JPS6172785A - Novel tetrahydro-beta-carboline derivative and its production - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (when R<1> is carboxyl, R<2>, R<3> are H, R<4> is lower alkyl, X is halogen, lower alkyl, hydroxyl, lower alkoxy, benzyloxy; when R<1> is H, carboxymethyl, both of R<2> and R<3> are H or one of them carboxyl or lower alkoxycarbonyl, while the other is H, R<4> is lower alkyl, halogenated benzyl, X is H). EXAMPLE:(3S)-6-Fluoro-2-(methylthio)thiocarbonyl-1,2,3,4-tetra-hy-dro- '-car borin-3-carboxylic acid. USE:Remedy and preventive for hepatopathy: it shows high safety. PREPARATION:The reaction between a compound of formula II, carbon disul fide, and another compound of the formula: R<4>-X'' (X' is halogen) such as methyl iodide is carried out, preferably in a solvent such as dimethyl sulfoxide in the presence of a base such as triethylamine at 10-30 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention provides novel tetrahydro-
The present invention relates to a β-calporin derivative and a method for producing the same.

(Prior art) The liver performs detoxification, tJM metabolism, lipid metabolism, protein metabolism, production and secretion of bile, production of blood coagulation factors, regulation of hormones, regeneration of hepatocytes, and biological components (e.g. fat, glycogen, protein). It is an organ that has various functions such as storing vitamins, vitamins, etc. However, these functions can be impaired acutely or chronically due to viruses, drugs, poisons, alcohol, malnutrition, hepatic circulatory system disorders, bile duct obstruction, etc., resulting in viral hepatitis, drug-induced hepatitis,
It manifests as alcoholic hepatitis, congestive hepatitis, liver damage due to cholestasis, fatty liver, yellowing, or eventually cirrhosis.

Vitamins, hormones, metabolic drugs, etc. are generally used as therapeutic agents for these liver disorders, but the reality is that there are still almost no satisfactory therapeutic agents.

(Problems to be Solved by the Invention) The present invention provides pharmaceutical compounds that can be used as prophylactic and therapeutic agents for various liver disorders.

(Structure and Effects of the Invention) The present invention is based on the general formula (a) where R' is a carboxy group, R2 and R3 are both a hydrogen atom, R4 is a lower alkyl group, and X is a halogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, or represents a benzyloxy group, or (b) R' is a hydrogen atom or a carboxymethyl group, R2 and R3 are both hydrogen atoms, or one of R2 and R3 is a carboxy group or a lower alkoxycarbonyl group; , the other one is a hydrogen atom, R4 is a lower alkyl group or a halogenated benzyl group, and X is a hydrogen atom. ) A novel tetrahydro-β-calporin derivative represented by
The present invention relates to a method for producing the derivative and a pharmaceutical composition containing the derivative as an active ingredient.

The objective compound (I) has an excellent therapeutic, alleviating or protective effect on liver damage. For example, when the protective effect against liver damage induced by carbon tetrachloride was investigated in mice, the compound of the present invention (3S)-6-fluoro-
2-(methylthio)thiocarbonyl-1,2,3,4-
The increase in relative liver weight can be suppressed by 20% or more by administering tetrahydro-β-arboline. Furthermore, compound (1) has low toxicity and is highly safe when used as a medicine.

Examples of target compounds include general formula (1) (a) R
' is a carboxyl group, R2 and R3 are both hydrogen atoms, R4 is a lower alkyl group such as methyl, ethyl, propyl, or butyl, and X is a halogen such as fluorine, chlorine, bromine, or iodine. Atom, methyl group. Lower alkyl groups such as ethyl group, propyl group, butyl group,
or (b) R' is a hydrogen atom or a carboxymethyl group, and R2 and R3 are both hydrogen atoms or , one of R2 and R3 is a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group,
A lower alkoxycarbonyl group such as a butoxycarbonyl group, where the other is a hydrogen atom, and R4 is a lower alkyl group such as a methyl group, ethyl group, propyl group, or butyl group, or a halogenated benzyl group such as a chlorobenzyl group or an iodobenzyl group. Examples include compounds where X is a hydrogen atom.

