JPH05201993A - Maillard reaction-inhibiting agent - Google Patents

Abstract

PURPOSE:To provide a new Maillard reaction-inhibiting agent containing a specific compound as an active ingredient and useful for the treatment of diseases accompanied by diabetic complications and aging. CONSTITUTION:The objective inhibiting agent contains one or more of a compound of formula I [R<1> is H, lower alkyl, etc.; R<2> is NHR<4>, N=R<6> (R<4> is H, phenylsulfonyl which may have one to three of substituents such as halogeno and nitro groups on the phenyl ring, etc.; R<6> is lower alkylidene, lower alkenylidene, etc.,); R<3> is two hydrogen atoms, phenyl lower alkylidene which may have R<3> is two hydrogen atoms, phenyl lower alkylidene which may have a substituent such as halogen on the phenyl ring; X is -S-, -N(R<7>) (R<7> is H, lower alkyl, etc.,); but R<1> and R<4>, R<4> and R<7> are combined with each other to form an oxoethylene group, etc.,] as an active ingredient. The compound of formula I is obtained by reacting a compound of formula II with a compound of formula III (R<8> is ester residue) in a solvent such as methanol preferably at 60-100 deg.C. For example, 2-isopropylidenehydrazonoimidazolidin-4-one.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel Maillard reaction inhibitor.

[0002]

2. Description of the Related Art The Maillard reaction in vivo begins with the free amino group present in a protein attacking the aldehyde group of a reducing sugar such as glucose by a nucleophilic reaction to form a Schiff base called aldimine.
Then, subsequently, transfer occurs to form a more stable Amadori compound (non-enzymatic glycation). The Amadori compound further undergoes a series of reactions with other protein-like amino groups to form a brown fluorescent substance and cause cross-linking between proteins. Historically, in 1912, Maillard reported that a mixture of amino acids and reducing sugars turned brown when heated [Maillard, L, C., Com.
pt.Rend.Soc.Biol., 72 , 599 (1912)], and since then, this reaction is called the Maillard reaction. At this time he already suggested that this reaction could occur in the living body. 19
In 1968, Rabbar et al. Found that hemoglobin A _1C, which is a minute fraction of hemoglobin, was increased in blood of diabetic patients [Rabbar, S., Clin.Chim.Acta., 22 , 296].
(1968)], and that this hemoglobin A _1C is bound to the N-terminal valine of the hemoglobin β chain in the form of Amadori transfer of glucose [Stevens, VJ, Vlassara, H.,
Abati, A., & Cerami, A., J. Biol. Chem., 252, 2998 (1977)]
Etc. were found, and the existence of non-enzymatic glycation in vivo was proved.

In recent years, it has been further confirmed that various biological proteins undergo the Maillard reaction. For example, the amount of glycated hemoglobin was increased about 3-fold in diabetic patients [Abraham, EC et al., J. La.
b. Clin. Med. 102, 187 (1983)]. The amount of glycation is also increased in serum albumin of diabetic patients [R. Do.
lhofer and OH Wieland, Diabetes , 29, 417 (1980)].
In addition, an increase in fluorescence has been observed in skin collagen obtained from diabetic patients [Vincent M. Monnier,
et al., Proc. Natl. Acad. Sci. USA, 81 , 583 (1984)]. Non-enzymatic glycation is a phenomenon that is also seen in healthy people, but the accumulation of this brown fluorescent substance is a protein with a slow turnover rate, and it is remarkably observed in diabetics where aging and blood sugar level rise. It This is because the accumulated amount of Maillard reaction products is determined by the blood sugar level and the turnover rate of its target protein.
ick) [Patrick, JS, Thor
pe, SR, Baynes, JWJournal of Gerontology 45,1, B18
-23 1990].

The relationship between such Maillard reaction products and various etiologies related to diabetes and aging has been discussed.
For example, 12 glycated serum proteins in mice
Intravenous administration over a period of weeks causes the typical renal damage seen in diabetes [BAMcVerry et al.
The Lancet 5 , 738 (1980)] has been reported. Involvement of non-enzymatic glycation of neuronal myelin protein is also considered as one of the causes of diabetic neuropathy [Monnier,
VMetal., Clin. Endocrinol. Metab. 11 .431 (1982)].

Ocular lens crystallin is a special protein that has no turnover after biosynthesis.
Rami) et al. found that when this crystallin is subjected to glycation, a colorless cross-linker having a disulfide bond and a cross-linker having a color and fluorescence are formed [Mo.
nnier, VM & Cerami, A., Science, 211, 491 (1981) Monn
ier, VM & Cerami, A., Biochim.Biophys.Acta , 760 , 97 (19
83)]. Polymerization, insolubilization, increased fluorescence, and browning caused by glycation of crystallin closely resembles age-related changes in lenses [Chiou, S.
H., et al., J. Biol. Chem. 256, 5176 (1981)].

[0006] Collagen and elastin, which are proteins that constitute connective tissue, are proteins with extremely slow turnover, but a binder with glucose has been found in renal glomerular basement membrane, skin, tendon, etc. [ Monnier, VM, et a
l., Maillard Reaction in Food, Prog.Food Nutr.Sci .5 ,
315, Pergamon Press, London]. Brown Lee
Lee et al. showed increased cross-linking of vascular wall collagen and accumulation of fluorescent substances in diabetic rats, and that this is due to a non-enzymatic mechanism [Brownlee, M. et al., Sc.
ience , 232 , 1629 (1986)], and its association with arterial stiffness [Rosenburg, H., et al., Biochem. Biophy
s., Res. Commun , 91, 498 (1979)].

As described above, the in vivo Maillard reaction is considered to be involved in various diseases related to diabetes and aging.

[0008]

DISCLOSURE OF THE INVENTION The object of the present invention is to provide a novel Maillard reaction inhibitor.

[0009]

According to the present invention, the following general formula (1)

[0010]

[Chemical 3]

[Wherein R ¹ is a hydrogen atom, a lower alkyl group, a carboxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a phenoxy lower alkanoyl group or a lower cycloalkyl group which may have a lower alkoxycarbonyl group on the phenyl ring. Represents a group, R ² is a group —N
HR ⁴ {R ⁴ is a hydrogen atom, a phenyl ring which may have 1 to 3 substituents selected from a halogen atom, a nitro group, a lower alkoxy group and a lower alkyl group on the phenyl ring, a phenyl lower alkanoyl group or a group. -C
O-NHR ⁵ (R ⁵ represents a lower alkyl group, a phenyl group which may have a halogen atom on the phenyl ring, a phenyl lower alkyl group or a naphthyl group)}.
Or R ² is a group —N═R ⁶ {R ⁶ is a lower alkylidene group,
A lower alkylidene group having 1 to 2 lower cycloalkyl groups, a halogen atom on the phenyl ring, a carboxyl group,
Phenyl lower alkylidene group which may have 1 to 3 substituents selected from lower alkoxycarbonyl group, nitro group, hydroxyl group, lower alkoxy group and halogenated lower alkyl group, phenyl which may have nitro group on the phenyl ring A lower alkenylidene group, a lower alkenylidene group, a lower cycloalkylidene group or a phenoxy lower alkylidene group which may have a carboxyl group on the phenyl ring. }, And R ³ represents a hydrogen atom, a phenyl lower alkylidene group or a phenyl lower alkenylidene group which may have a substituent selected from a halogen atom and a halogenated lower alkyl group on the phenyl ring,
X is -S- or ^{-N (R 7) - (.} R 7 is showing a hydrogen atom, a lower alkyl group, carboxy lower alkyl group or a lower alkoxycarbonyl-lower alkyl group) a, R ¹
And R ⁴ , or R ⁴ and R ⁷ may combine with each other to form an oxoethylene group. ] The Maillard reaction inhibitor containing at least 1 of the compound shown by these or its salt as an active ingredient is provided.

By inhibiting the Maillard reaction, the compound of the present invention and various salts thereof are associated with various diabetic complications such as coronary artery disease, peripheral circulatory disorder, cerebrovascular disorder, diabetic neuropathy, nephropathy and arteriosclerosis. It is useful for treating and / or preventing arteriosclerosis, cataract and retinopathy, and diseases caused by aging such as atherosclerosis and senile cataract.

More specifically, each group shown in the present specification is as follows.

The lower alkyl group, regardless of whether it is present independently or in another group, is a methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl group or the like. Carbon number of 1
The straight-chain or branched alkyl group of ~ 6 can be illustrated.

The lower alkoxy group, whether it is present independently or in another group, is methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyl. A straight-chain or branched alkoxy group having 1 to 6 carbon atoms such as an oxy group can be exemplified.

The halogen atom, whether it is independently present or present in another group, is
Indicates fluorine, chlorine, bromine and iodine atoms.

As the carboxy lower alkyl group, carboxymethyl, 2-carboxyethyl, 1-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl, 1,1-dimethyl-2-carboxyethyl, 5-carboxypentyl, 6- Examples thereof include a carboxyalkyl group in which the alkyl portion such as carboxyhexyl and 2-methyl-3-carboxypropyl group is a linear or branched alkyl group having 1 to 6 carbon atoms.

As the lower alkoxycarbonyl lower alkyl group, methoxycarbonylmethyl, ethoxycarbonylmethyl, 3-methoxycarbonylpropyl, 4-ethoxycarbonylbutyl, 6-propoxycarbonylhexyl, 5-isopropoxycarbonylpentyl, 1,
1-dimethyl-2-butoxycarbonylethyl, 2-methyl-3-tert-butoxycarbonylpropyl, 2-pentyloxycarbonylethyl, hexyloxycarbonylmethyl, etc., having 1 to 6 carbon atoms in the alkoxy moiety and carbon in the alkyl moiety The alkoxycarbonylalkyl group whose number is 1 to 6 can be exemplified.

As the phenoxy lower alkanoyl group,
2-phenoxyacetyl, 3-phenoxypropionyl, 4-phenoxybutyryl, 2-phenoxybutyryl, 6-phenoxyhexanoyl, 2-phenoxypropionyl, 3-phenoxybutyryl, 4-phenoxy-
3-methylbutyryl, 5-phenoxypentanoyl, 2
An alkanoyl moiety such as -methyl-3-phenoxypropionyl group may be a straight chain or branched phenoxy lower alkanoyl group having 2 to 6 carbon atoms.

The phenoxy lower alkanoyl group having a lower alkoxycarbonyl group on the phenyl ring is 2
-(4-Methoxycarbonylphenoxy) acetyl, 2
-(3,4-dimethoxycarbonylphenoxy) acetyl, 2- (3,4,5-trimethoxycarbonylphenoxy) acetyl, 2- (3-methoxycarbonylphenoxy) acetyl, 2- (2-methoxycarbonylphenoxy) acetyl, 3- (2-propoxycarbonylphenoxy) propionyl, 4- (4-pentyloxycarbonylphenoxy) butyryl, 5- (3-propoxycarbonylphenoxy) pentanoyl, 6- (4-isobutoxycarbonylphenoxy) hexanoyl, 2- (4
-Hexyloxycarbonylphenoxy) acetyl, 2
-(4-butoxyphenoxy) acetyl or the like having a phenoxy group having a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy moiety as a substituent on the phenyl ring, and having 2 to 7 carbon atoms directly A chain or branched alkanoyl group can be exemplified.

