# Patent

## Title
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.
In addition, the present invention also provides novel hydroxyformamidine derivatives or pharmaceutically-acceptable salts thereof.

## Background
CROSS-REFERENCE TO RELATED APPLICATION
This Application is a Divisional of U.S. application Ser. No. 09/869,103, filed Jun. 22, 2001 now U.S. Pat. No. 6,864,254; which is a 371 of PCT/JP00/07694, filed Nov. 1, 2000; the disclosure of which is incorporated herein by reference.


TECHNICAL FIELD
The present invention relates to hydroxyformamidinobenzene derivatives inhibiting a synthase of 20-hydroxyeicosatetraenoic acid (20-HETE) biosynthesized from arachidonic acid.
BACKGROUND ART
Prostaglandins produced by cyclooxygenase and leukotrienes 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
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.
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.
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:




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




[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,
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.
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; 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; 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], or alternatively,
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.
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 C3-8 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 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.
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.
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 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.
In addition, in the compounds of the general formula (2), the compounds wherein R11, R22, R44, and R55 represent a hydrogen atom, that is, only R33 at the para position of the hydroxyformamidino group on the benzene ring is a non-hydrogen atom substituent, are preferred.
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.
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.
The term “halogen atom” refers to a fluorine, chlorine, bromine, or iodine atom.
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.
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.
The term “C2-6 alkenyl” means a straight-chain or branched alkenyl 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.
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.
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.
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.
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.
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.
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.
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.
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-hydroxyethyl group, or a 3-hydroxypropyl group is in particular, preferable.
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.
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.
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 alkyl group. Therefore, a C2-6 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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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 butenyl group, or the like, and more particularly, a 1,5-dimethyl-4-hexenyl group, or the like.
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.
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.
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.
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.
Examples of the “C1-6 alkoxy C1-6 alkoxy C1-6 alkoxy group” include CH3OCH2CH2OCH2CH2O— and the like.
Examples of the “di(C1-6 alkyl)amino group” include —N(CH3)2, —N(CH2CH3)2, —N(CH2CH2CH3)2, and the like.
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.
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.
The “furyl group” includes a 2-furyl or 3-furyl group.
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.
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.
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.
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.
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.
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.
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.
The “piperidino group” refers to a mono-valent group derived by eliminating a hydrogen atom present on the nitrogen atom of piperidine.
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.
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.
The “pyrrolidino group” refers to a mono-valent group derived by eliminating a hydrogen atom present on the nitrogen atom of pyrrolidine.
The “pyrrolidon-1-yl group” includes a 2-pyrrolidon-1-yl or 3-pyrrolidon-1-yl group.
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.
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.
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.
The “thienyl group” includes a2-thienyl group, or a 3-thienyl group.
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.
The “morpholino group” refers to a mono-valent group derived by eliminating a hydrogen atom present on the nitrogen atom of morpholine.
The “furfuryl group” means a 2-furfuryl group.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.)
For example, the compounds of the present invention may be synthesized by reacting aniline derivatives substituted with R1 to R5 described below




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.

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 R3 is a group represented by the formula: —Y—(CR61R62)m—(CR63R64)n—R7, are employed.
At first, a compound represented by the formula (a):




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

R7(CR63R64)n—(CR61R62)mYH  (b)

(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).




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.




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.
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.
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.
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 OUT THE INVENTION
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
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).
Melting point: 131.5–134.0° C.
EXAMPLE 2
Synthesis of N-(4-tert-butylphenyl)-N′-hydroxy-formamidine
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).
Melting point: 113.5–114.5° C.
EXAMPLE 3
Synthesis of N-(4-methoxycarbonylphenyl)-N′-hydroxyformamidine
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.
Melting point: 167.0–167.5° C.
EXAMPLE 4
Synthesis of N-(2-aminosulfonylphenyl)-N′-hydroxyformamidine
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.
Melting point: 130.5–131.5° C.
EXAMPLE 5
Synthesis of N-[4-(pyridin-2-ylmethoxy) phenyl]-N′-hydroxyformamidine
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.
Melting point: 159.5–161.0° C.
EXAMPLE 6
Synthesis of N-[4-(benzylthio)phenyl]-N′-hydroxyformamidine
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.
Melting point: 166° C.
EXAMPLE 7
The compounds shown in Table 1 described below were obtained by carrying out the similar procedures as those of Example 1. The compounds obtained in Examples 1 to 6, together with the other compounds are also shown in Table 1.


















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




131.5–134.0
207
207

205
0.56
SiO2(NH)
EtOAc:MeOH = 95:5
100.5
3.5


 


Comp. 2




113.5–114.5
193

191

0.13
SiO2
Hexane:AcOEt = 2:1
97.0
7.8


 


Comp. 3




84.5–85.5
193

191

0.22
SiO2
Hexane:AcOEt = 2:1
98.9


 


Comp. 4




101.0–102.5


191

0.15
SiO2
Hexane:AcOEt = 2:1
107.6
3


 


Comp. 5




153.0–154.0
219

217

0.13
SiO2
Hexane:AcOEt = 2:1
99.9
3.8


 


Comp. 6




119.5–120.5
223

221

0.20
SiO2
Hexane:AcOEt = 2:1
99.9 


 


Comp. 7




122.5–124.0
207

205

0.14
SiO2
Hexane:AcOEt = 2:1
110.5
12.1


 


Comp. 8




141.0–142.0
193

191

0.21
SiO2
Hexane:AcOEt = 2:1
99.9


 


Comp. 9




108.0–110.0
221

219

0.15
SiO2
Hexane:AcOEt = 2:1
99.9
4.9


 


Comp. 10




143.5–144.5


151

0.12
SiO2
Hexane:AcOEt = 2:1
89.5
669.0


 


Comp. 11




151.0–152.5
185

183

0.18
SiO2
Hexane:AcOEt = 2:1
92.7
297.1


 


Comp. 12




139.5–140.5
155



0.08
SiO2
Hexane:AcOEt = 2:1
77.1
1415.5


 


Comp. 13




116.0–118.0
165

163

0.12
SiO2
Hexane:AcOEt = 2:1
95.9
117.9


 


Comp. 14




151.0–153.0


183

0.19
SiO2
Hexane:AcOEt = 2:1
91.7
162.8


 


Comp. 15




155.5–156.0
171

169

0.10
SiO2
Hexane:AcOEt = 2:1
92.9
287.7


 


Comp. 16




141.0–142.0
165

163

0.12
SiO2
Hexane:AcOEt = 2:1
97.6
6.6


 


Comp. 17




136.5–139.0
181

179

0.15
SiO2
Hexane:AcOEt = 2:1
85.3


 


Comp. 18




139.0–140.0
167

165

0.06
SiO2
Hexane:AcOEt = 2:1
94.6
45.2


 


Comp. 19




144.0–145.0
181

179

0.08
SiO2
Hexane:AcOEt = 2:1
88.0
337.6


 


