JPH06305964A - Inhibitor of maillard reaction - Google Patents

Abstract

PURPOSE:To obtain the inhibitor, containing a specific compound (salt) as an active ingredient, having low toxicity, excellent in the safety, stability and pharmacodynamic effect persistence and useful for treating, etc., diabetes, diabetic complication, etc. CONSTITUTION:The objective inhibitor contains one or more compounds selected from compounds of formula I [R<0> is H or lower alkyl; R<1> is H, lower alkyl, lower alkanoyl, etc.; R<2> is H, lower alkyl or lower alkanoyl; R<3> is H, lower alkanoyl, benzoyl or formula II (R<4> is phenyl or lower alkoxy); R<2> and R<3> together form lower alkylidene, diphenylmethylene, etc. ; X is S or N(R<5>) (R<5> is H, lower alkyl, etc.); R<3> and R<5> are bound to form 6- to 8-membered ring] such as 2-[2-(N-benzoylthiocarbamoyl)hydrazino]benzothiazole and salts thereof as an active ingredient. Furthermore, the daily dose of the active ingredient is preferably within the range of 0.1-100/kg (body weight).

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel Maillard reaction inhibitor and a novel active ingredient compound for the inhibitor.

[0002]

2. Description of the Related Art The Maillard reaction in the living body begins with a free amino group existing in a protein attacking an 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 forms a brown fluorescent substance by causing a series of reactions with amino groups in other proteins to cause cross-linking between the 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 had already suggested that this reaction could occur in living organisms. 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 a form in which glucose is subjected to Amadori transfer [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 bioproteins 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)]. Increased glycation level is also observed 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 diabetic conditions where aging and blood sugar level rise. It This is because the accumulated amount of Maillard reaction products is determined by the blood glucose 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 were added to mice.
Intravenous administration over a week 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 undergoes glycation, it forms a colorless cross-linker with a disulfide bond and a cross-linker with a color and fluorescence [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 very 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 it is due to a non-enzymatic mechanism [Brownlee, M. et al., Sc.
ience , 232 , 1629 (1986)], and it is also considered to be associated with hardening of the arterial wall [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 An object of the present invention is to provide a novel Maillard reaction inhibitor and a novel active ingredient compound for the inhibitor.

[0009]

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

[0010]

[Chemical 4]

[In the formula, R ¹ represents a hydrogen atom, a lower alkyl group or a lower alkanoyl group, R ² represents a hydrogen atom, a lower alkyl group or a lower alkanoyl group, and R ³ represents a hydrogen atom, a lower alkanoyl group or benzoyl. Group or group

[0012]

[Chemical 5]

(R ⁴ represents a phenyl group or a lower alkoxy group). R ² and R ³ may together represent a lower alkylidene group, diphenylmethylene group or phenyl lower alkylidene group. X is -S- or -N
(R ⁵ )-is shown. R ⁵ represents a hydrogen atom or a lower alkoxycarbonyl lower alkyl group. Further, R ² , R ³ and R ⁵ may combine with each other to form a 6- to 8-membered ring. ] The Maillard reaction inhibitor containing at least 1 of the compound shown by these and its salt as an active ingredient is provided.

According to the present invention, the following (1-1) useful as an active ingredient compound of the above Maillard reaction inhibitor is used.
The novel compounds of (1-3) and their salts are provided.

(1-1) In the general formula (1), R ⁰ represents a hydrogen atom, R ¹ represents a hydrogen atom, R ² represents a hydrogen atom, and R ³ represents a group.

[0016]

[Chemical 6]

(R ⁴ is a phenyl group or a lower alkoxy group) and X is --S--.

(1-2) In the general formula (1), R ⁰ represents a hydrogen atom, R ¹ represents a hydrogen atom, R ² represents a hydrogen atom, and X represents -N (R ⁵ )-. The compound represented by the formula, wherein R ³ and R ⁵ are combined to form a 6- to 8-membered ring.

(1-3) In the general formula (1), R ⁰ represents a hydrogen atom or a lower alkyl group, R ¹ represents a hydrogen atom or a lower alkoxycarbonyl lower alkyl group, and R ²
Represents a hydrogen atom or a lower alkyl group and R ³ represents a hydrogen atom respectively, or R ² and R ³ together represent a lower alkylidene group or a diphenylmethylene group, and X represents —N
(R ⁵ )-(R ⁵ represents a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl lower alkyl group or a phenyl lower alkyl group which may have a halogen atom as a substituent on the phenyl ring), but R ² And R ³ simultaneously represent a hydrogen atom, R ⁰ represents a lower alkyl group.