The lower cycloalkyl group has 3 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups.
Examples of the lower cycloalkyl group of ~ 8.

The phenyl lower alkanoyl group is phenylacetyl, 3-phenylpropionyl, 4-phenylbutyryl, 2,2-dimethyl-3-phenylpropionyl, 5-phenylpentanoyl, 6-phenylhexanoyl, 2-methyl-. Examples thereof include a phenylalkanoyl group which is a linear or branched alkanoyl group having 2 to 6 carbon atoms in the alkanoyl moiety such as a 3-phenylpropionyl group.

Halogen atom, nitro group, on the phenyl ring,
Examples of the phenylsulfonyl group which may have 1 to 3 substituents selected from a lower alkoxy group and a lower alkyl group include phenylsulfonyl, 2-chlorophenylsulfonyl, 3-chlorophenylsulfonyl, 4-chlorophenylsulfonyl, 2- Fluorophenylsulfonyl,
3-fluorophenylsulfonyl, 4-fluorophenylsulfonyl, 2-bromophenylsulfonyl, 3-bromophenylsulfonyl, 4-bromophenylsulfonyl, 2-iodophenylsulfonyl, 4-iodophenylsulfonyl, 3,5-dichlorophenylsulfonyl ,
2,6-dichlorophenylsulfonyl, 3,4-dichlorophenylsulfonyl, 3,4-difluorophenylsulfonyl, 3,5-dibromophenylsulfonyl, 3,
4,5-Trichlorophenylsulfonyl, 2-methylphenylsulfonyl, 3-methylphenylsulfonyl, 4
-Methylphenylsulfonyl, 2-ethylphenylsulfonyl, 3-ethylphenylsulfonyl, 4-ethylphenylsulfonyl, 3-isopropylphenylsulfonyl, 4-hexylphenylsulfonyl, 3,4-dimethylphenylsulfonyl, 2,5-dimethylphenylsulfonyl , 3,4,5-trimethylphenylsulfonyl,
2-methoxyphenylsulfonyl, 3-methoxyphenylsulfonyl, 4-methoxyphenylsulfonyl, 2-
Ethoxyphenylsulfonyl, 3-ethoxyphenylsulfonyl, 4-ethoxyphenylsulfonyl, 4-isopropoxyphenylsulfonyl, 4-hexyloxyphenylsulfonyl, 3,4-dimethoxyphenylsulfonyl, 3,4-diethoxyphenylsulfonyl, 3,
4,5-trimethoxyphenylsulfonyl, 2,5-dimethoxyphenylsulfonyl, 2-nitrophenylsulfonyl, 3-nitrophenylsulfonyl, 4-nitrophenylsulfonyl, 2,4-dinitrophenylsulfonyl, 3-methyl-4-chlorophenyl Sulfonyl, 2-
A halogen atom, a nitro group, a straight-chain or branched alkoxy group having 1 to 6 carbon atoms and a carbon number as a substituent on the phenyl ring such as chloro-6-methylphenylsulfonyl and 2-methoxy-3-chlorophenylsulfonyl group. A phenylsulfonyl group which may have 1 to 3 groups selected from 1 to 6 linear or branched alkyl groups can be exemplified.

The phenyl group which may have a halogen atom on the phenyl ring as a substituent is phenyl, 2
-Chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-
Bromophenyl, 4-bromophenyl, 2-iodophenyl, 4-iodophenyl, 3,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3 Examples thereof include a phenyl group which may have 1 to 3 halogen atoms such as a 5,5-dibromophenyl and a 3,4,5-trichlorophenyl group.

The phenyl lower alkyl group is benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1,1-dimethyl-2-phenylethyl, 5-phenylpentyl, 6-.
Examples thereof include a phenylalkyl group which is a linear or branched alkyl group having 1 to 6 carbon atoms in the alkyl moiety such as phenylhexyl and 2-methyl-3-phenylpropyl group.

Examples of the lower alkylidene group include linear or branched alkylidene groups having 1 to 6 carbon atoms such as methylene, ethylidene, propylidene, isopropylidene, butylidene, tert-butylidene, pentylidene and hexylidene groups.

Examples of the lower alkylidene group having 1 to 2 lower cycloalkyl groups include 2-cyclopropylethylidene, 1-cyclobutylethylidene, 3-cyclopentylpropylidene, 4-cyclohexylbutylidene, 1,
Number of carbon atoms such as 1-dimethyl-2-cycloheptylethylidene, 5-cyclooctylpentylidene, 6-cyclohexylhexylidene, 2-methyl-3-cyclohexylpropylidene, dicyclopropylmethylene and 2-dicyclopropylethylidene group. 1 to 3 to 8 cycloalkyl groups
The straight-chain or branched alkylidene group having 1 to 2 carbon atoms and having 1 to 2 carbon atoms can be exemplified.

As the phenyl lower alkylidene group, benzylidene, 2-phenylethylidene, 1-phenylethylidene, 3-phenylpropylidene, 4-phenylbutylidene, 1,1-dimethyl-2-phenylethylidene, 5-phenylpentylidene, Examples thereof include a phenylalkylidene group which is a linear or branched alkylidene group having 1 to 6 carbon atoms in the alkylidene moiety such as 6-phenylhexylidene and 2-methyl-3-phenylpropylidene group.

As the phenyl lower alkylidene group having 1 to 3 substituents selected from a halogen atom, a carboxyl group, a lower alkoxycarbonyl group, a nitro group, a hydroxyl group, a lower alkoxy group and a halogenated lower alkyl group on the phenyl ring, 2-chlorobenzylidene, 4-fluorobenzylidene, 2- (3-chlorophenyl) ethylidene, 1- (4-chlorophenyl) ethylidene, 3- (2
-Fluorophenyl) propylidene, 4- (3-fluorophenyl) butylidene, 1,1-dimethyl-2- (4
-Fluorophenyl) ethylidene, 5- (2-bromophenyl) pentylidene, 6- (3-bromophenyl) hexylidene, 2-methyl-3- (4-bromophenyl)
Propylidene, 3-iodobenzylidene, 2- (4-iodophenyl) ethylidene, 1- (3,5-dichlorophenyl) ethylidene, 2- (3,4-dichlorophenyl) ethylidene, 3- (2,6- Dichlorophenyl) propylidene, 4- (3,4-dichlorophenyl) butylidene, 1,1-dimethyl-2- (3,4-difluorophenyl) ethylidene, 5- (3,5-dibromophenyl) pentylidene, 6- (3,4,5-trichlorophenyl) hexylidene, 4-fluoromethylbenzylidene, 4-chloromethylbenzylidene, 4-bromomethylbenzylidene, 4-iodomethylbenzylidene, 4-difluoromethylbenzylidene, 4-trifluoromethylbenzylidene , 4-trichloromethylbenzylidene, 2
-(2-Fluoromethylphenyl) ethylidene, 1-
(3-chloromethylphenyl) ethylidene, 3- (3-
Bromomethylphenyl) propylidene, 4- [4- (2
-Fluoroethyl) phenyl] butylidene, 5- [4-
(2-chloroethyl) phenyl) propylidene, 6-
[3- (3-chloropropyl) phenyl] hexylidene, 2-methyl-3- [3- (4-chlorohexyl) phenyl] propylidene, 2- (3,4-difluoromethylphenyl) ethylidene, 2- (2,2. 5-dibromomethylphenyl) ethylidene, 2- (3,4,5-trichloromethylphenyl) ethylidene, 4-methoxybenzylidene, 3,4-dimethoxybenzylidene, 3,4,5-
Trimethoxybenzylidene, 1- (3-methoxyphenyl) ethylidene, 2- (2-methoxyphenyl) ethylidene, 3- (2-ethoxyphenyl) propylidene, 4
-(4-ethoxyphenyl) butylidene, 5- (3-ethoxyphenyl) pentylidene, 6- (4-isopropoxyphenyl) hexylidene, 4-butoxybenzylidene, 1,1-dimethyl-2- (4-hexyloxyphenyl) Ethylidene, 2-methyl-3- (3,4-dimethoxyphenyl) propylidene, 2- (3,4-dimethoxyphenyl) ethylidene, 2- (3,4-diethoxyphenyl) ethylidene, 2- (3,4,) 5-trimethoxyphenyl) ethylidene, 1- (2,5-dimethoxyphenyl) ethylidene, 2-carboxybenzylidene, 3-
Carboxybenzylidene, 4-carboxybenzylidene, 1- (2-carboxyphenyl) ethylidene, 2-
(4-Carboxyphenyl) ethylidene, 3- (2,4
-Dicarboxyphenyl) propylidene, 4- (3-carboxyphenyl) butylidene, 5- (2-carboxyphenyl) pentylidene, 6- (3-carboxyphenyl) hexylidene, 2-methoxycarbonylbenzylidene, 2- (2-ethoxycarbonyl) ) Benjiriden, 2
-Nitrobenzylidene, 3-Nitrobenzylidene, 4-
Nitrobenzylidene, 3,4,5-trinitrobenzylidene, 1- (2-nitrophenyl) ethylidene, 2-
(4-nitrophenyl) ethylidene, 3- (2,4-dinitrophenyl) propylidene, 4- (3-nitrophenyl) butylidene, 5- (3-nitrophenyl) pentylidene, 6- (3-nitrophenyl) hexylidene, Two
-Methoxy-3-chlorobenzylidene, 2-hydroxybenzylidene, 2- (3,4-dihydroxyphenyl)
Ethylidene, 1- (3,4-dihydroxyphenyl) ethylidene, 2- (3-hydroxyphenyl) ethylidene, 3- (4-hydroxyphenyl) propylidene, 6
-(3,4-hydroxyphenyl) hexylidene, 2,
4-dihydroxybenzylidene, 3,4,5-trihydroxybenzylidene, 4-methoxycarbonylbenzylidene, 3,4-dimethoxycarbonylbenzylidene, 3
-(2-ethoxycarbonylphenyl) propylidene,
6- (4-isopropoxycarbonylphenyl) hexylidene, 4-butoxycarbonylbenzylidene, 4-hexyloxycarbonylbenzylidene group, etc., having a linear or branched alkoxy group having 1 to 6 carbon atoms as a substituent on the phenyl ring, 1 is selected from a linear or branched halogenated alkyl group having 1 to 6 carbon atoms, a halogen atom, a carboxyl group, an alkoxycarbonyl group having an alkoxy moiety having 1 to 6 carbon atoms, a nitro group, and a hydroxyl group. A straight-chain or branched alkylidene group having 1 to 6 carbon atoms having a phenyl group having 3 to 3 can be exemplified.

