WO1998023606A1 - Cyclic dithio derivatives, remedies for diabetic kidney diseases, hypoglycemic agents, hypolipidemic agents, and lenitives for digestive disorders - Google Patents

Abstract

Cyclic dithio compounds of general formula I, wherein A is (a) or (b) [(wherein the substituents are each as defined in the claims)]; and remedies for diabetic kidney diseases, lenitives for digestive disorders, hypoglycemic agents or hypolipidemic agents containing the same.

Description

 Specification

 Cyclic dithio derivative, therapeutic agent for diabetic renal disease, hypoglycemic agent, lipid lowering agent, gastrointestinal disorder reducing agent

Technical field

 The present invention relates to a novel dithiocyclic compound, and more particularly, to a dithiocyclic compound having an inhibitory effect on renal disease progression, a hypoglycemic effect, a hypolipidemic effect, a gastrointestinal disorder-reducing effect, or a medicament thereof. Tolerable salts, intermediate compounds for producing them, and therapeutic agents for diabetic renal diseases, hypoglycemic agents, hypolipidemics, which contain dithiocyclic compounds and have few side effects such as gastrointestinal disorders. The present invention relates to a medicament useful as an agent or a gastrointestinal disorder reducing agent.

Background art

 Hitherto, it has been reported that some compounds containing one SH, —SS— group have a hypoglycemic effect [Pharmaceutical Magazine, Vol. 89, 1138-1143 (1969)].

 In recent years, it has been reported that lipoic acid (cholic acid), which is a cyclic SS-form, is effective for diabetic neuropathy in addition to hypoglycemic effect [Diabet ologia, 1995, 38, 1425-1433], one SS-body is expected to be effective for complications of diabetes. Among the complications of diabetes, there are few drugs for diabetic nephropathy, and the development of new drugs is expected. So far, lipoic acid (cholic acid) has not been studied for dysglycemic nephropathy, and the present inventors' studies on renal dysfunction using streptozotocin (STZ) have shown a strong effect. Did not.

Disclosure of the invention

 The present invention relates to a novel dithiocyclic compound, more specifically, a dithiocyclic compound having a renal disease progression-inhibiting action, a hypoglycemic action, a hypolipidemic action, or a gastrointestinal disorder-reducing action, or a pharmaceutically acceptable compound thereof. Salts, intermediate compounds for producing them, and therapeutic agents for diabetic renal diseases, hypoglycemic agents, lipid-lowering agents, or gastrointestinal tract, which contain dithiocyclic compounds and have few side effects such as gastrointestinal disorders. An object of the present invention is to provide a medicament that is useful as a disorder reducing agent.

The present inventors have developed a novel compound having less side effects such as gastrointestinal disorders as described above, inhibiting the progress of renal disease, lowering blood glucose, lowering lipids, or reducing gastrointestinal disorders. As a result of intensive studies, the following novel dithiopoid compound of the present invention or a pharmaceutically acceptable salt thereof has excellent inhibitory effect on renal disease progression, lowering blood sugar, lowering lipid or reducing gastrointestinal tract disorders. This led to the completion of the present invention.

 That is, the present invention relates to the following novel dithiocyclic compound or a pharmaceutically acceptable salt, an intermediate compound for producing the compound, and a pharmaceutical composition containing the dithiocyclic compound.

 That is, the present invention provides a compound represented by the general formula ()

[Where A is

Or

And

Here, m represents an integer of 37, and RR _c is the same or different and is a hydrogen atom, an alkyl group, an aryl group, a halogen atom, a carboxyl group, a carbamoyl group, one CONH (CH ₉ ), COR. Group (where 1 is an integer of 110, R is a hydroxyl group, an alkoxy group, an amino group, or an alkylamino group), — COR group (where

R represents an amino acid residue. ) Or adjacent R _b or R „ : R _b , R which forms a heavy bond or an aromatic ring and exists at any position on the force or ring

At least one of ^ is —CO— (CH ₉ ) j C OR— group

 C a

Further, n represents an integer of 1 to 7, R _d, RJ or the same or different, 7K atom, Al kill group, § Li - show Le group. ]

And a dithiocyclic compound represented by the formula:

 Further, the present invention relates to a compound of the general formula (I)

[Where A is

Or

And

Here, m represents an integer of 3 to 7, R and R _c are the same or different and each represents a hydrogen atom, an alkyl group, an aryl group, a halogen atom, a carboxyl group, a carbamoyl group, —CONH (CH ₀ ), COR. Groups (where 1 is an integer from :! to 10; R- represents a hydroxyl group, an alkoxy group, an amino group, or an alkylamino group); — a COR group (where R represents an amino acid residue). Existing or adjacent R _{b to} each other or R. R _b and R which form a double bond or an aromatic ring with each other and are present at an arbitrary position on the ring At least one of the — COR. , — (CH ₉ ) COR. A group, and, n is an integer of 1 to 7, R _d, R _e are the same or different, a hydrogen atom, Al kill group, § Li - show Le group.

However, m is 3-position one C00H when the 3, - (CH) ₄ C00H and single (CH _{2) 4} instead C0Nh _n, m is the 3-position when the 4 - C00H a and 6-position hydrogen atoms Not a child or a CO OH]

And a dithiocyclic compound represented by the formula:

 Preferred compounds are dithiocyclic compounds represented by the general formula (I) in which m is 5 to 7 or an alkyl group in which m is 3 and 4 and —COI ^ group (where R is the aforementioned d α And the dithiocyclic compound according to the general formula (I).

 In the terms of the present invention, the term "alkyl group" means an alkyl group having 1 to 20 carbon atoms which may be branched, specifically, a methyl group, an ethyl group, a propyl group, an isopropyl group, Butyl, isobutyl, tertiary butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl. Preferred are a methyl group, an ethyl group and a propyl group.

 "Alkylamino group" means an amino group substituted with the above-mentioned alkyl group. Specific examples include methylamino, dimethylamino, ethylamino, ethylamino, propylamino, isopropylamino, butylamino, and isobutylamino. , Sec-butylamino and tert-butylamino. Preferred are a methylamino group and a dimethylamino group.

 The “alkylamino group” may be a “heterocyclic group”, and the “heterocyclic group” means one or more selected from a nitrogen atom, an oxygen atom, and a sulfur atom other than a carbon atom as a ring-constituting atom. A 5- or 6-membered aromatic heterocyclic ring containing two hetero atoms, a saturated heterocyclic ring or a condensed heterocyclic ring obtained by condensing a heterocyclic ring with a benzene ring, specifically, a pyrrolyl group, imidazolyl Group, pyrazolyl group, thiazolidyl group, isothiazolidyl group, oxazolidyl group, isooxazolidyl group, morpholino group, piperazinyl group, piperidyl group, and indole group.

 “Halogen atom” means chlorine atom, bromine atom, fluorine atom and the like.

“Alkoxy group” means an alkoxy group which may be branched, and specifically, They are toxic, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

 The “cycloalkyl group” is specifically a cyclopropyl group, a cyclobutyl group

A cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.

 “Aryl group” means, for example, a phenyl group, a naphthyl group, a biphenyl group, etc.

The expression “may be substituted” means that the substituent may be substituted with 1 to 6 substituents, and the substituents may be the same or different. Further, the position of the substituent is arbitrary and is not particularly limited. Specifically, methyl, ethyl, propyl, butyl, tert-butyl, etc., hydroxyl, methoxy, ethoxy, propoxy, butoxy and other alkoxy, fluorine, chlorine, bromine, boron Halogen atom such as nitrogen, nitro group, cyano group, formyl group, acetyl group, propylyl group, etc., formyloxy group, acetylyloxy group such as propionyloxy group, etc. mercapto group, methylthio group, ethylthio group Alkylthio such as propylthio, isopropylthio, etc., alkylamino such as amino, methylamino, ethylamino, propylamino, butylamino, etc., dialkyl such as dimethylamino, getylamino, dipropylamino, dibutylamino, etc. Amino group, methoxy Carbonyl group, an ethoxycarbonyl group, flop port Po alkoxycarbonyl group is the amino-de group, a cyclopentyl group, a cycloalkyl group such as cyclohexyl group, phenyl group, Ashiruami de group such Puropioniruami de group

The “optionally substituted cycloalkyl group” means a cycloalkyl group optionally substituted with the same substituent.

 More specifically, the “optionally substituted aryl group” is the aforementioned pyrrolyl group which may be substituted with a halogen atom, a hydroxyl group, an alkyl group, an alkoxy group, or the like.

More specifically, the “optionally substituted heterocyclic group” refers to the aforementioned pyrrolyl group which may be substituted with a halogen atom, a hydroxyl group, an alkyl group, an alkoxy group, etc. It is.

 An “amino acid residue” is a residue derived from a natural or synthetic amino acid.

 Specifically, natural amino acid residues include glycine, alanine, phosphorus, oral isin, isoleucine, serine, threonine, cystine, cystine, methionine, proline, aspartic acid, glutamic acid, lysine, and ornithine. Examples include tin, arginine, tyrosine, fenylalanine, and tributofan. This amino acid residue may be L-, D- or racemic.

 "Pharmaceutically acceptable salt" means a salt which forms a salt with the dithiocyclic compound represented by the general formula (I) of the present invention. Salts, alkaline earth metal salts such as magnesium salts and calcium salts, ammonium salts, trimethylamine salts, triethylamine salts, pyridine salts, picoline salts, dicyclohexylamine salts, N, N'-dibenzylethylenediamine And organic bases such as lysine salts, and amino acid salts such as lysine salts and arginine salts.

 As the novel dithiocyclic compound represented by the general formula (I) of the present invention, the following compounds can be exemplified.

 (1) Dithiocyclic compound (5- or 6-membered ring)

 4-methyl-1,2-dithiolan-1-4-carboxylic acid,

 4-methyl-1,2-dithiolane 4-methyl ribonate,

 4-Methyl-1,2—dithiolane 4-ethyl ether ester

 4-Methyl-1, 2-Dithiolane 4-propyl ribonate,

 4-Methyl-1-, 2-dithiolan-1-amide

 4-Methyl-1,2-dithiolane-14 rubonic acid (N-methyl) amide, 4-methyl-1,2, -dithiolane-14 rubonic acid (N-carboxymethyl) amide,

 Thioic acid (N-ethoxycarbonylmethyl) amide,

 6-Propyl-1,2-dithiane-3-carboxylic acid, etc.

