3.1
Comp. 383	389			257	255	255	0.26	SiO2(NH)	AcOEt	116.2
Comp. 384	390	167.0-167.5		279	277		0.27	SiO2(NH)	AcOEt	117.3	2.8
Comp. 385	391			312	310	310	0.27	SiO2(NH)	AcOEt	109.0
Comp. 386	392			347	345		0.27	SiO2(NH)	AcOEt	105.2
Comp. 387	393	163.0-164.0	289	289			0.27	SiO2(NH)	AcOEt	97.8	0.9
Comp. 388	394			335	333	333	0.27	SiO2(NH)	AcOEt	96.2
Comp. 389	395	167.0-167.5		273		271	0.31	SiO2(NH)	AcOEt	105.5	1.6
Comp. 390	396	152.5-153.5		273		271	0.31	SiO2(NH)	AcOEt	112.8	2.7
Comp. 391	397	161.5-162.0		257	255	255	0.31	SiO2(NH)	AcOEt	113.4	2.4
Comp. 392	398	165.5-166.0	261	261	259		0.31	SiO2(NH)	AcOEt	109.6	2.4
Comp. 393	399	143.0-146.0		268	266	266	0.26	SiO2(NH)	AcOEt	124.3	1.1
Comp. 394	400	144.0-145.0	325	303		301	0.27	SiO2(NH)	AcOEt	119.9	3.9
Comp. 395	401	178.0-178.5	303	303		301	0.29	SiO2(NH)	AcOEt	111.6	2.1
Comp. 396	402		323	301	321	299	0.29	SiO2(NH)	AcOEt	102.7
Comp. 397	403			319			0.29	SiO2(NH)	AcOEt	99.3
Comp. 398	404		296	296	294	294	0.29	SiO2(NH)	AcOEt	95.2	2.4
Comp. 399	405	118-120	224	224	222	222	0.31	SiO2(NH)	AcOEt	102.3	98
Comp. 400	406	115.0-117.0	238	238		236	0.29	SiO2(NH)	AcOEt	116.9	48.7
Comp. 401	407	100.0-102.0	252	252	250	250	0.29	SiO2(NH)	AcOEt	117.4	37.6
Comp. 402	408	95.0-96.0	280	280	278	278	0.29	SiO2(NH)	AcOEt	118.8	18.7
Comp. 403	409	101.5-102.0	266	266	264	264	0.32	SiO2(NH)	AcOEt	118.3	28.5
Comp. 404	410	57.5-59.0	268	268	266	266	0.29	SiO2(NH)	AcOEt	114.9	115.6
Comp. 405	411		314	314	312	312	0.33	SiO2(NH)	AcOEt	116.0
Comp. 406	412			359	357	357	0.29	SiO2(NH)	AcOEt	73.7
Comp. 407	413	127.5-129.5	264	264	262	262	0.29	SiO2(NH)	AcOEt	94.3	4.9
Comp. 408	414	177.0-177.5	278	278	276	276	0.29	SiO2(NH)	AcOEt	103.0	4.2
Comp. 409	415	145.0-146.0		223	221	221	0.31	SiO2(NH)	AcOEt	113.2	6.7
Comp. 410	416	153.0-155.0		301	299	299	0.31	SiO2(NH)	AcOEt	117.3	1.0
Comp. 411	417	150.5-151.5	246	246	244	244	0.31	SiO2(NH)	AcOEt	122.4	3.1
Comp. 412	418	130.0-130.5	260	260	258	258	0.32	SiO2(NH)	AcOEt	119.4	1.5
Comp. 413	419	112.0-113.0		227	225	225	0.32	SiO2(NH)	AcOEt	120.2	2.3
Comp. 414	420	132.0-133.5	241	241	239	239	0.32	SiO2(NH)	AcOEt	113.2	1.0
Comp. 415	421	114-117	264	264	262	262	0.31	SiO2(NH)	AcOEt	103.7	17.6
Comp. 416	422	99.5-102.5	264	264		262	0.31	SiO2(NH)	AcOEt	85.8	16.3
Comp. 417	423	146.5-148	264	264		262	0.33	SiO2(NH)	AcOEt	102.8	90.0
Comp. 418	424			273	271	271	0.33	SiO2(NH)	AcOEt	120.4
Comp. 419	425		289	289	287	287	0.33	SiO2(NH)	AcOEt	116.1
Comp. 420	426	147-148.5	237	237	235	235	0.31	SiO2(NH)	AcOEt	118.6	8.0
Comp. 421	427	153-154.5	251	251	249	249	0.33	SiO2(NH)	AcOEt	113.3	3.9
Comp. 422	428	132.0-134.0	263	263	261	261	0.33	SiO2(NH)	AcOEt	121.6	1.5
Comp. 423	429	132.0-134.5	263	263		261	0.35	SiO2(NH)	AcOEt	118.4	2.2
Comp. 424	430	102.0-103.5									1.5
Comp. 425	431	>300									3.0
Comp. 426	432	101.5-104.0									5.1
Comp. 427	433	108.0-									2.6
Comp. 428	434	143.5-144.5									51.5
Comp. 429	435	159.0-141.0									79.1
Comp. 430	436	139.5-141.0									7.4
Comp. 431	437	113.0-115.0									47.7
Comp. 432	438	116.5-117.5									19.5
Comp. 433	439	125.0-127.0									1.5
Comp. 434	440	>300									3.2
Comp. 435	441	133.0-134.5									2.2
Comp. 436	442	140.5-141.0									79.2
Comp. 437	443			293	291	291	0.33	SiO2(NH)	AcOEt	96.1
Comp. 438	444			251	249	249	0.36	SiO2(NH)	AcOEt	87.9
Comp. 439	445	144.1-144.2		211	209	209	0.36	SiO2(NH)	AcOEt	92.3	2.9
Comp. 440	446			255		253	0.33	SiO2(NH)	AcOEt	102.8
Comp. 441	447	166		259	257	257	0.33	SiO2(NH)	AcOEt	94.2
Comp. 442	448			225	223	223	0.36	SiO2(NH)	AcOEt	95.7
Comp. 443	449			239	237	237	0.38	SiO2(NH)	AcOEt	103.0
Comp. 444	450	121.0		213	211	211	0.10	SiO2(NH)	AcOEt	100.7	12.1
Comp. 445	451	112.0		240	238	238	0.18	SiO2(NH)	AcOEt	95.1
Comp. 446	452			241		239	0.31	SiO2(NH)	AcOEt	95.9
Comp. 447	453			237	235	235	0.36	SiO2(NH)	AcOEt	95.9
Comp. 448	454	125.0-126.5		249	247	247	0.36	SiO2(NH)	AcOEt	109.8	1.9
Comp. 449	455	119.0-120.5		225	223	223	0.38	SiO2(NH)	AcOEt	105.1	1.8
Comp. 450	456			239	237	237	0.41	SiO2(NH)	AcOEt	105.9
Comp. 451	457			253	251	251	0.41	SiO2(NH)	AcOEt	97.6
Comp. 452	458			267	265	265	0.41	SiO2(NH)	AcOEt	112.3
Comp. 453	459			295	293	293	0.44	SiO2(NH)	AcOEt	95.3
Comp. 454	460			268	266	266	0.26	SiO2(NH)	AcOEt	105.8
Comp. 455	461			255		253	0.28	SiO2(NH)	AcOEt	105.6
Comp. 456	462	143.0-145.0		225	223	223	0.33	SiO2(NH)	AcOEt	94.4	6.3
Comp. 457	463			273	271	271	0.36	SiO2(NH)	AcOEt	116.0
Comp. 459	464	108-108.5		227	225	225	0.10	SiO2(NH)	AcOEt	119.0	2.4
*SiO2(NH): Merck pre-coated plates Silica gel 60 F254, SiO2(NH)(NH): TLCplateNH Fuji Silysia Chemical LTD.