As the phenyl lower alkenylidene group which may have a nitro group on the phenyl ring, phenylvinylidene, 4-nitrophenylvinylidene, 3-phenylarylidene, 3- (4-nitro) phenylarylidene, 4-phenyl -2-butenylidene, 4-phenyl-
The alkenylidene moiety such as 3-butenylidene, 1-methyl-3-phenylallylidene, 2-methyl-3-phenylallylidene, 5-phenyl-2-pentenylidene, 6-phenyl-2-hexenylidene group has 2 to 6 carbon atoms. And a phenylalkenylidene group having a linear or branched alkenylidene moiety and having 1 to 3 nitro groups on the phenyl ring.

Examples of the lower alkenylidene group include vinylidene, arylidene, 2-butenylidene, 3-butenylidene, 2-pentenylidene, 2-hexenylidene groups and the like linear or branched alkenylidene groups having 2 to 6 carbon atoms.

As a lower cycloalkenylidene group, 2
-Cyclopropenylidene, 2-cyclobutenylidene, 2
-Cyclopentenylidene, 2-cyclohexenylidene,
Examples thereof include cycloalkenylidene groups having 3 to 8 carbon atoms such as 2-cycloheptenylidene and 2-cyclooctenylidene groups.

As the phenoxy lower alkylidene group which may have a carboxyl group on the phenyl ring, phenoxymethylene, 2-phenoxyethylidene, 1-phenoxyethylidene, 3-phenoxypropylidene, 4-
Phenoxybutylidene, 1,1-dimethyl-2-phenoxyethylidene, 5-phenoxypentylidene, 6-phenoxyhexylidene, 2-methyl-3-phenoxypropylidene, 2-carboxylphenoxymethylene, 1
-(3-Carboxylphenoxy) ethylidene, 2-
(4-Carboxylphenoxy) ethylidene, 3- (2
-Carboxylphenoxy) propylidene, 4- (3-
Carboxylphenoxy) butylidene, 1,1-dimethyl-2- (4-carboxylphenoxy) ethylidene,
5- (2-carboxylphenoxy) pentylidene, 6
-(3-Carboxylphenoxy) hexylidene, 2-
A phenoxy lower alkylidene group which may have a carboxyl group on the phenyl ring in which the alkylidene group moiety such as methyl-3- (4-carboxylphenoxy) propylidene group is a linear or branched alkylidene group having 1 to 6 carbon atoms. Can be illustrated.

Examples of the phenyl lower alkylidene group which may have a substituent selected from a halogen atom and a halogenated lower alkyl group on the phenyl ring include benzylidene, 2-phenylethylidene, 1-phenylethylidene, 3-phenylpropylidene, and 4 -Phenylbutylidene, 1,1-dimethyl-2-phenylethylidene, 5-
Phenylpentylidene, 6-phenylhexylidene, 2
-Methyl-3-phenylpropylidene, 4-fluorobenzylidene, 4-chlorobenzylidene, 4-bromobenzylidene, 4-iodobenzylidene, 2- (2-fluorophenyl) ethylidene, 1- (3-chlorophenyl)
Ethylidene, 3- (3-bromophenyl) propylidene, 4-fluoromethylbenzylidene, 4-chloromethylbenzylidene, 4-bromomethylbenzylidene, 4-
Iodomethylbenzylidene, 4-difluoromethylbenzylidene, 4-trifluoromethylbenzylidene, 4-
Trichloromethylbenzylidene, 2- (2-fluoromethylphenyl) ethylidene, 1- (3-chloromethylphenyl) ethylidene, 3- (3-bromomethylphenyl) propylidene, 4- [4- (2-fluoroethyl)
Phenyl] butylidene, 5- [4- (2-chloroethyl) phenyl) propylidene, 6- [3- (3-chloropropyl) phenyl] hexylidene, 2-methyl-3-
[3- (4-chlorohexyl) phenyl] propylidene, 2- (3,4-difluoromethylphenyl) ethylidene, 2- (2,5-dibromomethylphenyl) ethylidene, 2- (3,4,5-trichloromethyl Phenyl)
A substituent having a halogen atom such as ethylidene and a straight-chain or branched alkylidene moiety having 1 to 6 carbon atoms, and a straight-chain or branched halogenated alkyl group having 1 to 6 carbon atoms on the phenyl ring. The phenylalkylidene group which may have 1 to 3 can be exemplified.

When R ¹ = H in the compound (1) of the present invention, the following isomer structures (1A) to (1C) are possible.

[0036]

[Chemical 4]

The present invention includes all of these isomers, other stereoisomers, optical isomers and geometric isomers.

The compounds (1) of the present invention include some known compounds, but most of them are novel compounds.

The compound (1) of the present invention can be produced by various methods, for example, the methods shown in the following reaction process formulas 1-10.

[Reaction Process Formula 1]

[0041]

[Chemical 5]

[In the formula, R ¹ , R ² and R ⁷ are the same as defined above.
R ⁸ represents a usual ester residue. Examples of the ester residue represented by R ⁸ include a lower alkyl group having 1 to 6 carbon atoms and a phenyl lower alkyl group.

This reaction is carried out in a suitable solvent at room temperature to 200 ° C.
The temperature is preferably about 60 to 100 ° C. Suitable solvents for this reaction include lower alcohols such as methanol, ethanol and isopropanol, dioxane, tetrahydrofuran (THF), ethers such as ethylene glycol dimethyl ether and diethyl ether, aromatic hydrocarbons such as benzene, toluene and xylene. , Tertiary amines such as triethylamine and tripropylamine,
Examples thereof include polar solvents such as dimethylformamide (DMF) and dimethylsulfoxide (DMSO). The compound of general formula (3) is used in an equimolar amount or more, preferably about 1 to 3 times the molar amount of the compound of general formula (2). Generally, the reaction is completed in about 1 to 24 hours.

[Reaction Process Formula 2]

[0045]

[Chemical 6]

[In the formula, R ¹ , R ² and R ⁸ are the same as defined above.
Y represents a halogen atom. This reaction is carried out in the presence of a deoxidizing agent using a usual solvent. Suitable deoxidizers include
Examples thereof include basic compounds such as potassium carbonate, sodium carbonate, sodium hydroxide, sodium hydrogen carbonate, triethylamine, tripropylamine, pyridine, quinoline, 4-dimethylaminopyridine and sodium acetate. A wide variety of ordinary solvents can be used,
For example, lower alcohols such as methanol, ethanol and isopropanol, dioxane, tetrahydrofuran (THF), ethers such as ethylene glycol dimethyl ether and diethyl ether, benzene, toluene,
Examples thereof include aromatic hydrocarbons such as xylene, tertiary amines such as triethylamine and tripropylamine, and polar solvents such as dimethylformamide (DMF) and dimethylsulfoxide (DMSO). The reaction temperature is from room temperature to about 150 ° C, preferably about 50 to 100 ° C. The amount of the compound of the general formula (5) used is equimolar or more, preferably about 1 to 3 times the molar amount of the compound of the general formula (4). The deoxidizer is used in an amount of about 1 to 10 times, preferably about 1 to 3 times the molar amount of the compound of the general formula (4). The reaction time is generally about 1 to 24 hours.

[Reaction Process Formula 3]

[0048]

[Chemical 7]

[In the formula, X, R ¹ and R ⁶ are the same as defined above.
A represents a halogen atom. When R ¹ is a lower alkyl group, a carboxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group or a lower cycloalkyl group, this reaction is carried out according to a usual substitution reaction in the presence of an alkali as a catalyst. Examples of suitable alkali used in this reaction include potassium carbonate, sodium carbonate, sodium hydroxide, sodium hydrogen carbonate, sodium amide, sodium hydride, triethylamine, tripropylamine and the like. Usual solvents can be widely used, for example, lower alcohols such as methanol, ethanol and isopropanol, dioxane, tetrahydrofuran (THF), ethers such as ethylene glycol dimethyl ether and diethyl ether, fragrances such as benzene, toluene and xylene. Group hydrocarbons, tertiary amines such as triethylamine and tripropylamine, dimethylformamide (DMF), dimethylsulfoxide (DMS)
Examples thereof include polar solvents such as O). Reaction temperature is 0
About 100 ° C is preferable. The reaction time is about 1 to 20 hours. The ratio of the compound of the general formula (6) to the compound of the general formula (1c) is about 1 to 3 times the molar amount. The amount of the alkali used may be about 1 to 3 mol per 1 mol of the compound of the general formula (1c).

[0050] formula (1c) X At a is -N (R ⁷⁾ -
And when R ⁷ is a hydrogen atom, the reaction is carried out by increasing the proportion of the compound of the general formula (6) used to 2 to 5 times the molar amount of the compound of the general formula (1c). At the same time, the above groups represented by R ¹ and R ⁷ (= R ¹ ) are introduced at both the 1-position and the 3-position.

When R ¹ is a phenoxy lower alkanoyl group which may have a lower alkoxycarbonyl group on the phenyl ring, this reaction is an ordinary amide bond forming reaction,
For example, it is performed according to the acid halide method. The above acid halide method is carried out in the presence of a deoxidizing agent in a suitable solvent. As the deoxidizing agent, various kinds of substances usually used for amide bond forming reaction, for example, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, pyridine, triethylamine and the like can be used. Solvents also commonly used, such as water,
Benzene, chloroform, methylene chloride, carbon tetrachloride,
Dioxane, tetrahydrofuran, etc. can be used. The ratio of the compound of the general formula (6) to be used is usually at least about equimolar, preferably equimolar to 3 with respect to the compound (1c).
It is appropriate that the amount is about twice the molar amount. Further, the amount of the deoxidizing agent used may be about 1 to 3 mol per 1 mol of the compound of the general formula (1c). The reaction temperature is generally -30 to 100 ° C, preferably room temperature to 80 ° C, and 20 minutes to 20 ° C.
The reaction ends in about time.

[Reaction Process Formula 5]

[0053]

[Chemical 8]

[In the formula, R ¹ and X are the same as defined above. R
^6a represents a lower alkylidene group, and R ^6b represents phenyl which may have 1 to 3 substituents selected from halogen atom, carboxyl group, nitro group, hydroxyl group, lower alkoxy group and halogenated lower alkyl group on the phenyl ring. A lower alkylidene group, a phenyl lower alkenylidene group or a phenoxy lower alkylidene group which may have a carboxyl group on the phenyl ring. ] The above reaction is carried out in a solvent,
It is carried out in the presence of a basic compound or an acidic compound. As the solvent, acetic acid, benzene, toluene, xylene, methanol, ethanol, propanol, pyridine, picoline, DMF, DMSO and the like can be used. As the basic compound, sodium acetate, potassium carbonate, sodium hydrogen carbonate, sodium alkoxide and the like can be used, and as the acidic compound, ammonium chloride, ammonium sulfate, concentrated sulfuric acid and the like can be used. The compound of the general formula (7) is generally used in an amount of at least about equimolar, preferably about 1 to 2 mol, based on 1 mol of the compound of the general formula (1d). Further, the basic compound or the acidic compound has the general formula (1
It is used in an amount of about 1 to 2 mol per mol of the compound d).
The reaction temperature is room temperature to about 150 ° C., preferably 50 to 10
The temperature is about 0 ° C., and the reaction is completed in about 1 to 60 hours.