 (2) Dicho cyclic compound (7-membered ring)

 1, 2-dichepan 1-rubonic acid,

1, 2-dichepan-1- 3-carboxylic acid methyl ester, 1,2-dichepan-1-ethyl carboxylate,

 1,2-dichepan-1-propyl ribonate,

 1, 2-dichepan 1-sulfonic acid amide,

 1,2-dichepan-1-carboxylic acid (N-methyl) amide,

 1,2-dicepan-13-carboxylic acid (N-ethoxycarbonylmethyl) amide ",

 4,5-dihydro-1H-2,3-benzodichepine-14-carboxylic acid, 4,5-dihydro-1H-2,3-benzodichepine-14-methylcarboxylate,

 7-ethyl-1,2-dichepan-1-3-carboxylic acid,

 7-ethyl-1,2-dichepan-3-methyl carbonate

 7-ethyl-1,2-dichepan-3-ethyl carboxylate,

 7-ethyl, 1,2-dicepan-3, propyl ribonate,

 7-ethyl-1,2-dichepan-3-carboxylic acid amide,

 7-ethyl-1,2-dichepan-1-carboxylic acid (N-methyl) amide, 7-ethyl-1,2-dicepan-13-carboxylic acid (N-ethoxycarbonylmethyl) amide,

 5-phenyl-1,2-dichepan-3-carboxylic acid, etc.

 (3) Dithio cyclic compound (8-membered ring)

 1,2—dithiocan-3—capillonic acid,

 1,2-dithiocan-1-3-methyl ribonate,

 1,2-dithiocan-3-ethyl carboxylate,

 1,2-dithiocan-3-carboxylic acid propyl ester,

 1,2-dithiocan-3-carboxylic acid amide,

 1,2-dithiocan-3-carboxylic acid (N-methyl) amide,

 1,2-dithiocan-1-carboxylic acid (N-ethoxycarbonylmethyl) amide, etc.

 (4) Dithio cyclic compound (9-membered ring)

1,2-dithionan-1-carboxylic acid, 1,2-dithionan-1-carboxylic acid methyl ester,

 1,2-dithionane-1-ethyl ribonate

 1,2-dithionan-3-propyl carboxylate,

 1,2-dithionan-3-carboxylic acid amide,

 1,2-dithionan-3-carboxylic acid (N-methyl) amide,

 1, 2-dithionan-3-carboxylic acid (N-ethoxycarbonylmethyl) amide, etc.

 (5) Tetrathiacyclic compound (8-20 membered ring)

 2,3,6,7-tetrathia-1,5-cyclooctanedicarboxylic acid,

 2,3,7,8-tetrathia-1,6-cyclodecanedicarboxylic acid,

 2, 3, 8, 9-tetrathia-1,7-cyclododecanedicarboxylic acid,

 2,3,9,10-tetrathia-1,8-cyclotetradecanedicarboxylic acid, 2,3,10,11-tetrathia-1,9-cyclohexadecanedicarboxylic acid, 2,3,11,12 —Tetrathia-1,10-cyclooctadecanedicarboxylic acid, 2,3,12,13-tetrathia-11,11-cycloeicosanedicarboxylic acid, etc. and their pharmacologically acceptable salts.

Embodiment of the Invention

 The compound of the present invention can be produced by the following methods, but the method of producing the compound of the present invention is not limited thereto.

 For the purpose of explanation, the method of producing 7-ethyl-1,2-diceban-3-butyric acid in the compound of the general formula (I) of the present invention will be specifically described with reference to the following reaction formula 1. .

 7-ethyl-1,2-dichepan-3-carboxylic acid is

 (Step 1) A step of reacting 6-bromooctanoic acid (A) with a thionyl halide such as thionyl chloride to obtain an active derivative (B) of a carboxylic acid by an acyl halide reaction.

(Step 2) the reaction product (B) and N- Puromosukushiimi halogenating agent such as de (in this example brominating agent) reacted presence of hydrobromic acid as a catalyst if required, halogen _α ones To obtain compound (C) by chlorination (chlorine or bromine) (Step 3) a step of subjecting the reaction product (C) to an esterification reaction with an alcohol such as methanol or ethanol to obtain a compound (D),

 (Step 4) a step of reacting the reaction product (D) with potassium thioacetate to obtain a diacetylthio compound (E);

 (Step 5) a step of subjecting the reaction product (E) to a hydrolysis reaction in a base, for example, an aqueous alkali solution such as sodium hydroxide to obtain a compound (F)

(Step 6) The reaction product (F) is represented by the formula (G) by a cyclization reaction step in which the reaction product (F) is oxidized in the presence of, for example, a catalytic amount of ferric chloride or at least an equimolar amount of iodine. Compounds can be prepared.

(Reaction formula 1)

Ridification reaction

The compound obtained in each of the above steps can be isolated and purified by a conventional method, for example, by silica gel column chromatography (methanol / chloroform), extraction or partitioning operation. Since each step proceeds with high purity and high yield, the above 1 to 5 steps or 1 to 6 steps can be performed in one pot without isolating the reaction product.

 Next, in the compound of the general formula (I), the benzodichepine derivative is a compound having a benzene skeleton as a starting material, for example, a dithiol compound is synthesized using o-phthalpenzaldehyde, and the same treatment is carried out as in the above reaction. Can be obtained. The reaction process will be described below with reference to the following reaction formula 2.

 (Step 1) o Phthalaldehyde and ethoxycarbonylmethyltriphenylphosphorane are reacted in an inert solvent such as benzene by the Wittig reaction under ice-cooling to obtain ethyl 3- (2-formylphenyl) 2-propenoate. Was.

 (Step 2) This compound was reacted with methanol in the presence of an acid such as concentrated sulfuric acid to protect the formyl group with acetal to obtain ethyl 3- (2,2 dimethylmethylphenyl) 2-propenoate.

 (Step 3) This compound is reduced with sodium hydrogenborohydride in methanol in the presence of a catalyst such as nickel chloride and the like, to give 3- (2,2-dimethylmethoxyphenyl) propionic acid The ethyl ester was obtained.

 (Step 4) This compound was subjected to a deprotection reaction in THF in the presence of an acid such as 2 N hydrochloric acid to give ethyl 3- (2-formylphenyl) propionate.

 (Step 5) This compound was reduced using sodium borohydride in an alcohol such as ethanol to obtain 3- (2-hydroxymethylphenyl) propionate ethyl ester.

 (Step 6) This compound was hydrolyzed by adding 4NNaOH in methanol to obtain 3- (2-hydroxymethylphenyl) propionic acid.

 (Step 7) This compound is reacted with thionyl chloride, and then reacted with NBS and hydrobromic acid in tetrachloride carbon under heating to give 3- (2-chloromethylphenyl) -2-bromopropione The acid was obtained.

(Step 8) The reaction product of this compound is reacted with potassium thioacetate in a solvent such as DMF to give 3- (2-acetylthiomethylphenyl) 2-acetylthiopropionate. Acid methyl ester was obtained.

 (Step 9) This compound was heated to reflux in a stream of nitrogen in 2 NNaOH and subjected to a hydrolysis reaction to obtain 3- (2-mercaptomethylphenyl) 2 mercaptopropionic acid.

 (Step 10) By subjecting this compound to a cyclization reaction in the same manner as described above, the desired 4,5-dihydro-1H-2,3-benzodichepine-14-carboxylic acid is obtained.

 By using a phthalaldehyde derivative having a substituent on a ring as a starting compound in place of o-phthalaldehyde as a starting material in the above reaction, it is possible to obtain various derivatives represented by the general formula (I) of the present invention. it can.

The above reaction can be performed without isolating and purifying the reaction product of each step.

J overflow 26: I

(1) (2)

 (4) (5)

CH (〇C

(6)

Hydrolysis

MeOH

In the compound of the general formula (I), the tetrathiacycloalkanedicarboxylic acid derivative can be obtained by the cyclization reaction. The yield of these compounds can be increased by controlling the reaction conditions as needed.

 In the above general formula (I) of the present invention, the ester derivative is obtained by converting the carboxyl group of the compound into an active derivative of a carboxylic acid by an ordinary method, for example, using an activator such as thionyl halide; And esterification in the presence of an acid such as trimethylsilyl chloride.

 The alcohols are alcohols having a linear or branched alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl group, heptyl, etc. It may have a substituent.

 The amide derivative is an active derivative of the above carboxylic acid and an amine compound, for example, ammoniums, alkylamines such as methylamine, dimethylamine, and getyreamine, pyrroline, imidazoline, imidazole, virazoline, thiazoline, isothiazolidine, oxazoline, and morpholine. It can be obtained by subjecting a heterocyclic amine compound such as piperazine, piperidine and indole to an amidation reaction according to a conventional method.

 Specific examples of the amino acids used in the amidation reaction include glycine, alanine, quinoline, leucine, isoleucine, serine, threonine, cystine, cystine, methionine, proline, aspartic acid, glutamic acid, lysine, and lysine. Examples include ordinine, arginine, tyrosine, phenylalanine, and tryptophan.

 When these amino acids have reactive substituents, the functional groups such as carboxylic acid, hydroxyl group, and thiol of these amino acids are protected with a protecting group used in a conventional manner in peptide synthesis. It is preferable to use it (Basics and experiments of peptide synthesis, Nobuo Izumiya et al., 1985).

 The compounds that can be used in the therapeutic agent for diabetic renal disease, hypoglycemic agent, lipid-lowering agent, and gastrointestinal disorder reducing agent of the present invention include the novel compounds of the present invention and known compounds.

