JPH10152468A - 3,3'-dithiobis(2,2-dimethylpropionamide) derivative, agent for treating renal disease and agent for treating hepatic disease - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide the subject new compound useful as an agent for the treatment of renal diseases such as nephrotic syndrome and diabetic nephropathy and an agent for the treatment of hepatic diseases such as hepatitis and toxic hepatopathy. SOLUTION: This compound is expressed by the formula I [R<1> is H, amino, hydroxyl group or a (substituted) alkyl; R<2> is H or a lower alkyl], e.g. 3,3'- dithiobis [2,2-dimethylpropion (N-carboxymethyl)amide]. The compound of formula I can be produced by converting a carboxylic acid of formula II into a reactive derivative of carboxylic acid (acid halide substituted with a halogen, active ester substituted with methyl, ethyl, p-nitrophenyl, etc., acid anhydride, etc., of the compound of formula II) with an activation agent and reacting the reactive derivative with an amine component expressed by the formula R<1> R<2> NH.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel dithiobis-
The present invention relates to (2,2-propionamide) derivatives, and therapeutic agents for kidney disease and liver disease containing these compounds as active ingredients.

[0002]

BACKGROUND OF THE INVENTION The present inventors have found that a compound having a -SS- bond in a molecule, for example, an alkyldithiobutanoic acid derivative is useful as a therapeutic agent for kidney disease and a therapeutic agent for liver disease. Filed.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel dithiobis- (2,2-dimethylpropionamide) derivative and an agent for treating renal disease and liver disease containing the same as an active ingredient. I do.

[0004]

Means for Solving the Problems In order to achieve the above object, the present inventors synthesized a novel dithiobis-2,2-dimethylpropionamide derivative and tested its therapeutic effect on kidney disease and liver disease. As a result, the general formula

[0005]

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(Wherein R ¹ represents a hydrogen atom, an amino group, a hydroxyl group, a linear or branched alkyl group, or an amino group, a hydroxyl group, an alkoxy group, a carboxyl group, an alkoxycarbonyl group, an aryl group and a carbamoyl group. A linear or branched alkyl group which may be substituted with at least one selected substituent, wherein R ² represents a hydrogen atom or a lower alkyl group, and 3,3′-dithiobis (2,2 -Dimethylpropionamide) derivatives, isomers or pharmacologically acceptable salts, and

[0007]

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(Wherein m represents an integer of 0 to 6), and the carboxylic acid amide derivative and the pharmacologically acceptable salt represented by the formula (1) exhibit excellent renal and liver disease therapeutic effects. I found it.

As the above R ¹ and R ² , an alkyl group which may be substituted with a substituent includes, for example, a C ¹ -C 1 alkyl group.
20 linear or branched alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s
Examples thereof include ec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, and nonadecyl groups.
Preferably, it is an alkyl group having 1 to 10 carbon atoms.

The substituent on the alkyl group chain is a substituent selected from the group consisting of an amino group, a hydroxyl group, an alkoxy group, a carboxyl group, an alkoxycarbonyl group, an aryl group and a carbamoyl group. May be protected.

The alkoxy group includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,
Tert-butoxy group and the like.

Examples of the alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-butoxycarbonyl and 2,3-dihydroxypropoxycarbonyl. As the aryl group, a phenyl group or an alkyl group, an alkoxy group, a hydroxyl group, phenyl substituted with a halogen atom,
For example, a toluyl, methoxyphenyl, hydroxyphenyl group and the like can be mentioned, and a phenyl group is preferable.

In the present invention, the term "protecting group for a substituent" is used for protecting a hydroxyl group, a carboxyl group, an amino group, a carbamoyl group and the like in the peptide synthesis, and can be easily prepared according to a known method described in the literature. (Basics and experiments on peptide synthesis, Nobuo Izumiya et al., Maruzen). The method for introducing the protecting group or the method for removing the protecting group varies depending on the type of the protecting group to be used, the method for preparing the reactive derivative of the carboxylic acid, or the type of the amino component to be reacted, etc., but usually it can be easily introduced,
In addition, a protecting group or a method which can be easily removed by catalytic reduction or mild acid treatment can be appropriately selected and used.

Specifically, as the amino protecting group, for example, urethane type, acyl type and alkyl type protecting groups are known. Examples of the urethane type include a benzyloxycarbonyl (Z) group, a tert-butoxycarbonyl (Boc) group,
Examples include a tertiary amylocarbonyl (Aoc) group, a 4-biphenylisopropyloxycarbonyl group, and a diisopropylmethyloxycarbonyl group.

The acyl type includes formyl, trifluoro, phthalyl, tosyl, o-nitrosulfenyl, benzoyl, 4-methoxy-2-nitrophenylsulfenyl, benzoyl, chloroacetyl,
An acetoacetyl group and the like can be mentioned. Examples of the alkyl type include a trityl group, a benzylidene group, a benzyl group, a 2-benzoyl-1-methylvinyl group, and a trimethylsilyl group.

Examples of the carboxyl protecting group include benzyl group, tert-butyl group, and alkyl groups such as methyl and ethyl groups.

The protecting group for the ω-carbamide group includes a xanthyl group, a bis-2,4-dimethoxybenzyl group,
4-dimethoxybenzyl group, 4,4'-dimethoxybenzhydryl and the like. As the substituent of the alkyl chain which may be substituted with a substituent, for example, a plurality of same substituents such as a 2,3-dihydroxypropyl group may be substituted, and 2-carboxy-2- A plurality of different groups such as a hydroxyethyl group may be substituted.

The compounds of the present invention include those wherein the amino acid residue represented by the R ¹ R ² N- group in the formula (I) is derived from a natural amino acid. Specifically, as the amino acid residue, glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine,
Examples include cystine, proline, asparagine, glutamic acid, histidine, lysine, ornithine, arginine, phenylalanine, tyrosine, tryptophan residues and the like. Preferred are glycine, alanine, valine, leucine, isoleucine, serine, threonine, proline, asparagine, glutamic acid, lysine, phenylalanine and tyrosine residues. The amino acid residue of the present invention naturally includes these optical isomers.

Particularly preferred compounds of the present invention are shown in the following table. In addition, the compound numbers in the table correspond to the example numbers described later.

[0020]

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[0021]

[Table 1]

Examples of the compound represented by the general formula (II) include compounds wherein m is 0 to 6, preferably 0 to 2.