The compound represented by the above formula (1) and a salt thereof inhibit various Maillard reaction, thereby causing various diabetic complications such as coronary artery disease, peripheral circulatory disorder, cerebrovascular disorder, diabetic neuropathy, It is useful for the treatment and / or prevention of nephropathy, arteriosclerosis, arteriosclerosis, cataracts and retinopathy, and diseases caused by aging, such as atherosclerosis and senile cataract. In particular, the above-mentioned compounds and salts thereof have characteristics such as long duration, excellent absorption in the body, low toxicity, high safety, excellent stability of compounds, and easy formulation.

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

The lower alkyl group, regardless of whether it is independently present or present in another group, is a methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl group or the like. Carbon number 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. Examples thereof include linear or branched alkoxy groups having 1 to 6 carbon atoms such as an oxy group.

The lower alkanoyl group, whether it is present independently or in any other group, is a formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl, hexanoyl group Examples thereof include linear or branched alkanoyl groups having 1 to 6 carbon atoms.

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

The phenyl lower alkylidene group is benzylidene, 2-phenylethylidene, 1-phenylethylidene, 3-phenylpropylidene, 4-phenylbutylidene, 1,1-dimethyl-2-phenylethylidene, 5-phenylpentylidene, A phenylalkylidene group in which the alkylidene moiety such as 6-phenylhexylidene or 2-methyl-3-phenylpropylidene group is a linear or branched alkylidene group having 1 to 6 carbon atoms can be exemplified.

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
An alkoxy moiety such as a pentyloxycarbonylethyl or hexyloxycarbonylmethyl group is a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, and an alkyl moiety is straight-chain or branched having 1 to 6 carbon atoms. The alkoxycarbonylalkyl group which is an alkyl group can be illustrated.

As the halogen atom, a fluorine atom, a bromine atom, a chlorine atom and an iodine atom can be exemplified regardless of whether they are independently present or present in other groups.

As the phenyl lower alkyl group which may have a halogen atom as a substituent on the phenyl ring,
For example, benzyl, 2-fluorobenzyl, 3-bromobenzyl, 4-chlorobenzyl, 4-iodobenzyl,
2-phenylethyl, 1- (4-chlorophenyl) ethyl, 3- (4-bromophenyl) propyl, 4- (2-
Fluorophenyl) butyl, 5- (3-bromophenyl) pentyl, 6-phenylhexyl, 2-methyl-3
An example of a phenylalkyl group that may have a halogen atom as a substituent on the phenyl ring in which the alkyl moiety such as a-(3-chlorophenyl) propyl group is a linear or branched alkyl group having 1 to 6 carbon atoms it can.

The compound represented by the above general formula (1) includes all stereoisomers, optical isomers, geometric isomers and the like.

Particularly preferred as the active ingredient compound of the inhibitor of the present invention is that in the general formula, R ⁰ represents a hydrogen atom or a lower alkyl group, R ¹ represents a hydrogen atom, and R ²
Is a hydrogen atom and R ³ is a hydrogen atom or a group

[0032]

[Chemical 7]

(R ⁴ represents a phenyl group) or R ² and R ³ together represent a lower alkylidene group, and X represents --S-- or --N (R ⁵ )-(R ⁵ represents A hydrogen atom, a lower alkyl group or a phenyl lower alkyl group which may have a halogen atom as a substituent on the phenyl ring), and R ³ and R ⁵ are combined to form 6 to 8
Examples thereof include compounds that may form a member ring and salts thereof.

Further, the novel active ingredient compounds for the inhibitor of the present invention can be roughly classified into the above-mentioned (1-1) to (1-3), and the compounds belonging to each group are preferable. Is. Particularly preferable examples of the compounds belonging to the above (1-3) include the following compounds (1-4) and (1-5).

(1-4) In the general formula (1), R ⁰ represents a hydrogen atom, R ¹ represents a hydrogen atom, R ² and R ³ together represent a lower alkylidene group, and X represents -N (R
⁵ )-, wherein R ⁵ represents a hydrogen atom, a lower alkyl group or a phenyl lower alkyl group which may have a halogen atom as a substituent on the phenyl ring.

(1-5) In the general formula (1), R ⁰ represents a lower alkyl group, R ¹ represents a hydrogen atom, and R ² and R ³ each represent a hydrogen atom, or R ² and R ³ R ³ together represents a lower alkylidene group, and X represents —NH—.

The active ingredient compound (1) of the Maillard reaction inhibitor of the present invention can be produced by various methods. For example, it can be produced by various methods shown below.

Reaction formula-1

[0039]

[Chemical 8]

[In the formula, R ⁰ , R ¹ and X are the same as defined above.
R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom, a lower alkyl group or a phenyl group. Among the compounds represented by the above general formula (1), compounds in which R ² and R ³ are taken together to represent a lower alkylidene group, a diphenylmethylene group or a phenyl lower alkylidene group can be prepared by the method shown in the above reaction process formula-1. Manufactured.