Comp. 20




149.0–150.0
181

179

0.07
SiO2
Hexane:AcOEt = 2:1
97.5
227.6


 


Comp. 21




115.5–116.5
165

163

0.14
SiO2
Hexane:AcOEt = 2:1
81.1


 


Comp. 22




139.0–141.0




0.16
SiO2
Hexane:AcOEt = 2:1
95.7


 


Comp. 23




110.0–111.5
171

169

0.12
SiO2
Hexane:AcOEt = 2:1
82.8
475.8


 


Comp. 24




119.0–120.5
205



0.10
SiO2
Hexane:AcOEt = 2:1
89.2
519.7


 


Comp. 25




142.5–144.5
189

187

0.15
SiO2
Hexane:AcOEt = 2:1
87.0


 


Comp. 26




155.0–156.5
201

199

0.18
SiO2
Hexane:AcOEt = 2:1
86.0
203.7


 


Comp. 27




140.5–142.0
205

203

0.10
SiO2
Hexane:AcOEt = 2:1
103.3
1.7


 


Comp. 28




119.0–120.5
235

233

0.15
SiO2
Hexane:AcOEt = 2:1
92.5
4.7


 


Comp. 29




93.0–94.5
179

177

0.13
SiO2
Hexane:AcOEt = 2:1
93.6


 


Comp. 30




143.0–143.5
179

177

0.12
SiO2
Hexane:AcOEt = 2:1
103.3
2.4


 


Comp. 31




131.0–132.0
179



0.12
SiO2
Hexane:AcOEt = 2:1
97.8
6.6


 


Comp. 32




114.0–115.0
179



0.16
SiO2
Hexane:AcOEt = 2:1
87.2


 


Comp. 33




171.0


291

0.23
SiO2
Hexane:AcOEt = 2:1
91.9


 


Comp. 34




163.0–163.5
293

291

0.17
SiO2
Hexane:AcOEt = 2:1
90.6
79.7


 


Comp. 35




161.0




0.17
SiO2
Hexane:AcOEt = 2:1
95.4
86.5


 


Comp. 36




163.0–164.0
215

213

0.10
SiO2
Hexane:AcOEt = 2:1
98.3
136.5


 


Comp. 37




167.0–167.5
195

193

0.06
SiO2
Hexane:AcOEt = 2:1
92.7


 


Comp. 38




151.0–152.5
185

183

0.13
SiO2
Hexane:AcOEt = 2:1
89.8
79.8


 


Comp. 39




110.0–113.0
221

219

0.10
SiO2
Hexane:AcOEt = 2:1
99.0
22


 


Comp. 40




160.0–161.0
205

203

0.16
SiO2
Hexane:AcOEt = 2:1
98.2


 


Comp. 41




161.0–161.5
229

227

0.13
SiO2
Hexane:AcOEt = 2:1
96.6
49.0


 


Comp. 42




144.0–145.0




0.44
SiO2
CHCl3:MeOH = 9:1
99.9


 


Comp. 43




123.0–124.0
169

167

0.30
SiO2
CHCl3:MeOH = 9:1

168.1


 


Comp. 44




145.0–146.0
223

221

0.32
SiO2
CHCl3:MeOH = 9:1

8.1


 


Comp. 45




163.5–164.5
243



0.45
SiO2
CHCl3:MeOH = 9:1
53.5


 


Comp. 46




100.5–102.0
205

203

0.24
SiO2
CHCl3:MeOH = 9:1
48.5
355.3


 


Comp. 47




166.0–166.5
277

275

0.37
SiO2
CHCl3:MeOH = 9:1
94.8
6.5


 


Comp. 48




155.0–156.0
335



0.52
SiO2
CHCl3:MeOH = 9:1



 


Comp. 49




122.5–124.0


271

0.44
SiO2
CHCl3:MeOH = 9:1
46.7


 


Comp. 50




155.5–156.5
173

171

0.34
SiO2
CHCl3:MeOH = 9:1

25.5


 


Comp. 51




157.0–158.0
229

227

0.42
SiO2
CHCl3:MeOH = 9:1
50.2
21.8


 


Comp. 52




145.0–146.0
181



0.43
SiO2
CHCl3:MeOH = 9:1



 


Comp. 53




159.0–160.0
271



0.66
SiO2
CHCl3:MeOH = 9:1



 


Comp. 54




162.5–163.5




0.43
SiO2
CHCl3:MeOH = 9:1



 


Comp. 55




130.5–132.0
277

275

0.5
SiO2
CHCl3:MeOH = 9:1
31.3


 


Comp. 56




144.0–145.5
190

188

0.42
SiO2
CHCl3:MeOH = 9:1
50.6


 


Comp. 57





193

191

0.22
SiO2
Hexane:AcOEt = 2:1
59.1


 


Comp. 58




146.5–148.0
257

255

0.21
SiO2
Hexane:AcOEt = 2:1
99.9
7.1


 


Comp. 59





167

165

0.13
SiO2
Hexane:AcOEt = 2:1
49.0


 


Comp. 60





181

179

0.15
SiO2
Hexane:AcOEt = 2:1



 


Comp. 61







163

0.17
SiO2
Hexane:AcOEt = 2:1



 


Comp. 62





151



0.12
SiO2
Hexane:AcOEt = 2:1
69.5


 


Comp. 63





165

163

0.15
SiO2
Hexane:AcOEt = 2:1
49.3


 


Comp. 64







163

0.13
SiO2
Hexane:AcOEt = 2:1



 


Comp. 65





167

165

0.08
SiO2
Hexane:AcOEt = 2:1
59.3


 


Comp. 66





181

179

0.10
SiO2
Hexane:AcOEt = 2:1
41.2


 


Comp. 67





185

183

0.15
SiO2
Hexane:AcOEt = 2:1
48.4


 


Comp. 68





205

203

0.15
SiO2
Hexane:AcOEt = 2:1



 


Comp. 69





189

187

0.15
SiO2
Hexane:AcOEt = 2:1
58.7


 


Comp. 70





249

247

0.15
SiO2
Hexane:AcOEt = 2:1
32.9


 


Comp. 71





179

177

0.18
SiO2
Hexane:AcOEt = 2:1
42.5


 


Comp. 72




168.0–169.0
179



0.12
SiO2
Hexane:AcOEt = 2:1
99.2


 


Comp. 73





297

295

0.18
SiO2
Hexane:AcOEt = 2:1
99.9


 


Comp. 74





243

241

0.11
SiO2
Hexane:AcOEt = 2:1
43.7


 


Comp. 75





215

213

0.16
SiO2
Hexane:AcOEt = 2:1
46.9


 


Comp. 76







195

0.06
SiO2
Hexane:AcOEt = 2:1
35.1


 


Comp. 77







281

0.17
SiO2
Hexane:AcOEt = 2:1
49.0


 


Comp. 78





197

195

0.03
SiO2
Hexane:AcOEt = 2:1
36.3


 


Comp. 79





155

153

0.15
SiO2
Hexane:AcOEt = 2:1
35.3


 


Comp. 80





239

237

0.32
SiO2
Hexane:AcOEt = 2:1
37.2


 


Comp. 81





205

203

0.14
SiO2
Hexane:AcOEt = 2:1
51.3


 


Comp. 82




133.5–134.5
215

213

0.12
SiO2
Hexane:AcOEt = 2:1
70.9


 


Comp. 83





249



0.46
SiO2
CHCl3:MeOH = 9:1



 


Comp. 84





221

219

0.27
SiO2
CHCl3:MeOH = 9:1



 


Comp. 85





229

227

0.37
SiO2
CHCl3:MeOH = 9:1



 


Comp. 86





185

183

0.29
SiO2
CHCl3:MeOH = 9:1
58.7


 


Comp. 87





187



0.22
SiO2
CHCl3:MeOH = 9:1



 


Comp. 88





231

229

0.31
SiO2
CHCl3:MeOH = 9:1



 


Comp. 89





210

208

0.32
SiO2
CHCl3:MeOH = 9:1



 


Comp. 90





235



0.33
SiO2
CHCl3:MeOH = 9:1
36.5


 


Comp. 91





263



0.27
SiO2
CHCl3:MeOH = 9:1
36.6


 


Comp. 92





230

228

0.51
SiO2
CHCl3:MeOH = 9:1



 


Comp. 93









0.21
SiO2
CHCl3:MeOH = 9:1



 


Comp. 94





226

224

0.29
SiO2
CHCl3:MeOH = 9:1
41.2


 


Comp. 95





210

208

0.32
SiO2
CHCl3:MeOH = 9:1
44.5


 


Comp. 96





335



0.40
SiO2
CHCl3:MeOH = 9:1



 


Comp. 97





239

237

0.32
SiO2
CHCl3:MeOH = 9:1



 


Comp. 98





185



0.21
SiO2
CHCl3:MeOH = 9:1
43.9


 


Comp. 99





197

195

0.29
SiO2
CHCl3:MeOH = 9:1
40.8


 


Comp. 100





370

368

0.38
SiO2
CHCl3:MeOH = 9:1
44.3


 


Comp. 101





201

199

0.24
SiO2
CHCl3:MeOH = 9:1
52.4


 


Comp. 102





375

373

0.41
SiO2
CHCl3:MeOH = 9:1
44.4


 


Comp. 103




143.0–146.0
227

225

0.21
SiO2
CHCl3:MeOH = 9:1



 


Comp. 104





181



0.39
SiO2
CHCl3:MeOH = 9:1
31.9


 


Comp. 105





303

301

0.12
SiO2
CHCl3:MeOH = 9:1
46.7


 


Comp. 106





165

163

0.25
SiO2
CHCl3:MeOH = 9:1



 


Comp. 107





196

194

0.37
SiO2
CHCl3:MeOH = 9:1



 


Comp. 108





231



0.39
SiO2
CHCl3:MeOH = 9:1
36.4


 


Comp. 109





196

194

0.13
SiO2
CHCl3:MeOH = 9:1



 


Comp. 110









0.13
SiO2
CHCl3:MeOH = 9:1



 


Comp. 111





191



0.37
SiO2
CHCl3:MeOH = 9:1



 


Comp. 112







160

0.24
SiO2
CHCl3:MeOH = 9:1
37.4


 


Comp. 113





196

194

0.08
SiO2
CHCl3:MeOH = 9:1



 


Comp. 114







223

0.21
SiO2
CHCl3:MeOH = 9:1



 


Comp. 115





239

237

0.4
SiO2
CHCl3:MeOH = 9:1


 


Comp. 116





197

195

0.37
SiO2
CHCl3:MeOH = 9:1



 


Comp. 117





249

247

0.39
SiO2
CHCl3:MeOH = 9:1
71.6


 


Comp. 118





225

223

0.41
SiO2
CHCl3:MeOH = 9:1



 


Comp. 119





249



0.27
SiO2
CHCl3:MeOH = 9:1



 


Comp. 120





173

171

0.37
SiO2
CHCl3:MeOH = 9:1



 


Comp. 121




166.5–167.0


237

0.29
SiO2
EtOAc:hexane = 1:2
72.0


 


Comp. 122




106.0–107.5
223

221

0.05
SiO2
EtOAc:hexane = 1:2
94.7
28.9


 


Comp. 123




167.0–167.5

195
193

0.47
SiO2(NH)
EtOAc:MeOH = 95:5
92.7


 


Comp. 124




100.0–102.0


227

0.12
SiO2
EtOAc:hexane = 1:2
92.2
354.5


 


Comp. 125




138.0–139.5(dec.)







67.6


 


Comp. 126




172.5–173.0(dec.)







34.9


 


Comp. 127




137.5–138.5

209

207
0.53
SiO2(NH)
EtOAc:MeOH = 95:5



 


Comp. 128




143.0–145.0
263



0.26
SiO2
CHCl3:MeOH = 9:1
102.0
7.0


 


Comp. 129




183.0–183.5

253
251

0.50
SiO2(NH)
EtOAc:MeOH = 95:5



 


Comp. 130




155.0–156.0
243

241

0.10
SiO2
EtOAc:hexane = 1:2
116.5
6.9


 


Comp. 131




144.0–145.5
229

227

0.09
SiO2
EtOAc:hexane = 1:2
89.2
26


 


Comp. 132




122.0–123.5







117.6
3.9


 


Comp. 133




116.5–117.5







48.6
720


 


Comp. 134




154.0–154.5







57.4
3625


 


Comp. 135





137

135

0.10
SiO2
EtOAc:hexane = 1:2
49.3


 


Comp. 136





243

2441

0.17
SiO2
EtOAc:hexane = 1:2



 


Comp. 137





229

227

0.15
SiO2
EtOAc:hexane = 1:2



 


Comp. 138





297

295

0.11
SiO2
EtOAc:hexane = 1:2
44.0


 


Comp. 139





179

177

0.13
SiO2
EtOAc:hexane = 1:2
69.7


 


Comp. 140






194
192

0.23
SiO2(NH)
AcOEt:EtOH = 90:10



 


Comp. 141






194
192

0.06
SiO2
CHCl3:MeOH = 95:5



 


Comp. 142







219

0.22
SiO2
AcOEt:EtOH = 90:10



 


Comp. 143






196
194

0.25
SiO2
CHCl3:MeOH = 95:5
37.3


 


Comp. 144






215
213

0.13
SiO2
CHCl3:MeOH = 95:5



 


Comp. 145







213

0.11
SiO2
CHCl3:MeOH = 95:5



 


Comp. 146






235
233

0.25
SiO2(NH)
AcOEt



 