[Reaction Process Formula 6]

[0056]

[Chemical 9]

[In the formula, R ¹ and X are the same as defined above. R
^2a is a group ^{-N = R 6a, -N = R} 6b or group -NHR ^4a (R ^6b
Is the same as above, R ^6a represents a lower alkylidene group, and R ^4a may have 1 to 3 substituents selected from a halogen atom, a nitro group, a lower alkoxy group and a lower alkyl group on the phenyl ring. Phenylsulfonyl group), R ^3a represents a phenyl lower alkylidene group or a phenyl lower alkenylidene group which may have a halogenated lower alkyl group on the phenyl ring, and R ^2b represents a group —N═R.
^3a, -N = R ^6b or group -NHR ^4a (R ^3a, R ^6b and R ^4a
Is the same as above). ] The above reaction is represented by the general formula (1f)
When R ^2a is a group —N═R ^6a , the compound of the general formula (8) is usually at least about 2 mol, preferably about 2 mol, relative to 1 mol of the compound of the general formula (1f) in the same manner as in the reaction process formula 5. It is carried out using about 2 to 3 moles to obtain a compound in which R ^2b is a group —N═R ^3a in the general formula (1g).

In the general formula (1f), R ^2a is a group —N═R.
^In the case of ^6b or —NHR ^4a , the compound of the general formula (8) is usually at least about equimolar to the compound of the general formula (1f) in the same manner as in the reaction step formula 5, preferably about 1 to 2 times the molar amount. Carried out in this way, thus obtaining compounds of the general formula (1g) in which R ^2b is a group —N═R ^6b or —NHR ^4a .

[Reaction Process Formula 7]

[0060]

[Chemical 10]

[In the formula, R ¹ , R ³ , R ⁶ and X are the same as defined above. This reaction is carried out in the presence of an organic or inorganic acidic compound. As the organic or inorganic acidic compound in the above, for example, hydrochloric acid, sulfuric acid, trifluoroacetic acid, acetic acid, formic acid or the like can be used, and among these, a dilute strong acid such as hydrochloric acid or sulfuric acid is particularly preferable. As the solvent, a usual acid-stable solvent can be used, and for example, methanol, ethanol, dioxane, THF, water or the like can be used. The amount of the acidic compound used is about 1 to 20 times the molar amount of the compound of the general formula (1d ′). The reaction is usually at about 30 to 120 ° C. for 5 to
It takes about 60 minutes.

[Reaction Process Equation 8]

[0063]

[Chemical 11]

[Wherein R ¹ , R ³ and X are the same as defined above]. R
⁹ is a substituent selected from a halogen atom, a nitro group, a lower alkoxy group and a lower alkyl group on the phenyl ring.
The phenyl group which may have 3 is shown. B represents a halogen atom. ] In the compound (1) of the present invention, R ⁴ is a phenylsulfonyl group which may have 1 to 3 substituents selected from a halogen atom, a nitro group, a lower alkoxy group and a lower alkyl group on the phenyl ring, , Can be synthesized by an ordinary sulfonation reaction according to Reaction Scheme 8. The above reaction is carried out, for example, with diethyl ether, dioxane, T
It is carried out in the presence of an alkali such as potassium carbonate in HF, water or the like or a mixture thereof. The compound (9) is usually used at about 1 to 3 mol per 1 mol of the compound of the general formula (1h). The reaction is usually performed at about 0 to 60 ° C. for about 1 to 24 hours.

[Reaction Process Formula 9]

[0066]

[Chemical 12]

[In the formula, R ³ , R ⁶ and X are the same as defined above. R
¹⁰ represents a lower alkyl group. ] [Reaction Process Formula 10]

[0068]

[Chemical 13]

[In the formula, R ¹ , R ³ , R ⁶ and X are the same as defined above. R ¹⁰ represents a lower alkyl group. ] In Reaction Scheme 9 or Reaction Scheme 10, when R ¹ and / or R ^{7 in the} compound (1) of the present invention is a lower alkoxycarbonylmethyl group, any of these groups and ═N at the 2-position can be used. It represents a reaction in which an —R ² group is bonded to form an oxoethylene group. The ring closure reaction is carried out in the same manner as in the reaction process formula 7. The reaction is usually at room temperature to about 150 ° C., preferably 30
It is carried out at about 120 ° C for about 5 to 60 minutes. The above reaction can also be carried out by sublimating the compound of general formula (1j) in vacuum.

In the general formula (1), R ¹ or R ⁷ is a lower alkoxycarbonyl lower alkyl group,
It can be converted into a compound having a corresponding carboxy lower alkyl group by usual ester hydrolysis.
A wide variety of ordinary solvents can be used in the above reaction, for example, methanol, ethanol, dioxane, THF, water and the like can be used. The reaction is usually carried out at room temperature to about 120 ° C., preferably room temperature to about 60 ° C., and usually for about 1 to 24 hours. In the above reaction, an alkali generally used for ester hydrolysis is used, and preferably an alkali such as sodium hydroxide or potassium hydroxide is used.

The compound (4) used as the raw material in the reaction process formula 2 includes a partly unknown compound. The production methods of these raw material compounds are shown below.

[Reaction Process Formula 11]

[0073]

[Chemical 14]

[In the formula, R ¹ and R ⁵ are the same as defined above. ] The above reaction is carried out in an inert solvent such as diethyl ether, TH
It is carried out in F, dioxane, water or a mixture thereof. Compound (11) is usually 1 per mol of Compound (10).
~ 3 mol is used. The reaction is usually performed at about 0 to 50 ° C. for about 1 to 20 hours.

Among the compounds of the present invention, the compounds represented by the following general formula are novel compounds.

[0076]

[Chemical 15]

[Wherein R ¹ is a hydrogen atom, a lower alkyl group, a carboxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a phenoxy lower alkanoyl group or a lower cycloalkyl group which may have a lower alkoxycarbonyl group on the phenyl ring. Represents a group, R ² is a group —N
HR ⁴ {R ⁴ is a hydrogen atom, a phenyl ring which may have 1 to 3 substituents selected from a halogen atom, a nitro group, a lower alkoxy group and a lower alkyl group on the phenyl ring, a phenyl lower alkanoyl group or a group. -C
O-NHR ⁵ (R ⁵ represents a lower alkyl group, a phenyl group which may have a halogen atom on the phenyl ring, a phenyl lower alkyl group or a naphthyl group)}.
Or R ² is a group —N═R ⁶ {R ⁶ is a lower alkylidene group,
A lower alkylidene group having 1 to 2 lower cycloalkyl groups, a halogen atom on the phenyl ring, a carboxyl group,
Phenyl lower alkylidene group which may have 1 to 3 substituents selected from lower alkoxycarbonyl group, nitro group, hydroxyl group, lower alkoxy group and halogenated lower alkyl group, phenyl which may have nitro group on the phenyl ring A lower alkenylidene group, a lower alkenylidene group, a lower cycloalkylidene group or a phenoxy lower alkylidene group which may have a carboxyl group on the phenyl ring. }, R ³ represents a hydrogen atom, a phenyl lower alkylidene group or a phenyl lower alkenylidene group which may have a substituent selected from a halogen atom and a halogenated lower alkyl group on the phenyl ring,
X represents —S— or —N (R ⁷ ) — (R ⁷ represents a hydrogen atom, a lower alkyl group, a carboxy lower alkyl group or a lower alkoxycarbonyl lower alkyl group), and R ¹
And R ⁴ or R ⁴ and R ⁷ may combine to form an oxoethylene group.

However, R ¹ is a hydrogen atom and R ³ is a hydrogen atom 2.
And X is —S—, R ² is a group —NHR ⁴ (R
⁴ is a hydrogen atom or a phenylsulfonyl group which may have a lower alkoxy group on the phenyl ring), or R ² is a group —N═R ⁶ (R ⁶ is a lower alkylidene group, a halogen atom on the phenyl ring, a nitro group, It must not be a phenyl lower alkylidene group which may have a substituent selected from a hydroxyl group and a lower alkoxy group or a phenyl lower alkenylidene group which may have a nitro group on the phenyl ring).

Further, R ¹ is a hydrogen atom and R ² is a group -N = R.
If ⁶ and X is -S- or -NH-, R ³ and R ⁶ should not be a phenyl-lower alkylidene group at the same time.

Furthermore, when R ² is a group —NHR ⁴ , R ³ has two hydrogen atoms and X is —S—, R ¹ and R ⁴ must not combine to form an oxoethylene group. .. The compound of the present invention includes addition salts of pharmaceutically acceptable acid or base compounds. The salt is easily formed by the action of the acid or base. Examples of the acid used for salt formation include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid, and in some cases, oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid and citric acid. Examples thereof include organic acids such as benzoic acid. Examples of the base compound used for the salt formation include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium hydrogen carbonate and the like.

The compound of the general formula (1) and the salt thereof produced by the above-mentioned methods can be isolated by usual separation means such as distillation method, recrystallization method, column chromatography, preparative thin layer chromatography, solvent extraction method and the like. Can be easily isolated and purified from the reaction system.

The Maillard reaction inhibitor of the present invention is generally used in the form of a general pharmaceutical preparation. The preparation is prepared by using a diluent or an excipient such as a filler, a filler, a binder, a moisturizer, a disintegrant, a surface active agent and a lubricant which are usually used. As this pharmaceutical preparation, various forms can be selected according to the therapeutic purpose, and typical examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories,
Examples include injections (solutions, suspensions, etc.), ointments and the like. When molded into a tablet form, as a carrier, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, excipients such as silicic acid, water, ethanol, propanol, simple syrup, Glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose,
Binders such as potassium phosphate, polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, etc. Disintegrants, sucrose, stearin, cocoa butter, disintegration inhibitors such as hydrogenated oil, quaternary ammonium bases, absorption promoters such as sodium lauryl sulfate, glycerin, moisturizers such as starch, starch, lactose, kaolin,
Adsorbents such as bentonite and colloidal silicic acid, refined talc, stearates, boric acid powders, lubricants such as polyethylene glycol and the like can be used. Further, the tablets may be coated with a usual coating as necessary, for example, sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets or double tablets,
It can be a multilayer tablet. For molding in the form of pills, carriers such as glucose, lactose, starch,
Excipients such as cocoa butter, hydrogenated vegetable oil, kaolin, talc,
Gum arabic powder, tragacanth powder, a binder such as gelatin and ethanol, a disintegrating agent such as laminaran and agar can be used. When molded into a suppository, a carrier such as polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides, etc. can be used. The capsules are prepared by a conventional method, usually by mixing the various carriers exemplified above with the compound of the present invention and filling them into hard gelatin capsules, hard capsules or the like. When prepared as an injection, a liquid preparation,
Emulsions and suspensions are preferably sterile and isotonic with blood. In molding into these forms, for example, water, lactic acid aqueous solution, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, etc. can be used as a diluent. In this case, a sufficient amount of sodium chloride, bute sugar or glycerin for preparing an isotonic solution may be contained in the pharmaceutical preparation, and a usual solubilizing agent,
You may add a buffering agent, a soothing agent, etc. Further, if necessary, a coloring agent, a preservative, a flavoring agent, a flavoring agent, a sweetening agent and the like and other pharmaceuticals may be contained in the pharmaceutical preparation. When formulating in the form of paste, cream and gel, for example, white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite and the like can be used as a diluent.

