JP3353903B2 - Condensed thiazole derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a condensed thiazole derivative or a salt thereof, and a prophylactic / therapeutic agent for liver disease containing the same, which has an excellent inhibitory action on hepatocellular degeneration / necrosis and an improvement on liver damage.

[0002]

2. Description of the Related Art
Treatment of liver disease includes rest, high protein, high calorie diet, general therapy such as abstinence, as well as general drug therapy such as vitamins and strong liver drugs, corticosteroids such as prednisolone, glycyrrhizin preparations, and immunity such as interferon. Activators have been used extensively. However, glycyrrhizin preparations and interferons, which are widely used clinically, are injections and are unsuitable for long-term administration. Further, these drugs and steroids have serious side effects.
Therefore, a prophylactic / therapeutic agent capable of oral administration, capable of long-term administration, and having few side effects has been desired.

[0003]

Means for Solving the Problems In view of the above circumstances, the present inventors have conducted intensive studies to obtain a novel substance that can be a prophylactic / therapeutic agent for liver disease. As a result, a condensed thiazole skeleton represented by the following general formula (1) is obtained. Based on the above, the present inventors have found that a compound having a specific substituent at the 3-position is an excellent agent for preventing and treating liver disease which has overcome the above problems, and has completed the present invention.

That is, the present invention provides the following general formula (1)

Embedded image (In the formula, Represents a double bond or a single bond; R ¹ represents a cyano group or a lower alkoxycarbonyl group; R ² and R ³ are the same or different and are a hydrogen atom; a lower alkyl group;
Cyclic alkyl group; cyclic alkyl lower alkyl group; lower alkyl group, lower alkoxy group, halogen atom, hydroxyl group, amino group, halogenoalkyl group, carboxyl group and carbamoyl group. Good aryl group; halogen atom, lower alkyl group, trihalogeno lower alkyl group, hydroxyl group, carboxyl group,
A 5- or 6-membered heterocyclic residue which may have at least one substituent selected from an amino group and a carbamoyl group; a lower alkyl group, a lower alkoxy group, a halogen atom, a hydroxyl group, an amino group, a halogeno An aralkyl group optionally having one or more substituents selected from an alkyl group, a carboxyl group and a carbamoyl group; a lower alkoxycarbonyl group; a carbamoyl group; a mono- or di-lower alkylaminocarbonyl group; a cyclic alkylaminocarbonyl group; A lower alkyl group; an acyloxy lower alkyl group; an acyl group having 1 to 5 carbon atoms or a halogen atom, wherein R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different and are a hydrogen atom; a lower alkyl group; An alkenyl group; a lower alkyl group, a lower alkoxy group, a halogen atom, water An aryl group optionally having one or more substituents selected from an acid group, an amino group, a halogenoalkyl group, a carboxyl group and a carbamoyl group; a halogen atom, a lower alkyl group, a trihalogeno lower alkyl group, a hydroxyl group, a carboxyl group, and an amino group -Or 6-membered heterocyclic residue which may have one or more substituents selected from a group and a carbamoyl group; a lower alkyl group, a lower alkoxy group, a halogen atom, a hydroxyl group, an amino group, a halogenoalkyl An aralkyl group optionally having one or more substituents selected from a group, a carboxyl group and a carbamoyl group; a lower alkoxycarbonyl group; a hydroxy lower alkyl group; a carbamoyl group; a mono- or di-lower alkylaminocarbonyl group; ~ 5 acyl groups; lower alkyl groups, lower alkoxy groups, halogens Child, a hydroxyl group, an amino group, halogenoalkyl group, a carboxyl group and an aryl group which may have a substituent selected from carbamoyl group one or more; or a hydroxyl group, or a halogen atom, or one of R ⁴ and R ⁵ And an aliphatic ring which may have a substituent selected from a lower alkyl group, a halogen atom, an amino group, a trihalogeno lower alkyl group, a carboxyl group and a carbamoyl group, together with a carbon atom to which one of R ⁶ and R ⁷ is bonded, An aromatic ring or a heterocyclic ring may be formed. Is a hydrogen atom; a lower alkyl group having 1 to 10 carbon atoms; one substituent selected from a lower alkyl group, an amino group, a lower alkoxy group, a halogen atom, a hydroxyl group, a carboxyl group, a carbamoyl group and a halogeno lower alkyl group A cyclic alkyl group having 3 to 7 carbon atoms which may have the above; a cyclic alkyl lower alkyl group; selected from a lower alkyl group, a lower alkoxy group, a halogen atom, a hydroxyl group, an amino group, a halogenoalkyl group, a carboxyl group and a carbamoyl group. Aryl group which may have at least one substituent selected from the group consisting of halogen atom, lower alkyl group, trihalogeno lower alkyl group, hydroxyl group, carboxyl group, amino group and carbamoyl group. Good 5- or 6-membered heterocyclic residue; lower alkyl group, lower alkoxy group, halogen Atom, a hydroxyl group, an amino group, a halogenoalkyl group, an aralkyl group which may have one or more substituents selected from a carboxyl group and carbamoyl group;
Hydroxy lower alkyl group; mono, di or trihalogeno lower alkyl group; mono, di or trihalogeno lower alkoxy group; lower alkoxycarbonyl group; carboxyl group; cyano group; carbamoyl group; mono or di lower alkylaminocarbonyl group; 1 to 5 acyl groups; a substituent selected from a lower alkyl group, a lower alkoxy group, a halogen atom, a hydroxyl group, an amino group, a halogenoalkyl group, a carboxyl group and a carbamoyl group;
A lower alkylthio group; a lower alkenylthio group; a substituent selected from a lower alkyl group, a lower alkoxy group, a halogen atom, a hydroxyl group, an amino group, a halogenoalkyl group, a carboxyl group and a carbamoyl group An arylthio group optionally having one or more substituents; the aryl moiety has at least one substituent selected from a lower alkyl group, a lower alkoxy group, a halogen atom, a hydroxyl group, an amino group, a halogenoalkyl group, a carboxyl group and a carbamoyl group. Aralkyloxy or aralkylthio groups which may be substituted; mono, di or trihalogeno lower alkylthio groups; hydroxy lower alkylthio groups; lower alkoxycarbonyl lower alkylthio groups; amino lower alkylthio groups; mono or disubstituted amino lower alkylthio groups; An aryloxy lower alkyl group optionally having at least one substituent selected from a lower alkyl group, a lower alkoxy group, a halogen atom, a hydroxyl group, an amino group, a halogenoalkyl group, a carboxyl group and a carbamoyl group; ; = S;