Comp. 147






273
271

0.26
SiO2(NH)
AcOEt



 


Comp. 148






327
325

0.32
SiO2(NH)
AcOEt



 


Comp. 149






265
263

0.34
SiO2(NH)
AcOEt
36.5


 


Comp. 150






262
260

0.15
SiO2(NH)
AcOEt
34.1


 


Comp. 151






203
201

0.20
SiO2(NH)
AcOEt
108.2


 


Comp. 152






255
253

0.28
SiO2(NH)
AcOEt



 


Comp. 153






203
201

0.29
SiO2(NH)
AcOEt
39.4


 


Comp. 154






237
235

0.24
SiO2(NH)
AcOEt



 


Comp. 155






246
244

0.23
SiO2(NH)
AcOEt



 


Comp. 156






327
325

0.32
SiO2(NH)
AcOEt
39.4


 


Comp. 157






277
275

0.28
SiO2(NH)
AcOEt
121.4


 


Comp. 158






195
193

0.24
SiO2(NH)
AcOEt



 


Comp. 159






209
207

0.26
SiO2(NH)
AcOEt



 


Comp. 160






181
179

0.21
SiO2(NH)
EtOAc:MeOH = 95:5



 


Comp. 161




156.0–157.0

169

167
0.51
SiO2(NH)
EtOAc:MeOH = 95:5
88.6
13.4


 


Comp. 162






183
181

0.49
SiO2(NH)
EtOAc:MeOH = 95:5
62.6


 


Comp. 163






207

205
0.61
SiO2(NH)
EtOAc:MeOH = 95:5
40.0


 


Comp. 164






186

184
0.55
SiO2(NH)
EtOAc:MeOH = 95:5
86.7


 


Comp. 165






169


0.54
SiO2(NH)
EtOAc:MeOH = 95:5
105.7


 


Comp. 166






200


0.56
SiO2(NH)
EtOAc:MeOH = 95:5



 


Comp. 167






221

219
0.58
SiO2(NH)
EtOAc:MeOH = 95:5



 


Comp. 168






228
226

0.57
SiO2(NH)
EtOAc:MeOH = 95:5
61.9


 


Comp. 169






272
270

0.57
SiO2(NH)
EtOAc:MeOH = 95:5
104.1


 


Comp. 170






186

184
0.50
SiO2(NH)
EtOAc:MeOH = 95:5
99.8


 


Comp. 171






181


0.23
SiO2(NH)
EtOAc:MeOH = 95:5
54.1


 


Comp. 172






181


0.21
SiO2(NH)
EtOAc:MeOH = 95:5



 


Comp. 173






181

179
0.30
SiO2(NH)
EtOAc:MeOH = 95:5



 


Comp. 174






202


0.22
SiO2(NH)
EtOAc:MeOH = 95:5
62.4


 


Comp. 175






193

191
0.56
SiO2(NH)
EtOAc:MeOH = 95:5
69.9


 


Comp. 176






230

228
0.51
SiO2(NH)
EtOAc:MeOH = 95:5
67.0


 


Comp. 177






244
242

0.53
SiO2(NH)
EtOAc:MeOH = 95:5
85.4


 


Comp. 178




121.0–122.5

193

191
0.52
SiO2(NH)
EtOAc:MeOH = 95:5
91.4
9.0


 


Comp. 179






179

177
0.54
SiO2(NH)
EtOAc:MeOH = 95:5
63.5


 


Comp. 180






206
204

0.59
SiO2(NH)
EtOAc:MeOH = 95:5



 


Comp. 181







227

0.54
SiO2(NH)
EtOAc:MeOH = 95:5



 


Comp. 182






216
214

0.56
SiO2(NH)
EtOAc:MeOH = 95:5
90.2


 


Comp. 183






209
207

0.50
SiO2(NH)
EtOAc:MeOH = 95:5
92.0


 


Comp. 184






255
253

0.48
SiO2(NH)
EtOAc:MeOH = 95:5



 


Comp. 185






180
178

0.36
SiO2(NH)
EtOAc:MeOH = 95:5



 


Comp. 186






197
195

0.29
SiO2(NH)
EtOAc:MeOH = 95:5



 


Comp. 187






195
193

0.50
SiO2(NH)
EtOAc:MeOH = 95:5



 


Comp. 188






223
221

0.50
SiO2(NH)
EtOAc:MeOH = 95:5
59.1


 


Comp. 189






237
235

0.50
SiO2(NH)
EtOAc:MeOH = 95:5
116.8


 


Comp. 190






225
223

0.51
SiO2(NH)
EtOAc:MeOH = 95:5
44.9


 


Comp. 191






269
267

0.50
SiO2(NH)
EtOAc:MeOH = 95:5



 


Comp. 192






230
228

0.56
SiO2(NH)
EtOAc:MeOH = 95:5



 


Comp. 193






209

207
0.52
SiO2(NH)
EtOAc:MeOH = 95:5



 


Comp. 194






197

195
0.44
SiO2(NH)
EtOAc:MeOH = 95:5
67.5


 


Comp. 195






197


0.51
SiO2(NH)
EtOAc:MeOH = 95:5



 


Comp. 196








220
0.52
SiO2(NH)
EtOAc:MeOH = 95:5
46.9


 


Comp. 197






190
188

0.57
SiO2(NH)
EtOAc:MeOH = 95:5



 


Comp. 198






197


0.50
SiO2(NH)
EtOAc:MeOH = 95:5
81.8


 


Comp. 199






209
207

0.50
SiO2(NH)
EtOAc:MeOH = 95:5
85.6


 


Comp. 200






274
272

0.50
SiO2(NH)
EtOAc:MeOH = 95:5
53.3


 


Comp. 201






321
319

0.50
SiO2(NH)
EtOAc:MeOH = 95:5
70.1


 


Comp. 202






244
242

0.53
SiO2(NH)
EtOAc:MeOH = 95:5
31.6


 


Comp. 203






217

215
0.45
SiO2(NH)
EtOAc:MeOH = 95:5
51.1


 


Comp. 204






181

179
0.30
SiO2(NH)
EtOAc:MeOH = 95:5



 


Comp. 205






167

165
0.25
SiO2(NH)
EtOAc:MeOH = 95:5



 


Comp. 206






217


0.49
SiO2(NH)
EtOAc:MeOH = 95:5



 


Comp. 207




138.0–140.0

181

179
0.29
SiO2(NH)
EtOAc:MeOH = 95:5
90.7
11.6


 


Comp. 208






253
251

0.53
SiO2(NH)
EtOAc:MeOH = 95:5



 


Comp. 209




169.5–170.0

167
165

0.27
SiO2(NH)
EtOAc:MeOH = 95:5
102.2
151.6


 


Comp. 210






313
311

0.58
SiO2(NH)
EtOAc:MeOH = 95:5
78


 


Comp. 211





183

181

0.35
SiO2
CHCl3:MeOH = 9:1



 