The amount of the compound of the present invention to be contained in the pharmaceutical preparation of the present invention is not particularly limited and is appropriately selected from a wide range, but it is usually 1 to 70% by weight in the pharmaceutical preparation.

The method of administration of the pharmaceutical preparation of the present invention is not particularly limited and variously determined depending on the age, sex and other conditions of the patient, the state of disease, various preparation forms, etc., but usually systemically or locally Orally or parenterally. For example, it is orally administered in the form of tablets, pills, solutions, suspensions, emulsions, granules, and capsules, and is intravenously, intramuscularly, or intradermally in the form of injections, optionally mixed with a normal replacement fluid. , Subcutaneously or intraperitoneally, or intrarectally as a suppository,
Alternatively, it is applied as an ointment.

The dose of the pharmaceutical preparation of the present invention to humans is appropriately selected according to age, body weight, symptoms, therapeutic effect, administration method, treatment time and the like, but usually about 0.1 per 1 kg of body weight per day.
The dosage may be in the range of 1 to 100 mg, and the preparation may be administered once to several times a day in divided doses. Of course, since the dose varies depending on various conditions as described above, a dose smaller than the above dose range may be sufficient in some cases, or a dose exceeding the range may be necessary in some cases.

[0086]

EXAMPLES The production examples of the compounds used in the present invention will be described below as Examples, and then the results of pharmacological tests and formulation examples of these compounds will be shown.

Example 1 (1) 1.61 g of metallic sodium was dissolved in 100 ml of methanol, and the prepared solution of sodium methoxide in methanol was charged with isopropylideneaminoguanidine.
00 g was added, the mixture was stirred at room temperature for 1 hour, glycine ethyl ester hydrochloride 5.88 g was added, and the mixture was heated under reflux for 16 hours. After cooling the reaction mixture, water and chloroform were added for partitioning, and the aqueous layer was extracted three times with chloroform.
The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was charged on silica gel column chromatography, and chloroform-methanol 10 was added.
Elution with a 0: 1 (V / V) mixed solvent gave 2-isopropylidenehydrazonoimidazolidin-4-one (0.81 g) as white crystals.

NMR (CD ₃ OD) δ ppm: 3.93 (s, 2H) 1.99 (d, J = 5.71 Hz, 6H) m.p. p. 182-187 ° C. The same operation as in (1) above was performed to obtain the following compound.

(2) 2-benzylidene hydrazonoimidazolidin-4-one m.p. p. 246-248 ° C.

(3) 2-α-methylcinnamylidene hydrazonoimidazolidin-4-one m.p. p. 243-245 ° C.

(4) 2-Cyclopentylidenehydrazonoimidazolidin-4-one NMR (DMSO-d ₆ ) δppm: 3.75 (s, 2H) 2.29 to 2.49 (m, 4H) 1. 65-1.88 (m, 4H).

(5) 2- (1-Cyclopropylethylidenehydrazono) imidazolidin-4-one NMR (DMSO-d ₆ ) δppm: 3.81 (s, 2H) 1.74 (s, 3H) 1. 50 to 1.63 (m, 1H) 0.64 to 0.85 (m, 4H) m.p. p. 169-172 ° C.

(6) 2-Cyclohexylmethylenehydrazonoimidazolidin-4-one NMR (DMSO-d ₆ ) δ ppm: 7.36 (d, J = 5.61 Hz, 1H) 3.76 (s, 2H) 2 .17 to 2.29 (m, 1H) 1.64-1.75 (m, 4H) 1.15 to 1.30 (m, 5H).

(7) 2-Cyclohexylidenehydrazonoimidazolidin-4-one NMR (DMSO-d ₆ ) δppm: 3.97 (s, 2H) 2.50 to 2.53 (m, 2H) 2. 28-2.31 (m, 2H) 1.66-1.69 (m, 6H).

(8) 2-n-Butylidene hydrazonoimidazolidin-4-one NMR (DMSO-d ₆ ) δppm: 7.47 (t, J = 5.61 Hz, 1H) 3.76 (s, 2H ) 2.17 to 2.29 (m, 2H) 1.41 to 1.57 (m, 2H) 0.90 (t, J = 7.26Hz, 3H) m.p. p. 158-162 ° C.

(9) 2-dicyclopropylmethylenehydrazonoimidazolidin-4-one NMR (DMSO-d ₆ ) δppm: 3.79 (s, 2H) 0.47 to 1.06 (m, 10H).

(10) 2- (1-Trifluoromethylethylidenehydrazono) imidazolidin-4-one NMR (DMSO-d ₆ ) δppm: 11.28 (s, 1H) 7.79 (s, 1H) 3 .98 (s, 2H) 2.06 (s, 3H).

(11) 2-Hexafluoroisopropylidenehydrazonoimidazolidin-4-one NMR (DMSO-d ₆ ) δppm: 3.99 (s, 2H).

Example 2 (1) To a methanol solution of sodium methoxide prepared by dissolving 2.30 g of metallic sodium in 150 ml of methanol, 5.70 g of benzylideneaminoguanidine was added.
Was added, and the mixture was stirred at room temperature for 1 hour, 11.35 g of iminodiacetate acid diethyl ester was added, and 17
Heated to reflux for hours.

After cooling the reaction mixture, water and chloroform were added and partitioned, and the aqueous layer was extracted three times with chloroform. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was charged on silica gel column chromatography and eluted with chloroform-methanol 100: 1 (V / V) mixed solvent to give 2-
2.61 g of benzylidenehydrazono-1-methoxycarbonylmethylimidazolidin-4-one was obtained.

NMR (CDCl ₃ ) δ ppm: 8.26 (s, 1H) 7.32 to 7.68 (m, 5H) 4.23 (s, 2H) 4.01 (s, 2H) 3.77 ( s, 3H) m. p. 149-153 ° C.

(2) To 2.61 g of the compound obtained above were added 40 ml of methanol and 14 ml of 2N sodium hydroxide, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, 10 ml of water was added to the residue, and the mixture was neutralized with 1N hydrochloric acid. The insoluble material was collected by filtration and washed with water and ether to obtain 1.82 g of 2-benzylidenehydrazono-1-carboxymethylimidazolidin-4-one.

NMR (DMSO-d ₆ ) δppm: 11.37 (brs, 1H) 8.16 (s, 1H) 7.34 to 7.86 (m, 5H) 4.08 (s, 2H) 4. 02 (s, 2H) m. p. 218-222 ° C.

The following compound was obtained by the same operation as above.

(3) 2-isopropylidenehydrazono-1
- methoxycarbonylmethyl imidazolidin-4-one _{NMR (CDCl 3) δppm: 4.15} (s, 2H) 4.02 (s, 2H) 3.76 (s, 3H) 1.97 (s, 3H) 1 .94 (s, 3H).

(4) 1-methoxycarbonylmethyl-2-
α-Methylcinnamylidene hydrazonoimidazolidine-
4-ON NMR (CDCl ₃ ) δppm: 8.04 (s, 1H) 7.26 (s, 5H) 6.72 (s, 1H) 4.22 (s, 2H) 4.09 (s, 2H) 3.78 (s, 3H).

(5) 2- (4-Carboxybenzylidenehydrazono) -1-carboxymethylimidazolidine-4
- one _{NMR (DMSO-d 6) δppm} : 11.47 (brs, 1H) 8.20 (s, 1H) 7.49 (brs, 4H) 4.08 (s, 2H) 3.84 (s, 2H ) M. p. 205-209 ° C.

Example 3 (1) 2-Isopropylidenehydrazonoimidazolidine-
4-one 154 mg, sodium acetate 198 mg, acetic acid 5 m
1, 317mg cinnamic aldehyde mixed solution at 60 ℃
It was stirred for 19 hours. Water and chloroform were added to the reaction mixture and partitioned, and the aqueous layer was further extracted with chloroform three times. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was charged on silica gel column chromatography and eluted with chloroform-ethyl acetate = 1: 1 (V / V) mixed solvent. 62 mg of cinnamylidene hydrazono-5-cinnamylidene imidazolidin-4-one were obtained. m. p. 154-156
° C.

The following compound was obtained by the same operation as above.

(2) 2-benzylidenehydrazono-5-benzylidenethiazolidin-4-one NMR (DMSO-d ₆ ) δppm: 8.49 (s, 1H) 7.21 to 7.93 (m, 11H).

(3) 2-Cinnamylidene hydrazono-5-
Cinnamylideneacetyl thiazolidin-4-one _{NMR (DMSO-d 6) δppm} : 12.35 (brs, 1H) 8.26 (d, J = 8.13Hz, 1H) 6.79~7.68 (m, 15H ).

(4) 2- (4-Trifluoromethylbenzylidenehydrazono) -5- (4-trifluoromethylbenzylidene) thiazolidin-4-one NMR (DMSO-d ₆ ) δppm: 8.61 (s, 1H ) 7.67 to 8.07 (m, 9H).

Example 4 (1) A mixture of 2-benzylidenehydrazono-1-methoxycarbonylmethylimidazolidin-4-one (1.10 g), sodium acetate (520 mg), acetic acid (10 ml) and cinnamic aldehyde (1.34 g) was added at 60 to 70. Stirred at 16 ° C for 16 hours.

After cooling the reaction mixture, water and ethyl acetate were added and partitioned, and the aqueous layer was further extracted 3 times with ethyl acetate. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was charged on silica gel column chromatography, and n-hexane-ethyl acetate =
Elution with a 1: 1 (V / V) mixed solvent gave 2-cinnamylidenehydrazono-5-cinnamylidene-1-methoxycarbonylmethylimidazolidin-4-one (620 mg).

NMR (CDCl ₃ ) δppm: 8.02 to 8.33 (m, 2H) 7.18 to 7.78 (m, 12H) 6.69 (d, J = 15.8Hz, 1H) 5. 95 (d, J = 11.4 Hz, 1H) 4.53 (s, 2H) 3.81 (s, 3H).

(2) To 620 mg of the compound obtained above, 20 ml of methanol and 2.4 ml of 2N sodium hydroxide were added, and the mixture was stirred at room temperature for 24 hours. 1N in the reaction mixture
The mixture was neutralized by adding hydrochloric acid. Concentrate under reduced pressure and recrystallize with ethanol to give 1-carboxymethyl-2-cinnamylidene hydrazono-5-cinnamylidene imidazolidine-4.
417 mg of one-on were obtained. m. p. 246-248 ° C.

Example 5 (1) 2.73 g of thiosemicarbazide was added to 80 ml of THF,
After dissolving in a mixed solvent of 20 ml of water, 3.57 g of phenyl isocyanate was added, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, 100 ml of water was added to the residue,
The precipitate was crushed, collected by filtration, washed with water, and then recrystallized with methanol to obtain 1.80 g of a white crystalline substance.

(2) This was dissolved in 80 ml of ethanol, and 1.26 g of ethyl chloroacetate and 84 of sodium acetate were added.
0 mg was added and the mixture was heated under reflux for 16 hours. The reaction mixture was cooled, and the precipitated crystals were collected by filtration to obtain 1.65 g of 2- (4-phenylsemicarbazono) thiazolidin-4-one.

NMR (DMSO-d ₆ ) δppm: 11.64 (brs, 1H) 9.01 (s, 1H) 8.92 (s, 1H) 6.82 to 7.52 (m, 5H) 3. 91 (s, 2H).

The same operation as above was performed to obtain the following compound.

(3) 2- (4-naphthylsemicarbazono)
Thiazolidin-4-one _{NMR (DMSO-d 6) δppm} : 11.56 (brs, 1H) 9.12 (s, 1H) 8.69 (s, 1H) 7.35~8.07 (m, 7H) 3.97 (s, 2H).

(4) 2- [4- (4-chlorophenyl) semicarbazono] thiazolidin-4-one NMR (DMSO-d ₆ ) δppm: 11.47 (brs, 1H) 9.02 (s, 2H) 7. 50 (d, J = 9.01 Hz, 2H) 7.26 (d, J = 8.79 Hz, 2H) 3.92 (s, 2H).

(5) 2- (4-benzylsemicarbazono)
Thiazolidin-4-one m. p. 218-220 ° C.

(6) 2- [4- (4-fluorophenyl)
Semicarbazono] thiazolidin-4-one m. p. 223-225 ° C (7) 2- (4-butylsemicarbazono) thiazolidine-
4- On _{NMR (DMSO-d 6) δppm} : 11.43 (brs, 1H) 8.56 (s, 1H) 6.41 (t, J = 5.9Hz, 1H) 3.88 (s, 2H) 2.87-3.19 (m, 2H) 1.25 (brs, 4H) 0.88 (t, J = 6.3Hz, 3H).

Example 6 (1) To 226 mg of 2-isopropylidenehydrazono-1-methoxycarbonylmethylimidazolidin-4-one,
10 ml of methanol and 1 ml of 2N sodium hydroxide
Was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was neutralized with 1N hydrochloric acid, concentrated under reduced pressure, and recrystallized from methanol to give 1,4,5,7-tetraazabicyclo [4,3,0] nonane-5-ene-3,3. 8-Zeon 7
5 mg was obtained. _{NMR (DMSO-d 6) δppm} : 11.00 (brs, 1H) 10.07 (brs, 1H) 3.79 (s, 2H) 3.73 (s, 2H) m. p. 300 ° C or higher.

Example 7 (1) 96 mg of 60% sodium hydride was suspended in 20 ml of DMF under ice cooling, and then 2-benzylidenehydrazono-1-methoxycarbonylmethylimidazolidine-4 was suspended in the suspension.
5 ml of DMF solution containing 548 mg of -one was gradually added to 30
After stirring for 1 minute, 254 mg of ethyl chloroacetate was slowly added dropwise, and the mixture was stirred at 80 ° C. for 1 hour. After cooling the reaction mixture, water and chloroform were added for partition, and the aqueous layer was further extracted with chloroform three times. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was recrystallized from chloroform-n-hexane to give 2-benzylidenehydrazono-3-ethoxycarbonylmethyl-1-methoxycarbonylmethyl. Imidazolidine-4-
Obtained 320 mg of on.

NMR (CDCl ₃ ) δppm: 8.13 (s, 1H) 7.25 to 7.60 (m, 5H) 4.71 (s, 2H) 4.41 (s, 2H) 4.14 ( s, 2H) 4.17 (q, J = 5.9Hz, 2H) 3.71 (s, 3H) 1.29 (t, J = 7.0Hz, 3H).

(2) Methanol (15 ml) and 2N sodium hydroxide (3 ml) were added thereto, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, 3 ml of water was added to the residue, and the mixture was neutralized with 1N hydrochloric acid. The insoluble material was filtered off, the filtrate was concentrated again under reduced pressure, and recrystallized from methanol to obtain 2-benzylidenehydrazono-1,3-dicarboxymethylimidazolidin-4-one (180 mg).

NMR (DMSO-d ₆ ) δppm: 8.12 (s, 1H) 7.33 to 7.79 (m, 5H) 4.67 (s, 2H) 4.26 (s, 2H) 4. 19 (s, 2H).

Example 8 (1) To 230 mg of 2-benzylidenehydrazono-3-ethoxycarbonylmethyl-1-methoxycarbonylmethylimidazolidin-4-one obtained in (1) of Example 7 was added 0.
10 ml of 5N hydrochloric acid was added, and steam distillation was performed for 40 minutes. After cooling the reaction mixture, it was concentrated under reduced pressure, and the residue was charged on silica gel column chromatography and eluted with a chloroform-ethyl acetate = 1: 2 (V / V) mixed solvent to obtain 7-ethoxycarbonylmethyl-1,4,5. , 7-
Tetraazabicyclo [4,3,0] nonane-5-ene-
60 mg of 3,8-dione was obtained.

NMR (DMSO-d ₆ ) δ ppm: 10.24 (s, 1H) 4.20 (s, 2H) 4.04 (q, J = 6.91 Hz, 2H) 3.98 (s, 2H) 1.20 (t, J = 6.81 Hz, 3H) m. p. 188-193 ° C.

(2) To this, 5 ml of ethanol and 0.3 ml of 2N sodium hydroxide were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water, neutralized with 1N hydrochloric acid, concentrated again under reduced pressure and recrystallized from methanol to give 7-carboxymethyl-1,4,5,5.
29 mg of 7-tetraazabicyclo [4,3,0] nonane-5-ene-3,8-dione were obtained.

NMR (DMSO-d ₆ ) δ ppm: 8.44 (brs, 1H) 4.33 (s, 2H) 4.09 (s, 2H) 3.93 (s, 2H).

Example 9 (1) 60% sodium hydride (192 mg) was added to DMF (20 ml).
To the suspension under ice-cooling, about 5 ml of a DMF solution of 716 mg of 2-isopropylidenehydrazonothiazolidin-4-one was gradually added thereto, and after stirring for 30 minutes, 588 mg of ethyl chloroacetate was slowly added dropwise. The mixture was stirred at room temperature for 3 hours.

Water and chloroform were added to the reaction mixture for partition, and the organic layer was washed twice with water and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was charged on silica gel column chromatography, and eluted with a mixed solvent of chloroform-ethyl acetate = 10: 1 (V / V), 3-ethoxycarbonylmethyl-2-isopropylidenehydrazonothiazolidin-4-one 870 mg Got

NMR (CDCl ₃ ) δ ppm: 4.49 (s, 2H) 4.21 (q, J = 7.03 Hz, 2H) 3.82 (s, 2H) 2.01 (d, J = 6. 38 Hz, 6 H) 1.26 (t, J = 7.25 Hz, 3 H) m. p. 60-62 ° C.

(2) To 870 mg of the compound obtained above was added 20 ml of methanol and 3 ml of sodium hydroxide under ice cooling.
Was added and stirred for 1 hour. The reaction mixture was neutralized with 1N hydrochloric acid, concentrated under reduced pressure, and recrystallized from ethanol to obtain 280 mg of 3-carboxymethyl-2-isopropylidenehydrazonothiazolidin-4-one.

NMR (DMSO-d ₆ ) δ ppm: 3.97 (s, 2H) 3.81 (s, 2H) 1.97 (s, 6H).

By the same operations as in (1) and (2) above, the following compounds were obtained using appropriate starting materials.

(3) 5-benzylidene-2-benzylidenehydrazono-3-carboxymethylthiazolidine-4-
ON NMR (DMSO-d ₆ ) δppm: 8.53 (s, 1H) 7.50 to 7.81 (m, 11H) 4.16 (s, 2H) m.p. p. 300 ° C or higher.

(4) 3- (3-carboxypropyl) -2
- cinnamylideneacetyl hydrazono-5- cinnamylideneacetyl thiazolidin-4-one _{NMR (DMSO-d 6) δppm} : 7.12 (d, J = 9.01Hz, 1H) 6.81~7.83 (m, 15H) 3.93 (t, J = 6.1Hz, 2H) 1.71-2.38 (m, 4H).

(5) 3- (5-carboxypentyl) -2
- cinnamylideneacetyl hydrazono-5- cinnamylideneacetyl thiazolidin-4-one _{NMR (CDCl 3) δppm: 8.21} (s, 1H) 6.83~7.59 (m, 15H) 3.91 (t, J = 6.03 Hz, 2H) 1.44-2.54 (m, 8H).

Example 10 (1) 3-Ethoxycarbonylmethyl-2-isopropylidenehydrazonothiazolidine-4 obtained in (1) of Example 9
2.0 g of -ON and 30 ml of 0.5N hydrochloric acid were added, and steam distillation was carried out for 15 minutes. The reaction mixture was cooled, the deposited precipitate was filtered off, and the filtrate was concentrated under reduced pressure. A saturated sodium hydrogen carbonate solution and chloroform were added to the residue for partition, and the organic layer was washed with water three times and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was charged on silica gel column chromatography, and eluted with a chloroform-ethyl acetate = 4: 1 (V / V) mixed solvent to give 3-ethoxycarbonylmethyl-2-hydrazonothiazolidine-4.
870 mg of one-on are obtained.

NMR (DMSO-d ₆ ) δppm: 5.26 (s, 2H) 4.29 (s, 2H) 4.12 (q, J = 7.03Hz, 2H) 1.19 (t, J = 7.04 Hz, 3H).

(2) Further, the saturated sodium hydrogen carbonate layer and the aqueous layer were combined and concentrated under reduced pressure, the residue was suspended in ethanol, the insoluble material was filtered off, and the filtrate was concentrated again under reduced pressure and reconstituted with water. Crystallization was carried out to give 2H-thiazolo [2,3
-C] [1,2,4] triazine-3,6 (4H, 7
315 mg of H) -dione were obtained.

NMR (DMSO-d ₆ ) δ ppm: 10.79 (s, 1H) 4.09 (s, 4H).

(3) To 200 mg of the compound obtained in (1) above, dioxane 15 ml, water 3 ml, potassium carbonate 7 was added under ice cooling.
After adding 6 mg and 2,4-dinitrobenzene sulfonyl chloride 300 mg, it stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was charged on silica gel column chromatography, and chloroform-
Elute with a mixed solvent of ethyl acetate = 1: 1 (V / V),
2- (2,4-dinitrobenzenesulfonohydrazono)
180 mg of -3-ethoxycarbonylmethylthiazolidin-4-one was obtained.

NMR (CDCl ₃ ) δppm: 8.63 (s, 1H) 8.54 (d, J = 8.57Hz, 1H) 8.26 (d, J = 8.35Hz, 1H) 4.29 ( s, 2H) 4.14 (q, J = 7.01Hz, 2H) 3.92 (s, 2H) 1.24 (t, J = 7.04Hz, 3H) m. p. 163-165 ° C.

(4) To 180 mg of the compound obtained in (3) above, 5 ml of ethanol and 0.5 ml of sodium hydroxide were added, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure,
Water was added to the residue and neutralized with 1N hydrochloric acid. The insoluble material was collected by filtration and washed with water and ether to obtain 130 mg of 3-carboxymethyl-2- (2,4-dinitrobenzenesulfonohydrazono) thiazolidin-4-one.

NMR (DMSO-d ₆ ) δppm: 8.86 (s, 1H) 8.63 (d, J = 8.57Hz, 1H) 8.23 (d, J = 8.57Hz, 1H) 4. 21 (s, 2H) 4.14 (s, 2H).

The following compounds were obtained by the same operations as in (3) to (4) above.

(5) 3-Carboxymethyl-2- (2-nitrobenzenesulfonohydrazono) thiazolidine-4-
ON NMR (CD ₃ OD) δ ppm: 7.59 to 8.04 (m, 4H) 4.21 (s, 2H) 3.95 (s, 2H).

(6) 2- (4-Bromobenzenesulfonohydrazono) -3-carboxymethylthiazolidine-4-
ON NMR (CD ₃ OD) δ ppm: 7.74 (s, 4H) 4.32 (s, 2H) 3.98 (s, 2H).

(7) 3-ethoxycarbonylmethyl-2-
Phenylacetylhydrazonothiazolidin-4-one NMR (CDCl ₃ ) δppm: 7.24 (s, 5H) 4.58 (s, 2H) 4.19 (q, J = 7.0Hz, 2H) 4.01 ( s, 2H) 3.72 (s, 2H) 1.23 (t, J = 6.9Hz, 3H) m. p. 200-203 ° C.

(8) 3-ethoxycarbonylmethyl-2-
(4-Methoxybenzenesulfonohydrazono) thiazolidin-4-one NMR (CDCl ₃ ) δppm: 7.80 (d, J = 8.79 Hz, 2H) 6.95 (d, J = 8.79 Hz, 2H) 4.35 (s, 2H) 4.13 (q, J = 7.25Hz, 2H) 3.86 (s, 5H) 1.22 (t, J = 7.0Hz, 3H).

Example 11 (1) 3-Ethoxycarbonylmethyl-2-isopropylidenehydrazonothiazolidine-4 obtained in (1) of Example 9
1.03 g of -one, 984 mg of sodium acetate, 1 part of acetic acid
Add 0 ml and cinnamaldehyde 2.54 g and add 110
Stirred at ~ 120 ° C for 16 hours. Water 20 in the reaction mixture
ml was added, and the precipitated crystals were collected by filtration and recrystallized from benzene-n-hexane to give 3-ethoxycarbonylmethyl-2-cinnamylidenehydrazono-5 as pale yellow crystals.
810 mg of cinnamylidethiazolidin-4-one were obtained. m. p. 210-212 ° C.

(2) By the same procedure as in Example 2 (2), 3-carboxymethyl-2-cinnamylidenehydrazono-5-cinnamylidethiazolidin-4-one was obtained.

NMR (DMSO-d ₆ ) δ ppm: 8.29 (d, J = 8.13 Hz, 1H) 6.89 to 7.72 (m, 15H) 4.48 (s, 2H) m.p. p. 300 ° C or higher.

The following compound was obtained by the same operation as above.

(3) 3-Carboxymethyl-2- (4-fluorobenzylidenehydrazono) -5- (4-fluorobenzylidene) thiazolidin-4-one was obtained.

NMR (DMSO-d ₆ ) δ ppm: 8.53 (s, 1H) 7.22 to 7.89 (m, 9H) 4.13 (s, 2H).

Example 12 (1) 1.31 g of 2-hydrazonothiazolidin-4-one
Under ice cooling, 20 ml of ether, 5 ml of water, 840 mg of sodium hydrogencarbonate and 3.20 g of 2,4-dinitrobenzenesulfonyl chloride were added, and the mixture was kept at the same temperature for 2 hours.
The mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, water and ethyl acetate were added to the residue for partitioning, the organic layer was washed 3 times with water, dried over anhydrous magnesium sulfate, concentrated again under reduced pressure, and the residue was re-dissolved with ethanol-water. Crystallization gave 2- (2,4-dinitrobenzenesulfonohydrazono) thiazolidin-4-one (600 mg) as slightly yellow needle crystals. m.
p. 204-206 ° C.

The following compound was obtained by the same operation as above.

(2) 2- (4-toluenesulfonohydrazono) thiazolidin-4-one m.p. p. 163-165 ° C.

(3) 2- (2,4-dinitrobenzenesulfonohydrazono) imidazolidin-4-one NMR (DMSO-d ₆ ) δppm: 8.85 (s, 1H) 8.69 (d, J = 8.58 Hz, 1H) 8.31 (d, J = 8.58 Hz, 1H) 3.87 (s, 2H).

Example 13 (1) 3-Ethoxycarbonylmethyl-2-isopropylidenehydrazonothiazolidine-4 obtained in (1) of Example 9
-One 514 mg, sodium acetate 197 mg, acetic acid 10 m
A mixed solution of 1 and 393 mg of terephthalaldehyde lic acid methyl ester was stirred at 80 ° C. for 3 hours. The reaction mixture is cooled, water is added, the precipitated crystals are filtered off, washed with water and ether and 710 mg of 3-ethoxycarbonylmethyl-2- (4-methoxycarbonylbenzylidenehydrazono) thiazolidin-4-one. Got

(2) 2- (4-Carboxybenzylidenehydrazono) -3-carboxymethylthiazolidin-4-one was obtained by the same hydrolysis reaction as in (2) of Example 2.

NMR (DMSO-d ₆ ) δ ppm: 8.52 (s, 1H) 7.71 to 8.12 (m, 4H) 4.41 (s, 2H) 4.09 (s, 2H).

The following compounds were obtained by the same operations as in (1) and (2) above.

(3) 3-Carboxymethyl-2-salicylidene hydrazonothiazolidin-4-one NMR (DMSO-d ₆ ) δppm: 10.72 (s, 1H) 8.68 (s, 1H) 6. 83-7.63 (m, 4H) 4.40 (s, 2H) 4.14 (s, 2H) m.p. p. 258-263 ° C.

Example 14 (1) In the same manner as (1) of Example 9, 3-cyclopentyl-
2-Isopropylidenehydrazonothiazolidin-4-one was obtained. m. p. 61-63 ° C.

The following compound was obtained in the same manner as above.

(2) 2-isopropylidenehydrazono-3
- phenoxyacetyl thiazolidin-4-one _{NMR (CDCl 3) δppm: 6.89~7.26} (m, 5H) 4.84 (s, 2H) 4.15 (s, 2H) 2.02 (s, 6H ) M. p. 172-175 ° C.

(3) 2-isopropylidenehydrazono-3
- methoxycarbonyl phenoxyacetyl thiazolidin-4-one _{NMR (CDCl 3) δppm: 7.98} (d, J = 8.35Hz, 2H) 6.94 (d, J = 8.35Hz, 2H) 4.89 (s , 2H) 4.16 (s, 2H) 3.87 (s, 3H) 2.01 (s, 6H).

(4) 2-Isopropylidenehydrazono-1
- methoxycarbonylmethyl-3-methyl-imidazolidin-4-one _{NMR (CDCl 3) δppm: 4.58} (s, 2H) 3.95 (s, 2H) 3.72 (s, 3H) 3.07 (s , 3H) 1.93 (d, J = 2.64 Hz, 6H) m.p. p. 90-92 ° C.

(5) 2-isopropylidenehydrazono-3
- methylimidazolidin-4-one _{NMR (CDCl 3) δppm: 5.65} (brs, 1H) 3.97 (s, 2H) 3.11 (s, 3H) 2.02 (d, J = 2.63Hz , 6H).

(6) 2-isopropylidenehydrazono-
1,3-Dimethylimidazolidin-4-one NMR (CDCl ₃ ) δppm: 3.83 (s, 2H) 3.37 (s, 3H) 3.05 (s, 3H) 1.99 (s, 6H) ..

Example 15 (1) 2-isopropylidenehydrazonothiazolidin-4-one 716 mg, sodium acetate 394 mg, acetic acid synthesized by a known method [Can. J. Chem., 37, 1597-1607 (1959)] 10 ml, terephthalaldehyde ric acid 72
The 0 mg mixture was stirred at 80 ° C. for 16 hours. Water and chloroform were added to the reaction mixture and partitioned, and the aqueous layer was further extracted with chloroform three times. Combine the organic layer and the extract,
After drying over anhydrous magnesium sulfate, concentration under reduced pressure, the residue was charged on silica gel column chromatography, and eluted with chloroform / methanol = 50: 1 (v / v) mixed solvent, 2- (4-carboxybenzylidenehydrazono). Thiazolidin-4-one was obtained.

NMR (DMSO-d ₆ ) δppm: 8.46 (s, 1H) 7.77 to 8.12 (m, 4H) 3.91 (s, 2H) m.p. p. 300 ° C or higher.

The following compounds were obtained by the same method as above.

(2) 2- (4-Carboxyphenoxyethylidenehydrazono) thiazolidin-4-one NMR (DMSO-d ₆ ) δppm: 12.20 (brs, 1H) 7.83 to 7.93 (m, 3H) ) 7.06 (d, J = 8.57 Hz, 2H) 4.86 (d, J = 4.62 Hz, 2H) 3.85 (s, 2H) m.p. p. 255-260 ° C.

(3) 2- (3,4,5-Trimethoxybenzylidenehydrazono) thiazolidin-4-one NMR (DMSO-d ₆ ) δppm: 11.87 (brs, 1H) 8.29 (s, 1H ) 7.07 (s, 2H) 3.81 (s, 9H) 3.71 (s, 2H).

(4) 2-Phenylpropylidenehydrazonothiazolidin-4-one NMR (DMSO-d ₆ ) δppm: 11.69 (brs, 1H) 7.71 (t, J = 5.1Hz, 1H) 7. 23 (s, 5H) 3.80 (s, 2H) 2.49 to 2.83 (m, 4H).

(5) 2- (2-Nitrocinnamylidenehydrazono) thiazolidin-4-one NMR (DMSO-d ₆ ) δppm: 7.0 to 8.25 (m, 7H) 3.81 (s, 2H) Example 16 (1) Regarding 2- (2,4-dinitrobenzenesulfonohydrazono) -3-ethoxycarbonylmethylthiazolidin-4-one obtained in (3) of Example 10 (1 of Example 4) )
Perform the same operation as for 5-cinnamylidene-2- (2,4
-Dinitrobenzenesulfonohitrazono) -3-ethoxycarbonylmethylthiazolidin-4-one was obtained.

