WO1995005369A1

WO1995005369A1 - Thiazoline-2-thione derivative and remedy for liver diseases

Info

Publication number: WO1995005369A1
Application number: PCT/JP1994/001306
Authority: WO
Inventors: Mitsuo Masaki; Tomio Yamakawa; Chiharu Inoue; Shinichi Yoshida
Original assignee: Nippon Chemiphar Co., Ltd.
Priority date: 1993-08-19
Filing date: 1994-08-09
Publication date: 1995-02-23
Also published as: AU7276294A

Abstract

A novel thiazoline-2-thione derivative represented by general formula (1) useful as an active ingredient of a remedy for liver diseases; another thiazoline-2-thione derivative useful as an intermediate for synthesizing the above derivative; and a remedy for liver diseases containing the above derivative. In said formula (1), R1 represents alkyl, cycloalkyl, alkenyl or alkynyl; R2 represents halogeno, hydroxy, alkoxy, alkyl, amino, alkylamino, dialkylamino, alkylthio, nitro, carboxy or alkoxycarbonyl; m represents an integer of 1 to 5, provided when m is 2 or above, two R2s may be combined together to represent alkylenedioxy; and m represents 0 or 1.

Description

Specification

Thiazoline-2-thione derivative and therapeutic agent for liver disease

[Technical field]

The present invention relates to a novel thiazoline-2-thione derivative, and a therapeutic agent for liver disease containing the novel thiazoline-2-thione derivative or a similar thiazoline-2-thione derivative as an active ingredient.

[Background technology]

Liver in the body, detoxification, carbohydrate metabolism, lipid metabolism, protein metabolism, production and secretion of bile, production of blood clotting factors, hormonal regulation, storage of various biological components such as fat, glycogen, protein, and vitamins Perform various functions such as viruses, drugs, poisons, alcohol, malnutrition, hepatic circulatory system disorders, bile duct obstruction, etc. Hepatitis, toxic hepatitis of drugs, alcoholic hepatitis, depressive hepatitis, liver damage due to the biliary depression, fatty liver, jaundice, or eventually cirrhosis.

An object of the present invention is to provide a novel thiazoline-12-thione derivative useful as an active ingredient of a therapeutic agent for liver disease, and a novel thiazoline-12-thione derivative or a similar thiazoline-2-thione derivative as an active ingredient. To provide a therapeutic agent for liver disease containing

[Disclosure of the Invention]

The present invention provides the following general formula (1):

(In the formula, R ¹ may have 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, and an alkoxyl group having 1 to 6 carbon atoms. Alkyl group, cycloalkyl group having 3 to 6 carbon atoms, alkenyl having 2 to 6 carbon atoms R ² represents a halogen atom; a hydroxyl group; a halogen atom, a hydroxyl group and a substituent selected from the group consisting of an alkoxyl group having 1 to 6 carbon atoms. An alkyloxy group having 1 to 6 carbon atoms; an alkyl group having 1 to 6 carbon atoms; an amino group; an alkylamino group having 1 to 6 carbon atoms; A dialkylamino group which is an alkyl group having 1 to 6 carbon atoms; an alkylthio 'group having 1 to 6 carbon atoms; a nitro group; a carboxyl group; or an alkoxycarbonyl group having 2 to 7 carbon atoms, and m is 1 to 5 When m is 2 or more, each R ² may be the same or different, and two R ² groups may be taken together to represent an alkylenedioxy group having 1 to 6 carbon atoms. Well, and n represents 0 or 1)

A novel thiazoline-2-thione derivative represented by

The thiazoline-2-thione derivative of the present invention can be used in vivo in a carbon tetrachloride acute liver injury model and a galactosamine acute liver injury model, using GOT (glutamine one-year quisaloacetic acid transaminase) and GPT (glutamine-pyruvate transaminase). It has an excellent inhibitory effect on departure and prolongation of prothrombin time, has an alleviating or treating liver injury, or has an excellent protective effect on liver injury, and is particularly useful as a therapeutic or preventive agent for liver diseases.

The thiazoline-2-thione derivative of the general formula (1) is represented by the following general formula (2):

(In the formula, R ¹ may have 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, and an alkoxyl group having 1 to 6 carbon atoms. Represents an alkyl group, a cycloalkyl group having 3 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms or an alkynyl group having 2 to 6 carbon atoms, wherein R ² is a halogen atom; a hidden xyl group; a halogen IS atom, hydroxyl And a substituent selected from G consisting of an alkoxyl group having 1 to 6 carbon atoms, which may be unique to 1 to 3 carbon atoms, or a substituent having 1 to 6 carbon atoms. A alkoxyl group; an alkyl group having 1 to 6 carbon atoms; an amino group; an alkylamino group having 1 to 6 carbon atoms; a dialkylamino group which is independently an alkylyl group having 1 to 6 carbon atoms; 6 represents an alkylthio group; a nitro group; a carboxyl group; or an alkoxycarbonyl group having 2 to 7 carbon atoms, m represents an integer of 1 to 5, and when m is 2 or more, each R ² is the same or different. May represent an alkylenedioxy group having 1 to 6 carbon atoms in association with ^two R ² forces S— and n represents 0 or 1)

Can be produced by using a method described later via a novel thiazolidine-12-thione derivative represented by the following formula:

According to the study of the present inventors, the following general formula (3) including the thiazoline-2-thione derivative represented by the general formula (1) and a compound similar thereto:

(3)

(In the formula, R ¹ may have 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, and an alkoxyl group having 1 to 6 carbon atoms. Represents an alkyl group, a cycloalkylyl group having 3 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, or an alkynyl group having 2 to 6 carbon atoms, wherein R ² is a halogen atom; a hydroxyl group; a halogen atom, a hydroxyl group; An alkoxyl group having 1 to 6 carbon atoms, which may have 1 to 3 substituents selected from the group consisting of an alkoxyl group having 1 to 6 carbon atoms; an alkyl group having 1 to 6 carbon atoms; an amino group; An alkylamino group having 1 to 6 carbon atoms; each alkyl group; a dialkylamino group independently having 1 to 6 carbon atoms; an alkylthio group having 1 to 6 carbon atoms; a nitro group; a carboxyl group; ~ 7 alkoxycarbonyl groups Represents, s is 0 an integer of 5, when s is 2 or more, each R ² may be the same or different, two of R ² force 'alkylene having 1 to 6 carbon atoms Te summer together May represent an alkoxy group, and t represents an integer of 0 to 4) A thiazoline-2-thione derivative represented by the following general formula (4):

( Four )

(In the formula, R ¹ may have 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, and an alkoxyl group having 1 to 6 carbon atoms. Represents an alkyl group, a cycloalkyl group having 3 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms or an alkynyl group having 2 to 6 carbon atoms, wherein R ² is a halogen atom; a hydryl xylyl group; a halogen atom, a hydroxyl group And an alkoxyl group having 1 to 6 carbon atoms, which may have 1 to 3 substituents selected from the group consisting of an alkoxyl group having 1 to 6 carbon atoms; an alkyl group having 1 to 6 carbon atoms; an alkyl group having 1 to 6 carbon atoms; An alkylamino group having 1 to 6 carbon atoms; a dialkylamino group having 1 to 6 carbon atoms in each alkyl group; an alkylthio group having 1 to 6 carbon atoms; a nitro group; a carboxyl group; 7 represents an alkoxycarbonyl group R ⁴ represents an alkyl group having 1 to 6 carbon atoms or a phenylalkyl group containing an alkyl group portion having 1 to 3 carbon atoms, and X represents a halogen atom, a methanesulfonyloxy group or a p-toluenesulfonyloxy group. S represents an integer of 0 to 5, and when s is 2 or more, each R ² may be the same or different, and two R ² forces s—in connection with the number of carbon atoms of 1 to 6 May represent an alkylenedioxy group, and t represents an integer from 0 to 4)

It has been found that the salt of the thiazoline-2-thione derivative represented by the formula (1) exhibits a therapeutic effect on liver disease and is effective as a therapeutic agent for liver disease.

The thiazoline-2-thione derivative represented by the general formula (3) and the salt of the thiazoline-2-thione derivative represented by the general formula (4) are used in the acute liver injury model as described above in G0T, GΡ It has an excellent inhibitory effect on departure and prolongation of prothrombin time, and exhibits an excellent protective effect against liver damage or liver damage, and is useful as an agent for treating and preventing liver diseases. Among the thiazoline-2-thione derivatives represented by the general formula (3), some compounds not included in the thiazoline-2-thione derivative of the general formula (1) are known. For example, 3-benzyl-4-methylthiazoline-2-thione is described as effective as a bactericide in Arch. Pharm., 296, 310-324 (1963). It is not known that the model has the effect of suppressing the deviation of G 0 Τ and G Ρ Τ. Also, 4-methyl-1- [2- (3,4-dimethyloxyphenyl) ethyl] thiazoline-2-thione is described in Bull. Chem. Soc. Fr., (9-10, Pt. 2), 2135-2140 ( 1974) describes its synthesis, but does not describe that it is useful as a therapeutic or prophylactic agent for liver disease.