[0132] Experimental Example [Inhibitory effect of 20-HETE synthase originated from rat kidney microsome]

[0133] Regarding the compounds listed in Table 1, their inhibitory activity to production of 20-HETE was examined. This examination was carried out based on the method described in J. Pharmacol. Exp. Ther., Vol. 268, pp. 474 (1994).

[0134] The subject compound for this examination was added to a buffer comprising 50 m M of 3-morpholinopropane sulfonic acid (pH7.4), 5 mM of magnesium chloride and 1 mM of ethylenediaminetetraacetic acid (EDTA) disodium salt.

[0135] After that, the rat kidney microsome (microsome fraction prepared from the kidney of a spontaneous hypertension rat (male, 6 weeks of age)) as an enzyme, [5,6,8,9,11,12,14,15] tritium-arachidonic acid (supplied by Amasham) as a substrate, and NADPH (supplied by Sigma) as a coenzyme were added and reacted for 1.5 hours at 37° C.

[0136] After the reaction, formic acid was added to stop the reaction, and then acetonitrile (final concentration of 50%) was added and left for 1.5 hours at room temperature.

[0137] The activity of 20-HETE synthase was measured by using a high performance liquid chromatograph having a detector for radioactive substances (supplied by Gilson), and equipped with a C18 reversed phase column (Biocyl C18, supplied by Bio-rad).

[0138] Setting an amount of 20-HETE production to 100% when no subject compound for examination was added, the concentration of the subject compound at which the production of the 20-HETE was inhibited to 50% and the inhibition rate at which 1 μM of the subject compound was added are presented together in Table 1.