The general formulas (I) and (II) of the present invention
The compound represented by the general formula

[0024]

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A carboxylic acid represented by the following formula:
II)] is converted into a reactive derivative of a carboxylic acid using an activator;

[0026]

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(Wherein R ¹ and R ² are the same as described above). The reactive derivative of a carboxylic acid refers to the compound (II)
I) is an acid halide substituted with a halogen such as bromine, chlorine, iodine or fluorine, an active ester substituted with methyl, ethyl, p-nitrophenyl or the like, or an acid anhydride. It is usually used for the reaction.

3,3 'which is a starting material of the compound of the present invention
-Dithiobis [2,2-dimethylpropionic acid [hereinafter, referred to as
Compound (III)] is a known compound and can be synthesized by a known method. The reactive derivative of the carboxylic acid of the compound (III) can be easily obtained by reacting the compound with thionyl halide in an inert solvent such as dioxane. This reaction can be performed more quickly in the presence of a catalytic amount of dimethylformamide.

Specific examples of the method for synthesizing the amide derivative of the present invention are shown below. The amide derivative of the present invention can be obtained by dissolving the reactive derivative of the carboxylic acid of the compound (III) in an inert solvent such as dioxane and reacting with an amine component. For example, (1) a method of reacting with ammonia water (ammonolysis), (2) a method of dropping in an aqueous solution of methylamine and reacting, (3) a method of dropping in an alcohol such as methanol to form a carboxylic acid ester, and The hydrazine hydrate is heated and reacted in an alcohol solvent such as methanol under a nitrogen atmosphere.
(4) An amine component such as glycine, isoleucine, isoserine, sarcosine, ethanolamine or ε-N-Boc-lysine is dissolved in a solvent such as pyridine in 1,1,1,3,
Reaction with a silylating agent such as 3,3-hexamethyldisilazane in the presence of a catalytic amount of ammonium sulfate (heating to reflux)
A method of preparing a TMS derivative and then reacting with a reactive derivative of the carboxylic acid. (5) a method of reacting D-valine ethyl ester hydrochloride with triethylamine and a catalytic amount of dimethylaminopyridine in dioxane at room temperature, (6) a method of reacting hydrazine hydrate with an aqueous solution, (7) A method of reacting ethylenediamine in methylene chloride under ice cooling can be exemplified.

The amide derivative of the present invention can be prepared by using the compound (I)
II) and serine methyl ester hydrochloride can also be synthesized in the presence of a base such as triethylamine in a suitable solvent such as DMF using a condensing agent such as diethyl cyanophosphate (DEPC). As the amine component, L-, D-,
Each isomer such as DL-isomer is used.

The compound of the present invention can also be synthesized by the following method. One specific example is 3-chloro-2,2-
Dimethylpropionyl chloride and valine are reacted in a conventional manner in a suitable solvent in the presence of a base to give 3-chloro-2,2-dimethylpropionyl-L-valine. It can be obtained by oxidizing in the presence of an amount of an oxidizing agent such as iron chloride. This reaction is represented by the following reaction formula.

[0032]

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In the compound of the present invention obtained by each of the above-mentioned production methods, a protecting group for a substituent such as a hydroxyl group, a carboxyl group, an amino group or a carbamoyl group can be removed according to a conventional method. For example, an ester bond can be easily removed by hydrolysis in the presence of an alkali, and a silyl group can be easily removed by the action of water.

The pharmacologically acceptable salts of the compound of the present invention can be prepared according to a conventional method. For example, when the skeleton has a carboxyl group, it can be obtained by dissolving in an equivalent amount of NaOH water and freeze-drying. When the skeleton has a basic moiety, it can be obtained by reacting with an equivalent amount of a pharmacologically acceptable acid such as hydrochloric acid, sulfuric acid or nitric acid in an appropriate solvent.

The following examples illustrate in more detail the methods for synthesizing the novel compounds of the present invention. Starting materials used in the present invention 3,
3'-dithiobis (2,2-dimethylpropionic acid)
The physicochemical properties of [Compound (III)] are shown below. H-NMR (90 MHz, δ ppm, CD ₃ OD):
1.25 (s, 12H), 3.05 (s, 4H)

Method for preparing active derivative of carboxylic acid of compound (III) (hereinafter referred to as active form): Compound (III)
0 g was suspended in 10 ml of dioxane, 3.0 ml of thionyl chloride and 3 drops of dimethylformamide (DMF) were added, and the mixture was stirred at room temperature. After 4 hours, the solvent of the reaction solution was distilled off, and the obtained residue was azeotroped three times with dioxane, and then dissolved in 20 ml of dioxane to obtain an acyl chloride solution.

[0037]

【Example】

(Example 1) 3,3'-dithiobis [2,2-dimethylpropion (N-carboxymethyl) amide]: 5.37 g of glycine hydrochloride ethyl ester, 11 ml of triethylamine and a catalytic amount of dimethylaminopyridine were dissolved in 20 ml of dioxane, At room temperature, an acyl chloride solution [compound (II
I) An active substance was prepared using 5 g. ] Was added dropwise. After stirring overnight, the solvent was distilled off, and the mixture was separated with an ethyl acetate-KHSO ₄ aqueous solution. The organic layer was dried over sodium sulfate. The residue obtained by distilling off the solvent was dissolved in 50 ml of methanol, 30 ml of an aqueous solution containing 3.0 g of NaOH was added under ice-cooling, and the mixture was stirred at the same temperature for 4 hours. An aqueous KHSO ₄ solution was added to make it acidic, and the solvent was distilled off. The obtained residue was separated with ethyl acetate-water, and the ethyl acetate layer was dried over sodium sulfate. The obtained residue was subjected to silica gel column chromatography, and 3% methanol /
Eluted with chloroform. The solvent of the corresponding fraction was distilled off to obtain 5.45 g of the target compound as a colorless powder (y. 81%). H-NMR (90 MHz, δ ppm, CD ₃ OD):
1.28 (s, 12H), 3.06 (s, 4H),
88 (s, 4H) C- NMR (CD 3 OD): 25.03,41.99,
44.59,52.45,172.83,179.01 Elemental analysis (C ₁₄ H ₂₄ N ₂ O as ₆ S ₂ 380.47) theory (%) 44.20 (C), 6.36 (H ), Measured value (%) 44.29 (C), 6.45 (H)

Example 2 3,3′-Dithiobis [2,2-dimethylpropion (N-2-carboxyethyl) amide]: H-NMR (90 MHz, δppm, CD ₃ OD):
1.23 (s, 12H), 2.52 (t, J = 6.8H)
z, 4H), 3.02 (s, 4H), 3.30-3.5.
5 (m, 4H) 7.55 to 7.8 (m, 2H) C-NMR (δ ppm, CD ₃ OD): 25.19,3
4.46, 36.57, 44.59, 52.50, 17
5.33,178.42 Elemental analysis (C ₁₆ H ₂₈ N ₂ as O ₆ S ₂ 408.52) theory (%) 47.04 (C), 6.91 (H), Found (%) 46 .91 (C), 6.99 (H)