[Best Mode for Carrying Out the Invention]

In the general formula (1), specific examples of the alkyl group having 1 to 6 carbon atoms represented by R ¹ include a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group and an isobutyl group. Group, sec-butyl group, t-butyl group, etc. Specific examples of the cycloalkyl group having 3 to 6 carbon atoms include cyclopropyl, cyclopentyl, cyclohexyl, etc. Specific examples of the alkenyl group include, but are not limited to, an ethyl group, a 2-propenyl group, a 2-methyl-2-propenyl group, a 3-butenyl group, and a 3-methyl-2-butenyl group. Specific examples of 2 to 6 alkynyl groups include an ethur group, a 2-propynyl group, a 2-butynyl group, a 3-buturyl group and the like. In addition, these alkyl group, alkenyl group and alkynyl group include a halogen atom (preferably, a fluorine atom, a chlorine atom and a bromine atom), a hydroxyl group and an alkoxyl group having 1 to 6 carbon atoms (for example, a methoxy group, an ethoxy group, It may have one to three substituents selected from the group consisting of a propoxy group and a butoxy group. Preferred specific examples of the above-mentioned alkyl group, alkenyl group and alkynyl group having such a substituent include monofluoromethyl, trifluoromethyl, methoxymethyl, ethoxymethyl, hydroxymethyl, And 3-fluoropropynyl group.

In the general formula (1), specific examples of the alkoxyl group having 1 to 6 carbon atoms represented by R ² include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, and an n-butoxy group. , Isobutoxy, sec-butoxy, t-butoxy, etc. It is. The alkoxy group includes a halogen atom (preferably, a fluorine atom, a chlorine atom, and a bromine atom), a hydroxyl group and an alkoxyl group having 1 to 6 carbon atoms (eg, a methoxy group, an ethoxy group, a propoxy group, a butoxy group). May have from 1 to 3 substituents selected from the group consisting of

In the general formula (1), examples of the alkylamino group having 1 to 6 carbon atoms represented by R ² include a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, an n-butylamino group, and an isobutyl group. Amino group, sec-butylamino group, t-butylamino group and the like. As the dialkylamino group represented by R ² , wherein each alkyl group is independently an alkyl group having 1 to 6 carbon atoms, a dialkylamino group having two alkyl groups of the above alkylamino group (an alkyl group) May be the same or different).

In the general formula (1), specific examples of the alkylthio group having 1 to 6 carbon atoms represented by R ² include a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, an n-butylthio group, and an isobutylthio group. , Sec-butylthio group, t-butylthio group and the like. '

In Formula (1), specific examples of the alkoxycarbonyl group having 2 to 7 carbon atoms represented by R ² include a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, and an isopropoxycarbonyl group. Groups, n-butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, t-butoxycarbonyl group and the like.

In the general formula (1), when m is 2 or more, R ² may be the same or different. When m is 2 or more, two R ² (preferably, R ² bonded to a carbon atom adjacent to the benzene ring) force ^s— a dioxyalkylene group having 1 to 6 carbon atoms represented by 0 (CH ₂ ) p0- (where p is an integer of 1 to 6)] is a group having the formula — 0—CH ₂ —0—, 10 (CH ₂ ) ₂₀ —, or the like. Power. In the general formula (1), R ¹ is an unsubstituted alkyl group having 1 to 6 carbon atoms (particularly, 1 to 4 carbon atoms), or a halogen atom, a hydroxyl group and 1 to 6 carbon atoms (particularly, It is preferably an alkyl group having 1 to 6 carbon atoms (particularly, 1 to 4 carbon atoms) having 1 to 3 substituents selected from the group consisting of alkoxyl groups having 1 to 4 carbon atoms. More preferably, R ² is an unsubstituted alkoxyl group having 1 to 6 carbon atoms (particularly, 1 to 4 carbon atoms), or a halogen atom, a hydroxyl group and 1 to 6 carbon atoms (particularly, 1 to 6 carbon atoms). The alkoxyl group having 1 to 3 carbon atoms (particularly, 1 to 4 carbon atoms) having 1 to 3 substituents selected from the group consisting of the alkoxyl group of 4) is preferable. In the general formula (1), m is preferably an integer of 1 to 3, and n is preferably 1.

Representative compounds of the thiazoline-12-thione derivative represented by the general formula (1) are shown in Table 1 below. In Table 1, the symbols R ¹¹ R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ and n represent the symbols represented by the following general formula (1A).

table 1

R ¹¹ n R ²¹ R ²² R ²³ R ²⁴ R ²⁵

CH _₃ 1 0CH ₃ HHHH

CH ₃ 1 N (CH ₃ ) 2 HHHH

CH ₃ 1 S CHa HHHH

CH ₃ 1 H-OCH 20-HH

Table 1 ^{^{^{of) n R 21 R 22 R 23}}} R 24 R 25 teeth _{3 H 7 1 0CH 3 OCHa OCHa} HH iso-C 3 H? 1 OCHa OCHa 0 CH 3 HH eye- C 3 HT 1 OCHa OCHa OCH3 HH

CH ₃ 1 OCH ₃ CH ₃ CH ₃ OCHa CH ₃

CH ₃ 1 0CH ₂ CH ₂ 0CH _a HHHH

CH ₃ 1 OCHsF HHHH

CH ₃ 0 H OCHa 0 CHa HH

CH ₂ 0CH ₃ OCHa OCHa 0 CH ₃ HH

Il2UU2il5 π u then * n w 3 re 3 rl 7 Ut then u H 3 T r Tl TT

Π

CH ₂ C≡CH CH ₃ HHHH Note: iso-C ₃ H ₇ represents a isopropyl group, eye- C ₃ H ₇ represents a cyclopropyl group.

Representative compounds of the thiazoline-2-thione derivative represented by the general formula (1) include the following.

4-methyl-3- (2,3,4-trimethoxybenzyl) thiazoline-2-thio on.

4-Isopropyl-1- (2,3,4-trimethoxybenzyl) thiazoline-2-thione.

4-Ethyl-13- (2,3,4-trimethoxybenzyl) thiazoline-12-thione. -

3- (2-Methoxybenzyl) 1-4-methylthiazoline-2-thione.

4-Methyl-3- (3,4,5-trimethoxybenzyl) thiazoline-2-thione.

4-Propyl-3- (2,3,4-trimethoxybenzyl) thiazoline-2-thione.

3- (2,5-dimethyloxybenzyl) 1-4-methylthiazoline-2-thione. 3- (3,5-Dimethoxy-4-hydroxybenzyl) -1-methylthiazoline-12-thione.

3- [2- (N, N-dimethylamino) benzyl] -1-4-methylthiazoline-2-thione.

4-Methyl-3- (2-methylthiobenzyl) thiazoline-1-thione.

4-cyclopropyl-1- (2,3,4-trimethoxybenzyl) thiazoline

4-Methyl-3- (3,4-methylenedioxybenzyl) thiazoline-2-thione.

3- (2,5-dimethoxy-3,4,6-trimethylbenzyl) -1-methylthiazoline-12-thione.

3- [2- (2-Methoxyethoxy) benzyl] -1-4-methylthiazoline-1-thione.

3- (2-fluoromethoxybenzyl) 1-4-methylthiazoline-2-thione.

3-(3-methylbenzoyl) -4-methylthiazoline-2-thione. 3- (2-Methoxymethylbenzyl) 1-4-methylthiazoline-2-thione. 3- (3-methoxy-6-nitrobenzyl) -1-methylthiazoline-2-ki on.

3-(3,4 dimethyloxyphenyl) 1-4-methylthiazoline-2-thione. 3- (1,4,1-benzodioxane-1-6-yl) -1,4-methylthiazoline-12-thione.

4-Fluoromethyl-3- (2,3,4-trimethoxybenzyl) thiazoline-2-thione.

4-1-Methoxymethyl-3- (2,3,4-trimethoxybenzyl) thiazoline-12-thione.

3- (2,5-dihydroxy-3,4,6-trimethylbenzyl) 1-4-methoxymethylthiazoline-2-thione.

3- (2,4-dimethoxy-3-propyloxybenzyl) 1-4-ethoxymethylthiazoline-2-thione.

4-Hydroxymethyl-3- (2,3,4-trimethoxybenzyl) thiazoline 2-thione.

4-Trifluoromethyl-3- (2,3,4-trimethoxybenzyl) thiazoline-12-thione.

3- (4-chloro-1--2-benzyl) -1-4-vinylthiazoline-2-thione.

4-aryl-3- (3-fluoro-4-methoxybenzyl) thiazoline-2-thione.

3-(2-Methylbenzyl) 1-41 (2-propynyl) thiazoline-2-thione.

—The thiazoline-2-thione derivative represented by the general formula (1) can be produced, for example, by the following synthesis route synthesis method. Z

(1) In the above reaction formula, R ¹ , R ² , m and n have the same meaning as defined in the general formula (1), and R ³ has 1 to 6 carbon atoms. M represents an alkyl group; Z represents a leaving group;

The method of synthesizing the above synthesis route will be described below.

Each unit reaction in the above synthesis method is a generally known reaction, and is described in, for example, Chem. Pharm. Bull., 30 (10), 3548-3554 (1982). Based on the above, a person skilled in the art can easily synthesize a thiazoline-2-thione derivative represented by the general formula (1).

The amine compound represented by the general formula (5) in the above self-reaction formula can be obtained as a commercial product, or can be synthesized by Gabriel reaction from halide via phthalimide.

The general formula (5) Amin compound represented by the formula R ³ 0M (where, R ³ represents an alkyl group of 1 to 6 carbon atoms, M represents an alkali metal) compound and carbon disulfide and the normal solvent By reacting in the reaction, the glutamine rubamine represented by the general formula (6) Synthesize the acid salt. R ³ is preferably a methyl group, an ethyl group, a propyl group, a t-butyl group or the like, and M is preferably sodium, potassium, lithium or the like. Instead of the compound of formula R ³ OM, triethylamine, 1,8-diazabicyclo

[5.4.0] Bases such as 7-indene (DBU) can also be used. As a solvent for this reaction, an alcohol such as ethanol or methanol is usually used. A polar solvent such as tetrahydrofuran, dimethyl sulfoxide, dimethylformamide or the like which does not adversely affect the reaction can be used. Carbon disulfide itself can be used as the solvent. This reaction usually proceeds sufficiently at room temperature for a reaction time of 10 minutes to 1 hour. Even at low temperatures, the reaction proceeds sufficiently by increasing the reaction time. Jichio force Rubamin acid salt represented by the general formula (6) can be used in the next reaction without force ^s isolated it is relatively unstable. Dithiolbamate represented by general formula (6) and general formula R ¹ -C0CH ₂ Z

(Wherein, R ¹ has the same meaning as defined in the general formula (1), and Z represents a leaving group), and is reacted with a ketone compound represented by the general formula (2) A thiazolidine-12-thione derivative is synthesized. The leaving group represented by Z is generally a halogen atom such as a chlorine atom or a bromine atom, but a group such as a methanesulfonyloxy group or a p-toluenesulfonyloxy group can also be used. . The solvent used for this reaction may be another solvent as long as it does not adversely affect the reaction, which is usually an alcohol such as ethanol, methanol or the like. This reaction can be carried out usually under ice cooling for a reaction time of several minutes to several hours. The reaction proceeds without any problem even at room temperature.

Thiazolidine-12-thione derivatives represented by the general formula (2) are classified into stable and unstable. The stable thiazolidine-12-thione derivative represented by the general formula (2) is isolated and purified, and then subjected to a dehydration reaction with an acid to obtain a thiazoline-2-thione derivative represented by the general formula (1). The acid used in this reaction is preferably an inorganic strong acid such as hydrochloric acid, sulfuric acid, or nitric acid, but may be an organic acid such as methanesulfonic acid or p-toluenesulfonic acid. This reaction usually proceeds sufficiently at room temperature for several minutes. The reaction can be performed at a temperature lower or higher than room temperature. When the thiazolidine-2-thione derivative represented by the general formula (2) is unstable, In this case, the produced thiazolidine-2-thione derivative immediately undergoes a dehydration reaction, and is converted into a thiazoline-2-thione derivative represented by the general formula (1). Accordingly, a thiazolidine represented by the general formula (2) is used as a product of a reaction for synthesizing a thiazolidine-2-thione derivative represented by the general formula (2) from the dithiol rubbamate represented by the general formula (6). A mixture S of the 2-thione derivative and the thiazoline-2-thione derivative represented by the general formula (1) may form. In this case, an acid is added to the reaction system to convert any remaining thiazolidine-2-thione derivative represented by the general formula (2) into a thiazoline-2-thione derivative represented by the general formula (1). it can.

A thiazoline-2-thione derivative represented by the general formula (1) is converted to a compound represented by the formula R ⁴ -X (where R ⁴ is a phenylalkyl containing an alkyl group having 1 to 6 carbon atoms or an alkyl group having 1 to 3 carbon atoms) X represents a halogen atom, a methanesulfonyloxy group or a p-toluenesulfonyloxy group), and is reacted with a compound represented by the general formula (7):

(Wherein, R ¹ , R ² , R ⁴ , m, n, and X are as defined above), and a salt of a thiazoline-2-thione derivative represented by the formula: The formula R ⁴ - methyl group as in R ⁴ in X, Echiru group, t one-butyl group, a benzyl group, Fuwenechiru group are preferable, especially a chlorine atom as a halogen atom, a bromine atom and an iodine atom. This reaction can be carried out by stirring a thiazoline-12-thione derivative represented by the general formula (1) in a compound represented by the formula R ⁴ —X at room temperature to reflux temperature for several hours. The salt of the thiazoline-2-thione derivative represented by (7) can be obtained in high yield. Particularly preferred as the compound represented by the formula R ⁴ -X are methyl bromide, methyl iodide and petit bromide. Butyl iodide, butyl iodide, benzyl chloride, benzyl bromide, etc. The salt of the thiazoline-2-thione derivative represented by the general formula (7) is characterized by having a higher solubility in an aqueous medium than the thiazoline-2-thione derivative represented by the general formula (1).

Representative compounds of the salt of the thiazoline-2-thione derivative represented by the general formula (7) include, for example, 4-methyl-3- (2,3,4-trimethoxybenzyl) thiazoline-l-thione and methyl iodide And 4-methyl-2-methylthio-3- (2,3,4-trimethoxybenzyl) -11,3-thiazol-1-dimethoxide.

The thiazolidine-12-thione derivative represented by the general formula (2) of the present invention is a novel compound, and is shown in the synthesis route for the thiazoline-2-thione derivative represented by the general formula (1). Thus, the compound is useful as an intermediate for synthesizing the thiazoline-2-thione derivative represented by the general formula (1). In the general formula (2), R ¹ , R ² , m and n are the same as those described for the general formula (1). -Representative compounds of the thiazolidine-2-thione derivative represented by the general formula (2) include the following.

4-hydroxy-4-methyl-3- (2,3,4-trimethoxybenzyl) thiazolidine-1-thione

4-Isopropyl-1-hydroxy-1-3- (2,3,4-trimethoxybenzene) thiazolidine-2-thione

4-Ethyl-4-hydroxy-3- (2,3,4-trimethoxybenzyl) thiazolidine-1-thione

4-hydroxy-1- (2-methoxybenzyl) -1-methylthiazolidine-1-thione

4-Hydroxy-4-propyl-1- 3- (2,3,4-trimethoxybenzyl) thiazolidine-2-thione

3- (2,5-dimethoxybenzyl) 1-4-hydroxy-4-methylthiazolidin-12-thione 4-hydroxy-4-methyl-3- (3,4,5-trimethoxybenzyl) thiazolidine-1-thione

3- (3,5-dimethoxy-4-hydroxybenzyl) 1-4-hydroxy-14-methylthiazolidine-1-thione

3- [2- (N, N-dimethylamino) benzyl] 1-41-hydroxy-4-methyl thiazolidine-12-thione

4-hydroxy-4-methyl-3- (2-methylthiobenzyl) thiazolidine

4-cyclopropyl-1-hydroxy-3- (2,3,4-trimethoxybenzyl) thiazolidine-1-thione.

4-hydroxy-1-methyl-3- (3,4-methylenedioxybenzyl) thiazolidine-12-thione.

3- (2,5-dimethoxy-3,4,6-trimethylbenzyl) -1-hydroxy-4-methylthiazolidine-12-thione.

4-hydroxy-3- [2- (2-methoxyethoxy) benzyl] -4-methylthiazolidine-12-thione.

3- (2-Fluoromethoxybenzyl) 4-hydroxy-4-methylthiazolidine-1-2-thione.

3- (3-Fluoromethylbenzyl) 1-4-hydroxy-4-methylthiazolidin-12-thione.

4-Hydroxy-3- (2-methoxymethylbenzyl) -4-methylthiazolidine-1-thione.

4-hydroxy-3- (3-methoxy-6-nitrobenzyl) -1-methylthiazolidine-12-thione.

3- (3,4-Dimethoxyphenyl) 1-4-hydroxy-14-methylthiazolidin-12-thione.

3- (1,4-Benzodioxane-1-6-yl) 1-4-Hydroxy-4-methylthiazolidine-12-Thii.

4 1-Fluoromethyl-1 4-hydroxy-1 3— (2,3,4 Jill) Thiazolidine-1-thione.

4-Hydroxy-4-methoxymethyl-1- (2,3,4-trimethoxybenzyl) thiazolidine-12-thione.

3- (2,5-dihydroxy-1,3,4,6-trimethylbenzyl) 1-4-hydroxy 4-methoxymethoxythiazolidine-12-thione. .

3- (2,4-dimethoxy-1-3-propyloxybenzyl) 1-4-ethoxymethyl-4-hydroxythiazolidine-12-thione.

4-Hydroxy-4-hydroxymethyl-3- (2,3,4-trimethoxybenzyl) thiazolidine-12-thione.

4-Hydroxy-4,1-trifluoromethyl-3- (2,3,4-trimethoxybenzyl) thiazolidine-12-thione.

3- (4-chloro-2--2-ethoxybenzyl) 1-4-hydroxy-4-vinylthiazolidine-12-thione.

4-arylu 3- (3-fluoro-4-methoxybenzyl) -1-hydroxythiazolidine-12-thione.

4-hydroxy-3- (2-methylbenzyl) -4- (2-propynyl) thiazolidine-1-thione.

The therapeutic agent for liver disease of the present invention contains, as an active ingredient, a thiazoline-1-thione derivative represented by the general formula (3) or a salt of a thiazoline-2-thione derivative represented by the general formula (4).