[0139] Referring to Table 1, it was confirmed that the compounds of the present invention have inhibitory activity for production of 20-HETE.

Industrial Applicability

[0140] The compounds represented by the general formula (1) or the pharmaceutically-acceptable salts thereof according to the present invention are useful as inhibitors for production of 20-HETE. Therefore, they are useful as medicines, and in particular, therapeutic agents for various diseases in human subjects and animals, which 20-HETE is implicated in, such as kidney diseases, cerebrovascular diseases, or circulatory diseases.

[0141] In addition, in the compounds represented by the general formula (1) or the pharmaceutically-acceptable salts thereof, the compounds wherein a non-hydrogen substituent is present at the para position of the hydroxyformamidino moiety on the benzene ring are, in particular, preferable.

[0142] In addition, the compounds represented by the general formula (1) or the pharmaceutically-acceptable salts thereof as recited in claims 5 or more are novel compounds and useful in themselves, and also, exhibit the excellent effects described above.

Claims

1. An inhibitor for production of 20-hydroxyeicosatetraenoic acid, comprising, as an effective ingredient, a hydroxyformamidine derivative represented by the formula:

2. The inhibitor for production of 20-hydroxyeicosatetraenoic acid, comprising, as an effective ingredient, a hydroxyformamidine derivative, according to claim 1, 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 C1-14 alkyl group substituted with 1 to 6 halogen atoms; 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(C16 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 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 to3C1-6 alkyl groups; a benzothiazolylthio group; a benzothiazolylthio group substituted with 1 to 3 halogen atoms; or 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—(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; a2,6-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 pharmaceutically-acceptable salt thereof.

3. The inhibitor for production of 20-hydroxyeicosatetraenoic acid, comprising, as an effective ingredient, a hydroxyformamidine derivative or a pharmaceutically-acceptable salt thereof, according to claim 2, wherein R1, R2, R4, and R5 represent hydrogen atoms.

4. The inhibitor for production of 20-hydroxyeicosatetraenoic acid, according to any one of claims 1 to 3, which is a therapeutic agent for kidney diseases, cerebrovascular diseases, or circulatory diseases.

5. A hydroxyformamidine derivative represented by the formula:

6. The hydroxyformamidine derivative or a pharmaceutically-acceptable salt thereof, according to claim 5, wherein at least one of R11 to R55 represents a C5-14 alkyl group; a C3-8 cycloalkoxy group; a C2-6 alkynyl group; a C3-8cycloalkyl 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 to3 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; 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, 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 R55are 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.

7. The hydroxyformamidine derivative or a pharmaceutically-acceptable salt thereof, according to claim 6, wherein at least one of R11 to R55 represents a C5-14 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 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 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 benzoyl group; 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 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; 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] 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.

8. The hydroxyformamidine derivative or a pharmaceutically-acceptable salt thereof, according to claim 5, wherein at least one of R11 to R55 represents 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; R77represents 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 C3-8 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; an 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 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], 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.

9. The hydroxyformamidine derivative or a pharmaceutically-acceptable salt thereof, according to claim 8, wherein at least one of R11 to R55 represents a group represented by the formula: —O—(CR61R62)m—(CR63R64)n—R77 [wherein 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 di(C1-6 alkyl)amino group; a di(C1-6 alkyl)amino C1-6 alkoxy group; a piperidyl group; a piperidinyl group substituted with a C1-6 alkyl group; a piperidino group; a piperidino group substituted with a C1-6 alkyl group; a pyridyl group; a pyridinyl group substituted with a C1-6 alkyl group; a pyridinyl group substituted with a C1-6 alkoxy group; a pyridylthio group; a pyrrolidino group; a pyrrolidino group substituted with a C1-6 alkyl group; a pyrrolidon-1-yl group; a pyrrolidinyl group; a pyrrolidinyl group substituted with a C1-6 alkyl group; a pyrrolyl group; a thienyl group; a thiazolyl group; a morpholino 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; or a homopiperidinyl group substituted with a C1-6 alkyl group; m is an integer of 1 to 6; and n is an integer of 0 to 6], 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.

10. The hydroxyformamidine derivative or a pharmaceutically-acceptable salt thereof, according to any one of claims 7 to 9, wherein R11, R22, R44, and R55 represent hydrogen atoms.

11. An inhibitor for production of 20-hydroxyeicosatetraenoic acid, comprising, as an effective ingredient, the hydroxyformamidine derivative or a pharmaceutically-acceptable salt thereof according to any one of claims 5 to 10.

12. The inhibitor for production of 20-hydroxyeicosatetraenoic acid, according to claim 11, which is a therapeutic agent for kidney diseases, cerebrovascular diseases, or circulatory diseases.