Example 3 3,3′-Dithiobis [2,2-dimethylpropion (N-ethoxycarbonylmethyl) amide]: H-NMR (90 MHz, δppm, CD ₃ OD):
1.26 (t, J = 7.1 Hz, 6H), 1.28
(S, 12H), 3.06 (s, 4H), 3.88
(S, 4H), 4.16 (q, J = 7.1 Hz, 4H) C-NMR (δ ppm, CD ₃ OD): 14.47,2
5.14, 42.42, 44.59, 52.45, 6
2.04,171.15,179.01 Elemental analysis (C ₁₈ H ₃₂ N ₂ O as ₆ S ₂ 436.58) theory (%) 49.52 (C), 7.39 (H), Found (%) 49.55 (C), 7.26 (H)

Example 4 3,3′-Dithiobis [2,2-dimethylpropion (N-isopropoxycarbonylmethyl) amide]: 25.0 g of glycine was suspended in 300 ml of isopropanol, and 30 ml of trimethylsilyl chloride was added. And refluxed for 6 hours. The residue obtained by evaporating the solvent of the reaction solution was dissolved in 200 ml of dioxane, and triethylamine 1
After adding 00 ml and a catalytic amount of dimethylaminopyridine, the acyl chloride solution [compound (III) 4
The active substance was prepared using 0 g. ] Was added dropwise. After 4 hours, the solvent was distilled off, and the mixture was separated with an ethyl acetate-KHSO ₄ aqueous solution, and the organic layer was dried over sodium sulfate. The residue obtained by evaporating the solvent was subjected to silica gel column chromatography, and eluted with chloroform. The solvent of the corresponding fraction was distilled off to obtain 56.0 g of the target compound as a colorless powder (y. 80%). H-NMR (90 MHz, δ ppm, CDCl ₃ ):
1.26 (d, J = 6.4 Hz, 12H), 1.30
(S, 12H), 3.06 (s, 4H), 3.98
(D, J = 5.1 Hz, 4H), 5.14 (m, 2
H), 6.53 (brt, 2H) C-NMR (δ ppm, CDCl ₃ ): 21.73,2
4.81, 41.83, 43.51, 51.36, 6
8.92,169.31,176.20 Elemental analysis _{(C 20 H 36 N 2 O} 6 S 2 as 464.63) theory (%) 51.70 (C), 7.81 (H), Found (%) 51.78 (C), 7.72 (H)

Example 5 3,3′-Dithiobis [2,2-dimethylpropion (N-1-carboxyethyl) amide]: H-NMR (90 MHz, δppm, CD ₃ OD):
1.26 (s, 6H), 1.28 (s, 6H), 1.4
1 (d, J = 7.3 Hz, 6H), 3.07 (s, 4
H), 4.39 (q, J = 7.3 Hz, 2H) C-NMR (δ ppm, CD ₃ OD): 17.50, 2
4.92, 25.25, 44.54, 49.47, 5
2.50,175.92,178.20 Elemental analysis (C ₁₆ H ₂₈ N ₂ O as ₆ S ₂ 408.52) theory (%) 47.04 (C), 6.91 (H), Found (%) 46.91 (C), 6.98 (H)

Example 6 3,3'-Dithiobis [2,2-dimethylpropion [N- (S) -1-carboxy-2-methylpropyl]
Amide]: 1 H-NMR (90 MHz, δ ppm, CD ₃ OD):
0.97 (d, J = 6.8 Hz, 12H), 1.29
(S, 12H), 1.98-2.4 (m, 2H), 3.
09 (s, 4H), 4.33 (d, J = 5.9 Hz, 2
H) Elemental analysis _{(C 20 H 36 N 2 O} 6 S 2 as 464.63) theory (%) 51.70 (C), 7.81 (H), Found (%) 51.78 (C) , 7.85 (H)

Example 7 3,3'-Dithiobis [2,2-dimethylpropion [N- (R) -1-carboxy-2-methylpropyl]
Amide]: 7.0 g of D-valine ethyl ester hydrochloride,
11 ml of triethylamine and a catalytic amount of dimethylaminopyridine were dissolved in 20 ml of dioxane, and the solution was prepared at room temperature using an acyl chloride solution [5 g of compound (III) according to the production method of Reference Example 2. ] Was added dropwise. After stirring overnight, the solvent was distilled off, and the mixture was separated with an ethyl acetate-KHSO ₄ aqueous solution. The organic layer was dried over sodium sulfate. The residue obtained by distilling off the solvent was dissolved in 50 ml of methanol and Na was added.
30 ml of an aqueous solution containing 3.0 g of OH was added under ice cooling,
The mixture was stirred at the same temperature for 4 hours. An aqueous KHSO ₄ solution was added to make it acidic, and the solvent was distilled off. The obtained residue was separated with ethyl acetate-water, and the ethyl acetate layer was dried over sodium sulfate. The obtained residue was subjected to silica gel column chromatography, eluted with 3% methanol / chloroform, and the solvent of the corresponding fraction was distilled off. Was obtained as a colorless solid (y. 81%). H-NMR (90 MHz, δ ppm, CD ₃ OD):
0.96 (d, J = 6.8 Hz, 12H), 1.28
(S, 12H), 1.9-2.4 (m, 2H), 3.0
9 (s, 4H), 4.36 (d, J = 5.6 Hz, 2
H) C-NMR (δ ppm, CD ₃ OD): 18.26, 1
9.34, 24.92, 25.25, 31.53, 4
4.37, 51.96, 58.08, 174.19, 1
77.33 Elemental analysis _{(C 20 H 36 N 2 O} 6 S 2 as 464.63) theory (%) 51.70 (C), 7.81 (H), Found (%) 51.78 (C ), 7.72 (H)