14-Corrected form (Rule 91) You. These known compounds include, for example, 1,2-dithiane-3,6-biscarboxylic acid prepared by the method of 1. N. Harpp et al. [J. Org. Chem., 46, 2072 (1981);], 1, 2 —Dithiolane-3-carboxylic acid was synthesized according to the method of G. Claeson [Ark. Kemi, Vol. 30, (26) 277 (1969)] using 5-bromopentanoic acid as a starting compound. Specific examples of known compounds used for the pharmaceutical application of the present invention include dithiane compounds such as 1,2-dithian-13-carboxylic acid and 1,2-dithian-13,6-dicarboxylic acid, and 1,2— Dithiolan-1-carboxylic acid, carboxylic acid, carboxylic acid amide, and the like.

 General formula (Π) which is a starting compound of the compound represented by general formula (I) of the present invention

 H S-A-S H

 (Where A is as defined above)

Are also novel compounds. These compounds are prepared by subjecting cycloalkanones such as cyclohexanone, cycloheptanone, and cyclooctanone to acidification according to a conventional method, for example, by the Bayavillaga reaction, and converting the resulting lactone compound to hydrogen halide, for example, hydrogen bromide. A ring opening reaction is carried out in the presence to synthesize a fatty acid in which the ω-position is halogenated, and then this compound is treated with 7-ethyl-1,2-dicepan-13-carboxylic acid in the same manner as in the above-mentioned production method using rubonic acid. Compounds can be induced.

 In particular,

 2, 6—dimercaptohexanoic acid,

 2,7-dimercaptoheptanoic acid,

 2, 6—dimercaptooctanoic acid,

 2,8—dimercaptooctanoic acid,

 3- (2-mercaptomethylphenyl) -1-2-mercaptopropionic acid, 2,2-dimercaptomethylpropionic acid,

 2, 6-dimercapto-3-methylhexanoic acid,

 2, 6-dimercapto-5-methylhexanoic acid,

 2,6-dimercapto-14-phenylhexanoic acid,

Derivatives and pharmaceutically acceptable salts. The pharmacologically acceptable salts of the cyclic dithio derivative of the present invention can be prepared by a conventional method.

 The compound represented by the general formula (I) of the present invention includes stereoisomers. If necessary, these stereoisomers can be isolated and purified by a conventional method, for example, by optical resolution.

 The compound used in the present invention can be synthesized by a method known in the literature or according to it. The methods for synthesizing the compounds represented by formulas (I) to (VI) of the present invention are described in detail in the following Examples and Reference Examples.

Example

 (Example 1)

 4-Methyl-1,2-dithiolane-4

 20 g of 2,2-dihydroxymethylpropionic acid and 24.4 g of cesium carbonate were dissolved in 300 ml of methanol, and the solvent was distilled off. After azeotroping with ethanol and dioxane, the residue was dissolved in 100 ml of DMF-20 ml of ethanol, 25 g of benzyl chloride was added, and the mixture was stirred at 50 ° overnight. 300 ml of water and 200 ml of hexane were added to the reaction solution, the layers were separated, and the aqueous layer was extracted with 500 ml of ethyl acetate. After the ethyl acetate layer was dried over sodium sulfate, the solvent was distilled off to obtain 27 g of a benzyl ester (81% yield).

27 g of this benzyl ester, 75.8 g of triphenylphosphine and 45 g of imidazole were dissolved in 400 ml of dioxane. To this solution, 74.5 g of iodine was added in portions while stirring under ice-cooling. After further stirring at 70 ° for 30 minutes, the solvent of the reaction solution was distilled off, water was added, and the mixture was extracted with ether. 100 ml of ether and 800 ml of hexane were added to the residue obtained by evaporating the solvent, and the mixture was ice-cooled. After the deposited precipitate was removed by filtration, the solvent of the filtrate was distilled off to obtain 50 g of an iodide compound (yield: 93%). A 50 g solution of DMF in 50 ml of DMF was added dropwise. After the reaction solution was stirred at room temperature overnight, water was added and extracted with benzene. After distilling off benzene, the residue was subjected to silica gel column chromatography and eluted with chloroform. The solvent of the corresponding fraction was distilled off to obtain 38 g of a dithioacetyl compound (quantitative yield). 44 g of the above dithioacetyl compound was added to 200 ml of a 2N aqueous sodium hydroxide solution, and the mixture was stirred under ice cooling. After 20 minutes, the temperature was returned to room temperature, and the mixture was further stirred for 2 hours. The reaction mixture was adjusted to pH 4 by adding 33 ml of concentrated hydrochloric acid, water was distilled off, water was added to the residue, and water was added to the residue.The mixture was extracted with ethyl acetate.o The ethyl acetate layer was successively added with sodium hydrogen carbonate, dilute hydrochloric acid, and sodium salt solution. After washing with, the solvent was distilled off to obtain 27 g of a dithiol compound (yield 81%).

 27 g of the above dithiol compound was dissolved in 100 ml of methanol and 200 ml of THF, 40 ml of a 2 g aqueous solution of sodium hydrogen carbonate and 50 mg of ferric chloride were added, and the mixture was stirred at room temperature. Two hours later, 4 ml of 6 N hydrochloric acid was added, insolubles were removed by filtration, and the solvent of the filtrate was distilled off. The residue was extracted with ethyl acetate, washed with aqueous sodium hydrogen carbonate solution and dilute hydrochloric acid, and then the organic layer was dried over sodium sulfate. The solvent was distilled off to obtain 25 g of a disulfide compound (yield: 93%).

 25 g of the above disulfide compound was dissolved in 100 ml of methanol and 200 ml of THF, and 100 ml of a 2N aqueous sodium hydroxide solution was added. After stirring at 70 ° for 1 hour, hydrochloric acid was added, and after neutralization, the solvent was distilled off. The residue was adjusted to pH 10 by adding an aqueous sodium hydroxide solution, and washed with ether. The aqueous layer was adjusted to pH 1 by adding diluted hydrochloric acid, and then extracted with ethyl acetate. After evaporating the solvent, the residue was recrystallized from ether-hexane to obtain 12.0 g of the desired product as yellow needles (yield 75%).

 H-NMR (90 MHz, 5 ppm, CDClg): 1.53 (s, 3H), 2.95 (d, J = 11.7 Hz, 2H), 3.69 (d, J = l 1.7 Hz, 2H), 10.15 (brs, 1H)

C-NMR (22.49MHz, 5ppm, CDClg): 24.06, 47.79, 57.43, ( as _{C 5 H 8 0 2 S 2} ) 180.32 elemental analysis

 Theoretical value (%) 36.57 (C), 4.91 (H)

 Actual value (%) 36.74 (C), 5.10 (H)

 (Example 2)

 Method for producing 4-methyl-1,2-dithiolane-4-carboxamide:

To 17.7 g of 4-methyl-1,2-dithiolane-14-carboxylic acid was added 13.4 g of thionyl chloride, 2 drops of DMF and 20 mL of ether, and the mixture was stirred at room temperature for 4 hours. After evaporating the solvent of the reaction solution, it was dissolved in dioxane 2 Oml. This solution was added dropwise to 127 ml of aqueous ammonia at 0 °. After stirring for 10 minutes, the solvent was distilled off, and ethyl acetate was removed. Extracted. After the ethyl acetate layer was dried over sodium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography. After elution with 1% methanol / chloroform, the solvent of the corresponding fraction was distilled off to obtain 9.7 g of the desired product as yellow needles (yield 54%).

 H-NMR (90 MHz, 5 ppm, CDCl ^): 1.46 (s, 3H), 3.00 (d, J = 12.0 Hz, 2H), 3.53 (d, J = 12.0 Hz, 2H), 5.3-6.4 (brs, 2H) )

C one NMR (22.49MHz, 5ppm, CDClg) : 23.89, 50.12, 56.57, ( as C ₅ H ₉ NOS ₂₎ 177.17 elemental analysis

 Theoretical value (%) 36.79 (C), 5.56 (H)

 Actual value (%) 36. 96 (C), 5.70 (H)

 (Example 3)

 Production method of 4-methyl-1,2-dithiolane-4 monorububonate (N-carboxymethyl) amide:

 To 4.0 g of 4-methyl-1,2-dithiolane-1.4 rubonic acid was added 4.35 g of salt dithiol, 2 drops of DMF and 20 ml of ether, and the mixture was stirred at room temperature for 4 hours. After the solvent of the reaction solution was distilled off, the residue was dissolved in 15 ml of THF. The solution was added dropwise at 0 ° to a mixture of 2.75 g of glycine and 3.66 g of sodium hydroxide in 35 ml of an aqueous solution and ether. After stirring for 2 hours as it was, ether was added and partitioned. The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was dried over sodium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography. After elution with 2% methanol-form, the corresponding fraction was evaporated to give 4.9 g of the desired product as yellow needles (yield 91%).

_{H-NMR (90MHz, 8 m} CDC1): 1.45 (s, 3H), 2.99 (d, J = ll.6Hz, 2 H), 3.59 (d, J = 11.6Hz, 2H), 3.91 (s, 2H)

 C-NMR (22.49 MHz, (5 pm, CDClg): 24.60, 42.26, 49.58, 58.41, 172.89, 177.44

Elemental analysis (as C ₇ H _u NO.S _2):

 Theoretical value (%) 38. 00 (C), 5.0 1 (H)

Actual value (%) 38.10 (C), 5.22 (H) (Example 4)

 1,2-Dichepan-1-3-Rubonic acid production method:

 20.0 g of 6-bromohexanoic acid, 28 ml of thionyl chloride and 3 drops of DMF were stirred at room temperature overnight. To the reaction mixture were added 50 ml of carbon tetrachloride, 21 g of N-promosuccimide and 7 drops of concentrated hydrobromic acid, and the mixture was refluxed for 2 hours. The solvent of the reaction solution was distilled off, dissolved in 30 ml of dioxane, and poured into 300 ml of methanol under ice-cooling. After the solvent was distilled off, the residue was partitioned between ethyl acetate and an aqueous sodium hydrogen carbonate solution, and then the solvent in the organic layer was distilled off. The residue was dissolved in 50 ml of DMF, 25 g of potassium thioacetate was added, and the mixture was stirred at room temperature overnight. After evaporating the solvent of the reaction solution, water was added, and the mixture was extracted with benzene. After the benzene layer was dried over sodium sulfate, the solvent was distilled off. The residue was dissolved in methanol (50 ml), 4 N sodium hydroxide (200 ml) was added, and the mixture was heated to reflux under a nitrogen atmosphere. After 4 hours, methanol was distilled off, the mixture was acidified with aqueous sulfuric acid, and extracted with ethyl acetate. After the organic layer was dried over sodium sulfate, the solvent was distilled off. The residue and sodium hydrogencarbonate (30 g) were dissolved in water (200 ml), a catalytic amount of ferric chloride was added, and the mixture was stirred at room temperature. After 4 hours, the precipitate was filtered off, the filtrate was acidified with potassium hydrogen sulfate, and extracted with ethyl acetate. After the ethyl acetate layer was dried over sodium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography. After elution with 2% methanol / chloroform, the solvent of the corresponding fraction was distilled off to obtain 4.60 g of the desired product as yellow needles (yield 26%).