The reaction between the compound (2) and the compound (3) is
It is carried out by heating the mixture of both in a solvent or without solvent. Examples of the solvent used in the reaction include lower alcohols such as methanol and ethanol, ethers such as dioxane, tetrahydrofuran and diethyl ether, aromatic hydrocarbons such as benzene and toluene, polar solvents such as dimethylformamide and dimethylsulfoxide. Etc. and a mixed solvent thereof and the like. The ratio of the compound (2) to the compound (3) used is not particularly limited and may be appropriately selected within a wide range. Usually, the latter is about 1 to 20 times mol, preferably 1 to 3 times the former. It is recommended to use about a mole. The reaction is usually 30 to 200
The reaction proceeds suitably at about 60 ° C, preferably about 60 to 100 ° C, and generally the reaction is completed in about 1 to 24 hours.

Reaction process formula-2

[0043]

[Chemical 9]

[Wherein R ⁰ , R ¹ , R ⁴ and X are the same as defined above. ] Of the compounds represented by the above general formula (1),
Based on R ³

[0045]

[Chemical 10]

[R ⁴ is the same as above. [Compound (6)] having the formula (1) is produced by the method shown in Reaction Scheme-2.

The reaction between the compound (2) and the compound (5) is
It is carried out in a suitable solvent. Examples of the solvent used in the reaction include ethers such as dioxane, tetrahydrofuran, diethyl ether and ethylene glycol dimethyl ether, aromatic hydrocarbons such as benzene and toluene, ethyl acetate, acetonitrile, dimethylformamide, dimethylsulfoxide, chloroform and acetone. And the like, and mixed solvents thereof and the like. The use ratio of the compound (2) and the compound (5) is not particularly limited and may be appropriately selected within a wide range, but the latter is usually about 1 to 10 times mol, preferably 1 to 2 times the former. It is recommended to use about a mole. The reaction is usually 0 to 150 ° C.
About 10 to 100 ° C.
Generally, the reaction is completed in about 5 minutes to 20 hours.

Reaction process formula-3

[0049]

[Chemical 11]

[In the formula, R ⁰ , R ¹ and X are the same as defined above.
X ¹ represents a halogen atom. Among the compounds represented by the above general formula (1), the compound in which R ³ represents a benzoyl group can be produced by the method shown in the reaction process formula-3.

The reaction between the compound (2) and the compound (7) is
It is carried out in a suitable solvent. As the solvent used in the reaction, for example, the solvent used in the reaction represented by the reaction formula-2 can be widely used. The ratio of the compound (2) to the compound (7) to be used is not particularly limited and may be appropriately selected within a wide range.
It is good to use about 10 times mol, preferably about 1 to 3 times mol. The reaction proceeds normally at about -30 to 100 ° C., preferably at about 0 to 80 ° C., generally for 30 minutes to
The reaction is completed in about 20 hours.

Reaction process formula-4

[0053]

[Chemical 12]

[In the formula, R ⁰ , R ¹ and X are the same as defined above.
X ² represents a halogen atom. R ⁹ represents a lower alkanoyl group. Among the compounds represented by the above general formula (1), compounds in which R ¹ is a hydrogen atom or a lower alkanoyl group, R ² is a hydrogen atom or a lower alkanoyl group, and R ³ is a lower alkanoyl group are represented by reaction process formula-4 It is manufactured by the method shown in.

The reaction between the compound (2) and the compound (9) is
It is carried out by heating a mixture of both in a solvent or without a solvent. Examples of the solvent used in the reaction include aromatic hydrocarbons such as benzene and toluene, solvents such as ethyl acetate, acetonitrile, dimethylformamide, dimethylsulfoxide and chloroform, and mixed solvents thereof. The ratio of the compound (2) to the compound (9) used is not particularly limited and may be appropriately selected within a wide range, but the latter is usually about 1 to 20 times mol, preferably 1 to 3 times the former. It is recommended to use about a mole.
The reaction is usually about 30 to 200 ° C., preferably 60 to
The reaction proceeds suitably at about 100 ° C., and generally the reaction is completed in about 30 minutes to 20 hours.

The reaction between compound (2) and compound (11) is carried out in a suitable solvent. Examples of the solvent used in the reaction include amines such as pyridine, polar solvents such as dimethylformamide and dimethylsulfoxide, and mixed solvents thereof. The ratio of the compound (2) to the compound (11) used is not particularly limited and may be appropriately selected within a wide range.
It is preferable to use about 10 to 10 times mol, preferably about 2 to 5 times mol. The reaction proceeds normally at about -10 to 50 ° C, preferably about 0 to 25 ° C, and generally 1 to 20 ° C.
The reaction is completed in about time.