—Specific examples of R ¹ and R ^{2 in} the general formula (3) are the same as those described for R ¹ and R ^{2 in the} general formula (1), respectively. In the general formula (3), s is preferably an integer of 1 to 3, and "t is preferably 1.

Representative compounds of the thiazoline-2-thione derivative represented by the general formula (3) include the following compounds in addition to the representative compounds of the thiazoline-2-thione derivative represented by the general formula (1). be able to.

3-benzyl-4-methylthiazoline-1-2-thione.

4-Methyl-3- [2- (3,4-dimethyloxyphenyl) ethyl] thiazoline 1-2-thione. 4-Methyl-3- [2- (2,3,4-trimethoxyphenyl) ethyl] thiazoline-1-2-thione.

The thiazoline-2-thione derivative represented by the general formula (3) can be produced by the same synthetic route as described for the synthesis of the thiazoline-2-thione derivative represented by the general formula (1). .

In the general formula (4), specific examples of R ¹ and are the same as those respectively described in the general formula (1) at Keru R ¹ and R ^2, also, specific examples of R ⁴ and X And are the same as those described for R ⁴ and X in the general formula (7). In the general formula (4), s is preferably an integer of 1-3, and t is preferably 1.

The salt of the thiazoline-2-thione derivative represented by the general formula (4) can be produced in the same manner as described for the production of the salt of the thiazoline-2-thione derivative represented by the general formula (7). The salt of the thiazoline-2-thione derivative represented by the general formula (4) is characterized by having a higher solubility in an aqueous medium than the thiazoline-2-thione derivative represented by the general formula (3). The representative compound of the salt of the thiazoline-2-thione derivative represented by the general formula (4) is the same as the representative compound of the salt of the thiazoline-2-thione derivative represented by the general formula (7).

Next, the results of pharmacological experiments on the thiazoline-2-thione derivative (including the novel thiazoline-2-thione derivative of the present invention) and its salt, which are the active ingredients of the therapeutic agent for liver disease of the present invention, are shown. The pharmacological experiments showed that the inhibitory effect on lipid peroxidation, the inhibitory effect of G0T and GPT departure and the prolongation of prothrombin time (PT) in the acute liver injury model of carbon tetrachloride, and the acute liver injury model of D-galactosamine GOT and GPT were examined in vivo for their ability to inhibit the escape and prothrombin time (PT) prolongation. Prothrombin time (PT) is a test method to evaluate the blood coagulation system. Blood coagulation factors are mainly produced in hepatocytes, and hepatic dysfunction prolongs PT. Therefore, the effect of suppressing PT elongation means suppressing liver function decline.

Experiment 1. Lipid peroxidation inhibitory action

experimental method

Test solution (dissolved in dimethylsulfoxide) in microsomal (0.5 mg, protein) 250 prepared from rat liver 2.5 u 1,0.5 M Tris-HCl buffer (PH7.4 147.51 Add 50 wl of 1,2 Omg / ml ADP and 5 mgZml β-NADPH501, mix and incubate at 37 ° C for 60 minutes. The reaction was stopped by adding 5 mg Zml butylhydroxytoluene 501, and further 250 ml of 8.1% sodium dodecyl sulfate, 1.75 ml of 20% acetic acid (pH 3.5) and 0.8% thiobarbituric acid (pH 3.5) After adding 1.5 ml, the mixture was heated in a boiling water bath for 60 minutes. After cooling in ice water, the mixture was centrifuged at 1,500 X g for 10 minutes, and the absorbance at 535 nm of the supernatant was measured. The amount of lipid peroxide was determined from a calibration curve prepared using tetraethoxypropane as a standard substance. The lipid peroxidation inhibitory action was represented by the inhibition rate obtained from the following equation. Lipid peroxide in the presence of test compound

Suppression rate (%) = X 100

Lipid peroxide in the absence of test compound

result

97.9% der in lipid peroxidation inhibition rate 10- ⁴ M of the compound obtained in Example 1 Ri, it was 8% 68. In 10 ⁵ ^ / 1.

When hepatocytes are damaged by administration of carbon tetrachloride or D-galactosamine, the transmigration of enzymes occurs, and various enzyme activities appear in the serum. Therefore, it is an effective method to measure the activity of serum transaminase as an indicator of disorders. Serum transaminases include GOT (glutamic acid-glutamic acid acetate transaminase) and GPT (glutamic acid-pyruvate transaminase). It was measured as an indicator of liver damage. In addition, PT is an index that has been widely recognized as being effective in determining liver parenchymal dysfunction (see Hepatobiliary, 14 (5), pp. 741-748 (1987), “Attention of liver function test methods”). ).

Experiment 2. GOT and GPT departure and Τ Τ prolongation inhibitory effects in a model of acute hepatic injury to carbon tetrachloride

experimental method

A test substance (10 Omg / kg) is orally administered to a Wistar male rat of 160 to 180; The test substance is suspended in 1% methylcellulose and administered at a dose of 1 Omi / kg. The control group receives 1% methylcellulose. Three hours after administration of the test substance, carbon tetrachloride (olive oil: carbon tetrachloride = 1: 1) dissolved in olive oil is orally administered at a dose of 1 ml / Zkg to cause acute liver injury. The normal group receives oral oil instead of carbon tetrachloride. Feed water 4 hours after the administration of carbon tetrachloride. Twenty-four hours after the administration of carbon tetrachloride, the rats were laparotomized under ether anesthesia, and blood was collected from the aorta. The collected blood was centrifuged at 300 Or.p.m. for 15 minutes, and the plasma was collected. G0T and GPT in plasma were measured with an autoanalyzer (Hitachi 705: Karmen method). The increase suppression rate (%) of GOT and GPT was determined by the following equation. Test substance group value-Normal group value

Increase suppression rate (%) 2 X 100 Value of positive control group-Value of normal group

In addition, PT uses protron as a plasma sample collected from the abdominal vena cava as described above. The thromboplastin reagent for bottle time measurement (Simplastin; Organon Techni Riki Co., Ltd.) was added, and the time required for fibrin formation (seconds) was measured. The PT elongation inhibition rate (%) was determined by the following equation. Test substance group value-Normal group value

PT extension suppression rate X 100

(%) Positive control group value-Normal group value

Table 2 shows the measured values of the compounds obtained in each Example.

Experiment 3. D-Galactosamine (D-GalN) Inhibition of G 0 T, G Ρ 逸脱 departure and Τ Τ prolongation in acute liver injury model

experimental method

A test substance (100 mgZkg) is orally administered to a Wistar male rat of 180 to 200 g that has been fasted for 24 hours, and glycyrrhizin (40 mg ml) is intraperitoneally administered at a dose of 5 mlZkg. The test substance is suspended in 1% methylcellulose and administered at a dose of 1 Om1 / kg. The control group receives 1% methylcellulose. Three hours after administration of the test substance, D-galactosamine solution (dissolve D-galactosamine in physiological saline, adjust the pH to about 7 with a small amount of aqueous sodium hydroxide solution, and adjust to a concentration of 160 mg / ml) Is adjusted subcutaneously at a dose of 5 ml 1 g to cause acute liver injury. The normal group receives subcutaneous saline instead of D-galactosamine. Twenty-four hours after administration of D-galactosamine, the rats were laparotomized under ether anesthesia, blood was collected from the aorta and abdominal vena cava, and the probed blood was processed in the same manner as in Experiment 2. Addition suppression rate (%) and PT extension suppression rate

{%).

Result

Table 2 shows the measured values of the compounds obtained in each Example.

2 〇 Table 2 Test carbon tetrachloride disorder model Galactosamine disorder model Compound GOT GPT PT GOT GPT PT Example 1 99% 99% 96% (300) 63% 64% 47% Example 1 (30) 96 91 85 65 67 61 Example 1 (10) 57 50 59 (30) 50 50 47 Example 2 34 46 46

Example 3 96 91 90

Example 4 99 98 90

Example 5 94 89 82

Example 6 86 84 77

Example 7 43 48 61 Note: (300) indicates that the dose of the test compound is 300 mgZkg.

In (30), the dose of the test compound is 30 mg / kg.

In (10), the dose of the test compound is 1 OmgZkg.

Unless otherwise indicated, the dose of the test compound is 100 mg / kg. From the above pharmacological experiments, the thiazoline-2-thione derivative, which is the active ingredient of the present invention, has excellent G0T and GPT departure suppression effects and PT elongation suppression effects in an in vivo acute liver injury model. Having glue.

As shown in Table 2, 4-hydroxy-14- which is an intermediate of 4-methyl-3- (2,3,4-trimethoxybenzyl) thiazoline-2-thione synthesized in (1) of Example 1 was used. When methyl-1- (2,3,4-trimethoxybenzyl) thiazolidine-12-thione was used as a test compound, G 0 T and G Ρ で were used in an excellent in vivo acute liver injury model. 4-hydroxy-14-methyl-3- (2,3,4-trimethoxybenzyl) thiazolidine-2-thione (the above-mentioned general formula (1) 2) is a compound represented by

2 I However, it is thought that when administered orally, stomach acid converts it to 4-methyl-3- (2,3,4-trimethoxybenzyl) thiazoline-2-thione and acts.

The thiazoline-2-thione derivative represented by the general formula (3) showed no remarkable change even in SOOmgZkg in rat 2-week repeated oral dose toxicity screening. -In addition, the thiazoline-2-thione derivative represented by the general formula (1) is a therapeutic agent for liver diseases, an anti-inflammatory agent, an anti-rheumatic agent, a therapeutic agent for gastrointestinal diseases, particularly, as is clear from the results of the above pharmacological experiments. It is a useful substance as an active ingredient of a therapeutic agent for liver disease. The therapeutic agent for liver disease of the present invention can be administered either orally or parenterally, and is usually in the form of a pharmaceutical composition together with a pharmaceutical carrier. As the carrier, diluents or excipients such as extenders, binders, disintegrants, lubricants and the like which are usually used for preparing a drug according to the use form are used. The preparation may be in any form such as injections, powders, capsules, granules and tablets. The dose varies depending on the degree of the patient's symptoms, but usually, the thiazoline-2-thione derivative of the present invention may be administered to the patient at a dose of about 10 mg to lg per day.

[Example]

Next, the present invention will be described in more detail by way of examples.

[Example 1]

4-Methyl-1- (2,3,4-trimethoxybenzyl) thiazoline-1-thione ''

(1) 4-Hydroxy-1-methyl-3- (2,3,4-trimethoxybenzyl) thiazolidine-1

2. Dissolve 3,4-trimethoxybenzylamine (1.0 g, 5.07 mmol) in ethanol (10 ml), and add carbon disulfide (0.31 ml, 5.1 mmol) to this solution. And stirred at room temperature for 15 minutes. To this mixture was added a 28% sodium methodonomethanol solution (1.0 g, 5.2 mmol), and the mixture was further stirred at room temperature for 15 minutes. After evaporating the solvent under reduced pressure, the residue was dissolved in ethanol (5 ml), and the solution was added to a solution of acetone (0.52 ml, 6.59 mmol) in ethanol (10 ml). The mixture was added over 5 minutes under cooling, and stirred at room temperature overnight. After the ethanol was distilled off under reduced pressure, water (10 ml) was added to the residue, extracted with chloroform (2 Om 1 X 2), and further washed with water (2 Om 1 X 2). After drying over anhydrous sodium sulfate, the solvent was distilled off from the resulting solution under reduced pressure, and the residue was purified by silica gel column chromatography (hexane Z ethyl acetate = 1Z1). The solvent was evaporated under reduced pressure to give the title compound as pale brown crystals, 0.861 g.

(51.5% yield).

Melting point: 109. 0-1 12.0 ° C (decomposition).

lH NMR (CDC 1, 40 ζ ζ) δ:

1.55 (3H, s), 3.32 (2H, s),

3.85, 3.87, 3.99 (9 H, each s), 4.06 (1 H, s),

4.95, 5.08 (2 H, each d, J = 15 Hz),

6.65 (1H, d, J = 9Hz), 7.24 (1H, d, J = 9Hz) .IR (KBr) cm- ':

3260, 3000, .2940, 2840, 2820, 1600, 1490, 1450, 1420, 1400, 1380, 1370, 1340, 1300, 1280, 1260, 1220, 1200, 1 170, 1 120, 1090, 1065, 1040, 1010, 990, 950, 930, 925, 885,

850, 820, 800, 770, 745, 710, 680, 640,

590, 570, 530, 500.

(2) 4-Methyl-3- (2,3,4-trimethoxybenzyl) thiazoline-1-thione

4-Hydroxy-4-methyl-13- (2,3,4-trimethoxybenzyl) thiazolidine-12-thione (0.894 g, 2.71 mmol) obtained in (1) above was dissolved in ethanol (18 ml). Concentrated hydrochloric acid (18 ml) was added to this solution under ice-cooling, and the mixture was stirred and reacted for 20 minutes. After completion of the reaction, the reaction solution was neutralized by adding a 4N aqueous sodium hydroxide solution (50 ml), ethanol was distilled off from the solution, and the mixture was extracted with chloroform (25 ml × 3). After drying over anhydrous sodium sulfate, the solvent was distilled off from the solution under reduced pressure to obtain 0.823 g (yield 97.4%) of the title compound as slightly brown crystals.

Melting point: 102.0-106.5 ° C (decomposition).

_{XH NMR (CD 3 0D, 400MHz} ) δ:

2.16 (3 H, d, J = 2 Hz),

3.81, 3.83, 3.94 (9H, each s), 5.48 (2H, s), 6.48 (1H, d, J = 8Hz), 6.68 (1H, d, J = 8Hz), 6.57 (1H, d, J = 1Hz).

IR (KB r) cm " ¹ :

3400, 3090, 3070, 2970, 2950, 2910, 2810, 1590, 1580, 1490, 1460, 1435, 1420, 1400, 1370, 1355, 131 5, 1290, 1260, 1250, 1220, 12 10, 1 190, 1 140, 1080, 1020, 1000, 980,

970, 930, 900, 830, 790, 760, 720, 700,

660, 600, 500, 460.

[Example 2]

4-Isopropyl-1-3- (2,3,4-trimethoxybenzyl) thiazoline 2 years old

(1) 4-Isopropyl-1-hydroxy-3- (2,3,4-trimethoxybenzyl) thiazolidine-1-thione

2,3,4-Trimethoxybenzylamine (0.986 g, 5.00 mmol) was dissolved in ethanol (10 ml), and carbon disulfide (0.3 ml, 5 mmol) was added to this solution. Was added and stirred at room temperature for 15 minutes. To this mixture, a 28% sodium methoxide Z methanol solution (0.965 g, 5.00 mmol) was added, and the mixture was further stirred at room temperature for 15 minutes. After evaporating the solvent under reduced pressure, the residue was dissolved in ethanol (10 ml), and this solution was dissolved in 1-bromo-1-methyl-12-butanone (0.825 g, 5.00 mmol) in ethanol (1 Oml). The mixture was added dropwise to the solution dissolved in the above with stirring under ice-cooling, stirred at 0 ° C. for 30 minutes, and then stirred at room temperature for 18 hours. After evaporating the solvent, water was added to the residue, and the organic layer extracted with ethyl acetate was washed once with a 5% aqueous carbonated solution (10 ml), twice with water (10 ml), and saturated saline (10 ml). , And dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 3Z1), the solvent was distilled off under reduced pressure, and the residue was ethanol (1 ml) Zn-hexane ( (1.5 ml). The precipitated crystals were collected by filtration, washed with n-hexane, and dried under reduced pressure (40 ° C) to give 1.07 g (IK rate 59.8%) of the title compound as a white crystalline powder. .

Melting point: 105.0--109.0 ° C.

'Η NMR (CD ₃ OD, 400MHz) δ:

0.71 (3H, d, J = 7Hz), 1.03 (3H, d, J = 7Hz),

2.25 (1 H, m),

3.13 (1 H, d, J = 13 Hz),

3.58 (1 H, d, J = 13 Hz),

3.82, 3.92 (9H, each s),

4.89 (1 H, d, J = 16 Hz),

5.06 (1 H, cl, J = 16 Hz),

6.69 (1H, d, J = 9Hz), 7.20 (1H, d, J = 9Hz). (2) 4-Isopropyl-3- (2,3,4-trimethoxybenzyl) thiazoline-1 2-thione

The 4-isopropyl-14-hydroxy-3- (2,3,4-trimethoxybenzyl) thiazolidine-12-thione (0.630 g, 1.76 mmol) obtained in (1) above was added to ethanol (4 ml). ), Concentrated hydrochloric acid (4 ml) was added to this solution under ice-cooling, and the mixture was stirred and reacted at room temperature for 20 minutes. After completion of the reaction, the reaction solution was ice-cooled again, and a 4N aqueous sodium hydroxide solution was added to make the mixture basic, and then the solvent was distilled off under reduced pressure, and the residue was extracted with chloroform. The extract was washed once with a saturated saline solution (1 Oml) and dried over anhydrous sodium sulfate. The solvent was distilled off from this solution under reduced pressure, and the residue was crystallized from ethanol (1 ml) and Zn-hexane (1.5 ml). The precipitated crystals were collected by filtration, washed with n-hexane, and dried under reduced pressure (40 ° C) to give 0.535 g (yield: 89.8%) of the title compound as white crystals.

Melting point: 92.5—93.5 ° C. '

'Η NMR (CDC 13, 400MHz) δ:

1.15 (1 H, s), 1.16 (1 H, s), 2.74 (lH, m), 3.82 (3H, s), 3.88 (6H, s),

5.54 (2H, s), 6.27 (1 H, s),

6.49 (1 H, d, J = 9 Hz), 6.57 (1 H, d, J = 9 Hz). IR (KB r) cm " ¹ :

2980, 2930, 1610, 1580, 1500, 1470, 1350,

1280, 1 170, 1 100, 1040, 990, 760.

[Example 3]

4-Ethyl 3- (2,3,4-trimethoxybenzyl) thiazoline-2-thione

(1) 4-Ethyl 4-hydroxy-1 3- (2,3,4-trimethoxybenzyl) thiazolidine-12-thione

2,3,4 Trimethoxybenzylamine (1.g, 5.07 mmol) was dissolved in ethanol (1 Om 1), and carbon disulfide (0.31 m (1 mmol) and stirred at room temperature for 15 minutes. To this mixture was added a 28% sodium methoxide / methanol solution (1.0 g, 5.2 mmol), and the mixture was further stirred at room temperature for 15 minutes. After evaporating the solvent under reduced pressure, the residue was added to a solution of 1-promo-2-butanone (0.789 g, 5.07 mmol) in ethanol (1 Oml) under ice-cooling for 5 minutes. Was added. After stirring at room temperature for 1 hour, the solvent was distilled off, water (10 ml) was added to the residue, and the mixture was extracted with chloroform (1 Om 1 X 3). The port-form layer was washed with water (10 ml) and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 2.07 g of a crude product of the title compound. The crude product was recrystallized from ethanol / hexane and further purified by silica gel column chromatography (hexane / ethyl acetate = 2/1), and the solvent was distilled off. Yield 46.7%) as a white crystalline powder.

Melting point: 106.5-108 ° C.

Ή NMR (CDC 1a, 400MHz) δ:

0.96 (3H, t, J = 7Hz), 1.85 (2H, q, J = 7Hz),

3.22 (1 H, d, J = 12 Hz), '

3.41 (1 H, d, J = 12 Hz),

3.84, 3.86, 3.98 (9H, each s),

4.01 (1 H, s),

4.96 (1 H, d, J = 15 Hz),

5.04 (1 H, d, J = 15Hz),

. 6. 65 (1 H, d , J = 9Hz), 7. 30 (1 H, d, J = 9Hz) IR (KB r) cm '1:

3433, 3199, 2983, 2951, 2947, 2845, 2829, 1599, 1497, 1456, 1454, 1408, 1385, 1348, 1333, 1292, 1288, 1259, 1 188, 1 184, 1 167, 1 1 19, 1095 , 1061, 1034, 1016, 993, 920, 916, 818, 796, 789, 698, 663, 584.521,

494.

(2) 4-Ethyl-3- (2,3,4-trimethoxybenzyl) thiazoline-1 2 —Thion

The 4-ethyl-4-hydroxy-3- (2,3,4-trimethoxybenzyl) thiazolidine-2-thione (0.385 g) obtained in (1) above was recrystallized from the mother liquor of the reaction of Kamimi (1), After combining with a compound other than the above compound separated by silica gel column chromatography and evaporating the solvent from the mixture, the residue was suspended in ethanol (10 ml) and concentrated hydrochloric acid (5 ml) was added to this suspension under ice-cooling. ) Was added and stirred for 25 minutes to react. After completion of the reaction, ethanol was distilled off from the reaction solution under reduced pressure.

(10 ml), extracted with chloroform (15 ml + 10 ml + 10 ml), and the pore form layer was dried over anhydrous sodium sulfate. The solvent was distilled off from this solution, and the residue was purified by silica gel column chromatography (hexane Z ethyl acetate = 3 Z 1), and further recrystallized from ethanol-hexane to give 0.559 g of the title compound as a white fiber. Obtained as a viscous powder.

Melting point: 96.5-97 ° C.

• H NMR (CDC 13, 400MHz) δ:

1.19 (3H, t, J = 7Hz),

2.44 (2H, dq, J = 1 Hz, 7Hz),

3.82, 3.89, 3.97 (9H, each s),

5.50 (2H, s), 6.23 (1H, s),

6.55 (1H, d, J = 9Hz), 6.58 (1H, d, J = 9Hz). IR (KB r) cur ¹ :

3103, 3001, 2970, 2941, 2939, 2837, 1606, 1583, 1498, 1468, 1466, 1439, 1419, 1373, 1365, 1360, 1352, 1304, 1265. 1234, 1213, 1 194, 1 146, 1093, 1032, 1012, 964, 931, 906, 854, 833, 793, 791, 766, 735, 671, 559, 501.

[Example 4]

3- (2-Methoxybenzyl) 1-4-methylthiazoline-2-thione

(1) 4-Hydroxy-1- (2-methoxybenzyl) -14-methylthiazolide Nichi 2-Thion

2-Methoxybenzylamine (1.5 g, 10.9 mmol) is dissolved in ethanol (15 ml), and carbon disulfide (0.66 ml, 10.9 mmol) is added to this solution. And stirred at room temperature for 15 minutes. To this mixture was added a 28% methanol solution of sodium methoxide Z (2.12 g, 11 mmol), and the mixture was further stirred at room temperature for 15 minutes. After evaporating the solvent under reduced pressure, the residue was added to a solution of acetone (1.14 ml, 14.3 mmol) in ethanol (10 ml) dissolved in ethanol (10 ml) over 5 minutes under ice-cooling. After stirring at room temperature for 2 hours, water (10 ml) was added to the mixture, ethanol was distilled off under reduced pressure, and the residue was extracted with chloroform (15 ml × 3). The dried form layer was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 3.86 g of a crude product of the title compound. The crude product was purified by silica gel column chromatography-(hexane Z ethyl acetate = 2Z1), the solvent was distilled off, and the residue was recrystallized from ethanol-hexane to give 2.27 g of the title compound (yield 77.3 %) Was obtained as a white crystalline powder.

JH NMR (CDC 1a, 400MHz) δ:

1.55 (3 H, d, J = 1 Hz),

3.3 1 (1 H, d, J = 12 Hz),

3.42 (1 H, d, J = 1 2 H z),

3.57 (1H, s), 3.90 (3H, s),

4.99 (1H, d, J = 16Hz),

5.17 (1H, d, J = 16Hz),

6.8 to 6.9 (2 H, m), 7.2 to 7.3 (1 H, m),

7.37 (1H, d, J = 7Hz).

(2) 3- (2-methoxybenzyl) -1-methylthiazoline-2-thione 4-hydroxy-3- (2-methoxybenzyl) -14-methylthiazolidine-1-thione obtained in (1) above (1. 28 g, 4.75 mmol) in ethanol

(12 ml), concentrated hydrochloric acid (3 ml) was added to the suspension under ice cooling, and the mixture was stirred for 20 minutes. The reaction solution was neutralized by adding 2N aqueous sodium hydroxide solution (17 ml), and the ethanol was distilled off under reduced pressure. The residue was extracted with chloroform (15 ml × 3). The roloform layer was dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from ethanol hexane to obtain 1.10 g (yield 92.2%) of the title compound as a white crystalline powder.

Melting point: 11-1-12 ° C.

NMR (CDC 1a, 400 MHz) δ:.

2.1 1 (3H, d, J = 1 Hz) ',

3.89 (3 H, s), 5.52 (2 H, s), 6.26 (1 H, s), 6.78 (1 H, d, J = 7 Hz),

6.8 to 6.9 (2 H, m), 7.2 to 7.3 (1 H, m).

IR (KB r) cm " ¹ :

3448, 3107, 2956, 2927, 2914, 2883, 2833, 1603, 1585, 1493, 1464, 1437, 1421, 1377, 1360, 1336, 1304, 1286, 1252, 1219, 1 184, 1 140, 1 109, 1049 , 1016, 1014, 989, 843, 812, 762, 760, 750, 729, 727, 681, 619, 561, 492. 467.

[Example 5]

4-Methyl-1- (3,4,5-trimethoxybenzyl) thiazoline-2-thione

3,4,5-Trimethoxybenzylamine (1.24 g, 6.29 mmol) is dissolved in ethanol (5 ml), and carbon disulfide (0.38 ml, 6.29 mmol) is added to this solution. And stirred at room temperature for 15 minutes. To this mixture was added a 28% sodium methoxide Z methanol solution (1.22 g, 6.32 mmol), and the mixture was further stirred at room temperature for 15 minutes. This solution was added to a solution of acetone (0.64 g, 6.92 mmol) in ethanol (2 ml) under ice-cooling, and the mixture was stirred at room temperature for 4 hours. Concentrated hydrochloric acid (4 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The extract was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Silica gel column chromatography (ethyl acetate hexane) The residue was recrystallized from a mixed solvent of ethanol Z hexane = 2Z1 (4.5 ml) to obtain 1.03 g (yield: 52.6%) of the title compound as pale orange crystals.

Melting point: 1 16. 5-121. 5 ° C.

Ή NMR (CDC 1a, 400MHz) δ:.

2. 20 (3H, d, J = 1 Hz),

3.81, 3.82 (6H, 3H, each s), 5.45 (2H, s), 6.26 (1H, d, J = 2Hz), 6.48 (2H, s).

IR (KB r) cm " ¹ :

3097, 1591, 1510, 1360, 1354, 1329, 1306, 1242, 1213, 1 171, 1128, 101 1.

[Example 6]

4-propyl-3- (2,3,4-trimethoxybenzyl) thiazoline-2

(1) 4-Hydroxy-4-propyl-1- (2,3,4-trimethoxybenzyl) thiazolidine-1-thione

2,3,4-Trimethoxybenzylamine (1.18 g, 6.0 mmol) was dissolved in ethanol (10 ml), and to this solution was added carbon disulfide (0.36 ml, 6.0 mmol). The mixture was stirred at room temperature for 15 minutes. To this mixture was added a 28% sodium methoxide Z methanol solution (1.16 g, 6.00 mmol), and the mixture was further stirred at room temperature for 15 minutes. After evaporating the solvent under reduced pressure, the residue was ethanol

(10 ml), and this solution was added dropwise to a solution of 1-chloro-1--2-phenynone (0.724 g, 6.00 mmol) in ethanol (10 ml) under ice-cooling and stirring. 2. Stirred for 5 hours. After evaporating the solvent under reduced pressure, water (20 ml) was added to the residue, and the organic layer extracted three times with chloroform (20 ml, 1 Om 1 X 2) was extracted with a 5% aqueous solution of carbon dioxide (10 ml). After washing with water (10 ml) and saturated saline solution (10 ml) once, the mixture was dried over sodium sulfate. The solvent was distilled off from the product under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 31), and the solvent was distilled off under reduced pressure to give the title compound 1.2 9 g (62.0% yield) was obtained as a pale yellow solid.

• H NMR (CDC 1a, 400MHz) δ:

0.86 (3Η, t, J = 7Hz),

1.20 to 1.35, 1.43 to 1.57 (2Η, each m),

1.78 (2 Η, m), ·

3.23 (1 H, d, J = 12 H z),

3.40 (1H, d, J = 12Hz),

3.85, 3.86, 3.99 (9 H, each s), 4.02 (1 H, s),

4.80 (1H, d, J = 16Hz),

5.02 (1 H, d, J = 16 Hz),

6.65 (1 H, d, J = 9 Hz), 7.31 (1 H, d, J = 9 Hz). (2) 4-Brovir-3- (2,3,4-trimethoxybenzyl) thiazoline

2—Thion

4-Hydroxy-4-propyl-13- (2,3,4-trimethoxybenzyl) thiazolidine-12-thione (0.717 g, 1.96 mmol) obtained in (1) above was added to ethanol (2 ml). The solution was dissolved, concentrated hydrochloric acid (3 ml) was added to the solution under ice-cooling, and the mixture was reacted by stirring at room temperature for 20 minutes. After completion of the reaction, the reaction mixture was cooled on ice again, and the reaction mixture was basified with 4N aqueous sodium hydroxide solution (6 ml) .The solvent was distilled off, and the residue was extracted with chloroform. did. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off from the solution under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane Z ethyl acetate = 3Z1). The crystals precipitated by replacing the solvent with ethanol were recrystallized (inoculated) with ethanol (1 ml), and the crystals were dried under reduced pressure (40 ° C) to give the title compound 0.579 S ( Yield 82.6%) as a white crystalline powder.

Melting point: 80.5-82.0 ° C.

lH NMR (CD ₃ OD, 40 OMH z) δ:

0.92 (3 H, t, J = 8 Hz),

1.57 (2 H, m),

2.43 (2 H, dt, J = 8 Hz, l Hz), 3.81, 3.84, 3.95 (9 H, each s), 5.49 (2 H, s),

6.48 (1 H, d, J = 9 Hz),

6.55 (1 H, t, J = 1 Hz),

6.67 (1 H, d, J = 9 Hz).

IR (KB r) cm " ¹ :.

2960, 2940, 1610, 1580, 1500, 1470, 1420, 1350, 1300, 1 180, 1 100, 1040, 1000, 790,

510.

[Example Ί]

4-Methyl-2-methylthio-1- (2,3,4-trimethoxybenzyl) 1-1,3-thiazole-1-dimodide

4-Methyl-3- (2,3,4-trimethoxybenzyl) thiazoline-12-thione (0.35 g, 1.12 mmol) synthesized in the same manner as in Example 1 was converted to methyl iodide. (3.5 ml) and stirred at room temperature for 10 minutes. Methyl iodide was distilled off from the reaction solution under reduced pressure, and a mixed solvent of acetone / hexane = 2/10 (2.4 ml) was added to the residue, and the precipitated crystals were collected by filtration. The crystals are washed with a mixed solvent (2.2 ml) of acetone X hexane = 1/1, then dried in vacuo and 0.50 g of the title compound

(Yield 98.2%) was obtained as pale yellow crystals.

Melting point: 117 ° C.

* H NMR (CDC la, 400 MHz) δ:

2.58 (3H, s), 2.97 (3 H, s),

3.83, 3.85, 3.87 (9 H, each s), 5.44 (2 H, s), 6.65 (1 H, d, J = 9 Hz), 6.78 (1 H, d, J = 9Hz).

IR (KB r) cm- ¹

3068, 2962, 2832, 1574, 1495, 1475, 1470, 1405, 1281, 1 103.

[Example 8]

3-Benzyl-1-methylthiazoline-2-thione

Benzylamine (1.0 g, 9.33 mmol) in ethanol (10 ml) After dissolution, carbon disulfide (0.56 ml, 9.33 mmol) was added to the solution, and the mixture was stirred at room temperature for 15 minutes. To this mixture was added a 28% sodium methoxide / methanol solution (1.8 g, 9.33 mmol), and the mixture was further stirred at room temperature for 15 minutes. The residue obtained by distilling off methanol from the solution under reduced pressure was added to a solution of acetone (0.97 ml, 12.1 mmol) in ethanol (1 Om 1) in ethanol for 5 minutes while cooling with ice. After the mixture was stirred at room temperature overnight, about half of ethanol was distilled off from the reaction solution under reduced pressure, and concentrated hydrochloric acid (6 ml) was added thereto under ice-cooling, followed by stirring for 20 minutes. The reaction solution was neutralized with a 4N aqueous sodium hydroxide solution (18 ml), ethanol was distilled off under reduced pressure, and the mixture was extracted with chloroform (2 Om 1 +15 m 1 +15 m 1). The dried form layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product of the title compound. The crude product was purified by simple silica gel column chromatography (hexane Z ethyl acetate = 1Z1), excluding the origin, and the solvent was distilled off. The residue was recrystallized from an ethanol-hexane mixed solvent. , Title compound

0.868 g (yield 42.0%) was obtained as a light brown crystalline powder.

Melting point: 85-85.5 ° C.

lH NMR (CDC 1a, 400MHz) δ:

2.14 (3Η, d, J = 1 Hz),

5.53 (2H, s), 6.24 (1H, s),

7.19—7.22, 7.25—7.35 (5H, m).

1 R (KB r) cm- ¹ :

3082, 3028, 2954, 2918, 1591, 1589, 1495,

1454, 1433, 1385, 1365, 1323, 1319, 1227, 1180, 1149, 1076, 1016, 991, 968, 841,

808, 721, 692, 623, 609, 563, 488.

[Example 9]

4-methyl-3- [2- (2,3,4-trimethoxyphenyl) ethyl] thiazoline-2-thione

Dissolve 2- (2,3,4-trimethoxyphenyl) ethylamine (1.5 s, 7.10 mmol) in ethanol (15 ml) and add carbon disulfide (0. 43 ml, 7.10 mmol) and stirred at room temperature for 20 minutes. A 28% sodium methoxide / methanol solution (1.37 g, 7.10 mmol) was added to the mixture, and the mixture was further stirred at room temperature for 20 minutes. After methanol was distilled off from this solution under reduced pressure, acetone (0.854 g, 9.23 mmol) in ethanol was added.

(10 ml) The solution was added over 5 minutes under ice-cooling. After the mixture was stirred at room temperature for a while, ethanol was distilled off from the reaction solution under reduced pressure, water (10 ml) was added, and the mixture was extracted with chloroform (15 ml × 3). After drying the dried form layer with anhydrous sodium sulfate, the solvent was distilled off to obtain 2.73 g of a crude product of the title compound. The crude product was purified by silica gel column chromatography (hexane Z acetone = 3/1), the solvent was distilled off, and the residue was recrystallized from a mixed solvent of ethanol and hexane to give the title compound 1.21 g (52.4% yield) as a white crystalline powder.

Melting point: 1 11.0-: I 11.5 ° C.

'Η NMR (CD ₃ OD, 400MHz) δ:

2.08 (3H, d, J = 1 Hz), 3.03 (2 H, t, J = 7 Hz),

3.80, 3.82, 3.89 (9 H, each s),

4.33 (2 H, t, J = 7 Hz), 6.45 (1 H, s),

6.68 (1H, d, J = 8Hz), 6.82 (1H, d, J = 8Hz). IR (KB r) cm- ¹ :

3448, 3442, 3103, 2980, 2976, 2943, 2939, 2914, 2833, 1605, 1589, 1493, 1468, 1446, 143 1, 141 7, 1 371, 1367, 1 325, 1 3 1 7, 1 28 1, 1 254, 1 232, 1 203, 1 171, 1 099, 106 1, 1002, 1001, 980, 937, 897, 793, 752, 750, 694, 474 .

[Example 10] (Powder)

10 parts of thiazoline-2-thione derivative obtained in Example 1

Heavy magnesium oxide 10 parts

Lactose 80 parts

The above-mentioned substances were uniformly mixed to obtain powder or fine granules to obtain a powder. [Example 11] (Powder)

10 parts of thiazoline-2-thione derivative obtained in Example 1

Synthetic aluminum silicate 10 parts

5 parts of calcium hydrogen phosphate

Lactose 7 5 parts.

The above-mentioned substances were uniformly mixed to obtain powder or fine granules to obtain a powder.

[Example 12] (Granules)

50 parts of the thiazoline-2-thione derivative obtained in Example 1

Starch 10 parts

Lactose 1 5 parts

Microcrystalline cellulose 20 parts

Polyvinyl alcohol 5 parts

30 parts of water

After uniformly mixing and kneading the above substances, one powder was dried, sieved to obtain granules. -[Example 13] (Sugar-coated tablets)

1 part of calcium stearate was mixed with 99 parts of the granules obtained in Example 12 and compression-molded to give a diameter of 1 Omm.

[Example 14] (Injection)

0.5 part of the thiazoline-2-thione derivative obtained in Example 1

2.5 parts of nonionic surfactant

Physiological saline 9 7 parts

The above substance was heated and mixed and then sterilized to give an injection.

[Example 15] (Capsule)

The powder obtained in Example 10 was filled in a commercially available capsule container to prepare a capsule.

[Industrial applicability]

The thiazoline-2-thione derivative represented by the general formula (1) of the present invention has an excellent G0T, GΡ 逸脱 departure inhibitory effect and prolonged prolongation time in an acute liver injury model. It has an inhibitory effect, reduces or treats liver damage, or has an excellent protective effect against liver damage.It is particularly useful as a treatment and prevention agent for liver diseases, and is also an anti-inflammatory, anti-rheumatic, and digestive agent. It is also useful as a therapeutic agent for vascular diseases, and the thiazolidine-2-thione derivative represented by the general formula (2) is useful as an intermediate for producing the thiazoline-2-thione derivative represented by the general formula (1) And a therapeutic agent for liver disease containing as an active ingredient a thiazoline-2-thione derivative represented by the general formula (3) or a salt of a thiazoline-2-thione derivative represented by the general formula (4) It has excellent efficacy for liver disease.

Claims

The scope of the claims

1. The following general formula (1):

(Wherein, R ¹ is unsubstituted or has 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group and an alkoxyl group having 1 to 6 carbon atoms, and has 1 to 6 carbon atoms. A cycloalkyl group having 3 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms or an alkynyl group having 2 to 6 carbon atoms, wherein R ² is a halogen atom; a hydroxyl group; unsubstituted or halogen An alkoxyl group having 1 to 6 carbon atoms having 1 to 3 substituents selected from the group consisting of an atom, a hydroxyl group and an alkoxyl group having 1 to 6 carbon atoms; an alkylyl group having 1 to 6 carbon atoms; an amino group; number

An alkylamino group having 1 to 6 carbon atoms; a dialkylamino group having 1 to 6 carbon atoms; an alkylthio group having 1 to 6 carbon atoms; a nitro group; a carboxyl group; 7 represents an alkoxycarbonyl group, m represents an integer of 1 to 5, and when m is 2 or more, each R ² may be the same or different, and two R ² atoms are joined together to form a carbon atom May represent an alkylenedioxy group of the number 1 to 6, and n represents 0 or 1)

A thiazoline-2-thione derivative represented by the formula:

2. In the general formula (1), R ¹ is a methyl group, an ethyl group, a propyl group, a monofluoromethyl group, a trifluoromethyl group, a methoxymethyl group, an ethoxymethyl group, a hydroxymethyl group, a vinyl group, or an aryl group. 2. The thiazoline-2-thione derivative according to claim 1, which is a group selected from the group consisting of a group and a probel group.

3. In the general formula (1), R ² is a chlorine atom, a fluorine atom, a hydroxyl group, a methyl group, a methoxy group, an ethoxy group, a propoxy group, a methylthio group, a methoxymethoxy group, a methoxyethoxy group, a fluorometer. 2. The thiazolyl according to claim 1, which is selected from the group consisting of a xy group, a dimethylamino group and a nitro group. 2-one thione derivative.

4. The thiazoline-12-thione derivative according to claim 1, wherein in formula (1), two adjacent R ² forces together form a methylenedioxy group or an ethylenedioxy group. .

5. 4-Methyl-3- (2,3,4-trimethoxybenzyl) thiazoline-2-thione.

6. 4-Isopropyl_3- (2,3,4-trimethoxybenzyl) thiazoline-2-thione.

7. 4-Ethyl-3- (2,3,4-trimethoxybenzyl) thiazoline-2-thione.

8. 3- (2-Methoxybenzyl) -1-methylthiazoline-2-thione.

9. 4-Methyl-3- (3,4,5-trimethoxybenzyl) thiazoline-2-thione.

10. 4-Propyl-1- (2,3,4-trimethoxybenzyl) thiazoline-2-thione.

1 1. The following general formula (2):

(Wherein, R ¹ is unsubstituted or has 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group and an alkoxyl group having 1 to 6 carbon atoms, and has 1 to 6 carbon atoms. A cycloalkyl group having 3 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms or an alkynyl group having 2 to 6 carbon atoms, wherein R ² is a halogen atom; a hydroxyl group; a halogen atom; Or an alkoxyl group having 1 to 3 carbon atoms having 1 to 3 substituents selected from the group consisting of a hydroxyl group and an alkoxyl group having 1 to 6 carbon atoms; an alkyl group having 1 to 6 carbon atoms; an amino group; number

1-6 alkylamino groups; each alkyl group is independently an alkyl group having 1-6 carbon atoms A dialkylamino group; an alkylthio group having 1 to 6 carbon atoms; a nitro group; a carboxy group; or an alkoxycarboyl group having 2 to 7 carbon atoms, m represents an integer of 1 to 5, and m represents 2 or more. Wherein each R ² may be the same or different, and the two R ² forces may together represent an alkylenedioxy group having 1 to 6 carbon atoms, and n represents 0 or 1. ).

A thiazolidine-12-thione derivative represented by the formula:

1 2. The following general formula (3):

(3)

(Wherein, R ¹ is unsubstituted or has 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group and an alkoxyl group having 1 to 6 carbon atoms, and has 1 to 6 carbon atoms. A cycloalkyl group having 3 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms or an alkynyl group having 2 to 6 carbon atoms, wherein R ² is a halogen atom; a hydroxyl group; unsubstituted or halogen An alkoxyl group having 1 to 6 carbon atoms having 1 to 3 substituents selected from the group consisting of an atom, a hydroxyl group and an alkoxyl group having 1 to 6 carbon atoms; an alkyl group having 1 to 6 carbon atoms; an amino group; Carbon number

A dialkylamino group having 1 to 6 carbon atoms; an alkylthio group having 1 to 6 carbon atoms; a nitro group; a carboxyl group; or 2 to 7 carbon atoms. represents alkoxy carbonylation Le group, s represents an integer of 0 to 5, when s is 2 or more, each R ² may be the same or different, connexion carbon atoms such together two of R ² May represent 1 to 6 alkylenedioxy groups, and t represents an integer of 0 to 4)

A therapeutic agent for liver disease, comprising a thiazoline-2-thione derivative represented by the following formula as an active ingredient:

1 3. In the general formula (3), R ¹ is a methyl group, an ethyl group, a propyl group, a monofluoromethyl group, a trifluoromethyl group, a methoxymethyl group, an ethoxymethyl 13. The therapeutic agent for liver disease according to claim 12, which is a group selected from the group consisting of a group represented by the following formula:

14. In formula (3), R ² is a chlorine atom, a fluorine atom, a hydroxyl group, a methyl group, a methoxy group, an ethoxy group, a propoxy group, a methylthio group, a methoxymethoxy group, a methoxyethoxy group, or a fluoromethoxy group. 13. The therapeutic agent for liver disease according to claim 12, which is selected from the group consisting of dimethylamino group and nitro group.

15. —The therapeutic agent for liver disease according to claim 12, wherein in general formula (3), two adjacent R ² groups together form a methylenedioxy group or an ethylenedioxy group. .

16. The therapeutic agent for liver disease according to claim 12, wherein in the general formula (3), s represents an integer of 1 to 5, and t is 0 or 1.

1 7. The following general formula (4):

X (4)

(Wherein, R ¹ is unsubstituted or has 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group and an alkoxyl group having 1 to 6 carbon atoms. Represents an alkyl group, a cycloalkyl group having 3 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms or an alkynyl group having 2 to 6 carbon atoms, wherein R ² is a halogen atom; a hydroxyl group; An alkoxyl group having 1 to 6 carbon atoms having 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group and an alkoxyl group having 1 to 6 carbon atoms; an alkyl group having 1 to 6 carbon atoms; an amino group; Carbon number

A dialkylamino group in which each alkyl group is independently an alkyl group having 1 to 6 carbon atoms; Alkylthio of 1-6; a nitro group; a carboxyl group; represents or alkoxycarbonyl two Le group having 2 to 7 carbon atoms, R ⁴ has a carbon number X represents a phenylalkyl group containing an alkyl group of 1 to 6 or an alkyl group having 1 to 3 carbon atoms, X represents a halogen atom, a methanesulfonyloxy group or a p-toluenesulfonyloxy group, and s represents 0 to When s is 2 or more, each R ² may be the same or different, and represents two alkylenedioxy groups having 1 to 6 carbon atoms in connection with ^two R ² forces s— And "b represents an integer of from 1 to 4). A therapeutic agent for liver disease, comprising a salt of a thiazoline-2-thione derivative represented by the following formula:

18. The salt of the thiazoline-12-thione derivative is 4-methyl-2-meththio-13- (2,3,4-trimethoxybenzyl) -11,3-thiazolu-1-dimethoxide. The therapeutic agent for liver disease according to claim 17.