 H-NMR (90 MHz, 5 pm, CD 0D): 1.5-2.4 (m, 6H), 2.5—3.1 (m, 2Η), 3.49 (dd, J = 5.5 Hz, 8.7 Hz, 1H)

Elemental analysis (as _{C 6 H 10 O 2 S 2} ):

 Theoretical value (%) 40.42 (C), 5.65 (H)

 Actual value (%) 40.38 (C), 5.72 (H)

 (Example 5)

 Preparation of 1,2-dichepan-3-ethyl carboxylate:

18 Omg of 1,2-dicepan-13-carboxylic acid was reacted with thionyl chloride in the same manner as in Example 3. After the reaction, the solvent of the reaction solution was distilled off under reduced pressure, and ethanol was added to the obtained residue to cause a reaction. Column chromatography in the same manner as above —Treatment gave 21 Omg of the desired compound (yield, quantitative).

 H-NMR (90 MHz, 5 ppm, CDClg): 1.27 (t, J = 7.1 Hz, 3H), 1.50-2.50 (m, 6H), 2.55-3.1 (m, 2H), 3.50 (dd, J = 8.7, J = 6.2Hz, 1H), 4.18 (t, J = 7. LHz, 2H)

 C-NMR (22.49MHz, 5ppm, CDClg): 14.14, 24.98, 30.56, 31.70, 40.6 4, 52.07, 61.17, 172.02

Elemental analysis (as C ₈ H _{140 2} S):

 Theoretical value (%) 46. 57 (C), 6.84 (H)

 Actual value (%) 46. 38 (C), 6.90 (H)

 (Example 6)

 Preparation of 1,2-dicepan-3-carboxylic acid (N-ethoxycarbonylmethyl) imide:

 18 Omg of 1,2-dicepan-3-butyric acid was reacted with thionyl chloride in the same manner as in Example 4. After the reaction, the solvent of the reaction solution was distilled off under reduced pressure, and the obtained residue was reacted with glycineethyl ester. Thereafter, column chromatography was performed in the same manner as described above to obtain 263 mg of the desired compound (yield, quantitative).

 H-NMR (90 MHz, 5 pm, CDClg): 1.29 (t, 1 = 1.1 Hz, 3H), 1.5 to 2.5 (m, 6H), 2.55 to 3.1 Cm, 2H), 3.53 (dd, J = 9.8Hz, 5.6Hz, 1H), 4.04 (d, J = 5.1Hz, 2H), 4.22 (t, J = 7.1Hz, 2H), 6.75-7.05 (m, 1H)

 C-NMR (22.49 MHz, 5 ppm, CDClg): 14.20, 25.36, 31.64, 31.97, 40.5 3, 41.67, 54.24, 61.55, 169.70, 171.75

Elemental analysis (C _{1 ()} as H ₁₇ N0 ₃ S _2):

 Theoretical value (%) 45.6 1 (C), 6.51 (H)

 Actual value (%) 45.3 1 (C), 6.60 (H)

 (Example 7)

 Preparation of 7-ethyl-1,2-dichepan-3-carboxylic acid:

 The reaction was carried out in the same manner as in Reference Example 1 using 21.0 g of 6-bromooctanoic acid to obtain 5.2 g of 2,6-dimercaptooctanoic acid.

H-NMR (90 MHz, <5 ppm, CDClg): 0.99 (t, J = 7.2 Hz), 1.20 to 2.1 (m, 8H ), 1.34 (d, J = 6.8 Hz, 1H), 2.13 (d, J = 9.0 Hz, 1H), 2.5-2.9 (m, 1H), 3.2-3.5 (m, 1H), 9.74 (brs, 1H)

 1.0 g of 2, 6-dimercaptooctanoic acid and triethylamine 2. Oml of mouth solution 10 Oml of iodine 1.2 g of chloroform solution 15 Oml was slowly added dropwise to 10 Oml under ice-cooling. did. After stirring at the same temperature for 1 hour, the reaction solution was washed with aqueous citric acid, and the organic layer was dried over sodium sulfate. The residue obtained by evaporating the solvent was subjected to silica gel column chromatography (2% ethanol / chloroform) to obtain 0.72 g of the desired compound (72.8%).

 As a result of instrumental analysis, the target compound was a mixture of two stereoisomers.

H-NMR (90 MHz, 5 ppm, CDCl _g ): 0.96 (t, J = 6.8 Hz, 3H), 1.00 (t, J = 6.6, 3H), 1.3-2.50 (m, 16H), 2.6-3.0 (m, 2H), 3.50 (t, J = 7.2Hz, 1H), 3.57 (t, J = 7.0Hz, 1H), 9.95 (brs, 2H)

 C-NMR (22.4 Hz, 5 ppm, CDClg) 11.92, 12.03, 22.43, 24.00, 27.47, 28.55, 30.40, 30.50, 35.87, 37.93, 50.71, 52.23, 52.39, 57.59, 177.87, 178.30

 (Example 8)

 Method for producing 4,5-dihydro-1H-2,3-benzodichepin-14-carboxylic acid:

 A benzene solution of 31.4 g of ethoxycarbonylmethyltriphenylphosphorane (5 Oml) was added dropwise to a benzene solution (10 Oml) of 11 g of o-phthalaldehyde over 30 minutes under ice-cooling. After the dropwise addition, the temperature of the reaction solution was returned to room temperature and stirred. One hour later, the reaction solution was concentrated to dryness, and 50 Oml of petroleum ether was added to the residue, followed by stirring for 30 minutes. The precipitate was removed by filtration, and the precipitate was washed with petroleum ether. The filtrate and the washing were combined and concentrated to dryness. 10 g of 3- (2-formylphenyl) -2-ethyl propenoate was obtained as a yellow liquid (93% yield).

 H-NMR (90 MHz, 5 ppm, CDCl): 1.21 (3H, t), 4.21 (2H, q), 6.46 (1H, d, J = 16 Hz), 8.2-7.3 (4H, m), 8.51 (1H, d , J = 16Hz), 10.3 (1H, s

)

This 3- (2-formylphenyl) -1-2-propenoic acid ester 9.78 g was dissolved in 300 ml of methanol, and 3 ml of concentrated sulfuric acid was added. After stirring at room temperature for 3 hours, the reaction solution was concentrated to about half and poured into saturated aqueous sodium hydrogen carbonate for neutralization. After extraction with ethyl acetate and drying over sodium sulfate, the solvent was distilled off. Residues and NiC ₁₂ · 6H. 1.2 g of 0 was dissolved in 200 ml of methanol, and 3.8 g of sodium borohydride was added little by little while stirring under ice cooling. After the addition, the temperature was returned to room temperature, and the mixture was further stirred for 30 minutes. After the precipitate was removed by filtration, the filtrate was concentrated to dryness, and the residue was separated with dilute hydrochloric acid and chloroform. After drying the chloroform layer with sodium sulfate

The solvent was distilled off.

 The obtained residue was dissolved in 100 ml of THF, 200 ml of 2N-HC1 was added, and the mixture was stirred at room temperature for 2 hours. After the reaction solution was extracted with ethyl acetate and dried over sodium sulfate, the solvent was distilled off. The obtained residue was dissolved in 100 ml of ethanol, 0.60 g of sodium borohydride was added, and the mixture was stirred at room temperature for 1 hour. After the reaction solution was concentrated to dryness, the residue was partitioned between dilute hydrochloric acid and chloroform. The dried form layer was dried over sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and eluted with black hole form. The corresponding fraction was concentrated to dryness to give 8.13 g of 3- (2-hydroxymethylphenyl) propionic acid ethyl ester as a colorless syrup (yield: 81.5%).

 H-NMR (90 MHz, <5 ppm, CDCl ^): 1.21 (3H, t), 2.8-2.5 (2H, m), 3.2-2.9 (2H, m), 4.12 (2H, q), 4.69 (2H , s), 7.5-7.1 (4H, m)

 8.13 g of the above 3- (2-hydroxymethylphenyl) propionic acid ester was dissolved in 50 ml of methanol, 25 ml of 4N Na0H was added, and the mixture was heated to reflux. One hour later, the reaction solution was concentrated, and partitioned with diluted hydrochloric acid and ethyl acetate. After the ethyl acetate layer was dried over sodium sulfate, the solvent was distilled off to obtain 5.51 g of 3- (2-hydroxymethylphenyl) propionic acid as a white solid (yield: 78.5%).

 H-NMR (90MHz, 5ppm, CD.OD): 2.8-2.5 (2H, m), 3.2-2.8 (2H, m), 4.68 (2H, s), 7.5-7.1 (4H, m)

Three drops of DMF were added to 5.51 g of the 3- (2-hydroxymethylphenyl) propionic acid and 20 ml of thionyl chloride, and the mixture was heated and stirred at 60 ° C. One hour later, 40 ml of carbon tetrachloride, 6.5 g of NBS and 7 drops of concentrated hydrobromic acid were added, and the mixture was heated and stirred at 80 ° C. After 3 hours, the reaction solution was concentrated to dryness, and 10 Oml of methanol was added to the residue under ice-cooling. The mixture was returned to room temperature and further stirred at room temperature for 1 hour. The reaction solution was concentrated to dryness, and separated with ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate. After the ethyl acetate layer was dried over sodium sulfate, the solvent was distilled off. This residue was dissolved in 50 ml of DMF, 9.2 g of potassium thioacetate was added, and the mixture was stirred at room temperature under a nitrogen stream. After 3 hours, the reaction solution was concentrated and partitioned between ethyl acetate and a saturated saline solution. After the ethyl acetate layer was dried over sodium sulfate, the solvent was distilled off. The residue was subjected to silica gel column chromatography, and eluted with chloroform. The corresponding fractions were concentrated to dryness to give 5.54 g of 3- (2-acetylthiomethylphenyl) -12-acetylthiopropionic acid methyl ester as a light brown syrup (yield 55%).