Example 8 3,3′-Dithiobis [2,2-dimethylpropion [N-1-carboxy-2-methylbutyl) amide]:
7.0 g of L-isoleucine was suspended in 50 ml of pyridine, and 1,1,3,3,3-hexamethyldisilazane
ml and ammonium sulfate were added to one spatula and heated to reflux. Two hours later, the solvent obtained by distilling off the solvent of the reaction solution was dissolved in 40 ml of dioxane, and an active substance was prepared using an acyl chloride solution [7 g of compound (III)] in this solution. ] Was added dropwise at room temperature. After 1 hour, the solvent was distilled off, dioxane and water were added, and the mixture was stirred at room temperature for 1 hour.
The residue obtained by evaporating the solvent was subjected to silica gel column chromatography, and eluted with 3% methanol / chloroform. Evaporate the solvent of the corresponding fraction,
11.65 g of the target compound was obtained as a colorless powder (y. 90%). The above compound (11.65 g) was dissolved in methanol, an aqueous NaOH solution (containing 1.7 g of NaOH) was added, the solvent was distilled off, and the residue was freeze-dried.
12.02 g of salt a was obtained as a colorless powder (y.95
%). H-NMR (90 MHz, δ ppm, CD ₃ OD):
0.8 to 1.1 (d, t, J = 6.8 Hz, 12H),
1.1 to 1.7 (s, m, 16H), 2.1 to 1.7
(M, 2H), 3.07 (s, 4H), 4.15 (d,
J = 5.6 Hz, 2H) C-NMR (δ ppm, CD ₃ OD): 11.81, 1
6.04, 24.92, 25.19, 25.74, 3
8.52, 44.27, 52.23, 60.52, 17
6.63,178.09 Elemental analysis _{(C 22 H 38 N 2 Na} 2 O 6 S 2 as 536.6
5) Theoretical value (%) 49.24 (C), 7.14 (H), measured value (%) 49.33 (C), 7.29 (H)

Example 9 3,3′-Dithiobis [2,2-dimethylpropion (N-1-carboxy-2-phenylethyl) amide]: H-NMR (90 MHz, δppm, CD ₃ OD):
1.13 (s, 6H), 1.16 (s, 6H), 2.9
3 (s, 4H), 3.0 to 3.3 (m, 4H), 4.6
8 (dd, J = 8.4 Hz, J = 5.5 Hz, 2H) C-NMR (δ ppm, CD ₃ OD): 24.92, 2
5.14, 38.03, 44.70, 52.34, 5
4.83, 127.76, 129.33, 130.3
6,138.32, 174.57, 178.15 Elemental analysis (560.72 as C ₂₈ H ₃₆ N ₂ O ₆ S ₂ ) Theoretical value (%) 59.98 (C), 6.47 (H), Measured value (%) 60.07 (C), 6.55 (H)

Example 10 3,3′-Dithiobis [2,2-dimethylpropion (N-1,3-dicarboxypropyl) amide]: H-NMR (90 MHz, δppm, CD ₃ OD):
1.27 (s, 6H), 1.29 (s, 6H), 1.8
5 to 2.60 (m, 8H), 3.07 (s, 4H),
4.43 (dd, J = 4.4 Hz, J = 3.7 Hz, 2
H) C-NMR (δ ppm, CD ₃ OD): 25.03,2
5.30,27.36,31.37,44.75,5
2.45, 53.37, 174.78, 176.57,
_{178.63 C 20 H 32 N 2 O} 10 S 2: 524.60 theory (%) 45.79 (C), 6.15 (H), Found (%) 45.91 (C), 6. 34 (H)

Example 11 3,3′-Dithiobis [2,2-dimethylpropion (N-1-carboxy-2-hydroxyethyl) amide]: 5.0 g of compound (III), serine methyl ester hydrochloride 6 2.0 g and 11.0 ml of triethylamine in D
After dissolving in 50 ml of MF, 6.0 ml of DEPC was added dropwise under ice cooling. After stirring at room temperature for 4 hours, the solvent was distilled off, and the mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was dried over sodium sulfate. The residue obtained by distilling off the solvent was subjected to silica gel column chromatography, and eluted with 7% methanol / chloroform. The solvent of the corresponding fraction was distilled off to obtain a colorless amide. Further, this was dissolved in 50 ml of methanol, and an aqueous solution of sodium hydroxide (3.2 g / 20 ml of NaOH) was added under ice-cooling, followed by stirring at the same temperature for 4 hours. KHSO ₄ aqueous solution (KHSO ₄ 11 g /
20 ml) and neutralized, and the residue obtained by evaporating the solvent was subjected to silica gel column chromatography.
Elution was carried out with 10% methanol / chloroform. The solvent of the corresponding fraction was distilled off to obtain 4.0 g of the target compound as a colorless solid (y. 48%). H-NMR (90 MHz, δ ppm, CD ₃ OD):
1.30 (s, 12H), 3.08 (s, 4H),
85 (dd, J = 11 Hz, J = 3.9 Hz, 2H),
3.95 (dd, J = 11.0 Hz, 3.9 Hz, 2
H), 4.48 (t, J = 3.9 Hz, 2H) C-NMR (δ ppm, CD ₃ OD): 24.76,2
4.98, 44.27, 51.96, 55.48, 6
2.53,172.89,177.76 Elemental analysis (C ₁₆ H ₂₈ N ₂ O as ₈ S ₂ 440.52) theory (%) 43.63 (C), 6.41 (H), Found (%) 43.81 (C), 6.56 (H)

Example 12 3,3'-Dithiobis [2,2-dimethylpropion]
(N-2-carboxy-2-hydroxyethyl) amide]: 7.0 g of isoserine is suspended in 30 ml of pyridine, and 30 ml of 1,1,1,3,3,3-hexamethyldisilazane and one cup of ammonium sulfate spatula are added. The mixture was heated under reflux. Two hours later, the solvent was distilled off, 40 ml of dioxane was added to the residue, and an acyl chloride solution [the active substance was prepared using 7 g of compound (III)]. ]
Was added dropwise at room temperature. After 1 hour, the solvent of the reaction solution was distilled off, dioxane and water were added, and the mixture was stirred at room temperature for 1 hour. The residue obtained by evaporating the solvent was subjected to silica gel column chromatography, and eluted with 7% methanol / chloroform. The solvent of the corresponding fraction was distilled off to obtain 8.2 g of the target compound as a colorless candy (y. 71%). H-NMR (90 MHz, δ ppm, CD ₃ OD):
1.26 (s, 12H), 3.04 (s, 4H),
4-3.7 (m, 4H), 4.26 (dd, J = 4.8)
Hz, 6.6 Hz, 2H) C-NMR (δ ppm, CD ₃ OD): 25.03,4
3.89, 44.37, 52.12, 70.33, 17
_{5.33,178.63 C 16 H 28 N 2 O} 8 S 2: 440.52 theory (%) 43.63 (C), 6.41 (H), Found (%) 43.55 (C ), 6.30 (H)