NMR (CDCl ₃ ) δppm: 8.68 (s, 1H) 8.55 (d, J = 8.35 Hz, 1H) 8.27 (d, J = 8.57 Hz, 1H) 6.63 ~ 7.60 (m, 8H) 4.41 (s, 2H) 4.15 (q, J = 6.81Hz, 2H) 1.23 (t, J = 5.49Hz, 3H).

The following compound was obtained by the same operation as above.

(2) 2- (2,4-dinitrobenzenesulfonohydrazono) -3-ethoxycarbonylmethyl-5
-(2-α-Methylcinnamylidene) thiazolidine-4
- one _{NMR (CDCl 3) δppm: 8.69} (s, 1H) 8.55 (d, J = 8.79Hz, 1H) 8.28 (d, J = 7.92Hz, 1H) 6.80~7 .59 (m, 7H) 4.42 (s, 2H) 4.15 (q, J = 7.25Hz, 2H) 2.30 (s, 3H) 1.23 (t, J = 6.59Hz, 3H ).

Pharmacological Test 1 The effect of the compound of the present invention for inhibiting the Maillard reaction in vitro was measured according to the following method. That is, pH
100mg / in 0.5M sodium phosphate buffer of 7.4
Bovine serum albumin at a concentration of ml, glucose at a concentration of 400 mM, and a test drug at a concentration of 5 mM were dissolved.
The cells were cultured at 0 ° C for 2 weeks. However, among the test agents, Example 1 (3), Example 2 (5), Example 5 (3) and (4), Example 6 (1), Example 9 (2), Example 10
Each compound of (5), Example 12 (1) and Example 15 (1) was dissolved to a concentration of 6 mM.
Culture was performed at 12 ° C for 12 days. After culturing, 0.01% of culture solution
(W / v) 100-fold diluted with phosphate buffered saline containing Tween 80, excitation wavelength 370 nm, fluorescence wavelength 44
Fluorescence was measured at 0 nm. The inhibition rate was calculated by the following formula.

Inhibition rate (%) = {[(AB)-(C-
D)] / (A−B)} × 100 [wherein A is the fluorescence of (bovine serum albumin + glucose), B is the fluorescence of bovine serum albumin, and C is the (bovine serum albumin + glucose + the present invention). Compound) fluorescence,
D represents the fluorescence of (bovine serum albumin + the compound of the present invention). The results are shown in Table 1 below.

[0190]

[Table 1]

Pharmacological test 2 The test was carried out according to the method described in DIABETES, Vol. 40, pp. 1328-1334 (1991).
That is, fasted male SD rats (body weight 170 to 200 g)
To streptozocin (hereinafter referred to as "STZ") (50
(mg / kg), and blood glucose was measured 6 days later.
The one showing mg / dl or more was used. About this STZ diabetic rat, E
It was quantified by LISA, divided into 2 groups, and 1 group (n = 7) was divided into test agents (compound of Example 12 (1), 10 mg / k).
g) was administered to one group (n = 7) as a control group by administering a solution containing no test drug. The test drug solution contains 0.0
Using a saline solution containing 1% polysorbate 80,
Only this lysate was administered to the control group. In addition, a non-treated syngeneic rat was used as a normal control group (n = 6) for comparison. The administration method was intraperitoneal administration, and the administration was performed once a day for 6 weeks. Urinary albumin excretion was determined 2 weeks, 4 weeks, and 6 weeks after the start of administration. The results are shown in Figure 1.

The following can be seen from FIG. That is, in the amount of excreted albumin in urine, an inhibitory effect was observed in the test drug administration group from 2 weeks after the administration. Then, this inhibitory effect continued for 6 weeks thereafter, and finally showed 54% inhibition when compared with the control group.

Formulation Example The following components were admixed in a conventional method and punched out to obtain 100 tablets each having 50 mg of active ingredient.

(3) of Example 10 5 g Sodium lauryl sulfate 0.2 g Magnesium stearate 0.2 g Crystalline cellulose 4.6 g

[Brief description of drawings]

FIG. 1 is a graph showing changes over time in urinary albumin excretion.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location C07D 277/54 9051-4C 487/04 144 7019-4C 513/04 341 8415-4C (72) Invention Shintaro Ishikawa 8-59 Yamabata, Sakyo-ku, Kyoto Prefecture Kyoto Prefecture Housing A-302 (72) Inventor Koichi Yasumura 8-11-401 Uchidehama, Otsu City, Shiga Prefecture

Claims (4)

[Claims] 1. A general formula: [Wherein R ¹ represents a hydrogen atom, a lower alkyl group, a carboxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a phenoxy lower alkanoyl group or a lower cycloalkyl group which may have a lower alkoxycarbonyl group on the phenyl ring. R ² is a group —NHR ⁴ {R ⁴ is a hydrogen atom, a phenylsulfonyl group which may have 1 to 3 substituents selected from a halogen atom, a nitro group, a lower alkoxy group and a lower alkyl group on the phenyl ring, A phenyl lower alkanoyl group or a group —CO—NHR ⁵ (R ⁵ represents a lower alkyl group, a phenyl group which may have a halogen atom on the phenyl ring, a phenyl lower alkyl group or a naphthyl group.)}, Or R ² is a group —N═R ⁶ {R ⁶ has 1 to 2 lower alkylidene group and lower cycloalkyl group Lower alkylidene group, phenyl lower alkylidene which may have 1 to 3 substituents selected from halogen atom, carboxyl group, lower alkoxycarbonyl group, nitro group, hydroxyl group, lower alkoxy group and halogenated lower alkyl group on phenyl ring Group, a phenyl lower alkenylidene group that may have a nitro group on the phenyl ring, a lower alkenylidene group, a lower cycloalkylidene group, or a phenoxy lower alkylidene group that may have a carboxyl group on the phenyl ring. }, R ³ represents two hydrogen atoms, a phenyl lower alkylidene group or a phenyl lower alkenylidene group which may have a substituent selected from a halogen atom and a halogenated lower alkyl group on the phenyl ring, and X represents —S - or -N (R ⁷⁾ - (. R ⁷ is showing a hydrogen atom, a lower alkyl group, carboxy lower alkyl group or a lower alkoxycarbonyl-lower alkyl group) a, R ¹ and R ^4, or R ⁴ and R ⁷ May combine with each other to form an oxoethylene group. However, R ¹ is a hydrogen atom, R
^{When 3} is 2 hydrogen atoms and X is -S-, R ² is a group -NHR ⁴ (R ⁴ is a hydrogen atom or a phenylsulfonyl group which may have a lower alkoxy group on the phenyl ring), or R ² is a group -N = R ⁶ (where R ⁶ is a lower alkylidene group, a phenyl lower alkylidene group which may have a substituent selected from a halogen atom, a nitro group, a hydroxyl group and a lower alkoxy group on the phenyl ring or a phenyl ring). Phenyl lower alkenylidene group which may have a nitro group). Further, R ¹ is a hydrogen atom, R
If ² is a group -N = R ⁶ and X is -S- or -NH-, R ³ and R ⁶ should not be a phenyl-lower alkylidene group at the same time. Furthermore, R ² is a group —NHR ⁴ , R
^{When 3} is two hydrogen atoms and X is -S-, R ¹ and R
⁴ must not combine to form an oxoethylene group. ] The compound shown by these, or its salt. 2. R ¹ is a hydrogen atom, a lower alkyl group, a carboxy lower alkyl group or a lower alkoxycarbonyl lower alkyl group, R ² is a group —NHR ⁴ , or R ² is a group —N═R ⁶
{R ⁶ is a lower alkylidene group, a lower alkylidene group having 1 to 2 lower cycloalkyl groups, a phenyl lower alkylidene group which may have a carboxyl group on the phenyl ring, a phenyl lower alkenylidene group, a lower alkenylidene group or a lower cycloalkylidene group. Indicates a group. }, R ³ is 2 hydrogen atoms or a phenyl lower alkenylidene group, X is —N (R ⁷ ) —, R ¹ and R ⁴ are not bonded to each other to form an oxoethylene group, The compound or salt thereof according to claim 1, wherein when R ² is a group —NHR ⁴ , R ⁴ and R ⁷ always bond to form an oxoethylene group. 3. R ² is a hydrogen atom, a carboxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a phenoxy lower alkanoyl group or a lower cycloalkyl group which may have a lower alkoxycarbonyl group on the phenyl ring, and R ² Is a group -NHR ⁴ or R
² is a group -N = R ⁶ {R ⁶ is a lower alkylidene group, a phenyl ring which may have a substituent selected from a halogen atom, a carboxyl group, a lower alkoxycarbonyl group, a hydroxyl group and a halogenated lower alkyl group on the phenyl ring. An alkylidene group, a phenyl lower alkenylidene group which may have a nitro group on the phenyl ring, or a phenoxy lower alkylidene group which may have a carboxyl group on the phenyl ring are shown. }, R ³ is 2 hydrogen atoms, a phenyl lower alkylidene group or a phenyl lower alkenylidene group which may have a substituent selected from a halogen atom and a halogenated lower alkyl group on the phenyl ring, and X is —S -The compound according to claim 1, wherein R ¹ and R ⁴ and R ⁴ and R ⁷ do not combine to form an oxoethylene group, or a salt thereof. 4. A general formula: [Wherein R ¹ represents a hydrogen atom, a lower alkyl group, a carboxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a phenoxy lower alkanoyl group or a lower cycloalkyl group which may have a lower alkoxycarbonyl group on the phenyl ring. R ² is a group —NHR ⁴ {R ⁴ is a hydrogen atom, a phenylsulfonyl group which may have 1 to 3 substituents selected from a halogen atom, a nitro group, a lower alkoxy group and a lower alkyl group on the phenyl ring, A phenyl lower alkanoyl group or a group —CO—NHR ⁵ (R ⁵ represents a lower alkyl group, a phenyl group which may have a halogen atom on the phenyl ring, a phenyl lower alkyl group or a naphthyl group.)}, Or R ² is a group —N═R ⁶ {R ⁶ has 1 to 2 lower alkylidene group and lower cycloalkyl group Lower alkylidene group, phenyl lower alkylidene which may have 1 to 3 substituents selected from halogen atom, carboxyl group, lower alkoxycarbonyl group, nitro group, hydroxyl group, lower alkoxy group and halogenated lower alkyl group on phenyl ring Group, a phenyl lower alkenylidene group that may have a nitro group on the phenyl ring, a lower alkenylidene group, a lower cycloalkylidene group, or a phenoxy lower alkylidene group that may have a carboxyl group on the phenyl ring. }, R ³ represents two hydrogen atoms, a phenyl lower alkylidene group or a phenyl lower alkenylidene group which may have a substituent selected from a halogen atom and a halogenated lower alkyl group on the phenyl ring, and X represents —S - or -N (R ⁷⁾ - (. R ⁷ is showing a hydrogen atom, a lower alkyl group, carboxy lower alkyl group or a lower alkoxycarbonyl-lower alkyl group) a, R ¹ and R ^4, or R ⁴ and R ⁷ May combine with each other to form an oxoethylene group. ] The Maillard reaction inhibitor containing at least 1 of the compound shown by these or its salt as an active ingredient.