 H-NMR (90MHz, 5pm, CDClg): 2.34 (3H, s), 2.36 (3H, s), 3.11 (1H, dd, J = 8Hz, 16Hz), 3.31 (1H, dd, J = 9Hz, 16Hz) ), 3.68 (3H, s), 4.26 (2H, s), 4.48 (1H, dd, J = 8Hz, 9Hz), 7.4—7.1 (4H, m)

 5.54 g of this 3- (2-acetylthiomethylphenyl) -12-acetylthiopropionic acid methyl ester was dissolved in 50 ml of methanol, 50 ml of 2N NaOH was added, and the mixture was heated to reflux under a nitrogen stream. After 3 hours, methanol was distilled off, acidified with dilute hydrochloric acid, and extracted with ethyl acetate. After the ethyl acetate layer was dried over sodium sulfate, the solvent was distilled off. This residue was dissolved in 50 ml of black-mouthed form, 10 ml of triethylamine was added, and a solution of 4.3 g of iodine dissolved in 300 ml of black-mouthed form was added dropwise with stirring under ice-cooling. An aqueous solution of citrate was added to the reaction solution, and the mixture was separated. After drying the pore layer with sodium sulfate, the solvent was distilled off. The residue was subjected to silica gel column chromatography, and eluted with 1% methanol-chloroform. The corresponding fraction was concentrated to dryness to obtain 2.1 g of 4,5-dihydro-1H-2,3-dicepin-13-carboxylic acid as a white solid (yield 64%).

 H-NMR (90MHz, 5pm, CDClg): 3.6-3.0 (3H, m), 4.01 (1H, d, J = l 2Hz), 4.31 (1H, d, J = 12Hz), 7.4-7.1 (4H, m), 7.9 (1H, brs)

 C-NMR (22.49 MHz, (5 ppm, CD 0D): 35.98, 40.53, 49.63, 128.52, 128.95, 130.63, 131.12, 135.61, 138.65, 174.02

Elemental analysis (as _{C 10 H 10 O 2 S 2} ): Theoretical value (%) 53. 07 (C), 4.45 (H)

 Actual value (%) 52.8 1 (C), 4.60 (H)

 (Example 9)

 Preparation of 4,5-dihydro-1H-2,3-benzodichepine-14-methylester

 0.5 g of 4,5-dihydro 1H-2,3-benzodichepine-14-carboxylic acid was dissolved in 50 ml of methanol, 10 ml of trimethylsilyl chloride (TMS C 1) was added, and the mixture was heated to reflux. After 3 hours, the reaction solution was concentrated to dryness, and separated with ethyl acetate and saturated aqueous sodium hydrogen carbonate. After the ethyl acetate layer was dried over sodium sulfate, the solvent was distilled off to obtain 5 g of 4,5-dihydro2,3-1-1H-benzodichepine-14-methyl ribonate as a colorless syrup (5 g). Yield 94%).

 H-NMR (90MHz, 5pm, CDClg): 3.6-3.0 (3H, m), 3.75 (3H, s), 3.96 (1H, d, J = 12Hz), 4.31 (1H, d, J = 12Hz) ), 7.4— 7.0 (4Η, · m)

 C-NMR (22.49MHz, 5ppm, CDClg): 34.84, 39.77, 47.95, 52.45, 127.92, 128.30, 129.76, 130.47, 134.10, 137.13, 171.04

Elemental analysis (as _{C u H 12 0 2 S.)} :

 Theoretical value (%) 54. 97 (C), 5.03 (H)

 Actual value (%) 54.81 (C), 5.60 (H)

 (Example 10)

 Method for producing 5-phenyl-1,2-dichepan-3 carboxylic acid:

 10 Omg of 2,6-dimercapto-4-phenylhexanoic acid was subjected to a cyclization reaction in the same manner as in Example 7 to obtain 4 lmg of the desired compound (yield 41%).

Elemental analysis (as _{C 12 H 1 / f O.S 2} ):

 Theoretical value (%) 56.66 (C), 5.55 (H)

 Actual value (%) 56.50 (C), 5.60 (H)

 (Example 11)

 Method for producing 1,2-dithiocan-3-carboxylic acid:

 Cyclization reaction of 5.0 g of 2,7-dimercaptoheptanoic acid in the same manner as in Example 7

.twenty four-

The corrected form (Rule 91, As a result, 2.88 g of the desired compound was obtained (yield: 57.6%).

 H-NMR (90 MHz, <5 ppm, CDClg): 1.45 to 2.55 (m, 8H), 2.55 to 2.90 (m, 2H), 3.35 (dd, J = 3.4 Hz, J = 10.3 Hz, 1H), 10.60 (brs, 1H)

 C Marauder R (22.49MHz, δ ppm, CDC1): 24.22, 24.44, 25.09, 28.07, 38.63, 49.85, 178.52

 (Example 1 2)

 1,2-dithionan-3-carboxylic acid:

 Starting from 3.4 g of 2,8-dimercaptooctanoic acid as a starting compound and treating in the same manner as in Example 4, 0.50 g of the target compound was obtained as colorless needles (yield 14. 8%).

 H-NMR (90 MHz, 5 ppm, CDC1): 1.2-2.45 (m, 10H), 2.5-3.05 (m, 2H), 3.15-3.55 (m, 1H), 8.45-9.15 (ra, 1H)

 MS mZz 20 6 (M +)

 (Example 13)

 Preparation of 2,3,1 1,1 2—tetrathia-1,10-cyclooctadecanedicarboxylic acid:

 From the reaction product of Example 12 was obtained 0.85 g of the target compound by column chromatography (yield: 12.6%).

 H-NMR (90MHz, δρρπι, CDgOD): 1.2- 2.05 On, 20H), 2.77 (t, J = 7.0 Hz, 4H), 3.41 (t, J = 7.3Hz, 2H)

C-NMR (22.49 MHz, 5 ppm, CD _o 0D): 27.52, 28.88, 29.158, 29.85, 32, 0 8, 40.26, 40.36, 54.89, 55.10, 175.22

 MS m / z; 4 1 2 (M +)

 (Examples 14 to 16)

 The reaction product of the corresponding example was isolated and purified by column chromatography.

 (Example 14)

 2, 6-dimercaptohexanoic acid,

(Example 15) 2,7-dimercaptoheptanoic acid,

H-NMR (90 MHz, Sppm, CDCl ₃ ): 1.35 (t, 1H), 1.30 to 2.20 (m, 8H), 2.12 (d, J = 9 Hz, 1H), 2.35 to 2.70 (m, 2H), 3.35 (dt, J = 9.0Hz, 7.2Hz, 1H), 9.70 (brs, 1H)

C-NMR (22.49 MHz, δ ppm, CDClg): 24.38, 26.66, 27.69, 33.59, 34.89, 40.69, 17 9.34

 (Example 16)

 2,7-dimercaptooctanoic acid:

 H-NMR (90 MHz.δ ppm, CDClg): 1.33 (t, J = 7.6 Hz, 1H), 1.25 to 2.10 (m, 10H), 2.10 (d, J = 9.0 Hz, 1H), 2, 25 ~ 2.70 (m, 2h), 3.34 (dt, J = 9.0Hz, J = 7.1Hz, 1H)

 (Example 17)

 Method for producing diastereomeric mixture of 2,6-dimercapto-3-methylhexanoic acid:

 3-Methylcyclohexanone (10 g) was dissolved in chloroform (300 ml), m-chloroperoxybenzoic acid (22 g) was added, and the mixture was refluxed under 1 B without heating. The reaction solution was concentrated to dryness, and partitioned between methylene chloride and aqueous solution of carbonated lime. The organic layer was dried over sodium sulfate and concentrated to obtain 10 g of a 1: 1 mixture of 5-methyl-16-hexanoyllactone and 3-methyl-16-hexanoyllactone as a colorless oil (yield 77%).

 H-NMR (90 MHz, 5 ppm, CDClg): 1.03 (d, J = 6 Hz, 3H), 1.08 (d, J = 6 Hz, 3H), 2.3-1.3 (m, 5H), 2.5-2.7 (m , 2H), 4.0-4.4 (m, 2H)

10 g of the lactone was dissolved in 200 ml of HBr-acetic acid, and the mixture was heated and stirred at 100 ° C. After 6 hours, the reaction solution was concentrated, and the residue was subjected to silica gel column chromatography, and eluted with chloroform. From the corresponding fraction, 4.6 g (yield 32%) of 6-bromo-3-methylhexanoic acid and 4.9 g (38% yield) of 6-acetoxy-5-methylhexanoic acid were obtained as a colorless oil. Obtained as a product.

 6-promo 3-methylhexanoic acid:

H-NMR (90 MHz, 5 ppm, CDClg): 0.98 (d, J = 6 Hz, 3H), 1.2 to 2.Km, 5H), 2.29 (t, J = 8 Hz, 2H), 3.40 (t ₍ J = 8.2 (Hz, 2H)

 6-acetoxy 5-methylhexanoic acid:

H-NMR (90MHz, 5pm, CDClg): 0.96 (d, J = 6Hz, 3H), 1.G 2.Km, 5H), 2.07 (s, 3 H), 2.2 ~ 2.5 (m, 2H), 3.94 (d, J = 8Hz, 2H)

 4.9 g of 6-acetoxy-5-methylhexanoic acid was dissolved in 20 mL of HBr-acetic acid, and the mixture was heated and stirred at 100 ° C overnight. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography, and eluted with chloroform. From the corresponding fraction, 3.1 g of 6-promo 5-methylhexanoic acid was obtained as a colorless oil (yield 57%).