Example 13 3,3′-Dithiobis [2,2-dimethylpropion (N-2-ethoxycarbonyl-2-hydroxyethyl) amide]: 1 H-NMR (90 MHz, δ ppm, CD ₃ OD):
1.24 (s, 12H), 1.28 (t, J = 7.1H)
z, 6H), 3.03 (s, 4H), 3.49 (d, J
= 5.9 Hz, 4H), 4.19 (q, J = 7.1H)
z, 4H), 4.26 (t, J = 5.9 Hz, 2H) C-NMR (δ ppm, CD ₃ OD): 14.52, 2
5.19, 44.21, 44.81, 52.61, 6
2.36,70.87,174.08,178.90 Elemental analysis _{(C 20 H 36 N 2 O} 8 S 2 as 496.63) theory (%) 48.37 (C), 7.31 (H ), Actual value (%) 48.49 (C), 7.40 (H)

Example 14 3,3′-Dithiobis [2,2-dimethylpropion (N-2-hydroxyethyl) amide]: 1,1,1,3,3,3-ethanol 5.0 g 36 ml of hexamethyldisilazane and ammonium sulfate are spatula 1
A cup was added and heated to reflux. After 2 hours, the solvent was distilled off, this was dissolved in 40 ml of dioxane, and the active substance was prepared using 10 g of acyl chloride [compound (III)]. ] Was added dropwise at room temperature. After 1 hour, the solvent of the reaction solution was distilled off, dioxane and water were added, and the mixture was stirred at room temperature for 1 hour. The residue obtained by evaporating the solvent was subjected to silica gel column chromatography, and eluted with 7% methanol / chloroform. The solvent of the corresponding fraction was distilled off to obtain 12.0 g of the target compound as a colorless candy (y. 91%). H-NMR (90 MHz, δ ppm, CDCl ₃ ):
1.26 (s, 12H), 3.04 (s, 4H),
3.3 to 3.6 (m, 4H), 3.6 to 3.9 (m, 4
H), 4.21 (brs, 2H), 6.78 (brt,
2H) C-NMR (δ ppm, CDCl ₃ ): 25.03,4
2.59, 43.67, 51.74, 61.44, 17
7.06 Elemental analysis _{(C 14 H 28 N 2 O} 4 as S ₂ 352.50) theory (%) 47.70 (C), 8.01 (H), Found (%) 47.62 (C ), 8.14 (H)

Example 15 3,3'-dithiobis [2,2-dimethylpropion (N-2,3-dihydroxypropyl) amide]: 3-
To 8.0 g of amino-1,2-propanediol was added 100 ml of pyridine, 60 ml of 1,1,1,3,3,3-hexamethyldisilazane and one cup of ammonium sulfate, and the mixture was heated under reflux overnight. After the reaction, the solvent was distilled off, the residue was dissolved in 40 ml of dioxane, and an active compound was prepared using 10 g of an acyl chloride solution [compound (III). ] Was added dropwise at room temperature. After 1 hour, the solvent was distilled off, dioxane and 0.1N hydrochloric acid were added, and the mixture was stirred at room temperature for 1 hour.
The residue obtained by evaporating the solvent was subjected to silica gel column chromatography, and eluted with 10% methanol / chloroform. The solvent of the corresponding fraction was distilled off to obtain 12.98 g of the target compound as a colorless candy (y.
84%). H-NMR (90 MHz, δ ppm, CD ₃ OD):
1.27 (s, 12H), 3.05 (s, 4H),
2 to 3.4 (m, 4H), 3.4 to 3.6 (m, 4
H), 3.6-3.9 (m, 2H) C-NMR (δ ppm, CD ₃ OD): 25.14,4.
3.24, 44.43, 52.28, 64.58, 7
1.48, 178.74 Elemental analysis (412.55 as C ₁₆ H ₃₂ N ₂ O ₆ S ₂ ) Theoretical value (%) 46.58 (C), 7.82 (H), measured value (%) 46 .71 (C), 7.98 (H)

Example 16 3,3'-dithiobis [2,2-dimethylpropionamide]: acyl chloride solution [compound (III) 50]
The active substance was prepared using g. Is 100 m
This solution was added dropwise to 200 ml of aqueous ammonia under ice-cooling. The resulting precipitate was collected by filtration and washed with aqueous sodium hydrogen carbonate to obtain 47 g of the target compound as a colorless powder (y. 9).
5%). H-NMR (90 MHz, δ ppm, CD ₃ OD):
1.16 (s, 12H), 2.99 (s, 4H),
92 (brs, 2H), 7.20 (brs, 2H) C-NMR (δ ppm, CD ₃ OD): 23.79,4
2.86,50.93,179.82 Elemental analysis _{(C 10 H 20 N 2 O} 2 S 2 as 264.40) theory (%) 45.43 (C), 7.62 (H), Found (%) 45.55 (C), 7.70 (H)

Example 17 3,3′-Dithiobis [2,2-dimethylpropion (N-hydroxy) amide]: H-NMR (90 MHz, δppm, CD ₃ OD):
1.23 (s, 12H), 3.04 (s, 4H) C-NMR (δ ppm, CD ₃ OD): 24.87, 4
3.62, 52.50, 175.43 Elemental analysis (296.39 as C ₁₀ H ₂₀ N ₂ O ₄ S ₂ ) Theoretical value (%) 40.52 (C), 6.80 (H), measured value (%) 40.70 (C), 6.92 (H)

Example 18 3,3′-dithiobis (2,2-dimethylpropion hydrazide): acyl chloride solution [compound (III)
The active was prepared using 10 g. ] To methanol 10
The mixture was added dropwise to 0 ml under ice cooling. After completion of the dropwise addition, the solvent of the reaction solution was distilled off to obtain a methyl ester compound. H-NMR (90 MHz, δ ppm, CDCl ₃ ):
1.27 (12H, s), 3.02 (4H, s), 3.
69 (6H, s) This methyl ester was dissolved in 50 ml of hydrazine hydrate and 50 ml of methanol, and the mixture was refluxed overnight at 80 ° C. under a nitrogen atmosphere. After evaporating the solvent of the reaction solution and separating with chloroform-water, the organic layer was dried and the solvent was distilled off. The obtained residue was subjected to silica gel chromatography and eluted with 10% methanol / chloroform. The solvent of the corresponding fraction was distilled off to obtain 7.6 g of the target compound as a colorless candy (y. 69%). H-NMR (90 MHz, δ ppm, CDCl ₃ ):
1.28 (s, 12H), 3.03 (s, 4H),
4.07 (brs, 4H), 8.07 (brs, 2H) C-NMR (δ ppm, CDCl ₃ ): 24.87, 4
_{2.77,50.77,176.57 C 10 H 22 N 4 O} 2 S 2: 294.43 theory (%) 40.79 (C), 7.53 (H), Found (%) 40 .98 (C), 7.65 (H)

Example 19 3,3′-Dithiobis [2,2-dimethylpropion (N-carboxymethyl-N-methyl) amide]: 10.0 g of sarcosine was suspended in 50 ml of pyridine, and
1,1,3,3,3-hexamethyldisilazane 50 ml
And one cup of ammonium sulfate spatula were added and heated to reflux. After 2 hours, the solvent of the reaction solution was distilled off, and dioxane 40 m
After dissolving in an acyl chloride solution [compound (II)
I) The active substance was prepared using 7 g. ] Was added dropwise at room temperature. After 1 hour, the solvent of the reaction solution was distilled off, and then dioxane and water were added, followed by stirring at room temperature for 1 hour. The precipitated solid was collected by filtration to obtain 65 g of the target compound as a colorless powder (y. 9).
9%). H-NMR (90 MHz, δ ppm, CD ₃ OD):
1.28 (s, 12H), 3.14 (s, 4H),
3.19 (s, 6H), 4.06 (s, 4H) C-NMR (δ ppm, CD ₃ OD): 25.41,3
8.36,44.86,52.56,54.99,17
2.02, 177.38 Elemental analysis (408.52 as C ₁₆ H ₂₈ N ₂ O ₆ S ₂ ) Theoretical value (%) 47.04 (C), 6.91 (H), Actual value (%) 47 .19 (C), 7.02 (H)

Example 20 3,3'-dithiobis [2,2-dimethylpropion (N-methyl) amide]: 100 m aqueous methylamine solution
An active substance was prepared by using 7 g of an acyl chloride solution [compound (III)] for 1. ] Was added dropwise under ice cooling. After stirring for 10 minutes at room temperature after completion of the dropwise addition, the solvent of the reaction solution was distilled off. After separating the obtained residue with ethyl acetate and water, the organic layer was dried and the solvent was distilled off to give the target compound 7 as a colorless powder.
g was obtained. (Y. 91%) 1 H-NMR (90 MHz, δ ppm, CDCl ₃ ):
1.26 (s, 12H), 2.82 (d, J = 4.6H)
z, 6H), 3.03 (s, 4H), 6.10 (br
s, 2H) C-NMR (δ ppm, CDCl ₃ ): 25.09,2
6.66,43.56,51.63,176.57 Elemental analysis _{(C 12 H 24 N 2 O} 2 S 2 as 292.45) theory (%) 49.28 (C), 8.27 (H ), Measured value (%) 49.41 (C), 8.38 (H)

Example 21 3,3′-Dithiobis [2,2-dimethylpropion (N-1-carboxy-3-carbamoylpropyl) amide]: H-NMR (90 MHz, δ ppm, CD ₃ OD):
1.27 (s, 6H), 1.29 (s, 6H), 1.9
0 to 2.45 (m, 8H), 3.07 (s, 4H),
4.25~4.45 (m, 2H) Elemental analysis _{(C 20 H 34 N 4 O} 8 S 2 as 522.63) theory (%) 45.96 (C), 6.56 (H), measured Value (%) 46.21 (C), 6.72 (H)

Example 22 3,3′-Dithiobis [2,2-dimethylpropion (N-1-carboxy-5-aminopentyl) amide]: 9.0 g of ε-N-Boc-lysine was added to pyridine 30
and 1,1,1,3,3,3-hexamethyldisilazane 20 ml and ammonium sulfate spatula 1
A cup was added and heated to reflux. After 2 hours, the solvent was distilled off, dissolved in dioxane (30 ml), and an acyl chloride solution [the active substance was prepared using 5 g of compound (III)]. ] Was added dropwise at room temperature. One hour later, the solution was distilled off, dioxane and water were added, and the mixture was stirred at room temperature for 1 hour. After evaporating the solution, the obtained residue was subjected to silica gel column chromatography, and eluted with 7% methanol / chloroform. The solvent of the corresponding fraction was distilled off to obtain 11.1 g of a colorless amide-like amide (y. 82%). 11.1 g of this amide was dissolved in 50 ml of 90% formic acid and stirred overnight at room temperature. 3 ml of concentrated hydrochloric acid was added to the reaction solution, and the solvent was distilled off. 2 ml of concentrated hydrochloric acid and 100 ml of water were added to the residue, and the water was distilled off. 9.0 g of the target compound was obtained as a millet-like substance (y. 98%). H-NMR (90 MHz, δ ppm, CD ₃ OD):
1.29 (s, 6H), 1.31 (s, 6H), 1.2
~ 2.1 (m, 6H), 3.10 (brt, J = 7.6)
Hz, 4H), 4.37 (brt, J = 6.7 Hz, 2
H) C-NMR (δ ppm, CD ₃ OD): 23.68, 2
5.09, 25.19, 27.52, 31.10, 4
0.20, 44.43, 52.34, 53.48, 17
3.65,178.30

Example 23 3,3'-Dithiobis [2,2-dimethylpropion (N-2,3-dihydroxypropoxycarbonylmethyl) amide]: 9.28 g of glycine 2,3-O-isopropylidenepropyl ester and triethylamine 7.0
ml of DMAP and a catalytic amount of DMAP are dissolved in 100 ml of dioxane, and an acyl chloride solution [6.0 g of compound (III)] is dissolved.
Was used to prepare the active. ] Was added dropwise at room temperature. Two hours later, the solution was distilled off, and the residue was partitioned between chloroform and a sodium hydrogen carbonate solution. After drying the organic layer, the solvent was distilled off, and the residue was subjected to column chromatography (1% methanol / chloroform). The solvent of the corresponding fraction was distilled off, and the amide compound 6.5 as a colorless syrup was obtained.
g was obtained. 6.5 g of this amide was dissolved in 50 ml of 90% trifluoroacetic acid and left at room temperature. The solvent of the reaction solution was distilled off, the residue was subjected to silica gel column chromatography (7% methanol / chloroform), and the solvent of the corresponding fraction was distilled off to obtain 3.57 g of the target compound as a colorless syrup. (Y. 63%). H-NMR (90 MHz, δ ppm, CD ₃ OD):
1.29 (s, 12H), 3.06 (s, 4H),
50 to 3.75 (m, 4H), 3.8 to 4.0 (m, 2
H), 3.95 (s, 4H), 4.18 (m, 4H),
4.20 (d, J = 5.0 Hz) C-NMR (δ ppm, CD ₃ OD): 25.03,4
2.15,44.43,52.28,63.72,6
6.91,70.65,171.00,178.80 Elemental analysis (C ₂ 0H36N2O10S ₂ as 528.64) theory (%) 45.44 (C), 6.86 (H), Found (% ) 45.43 (C), 6.83 (H)

[0060] (Example 24) In the general formula (I), R ₁ R ₂ of N- group R ^1, R ² is a proline residue taken together compounds: L-proline methyl ester hydrochloride 5.0g , 9 ml of triethylamine and a catalytic amount of dimethylaminopyridine were dissolved in 20 ml of dioxane, and the above acyl chloride solution [compound (II)
I) The active was prepared using 4.0 g. ] Was added dropwise. After stirring overnight, the solvent was distilled off and ethyl acetate-KHSO
After liquid separation with ₄ aqueous solutions, the organic layer was dried over sodium sulfate. The residue obtained by distilling off the solvent was subjected to silica gel column chromatography and eluted with chloroform. The solvent of the corresponding fraction was distilled off to obtain 6.2 g of an ester as a colorless solid (y. 84%). 6.2 g of this ester compound was dissolved in 10 ml of methanol and 10 ml of tetrahydrofuran (THF), 10 ml of an aqueous solution containing 2.0 g of sodium hydroxide was added under ice cooling, and the mixture was stirred at the same temperature for 4 hours. An aqueous solution containing 4.7 g of KHSO ₄ was added, the solvent was distilled off, and the obtained residue was subjected to silica gel column chromatography, and eluted with 10% methanol / chloroform. The solvent of the corresponding fraction was distilled off to obtain 2.9 g of the target compound as a colorless solid (y. 50%). H-NMR (90 MHz, δ ppm, CD ₃ OD):
1.34 (s, 6H), 1.39 (s, 6H), 1.7
~ 2.4 (m, 8H), 3.12 (s, 4H), 3.8
0 (pst, 4H), 4.43 (pst, 2H) C-NMR (δ ppm, CD ₃ OD): 24.49, 2
5.45, 26.17, 28.44, 44.75, 5
3.48,61.93,175.17,175.65 Elemental analysis _{(C 20 H 32 N 2 O} 6 S 2 as 460.60) theory (%) 52.15 (C), 7.00 (H ), Measured value (%) 52.30 (C), 7.14 (H)

(Example 25) Compound of formula (II) wherein m is 0: Acyl chloride solution [20 g of hydrazine hydrate and 20 ml of water under ice-cooling] [Preparation of active substance using 10 g of compound (III)] did. ] The solution was added dropwise. After stirring at the same temperature for 4 hours, the deposited precipitate was collected by filtration and washed with methanol to obtain 5.0 g of the desired compound as colorless crystals (y. 51%). H-NMR (90 MHz, δ ppm, DMSO-d ₆ ):
1.24 (s, 12H), 3.06 (s, 4H), 9.
48 (brs, 2H) Elemental analysis _{(C 10 H 18 N 2 O} 2 S 2 as 262.38) theory (%) 45.78 (C), 6.91 (H), Found (%) 45. 85 (C), 7.02 (H)

(Example 26) In formula (II), a compound in which m is 2: 25 ml of ethylenediamine is dissolved in 50 ml of methylene chloride, and an acyl chloride solution [the active substance is prepared using 10 g of compound (III) under ice-cooling] did. ] Was added dropwise. After stirring at the same temperature for 1 hour, liquid separation was performed with chloroform-water, and the organic layer was dried over sodium sulfate. The residue obtained by distilling off the solvent was subjected to silica gel column chromatography, and eluted with 10% methanol / chloroform. The solvent of the corresponding fraction was distilled off, and the target compound (6.0 g) was obtained as a colorless candy.
(Y. 55%). H-NMR (90 MHz, δ ppm, CD ₃ OD):
1.26 (s, 12H), 3.04 (s, 4H),
32 (brs, 4H) Elemental analysis _{(C 12 H 22 N 2 O} 2 as S ₂ 290.43) theory (%) 49.63 (C), 7.63 (H), Found (%) 49. 88 (C), 7.82 (H)

Liver Disease Action Test Therapeutic Effect on Ethionine Liver Injury: (Test Method) Wistar rats were fasted overnight (body weight 2
(00 to 230 g), and used as 4 to 5 animals per group. Ethionine was suspended in 5% gum arabic saline, and 1 g /
Ip administration at a dose of 10 ml / kg. The compound of Example 1 was dissolved in physiological saline (neutralized with 2 equivalents of sodium bicarbonate), and 3 hours after administration of ethionine, 2 mmol / 5 ml
Iv was administered at a dose of / kg, blood was collected 24 hours after administration, and serum was separated. Serum GOT, GP with automatic serum analyzer
T, ALP and BIL were measured. The animals were fed 5 hours after the administration of ethionine. The results were as shown in the following table. In the drug administration group, liver damage due to ethionine has been improved and suppressed to a value close to the normal value.

[0064]

[Table 2]

Streptozotocin (STZ) effect on diabetic nephropathy model Test method: Streptozotocin (40 mg / kg) was intravenously administered (day 1) and blood was collected on days 41 to 48 using male Wistar rats (8 weeks old). A serum biochemical test was performed. Blood sugar level, CHO level, urinary ALB
Each test drug was orally administered by grouping the values and body weights as indices. The test drug is daily from day 50 to 65 (5 days a week,
0.1-1.0 mmol / kg / day). The control group was administered with physiological saline, and the following items were changed: body weight change, plasma GLU, plasma BUN, plasma CRE,
Plasma CHO, plasma TG, plasma ALB, plasma TP, plasma G
OT, plasma GPT, urine volume, urinary glucose, urine total protein, urinary ALB, etc. were measured every 2-3 weeks. As a result, the compound of the present invention showed a plasma GLU,
Kidney damage was reduced by suppressing increases in plasma BUN, plasma CHO, plasma TG, and urinary ALB levels.

[0066]

[Table 3]

[0067]

[Table 4]

[0068]

[Table 5]

[0069]

[Table 6]

[0070]

[Table 7]

[0071]

[Table 8]

[0072]

[Table 9]

[0073]

[Table 10]

[0074]

[Table 11]

From the above results, the compound of the present invention is useful as a remedy for renal diseases since it improves all indicators of renal impairment (such as CHO, TG and urinary albumin). In addition, the compounds of the present invention have the effect of lowering blood lipids and have improved ethionine hepatic injury, and are therefore useful as therapeutic agents for liver diseases.

The compound of the present invention and a pharmacologically acceptable salt thereof suppressed renal disorder (increase in urinary ALB) associated with diabetes. Therefore, the compound of the present invention can be used as a therapeutic drug for diabetic kidney disease. Useful.