Among these, more preferable compounds include the general formula (1
), (a) R' is a carboxy group, R2 and R3 are both hydrogen atoms, R4 is a methyl group, and X is a chlorine atom, a fluorine atom, a methyl group, a hydroxyl group, or a benzyloxy group, or (b) ) R' is a hydrogen atom or a carboxymethyl group, R2 and R3 are both hydrogen atoms, or one of R2 and R3 is a carboxyl group or a methoxycarbonyl group and the other is a hydrogen atom, and R4 is Examples include a methyl group, a chlorobenzyl group, and a compound in which X is a hydrogen atom.

More preferred compounds include general formula (I) in which (a) R' is a carboxy group, R2 and R3 are both hydrogen atoms, R4 is a methyl group, and X is a fluorine atom, methyl group or methoxy group; or (b) R' is a hydrogen atom or a carboxymethyl group, R2 is a hydrogen atom,
Examples include compounds in which R3 is a hydrogen atom or a carboxy group, R4 is a methyl group, and X is a hydrogen atom.

When at least one of R1, R2 and R3 is a carboxy group or a carboxymethyl group, the target compound (1) can be used in the form of either a free base or a pharmacologically acceptable salt.

As the salt of the target compound (I), for example, metal salts such as sodium salt, potassium salt, calcium salt, ammonium salt or organic amine salt such as trimethylamine salt, triethylamine salt, 2-aminoethanol salt, etc. can be suitably used. . In the target compound (1), R1, R2
and R3 is a carboxy group, a carboxymethyl group, or a lower alkoxycarbonyl group, two types of optical isomers exist; R1 is a carboxymethyl group, and either R2 or R3 is a carboxy group or a lower When it is an alkoxycarbonyl group, there are two types of stereoisomers and four types of optical isomers.

The scope of the present invention includes any of these stereoisomers, optical isomers, and/or mixtures thereof.

According to the present invention, the target compound (I) has the general formula (where R1
, R2, R3 and X have the same meanings as above. ) or a salt thereof, and carbon disulfide and a compound represented by the general formula % ([) (where Xo represents a halogen atom and R4 represents the same meaning as above). can be manufactured.

6 In general formula (I), one of R2 and R3 is a carboxyl group and the other is a hydrogen atom, the compound of the general formula obtained above (however, R7 and R@ is lower alkoxycarbonyl) (wherein the other is a hydrogen atom, and R1, R4 and X have the same meanings as above).

Preferred examples of the salt of the raw material compound (n) include hydrochloride, hydrobromide, and the like. On the other hand, halogen compounds (I[
As [), a compound in which Xo is a chlorine atom, a bromine atom, or an iodine atom can be suitably used.

The reaction between the compound (n) or a salt thereof and the halogen compound (■) can be suitably carried out in a suitable solvent in the presence of a base. Examples of bases include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, sodium carbonate,
Included are alkali metal carbonates such as potassium carbonate and organic bases such as triethylamine, N-methylmorpholine, N,N-dicyclohexylamine. As the solvent, alkanols such as methanol and ethanol, dimethyl sulfoxide, N,N-dimethylformamide, dioxane, tetrahydrofuran, water, or a mixture thereof can be used as appropriate. The reaction is preferably carried out at 0 to 50°C,
In particular, it is preferable to carry out at 10 to 30°C. on the other hand,
Hydrolysis of compound (1-a'') can be suitably carried out in a solvent in the presence of a base. Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, sodium carbonate, and potassium carbonate. Alkali metal carbonates such as sodium bicarbonate, alkali metal bicarbonates such as potassium bicarbonate, etc. can be suitably used. Examples of solvents include hydrous alkanols such as hydrous methanol and hydrous ethanol, hydrous tetrahydrofuran, hydrous dioxane, etc. Preferably, the reaction is carried out at a temperature of 10 to 80°C.

Among the target compounds (I), compounds in which R1 is a carboxy group or a carboxymethyl group and/or one of R2 and R3 is a carboxyl group may be used with an inorganic base (
(e.g., alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, or ammonia) or organic bases (e.g., trialkylamines such as triethylamine, trimethylamine, 2-aminoethanol, etc.) can be processed to form a pharmacologically acceptable salt.

Although the starting material compound (II) of the present invention may exist in two types of optical isomers, two types of stereoisomers, and four types of optical isomers, the process of the present invention proceeds without racemization. Therefore, if the optically active form of the corresponding raw material compound (n) is used, the target compound (1) can also be obtained as an optically active form.

The raw material compound (n) can be produced, for example, according to the following reaction formula.

(However, R1, R2, R3 and X have the same meanings as above.) Compound (■) or its salt and aldehyde compound (V)
The reaction with can be carried out in a solvent at 20 to 100°C. In addition, among the raw material compounds (II), compounds in which either R2 or R3 is a carboxyl group are R2 and R3.
'', one of which is a lower alkoxycarbonyl group, is obtained by hydrolyzing the corresponding raw material compound (n) according to a conventional method.On the other hand, among the raw material compounds (n), 1.
The method for producing 2,3.4-tetrahydro-β-carboline-4-acetic acid is as shown in Production Example 9. In the production of the above raw material compound, the optically active form of the raw material compound (n) can be obtained by using the optically active form as its corresponding starting material.

The object compound (I) of the present invention is particularly effective against liver disorders with centrilobular necrosis, liver disorders with perilobular necrosis, liver disorders with scattered lobular necrosis and mesenchymal reactions, fatty liver, drug-induced hepatitis, It is highly effective in treating, preventing and alleviating congestive hepatitis. Therefore, the object compound (1) of the present invention is
It is useful as a treatment and prevention agent for liver disorders in animals including humans, such as viral hepatitis, drug-induced hepatitis, alcoholic hepatitis, fatty liver, yellow liver disease, and even cirrhosis, which is the final stage of these. It can be used for mitigation or prevention.

The object compound (1) of the present invention can be administered orally or parenterally (for example, by intravenous, intramuscular or subcutaneous injection). The dosage of compound (I) varies depending on the patient's age, weight, condition, degree of disease, etc., but the daily dosage is usually 0.01 to 250 μ/kg, preferably 0.
．． 1~50■/kg. In particular, when compound (I) is administered orally, the dosage is 0.1 to 0.1 per day.
Preferably it is 250 mg/kg, especially 0.5 to 50 μ/kg.

The object compound (I) of the present invention can also be used in the form of a mixture with excipients suitable for conventional oral or parenteral administration. Such excipients may include, for example, gelatin, lactose, glucose, sodium chloride, starch, magnesium stearate, talc, vegetable oils, and the like. Further, the dosage form may be a solid preparation such as a tablet, sugar-coated tablet, pill, capsule, or powder, or a liquid preparation such as a solution, suspension, or emulsion. These preparations may be sterilized and may contain adjuvants such as stabilizers, wetting agents or emulsifiers.

In this specification, the terms "lower alkyl group" and "lower alkoxy group" mean an alkyl group and an alkoxy group having 1 to 4 carbon atoms, respectively.

Experimental Example 1 (Effect on acute carbon tetrachloride liver injury) (Experimental method) A sample suspended in a 0.5% carboxymethylcellulose solution (dose: 100 μ/10 ml/kg) was administered to ddY male mice (5 to 6 weeks old). age, weight 25-30g, 3 animals per group)
was orally administered to mice, and the mice were fasted. Three hours later carbon tetrachloride dissolved in olive oil (50 μl 15 ml olive oil/kg) was administered orally. Further, 3 hours later, the same amount of the specimen as above was orally administered again. Carbon tetrachloride administration 24
After measuring the weight of the mouse, the liver was immediately removed.
Measure the weight, as well as the color tone and lobule image of the liver.
l observed. The normal control group was orally administered with 0.5% carboxymethyl cellulose solution and olive oil instead of the specimen suspension and carbon tetrachloride solution, while the carbon tetrachloride control group was orally administered with 0.5% carboxymethyl cellulose solution and olive oil instead of the specimen suspension and carbon tetrachloride solution. Carbon chloride solution was administered orally.

The protective effect of the specimen against liver damage was determined based on the relative weight (weight per 100 g body weight) increase inhibition rate calculated by the following formula and visual observation of liver color and lobule image.

Relative liver weight increase suppression rate (%) = Measured weight increase suppression rate is ``20% or more'', ``-
There were three groups: ``20% or more and less than 20%'' and ``less than -20%.'' Macroscopic observation of liver color and lobular image was ``almost the same as the normal control group,'' and ``improved compared to the carbon tetrachloride control group.'' The evaluation criteria were divided into three groups: ``obviously observed'' and ``substantially the same as the carbon tetrachloride control group.''

(Results) The following compounds all exhibited liver color tone and lobular appearance similar to those of the normal control group, as well as 2.
It showed a relative liver weight increase inhibition rate of 0% or more.

Example 1 65 mg of (3S)-6-fluoro-1,2,3,4-tetrahydro-β-carpoline-3-carboxylic acid are dissolved in a mixture of 1 ml of dimethyl sulfoxide and 0.5 ml of water. 0.093 ml of triethylamine and 0.02 ml of carbon disulfide were added to the solution, and the mixture was heated at room temperature for 20 min.
Stir for a minute. Add 0.021 ml of methyl iodide to the reaction solution.
and further stirred at room temperature for 16 hours. Water was added to the reaction solution, and the aqueous layer was made acidic with 10% hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried, and the solvent is distilled off.

The residue was purified by silica gel thin layer chromatography (solvent: chloroform:methanol:acetic acid = 93:6:1) to obtain (3S)-6-fluoro-2-(methylthio)thiocarbonyl 1,2,3. 4-tetrahydro-
β-Carboline-3-carboxylic acid is obtained as a pale yellow powder.

[α) +205.0° (C=0.2, methanol) NMR (CDCl3, δ): 2.68 (S, 3
H, -CSSCH3) Mass (m/e): 32
4(M'), 276 (M''-CH5S[l)
Examples 2 to 6 The following compounds are obtained by treating the corresponding raw material compounds in the same manner as in Example 1.

Table 2 Mass (m/e): 342.340 (M”),
294,292 (M”-CHzSH)2.72
(S, 3H, -C5SCH3)Mass (m/
e): 320 (n”).

272 (M'-CH5SH') Target product of Example 4: NMR (CDCl3 + DMSO-di, δ): 2
．． 71 (S,3H,-CSSCH3) Target of Example 5: NMR (CDC1z, δ): 2.66 (
S, 3H, -CSSCH3) 3.80 (S, 3H, -O
CH3) Mass (m/e): 336 (M”),
288 (M”-CH5SH) Object of Example 6: , I NMR (CDCl3, δ): 2.64 (s, 3
H, -CSSCHi)5.00 (s, 2H, -0-C
Hz K)) Mass (m/e): 364 (
M''-CH:l5H) Example 7 610 mg of (3S)-8-methyl-1,2,3,4-tetrahydro-β-carboline methyl ester was dissolved in 20 ml of methanol, and 10% aqueous sodium hydroxide solution 2
ml is added to the solution and stirred at room temperature for 3 hours. 1 ml of 10% aqueous sodium hydroxide solution and 228 μm of carbon disulfide were added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. Next, 355 mg of methyl iodide was added to the mixture and reacted at the same temperature for 2 hours, and then the solvent was distilled off. Dissolve the residue in water and extract with ethyl acetate. The aqueous layer is made acidic by adding 10% hydrochloric acid and then extracted. After washing the extract with water and drying,
The solvent is distilled off. Add n-hexane to the residue and collect the resulting precipitate. (3S)-8-methyl-2-(methylthio)thiocarbonyl-1,2,3,4-tetrahydro-β
200 μl of -carboline-3-carboxylic acid are obtained as a white powder.

2.68 (S, 3H, -COOCH3) H3
CHMass (rn/e): 320 (M”),
272 (M''-CH5SH) Example 8 (3S) -1,2,3,4-tetrahydro-β-carboline-3-acetic acid 235 mg was dimethyl sulfoxide 2
Dissolve in ml. 0.42 ml of triethylamine and 0.07 ml of carbon disulfide are added to the mixture and stirred for 30 minutes at room temperature. Next, 0.07 ml of methyl iodide was added to the reaction solution, and the mixture was further stirred at room temperature for 2 hours. Subsequently, the solvent is distilled off from the reaction solution, and the residue is dissolved in water.

The aqueous layer is made acidic using 5% hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried, and the solvent is distilled off. Add aqueous ethanol to the remainder and collect the resulting precipitate. The above treatment yields 102 mg of white powder of (3S)-2-(methylthio)thiocarbonyl-1,2,3,4-tetrahydro-β-carboline-3-acetic acid.

NMR (DMSO-d6.δ): 2.62 (S,
3H, -CSSCH3)' Mass (m/e)
: 320 (M'), 272 (gate" -CH
8S11) [α) +184.0' (C=0.
1. Methanol) Examples 9 to 10 The following compounds are obtained by treating the corresponding raw material compounds in the same manner as in Example 8.

(Book)
(I-C) Table 3 (N) Under the reaction conditions of Examples 9 and 10, dimethyl sulfoxide and 50% ethanol were used as solvents, respectively.
ION sodium hydroxide and IN potassium hydroxide were used as bases (Kimoto) Example 9: NMR (CDCI3+DMSO
-da, δ): 2.69 (S, 3H, -CSSCH
:I) Example 10: NMR (DMSO-d6.δ
): 4.60 (S, 2) 1. -C) 1m <knee CI
>Example 11 (4RS) 110 mg of -1,2,3,4-tetrahydro-β-carboline-4-carboxylic acid methyl ester was dissolved in 1 ml of dimethyl sulfoxide, and 0.12 ml of triethylamine and 0.5 ml of carbon disulfide were added to the solution. Add 03ml. After stirring the mixture at room temperature for 1 hour, 0.03 ml of methyl iodide was added and the mixture was further stirred at room temperature for 3 hours. After the reaction, the mixture was poured into water and the aqueous layer was extracted with ethyl acetate. After washing the extract with water and drying, the solvent is distilled off. (4R3
)-2-(methylthio)thiocarbonyl-1,2,3,
120 mg of white powder of 4-tetrahydro-β-carboline-4-carboxylic acid methyl ester is obtained. Yield: 92
%NMR (CDCl2.δ): 3.72 (S, 3H, -
COOCH3).

2.67(S,3H,-C3SCH3)Mass(m/
e): 320 (71”) Example 12 85 mg of (4R3)-(methylthio)thiocarbonyl-1,2,3,4-tetrahydro-β-carboline-4-carboxylic acid methyl ester obtained in Example 11 was dissolved in methanol. Add 0.52 ml of IN sodium hydroxide to the solution.The mixture is stirred at room temperature for 20 hours.Subsequently, the solvent of the reaction solution is distilled off and the residue is dissolved in water.
．． 5. Acidify by adding M citric acid and extract with ethyl acetate. After washing the extract with water and drying, the solvent is distilled off. The remaining gold is recrystallized from a mixture of ethanol and water. Through these treatments, (4R3)-2-(methylthio)thiocarbonyl-1,2,3,4-tetrahydro-β-carboline-4
- Obtain 70 mg of pale yellow prism crystals of carboxylic acid.

Yield: 86%, M, p, 202-204°C NMR (
CDCI: ++DMSO-d6. δ): 2.68(
S, 3H, -C3SCH3) Mass (m/e): 3
06 (M”) (Production method of raw material compound) Production example 1 A mixture of 111 mg of 5-fluorotryptophan, 5 Qmg of 35% formalin, 0.8 ml of 0.IN sulfuric acid, 0.4 ml of ethanol, and 0.3 ml of water was brought to room temperature. The precipitate is collected by filtration, washed with water and ethanol in turn, and dried to give (33)-6-fluoro-1,2,3,4-tetrahydro-β-carboline-3.
- 80 mg of a white powder of carboxylic acid are obtained.

Yield: 69% Mass (m/e): 234 (M”) Production Example 2
~8 The following compound is obtained by treating the corresponding raw material compound in the same manner as in Production Example 1.

(Production Examples 2 to 7) (''M Production Example 8 (*) By recrystallizing HH sample from methanol, (3S)-
4.42 g of colorless needle-like crystals of L2,3.4-tetrahydro-β-carboline-3-carboxylic acid methyl ester are obtained. M, p, 250 DEG -253 DEG C. (b) 15 g of the ice-crystalline free base are reduced with sodium borohydride in 80% ethanol, the catalyst is filtered off and the solvent is distilled off. Add water to the residue, stir, filter the precipitate, dry and recrystallize from ethanol to obtain colorless (3S)-3-hydroxymethyl-1,2,3,4-tetrahydro-β-carboline. Obtain 9.03 g of needle-shaped crystals. Add carbonyl chloride dropwise. After stirring the mixture, the solvent was distilled off, the residue was dissolved in ethyl acetate, washed with water, dried, and the solvent was distilled off to give (3S)-2-benzyloxycarbonyl-3-
Hydroxymethyl-1゜2.3.4-tetrahydro-β
- 2.90 g of a colorless oil of carboline are obtained.

(d) 1)-Toluenesulfonyl chloride is added dropwise to a pyridine solution containing 11.24 g of ice crystals, and the mixture is stirred. Subsequently, the solvent was distilled off, the residue was dissolved in ethyl acetate, and the solution was washed.
After drying, the solvent is distilled off. The residue is dissolved in dimethylformamide and added dropwise to the sodium cyanide suspension. After stirring the suspension, the solvent was distilled off, water was added to the residue, and the mixture was extracted with ethyl acetate. After washing the extract with water and drying, the solvent was distilled off and purified by silica gel column chromatography to obtain (3S)-2-benzyloxycarbonyl-
3-cyanmethyl-1,2,3,4-tetrahydro-β
- 3.78 g of carboline pale red oil are obtained.