 6-bromo-5-methylhexanoic acid:

 HNR (90 MHz, 5 pm, CDClg): 1.04 (d, J = 6 Hz, 3H), 2-3. Km, 5H), 2.31 (t, J = 8 Hz, 2H), 3.36 (d, J = 7 Hz) , 2H)

 3.13 g of 6-promo 5-methylhexanoic acid was dissolved in 10 ml of thionyl chloride, 3 drops of DMF was added, and the mixture was heated and stirred at 60 ° C. One hour later, 3.2 g of carbon tetrachloride 2 Om1, NBS and 7 drops of concentrated HBr were added, and the mixture was heated and stirred at 80 ° C. After 2 hours, the reaction solution was concentrated to dryness, 100 ml of methanol was added to the residue, and the mixture was stirred at room temperature. Two hours later, the reaction solution was concentrated, and separated with ethyl acetate and aqueous sodium hydrogen carbonate. After the ethyl acetate layer was dried over sodium sulfate, the solvent was distilled off. The obtained residue was dissolved in 5 mL of DMF, 6.8 g of KSAc was added, and the mixture was stirred at room temperature under a nitrogen atmosphere. The reaction solution was concentrated to dryness, and separated with ethyl acetate and aqueous sodium bicarbonate. After the ethyl acetate layer was dried over sodium sulfate, the solvent was distilled off, and the obtained residue was subjected to silica gel column chromatography, and eluted with chloroform. From the corresponding fraction, 3.5 g of a diastereomeric mixture of 2,6-diacetylthio-5-methylhexanoic acid methyl ester was obtained as a yellow oil (yield: 80%).

 H-NMR (90 MHz, 5 ppm, CDC1): 0.98 (d, J = 8 Hz, 3H), 1.1 to 2.2 (m, 5H), 2.33 (s, 3H), 2.36 (s, 3H), 2.7 2.9 (m, 2H), 3.73 (s, 3H), 4.18 (t, J = 8Hz, 1H)

3.46 g of 2,6-diacetylthio-5-methylhexanoic acid methyl ester was dissolved in 30 ml of methanol, 30 ml of a 1N—Na0H aqueous solution was added, and the mixture was heated to reflux under a nitrogen stream. After 3 hours, the reaction solution was concentrated, acidified with dilute hydrochloric acid, and extracted with ethyl acetate. After the ethyl acetate layer was dried over sodium sulfate, the solvent was distilled off, and the obtained residue was subjected to silica gel column chromatography, and eluted with chloroform. 2,6-Dimercapto-5-methylhexanoic acid 1.2 g of the stereo mixture was obtained as a yellow oil (yield 52%).

H-NMR (90MHz, 5ppm, CD 3 0D): 1.02 and 0.98 (each d, J = 8Hz, 3H) , 1.1~2.2 (m, 5H), 2.4~2.6 (m, 2H), 3. Bok 3.4 ( m, 1H)

Elemental analysis (as _{C 7 7H 14 0 2 S 2} ):

 Theoretical (%) 43.27 (C), 7.26 (H),

 Actual value (%) 43. 08 (C), 7.41 (H)

4.63 g of 6-bromo-3-methylhexanoic acid was dissolved in 1 Om1 of thionyl chloride, 3 drops of DMF was added, and the mixture was heated and stirred at 60 ° C. One hour later, carbon tetrachloride (42 Om1), 5.0 _{g of} NBS and 7 drops of concentrated HBr were added, and the mixture was heated and stirred at 80 ° C. Two hours later, the solvent of the reaction solution was distilled off, and 100 ml of methanol was added to the obtained residue, followed by stirring at room temperature. Two hours later, the solvent of the reaction solution was concentrated, and separated with ethyl acetate and aqueous sodium hydrogen carbonate. After the ethyl acetate layer was dried over sodium sulfate, the solvent was distilled off. The obtained residue was dissolved in 5 mL of DMF, 6.0 g of KS Ac was added, and the mixture was stirred at room temperature under a nitrogen atmosphere at room temperature for 1 B. The reaction solution was concentrated to dryness, and partitioned between ethyl acetate and aqueous sodium hydrogen carbonate. After the ethyl acetate layer was dried over sodium sulfate, the solvent was distilled off, and the obtained residue was subjected to silica gel column chromatography, and eluted with chloroform. From the corresponding fraction, 3.7 g of a diastereo mixture of 2,6-diacetylthio-13-methylhexanoic acid methyl ester was obtained as a yellow oil (yield 57%).

 H-NMR (90 MHz, Sppm, CDClg): 0.95 to 0.99 (d, J = 8 Hz, 3H, respectively), 1.1 to 2.3 (m, 5H), 2.33 (s, 3H), 2.38 and 2.39 (s, 3H) , 2.7 to 3.0 (m, 2H), 3.74 (s, 3H), 4.20 and 4.26 (d, J = 6Hz, 1H, respectively)

 3.6 g of 2,6-diacetylthio-3-methylhexanoic acid methyl ester was dissolved in 30 ml of methanol, an aqueous NaOH solution (5.0 g / 3 Om1) was added, and the mixture was heated to reflux under a nitrogen stream. After 3 hours, the reaction solution was concentrated, acidified with dilute hydrochloric acid, and extracted with ethyl acetate. After the ethyl acetate layer was dried over sodium sulfate, the solvent was distilled off, and the obtained residue was subjected to silica gel column chromatography and eluted with chloroform. From the corresponding fraction, 1.5 g of a diastereomeric mixture of 2,6-dimercapto-3-methylhexanoic acid was obtained as a yellow oil (yield: 61%).

H-NMR (90 MHz, 5 ppm, CD ₃ OD): 1.02 and 1.04 (d, J = 8 Hz, 3H, respectively), 1.1 to 2.3 ( m, 5H), 2.4 ~ 2.7 (m, 2H), 3.3.4 (m, 1H)

Elemental analysis (as _{C 7 H 14 0 2 S 2} ):

 Theoretical value (%) 43. 27 (C), 7.26 (H),

 Actual value (%) 43.1 0 (C), 7.31 (H)

 (Example 18)

 6-Propyl-1,2-dithiane-3-carboxylic acid:

 The cis and trans forms of the target compound were obtained from 2,5-dimercaptooctanoic acid.

 H-NMR (90 MHz, 5 ppm, CDClg): 0.8 to 1.05 (m, 3H), 1 to 2.55 (m, 8H), 2.75 to 3.05 (m, 1H), 3.55 to 3.75 (m, 1H), 3.61 ( dd, J = 3.4Hz, J = 5.6 Hz, 1H), 4.2-5.0 (m, 1H)

H-NMR (90MHz, 5ppm, CDC1 3):. 0.8~1.10 (m, 3H), 1.20~2.60 (m, 8H), 3.65~3.85 (m, 1H), 3.73 (dd, J = 2 7Hz, J = 10.7Hz, 1H), 6.6-7.2 (m, 1H)

 The compound represented by the general formula (I) of the present invention is useful as a therapeutic agent for diabetic renal disease, a blood sugar lowering agent, a lipid lowering agent and a gastrointestinal disorder reducing agent.

 The compounds (1) used in the present invention, (1) a test for inhibiting the progression of renal disease, (2) a test for lowering blood glucose, (3) a test for lowering lipids, and (4) a gastrointestinal disorder-reducing agent are described in more detail in the following test examples. Will be described.

Acute toxicity test

 The compound used in the present invention was orally administered (po: 402 to 1508 mg / kg), using three Wistar male rats weighing 200 g per group. The death status was observed 7 days after administration, and the MLD (minimum mortality) value was determined.

 Acute toxicity ML D (mg / kg) p o 603 mg / kg

 The (1) renal disease progression inhibitory test, (2) hypoglycemic effect test, and (3) lipid lowering effect test are described below.

Test example 1

 Test method

Using a male wistar rat (8 weeks old), streptozotocin (STZ) (4 Omg / kg) was administered intravenously (day 1), blood was collected on days 35-36, and serum biochemical examination was performed. Blood glucose, CHO, urinary ALB, and body weight were used as indices, and the test drug (1,2-dicepan-13-carboxylic acid, hereinafter referred to as a compound) was neutralized and dissolved in sodium hydrogen carbonate. lmmol / kg orally from day49 to 5 days a week, and blood is collected periodically every 2-3 weeks until dayl16, BUN (mg / dl), CHO (mg / dl), TG ( mg / dl), GLU (mg / dl) and urinary ALB (mg / day) values were measured.

 Preparation method of drug:

 The test compound was neutralized and dissolved with water using sodium bicarbonate to give a 5 ml Zkg aqueous solution.

 Water was administered to the control group.

Test example 2

 The test drug (1,2-dicepan-13-carboxylic acid) was neutralized and dissolved in water using sodium bicarbonate to give a concentration of 0.311111101-1 (administered 5 days a week from 1 & 49. 32 Treated as in Example 1.

Comparative Example 1

 The test was performed in the same manner as in Test Example 1 using metformin (commercially available) as the test drug.

The test results of Test Examples 1 and 2 and Comparative Example 1 are as shown in Tables 1 to 5. Table 1 shows [BUN (mg / dl)], Table 2 shows [CHO (mg / dl)], Table 3 shows [TG (mg / dl)], Table 4 shows [GLU (mg / dl)] and Table 5 Indicates the results of [urine ALB (mg / day)].

table 1

 BUN (mg / dl)

From the results, it can be seen that the compound decreases the C Η 0 value in a dose-dependent manner! ^ Table 3

 TG (mg / dl)

The results show that the compound dose-dependently and significantly reduced the GLU value. Table 5

 Urine ALB (mg / day)

These results indicate that the compound of the present invention significantly and significantly suppressed urinary ALB in a dose-dependent manner.