From the above results, it is understood that the compound of the present invention and its pharmacologically acceptable salts have excellent pharmacological actions. That is, the compound of the present invention and a pharmacologically acceptable salt thereof are extremely useful as a therapeutic agent for renal disease. Nephrotic syndrome, nephrotic syndrome, diabetic nephropathy, cataract due to diabetic nephropathy, renal disorder due to hyperuricemia, renal disorder due to gout kidney, renal disorder due to acute renal failure, renal disease are induced by drugs The present invention is useful as a therapeutic agent for renal disease which is a renal disorder or a renal disease wherein renal disease is a renal disorder induced by heavy metals. Further, the compound of the present invention and pharmacologically acceptable salts thereof are therapeutic agents for liver disease, for example, liver disease, hepatitis, fatty liver,
It is extremely useful as a therapeutic agent for liver diseases that are liver diseases derived from toxic liver damage, cirrhosis or diabetes.

The compound of the present invention can be orally or parenterally administered to a patient by a usual administration method. Further, the compounds of the present invention can be used alone or by formulation with a compatible pharmaceutical carrier. Carrier materials include water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oil,
Organic or inorganic inert carrier materials suitable for intestinal, transdermal or parenteral administration, such as polyalkylene glycols and petrolatum. Formulations include tablets, sugar-coated tablets, enteric-coated tablets, granules,
Solid preparations such as powders, suppositories, capsules, enteric capsules and the like, semisolid preparations such as ointments, and liquid preparations such as solutions, suspensions and emulsions. Each of the above preparations can be produced according to a conventional method. In addition, auxiliary agents such as preservatives, stabilizers, setting agents, emulsifiers, flavor improvers, salts, and buffers can also be added.

When the compound of the present invention is used as a medicine, it can be used alone or in combination of two or more different compounds. The amount used is about 0.1 to 99.5%, preferably 0.5 to 95%, by total weight of the pharmaceutical composition.

The daily dosage of the compound of the present invention for a patient will vary depending on the use, body weight, age, and the condition to be treated, but is generally 0.5 to 50 mg / capita.
In the range of 3000 mg, preferably about 3 to 1000 m
g.

Formulation Example 1 Tablets are prepared by the usual method using the following composition. Compound of Example 1 25 mg Lactose 60 mg Potato starch 40 mg Polyvinyl alcohol 2 mg Magnesium stearate 1 mg

Formulation Example 2 Granules having the following composition are prepared by a conventional method. Compound of Example 1 50 mg Lactose 15 mg Maize starch 10 mg Hydroxypropyl cellulose 20 mg Polyvinyl alcohol 5 mg

Formulation Example 3 A powder is prepared in the usual manner by the following composition. Compound of Example 1 25 mg Lactose 275 mg

Formulation Example 4 The powder obtained in Formulation Example 3 is filled into a capsule container to prepare a capsule. Compound of Example 1 25 mg Lactose 275 mg

[0085]

According to the present invention, it is possible to provide a novel 3,3'-dithiobis (2,2-propionamide) derivative, and a therapeutic agent for renal disease and liver disease containing the derivative as an active ingredient. Was.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/27 A61K 31/27 C07D 285/00 C07D 285/00 (72) Inventor Tomokazu Sugawara Kamiichi-cho, Nakashinagawa-gun, Toyama Prefecture 55, Hoonji Temple, Fuji Chemical Industry Co., Ltd. (72) Inventor Yukie Moriguchi Yokohoonji, Nakayama, Gunma, Toyama Prefecture 55: Inside Fuji Chemical Industry Co., Ltd. (72) Inventor, Takeshi Endo 55 Hoonji Temple Fuji Chemical Industry Co., Ltd.

Claims (5)

[Claims] 1. A compound of the general formula (Wherein, R ¹ is at least selected from the group consisting of a hydrogen atom, an amino group, a hydroxyl group, a linear or branched alkyl group, or an amino group, a hydroxyl group, an alkoxy group, a carboxyl group, an alkoxycarbonyl group, an aryl group, and a carbamoyl group. 1
Represents a straight-chain or branched alkyl group which may be substituted by three substituents, and R ² represents a hydrogen atom or a lower alkyl group) and 3,3′-dithiobis (2,2-dimethylpropionamide) ) Derivatives, isomers or pharmacologically acceptable salts. (2) 3,3′-dithiobis [2,2-dimethylpropion (N-carboxymethyl) amide],
3'-dithiobis [2,2-dimethylpropion (N-
Carboxyethyl) amide], 3,3′-dithiobis [2,2-dimethylpropion (N-ethoxycarbonylmethyl) amide], 3,3′-dithiobis [2,2-
Dimethylpropion (N-isopropoxycarbonylmethylamide), 3,3′-dithiobis [2,2-dimethylpropion (N-1-carboxyethyl) amide],
3,3′-dithiobis [2,2-dimethylpropion (N-1-carboxy-2-methylpropyl) amide], 3,3′-dithiobis [2,2-dimethylpropion (N-1-carboxy-2-) Methylbutyl) amide], 3,3′-dithiobis [2,2-dimethylpropion (N-1-carboxy-2-phenylethyl) amide], 3,3′-dithiobis [2,2-dimethylpropion (N-1 , 3-dicarboxypropyl) amide],
3,3′-dithiobis [2,2-dimethylpropion (N-1-carboxy-2-hydroxyethyl) amide], 3,3′-dithiobis [2,2-dimethylpropion (N-2-carboxy-2- Hydroxyethyl) amide], 3,3′-dithiobis [2,2-dimethylpropion (N-2-ethoxycarbonyl-2-hydroxyethyl) amide], 3,3′-dithiobis [2,2-dimethylpropion (N -Hydroxy) amide], 3,
3'-dithiobis [2,2-dimethylpropion (N-
2-hydroxyethyl) amide], 3,3′-dithiobis [2,2-dimethylpropion (N-2,3-dihydroxypropyl) amide], 3,3′-dithiobis [2,2-dimethylpropionamide], 3,3′-dithiobis [2,2-dimethylpropion hydrazide],
3,3′-dithiobis [2,2-dimethylpropion (N-carboxymethyl-N-methyl) amide], 3,
3'-dithiobis [2,2-dimethylpropion (N-
Methyl) amide], 3,3′-dithiobis [2,2-dimethylpropion (1-carboxy-3-carbamoylpropyl) amide], 3,3′-dithiobis [2,2-
Dimethylpropion (1-carboxy-5-aminopentyl) amide], 3,3'-dithiobis [2,2-dimethylpropion-N- (2,3-dihydroxypropoxycarbonylmethyl) amide]. 3. A compound of the general formula (In the formula, m represents an integer of 0 to 6.) and a pharmacologically acceptable salt thereof. 4. A remedy for renal diseases comprising the compound according to claim 1 as an active ingredient. 5. A therapeutic agent for liver disease comprising the compound according to claim 1 as an active ingredient.