Embedded image Wherein R ⁸ and R ⁹ are the same or different and are a hydrogen atom; a lower alkyl group having 1 to 10 carbon atoms;
7 cyclic alkyl groups; alkenyl groups; alkynyl groups;
An aryl group optionally having one or more substituents selected from a lower alkyl group, a lower alkoxy group, a halogen atom, a hydroxyl group, an amino group, a halogenoalkyl group, a carboxyl group and a carbamoyl group;
Lower alkoxy group, halogen atom, hydroxyl group, amino group,
An aralkyl group optionally having one or more substituents selected from a halogenoalkyl group, a carboxyl group, and a carbamoyl group; a lower alkyl group, an amino group, a lower alkoxy group, a halogen atom, a hydroxyl group, a carboxyl group, a carbamoyl group, and a halogeno group A cyclic alkyl group optionally having one or more substituents selected from lower alkyl groups; a lower alkyl group, an amino group, a lower alkoxy group, a halogen atom, a hydroxyl group, a carboxyl group, a carbamoyl group and a halogeno lower group in the cyclic alkyl moiety A cyclic alkyl lower alkyl group which may have one or more substituents selected from alkyl groups; a hydroxyl group; a lower alkoxy group; an amino group; a mono- or di-lower alkylamino lower alkyl group; a hydroxy lower alkyl group; Or trihalogeno lower alkyl group; lower alkoxy Or shows a carbonyl-lower alkyl group, or R ⁸ and R ⁹ together with the adjacent nitrogen atom, may contain another hetero atom and further a halogen atom, a lower alkyl group, a trihalogeno lower alkyl group, a hydroxyl group May form a heterocyclic residue which may have a substituent selected from a carboxyl group, an amino group and a carbamoyl group. R ¹⁰ is a hydrogen atom; a lower alkyl group having 1 to 10 carbon atoms; a lower alkoxycarbonyl group; a lower alkyl group, a lower alkoxy group, a halogen atom, a hydroxyl group, an amino group, a halogenoalkyl group, a carboxyl group and a carbamoyl group in the aryl portion An aralkyl group optionally having one or more substituents selected from the group consisting of: an aryl group; a heterocyclic residue or a cyano group; R ¹¹ is a hydroxyl group; a lower alkoxy group; a lower alkyl group, a lower alkoxy group, a halogen atom An aryloxy or arylthio group optionally having one or more substituents selected from a hydroxyl group, an amino group, a halogenoalkyl group, a carboxyl group and a carbamoyl group; a heterocyclic residue; a lower alkyl group and a lower alkoxy Group, halogen atom, hydroxyl group, amino group, halogenoalkyl group, carboxyl group And an aralkyl group optionally having one or more substituents selected from carbamoyl groups; selected from lower alkyl groups, lower alkoxy groups, halogen atoms, hydroxyl groups, amino groups, halogenoalkyl groups, carboxyl groups, and carbamoyl groups in the aryl moiety. An aralkyloxy group which may have one or more substituents selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen atom, a hydroxyl group, an amino group, a halogenoalkyl group, a carboxyl group and a carbamoyl group. Represents an aralkylthio group or a trihalogeno lower alkoxy group which may have one or more, R ¹² and R ¹³ represent a hydrogen atom or a lower alkyl group having 1 to 10 carbon atoms which may be the same or different, and n represents 0 to 6). However, between 2nd and 3rd place Represents a double bond, only R ² is substituted on the 2-position carbon atom and Represents a single bond. Z is a methylene group, an ethylene group,
Oxygen atom, sulfur atom, SO, SO ² , NR ¹⁴ (R ¹⁴
Represents a hydrogen atom, a halogen atom or a lower alkyl group having 1 to 10 carbon atoms which may have a hydroxyl group). ] The fused thiazole derivative represented by these, or its salt is provided.

In the general formula (1), the substituent of R ¹ is a lower alkoxycarbonyl group, a cyclic alkyloxycarbonyl group, a lower alkenyloxycarbonyl group, a lower alkynyloxycarbonyl group, a cyano group, a C 1-5 carbon atom. And an arylcarbonyl group which may have one or more substituents. As the substituent for R ² and R ^3, a lower alkyl group, a cyclic alkyl group having 3 to 7 carbon atoms, a cyclic alkyl lower alkyl group, an aryl group which may have one or more substituents, and one substituent A 5- or 6-membered heterocyclic residue which may have one or more, an aralkyl group, a lower alkoxycarbonyl group, a carbamoyl group, a mono- or di-lower alkylaminocarbonyl which may have one or more substituents in the aryl moiety Groups, a cyclic alkylaminocarbonyl group, a hydroxy lower alkyl group, an acyloxy lower alkyl group, an acyl group having 1 to 5 carbon atoms or a halogen atom. R ⁴ , R ⁵ , R ⁶
And a substituent of R ⁷ is a lower alkyl group,
To 7 cyclic alkyl groups, alkenyl groups, aryl groups optionally having one or more substituents, 5- or 6-membered heterocyclic residues optionally having one or more substituents, An aralkyl group, a lower alkoxycarbonyl group, a hydroxy lower alkyl group, a carbamoyl group, a mono- or di-lower alkylaminocarbonyl group which may have one or more substituents, an acyl group having 1 to 5 carbon atoms, And an arylcarbonyl group, a hydroxyl group, a halogen atom, and the like which may have one or more groups. In the present invention, "lower" means a straight, branched or cyclic carbon chain having 1 to 10 carbon atoms unless otherwise specified. Accordingly, specific examples of the lower alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, and a t-butyl group.
tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2 -Methylpentyl group, 3-methylpentyl group,
1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, Examples thereof include a 1,2-trimethylpropyl group, an octyl group, and a decyl group. When the lower alkyl group has a substituent, examples of the substituent include a halogen atom and a hydroxyl group.

The cyclic alkyl group has 3 carbon atoms.
Preferred are from 7 to 7, specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Examples of the substituent of the cyclic alkyl group include a lower alkyl group, an amino group, a lower alkoxy group, a halogen atom, a hydroxyl group, a carboxyl group, a carbamoyl group, and a halogeno lower alkyl group. Examples of the aryl group include aromatic hydrocarbon residues such as phenyl and naphthyl, and 5- or 6-membered heterocyclic residues such as furyl, thienyl, pyridyl and pyrimidinyl. Examples of the substituent of the aryl group which may have a substituent include a lower alkyl group, a lower alkoxy group, a halogen atom, a hydroxyl group, an amino group, a halogenoalkyl group, a carboxyl group, and a carbamoyl group. As the aralkyl group, a group in which an arbitrary hydrogen atom of the lower alkyl group is substituted with the aryl group and an aryl group which may have a substituent is preferable. Specifically, a benzyl group, a phenethyl group, a 3-phenylpropyl group And so on.

Specific examples of the lower alkoxy group include a linear or branched alkoxy group having 1 to 6 carbon atoms such as a methoxy group, an ethoxy group, a propoxy group and an isopropoxy group. As the lower alkoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, se
c-butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, isopentyloxycarbonyl group, neopentyloxycarbonyl group,
Hexyloxycarbonyl group, octyloxycarbonyl group, decyloxycarbonyl group, cyclopropoxycarbonyl group, cyclobutoxycarbonyl group, cyclopentyloxycarbonyl group, cyclohexyloxycarbonyl group, cycloheptyloxycarbonyl group, 2-methylpentenyloxycarbonyl group, etc. Examples thereof include groups in which an ester is formed by a group and a linear, branched, or cyclic lower alcohol having 1 to 10 carbon atoms.

Examples of the acyl group include lower alkanoyl groups such as formyl group, acetyl group, propionyl group and butyryl group, aralcanoyl groups such as benzylcarbonyl group, benzoyl group, o, m and p-chlorobenzoyl groups, o, m
Or an unsubstituted or substituted arylcarbonyl group such as a p-fluorobenzoyl group. As the hydroxy lower alkyl group, a hydroxymethyl group,
Examples thereof include a hydroxyethyl group and a hydroxypropyl group.

The mono, di to trihalogeno lower alkyl groups include 2,2,2-trifluoroethyl, 2-fluoroethyl, 2-chloroethyl and the like. Alkenyl groups include vinyl, allyl, butenyl,
Examples of the alkynyl group as the 2-methylbutenyl group include a propynyl group. Examples of the alkylaminoalkyl group include an N, N-dimethylaminoethyl group, an N, N-dimethylaminopropyl group, an N, N-diethylaminoethyl group,
And N, N-diethylaminopropyl group.

[0010] Examples of the alkoxycarbonylalkyl group include an ethoxycarbonylmethyl group and an ethoxycarbonylethyl group. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

Examples of the heterocyclic residue include a saturated or unsaturated 5- to 7-membered ring containing one or more selected from oxygen, sulfur and nitrogen atoms. Examples thereof include thiophene, furan, pyrrole and pyrroline. , Pyrrolidine, piperidine, piperazine, homopiperazine, pyrazolidine, isoxazole, isoxazoline, oxazole, oxazolidine, pyridine, 1,2-dihydropyridine, 1,
2,3,4-tetrahydropyridine, thiazole, thiazoline, thiazolidine, pyridine, pyrimidine, 1,
2,3,4-tetrahydropyrimidine, 1,2,5,6
-Tetrahydropyrimidine, 1,4-thiazine, 1,4
Groups derived from -oxazine, 2,3-dihydro-1,4-oxazine, triazole, 1,3,5-triazine, azepine, 1,2-dihydroazepine, 1,2,3,4-tetrahydroazepine and the like. Can be mentioned. Examples of the substituent which the residue may have include a halogen atom, a lower alkyl group, a trihalogeno lower alkyl group, a hydroxyl group, a carboxyl group, an amino group, and a carbamoyl group. Examples of the heterocyclic residue which R ⁸ and R ⁹ form together with the adjacent nitrogen atom and which may further contain another hetero atom include pyrrole, pyrroline, pyrrolidine, piperidine, piperazine, homopiperazine , Pyrazolidine, isoxazole, isoxazoline, oxazole, oxazolidine, pyridine, 1,
2-dihydropyridine, 1,2,3,4-tetrahydropyridine, thiazoline, thiazolidine, pyridine, pyrimidine, 1,2,3,4-tetrahydropyrimidine,
1,2,5,6-tetrahydropyrimidine, 1,4-thiazine, 1,4-oxazine, 2,3-dihydro-1,
4-oxazine, 1,3,5-triazine, azepine,
Examples include groups derived from 1,2-dihydroazepine, 1,2,3,4-tetrahydroazepine and the like. These heterocyclic residues may further have a substituent as described above. One of R ⁴ and R ⁵ and R ⁶ and R ⁷
An aliphatic ring formed together with the carbon atom to which one of the above is bonded means an aliphatic hydrocarbon ring related to the above-mentioned cyclic alkyl, and an aromatic ring similarly formed is an aliphatic aromatic ring related to the above-mentioned aryl The term "ring" means a heterocyclic ring which is formed in the same manner as the above-mentioned heterocyclic residue. Examples of the substituent which these rings may have include a lower alkyl group, a halogen atom, an amino group, a trihalogeno lower alkyl group, a carboxyl group, and a carbamoyl group. The compound of the present invention is represented by the general formula (1), wherein the 2-position, 5-position, 6-position and R ¹⁰ , R ¹² , R
Asymmetric carbon and geometric isomers may be contained at the position where ¹³ is bonded and further various substituents, and optical isomers and geometric isomers derived therefrom and mixtures thereof are included in the scope of the present invention. Further, the compound of the formula (1) has the following geometric isomers.

Embedded image The present invention also includes each of these separated isomers and mixtures thereof.

Further, as specific examples of the present invention, the following Tables 1 to
The compounds described in Table 13 can be mentioned.

[0013]

[Table 1]

[0014]

[Table 2]

[0015]

[Table 3]

[0016]

[Table 4]

[0017]

[Table 5]

[0018]

[Table 6]

[0019]

[Table 7]

[0020]

[Table 8]

[0021]

[Table 9]

[0022]

[Table 10]

The compound of the formula (1) of the present invention can be produced by various methods, and typical production methods are shown below. Manufacturing method A

Embedded image Haloacetaldehyde, haloacetone, 2-halopropylaldehyde, 2-halo-3-oxobutane, ω-haloacetophenone, 2-halo-2-phenylacetaldehyde, 2-halo-2-phenylacetophenone, lower alkyl ester of halopyruvate, 2- Halo-2-formyl acetate, 1-halo-2,3-butanedione, 2-
Haloacetoacetic acid lower alkyl ester, 3-halo-2,
4-pentanedione, 2-haloacetylacetaldehyde, β-halo-β-alkoxycarbonylpyruvic acid lower alkyl ester, 1-halo-3-phenyl-2,3
-Propanedione, 4-haloacetoacetic lower alkyl ester, N-aryl-4-haloacetoacetamide, 4
-Halo-2-methylacetoacetic acid lower alkyl ester,
N-lower alkyl-2-haloacetoacetamide, 5-acetoxy-3-halo-2-pentanone and its lower alkyl or aryl-substituted derivatives and an organic solvent, preferably in an organic acid such as acetic acid, at room temperature to 100 ° C. Or react with 1,1-dihalo-2-hydroxypropane and 2,2-dihalo-1-phenylethanol in alcoholic sodium hydroxide or potassium hydroxide at 50 to 80 ° C. for several hours. After treatment with acetic acid or p-toluenesulfonic acid, the formula (1)
The compound of a) can be prepared.

Manufacturing method B

Embedded image The compound of the formula (2) is treated in the presence of a deoxidizing agent in an alcoholic solvent or a suitable organic solvent such as dimethylformamide, a haloacetic acid lower alkyl ester, a mixture of an aqueous alkali solution and dichloromethane, a haloacetyl halide or dihaloacetyl. In a halide or alcohol solvent, 2,2-
Reacting with dicyano-3-phenyloxirane or 2,2-dichloro-3-phenyloxirane and its lower alkyl, cyclic alkyl, cyclic alkyl lower alkyl, aryl or aralkyl substituted derivative optionally having one or more substituents Thus, the compound of the formula (1b) can be produced. Examples of the deoxidizing agent include sodium acetate, potassium acetate, sodium carbonate, potassium carbonate, triethylamine and the like. Examples of the alkali of the aqueous alkali solution include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and sodium hydrogen carbonate. Examples of the alcohol-based solvent include methanol, ethanol, and isopropyl alcohol. The reaction is usually performed at 0 ° C. to 100 ° C. for several hours, but the haloacetyl halide and a substituted derivative thereof,
In the case of reaction with dihaloacetyl halide, the temperature is preferably from 0 ° C. to room temperature.

Production method C

Embedded image The compound of the formula (1d) is produced by reacting the compound of the formula (1c) with benzene which may have one or more substituents in the presence of stannic chloride or the like in an organic solvent such as dichloromethane or dichloroethane. be able to. The reaction is usually performed at a temperature at which the solvent refluxes for 0.5 to 5 hours.

Manufacturing method D

Embedded image Producing a compound of the formula (1e) by reacting a compound of the formula (1b) with a reducing agent such as lithium aluminum hydride in an organic solvent such as tetrahydrofuran and then reacting with acetic acid or paratoluenesulfonic acid or the like. Can be. The reaction with the reducing agent is usually performed at about 0 ° C. to room temperature, and the reaction with acetic acid or p-toluenesulfonic acid is generally performed at room temperature to 50 ° C. for 0.5 hour to 2 hours.

Manufacturing method E

Embedded image The compound of the formula (1g) can be produced by reacting the compound of the formula (1f) with a reducing agent such as lithium aluminum hydride or sodium borohydride in an organic solvent such as tetrahydrofuran. The reaction is usually at room temperature to 50
C. for 0.5 to several hours.

Manufacturing method F

Embedded image The compound of the formula (1b) is dissolved in an organic solvent such as benzene, toluene, xylene or acetonitrile in a Lawesso.
The compound of the formula (1h) can be produced by reacting with n's reagent or phosphorus pentasulfide or the like. The reaction is usually performed at a temperature of 50 to 100 ° C. for 1 hour to 10 hours.

Manufacturing method G

Embedded image Thereby, the compound of the formula (1i) can be produced. Alternatively, the above halide in an aqueous solution of an inorganic base is represented by the formula (1
The compound of formula (1i) can also be produced by reacting with the compound of h). Examples of the inorganic base include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and sodium hydrogen carbonate. The reaction is usually performed at about 0 ° C. to about room temperature for 0.5 to 3 hours.

Production method H

Embedded image Examples of the solvent include water, methanol, ethanol, isopropyl alcohol, dioxane, tetrahydrofuran and the like. The reaction is usually carried out at 0 to 100 ° C. for several hours to day and night.

Production method I

Embedded image The compound of the formula (2) is converted to a compound of the formula (XC (R ² ) (R ³ ) -CO
A compound represented by ^{-CH (R 10) -COR 11)} , such as 4 Harogenoaseto acid lower alkyl ester, 4-Harogenoaseto acetate 4-nitrophenyl ester, 4-
Halogenoacetoacetic acid-2,4,6-trichlorophenyl ester, 4-halogenoacetothioacetic acid phenyl ester, 4-halogenoacetoacetic acid 3,2,3-trichloroethyl ester, halogenoacetylmalonic acid di-lower alkyl ester or N-aryl-4 By reacting -halogeno-3-oxobutanamide with or without a deoxidizing agent in a suitable organic solvent, a compound of the formula (11) can be produced. Examples of the solvent include alcohol solvents such as methanol, ethanol, and isopropyl alcohol, and benzene solvents such as benzene, toluene, and xylene. Examples of the deacidifying agent include inorganic bases such as potassium carbonate, sodium carbonate, and sodium hydrogen carbonate, and organic bases such as sodium acetate, potassium acetate, and triethylamine. The reaction is usually performed at room temperature to 100 ° C. for several hours.

Manufacturing method J

Embedded image The compound of formula (1m) is hydrolyzed with zinc powder in water or aqueous alcohol in the presence of an alkali such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, or an acid such as acetic acid in water or a hydrous alcohol. ) Can be produced. The reaction is carried out at room temperature to 80 ° C for several hours.

Manufacturing method K

Embedded image

Manufacturing method L

Embedded image The compound of the formula (1p) can be produced by reacting the compound of the formula (1o) with trifluoroacetic anhydride in the presence of pyridine in an organic solvent such as dioxane, dichloromethane, dichloroethane or chloroform. The reaction is usually performed at 0 ° C. to 50 ° C., preferably at room temperature for several hours.

Manufacturing method M

Embedded image By reacting the compound of the formula (1q) with an arylphenol optionally having one or more substituents in an organic solvent such as tetrahydrofuran in the presence of triphenylphosphine and a dialkylazodicarboxylate,
Can be produced. The reaction is usually at room temperature to 5
Performed at 0 ° C. for several hours.

The method of administering the compound (1) of the present invention may be oral or parenteral, but oral administration is generally preferred. The dose of the compound of the present invention may be appropriately increased or decreased depending on the condition, age, body weight, etc. of the patient. In general, in the case of oral administration, 1 mg to 300 mg / adult is required.
mg / day, preferably 10 mg to 200 mg / day is suitable. Dosage forms include tablets, capsules, powders, granules and the like, which can be produced by known formulation techniques together with usual excipients, lubricants, binders and other additives.

[0037]

EFFECT OF THE INVENTION The compound of the present invention showed an excellent hepatic disorder improving effect in an experimental liver injury (hepatitis) model induced by D-galactosamine. Further, the compound of the present invention can be used in a rat complement-dependent hepatic injury model (iv.
79-180 (1988)). Therefore, the compound of the present invention is excellent as an agent for preventing and treating liver diseases such as liver damage accompanied by necrosis of hepatic parenchymal cells, chronic hepatitis, and liver cirrhosis.

[0038]

EXAMPLES Hereinafter, the present invention will be further described with reference to Examples and Test Examples, but the present invention is not limited thereto.

Example 1 Ethyl 5,6-dihydrothiazolo [2,3-C]
[1,4] thiazine-8-carboxylate ethyl 2.0 g of 3-thioxomorpholine-2-carboxylate and 2.1 g of chloroacetaldehyde (40% aqueous solution) are dissolved in 40 ml of acetic acid and stirred at 50 ° C. for 2 hours. . The residue obtained by distilling off acetic acid is dissolved in chloroform and washed with an aqueous solution of sodium hydrogen carbonate and further with water. The residue obtained by distilling off the solvent was purified by silica gel column chromatography, and recrystallized from isopropyl ether to obtain 0.9 g of the title compound. 86 ° C. Elemental analysis (as C ₉ H ₁₁ NO ₂ S) Calculated (%): C 47.14 H 4.84 N 6.11 Found (%): C 46.89 H 4.67 N 5 .94 NMR spectrum δ (CDCl ₃ ): 1.30 (3H, t), 2.93 (2H, brt), 4.16 (2H, brt), 4.22 (2H, q), 6. 26 (1H, d), 6.58 (1H, d). The compounds of Examples 2 to 50 were produced in the same manner as in Example 1.

Example 2 Ethyl 6,7-dihydro-5H-thiazolo [3,2-
a] Pyridine-8-carboxylate Melting point 62 ° C Elemental analysis (as C ₁₀ H ₁₃ NO ₂ S) Calculated (%): C 56.84 H 6.20 N 6.63 Actual (%): C 56 .59 H 6.35 N 6.61 NMR spectrum δ (CDCl ₃ ): 1.28 (3H, t), 1.94 (2H, q), 2.52 (2H, t), 3.78 (2H) , T), 4.20 (2H, q), 6.10 (1H, d), 6.54 (1H, d).

Example 3 6,7-Dihydro-5H-thiazolo [3,2-a] pyridine-8-carbonitrile Melting point 50-51 ° C. Elemental analysis (as C ₈ H ₈ N ₂ S) Calculated (%) ): C 58.51 H 4.91 N 17.06 Found (%): C 58.46 H 5.01 N 16.75 NMR spectrum δ (CDCl ₃ ): 1.94 (2H, m), 2 .39 (2H, t), 3.70 (2H, t), 5.69 (1H, d), 6.39 (1H, d).

Example 4 Ethyl 2-methyl-6,7-dihydro-5H-thiazolo [3,2-a] pyridine-8-carboxylate

Melting point: 119 to 121 ° C. Elemental analysis value (as C ₁₁ H ₁₅ NO ₂ S) Calculated value (%): C 58.64 H 6.71 N 6.22 Actual value (%): C 58.62 H 6.63 N 6.20 NMR spectrum δ (CDCl ₃ ): 1.29 (3H, t), 1.7 to 2.1 (2H, m), 2.13 (3H, d), 2.51 ( 2H, br t), 3.71 (2H, br t), 4.20 (2H, q), 6.23 (1H, q).

Example 5 Ethyl 2-methyl-5,6-dihydrothiazolo [2,
3-c] [1,4] thiazine-8-carboxylate Melting point 142-143 ° C Elemental analysis (as C ₁₀ H ₁₃ NO ₂ S ₂ ) Calculated (%): C 49.36 H 5.38 N 5 .76 Found (%): C 49.35 H 5.35 N 5.74 NMR Spectrum δ (CDCl ₃ ): 1.32 (3H, t), 2.15 (3H, d), 2.8- 3.0 (4H, m), 4.25 (2H, q), 6.28 (1H, q).

Example 6 Ethyl 3-methyl-6,7-dihydro-5H-thiazolo [3,2-a] pyridine-8-carboxylate Melting point: 120-121 ° C. Elemental analysis (as C ₁₁ H ₁₅ NO ₂ S) ) Calculated value (%): C 58.64 H 6.71 N 6.22 Actual value (%): C 58.45 H 6.66 N 6.25 NMR spectrum δ (CDCl ₃ ): 1.29 (3H) , T), 1.97 (2H, m), 2.09 (3H, d), 2.52 (2H, t), 3.70 (2H, t), 4.20 (2H, q), 5 .78 (1H, d).

Example 7 3-Methyl-5,6,7,8-tetrahydrothiazolo [3,2-a] azepine-9-carbonitrile Melting point: 99-100 ° C. Elemental analysis (C ₁₀ H ₁₂ N ₂ S) Calculated value (%): C 62.46 H 6.29 N 14.57 Actual value (%): C 62.45 H 6.28 N 14.48 NMR spectrum δ (CDCl ₃ ): 1.8 to 2.1 (4H, m), 2.03 (3H, s), 2.4 to 2.6 (2H, m), 3.6 to 3.9 (2H, m), 5.67 (1H, s).

Example 8 Ethyl 3-methyl-5,6-dihydrothiazolo [2
3-c] [1,4] thiazine-8-carboxylate Melting point 129-130 ° C Elemental analysis (as C ₁₀ H ₁₃ NO ₂ S ₂ ) Calculated (%): C 49.36 H 5.38 N 5 .76 found (%): C 49.03 H 5.30 N 5.83 NMR spectrum δ (CDCl ₃ ): 1.35 (3H, t), 2.19 (3H, d), 2.9- 3.1 (2H, m), 4.1 to 4.3 (2H, m), 4.28 (2H, q), 6.01 (1H, q).

Example 9 Isopropyl 1-methylthiazolo [2,3-c]
[1,4] benzothiazine-4-carboxylate Melting point 74-75 ° C Elemental analysis (as C ₁₅ H ₁₅ NO ₂ S ₂ ) Calculated (%): C 58.99 H 4.95 N 4.59 Measured (%): C 59.01 H 5.04 N 4.51 NMR spectrum δ (CDCl ₃ ): 1.31 (6H, d), 2.38 (3H, s), 5.11 (1H, m) , 6.20 (1H, brs), 6.8-7.2 (4H, m).

Example 10 Ethyl 2,3-dimethyl-6,7-dihydro-5H-
Thiazolo [3,2-a] pyridine-8-carboxylate Melting point 80-82 ° C Elemental analysis (as C ₁₂ H ₁₇ NO ₂ S) Calculated (%): C 60.22 H 7.16 N 5.85 Obtained value (%): C 59.93 H 7.02 N 5.65 NMR spectrum δ (CDCl ₃ ): 1.26 (3H, t), 1.8 to 2.1 (2H, m), 97 (3H, s), 2.03 (3H, s), 2.4 to 2.6 (2H, t), 3.5 to 3.7 (2H, t), 4.15 (2H, q) .

Example 11 2,3-Dimethyl-5,6,7,8-tetrahydrothiazolo [3,2-a] azepine-9-carbonitrile Melting point: 120-122 ° C. Elemental analysis (C ₁₁ H ₁₄ N) Calculated value (%): C 60.55 H 7.10 N 12.84 Actual value (%): C 60.42 H 6.85 N 12.76 NMR spectrum δ (as ₂ S · 0.3 H ₂ O) CDCl ₃ ): 1.91 (3H, s), 1.98 (3H, s), 1.8 to 2.0 (4H, m), 2.3 to 2.6 (2H, m), 6-3.8 (2H, m).

Example 12 Ethyl 2,3-dimethyl-5,6-dihydrothiazolo [2,3-c] [1,4] thiazine 8-carboxylate Melting point: 118-120 ° C. Elemental analysis (C ₁₁ H ₁₅₎ (As NO ₂ S ₂ ) Calculated (%): C 51.34 H 5.87 N 5.44 Actual (%): C 51.40 H 5.87 N 5.49 NMR spectrum δ (CDCl ₃ ): 1.34 (3H, t), 2.08 (3H, s), 2.12 (3H, s), 2.8 to 3.1 (2H, m), 4.0 to 4.3 (2H, m), 4.26 (2H, q).

Example 13 Isopropyl [3- (3,5-di-tert-butyl-
4-hydroxyphenyl)]-6,7-dihydro-5H
- thiazolo [3,2-a] pyridine-8-carboxylate melting point 192-194 ° C. Elemental analysis (C ₂₅ H ₃₅ NO ₃ as S) Calculated (%): C 69.90 H 8.59 N 3. 26 actual value (%): C 69.58 H 8.13 N 3.11 NMR spectrum δ (CDCl ₃ ): 1.27 (6H, d), 1.45 (18H, s), 1.7-2. 2.0 (2H, m), 2.4 to 2.7 (2H, m), 3.5 to 3.7 (2H, m), 5.08 (1H, sept), 5.90 (1H, s) ), 7.02 (2H, s).

Example 14 3- (3,5-Di-tert-butyl-4-hydroxyphenyl) -6,7-dihydro-5H-thiazolo [3
2-a] pyridine-8-carbonitrile mp two hundred thirty-six to two hundred thirty-eight ° C. Elemental analysis _{(C 22 H 28 N 2 OS} · 0.5H as ₂ O) Calculated (%): C 69.98 H 7.61 N 7 .42 found (%): C 69.66 H 7.57 N 7.29 NMR spectrum δ (CDCl ₃ ): 1.48 (18H, s), 1.93 (2H, m), 2.42 ( 2H, t), 3.60 (2H, t), 5.88 (1H, s), 7.18 (2H, s).

Example 15 Ethyl [3- (3,5-di-tert-butyl-4-hydroxyphenyl)]-5,6-dihydrothiazolo [2,3-c] [1,4] thiazine-8 -Carboxylate Melting point 210-212 ° C Elemental analysis (as C ₂₃ H ₃₁ NO ₃ S ₂ ) Calculated (%): C 63.71 H 7.21 N 3.23 Actual (%): C 63.97 H 7.54 N 3.16 NMR spectrum δ (CDCl ₃ ): 1.36 (3H, t), 1.46 (18H, s), 2.7-3.0 (2H, m), 3.9 -4.2 (2H, m), 4.30 (2H, q), 6.16 (1H, s), 7.92 (2H, s).

Example 16 Ethyl [3- (3,5-di-tert-butyl-4-hydroxyphenyl)]-5,6,7,8-tetrahydrothiazolo [3,2-a] azepine-9- Carboxylate Melting point 148-149 ° C Elemental analysis (as C ₂₅ H ₃₅ NO ₃ S) Calculated (%): C 69.90 H 8.59 N 3.26 Found (%): C 69.65 H 8 .26 N 3.18 NMR spectrum δ (CDCl ₃ ): 1.29 (3H, t), 1.47 (18H, s), 1.98 (4H, m), 2.77 (2H, m), 3.72 (2H, m), 4.17 (2H, q), 5.96 (1H, s), 7.09 (2H, s).

Example 17 3-phenyl-6,7-dihydro-5H-thiazolo [3,2-a] pyridine-8-carbonitrile Melting point 100-101 ° C. Elemental analysis (as C ₁₄ H ₁₂ N ₂ S) Calculated value (%): C 69.97 H 5.03 N 11.66 Actual value (%): C 70.07 H 5.06 N 11.67 NMR spectrum δ (CDCl ₃ ): 1.89 (2H, m), 2.40 (2H, t), 3.55 (2H, t), 5.87 (1H, s), 7.5-7.2 (5H, m).

Example 18 Ethyl 3-phenyl-5,6,7,8-tetrahydrothiazolo [3,2-a] azepine-9-carboxylate Melting point: 148 to 150 ° C. Elemental analysis (C ₁₇ H ₁₉ NO ₂₎ (Calculated as S) Calculated value (%): C 67.75 H 6.35 N 4.65 Observed value (%): C 67.43 H 6.26 N 4.52 NMR spectrum δ (CDCl ₃ ): 1.29 (3H, t), 1.9 to 2.1 (4H, m), 2.7 to 2.9 (2H, m), 3.6 to 3.8 (2H, m), 4.19 (2H , Q), 6.07 (1H, s), 7.34 (5H, s).

Example 19 Ethyl 3-phenyl-5,6-dihydrothiazolo [2,3-c] [1,4] thiazine-8-carboxylate Melting point: 156-157 ° C. Elemental analysis (C ₁₅ H ₁₅ NO (Calculated as ₂ S) Calculated (%): C 58.99 H 4.95 N 4.59 Found (%): C 58.73 H 4.80 N 4.65 NMR spectrum δ (CDCl ₃ ): 1. 32 (3H, t), 2.7 to 3.0 (2H, m), 3.9 to 4.2 (2H, m), 4.82 (2H, q), 6.21 (1H, s) , 7.3-7.6 (5H, m).

Example 20 Ethyl 2,3-diphenyl-6,7-dihydro-5H
- thiazolo [3,2-a] pyridine-8-carboxylate melting point 159-161 ° C. Elemental analysis (C ₂₂ H ₂₁ NO ₂ as S) Calculated (%): C 72.70 H 5.82 N 3. 85 Found (%): C 72.68 H 5.83 N 3.87 NMR spectrum δ (CDCl ₃ ): 1.32 (3H, t), 1.7-2.1 (2H, m), 2 .56 (2H, br t), 3.49 (2H, br t), 4.26 (2H, q), 6.9-7.6 (10H, m).

Example 21 Ethyl 2,3-diphenyl-5,6,7,8-tetrahydrothiazolo [3,2-a] azepine-9-carbonitrile Melting point: 208-210 ° C. Elemental analysis (C ₂₃ H ₂₃₎ (As NO ₂ S) Calculated (%): C 76.33 H 5.49 N 8.48 Found (%): C 76.67 H 5.61 N 8.43 NMR spectrum δ (CDCl ₃ ): 1 0.7 to 2.2 (4H, m), 2.4 to 2.7 (2H, m), 3.4 to 3.6 (2H, m), 6.9 to 7.5 (10H, m) .

Example 22 Diethyl 6,7-dihydro-5H-thiazolo [3,2
-A] Pyridine-2,8-dicarboxylate Melting point 170-172 ° C Elemental analysis (as C ₁₃ H ₁₇ NO ₄ S) Calculated (%): C 55.11 H 6.05 N 4.94 Found (%): C 54.90 H 5.92 N 5.05 NMR spectrum δ (CDCl ₃ ): 1.31 (6H, t), 1.7 to 2.1 (2H, m), 2.51 ( 2H, brt), 3.82 (2H, brt), 4.23 (2H, q), 4.26 (2H, q), 7.36 (1H, s).

Example 23 Ethyl 9-cyano-5,6,7,8-tetrahydrothiazolo [3,2-a] azepine-2-carboxylate Melting point: 122-123 ° C. Elemental analysis (C ₁₂ H ₁₄ N ₂₎ (As O ₂ S) Calculated (%): C 57.58 H 5.64 N 11.19 Found (%): C 57.30 H 5.54 N 11.09 NMR spectrum δ (CDCl ₃ ): 1 0.32 (3H, t), 1.7 to 2.1 (4H, m), 2.3 to 2.6 (2H, m), 3.7 to 4.0 (2H, m), 4.26 (2H, q), 7.12 (1H, s).

Example 24 Diethyl 5,6-dihydrothiazolo [2,3-c]
[1,4] thiazine-2,8-dicarboxylate mp one hundred ninety-five to one hundred and ninety-six ° C. Elemental analysis (C ₁₂ H ₁₅ NO ₄ as S ₂₎ Calculated (%): C 47.82 H 5.02 N 4. 65 actual value (%): C 47.65 H 4.84 N 4.71 NMR spectrum δ (CDCl ₃ ): 1.36 (3H, t), 1.37 (3H, t), 2.8 to 3 .1 (2H, m), 4.0 to 4.3 (2H, m), 4.28 (4H, q), 7.37 (1H, s).

Example 25 Diethyl 3-methyl-6,7-dihydro-5H-thiazolo [3,2-a] pyridine-2,8-dicarboxylate Melting point 196 ° -198 ° C. Elemental analysis (C ₁₄ H ₁₉ NO (Calculated as ₄ S) Calculated (%): C 56.54 H 6.44 N 4.71 Found (%): C 56.56 H 6.32 N 4.68 NMR spectrum δ (CDCl ₃ ): 31 (6H, t), 1.8 to 2.2 (2H, m), 2.50 (3H, s), 2.52 (2H, t), 3.74 (2H, t), 4.27 (4H, q).