The hypoglycemic effect of the compound of the present invention is considered to be correlated with the gluconeogenesis inhibitory effect on hepatocytes. The effect of the compound on gluconeogenesis from lactic acid was determined by isolating rat hepatocytes, preparing them at ⁶ × 10 ⁶ cells, adding 1 OmM lactic acid, and measuring the amount of glucose released into the ground. Measured and determined. The results are shown in the table below. In the table, each compound is

 (Example 4) 1,2-dicheban-3-carboxylic acid,

 (Example 7) 7-ethyl-1, 2-dichepan-1-3-carboxylic acid,

 (Example 8) 4,5-dihydro-1H-2,3-benzodichepin-14-carboxylic acid,

 (Example 12) 1,2-dithionan-1-carboxylic acid,

 (Example 14) 2,6-dimercaptohexanoic acid,

 (Compound 15) 2,7-dimercaptoheptanoic acid,

 (Compound 16) 2,8-dimercaptooctanoic acid

Is shown. Table 6

 Effects of compounds on gluconeogenesis from lactic acid

From the above results, the compound of the present invention showed an improving effect of BUN value, CHO value, TG value, GLU value, urinary ALB value and the like on an STZ-induced renal disorder model, and was used as a therapeutic agent for diabetic nephropathy. Useful as Further, the compound of the present invention has an action of lowering the GLU value and is useful as a hypoglycemic agent. Furthermore, the compounds of the present invention lower the CH 0 value and TG value, and are therefore useful as lipid lowering agents.

 (4) Gastrointestinal disorder reduction

 The effects of the compounds used in the present invention on gastrointestinal disorders are described below. There are no effective measures against gastrointestinal disorders, especially diarrhea, when administering antineoplastic drugs. If the disorder is severe, the drug must be reduced or the administration stopped. Therefore, clinically, it has been desired to develop a compound that reduces gastrointestinal disorders without affecting the antitumor effect when using these drugs. Specific examples of this gastrointestinal tract disorder include, for example, drugs commonly used in the treatment of gastrointestinal cancers, such as 5-fluorouracil (5FU) and its derivatives such as tegafur and 5-deoxyfluorouridine (5DFUR). However, its use is known to cause major side effects such as gastrointestinal disorders (nausea, vomiting, diarrhea) and bone marrow disorders.

 Test method for effects on gastrointestinal disorders

An antitumor agent, for example, 5FU is dissolved in 5 Wistar male rats (7 weeks old; body weight: 200-230 g) in water and administered orally for 3 days (day 1-3) did. The test drug was dissolved in water or suspended in 3% gum arabic immediately before administration of the antitumor agent and orally administered for 3 days. After the administration of the test drug, changes in body weight and the occurrence of diarrhea were observed. The degree of diarrhea was scored in four steps based on the shape of feces.

 The compounds of the present invention reduced weight loss and significantly reduced the occurrence of diarrhea.

 A commercially available fluoropyrimidine-based antitumor agent was used in the above digestive tract disorder reducing action test.

 Specifically, examples of fluor-oral pyrimidine antitumor agents include 5-fluorouracil (5FU), tegafur, doxyfluridine, 5-deoxy-5-fluorouridine (FUDR), carmofur, or a combination drug consisting of tegafur and peracil ( UFT) and so on.

 The N-1 or N-3 position of the skeleton of these fluoropyrimidine-based antitumor agents may be protected with a protecting group, and when these compounds are administered to a living body, the antitumor effect is reduced. L, which is not particularly limited as long as it can demonstrate.

 The gastrointestinal disorder reducing agent of the present invention is described in more detail in the following Test Examples.

 (Test Example 1)

 5 FU (8 Omg / kg) was dissolved in 5 Wistar male rats (7 weeks old; weight: 200 to 230 g) per group for 3 days (day 1 to 10). 3) Oral administration. The test drug (butyric acid, hereinafter referred to as compound A) was orally administered for 3 days immediately before administration of 5FU by dissolving 0.5 to 2 IMO1 / kg in water after neutralizing with sodium bicarbonate. The control group received water. After administration of the test drug, changes in body weight and the occurrence of diarrhea were observed, and the degree of diarrhea was scored on a four-point scale based on the shape of feces.

 The fecal status was evaluated on the following four scales. 0: Normal stool (hard fecal mass with low water content), 1: Loose stool (fecal type collapsed, soft with lots of water), 2: Diarrhea stool (fecal type completely collapsed, soft with lots of water), 3: Water soluble Diarrhea stool (watery stool without any fecal type).

(Test Example 2)

 The test was carried out in accordance with Test Example 1 using thiotamide (hereinafter referred to as Compound B) as a test drug.

Table 7 shows the results. The change in body weight is the mean value of the group from day 1 on day 6 with the largest weight loss after administration of 5 FU, and the fecal status was 0 to 3. Scored into stages and expressed as the mean of the group _c Table 7

When 5 FU was continuously administered at 80 mg / kg for 3 days, weight loss increased the most on day 6. In contrast, when the compound used in the present invention was used in combination, the weight loss was reduced. Diarrhea was also scored, and the degree of diarrhea was examined.On the 5th day, water-soluble diarrhea was observed in all subjects in the 5FU administration group on the 5th day, whereas no diarrhea was observed in the group combined with the compound used in the present invention. Diarrhea was absent or very mild.

CDF 1 mice (body weight 23 - 2 5 g) and murine leukemia cell L 1 2 1 0 and 1 0 ⁷ implanted intraperitoneally (dayo). Next, 5 FU (3 Omg / kg) was dissolved in water and orally administered from day 1 to 5 days. The test drug was administered orally by dissolving 1-4 mmol Zkg in water immediately before administration of 5FU. Six mice were used per group, and water alone was administered to a control group (control). The antitumor effect was determined by calculating the life extension rate (ILS) by the following formula from the average survival days (C) of the control group and the average survival days (T) of the 5FU administration group.

 I L S (%) = (T / C- 1) X 100

 The compound of the present invention did not affect the antitumor effect even when 0.5 to 2 mmol / kg was used in combination with 5FU.

When the compound of the present invention or a pharmaceutically acceptable salt thereof is used as a pharmaceutical preparation, it is usually a pharmaceutically acceptable carrier, excipient, diluent, bulking agent, disintegrant, It can be used by formulating with stabilizers, preservatives, buffers, emulsifiers, fragrances, coloring agents, sweeteners, thickeners, flavoring agents, solubilizing agents, and the like. Carrier substances include water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oil, polyalkylene glycol, and serine, and other organic or inorganic inert carriers suitable for intestinal, transdermal, or parenteral administration. Substance. Pharmaceutical preparations include tablets, dragees, enteric-coated tablets, granules, powders, suppositories and tablets which can be produced in accordance with the usual methods. Capsules, enteric capsules and other solid preparations or solutions, suspensions and liquid preparations such as emulsions and the like, and can be administered orally or parenterally.

 When used as a therapeutic agent for diabetic renal disease, a hypoglycemic agent, a lipid-lowering agent and an agent for reducing gastrointestinal tract disorders, the compound of the present invention may be used alone or in combination of two or more different compounds such as inulin and the like. Can be used in combination. The amount used is about 0.1 force per weight of the pharmaceutical composition, such as 99.5%, preferably 0.5 to 95%.

 The dosage of the drug of the present invention varies depending on the type of patient, the compound to be administered and the administration route, the age, sex, weight and the like of the patient. For example, a therapeutic agent for diabetic renal disease, a blood glucose lowering agent, and a lipid lowering agent When used as a general formula, it is generally in the range of 20 to 20 mg per person, preferably 60 to 12 O mg.

 In the case of oral administration of a gastrointestinal disorder reducing agent, it may vary depending on the type, dosage, administration method, etc. of the antitumor agent. For example, 0.01 to 20 mol, preferably 1 mol to 1 mol of the antitumor agent is preferable. Is 0.01 to 6 mol. The timing of administration of the drug is not particularly limited, and it may be before or after administration of the fluoropyrimidine-based antitumor agent or simultaneously, even if administered simultaneously.

Formulation Example 1

 Tablets are prepared by the usual method using the following composition.

 Compound 25 of Example 1

 Lactose 6 O mg

 Potato starch 40 mg

 Polyvinyl alcohol 2 mg

 Magnesium stearate 1 mg

Formulation Example 2

 A granule is prepared by the usual method using the following composition.

 Compound 5 O mg of Example 1

 Lactose 15 mg

 Corn starch 1 O mg

Hydroxypropylcellulose 2 O mg Polyvinyl alcohol 5 mg

Formulation Example 3

 A powder is prepared by the usual method with the following composition.

 Compound 25 of Example 1

 Lactose 2 7 5 mg

Formulation Example 4

 The powder obtained in Formulation Example 3 is filled into a forceps container to form a capsule.

 Compound 25 of Example 1

 Lactose 2 7 5 mg

The invention's effect

 According to the present invention, a dithiocyclic compound or a pharmaceutically acceptable salt thereof having a disease progress-inhibiting action, a blood glucose-lowering action, a lipid-lowering action, or a gastrointestinal disorder-reducing action, an intermediate compound for producing them, To provide a medicament useful as a diabetic renal disease therapeutic agent I which contains these dithiocyclic compounds and has few side effects such as gastrointestinal disorders, a hypoglycemic agent, a lipid lowering agent, and a gastrointestinal disorder relieving agent. Was completed.

Claims

1-a general formula (I) wherein A is an enclosing group or, where m is an integer of 3 to 7, Rb and Re are the same or different and are each a tertiary atom, an alkyl group , Aryl group, halogen atom, carboxyl group, carbamoyl group, —C (where 1 represents an integer of 1 to 10, Ra represents a hydroxyl group, an alkoxy group, an amino group, an alkylamino group.), A C0R group (Where R represents an amino acid residue), or adjacent Rb or Rc form a double bond or an aromatic ring, and are present at any position on the ring At least one of Rb and R „is one C0RQ, one (CH) C0R group, and n represents an integer of 1 to 7, and R ^ and RJ are the same or different, and are a hydrogen atom, an alkyl group. But when m is 3, the 3-position is not C00H,-(CH2) 4C00H or 1 (CH2) 4CONH2, but m is 4 When position 3 is 1 COOH and position 6 is not a hydrogen atom or 1 COOH], or a pharmacologically acceptable salt thereof, wherein m is 5 to 7, 2. The dithiocyclic compound or a pharmacologically acceptable salt thereof according to claim 1. 3. m is 3, and an alkyl group or 1 COR group at the 4-position, wherein R is α d 2. The dithiocyclic compound or a pharmacologically acceptable salt thereof according to claim 1, which is substituted with: 4. A compound selected from the following dithiocyclic compound group or a pharmacologically acceptable salt thereof. Salts obtained.