The reaction of compound (2) with compound (13) is carried out in a suitable solvent. Examples of the solvent used in the reaction include amines such as pyridine, polar solvents such as dimethylformamide and dimethylsulfoxide, and mixed solvents thereof. The ratio of the compound (2) to the compound (13) used is not particularly limited and may be appropriately selected within a wide range, but the latter is usually 3 to the former.
It is preferable to use about 10 to 10 times mol, preferably about 3 to 5 times mol. The reaction proceeds normally at about -10 to 50 ° C, preferably at about -10 to 10 ° C, and generally 1 to 10 ° C.
The reaction is completed in about 20 hours.

Reaction process formula-5

[0059]

[Chemical 13]

[In the formula, R ⁰ , R ¹ and X are the same as defined above.
X ³ represents a halogen atom. R ¹⁰ and R ¹¹ are the same or different and each represents a hydrogen atom, a lower alkyl group or a lower alkanoyl group. R ¹⁰ and R ¹¹ may together represent a diphenylmethylene group. Among the compounds represented by the general formula (1), a compound in which R ² and R ³ represent a hydrogen atom, a lower alkyl group or a lower alkanoyl group, and a compound in which R ² and R ³ together represent a diphenylmethylene group Is produced by the method shown in Reaction Scheme-5.

The reaction of compound (15) with compound (16) is carried out in a suitable solvent or without solvent. Examples of the solvent used in the reaction include benzene, toluene,
Aromatic hydrocarbons such as xylene, alcohols such as methanol, ethanol and propanol, acetic acid, pyridine,
Examples thereof include solvents such as dimethylformamide and dimethylsulfoxide, and mixed solvents thereof. The ratio of the compound (15) to the compound (16) used is not particularly limited and may be appropriately selected within a wide range, but the latter is usually about 1 to 30 times mol, preferably 1 to 5 times the former. It is recommended to use about a mole. The reaction normally proceeds suitably at about 100 to 200 ° C, preferably about 130 to 160 ° C,
Generally, the reaction is completed in about 1 to 20 hours.

Reaction process formula-6

[0063]

[Chemical 14]

[In the formula, R ⁰ and X ³ are the same as defined above. X ⁴ represents a halogen atom. R ¹² represents a lower alkoxycarbonyl lower alkyl group. ] Compound (15) and Compound (1
The reaction with 8) is carried out in the presence of a basic compound in a suitable solvent. Examples of the solvent used in the reaction include amines such as pyridine, polar solvents such as dimethylformamide and dimethylsulfoxide, ethers such as dioxane, tetrahydrofuran, diethyl ether and ethylene glycol dimethyl ether, and mixed solvents thereof. . Examples of the basic compound include inorganic basic compounds such as potassium carbonate and sodium hydrogen carbonate,
Examples thereof include organic basic compounds such as sodium acetate.
Such a basic compound is usually 1 relative to the compound (15).
It is recommended to use about 5 to 5 times mol, preferably about 1 to 2 times mol. The ratio of the compound (15) to the compound (18) to be used is not particularly limited and may be appropriately selected within a wide range, but usually the latter is about 1 to 10-fold mol relative to the former,
It is preferable to use 1 to 3 times mol. The reaction normally proceeds suitably at about 0 to 100 ° C., preferably about 60 to 90 ° C., and generally the reaction is completed in about 1 to 20 hours.

In the method shown in the above reaction scheme-6, instead of the compound (18), R ⁵ -X ⁴ (R ⁵ and X
By using the compound represented by the formula ( ⁴ ) is the same as the above), a desired starting compound in which the group R ⁵ is introduced into the compound (15) can be obtained.

The reaction between compound (19) and hydrazine is
It is carried out in a suitable solvent or without solvent. Examples of the solvent used in the reaction include aromatic hydrocarbons such as benzene and toluene, alcohols such as methanol and ethanol, amines such as acetic acid and pyridine, polar solvents such as dimethylformamide and dimethylsulfoxide, and the like. Examples include mixed solvents. The ratio of the compound (19) to hydrazine used is not particularly limited and may be appropriately selected within a wide range. Usually, the latter is used in an amount of about 1 to 30 times mol, preferably about 1 to 5 times mol of the former. Good to do. The reaction generally proceeds at about 100 to 200 ° C, preferably about 140 to 170 ° C, and generally 1 to 20 ° C.
The reaction is completed in about time.

Reaction process formula-7

[0068]

[Chemical 15]

[In the formula, R ⁰ , R ² , R ³ , R ¹² and X ⁴
Is the same as above. The reaction of compound (21) with compound (18) is carried out in the presence of a deoxidizing agent in a suitable solvent.
Examples of the deoxidizing agent include alkali metal alcoholates such as sodium methoxide and sodium ethoxide, potassium carbonate, sodium carbonate, sodium hydroxide, sodium hydrogen carbonate, triethylamine, tripropylamine, pyridine, quinoline, 4-dimethylaminopyridine. And basic compounds such as sodium acetate. As the solvent used in the reaction, methanol, ethanol, lower alcohols such as isopropanol, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, ethers such as diethyl ether, benzene, toluene, aromatic hydrocarbons such as xylene, triethylamine, Examples thereof include tertiary amines such as tripropylamine, polar solvents such as dimethylformamide, dimethylsulfoxide, and the like.

The amount of the compound (18) used is the same as that of the compound (21).
On the other hand, it is usually 2 times or more molar amount, preferably about 2 to 5 times molar amount. The above reaction is usually -10 to 1
The reaction proceeds suitably at about 00 ° C., preferably about 0 to 30 ° C., and generally the reaction is completed in about 1 to 24 hours.

The starting materials used in the above reaction schemes are all known compounds, and are readily available compounds.

The compound of the present invention can easily form an addition salt of a pharmaceutically acceptable acid or base compound by reacting it with a suitable acid or base, and such salt is also in a free form. Like the active ingredient compound, it can be advantageously used as the active ingredient compound of the inhibitor of the present invention. Examples of the acid used for forming the salt 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 acids and 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 usually 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. Various forms of this pharmaceutical preparation 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.

In the case of molding in the form of tablets, as a carrier, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc. excipients, water, ethanol, propanol, Simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binders such as polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, poly Oxyethylenesorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, disintegrating agents such as lactose, sucrose, stearin,
Decay inhibitor for cocoa butter, hydrogenated oil, quaternary ammonium base, absorption promoter for sodium lauryl sulfate, humectant for glycerin, starch, adsorption of starch, lactose, kaolin, bentonite, colloidal silicic acid, etc. Agents, purified talc, stearates, boric acid powder, lubricants such as polyethylene glycol, and the like can be used. Further, the tablet is a tablet coated with a usual coating as necessary, for example, a sugar-coated tablet,
It may be a gelatin-coated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, or a multi-layer tablet.

In the case of molding in the form of pills, as carriers, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, gum arabic powder, tragacanth powder, gelatin, ethanol and the like are bound. Agent,
A disintegrating agent such as laminaran or agar can be used. In the case of molding into a suppository, as a carrier, for example, polyethylene glycol, cacao butter, higher alcohol, esters of higher alcohol, gelatin, semisynthetic glyceride and the like 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, the solution, emulsion and suspension are preferably sterilized and isotonic with blood. When molded into these forms, for example, water, lactic acid aqueous solution, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, as a diluent,
Polyoxyethylene sorbitan fatty acid esters and the like can be used. In this case, a sufficient amount of salt, bute sugar or glycerin for preparing an isotonic solution may be contained in the pharmaceutical preparation, and a usual solubilizing agent, buffer, soothing agent, etc. May be added. Further, if necessary, a colorant, a preservative, a fragrance, a flavoring agent, a sweetening agent and the like and other pharmaceuticals may be contained in the pharmaceutical preparation.

In the case of formulation in the form of paste, cream and gel, white petrolatum, paraffin, glycerin, cellulose derivative, 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 administration method of the pharmaceutical preparation of the present invention is not particularly limited, and is variously determined according to the age, sex and other conditions of the patient, disease state, etc., and various formulation forms, etc., but usually systemically or locally, orally Or it is administered 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. In addition to being administered subcutaneously or intraperitoneally, it is administered rectally as a suppository or applied as an ointment.

The dose of the pharmaceutical preparation of the present invention to humans is appropriately selected depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is usually about 0.
The dosage may be in the range of 1 to 100 mg, and the formulation may be administered once to several times a day. 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.

[0081]

[Examples] Production examples of 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 Preparation of 2- [2- (N-benzoylthiocarbamoyl) hydrazino] benzothiazole A mixture of 0.66 g of 2-hydrazinobenzothiazole, 0.65 g of benzoyl isothiocyanate and 5 ml of tetrahydrofuran was stirred at room temperature. Stir for 16 hours. The precipitated crystals were collected by filtration, and methanol-methylene chloride (1: 1,
V / V) to recrystallize the above target compound to 0.7.
9 g were obtained.

NMR (DMSO-d ₆ ) δ ppm: 7.
08-8.01 (m, 9H), 10.89 (brs, 1
H), 11.68 (brs, 1H), 12.64 (br
s, 1H).

Example 2 Preparation of 2- [2- (N-ethoxycarbonylthiocarbamoyl) hydrazino] benzothiazole Benzylyl isothiocyanate was replaced by ethoxycarbonyl isothiocyanate and the same purpose as in Example 1 was applied. The compound was obtained.

NMR (DMSO-d ₆ ) δ ppm: 1.
27 (t, 3H, J = 6.93 Hz), 4.22 (q,
2H, J = 6.93 Hz), 7.07 to 7.76 (m,
4H), 8.16 (brs, 1H), 11.35 (br
s, 1H), 11.57 (brs, 1H).

Example 3 Preparation of 2- (2-benzoylhydrazino) benzothiazole 0.50 g of 2-hydrazinobenzothiazole was dissolved in 10 ml of tetrahydrofuran, 0.42 g of benzoyl chloride was added under ice cooling, and the mixture was kept at room temperature for 5 hours. It was stirred. The precipitated crystals were collected by filtration and purified by silica gel column chromatography (eluent; methylene chloride: methanol = 9: 1) to obtain 0.48 g of the above target compound.

NMR (DMSO-d ₆ ) δ ppm: 7.
08 to 7.95 (m, 9H), 10.02 (brs, 1
H), 10.96 (brs, 1H).

Example 4 Preparation of 2-isopropylidenehydrazinobenzimidazole N.V. P. Bednyagina, I.D. Ya. Posto
vskii, Zhur. Obshchei, Khim,
30-1431 (1960) synthesized 2-hydrazinobenzimidazole 0.80 g and acetone 20
The ml mixture was heated to reflux for 1 hour. Acetone was distilled off under reduced pressure to obtain 1.02 g of the above target compound.

NMR (DMSO-d ₆ ) δ ppm: 1.
93 (s, 3H), 2.00 (s, 3H), 6.88-
6.93 (m, 2H), 7.17 to 7.20 (m, 2)
H).

Example 5 Preparation of 2-diphenylmethylidenehydrazinobenzimidazole A mixture of 0.15 g of 2-chlorobenzimidazole, 0.98 g of benzophenonehydrazone and 7 ml of ethanol was heated to 150 ° C. in a sealed tube. After 2 hours, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 10: 1) to obtain 0.20 g of the above target compound.

Melting point: 245-247 ° C. Example 6 Preparation of 2- (2-methylhydrazino) benzimidazole 0.30 g of 2-chlorobenzimidazole and methylhydrazine synthesized by the method described in JP-B-41-14118. 0.53 ml of the mixture in a sealed tube at 150 ° C
It was stirred for 2 hours. After cooling, 10 ml of water was added, and the produced crystals were collected by filtration to obtain 0.22 g of the desired compound.

NMR (DMSO-d ₆ ) δ ppm: 3.
20 (s, 3H), 4.78 (brs, 1H), 6.8
4 to 6.97 (m, 3H), 7.12 to 7.17 (m,
2H), 10.58 (s, 1H).

Example 7 3-oxo-1,2,3,4-tetrahydro- [1,
Production of 2,4] triazino [4,3-a] benzimidazole 1.53 g of 2-chlorobenzimidazole and 1.47 g of ethyl chloroacetate synthesized by the method described in JP-B-41-14118 were added to 10 m of dimethylformamide.
It was dissolved in 1 l, 0.83 g of potassium carbonate was added, and the mixture was stirred at 80 ° C for 2 hours. The reaction solution was poured into 150 ml of ice water and extracted with 150 ml of ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane-ethyl acetate = 4: 1) to give 2-chloro-1-
Ethoxycarbonylmethylbenzimidazole 1.2
5 g was obtained.

A mixture of 0.72 g of 2-chloro-1-ethoxycarbonylmethylbenzimidazole obtained above and 1.92 ml of anhydrous humanazine was sealed at 150 ° C. in a sealed tube.
And stirred for 3 hours. After cooling, 10 ml of water was added, and the produced crystals were collected by filtration to obtain 0.22 g of the desired compound.

NMR (DMSO-d ₆ ) δ ppm: 4.
61 (s, 2H), 6.86 to 7.32 (m, 5H),
10.13 (s, 1H).

Example 8 Preparation of 2-isopropylidenehydrazino-1-methylbenzimidazole N.V. P. Bednyagina, I.D. Ya. Posto
vskii, Zhur. Obshchei, Khim,
The above-mentioned target compound was obtained in the same manner as in Example 4 except that 2-hydrazino-1-methylbenzimidazole synthesized according to No. 30, 1431 (1960) was used as a starting material.

NMR (DMSO-d ₆ ) δ ppm: 2.
15 (s, 3H), 2.20 (s, 3H), 3.39
(S, 3H), 7.30 to 7.63 (m, 4H), 1
3.13 (brs, 1H).

Example 9 Preparation of 1-ethoxycarbonylmethyl-2- (1-ethoxycarbonylmethyl-2-isopropylidenehydrazino) benzimidazole 1.88 g of 2-isopropylidenehydrazinobenzimidazole prepared in Example 4 To a suspension of 1.2 g of 60% sodium hydride in 50 ml of dimethylformamide and stirred under ice cooling, 1 hour later, 4.9 g of ethyl chloroacetate was added, and stirred at room temperature for 1 hour. Ice water was added to the reaction solution. In addition, it was extracted with methylene chloride. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane-ethyl acetate = 1: 1) to obtain 1.58 g of the above target compound.

NMR (CDCl ₃ ) δppm: 1.25
(T, 6H, J = 7.26 Hz), 1.89 (s, 3)
H), 1.93 (s, 3H), 4.21 (q, 4H, J
= 7.26 Hz), 4.59 (s, 2H), 5.13
(S, 2H), 6.71 to 6.83 (m, 4H), 6.
88-7.01 (m, 2H).

Example 10 Preparation of 2-hydrazino-5-methylbenzimidazole L. S. Efros, B .; A. Porai-Koshi
ts, S. G. Farbenshtein, Zhur.
Obshch, Khim, 23, 1691 (1953)
Example 2 using 2-chloro-5-methylbenzimidazole synthesized according to
The target compound was obtained in the same manner as.

NMR (DMSO-d ₆ ) δ ppm: 1.
92 (s, 3H), 1.99 (s, 3H), 2.32
(S, 3H), 6.73 (d, 1H, J = 7.59H
z), 6.99 (s, 1H), 7.06 (d, 1H, J
= 7.92 Hz).

Example 11 Preparation of 2-isopropylidenehydrazino-5-methylbenzimidazole The 2-hydrazino-5-methylbenzimidazole prepared in Example 10 was used as a starting material, and the same purpose as in Example 4 was carried out. The compound was obtained.

NMR (DMSO-d ₆ ) δ ppm: 1.
91 (s, 3H), 1.99 (s, 3H), 2.32
(S, 3H), 6.75 (d, 1H, J = 9.57H
z), 6.98 to 7.06 (m, 2H), 9.92 (b
rs, 1H), 11.02 (brs, 1H).

Example 12 Preparation of 1-benzyl-2-isopropylidenehydrazinobenzimidazole 2 g of 2-chlorobenzimidazole, 4 ml of benzyl chloride and ethanol solution 2 of 30% sodium hydroxide 2
ml was dissolved in 10 ml of ethanol and heated under reflux for 1 hour. After allowing to cool, water was added and the mixture was extracted with methylene chloride. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane-ethyl acetate = 7: 3) to obtain 1.28 g of 1-benzyl-2-chlorobenzimidazole.

Using 1.28 g of this, 1-benzyl-2-hydrazinobenzimidazole was obtained in the same manner as in Example 10.

Further, this was operated in the same manner as in Example 4 to obtain 0.28 g of the above objective compound.

NMR (DMSO-d ₆ ) δ ppm: 2.
13 (s, 3H), 2.16 (s, 3H), 5.73
(S, 2H), 7.28 to 7.53 (m, 9H).

Example 13 1-Benzyl-2- (1-ethoxycarbonylmethyl-
Production Method of 2-Isopropylidenehydrazino) benzimidazole The above target compound was obtained in the same manner as in Example 9 using 1-benzyl-2-isopropylidenehydrazinobenzimidazole produced in Example 12 as a starting material.

NMR (CDCl ₃ ) δppm: 1.25
(T, 3H, J = 7.26 Hz), 1.91 (s, 3
H), 1.95 (s, 3H), 4.20 (q, 2H, J
= 7.26 Hz), 4.57 (s, 2H), 5.12
(S, 2H), 6.74 to 6.86 (m, 1H), 6.
87-6.98 (m, 1H), 7.19-7.35
(M, 7H).

Example 14 Preparation of 1- (4-chlorobenzyl) -2-isopropylidenehydrazinobenzimidazole In place of benzyl chloride, 4-chlorobenzyl chloride was used and in the same manner as in Example 12, the above target compound was prepared. Got

NMR (DMSO-d ₆ ) δ ppm: 2.
09 (s, 3H), 2.12 (s, 3H), 5.10.
(S, 2H), 6.99 to 7.02 (m, 1H), 7.
11 to 7.15 (m, 1H), 7.29 to 7.49
(M, 6H).

Pharmacological test The Maillard reaction inhibitory action of the compound of the general formula (1) was confirmed by the screening system described below.

10 mg each of lysozyme and fructose was added to 0.2 M sodium phosphate buffer (pH 7.4).
/ Ml, dissolve to a concentration of 100 mM, 37 ℃
After incubating for 3 days, a fixed amount was taken out and subjected to electrophoresis using SDS-PAGE. After electrophoresis, 0.2% Commerce Brilliant Blue R-
After staining with 250, the production amount of the duplex was quantified with a densitometer.

The test compound was added before the incubation, and the inhibitory effect on the formation of the duplex at various concentrations was examined to determine the IC ₅₀ value. Aminoguanidine, which is a known compound as a glycation inhibitor, was used as a solubility target, and the ratio of aminoguanidine to aminoguanidine using the IC ₅₀ value (IC ₅₀ value of aminoguanidine / IC of test compound) was used.
₅₀ values) were calculated.

The feed compounds are as follows:

1. Acetone benzothiazolyl-2-hydrazone 2.2- [2- (N-benzoylthiocarbamoyl) hydrazino] benzothiazole 3.2- [2- (N-Ethoxycarbonylthiocarbamoyl) hydrazino] benzothiazole 4.2- (2-benzoylhydrazino) benzothiazole 5.2- (2,2-diacetylhydrazino) benzothiazole 6.2- (2-acetylhydrazino) benzothiazole 7.2- (1,2,2-triacetyl Hydrazino) benzothiazole 8.2-Hydrazino benzimidazole 9.2-Isopropylidene hydrazinobenzimidazole 10.2-Diphenylmethylidene hydrazinobenzimidazole 11.3-oxo-1,2,3,4-tetrahydro −
[1,2,4] Triazino [4,3-a] benzimidazole 12.2- (2-methylhydrazino) benzimidazole 13.2-hydrazino-1-methylbenzimidazole 14.2-isopropylidenehydrazino- 1-Methylbenzimidazole 15.1-Ethoxycarbonylmethyl-2- (1-ethoxycarbonylmethyl-2-isopropylidenehydrazino) benzimidazole 16.2-Hydrazino-5-methylbenzimidazole 17.2-Isopropylidenehydrazino -5-Methylbenzimidazole 18.1-Benzyl-2-isopropylidenehydrazinobenzimidazole 19.1-Benzyl-2- (1-ethoxycarbonylmethyl-2-isopropylidenehydrazino) benzimidazole 20.1- (4 -Chlorobenzyl) -2-isopropy Table 1 shows the den hydrazino benzimidazole results.

[0117]

[Table 1]

Formulation Example After mixing the following components, the mixture was tableted to give 50 mg in one tablet.
100 tablets having the active ingredient of were obtained.

2- [2- (N-ethoxycarbonylthiocarbamoyl) hydrazino] benzothiazole 5 g sodium lauryl sulfate 0.2 g magnesium stearate 0.2 g crystalline cellulose 4.6 g

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Internal reference number FI Technical display location C07D 277/82 487/04 144 7019-4C (72) Inventor Yuko Toyama Takashiro Shiga-cho, Shiga-gun, Shiga Prefecture 192-163 (72) Inventor Kazuhisa Sugiyama 1-17-28 Hirats, Otsu City, Shiga Sejuru Hirats B-202

Claims (2)

[Claims] 1. A general formula: [In the formula, R ⁰ represents a hydrogen atom or a lower alkyl group,
R ¹ represents a hydrogen atom, a lower alkyl group, a lower alkanoyl group or a lower alkoxycarbonyl lower alkyl group,
R ² represents a hydrogen atom, a lower alkyl group or a lower alkanoyl group, and R ³ represents a hydrogen atom, a lower alkanoyl group, a benzoyl group or a group (R ⁴ represents a phenyl group or a lower alkoxy group). R ² and R ³ may together represent a lower alkylidene group, diphenylmethylene group or phenyl lower alkylidene group. X is -S- or -N (R ⁵⁾ - shows the. R ⁵ represents a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl lower alkyl group or a phenyl lower alkyl group which may have a halogen atom as a substituent on the phenyl ring. Further, R ³ and R ⁵ may combine with each other to form a 6- to 8-membered ring. ] The Maillard reaction inhibitor containing at least 1 of the compound shown by these and its salt as an active ingredient. 2. In the general formula shown in claim 1, (1-1) R
⁰ represents a hydrogen atom, R ¹ represents a hydrogen atom, R ² represents a hydrogen atom, and R ³ represents a group (R ⁴ is a phenyl group or a lower alkoxy group) and X is —S—, (1-2) R ⁰ represents a hydrogen atom, R ¹ represents a hydrogen atom, and R ² represents a hydrogen atom. Shows,
X is -N (R ⁵⁾ - are shown, R ³ and R ⁵ combine to 6
A compound forming an 8-membered ring, and (1-3) R ⁰ represents a hydrogen atom or a lower alkyl group, R ¹ represents a hydrogen atom or a lower alkoxycarbonyl lower alkyl group, and R ² represents a hydrogen atom or lower alkyl. Group and R ³ each represents a hydrogen atom, or R ² and R ³ together represent a lower alkylidene group or diphenylmethylene group, and X is —N
(R ⁵ )-(R ⁵ represents a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl lower alkyl group or a phenyl lower alkyl group which may have a halogen atom as a substituent on the phenyl ring), but R ² When R ³ and R ³ simultaneously represent a hydrogen atom, R ⁰ represents a lower alkyl group, or a compound thereof.