(e) A methanol solution containing 1.89 g of ice crystals is saturated with hydrogen chloride and left for 1 hour. Then, the solvent was distilled off,
The residue was dissolved in ethyl acetate, washed with water, dried, and the solvent was distilled off. By purifying the residue by silica gel column chromatography, colorless needle crystals of (3S)-2-benzyloxycarbonyl-1,2°3.4-tetrahydro-β-carboline-3-acetic acid methyl ester were obtained.
g is obtained.

M, p, 174-176°C (f) Add IN sodium hydroxide to the tetrahydrofuran solution of the main island and stir at room temperature for 16 hours.

Subsequently, the solvent is distilled off, the residual aroma is dissolved in water, and extracted with ethyl acetate. Next, the aqueous layer was acidified with hydrochloric acid, extracted with ethyl acetate, and after drying, the solvent was distilled off to obtain (3S)-
Pale yellow powder of 2-benzyloxycarbonyl-1,2,3,4-tetrahydro-β-carpoline-3-acetic acid 63
Obtain 0 mg.

(g) Add 10% palladium on carbon and 10% hydrochloric acid to 0.55 g of a water-containing ethanol solution and perform catalytic reduction in a hydrogen atmosphere. After removing the catalyst by filtration, the catalyst was washed with ethanol, the solvent was distilled off from the filtrate and the washing liquid, and the residual aroma was recrystallized from ethyl acetate to obtain (3S)-1,2,3,4-tetrahydro-β-carboline. -290 mg of pale yellow needle crystals of 3-acetic acid hydrochloride are obtained.

Claims (1)

[Claims] 1. General formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) (However, (a) R^1 is a carboxy group, R^2 and R^3 are both hydrogen atoms, R^ 4 represents a lower alkyl group, X represents a halogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, or a benzyloxy group; Both ^3 are hydrogen atoms, or one of R^2 and R^3 represents a carboxy group or a lower alkoxycarbonyl group, and the other represents a hydrogen atom, and R^4 is a lower alkyl group or a halogenated benzyl group, X represents a hydrogen atom) or a pharmacologically acceptable salt thereof. 2. A pharmaceutically acceptable salt of the compound according to claim 1, wherein R^1 is a carboxy group or a carboxymethyl group, and/or one of R^2 and R^3 is a carboxyl group. . 3. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) (However, the symbols indicate the meanings given below.) A compound or its salt, carbon disulfide, and the general formula R^4-X' (III) (However, X' represents a halogen atom, and R^4 represents the meaning described below.) There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▼ (I) that are characterized by reacting with the compound shown by A method for producing the compound shown in (However, in the above formula, (a) R^1 is a carboxy group, R^2 and R^3 are both hydrogen atoms, R^4 is a lower alkyl group, and X is a halogen atom, lower alkyl group, hydroxyl group, lower alkoxy group or represents a benzyloxy group, or (b) R^
1 is a hydrogen atom or a carboxymethyl group, R^2 and R^3 are both hydrogen atoms, or R^2 and R
One of ^3 is a carboxy group or a lower alkoxycarbonyl group, the other is a hydrogen atom, R^4 is a lower alkyl group or a halogenated benzyl group, and X is a hydrogen atom. ) 4. Compounds of general formula (I) in which R^1 is a carboxy group or a carboxymethyl group and/or either R^2 and R^3 are a carboxyl group are further pharmacologically acceptable. The manufacturing method according to claim 3, characterized in that it is made into a salt. 5. Hydrolyze the compound represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( I -a') (However, the symbols indicate the meanings given below.) If necessary, the product can be further evaluated pharmacologically. General formulas that are characterized by acceptable salts ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( I -a) (However, in the above formula, R^1 is a hydrogen atom or a carboxymethyl group, and R^4 is a lower alkyl group or a halogenated benzyl group, one of R^5 and R^6 is a carboxy group and the other is a hydrogen atom, and R^7 and R^8 are one of a lower alkoxycarbonyl group and the other is a hydrogen atom. , X represents a hydrogen atom) or a pharmaceutically acceptable salt thereof. 6. A hepatoprotective agent comprising the compound according to claim 1 as an active ingredient.