 (1) Dithio cyclic compound (5-membered ring, 6-membered ring)

 4-methyl-1,4-dithiolan-1-carboxylic acid,

 4-methyl-1,2-dithiolan-1-carboxylic acid methyl ester,

 4-Methyl-1-, 2-dithiolane-4 Ethyl rubonate,

 4-Methyl-1,2-dithiolane-4 propyl rubonate,

 4-methyl-1,2-dithiolane-4-carboxylic acid amide,

 4-methyl-1,2-dithiolane-1-carboxylic acid (N-methyl) amide, 4-methyl-1,2-dithiolane-14-carboxylic acid (N-carboxymethyl) amide,

 Thioic acid (N-ethoxycarbonylmethyl) amide,

 6-propyl-1,2-dithiane-3-carboxylic acid, etc.

 (2) Dithio cyclic compound (7-membered ring)

 1, 2-dichepan 1-rubonic acid,

 1,2-dicepan-1-carboxylic acid methyl ester,

 1,2-dicepan-1-ethyl carboxylate,

 1,2-dicepan-1-carboxylic acid propyl ester,

 1,2-dichepan-3-carboxylic acid amide,

 1,2-dichepan-3-carboxylic acid (N-methyl) amide,

1,2-dichepan-1-carboxylic acid (N-ethoxycarbonylmethyl) '

 4,5-dihydro-1H-2,3-benzodichepine-14-carboxylic acid, 4,5-dihydro-1H-2,3-benzodichepine-14-carboxylic acid methyl ester,

 7-ethyl-1 and 2-dichepan-1 3-potassium

 7-ethyl-1,2-dichepan-1-carboxylic acid methyl ester,

 7-ethyl-1,2-dichepan-3-ethyl carboxylate,

 7-ethyl-1,2-dichepan-1-carboxylic acid propyl ester,

 7-ethyl-1,2-dichepan-1 3-potassium amide

 7-ethyl-1,2-dichepan-13-carboxylic acid (N-methyl) amide, 7-ethyl-1,2-dichepan-3-3-carboxylic acid (N-ethoxycarbonylmethyl) amide,

 5-phenyl-1,2-dichepan-3-Rubonic acid, etc.

 (3) Dithio cyclic compound (8-membered ring)

 1,2-dithiocan-3-carboxylic acid,

 1,2-dithiocan-3-carboxylic acid methyl ester,

 1,2-dithiocan-3-ethyl ether ester,

 1,2-dithiocan-3-carboxylic acid propyl ester,

 1,2-dithiocan-3-carboxylic acid amide,

 1,2-dithiocan-1-fluorocarboxylic acid (N-methyl) amide,

 1,2-dithiocan-1-carboxylic acid (N-ethoxycarbonylmethyl) amide, etc.

 (4) Dithio cyclic compound (9-membered ring)

 1,2-dithionan-1-carboxylic acid,

 1,2-dithionan-1-carboxylic acid methyl ester,

 1,2-dithionane-1-ethyl ribonate

 1,2-dithionane-1,3-butyric acid propyl ester,

 1,2-dithionan-1-carboxylic acid amide,

1,2-dithionan-3-carboxylic acid (N-methyl) amide, 1,2-dithionane-13-carboxylic acid (N-ethoxycarbonylmethyl) amide, etc.

 (5) Tetrathiacyclic compound (8-20 membered ring)

 2,3,6,7-tetrathia-1,5-cyclooctanedicarboxylic acid,

 2,3,7,8-tetrathia-1,6-cyclodecanedicarboxylic acid,

 2,3,8,9-tetrathia-1,7-cyclododecanedicarboxylic acid,

 2,3,9,10-Tetrathia-1,8-cyclotetradecanedicarboxylic acid, 2,3,10,1-tetrathia-1,1,9-cyclohexadecanedicarboxylic acid, 2,3,1,1,12— Tetrathia-1,10-cyclooctadecanedicarboxylic acid, 2,3,12,13-tetrathia-1,1,1-cycloeicosandicarboxylic acid, 5. General formula II,

 HS-A-SH (II)

 [Where A is

And

Here, m represents an integer of 3 to 7, and R _b and RJ are the same or different, and are an atom, an alkyl group, an aryl group, a halogen atom, a carboxyl group, a carbamoyl group, —CONH (CH o) j COR . A group (where 1 is an integer of 1 to 10, R- represents a hydroxyl group, an alkoxy group, an amino group, or an alkylamino group), or — a CQR group (where R represents an amino acid residue) or adjacent R _b together or R _e together are to form a double bond or an aromatic ring, and present in any position on the ring R _b, R - at least one of one C0R. , One (CH ₉ ), COR. A group wherein, m is 3-position one C00H when the _{3, - (CH 2) 4} C00H and - (CH _{2) 4} CONH instead _2, m is the 3-position when the 4 - in CO OH And the 6th position is not hydrogen atom or 1 CO 0H]

Or a pharmacologically acceptable salt thereof.

6. Compounds selected from the following compounds or their pharmacologically acceptable salts

2, 6-dimercaptohexanoic acid,

 2, 7-dimercaptoheptanoic acid,

 2, 6-dimercaptooctanoic acid,

 2, 8—dimercaptooctanoic acid,

 3- (2-mercaptomethylphenyl) -1-2-thiopropionic acid,

 2,2-dimercaptomethylpropionic acid.

 2,6-dimercapto-3-methylhexanoic acid,

 2,6-dimercapto-5-methylhexanoic acid,

 2,6-dimercapto-14-phenylhexanoic acid,

7. General formula (I ')

[Where A is

Or

And Here, m represents an integer of 3 to 7, R _b and R _c are the same or different and each represents a hydrogen atom, an alkyl group, an aryl group, a halogen atom, a carboxyl group, a carbamoyl group, -CONH (CH ₂ ) _} COR. A group (where 1 is an integer of 1 to 10, RJ or a hydroxyl group, an alkoxy group, an amino group or an alkylamino group); —C —R group (where R represents an amino acid residue) Or at least one of R _b and R — at which R _b or R _e adjacent to each other forms a double bond or an aromatic ring and is present at an arbitrary position on the ring, is —CO. , -. (A CH <C OR group, and, n represents an integer of 1-7, indicating R _d, R _e are the same or different, a hydrogen atom, Al kill group, a § Li Ichiru group .]

A therapeutic agent for diabetic renal disease, comprising a dithiocyclic compound represented by the formula or a pharmacologically acceptable salt thereof.

8. Compound of general formula (Γ)

 [Where A is

Or

And Here, m represents an integer of 37, and R _b R _c are the same or different, and represent a hydrogen atom, an alkyl group, an aryl group, a halogen atom, a carboxyl group, a carbamoyl group, —CONH (CHo), COR. Groups (where 1 is an integer from :! to 10; R represents a hydroxyl group, an alkoxy group, an amino group, or an alkylamino group); —COR group (where R represents an amino acid residue) Or adjacent R _b or R _c form a double bond or an aromatic ring, and at least one of R _b R present at any position on the force or ring is —C 0R

 α. , One (CH! C 0R

C ₉ ) d. N is an integer of 17, and R _d R is the same or different and represents a hydrogen atom, an alkyl group, or an aryl group.]

A dithiocyclic compound represented by the formula (I) or a pharmacologically acceptable salt thereof, comprising:

9. General formula (I)

(I)

[Where A is

Or

And Here, m represents an integer of 3 to 7, R _b and R _c are the same or different and each represents a hydrogen atom, an alkyl group, an aryl group, a halogen atom, a carboxyl group, a carbamoyl group, -CONH (CH ₉ ), COR group (where 1 is an integer of 1 to 10, R is a hydroxyl group, an alkoxy group, an amino group, or an alkylamino group), —COR group (where R represents an amino acid residue). Or at least one of R _b and R — at which R _b or R _e adjacent to each other forms a double bond or an aromatic ring, and is present at an arbitrary position on the ring. , — (CH ₉ ), COR. A group, and, n is an integer of 1 to 7, R _d, and R _e same or different, a hydrogen atom, Al kill group, Ryori - shows the Le group.

However, 3-position one CO 0H when m is 3, one (CHJ ₄ C00H and - (CH _{2) 4} In CONH ₂ rather than the 3-position is CO 0H a and 6-position is a hydrogen atom when m is 4 Or not CO 0H]

A hypoglycemic agent, comprising a dithiocyclic compound represented by the formula or a pharmacologically acceptable salt thereof.

 10. General formula (I)

[Where A is

Or d

 CH (COOH) — S S- -CH (COOH)-

And

Here, m represents an integer of 3 to 7, and R _b and R _c are the same or different, and represent a hydrogen atom, an alkyl group, an aryl group, a halogen atom, a carboxyl group, a carbamoyl group, —CONH (CH ₉ ), COR. A group (where 1 is an integer of 1 to 10; R is a hydroxyl group, an alkoxy group, an amino group, or an alkylamino group is a CR RII); — a COR group (where R is an amino acid residue) Or adjacent R _b or R _e form a double bond or an aromatic ring, and at least one of R _b and R present at an arbitrary position on the ring is —COR. ,-(CH), COR. A group, and, n is an integer of 1 to 7, R _d, R _e are the same or different, a hydrogen atom, Al kill group, § Li - show Le group.

However, when m is 3, position 3 is not —COOH,-(CH ₂ ) ₄ COOH and — (CH ₂ ) ₄ CONH ₂ ; when m is 4, position 3 is COOH and position 6 is a hydrogen atom Or-not COOH]

A dithiocyclic compound represented by the formula (I) or a pharmacologically acceptable salt thereof, characterized by comprising: