JPH0753532A - Thiazoline-2-thione derivative - Google Patents

Abstract

(57) [Summary] [Object] To provide a novel thiazolin-2-thione derivative useful as an active ingredient of a therapeutic agent for liver diseases and a thiazolidine-2-thione derivative useful as an intermediate for synthesizing this compound. [Structure] The following general formula (1): (In the formula, R ¹ represents an alkyl group, a cycloalkyl group, an alkenyl group or an alkynyl group, and R ² represents a halogen atom; a hydroxyl group; an alkoxyl group; an alkyl group; an amino group; an alkylamino group; a dialkylamino group; Alkylthio group; nitro group; carboxyl group; or alkoxycarbonyl group, m represents an integer of 1 to 5, and m
Is 2 or more, two R ^{2 s} may together represent an alkylenedioxy group, and n represents 0 or 1). Corresponding thiazolidine-2-thione derivative.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel thiazolin-2-thione derivative useful as an active ingredient of a therapeutic agent for liver diseases and a thiazolidine-2-thione derivative useful as an intermediate for synthesizing this compound.

[0002]

2. Description of the Related Art The liver has various biological components such as detoxification, carbohydrate metabolism, lipid metabolism, protein metabolism, bile production / secretion, blood coagulation factor production, hormone regulatory action, fat, glycogen, protein and vitamin. It has various functions such as storage. But these features are also viruses,
Acute or chronic damage caused by drugs, toxic substances, alcohol, malnutrition, hepatic circulatory system disorder, bile duct obstruction, etc., viral hepatitis, drug toxic hepatitis, alcoholic hepatitis, depressive hepatitis, bile depressive band Due to liver damage, fatty liver,
It manifests as jaundice, or eventually a disease such as cirrhosis.

The present inventors have studied therapeutic agents for the above-mentioned liver diseases, and as a result, have shown the general formula (1);

[0004]

[Chemical 3]

(In the formula, R ¹ has ¹ to 3 carbon atoms, which 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. 6 alkyl group, C 3-6 cycloalkyl group, C 2-6 alkenyl group or C 2-6
R ² represents a halogen atom; a hydroxyl group; a halogen atom, a hydroxyl group and a carbon number of 1
To C6 alkoxyl groups, which may have 1 to 3 substituents selected from the group consisting of C1 to C6 alkoxyl groups; C1 to C6 alkyl groups; amino groups;
A dialkylamino group in which each alkyl group is independently 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 represents 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 may be the same or different, and two R ² together represent an alkylenedioxy group having 1 to 6 carbon atoms. , And n represents 0 or 1), a novel thiazoline-2-thione derivative represented by GOT (glutamine-oxalo) in an in vivo carbon tetrachloride acute liver injury model and a galactosamine acute liver injury model. Acetate transaminase) and GPT (glutamine-pyruvate transaminase) have excellent deviant inhibitory action and prothrombin time extension inhibitory action, and reduce or treat liver damage.
It has also been found that it has an excellent protective action against liver damage and is useful as a therapeutic or prophylactic agent for liver diseases.

Further, the following general formula (2):

[0007]

[Chemical 4]

(In the formula, R ¹ has ¹ to 3 carbon atoms, which 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. 6 alkyl group, C 3-6 cycloalkyl group, C 2-6 alkenyl group or C 2-6
R ² represents a halogen atom; a hydroxyl group; a halogen atom, a hydroxyl group and a carbon number of 1
To C6 alkoxyl groups, which may have 1 to 3 substituents selected from the group consisting of C1 to C6 alkoxyl groups; C1 to C6 alkyl groups; amino groups;
A dialkylamino group in which each alkyl group is independently 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 represents 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 may be the same or different, and two R ² together represent an alkylenedioxy group having 1 to 6 carbon atoms. And n represents 0 or 1), and a novel thiazolidine-2-thione derivative represented by the general formula (1) is used as an intermediate for synthesizing the thiazolin-2-thione derivative. I found it useful.

[0009]

DISCLOSURE OF THE INVENTION The object of the present invention is to provide a novel thiazoline-2 useful as an active ingredient of a therapeutic agent for liver diseases.
-To provide a thione derivative and a thiazolidine-2-thione derivative useful as an intermediate for synthesizing this compound.

[0010]

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

[0011]

[Chemical 5]

(In the formula, R ¹ has ¹ to 3 carbon atoms, which 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. 6 alkyl group, C 3-6 cycloalkyl group, C 2-6 alkenyl group or C 2-6
R ² represents a halogen atom; a hydroxyl group; a halogen atom, a hydroxyl group and a carbon number of 1
To C6 alkoxyl groups, which may have 1 to 3 substituents selected from the group consisting of C1 to C6 alkoxyl groups; C1 to C6 alkyl groups; amino groups;
A dialkylamino group in which each alkyl group is independently 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 represents 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 may be the same or different, and two R ² together represent an alkylenedioxy group having 1 to 6 carbon atoms. And n represents 0 or 1), which is a thiazoline-2-thione derivative.

Another aspect of the present invention is the following general formula (2):

[0014]

[Chemical 6]

(In the formula, R ¹ has ¹ to 3 carbon atoms, which 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. 6 alkyl group, C 3-6 cycloalkyl group, C 2-6 alkenyl group or C 2-6
R ² represents a halogen atom; a hydroxyl group; a halogen atom, a hydroxyl group and a carbon number of 1
To C6 alkoxyl groups, which may have 1 to 3 substituents selected from the group consisting of C1 to C6 alkoxyl groups; C1 to C6 alkyl groups; amino groups;
A dialkylamino group in which each alkyl group is independently 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 represents 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 may be the same or different, and two R ² together represent an alkylenedioxy group having 1 to 6 carbon atoms. And n represents 0 or 1), a thiazolidine-2-thione derivative.

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,
Examples thereof include an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, and a t-butyl group. Specific examples of the cycloalkyl group having 3 to 6 carbon atoms include cyclopropyl and cyclopentyl. , Cyclohexyl and the like, and specific examples of the alkenyl group having 2 to 6 carbon atoms include an ethenyl group, a 2-propenyl group, a 2-methyl-2-propenyl group, a 3-butenyl group and a 3-methyl-2.
-Butenyl group and the like can be mentioned, and specific examples of the alkynyl group having 2 to 6 carbon atoms include ethynyl group, 2-propynyl group,
Examples thereof include a 2-butynyl group and a 3-butynyl group. Also,
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, a propoxy group). , Butoxy group), and may have 1 to 3 substituents selected from the group consisting of Preferred specific examples of the above-mentioned alkyl group, alkenyl group and alkynyl group having such a substituent include monofluoromethyl, trifluoromethyl group, methoxymethyl group, ethoxymethyl group, hydroxymethyl group and 3-fluoropropynyl group. Etc. can be mentioned.

In the general formula (1), specific examples of the alkoxyl group having 1 to 6 carbon atoms represented by R ² are methoxy group, ethoxy group, n-propoxy group, isopropoxy group and n-butoxy group. Group, isobutoxy group, sec-butoxy group, t-butoxy group and the like. This alkoxy group is a group consisting of a halogen atom (preferably a fluorine atom, a chlorine atom, a bromine atom), a hydroxyl group and an alkoxyl group having 1 to 6 carbon atoms (for example, a methoxy group, an ethoxy group, a propoxy group, a butoxy group). It may have 1 to 3 substituents selected from

In the general formula (1), specific examples of the alkylamino group having 1 to 6 carbon atoms represented by R ² include methylamino group, ethylamino group, propylamino group, isopropylamino group and n. -Butylamino group, isobutylamino group, sec-butylamino group, t-butylamino group and the like. Further, as the dialkylamino group represented by R ^{2 in} which 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 (the alkyl groups are the same But they may be different).

In the general formula (1), specific examples of the alkylthio group having 1 to 6 carbon atoms represented by R ² include methylthio group, ethylthio group, propylthio group, isopropylthio group, n-butylthio group, Examples thereof include an isobutylthio group, a sec-butylthio group and a t-butylthio group.

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

In the general formula (1), when m is 2 or more, R ² may be the same or different. Also, m is 2
For more than, two of R ² (preferably, R ² bonded to the carbon atom adjacent the benzene ring) dioxyalkylene group having 1 to 6 carbon atoms representing together [-O (CH _{2) p} O
Specific examples of — (wherein p is an integer of 1 to 6)] include groups having the formula —O—CH ₂ —O—, —O (CH ₂ ) ₂ O—, and the like.

In the general formula (1), R ¹ is an alkyl group having 1 to 6 carbon atoms (in particular, 1 to 4 carbon atoms) having no substituent, or a halogen atom, a hydroxyl group and 1 to 1 carbon atoms.
1 to 6 carbon atoms having 1 to 3 substituents selected from the group consisting of 6 (particularly 1 to 4 carbon atoms) alkoxyl groups
(In particular, an alkyl group having 1 to 4 carbon atoms is preferable, and R ² has 1 to 6 carbon atoms having no substituent (in particular,
An alkoxyl group having 1 to 4 carbon atoms, or a halogen atom,
Hydroxyl group and C1-6 (especially C1-C6
4) having 1 to 3 substituents selected from the group consisting of alkoxyl groups, and having 1 to 6 carbon atoms (especially 1 to 6 carbon atoms).
It is preferably the alkoxy group 4).

In the general formula (1), m is preferably an integer of 1 to 3 and n is preferably 1.

Thiazoline-2-represented by the general formula (1)
Representative compounds of thione derivatives are shown in Table 1 below. In Table 1, R ¹¹ , R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵
And the symbols of n represent the symbols shown in the following general formula (1A).

[0025]

[Chemical 7]

[0026]

[Table 1]

[0027]

[Table 2]

Thiazoline-2-represented by the general formula (1)
Typical compounds of the thione derivative include the following. 4-Methyl-3- (2,3,4-trimethoxybenzyl) thiazoline-2-thione. 4-Isopropyl-3- (2,3,4-trimethoxybenzyl) thiazoline-2-thione. 4-Ethyl-3- (2,3,4-trimethoxybenzyl) thiazoline-2-thione. 3- (2
-Methoxybenzyl) -4-methylthiazolin-2-thione. 4-Methyl-3- (3,4,5-trimethoxybenzyl) thiazoline-2-thione. 4-propyl-3-
(2,3,4-trimethoxybenzyl) thiazoline-2
-Thion. 3- (2,5-dimethoxybenzyl) -4-
Methylthiazoline-2-thione. 3- (3,5-dimethoxy-4-hydroxybenzyl) -4-methylthiazolin-2-thione. 3- [2- (N, N-dimethylamino) benzyl] -4-methylthiazolin-2-thione.
4-Methyl-3- (2-methylthiobenzyl) thiazoline-2-thione. 4-cyclopropyl-3- (2,3,
4-trimethoxybenzyl) thiazoline-2-thione.
4-Methyl-3- (3,4-methylenedioxybenzyl) thiazoline-2-thione. 3- (2,5-dimethoxy-3,4,6-trimethylbenzyl) -4-methylthiazolin-2-thione. 3- [2- (2-Methoxyethoxy) benzyl] -4-methylthiazoline-2-thione. 3- (2-Fluoromethoxybenzyl) -4-methylthiazolin-2-thione. 3- (3-Fluoromethylbenzyl) -4-methylthiazolin-2-thione. 3-
(2-Methoxymethylbenzyl) -4-methylthiazolin-2-thione. 3- (3-Methoxy-6-nitrobenzyl) -4-methylthiazolin-2-thione. 3-
(3,4-dimethoxyphenyl) -4-methylthiazoline-2-thione. 3- (1,4-benzodioxane-6
-Yl) -4-methylthiazolin-2-thione. 4-Fluoromethyl-3- (2,3,4-trimethoxybenzyl) thiazoline-2-thione. 4-methoxymethyl-3
-(2,3,4-trimethoxybenzyl) thiazoline-
2-Thion. 3- (2,5-dihydroxy-3,4,6
-Trimethylbenzyl) -4-methoxymethylthiazoline-2-thione. 3- (2,4-dimethoxy-3-propyloxybenzyl) -4-ethoxymethylthiazoline-2-thione. 4-hydroxymethyl-3- (2,3,
4-trimethoxybenzyl) thiazoline-2-thione.
4-Trifluoromethyl-3- (2,3,4-trimethoxybenzyl) thiazoline-2-thione. 3- (4-chloro-2-ethoxybenzyl) -4-vinylthiazoline-2-thione. 4-allyl-3- (3-fluoro-4-
Methoxybenzyl) thiazoline-2-thione. 3- (2
-Methylbenzyl) -4- (2-propynyl) thiazoline-2-thione.

Thiazoline-2-represented by the general formula (1)
The thione derivative can be produced, for example, by the synthetic method of the synthetic route shown below.

[0030]

[Chemical 8]

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 is an alkyl group having 1 to 6 carbon atoms. Represents a group, M represents an alkali metal, and Z represents a leaving group.

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

The amine compound represented by the general formula (3) in the above reaction formula can be obtained as a commercial product,
It can also be synthesized from a halide by a Gabriel reaction via phthalimide.

The amine compound represented by the general formula (3) is
By reacting a compound of the formula R ³ OM (wherein R ³ represents an alkyl group having 1 to 6 carbon atoms and M represents an alkali metal) and carbon disulfide in a usual solvent, a compound of the general formula (4)
A dithiocarbamate represented by is synthesized. R ³ above
Are preferably methyl group, ethyl group, propyl group, t-butyl group and the like, and M is preferably sodium, potassium, lithium and the like. Instead of the compound of formula R ³ OM,
Triethylamine, 1,8-diazabicyclo [5.4.
It is also possible to use bases such as 0] -7-undecene (DBU). As the solvent for this reaction, alcohols such as ethanol and methanol are usually used, but it is also possible to use polar solvents such as tetrahydrofuran, dimethyl sulfoxide, and dimethylformamide, which do not adversely affect the reaction. It is also possible to use carbon disulfide itself as a solvent. This reaction usually proceeds sufficiently at room temperature for a reaction time of 10 minutes to 1 hour. Even if the temperature is low, the reaction proceeds sufficiently by lengthening the reaction time. The dithiocarbamate represented by the general formula (4) is relatively unstable, but can be used in the next reaction without isolation.

The dithiocarbamate represented by the general formula (4) and the general formula R ¹ —COCH ₂ Z (where R ¹ has the same meaning as defined in the general formula (1), and Z is a (Representing a leaving group) is reacted with a ketone compound to synthesize a thiazolidine-2-thione derivative represented by the general formula (2). As the leaving group represented by Z,
A halogen atom such as a chlorine atom or a bromine atom is generally used, but a group such as a methanesulfonyloxy group or a p-toluenesulfonyloxy group can also be used. The solvent used in this reaction is usually an alcohol such as ethanol or methanol, but other solvents may be used as long as they do not adversely affect the reaction. This reaction can usually be carried out under ice cooling for a reaction time of several minutes to several hours.
The reaction proceeds without problems even at room temperature.

Thiazolidine-represented by the general formula (2)
The 2-thione derivative is stable or unstable. Stable thiazolidine-2 represented by the general formula (2)
The thione derivative is isolated and purified, and then dehydrated with an acid to obtain a thiazoline-2-thione derivative represented by the general formula (1). The acid used in this reaction is preferably a strong inorganic 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 with a reaction time of several minutes. It is also possible to react at a temperature lower or higher than room temperature. When the thiazolidine-2-thione derivative represented by the general formula (2) is unstable, the produced thiazolidine-2-thione derivative immediately undergoes a dehydration reaction to cause the thiazolin-2-thione represented by the general formula (1). Change to derivative. Therefore, as a product of the reaction for synthesizing the thiazolidine-2-thione derivative represented by the general formula (2) from the dithiocarbamate represented by the general formula (4), the thiazolidine-2 represented by the general formula (2) is obtained.
-A mixture of a thione derivative and a thiazoline-2-thione derivative represented by the general formula (1) may be produced.
In this case, an acid may be added to the reaction system to convert all the remaining thiazolidine-2-thione derivative represented by the general formula (2) into the thiazolin-2-thione derivative represented by the general formula (1). .

Thiazoline-2 represented by the general formula (1)
-The thione derivative is represented by the formula R ⁴ -X (wherein R ⁴ is 1 carbon atom
To a phenylalkyl group containing an alkyl group having 6 to 6 or an alkyl group having 1 to 3 carbon atoms, and X represents a halogen atom, a methanesulfonyloxy group or a p-toluenesulfonyloxy group). Accordingly, the general formula (5):

[0038]

[Chemical 9]

A salt of a thiazoline-2-thione derivative represented by the formula (wherein R ⁴ and X are as defined above) can be prepared. The formula R ⁴ methyl group as in R ⁴ to -X, ethyl, t- butyl group, a benzyl group, phenethyl group are preferable, and a chlorine atom as a halogen atom, a bromine atom and an iodine atom. This reaction is represented by the general formula (1): thiazoline-2-
A thione derivative in a compound of formula R ⁴ -X
It can be carried out by stirring at room temperature to reflux temperature for several hours, and a salt of the thiazoline-2-thione derivative represented by the general formula (5) can be obtained in high yield. Formula R ⁴ −
Particularly preferred compounds represented by X are methyl bromide, methyl iodide, butyl bromide, butyl iodide, ethyl iodide, benzyl chloride, benzyl bromide and the like. The salt of the thiazoline-2-thione derivative represented by the general formula (5) is characterized by having a higher solubility in an aqueous medium than the thiazoline-2-thione derivative represented by the general formula (1).

Thiazoline-2 represented by the general formula (5)
-Representative compounds of salts of thione derivatives include, for example:
4-Methyl-3- (2,3,4-trimethoxybenzyl) thiazolin-2-thione, 4-methyl-2-methylthio-3- (2,3,4-, which is a salt of methyl iodide.
Mention may be made of trimethoxybenzyl) -1,3-thiazol-1-ium iodide.

Another thiazolidine-2-thione derivative represented by the general formula (2) of the present invention is a novel compound, and is a thiazoline-formula represented by the general formula (1).
As shown in the synthetic route of 2-thione derivative, it is a compound 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 in the general formula (1).

Thiazolidine-represented by the general formula (2)
The following compounds can be given as typical compounds of the 2-thione derivative. 4-Hydroxy-4-methyl-3- (2,3,4-trimethoxybenzyl) thiazolidine-2-thione 4-isopropyl-4-hydroxy-3- (2,3,4
-Trimethoxybenzyl) thiazolidine-2-thione 4-ethyl-4-hydroxy-3- (2,3,4-trimethoxybenzyl) thiazolidine-2-thione 4-hydroxy-3- (2-methoxybenzyl) -4 −
Methylthiazolidine-2-thione 4-hydroxy-4-propyl-3- (2,3,4-trimethoxybenzyl) thiazolidine-2-thione 3- (2,5-dimethoxybenzyl) -4-hydroxy-4-methyl Thiazolidine-2-thione 4-hydroxy-4-methyl-3- (3,4,5-trimethoxybenzyl) thiazolidine-2-thione 3- (3,5-dimethoxy-4-hydroxybenzyl)
-4-Hydroxy-4-methylthiazolidine-2-thione 3- [2- (N, N-dimethylamino) benzyl] -4
-Hydroxy-4-methylthiazolidine-2-thione 4-hydroxy-4-methyl-3- (2-methylthiobenzyl) thiazolidine-2-thione 4-cyclopropyl-4-hydroxy-3- (2,3,3
4-trimethoxybenzyl) thiazolidine-2-thione. 4-Hydroxy-4-methyl-3- (3,4-methylenedioxybenzyl) thiazolidine-2-thione. Three
-(2,5-Dimethoxy-3,4,6-trimethylbenzyl) -4-hydroxy-4-methylthiazolidine-2
-Thion. 4-Hydroxy-3- [2- (2-methoxyethoxy) benzyl] -4-methylthiazolidine-2-
Thion. 3- (2-fluoromethoxybenzyl) -4-
Hydroxy-4-methylthiazolidine-2-thione. Three
-(3-Fluoromethylbenzyl) -4-hydroxy-
4-Methylthiazolidine-2-thione. 4-Hydroxy-3- (2-methoxymethylbenzyl) -4-methylthiazolidine-2-thione. 4-hydroxy-3- (3-
Methoxy-6-nitrobenzyl) -4-methylthiazolidine-2-thione. 3- (3,4-dimethoxyphenyl) -4-hydroxy-4-methylthiazolidine-2-
Thion. 3- (1,4-benzodioxan-6-yl)
-4-Hydroxy-4-methylthiazolidine-2-thione. 4-fluoromethyl-4-hydroxy-3- (2,
3,4-trimethoxybenzyl) thiazolidine-2-thione. 4-hydroxy-4-methoxymethyl-3-
(2,3,4-trimethoxybenzyl) thiazolidine-
2-Thion. 3- (2,5-dihydroxy-3,4,6
-Trimethylbenzyl) -4-hydroxy-4-methoxymethylthiazolidine-2-thione. 3- (2,4-dimethoxy-3-propyloxybenzyl) -4-ethoxymethyl-4-hydroxythiazolidine-2-thione.
4-hydroxy-4-hydroxymethyl-3- (2,
3,4-trimethoxybenzyl) thiazolidine-2-thione. 4-hydroxy-4-trifluoromethyl-3-
(2,3,4-trimethoxybenzyl) thiazolidine-
2-Thion. 3- (4-chloro-2-ethoxybenzyl) -4-hydroxy-4-vinylthiazolidine-2-
Thion. 4-allyl-3- (3-fluoro-4-methoxybenzyl) -4-hydroxythiazolidine-2-thione. 4-hydroxy-3- (2-methylbenzyl) -4
-(2-Propinyl) thiazolidine-2-thione.

Next, the results of pharmacological experiments on the thiazoline-2-thione derivative of the present invention will be shown. Pharmacological experiment was carried out by inhibiting lipid peroxidation, GO in a carbon tetrachloride acute liver injury model.
T and GPT deviation suppressive action and prothrombin time (P
T) Prolongation inhibitory action, GOT and GPT deviation inhibitory action and prothrombin time (PT) prolongation inhibitory action in a D-galactosamine acute liver injury model were performed in vivo. The prothrombin time (PT) is a test method for evaluating the blood coagulation system. Blood coagulation factors are mainly produced in hepatic parenchymal cells, and PT is prolonged due to impaired liver function.
Therefore, the PT prolongation inhibitory action means suppression of liver function decline.

Experiment 1. Lipid Peroxidation Inhibitory Action Experimental Method To 250 μl of microsomes (0.5 mg, protein) prepared from rat liver, 2.5 μl of test compound solution (dissolved in dimethyl sulfoxide), 0.5 M Tris-HCl buffer (pH 7.4) ) 147.5 μl, 20 mg / ml A
DP 50 μl and 5 mg / ml β-NADPH 50 μ
After adding 1 and mixing, it incubated at 37 degreeC for 60 minute (s). 5 mg / ml butyl hydroxytoluene 50μ
The reaction was stopped by adding 1 liter, and 250 μl of 8.1% sodium dodecyl sulfate and 20% acetic acid (pH 3.5) were added.
75 ml and 0.8% thiobarbituric acid (pH 3.
5) After adding 1.5 ml, it was heated in a boiling water bath for 60 minutes. After cooling in ice water, centrifugation was performed at 1,500 × g for 10 minutes, and the absorbance of the supernatant was measured at 535 nm. The amount of lipid peroxide was determined from a calibration curve prepared using tetraethoxypropane as a standard substance. The inhibitory effect on lipid peroxidation was represented by the inhibitory rate obtained from the following equation.

[0045]

[Equation 1]

Results The compound obtained in Example 1 had a lipid peroxidation inhibition rate of 10 ^-4.
It was 97.9% in M and 68.8% in 10 ^-5 M.

When hepatocytes are damaged by the administration of carbon tetrachloride or D-galactosamine, the enzyme transmigrates and various enzyme activities appear in serum. Therefore, it is an effective method to measure the activity of serum transaminase as an index of disorder, and GOT (glutamic acid-oxaloacetate transaminase) and GPT (glutamic acid-pyruvate transaminase) are available as serum transaminase, which were measured as indicators of liver damage. . Further, PT is an index recognized to be effective as an index for determining liver parenchymal disorder (hepato-biliary-pancreatic, 14 (5), pp. 741-748 (198).
7) See "Notable Liver Function Tests").

Experiment 2. Carbon tetrachloride acute liver injury model GOT, GPT deviation suppression effect and PT prolongation suppression effect

Experimental Method 160 to 180 g of Wistar male rats fasted for 24 hours were orally administered with the test substance (100 mg / kg), and water was absent. The test substance is suspended in 1% methylcellulose and administered at a dose of 10 ml / kg. 1% for control group
Administer methylcellulose. Three hours after the administration of the test substance, carbon tetrachloride dissolved in olive oil (olive oil:
Carbon tetrachloride = 1: 1) is orally administered at a dose of 1 ml / kg to induce acute liver injury. Oral olive oil instead of carbon tetrachloride is given to the normal group. Feeding water is given 4 hours after the administration of carbon tetrachloride. Twenty-four hours after the administration of carbon tetrachloride, the rat was subjected to laparotomy under ether anesthesia, blood was collected from the aorta, and the collected blood was centrifuged at 3000 rpm for 15 minutes, and then plasma was collected. GOT and GPT in plasma were measured by an autoanalyzer (Hitachi 705: Karmen method). The increase suppression rate (%) of GOT and GPT was calculated by the following formula.

[0050]

[Equation 2]

For PT, a thromboplastin reagent for measuring prothrombin time (Symplastin; Organon Technica Co., Ltd.) was added to a plasma sample collected from the abdominal vena cava as described above, and the time required for fibrin formation (seconds) was measured. It was measured. The PT extension suppression rate (%) was calculated by the following formula.

[0052]

[Equation 3]

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

Experiment 3. D-Galactosamine (D-Gal
N) GOT and GPT deviation suppressive action and PT prolongation inhibitory action in an acute liver injury model

Experimental Method 180 to 200 g of Wistar male rats fasted for 24 hours were orally administered with a test substance (100 mg / kg),
Glycyrrhizin (40 mg / ml) is administered intraperitoneally at a dose of 5 ml / kg. The test substance is suspended in 1% methylcellulose and administered at a dose of 10 ml / kg. The control group receives 1% methylcellulose. Three hours after the administration of the test substance, a D-galactosamine solution (dissolving D-galactosamine in a physiological saline solution, adjusting the pH to about 7 with a small amount of a strong sodium hydroxide aqueous solution, and then adjusting the concentration to 160 mg / ml) was used. Subcutaneously at a dose of 5 ml / kg,
Causes acute liver injury. In the normal group, physiological saline is subcutaneously administered instead of D-galactosamine. Twenty-four hours after the administration of D-galactosamine, the rat was subjected to laparotomy under ether anesthesia, blood was collected from the posterior aorta and abdominal vena cava, and the collected blood was treated in the same manner as in Experiment 2 to obtain GOT and GPT.
The increase suppression rate (%) and the PT extension suppression rate (%) were obtained.

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

[0057]

[Table 3]

From the above-mentioned pharmacological experiments, it was revealed that the thiazoline-2-thione derivative of the present invention has an excellent inhibitory action on GOT and GPT in an in vivo model of acute liver injury and an inhibitory action on PT prolongation.

Further, the thiazoline-2-thione derivative of the present invention did not show any significant change even at 500 mg / kg in rat 2-week repeated oral administration toxicity screening.

As is clear from the results of the above-mentioned pharmacological experiments, the thiazoline-2-thione derivative of the present invention contains a therapeutic agent for liver disease, an anti-inflammatory agent, an antirheumatic agent, a therapeutic agent for digestive tract disease,
Particularly, it is a substance useful as an active ingredient of a therapeutic agent for liver diseases.

[0061]

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

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

(1) 4-hydroxy-4-methyl-3-
(2,3,4-trimethoxybenzyl) thiazolidine-
2-Thion 2,3,4-trimethoxybenzylamine (1.00
g, 5.07 mmol) was dissolved in ethanol (10 ml), and carbon disulfide (0.31 ml, 5.1) was added to this solution.
Mmol) was added and the mixture was stirred at room temperature for 15 minutes. To this mixture was added 28% sodium methoxide / methanol solution (1.0 g, 5.2 mmol) and the mixture was further stirred at room temperature for 1 hour.
Stir for 5 minutes. After the solvent was distilled off under reduced pressure, the residue was dissolved in ethanol (5 ml), and this solution was mixed with chloroacetone (0.52 ml, 6.59 mmol) in ethanol (1 ml).
0 ml) was added to the solution dissolved in 0 ml) over 5 minutes under ice cooling, and the mixture was stirred overnight at room temperature. After ethanol was distilled off under reduced pressure, water (10 ml) was added to the residue and chloroform (2 ml) was added.
It was extracted with 0 ml × 2) and further washed with water (20 ml × 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 / ethyl acetate = 1/1). The solvent was distilled off under reduced pressure to obtain 0.861 g (yield 51.5%) of the title compound as light brown crystals.

Melting point: 109.0-112.0 ° C. (decomposition). ¹ H NMR (CDCl ₃ , 400 MHz) δ: 1.5
5 (3H, s), 3.32 (2H, s), 3.85,
3.87, 3.99 (9H, each s), 4.06 (1
H, s), 4.95, 5.08 (2H, each d, J =
15Hz) 6.65 (1H, d, J = 9Hz), 7.24 (1H,
d, J = 9 Hz). IR (KBr) cm ⁻¹ : 3260, 3000, 294
0,2840,2820,1600,1490,145
0,1420,1400,1380,1370,134
0, 1300, 1280, 1260, 1220, 120
0, 1170, 1120, 1090, 1065, 104
0,1010,990,950,930,925,88
5,850,820,800,770,745,71
0,680,640,590,570,530,50
0.

(2) 4-Methyl-3- (2,3,4-trimethoxybenzyl) thiazoline-2-thione 4-hydroxy-4-methyl-3-thion obtained in the above (1).
(2,3,4-trimethoxybenzyl) thiazolidine-
2-Thion (0.894 g, 2.71 mmol) was dissolved in ethanol (18 ml), concentrated hydrochloric acid (18 ml) was added to the solution under ice cooling, and the mixture was stirred for 20 minutes for reaction. After completion of the reaction, 4N aqueous sodium hydroxide solution (50 ml) was added to the reaction solution for neutralization, ethanol was distilled off therefrom, and the mixture was extracted with chloroform (25 ml × 3). After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give the title compound (0.823) as slightly brown crystals.
g (yield 97.4%) was obtained.

Melting point: 102.0-106.5 ° C. (decomposition). ¹ H NMR (CD ₃ OD, 400 MHz) δ: 2.1
6 (3H, d, J = 2Hz), 3.81, 3.83,
3.94 (9H, each s), 5.48 (2H, s),
6.48 (1H, d, J = 8Hz), 6.68 (1H,
d, J = 8 Hz), 6.57 (1H, d, J = 1 Hz) IR (KBr) cm ⁻¹ : 3400, 3090, 307
0,2970,2950,2910,2810,159
0,1580,1490,1460,1435,142
0, 1400, 1370, 1355, 1315, 129
0, 1260, 1250, 1220, 1210, 119
0, 1140, 1080, 1020, 1000, 98
0,970,930,900,830,790,76
0,720,700,660,600,500,46
0.

Example 2 4-Isopropyl-3- (2,3,4-trimethoxybenzyl) thiazoline-2-thione

(1) 4-isopropyl-4-hydroxy-3- (2,3,4-trimethoxybenzyl) thiazolidine-2-thione 2,3,4-trimethoxybenzylamine (0.986
g, 5.00 mmol) was dissolved in ethanol (10 ml), carbon disulfide (0.3 ml, 5 mmol) was added to this solution, and the mixture was stirred at room temperature for 15 minutes. A 28% sodium methoxide / methanol solution (0.965 g, 5.00 mmol) was added to this mixture, and the mixture was further stirred at room temperature for 15 minutes. After the solvent was distilled off under reduced pressure, the residue was dissolved in ethanol (10 ml), and this solution was mixed with 1-bromo-3-methyl-2-butanone (0.825 g, 5.
(00 mmol) was added dropwise to a solution prepared by dissolving ethanol (10 ml) under ice-cooling with stirring, stirred at 0 ° C. for 30 minutes, and at room temperature for 18 hours. After the solvent was distilled off, water was added to the residue, and the organic layer extracted with chloroform was washed once with 5% aqueous potassium carbonate solution (10 ml) and water (10 ml).
After being washed twice with and once with a saturated saline solution (10 ml), it was dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure,
The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 3/1), the solvent was evaporated under reduced pressure, and the residue was crystallized from ethanol (1 ml) / n-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 of the title compound (yield 59.8).
%) As a white crystalline powder.

Melting point: 105.0-109.0 ° C. ¹ H NMR (CD ₃ OD, 400 MHz) δ: 0.7
1 (3H, d, J = 7Hz), 1.03 (3H, d, J
= 7 Hz). 2.25 (1H, m), 3.13 (1H,
d, J = 13 Hz), 3.58 (1H, d, J = 13H
z), 3.82, 3.92 (9H, each s), 4.8.
9 (1H, d, J = 16Hz), 5.06 (1H, d,
J = 16Hz), 6.69 (1H, d, J = 9Hz),
7.20 (1H, d, J = 9 Hz).

(2) 4-isopropyl-3- (2,3,
4-Trimethoxybenzyl) thiazolin-2-thione 4-isopropyl-4-hydroxy-obtained in the above (1)
3- (2,3,4-Trimethoxybenzyl) thiazolidine-2-thione (0.630 g, 1.76 mmol) was dissolved in ethanol (4 ml), and concentrated hydrochloric acid (4 ml) was added to this solution under ice cooling. The reaction mixture was added and stirred at room temperature for 20 minutes. After completion of the reaction, the reaction solution was ice-cooled again, and 4N aqueous sodium hydroxide solution was added to make the solution basic,
From this, the solvent was distilled off under reduced pressure, and the residue was extracted with chloroform. The extract was washed once with saturated saline (10 ml) and then 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) / n-hexane (1.5 ml). The precipitated crystals were collected by filtration, washed with n-hexane, and dried under reduced pressure (40 ° C).
This gave 0.535 g of the title compound (yield 89.
8%) was obtained as white crystals.

Melting point: 92.5-93.5 ° C. ¹ H NMR (CDCl ₃ , 400 MHz) δ: 1.1
5 (1H, s), 1.16 (1H, s), 2.74 (1
H, m), 3.82 (3H, s), 3.88 (6H,
s), 5.54 (2H, s), 6.27 (1H, s),
6.49 (1H, d, J = 9Hz), 6.57 (1H,
d, J = 9 Hz), IR (KBr) cm ⁻¹ : 2980, 2930, 161
0,1580,1500,1470,1350,128
0, 1170, 1100, 1040, 990, 760.

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

(1) 4-Ethyl-4-hydroxy-3-
(2,3,4-trimethoxybenzyl) thiazolidine-
2-Thion 2,3,4-trimethoxybenzylamine (1.0 g,
5.07 mmol) was dissolved in ethanol (10 ml), carbon disulfide (0.31 ml, 5.1 mmol) was added to this solution, and the mixture was stirred at room temperature for 15 minutes. To this mixture was added 28% sodium methoxide / methanol solution (1.0 g, 5.2 mmol) and the mixture was further stirred at room temperature for 1 hour.
Stir for 5 minutes. After the solvent was distilled off under reduced pressure, the residue was converted into 1-
Bromo-2-butanone (0.789 g, 5.07 mmol) was added to a solution of ethanol (10 ml) dissolved in ice over 5 minutes. After stirring at room temperature for 1 hour, the solvent was evaporated, water (10 ml) was added to the residue, and the mixture was extracted with chloroform (10 ml × 3). Chloroform layer,
After washing with water (10 ml), it was dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 2.07 g of a crude product of the title compound.
Got This crude product was recrystallized from ethanol-hexane,
Further silica gel column chromatography (hexane /
After purification by ethyl acetate = 2/1), the solvent was distilled off to obtain 0.815 g (yield 46.7%) of the title compound as a white crystalline powder.

Melting point: 106.5-108 ° C. ¹ H NMR (CDCl ₃ , 400 MHz) δ: 0.9
6 (3H, t, J = 7Hz), 1.85 (2H, q, J
= 7 Hz). 3.22 (1H, d, J = 12Hz),
3.41 (1H, d, J = 12 Hz), 3.84, 3.
86, 3.98 (9H, each s), 4.01 (1H,
s) 4.96 (1H, d, J = 15Hz), 5.04 (1
H, d, J = 15 Hz), 6.65 (1H, d, J = 9)
Hz), 7.30 (1H, d, J = 9 Hz). IR (KBr) cm ⁻¹ : 3433, 3199, 298
3,2951,2947,2845,2829,159
9, 1497, 1456, 1454, 1408, 138
5,1348,1333,1292,1288,125
9, 1188, 1184, 1167, 1119, 109
5,1061,1034,1016,993,920,
916, 818, 79, 789, 698, 663, 5
84,521,494.

(2) 4-Ethyl-3- (2,3,4-trimethoxybenzyl) thiazoline-2-thione 4-Ethyl-4-hydroxy-3-thion obtained in the above (1).
(2,3,4-trimethoxybenzyl) thiazolidine-
2-Thion (0.385 g) was combined with the recrystallization mother liquor in the reaction of the above (1), other than the above compound separated by silica gel column chromatography, the solvent was distilled off from the mixture, and the residue was diluted with ethanol (10 ml). ), Concentrated hydrochloric acid (5 ml) was added to the suspension under ice cooling,
Stir for 25 minutes to react. After completion of the reaction, ethanol was distilled off from the reaction solution under reduced pressure, water (10 ml) was added,
It was extracted with chloroform (15 ml + 10 ml + 10 ml), and the chloroform layer was dried over anhydrous sodium sulfate.
The solvent was distilled off from this solution, the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1), and recrystallized from ethanol-hexane to give 0.559 g of the title compound as a white crystalline powder. Obtained.

Melting point: 96.5-97 ° C. ¹ H NMR (CDCl ₃ , 400 MHz) δ: 1.1
9 (3H, t, J = 7Hz), 2.44 (2H, dq,
J = 1 Hz, 7 Hz), 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 (KBr) cm ⁻¹ : 3103, 3001, 297
0,2941,2939,2837,1606,158
3,1498,1468,1466,1439,141
9, 1373, 1365, 1360, 1352, 130
4,126,1234,1213,1194,114
6,1093,1032,1012,964,931,
906, 854, 833, 793, 791, 766, 7
35, 671, 559, 501.

Example 4 3- (2-Methoxybenzyl) -4-methylthiazolin-2-thione

(1) 4-Hydroxy-3- (2-methoxybenzyl) -4-methylthiazolidine-2-thione 2-methoxybenzylamine (1.5 g, 10.9 mmol) was dissolved in ethanol (15 ml). Carbon disulfide (0.66 ml, 10.9 mmol) was added to this solution, and the mixture was stirred at room temperature for 15 minutes. To this mixture was added 28% sodium methoxide / methanol solution (2.12 g, 1
1 mmol) was added, and the mixture was further stirred at room temperature for 15 minutes.
After the solvent was distilled off under reduced pressure, the residue was converted into chloroacetone (1.
14 ml, 14.3 mmol) in ethanol (10 m
The solution dissolved in 1) was added over 5 minutes under ice cooling.
After stirring at room temperature for 2 hours, water (10 ml) was added to the mixture, ethanol was evaporated under reduced pressure, and the residue was extracted with chloroform (15 ml × 3). After the chloroform layer was dried over anhydrous sodium sulfate, the solvent was distilled off to obtain 3.86 g of the crude title compound. This crude product was subjected to silica gel column chromatography (hexane / ethyl acetate = 2 /
Purified by (1), 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%) as a white crystalline powder.

¹ H NMR (CDCl ₃ , 400 MH
z) δ: 1.55 (3H, d, J = 1 Hz), 3.31
(1H, d, J = 12Hz), 3.42 (1H, d, J
= 12 Hz), 3.57 (1 H, s), 3.90 (3
H, s), 4.99 (1H, d, J = 16Hz), 5.
17 (1H, d, J = 16Hz), 6.8 to 6.9 (2
H, m), 7.2-7.3 (1H, m), 7.37 (1
H, d, J = 7 Hz).

(2) 3- (2-methoxybenzyl) -4
-Methylthiazolin-2-thione 4-hydroxy-3- (2-methoxybenzyl) -4-methylthiazolidine-2-thione (1.28 g, 4.75 mmol) obtained in (1) above was added to ethanol (12
ml), and the suspension was concentrated under ice cooling with concentrated hydrochloric acid (3 ml).
Was added and stirred for 20 minutes. The reaction mixture was neutralized with 2N aqueous sodium hydroxide solution (17 ml), ethanol was evaporated under reduced pressure, the mixture was extracted with chloroform (15 ml × 3), and the chloroform layer was dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was recrystallized from ethanol-hexane to give the title compound (1.10 g, yield 92.2%) as a white crystalline powder.

Melting point: 111-112 ° C. ¹ H NMR (CDCl ₃ , 400 MHz) δ: 2.1
1 (3H, d, J = 1 Hz), 3.89 (3H, s),
5.52 (2H, s), 6.26 (1H, s), 6.7
8 (1H, d, J = 7 Hz), 6.8 to 6.9 (2H,
m), 7.2-7.3 (1H, m), IR (KBr) cm ⁻¹ : 3448, 3107, 295.
6,2927,2914,2883,2833,160
3,1585, 1493, 1464, 1437, 142
1,1377,1360,1336,1304,128
6,1252,1219,1184,1140,110
9, 1049, 1016, 1014, 989, 843
812, 762, 760, 750, 729, 727, 6
81, 619, 561, 492, 467.

Example 5 4-Methyl-3- (3,4,5-trimethoxybenzyl) thiazoline-2-thione 3,4,5-trimethoxybenzylamine (1.24)
g, 6.29 mmol) was dissolved in ethanol (5 ml) and carbon disulfide (0.38 ml, 6.29) was added to this solution.
Mmol) was added and the mixture was stirred at room temperature for 15 minutes. To this mixture was added 28% sodium methoxide / methanol solution (1.22 g, 6.32 mmol) and further stirred at room temperature for 15 minutes. This solution was added to chloroacetone (0.64 g, 6.92 mmol) in ethanol (2 m).
l) The solution was added under ice cooling and stirred at room temperature for 4 hours. Concentrated hydrochloric acid (4 ml) was added to the reaction solution, the mixture was stirred at room temperature for 30 minutes, the solvent was evaporated under reduced pressure, and the mixture was extracted with chloroform.
The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 2/1) and recrystallized from ethanol / hexane = 2/1 mixed solvent (4.5 ml) to give 1.03 g of the title compound as pale orange crystals.
(Yield 52.6%) was obtained.

Melting point: 116.5-121.5 ° C. ¹ H NMR (CDCl ₃ , 400 MHz) δ: 2.2
0 (3H, d, J = 1 Hz), 3.81, 3.82 (6
H, 3H, each s), 5.45 (2H, s), 6.2
6 (1H, d, J = 2Hz), 6.48 (2H, s) IR (KBr) cm ^-1 : 3097, 1591, 151
0, 1360, 1354, 1329, 1306, 124
2,1213,1171,1128,1011.

Example 6 4-Propyl-3- (2,3,4-trimethoxybenzyl) thiazoline-2-thione

(1) 4-hydroxy-4-propyl-3
-(2,3,4-Trimethoxybenzyl) thiazolidine-2-thione 2,3,4-trimethoxybenzylamine (1.18
g, 6.00 mmol) was dissolved in ethanol (10 ml) and carbon disulfide (0.36 ml, 6.0) was added to this solution.
Mmol) was added and the mixture was stirred at room temperature for 15 minutes. A 28% sodium methoxide / methanol solution (1.16 g, 6.00 mmol) was added to this mixture, 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-chloro-2-pentanone (0.724 g, 6.00 mmol) in ethanol (10 ml) under ice-cooling stirring. Was added dropwise to the mixture and stirred at the same temperature for 2.5 hours. The solvent was distilled off under reduced pressure, water (20 ml) was added to the residue, and chloroform (2 ml) was added.
The organic layer extracted three times with 0 ml, 10 ml × 2) was 5%.
The organic layer was washed once with an aqueous potassium carbonate solution (10 ml), water (10 ml) and saturated saline (10 ml), and then dried over anhydrous sodium sulfate. The solvent was distilled off from the resulting solution under reduced pressure, and the residue was subjected to silica gel column chromatography (n-
After purification with hexane / ethyl acetate = 3/1), the solvent was evaporated under reduced pressure to give the title compound (1.29 g, yield 62.
0%) as a pale yellow solid.

¹ H NMR (CDCl ₃ , 400 MH
z) δ: 0.86 (3H, t, J = 7Hz), 1.20
~ 1.35, 1.43 ~ 1.57 (2H, each m),
1.78 (2H, m), 3.23 (1H, d, J = 12)
Hz), 3.40 (1H, d, J = 12 Hz), 3.8
5, 3.86, 3.99 (9H, each s), 4.02
(1H, s), 4.80 (1H, d, J = 16Hz) 5.02 (1H, d, J = 16Hz) 6.65 (1H, d, J = 9Hz), 7.31 (1H,
d, J = 9 Hz).

(2) 4-propyl-3- (2,3,4-
Trimethoxybenzyl) thiazolin-2-thione 4-hydroxy-4-propyl-3-obtained in the above (1)
(2,3,4-trimethoxybenzyl) thiazolidine-
2-Thion (0.717 g, 1.96 mmol) was dissolved in ethanol (2 ml), concentrated hydrochloric acid (3 ml) was added to this solution under ice cooling, and the mixture was reacted at room temperature for 20 minutes with stirring. After completion of the reaction, the mixture was ice-cooled again, and the reaction mixture was basified by adding 4N aqueous sodium hydroxide solution (6 ml), the solvent was distilled off therefrom, and the residue was extracted with chloroform. 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 / ethyl acetate = 3).
/ 1). 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 0.579 g of the title compound (yield 82.6%). Was obtained as a white crystalline powder.

Melting point: 80.5-82.0 ° C. ¹ H NMR (CD ₃ OD, 400 MHz) δ: 0.9
2 (3H, t, J = 8Hz), 1.57 (2H, m),
2.43 (2H, dt, J = 8Hz, 1Hz), 3.8
1,3.84,3.95 (9H, each s), 5.49
(2H, s), 6.48 (1H, d, J = 9Hz) 6.55 (1H, t, J = 1Hz). 6.67 (1H,
d, J = 9 Hz) IR (KBr) cm ⁻¹ : 2960, 2940, 161
0,1580,1500,1470,1420,135
0, 1300, 1180, 1100, 1040, 100
0,790,510.

Example 7 4-Methyl-2-methylthio-3- (2,3,4-trimethoxybenzyl) -1,3-thiazol-1-ium iodide Same as in Example 1. 4-Methyl-3 synthesized
-(2,3,4-trimethoxybenzyl) thiazoline-
2-Thion (0.35 g, 1.12 mmol) was dissolved in methyl iodide (3.5 ml) and stirred at room temperature overnight.
Methyl iodide was distilled off from the reaction solution under reduced pressure, 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 were washed with a mixed solvent of acetone / hexane = 1/10 (2.2 ml) and then dried under vacuum to obtain 0.50 g (yield 98.2%) of the title compound as pale yellow crystals.

Melting point: 117 ° C. ¹ H NMR (CDCl ₃ , 400 MHz) δ: 2.5
8 (3H, s), 2.97 (3H, s), 3.83,
3.85, 3.87 (9H, each s), 5.44 (2
H, s), 6.65 (1H, d, J = 9 Hz), 6.7
8 (1H, d, J = 9 Hz). IR (KBr) cm ^-1 : 3068, 2962, 283
2,1574,1495,1475,1470,140
5,1281,1103.

[0091]

INDUSTRIAL APPLICABILITY The thiazolin-2-thione derivative of the present invention is a novel compound useful as an active ingredient of a therapeutic agent for liver diseases, and the thiazolidine-2-thione derivative of the present invention is a thiazoline-2 of the present invention. -A novel compound useful as an intermediate for the production of thione derivatives.

Claims (2)

[Claims] 1. The following general formula (1): (In the formula, R ¹ is an alkyl group having 1 to 6 carbon atoms, which 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. Group, cycloalkyl group having 3 to 6 carbon atoms, 2 carbon atoms
It represents a 6 alkenyl or alkynyl group having 2 to 6 carbon atoms, R ² is 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 alkoxyl group having 1 to 6 carbon atoms which may have 1 to 3 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; an alkylthio group having 1 to 6 carbon atoms; a nitro group; a carboxyl group; or a carbon number 2
~ 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 together form a carbon number. 1 to
6 may represent an alkylenedioxy group, and n
Represents 0 or 1), a thiazoline-2-thione derivative. 2. The following general formula (2): (In the formula, R ¹ is an alkyl group having 1 to 6 carbon atoms, which 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. Group, cycloalkyl group having 3 to 6 carbon atoms, 2 carbon atoms
It represents a 6 alkenyl or alkynyl group having 2 to 6 carbon atoms, R ² is 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 alkoxyl group having 1 to 6 carbon atoms which may have 1 to 3 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; an alkylthio group having 1 to 6 carbon atoms; a nitro group; a carboxyl group; or a carbon number 2
~ 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 together form a carbon number. 1 to
6 may represent an alkylenedioxy group, and n
Represents 0 or 1), a thiazolidine-2-thione derivative.