Comp. 212





251

249

0.35
SiO2
CHCl3:MeOH = 9:1



 


Comp. 213





279



0.15
SiO2
CHCl3:MeOH = 9:1


 


Comp. 214





181

179

0.12
SiO2
CHCl3:MeOH = 9:1
31.9


 


Comp. 215







225

0.25
SiO2
CHCl3:MeOH = 9:1
36.1


 


Comp. 216







167

0.31
SiO2
CHCl3:MeOH = 9:1



 


Comp. 217





253



0.4
SiO2
CHCl3:MeOH = 9:1



 


Comp. 218





194



0.08
SiO2
CHCl3:MeOH = 9:1



 


Comp. 219





221

219

0.38
SiO2
CHCl3:MeOH = 9:1



 


Comp. 220





176

174

0.28
SiO2
CHCl3:MeOH = 9:1



 


Comp. 221





193

191

0.35
SiO2
CHCl3:MeOH = 9:1



 


Comp. 222







225

0.29
SiO2
CHCl3:MeOH = 9:1



 


Comp. 223





290

288

0.34
SiO2
CHCl3:MeOH = 9:1
52.2


 


Comp. 224





237

235

0.31
SiO2
CHCl3:MeOH = 9:1
47.1


 


Comp. 225





343

341

0.05
SiO2
CHCl3:MeOH = 9:1



 


Comp. 226





277

275

0.37
SiO2
CHCl3:MeOH = 9:1



 


Comp. 227




139.0–141.0
191

189

0.31
SiO2
AcOEt
117.8
39.7


 


Comp. 228







267

0.15
SiO2
EtOAc:hexane = 1:2
72.0


 


Comp. 229




194.0–195.0
238

236

0.34
SiO2
CHCl3:MeOH = 9:1
99.3
16.0


 


Comp. 230




165.0–165.5
181

179

0.07
SiO2
EtOAc:hexane = 1:2



 


Comp. 231




168.5–169.0
191

189

0.16
SiO2
EtOAc:hexane = 1:2
92.9
196.5


 


Comp. 232




154.0–155.0







86.0
6.6


 


Comp. 233




118.0–119.5
227

225

0.10
SiO2
EtOAc:hexane = 1:2
87.5
51.9


 


Comp. 234




111.0–113.0
213

211

0.15
SiO2
EtOAc:hexane = 1:2
74.1


 


Comp. 235




167.5–168.0


263

0.13
SiO2
EtOAc:hexane = 1:2
77.8
5915.9


 


Comp. 236




130.5–131.5



 


Comp. 237




197.5–198.0


237

0.17
SiO2
EtOAc:hexane = 1:2
96.6
26.2


 


Comp. 238




142.5–144.0
177

175

0.12
SiO2
EtOAc:hexane = 1:2
101.6
30.0


 


Comp. 239




182.5–183.0








4078


 


Comp. 240





227

225

0.15
SiO2
EtOAc:hexane = 1:2



 


Comp. 241





243



0.15
SiO2
EtOAc:hexane = 1:2



 


Comp. 242





187

185

0.13
SiO2
EtOAc:hexane = 1:2
50.6


 


Comp. 243





213

211

0.11
SiO2
EtOAc:hexane = 1:2



 


Comp. 244






330
328
328
0.49
SiO2
CHCl3:MeOH = 95:5
32.7


 


Comp. 245






276
274
274
0.38
SiO2(NH)
AcOEt:EtOH = 90:10
55.4


 


Comp. 246






220
218
218
0.22
SiO2
CHCl3:MeOH = 95:5



 


Comp. 247






193
191
191
0.15
SiO2
CHCl3:MeOH = 95:5



 


Comp. 248






206
204

0.64
SiO2
AcOEt:EtOH = 90:10



 


Comp. 249






206
204

0.6
SiO2
AcOEt:EtOH = 90:10



 


Comp. 250






306
304
304
0.3
SiO2(NH)
AcOEt:EtOH = 90:10



 


Comp. 251






302
300
300
0.3
SiO2
CHCl3:MeOH = 95:5


 


Comp. 252







295

0.24
SiO2
CHCl3:MeOH = 95:5



 


Comp. 253






216
214
214
0.27
SiO2(NH)
AcOEt:EtOH = 90:10



 


Comp. 254







233

0.56
SiO2(NH)
AcOEt:EtOH = 90:10



 


Comp. 255






354
352
352
0.57
SiO2
AcOEt:EtOH = 90:10



 


Comp. 256







321

0.28
SiO2
CHCl3:MeOH = 95:5



 


Comp. 257






388
386
386
0.15
SiO2
CHCl3:MeOH = 95:5



 


Comp. 258






225
223
223
0.08
SiO2
CHCl3:MeOH = 95:5



 


Comp. 259






244
242

0.33
SiO2(NH)
AcOEt:EtOH = 90:10
52.8


 


Comp. 260






177
175
175
0.21
SiO2
CHCl3:MeOH = 95:5



 


Comp. 261






178
176
176
0.04
SiO2
CHCl3:MeOH = 95:5



 


Comp. 262






176

174
0.03
SiO2
CHCl3:MeOH = 95:5



 


Comp. 263






389
387
387
0.26
SiO2
CHCl3:MeOH = 95:5



 


Comp. 264






311
309
309
0.25
SiO2
CHCl3:MeOH = 95:5



 


Comp. 265






295

293
0.19
SiO2
CHCl3:MeOH = 95:5



 


Comp. 266






317
315

0.24
SiO2
CHCl3:MeOH = 95:5



 


Comp. 267







334

0.31
SiO2
CHCl3:MeOH = 95:5



 


Comp. 268






299
297
297
0.05
SiO2
CHCl3:MeOH = 95:5



 


Comp. 269






219
217
217
0.17
SiO2
CHCl3:MeOH = 95:5



 


Comp. 270






322
320
320
0.05
SiO2
CHCl3:MeOH = 95:5



 


Comp. 271






288
286
286
0.37
SiO2(NH)
AcOEt



 


Comp. 272






274
272
272
0.33
SiO2(NH)
AcOEt



 


Comp. 273




165.0–167.0

271
269
269
0.20
SiO2(NH)
AcOEt
89.2
96.8


 


Comp. 274






303
301
301
0.16
SiO2(NH)
AcOEt
94.5


 


Comp. 275






261
259
259
0.16
SiO2(NH)
AcOEt



 


Comp. 276




207.0–207.5

304
302
302
0.16
SiO2(NH)
AcOEt
71.8
55.9


 


Comp. 277






257
255
255
0.22
SiO2(NH)
AcOEt
76.4


 


Comp. 278






256
254

0.15
SiO2(NH)
AcOEt
65.3


 


Comp. 279






334
332
332
0.21
SiO2(NH)
AcOEt
42.8


 


Comp. 280






337
335
335
0.21
SiO2(NH)
AcOEt



 


Comp. 281






350
348
348
0.21
SiO2(NH)
AcOEt
50.9


 


Comp. 282






282

280
0.17
SiO2(NH)
AcOEt
122.9


 


Comp. 283






252
250
250
0.16
SiO2(NH)
AcOEt
62.6


 


Comp. 284






286
284
284
0.16
SiO2(NH)
AcOEt



 


Comp. 285






302
300
300
0.16
SiO2(NH)
AcOEt



 


Comp. 286






289
287
287
0.16
SiO2(NH)
AcOEt



 


Comp. 287






289
287
287
0.17
SiO2(NH)
AcOEt



 


Comp. 288






208
206
206
0.14
SiO2(NH)
AcOEt



 


Comp. 289






221
210
219
219
0.13
SiO2(NH)
AcOEt



 


Comp. 290






212
210
210
0.42
SiO2(NH)
EtOAc:MeOH = 95:5



 


Comp. 291






222
220

0.48
SiO2(NH)
EtOAc:MeOH = 95:5



 


Comp. 292






188
186
186
0.36
SiO2(NH)
EtOAc:MeOH = 95:5



 


Comp. 293






220
218
218
0.59
SiO2(NH)
EtOAc:MeOH = 95:5



 


Comp. 294




162.0–162.5

220

218
0.47
SiO2(NH)
EtOAc:MeOH = 95:5
103.2
4.9


 


Comp. 295






202

200
0.37
SiO2(NH)
EtOAc:MeOH = 95:5
73.8


 


Comp. 296






229

227
0.41
SiO2(NH)
EtOAc:MeOH = 95:5



 


Comp. 297






188

186
0.35
SiO2(NH)
EtOAc:MeOH = 95:5
71.1


 


Comp. 298






203

201
0.33
SiO2(NH)
EtOAc:MeOH = 95:5



 


Comp. 299






232
230
230
0.40
SiO2(NH)
EtOAc:MeOH = 95:5



 


Comp. 300




182.0–182.5

222

220
0.44
SiO2(NH)
EtOAc:MeOH = 95:5
96.3
5.7


 


Comp. 301






208

206
0.36
SiO2(NH)
EtOAc:MeOH = 95:5
62.1


 


Comp. 302




177.5–178.0

257

255
0.47
SiO2(NH)
EtOAc:MeOH = 95:5
96.5
1.9


 


Comp. 303






249
247
247
0.35
SiO2(NH)
EtOAc:MeOH = 95:5



 


Comp. 304






205
203

0.33
SiO2(NH)
EtOAc:MeOH = 95:5
68.5


 


Comp. 305






245

243
0.14
SiO2(NH)
EtOAc:MeOH = 95:5



 


Comp. 306







216

0.10
SiO2
CHCl3:MeOH = 9:1




 


Comp. 307





201



0.40
SiO2
CHCl3:MeOH = 9:1




 


Comp. 308





332

330

0.08
SiO2
CHCl3:MeOH = 9:1



 


Comp. 309





194



0.17
SiO2
CHCl3:MeOH = 9:1




 


Comp. 310





316

314

0.25
SiO2
CHCl3:MeOH = 9:1



 


Comp. 311





344

342

0.25
SiO2
CHCl3:MeOH = 9:1



 


Comp. 312





315



0.15
SiO2
CHCl3:MeOH = 9:1



 


Comp. 313





286

284

0.25
SiO2
CHCl3:MeOH = 9:1



 


Comp. 314





290



0.38
SiO2
CHCl3:MeOH = 9:1



 


Comp. 315





371

369

0.48
SiO2
CHCl3:MeOH = 9:1
50.7


 


Comp. 316




144.0–146.0
195

193

0.09
SiO2
Hexane:AcOEt = 2:1
97.9
24.0


 


Comp. 317




132.0–133.0

195


0.51
SiO2(NH)
EtOAc:MeOH = 95:5
93.8
3.5


 


Comp. 318




136.5–137.5
209

207

0.09
SiO2
Hexane:AcOEt = 2:1

9.9


 


Comp. 319




126.0–137.5
223

221

0.13
SiO2
Hexane:AcOEt = 2:1
99.9
3.8


 


Comp. 320




125.0–126.0
237

235

0.11
SiO2
Hexane:AcOEt = 2:1
92.5
1.3


 


Comp. 321




121–122.5
251

249

0.36
SiO2(NH)
AcOEt
99.9
3.7


 


Comp. 322





265

263

0.36
SiO2(NH)
AcOEt
117.5



 


Comp. 323




128.0–130.0
279

277

0.12
SiO2
Hexane:AcOEt = 2:1

25.9


 


Comp. 324




148.5–149.5
223

221

0.22
SiO2
AcOEt
99
3.7


 


Comp. 325




123.0–125.0
237

235

0.23
SiO2
AcOEt
106
2.6


 


Comp. 326





237

235

0.35
SiO2(NH)
AcOEt
110.8


 


Comp. 327






237
235

0.35
SiO2(NH)
AcOEt
110.1


 


Comp. 328





233

221

0.33
SiO2(NH)
AcOEt
121.4


 


Comp. 329




127.0–128.0

221
219

0.33
SiO2(NH)
AcOEt
121.1
0.7


 


Comp. 330




122.0–124.0
207

205

0.33
SiO2(NH)
AcOEt
118.8
2.4


 


Comp. 331




139.0–139.5

219
217

0.31
SiO2(NH)
AcOEt
118.8
3.2


 


Comp. 332




169.5–170.0
233

231

0.31
SiO2(NH)
AcOEt
110.6
2.1


 


Comp. 333




171.5–172.0
205

203

0.3
SiO2(NH)
AcOEt
119.3
2.2


 


Comp. 334




125.0–126.0
221



0.23
SiO2
AcOEt
105
3.2


 


Comp. 335




139.0–141.0
205



0.23
SiO2
AcOEt
110
1.4


 


Comp. 336




142.5–146.0
207

205

0.31
SiO2(NH)
AcOEt
117.6
3.2


 


Comp. 337




135.0–136.5
219

217

0.31
SiO2(NH)
AcOEt
119.4
2.1


 


Comp. 338




100.0–102.0
221


219
0.33
SiO2(NH)
AcOEt
119.8
0.9


 


Comp. 339




113.5–114.5
250

248

0.11
SiO2
AcOEt
88
124.2


 


Comp. 340




157.5–158  







97.4
3.0


 


Comp. 341




129.5–133  
263

261

0.23
SiO2
AcOEt
104
1.2


 


Comp. 342




174.5–175.5







98.5
5.3


 


Comp. 343




166.5–167.0







84.5
3.3


 


Comp. 344




  180–180.5
244



0.12
SiO2
AcOEt
107
37.5


 


Comp. 345




159.5–161  
244



0.14
SiO2
AcOEt
107
37.5


 


Comp. 346




104.0–107.0







106.2
8.9


 


Comp. 347




80.5–81.5
255

253

0.18
SiO2
AcOEt
105
3.7


 


Comp. 348




128.5–129.5
267

265

0.21
SiO2
AcOEt
103
3.4


 


Comp. 349




152.5–153.0
271

269

0.21
SiO2
AcOEt
100
1.6


 


Comp. 350




168.0–168.5
249



0.19
SiO2
AcOEt
91
1.4


 


Comp. 351





252

250

0.18
SiO2
AcOEt
89


 


Comp. 352




158.5–159.5
233



0.2
SiO2
AcOEt
97
4.6


 


Comp. 353




158.0–160.0
278

276

0.14
SiO2
AcOEt
105
3.7


 


Comp. 354




113.0–114.0
239

237

0.23
SiO2
AcOEt
106
3.0


 


Comp. 355




141.0–142.0
266

264

0.14
SiO2
AcOEt
107
5.9


 


Comp. 356




141.0–142.5
207



0.23
SiO2
AcOEt
102
2.6


 


Comp. 357





264

262

0.16
SiO2
AcOEt
98


 


Comp. 358




138.0–139.5
272

270

0.14
SiO2
AcOEt
103
3.1


 


Comp. 359




132.5–134.5
290

288

0.2
SiO2
AcOEt
102
1.4


 


Comp. 360





279

277

0.22
SiO2
AcOEt



 


Comp. 361




104.0–106.0
241

239

0.22
SiO2
AcOEt
106
2.1


 


Comp. 362




156.0–157.0
244



0.11
SiO2
AcOEt
106
2.1


 


Comp. 363




154.0–155.0
272

270

0.11
SiO2
AcOEt
105
0.78


 


Comp. 364




136.5–137.5
295

293

0.21
SiO2
AcOEt
104
2.0


 


Comp. 365




143.5–145.0
287

285

0.19
SiO2
AcOEt
105
1.4


 


Comp. 366




188.0–189.0
272



0.09
SiO2
AcOEt
105
1.2


 


Comp. 367




165.0–166.0
249



0.18
SiO2
AcOEt
103
2.1


 


Comp. 368




165.5–166.0
233



0.19
SiO2
AcOEt
96
2.5


 


Comp. 369




146.5–149.0
258



0.16
SiO2
AcOEt
105
3.1


 


Comp. 370





263
263
261
261
0.33
SiO2(NH)
AcOEt
113.7


 


Comp. 371




93.0–94.0
239
239
237
237
0.31
SiO2(NH)
AcOEt
110.4
0.9


 


Comp. 372






271
269
269
0.31
SiO2(NH)
AcOEt
100.5


 


Comp. 373




97.0–99.0

253
251
251
0.31
SiO2(NH)
AcOEt
115.3
0.8


 


Comp. 374





331
331
329
329
0.3
SiO2(NH)
AcOEt
119.1


 


Comp. 375






301
299
299
0.3
SiO2(NH)
AcOEt
117.7


 


Comp. 376






336
333
334
0.3
SiO2(NH)
AcOEt
114.9


 


Comp. 377






336
334
334
0.3
SiO2(NH)
AcOEt
107.4


 


Comp. 378






295
293
293
0.3
SiO2(NH)
AcOEt
102.4


 


Comp. 379






287
285
285
0.27
SiO2(NH)
AcOEt
105.4


 


Comp. 380






291
289
289
0.26
SiO2(NH)
AcOEt
118.9


 


Comp. 381






285
283
283
0.27
SiO2(NH)
AcOEt
116.0


 


Comp. 382




153.0–153.5

273


0.26
SiO2(NH)
AcOEt
122.5
3.1


 


Comp. 383






257
255
255
0.26
SiO2(NH)
AcOEt
116.2


 


Comp. 384




167.0–167.5

279
277

0.27
SiO2(NH)
AcOEt
117.3
2.8


 


Comp. 385






312
310
310
0.27
SiO2(NH)
AcOEt
109.0


 


Comp. 386






347
345

0.27
SiO2(NH)
AcOEt
105.2


 


Comp. 387




163.0–164.0
289
289


0.27
SiO2(NH)
AcOEt
97.8
0.9


 


Comp. 388






335
333
333
0.27
SiO2(NH)
AcOEt
96.2


 


Comp. 389




167.0–167.5

273

271
0.31
SiO2(NH)
AcOEt
105.5
1.6


 


Comp. 390




152.5–153.5

273

271
0.31
SiO2(NH)
AcOEt
112.8
2.7


 


Comp. 391




161.5–162.0

257
255
255
0.31
SiO2(NH)
AcOEt
113.4
2.4


 


Comp. 392




165.5–166.0
261
261
259

0.31
SiO2(NH)
AcOEt
109.6
2.4


 


Comp. 393




143.0–146.0

268
266
266
0.26
SiO2(NH)
AcOEt
124.3
1.1


 


Comp. 394




144.0–145.0
325
303

301
0.27
SiO2(NH)
AcOEt
119.9
3.9


 


Comp. 395




178.0–178.5
303
303

301
0.29
SiO2(NH)
AcOEt
111.6
2.1


 


Comp. 396





323
301
321
299
0.29
SiO2(NH)
AcOEt
102.7


 


Comp. 397






319


0.29
SiO2(NH)
AcOEt
99.3


 


Comp. 398





296
296
294
294
0.29
SiO2(NH)
AcOEt
95.2
2.4


 


Comp. 399




118–120
224
224
222
222
0.31
SiO2(NH)
AcOEt
102.3
98


 


Comp. 400




115.0–117.0
238
238

236
0.29
SiO2(NH)
AcOEt
116.9
48.7


 


Comp. 401




100.0–102.0
252
252
250
250
0.29
SiO2(NH)
AcOEt
117.4
37.6


 


Comp. 402




95.0–96.0
280
280
278
278
0.29
SiO2(NH)
AcOEt
118.8
18.7


 


Comp. 403




101.5–102.0
266
266
264
264
0.32
SiO2(NH)
AcOEt
118.3
28.5


 


Comp. 404




57.5–59.0
268
268
266
266
0.29
SiO2(NH)
AcOEt
114.9
115.6


 


Comp. 405





314
314
312
312
0.33
SiO2(NH)
AcOEt
116.0


 


Comp. 406






359
357
357
0.29
SiO2(NH)
AcOEt
73.7


 


Comp. 407




127.5–129.5
264
264
262
262
0.29
SiO2(NH)
AcOEt
94.3
4.9


 


Comp. 408




177.0–177.5
278
278
276
276
0.29
SiO2(NH)
AcOEt
103.0
4.2


 


Comp. 409




145.0–146.0

223
221
221
0.31
SiO2(NH)
AcOEt
113.2
6.7


 


Comp. 410




153.0–155.0

301
299
299
0.31
SiO2(NH)
AcOEt
117.3
1.0


 


Comp. 411




150.5–151.5
246
246
244
244
0.31
SiO2(NH)
AcOEt
122.4
3.1


 


Comp. 412




130.0–130.5
260
260
258
258
0.32
SiO2(NH)
AcOEt
119.4
1.5


 


Comp. 413




112.0–113.0

227
225
225
0.32
SiO2(NH)
AcOEt
120.2
2.3


 


Comp. 414




132.0–133.5
241
241
239
239
0.32
SiO2(NH)
AcOEt
113.2
1.0


 


Comp. 415




114–117
264
264
262
262
0.31
SiO2(NH)
AcOEt
103.7
17.6


 


Comp. 416




 99.5–102.5
264
264

262
0.31
SiO2(NH)
AcOEt
85.8
16.3


 


Comp. 417




146.5–148  
264
264

262
0.33
SiO2(NH)
AcOEt
102.8
90.0


 


Comp. 418






273
271
271
0.33
SiO2(NH)
AcOEt
120.4


 


Comp. 419





289
289
287
287
0.33
SiO2(NH)
AcOEt
116.1


 


Comp. 420




  147–148.5
237
237
235
235
0.31
SiO2(NH)
AcOEt
118.6
8.0


 


Comp. 421




  153–154.5
251
251
249
249
0.33
SiO2(NH)
AcOEt
113.3
3.9


 


Comp. 422




132.0–134.0
263
263
261
261
0.33
SiO2(NH)
AcOEt
121.6
1.5


 


Comp. 423




132.0–134.5
263
263

261
0.35
SiO2(NH)
AcOEt
118.4
2.2


 


Comp. 424




102.0–103.5








1.5


 


Comp. 425




>300








3.0


 


Comp. 426




101.5–104.0








5.1


 


Comp. 427




108.0–








2.6


 


Comp. 428




143.5–144.5








51.5


 


Comp. 429




159.0–141.0








79.1


 


Comp. 430




139.5–141.0








7.4


 


Comp. 431




113.0–115.0








47.7


 


Comp. 432




116.5–117.5








19.5


 


Comp. 433




125.0–127.0








1.5


 


Comp. 434




>300








3.2


 


Comp. 435




133.0–134.5








2.2


 


Comp. 436




140.5–141.0








79.2


 


Comp. 437






293
291
291
0.33
SiO2(NH)
AcOEt
96.1


 


Comp. 438






251
249
249
0.36
SiO2(NH)
AcOEt
87.9


 


Comp. 439




144.1–144.2

211
209
209
0.36
SiO2(NH)
AcOEt
92.3
2.9


 


Comp. 440






255

253
0.33
SiO2(NH)
AcOEt
102.8


 


Comp. 441




166  

259
257
257
0.33
SiO2(NH)
AcOEt
94.2


 


Comp. 442






225
223
223
0.36
SiO2(NH)
AcOEt
95.7


 


Comp. 443






239
237
237
0.38
SiO2(NH)
AcOEt
103.0


 


Comp. 444




121.0

213
211
211
0.10
SiO2(NH)
AcOEt
100.7
12.1


 


Comp. 445




112.0

240
238
238
0.18
SiO2(NH)
AcOEt
95.1


 


Comp. 446






241

239
0.31
SiO2(NH)
AcOEt
95.9


 


Comp. 447






237
235
235
0.36
SiO2(NH)
AcOEt
95.9


 


Comp. 448




125.0–126.5

249
247
247
0.36
SiO2(NH)
AcOEt
109.8
1.9


 


Comp. 449




119.0–120.5

225
223
223
0.38
SiO2(NH)
AcOEt
105.1
1.8


 


Comp. 450






239
237
237
0.41
SiO2(NH)
AcOEt
105.9


 


Comp. 451






253
251
251
0.41
SiO2(NH)
AcOEt
97.6


 


Comp. 452






267
265
265
0.41
SiO2(NH)
AcOEt
112.3


 


Comp. 453






295
293
293
0.44
SiO2(NH)
AcOEt
95.3


 


Comp. 454






268
266
266
0.26
SiO2(NH)
AcOEt
105.8


 


Comp. 455






255

253
0.28
SiO2(NH)
AcOEt
105.6


 


Comp. 456




143.0–145.0

225
223
223
0.33
SiO2(NH)
AcOEt
94.4
6.3


 


Comp. 457






269
267
267
0.33
SiO2(NH)
AcOEt
112.6


 


Comp. 458






273
271
271
0.36
SiO2(NH)
AcOEt
116.0


 


Comp. 459




  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.






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

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).
The subject compound for this examination was added to a buffer comprising 50 mM of 3-morpholinopropane sulfonic acid (pH7.4), 5 mM of magnesium chloride and 1 mM of ethylenediaminetetraacetic acid (EDTA) disodium salt.
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.
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.
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).
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.
Referring to Table 1, it was confirmed that the compounds of the present invention have inhibitory activity for production of 20-HETE.
INDUSTRIAL APPLICABILITY
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.
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.
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. A therapeutic method for treatment of stroke, said method comprising administering to a subject having stroke an effective amount of the hydroxyformamidine compound represented by the formula:



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- or di-substituted with C1-6 alkyl or phenyl groups; an N—(N′,N′-di(C1-6 alkyl)amino C1-6 alkyl)carbamoyl group; a cyano group; a cyano C1-6 alkyl group; a nitro group; a thiol group; a phenoxy group; a phenoxy group substituted with 1 to 3 substituents selected from the group consisting of C1-6 alkyl groups, C1-6 alkoxy groups, and halogen atoms; a phenylthio group; a nitrophenylthio group; a C1-6 alkylsulfonyl group; a phenylsulfonyl group; a C1-6 alkylthio C1-6 alkyl group; a phenylsulfonyl C1-6 alkylthio wherein the benzene ring is substituted with 1 to 5 halogen atoms; a phenyl group; a benzyl group; a phenyl group substituted with 1 to 3 substituents selected from the group consisting of cyano groups, halogen atoms, C1-6 alkyl groups, and C1-6 alkoxy groups; a biphenyl group; an α-cyanobenzyl group; an α-cyanobenzyl group substituted with 1 to 5 halogen atoms; a benzyl group substituted with a bicyclo[2.2.1]-hept-5-en-2,3-dicarboxyimidyl group; a benzoyl group; a styryl group; a styryl group substituted with 1 to 5 substituents selected from the group consisting of C1-6 alkoxy groups and di(C1-6 alkyl)amino alkyl groups; a pyrrolidino group; a piperidino group; a morpholino group; a pyridyl group; a pyrimidinyl group; a pyrimidinyl group substituted with 1 to 3 substituents selected from the group consisting of C1-6 alkyl groups and C1-6 alkoxy groups; a phthalimidoyl group; a phthalimidoyl group substituted with 1 to 3 halogen atoms; an N-carbazolyl group; a dioxopiperidinyl group substituted with 1 to 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]; 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 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.