Example 26 Ethyl 8-cyano-3-methyl-6,7-dihydro-
5H-thiazolo [3,2-a] pyridine-2-carboxylate Melting point 140 ° C. Elemental analysis (as C ₁₂ H ₁₄ N ₂ O ₂ S) Calculated (%): C 57.58 H 5.64 N 11 .19 found (%): C 57.74 H 5.65 N 11.26 NMR spectrum δ (CDCl ₃ ): 1.31 (3H, t), 1.96 (2H, m), 2.39 ( 2H, t), 2.44 (3H, s), 3.68 (2H, t), 4.24 (2H, q).

Example 27 Ethyl 9-cyano-3-methyl-5,6,7,8-tetrahydrothiazolo [3,2-a] azepine-2-carboxylate Melting point 172-173 ° C. Elemental analysis (C ₁₃ (Calculated as H ₁₆ N ₂ O ₂ S) Calculated value (%): C 59.07 H 6.10 N 10.60 Observed value (%): C 58.83 H 6.04 N 10.55 NMR spectrum δ (CDCl ₃ ): 1.30 (3H, t), 2.4 to 2.6 (2H, m), 2.42 (3H, s), 2.8 to 3.2 (4H, m), 3.7 3.9 (2H, m), 4.23 (2H, q).

Example 28 Diethyl 3-methyl-5,6-dihydrothiazolo [2,
3-c] [1,4] thiazine-2,8-carboxylate Melting point 223 to 225 ° C. Elemental analysis value (as C ₁₃ H ₁₇ NO ₄ S ₂ ) Calculated value (%): C 49.51 H 5.43 N 4.44 found (%): C 59.24 H 5.23 N 4.43 NMR spectrum δ (CDCl ₃ ): 1.34 (3H, t), 1.36 (3H, t), 2. 59 (3H, s), 2.9-3.2 (2H, m), 4.1-4.4 (2H, m), 4.30 (2H, q), 4.32 (2H, q) .

Example 29 Diethyl 6,7-dihydro-5H-thiazolo [3,2
-A] Pyridine-3,8-dicarboxylate Melting point 84 ° C Elemental analysis (as C ₁₃ H ₁₇ NO ₄ S) Calculated (%): C 55.10 H 6.05 N 4.94 Found (%) ): C 54.87 H 5.91 N 4.80 NMR spectrum δ (CDCl ₃ ): 1.31 (3H, t), 1.36 (3H, t), 1.94 (2H, q), 2 .50 (2H, t), 4.1-4.5 (6H, m), 7.20 (1H, s).

Example 30 Ethyl 8-cyano-6,7-dihydro-5H-thiazolo [3,2-a] pyridine-3-carboxylate Melting point: 89-90 ° C. Elemental analysis (C ₁₁ H ₁₂ N ₂ O ₂₎ (Calculated as S) Calculated value (%): C 55.91 H 5.12 N 11.86 Actual value (%): C 56.03 H 5.21 N 11.92 NMR spectrum δ (CDCl ₃ ): 1.34 (3H, t), 1.7 to 2.1 (2H, m), 2.35 (2H, brt), 4.13 (2H, brt), 4.28 (2H, q), 6. 96 (1H, s).

Example 31 Ethyl 9-cyano-5,6,7,8-tetrahydrothiazolo [3,2-a] azepine-3-carboxylate Melting point: 83-85 ° C. Elemental analysis (C ₁₂ H ₁₄ N ₂₎ (Calculated as O ₂ S) Calculated (%): C 57.58 H 5.64 N 11.19 Found (%): C 57.43 H 5.77 N 11.10 NMR spectrum δ (CDCl ₃ ): 1 .33 (3H, t), 1.8 to 2.1 (4H, m), 2.4 to 2.6 (2H, m), 3.8 to 4.1 (2H, m), 4.26 (2H, q), 6.98 (1H, s).

Example 32 Diethyl 5,6-dihydrothiazolo [2,3-c]
[1,4] thiazine-3,8-dicarboxylate mp 132-133 ° C. Elemental analysis (C ₁₂ H ₁₅ NO ₄ as S ₂₎ Calculated (%): C 47.82 H 5.02 N 4. 65 actual value (%): C 47.61 H 4.83 N 4.66 NMR spectrum δ (CDCl ₃ ): 1.33 (3H, t), 1.36 (3H, t), 2.8-3 0.0 (2H, m), 4.26 (2H, q), 4.30 (2H, q), 4.5-4.7 (2H, m), 7.30 (1H, s).

Example 33 Diethyl thiazolo [2,3-c] [1,4] benzothiazine-1,4-dicarboxylate Melting point: 106 ° C. Elemental analysis value (as C ₁₆ H ₁₅ NO ₄ S ₂ ) Calculated value (%) ): C 54.99 H 4.33 N 4.01 Found (%): C 54.85 H 4.25 N 4.06 NMR spectrum δ (CDCl ₃ ): 1.28 (3H, t), 1 .34 (3H, t), 4.28 (2H, q), 4.34 (2H, q), 6.5-7.3 (4H, m), 7.54 (1H, s).

Example 34 Triethyl 6,7-dihydro-5H-thiazolo [3
2-a] pyridine-2,3,8-tricarboxylate Melting point 76-78 ° C Elemental analysis (as C ₁₆ H ₂₁ NO ₆ S) Calculated (%): C 54.07 H 5.96 N 94 Observed value (%): C 54.31 H 5.95 N 4.03 NMR spectrum δ (CDCl ₃ ): 1.30 (6H, t), 1.40 (3H, t), 1.8 to 2 .2 (2H, m), 2.50 (2H, brt), 3.72 (2H, brt), 4.23 (2H, q), 4.25 (2H, q), 4.44 ( 2H, q).

Example 35 Triethyl 5,6-dihydrothiazolo [2,3-c]
[1,4] thiazine-2,3,8-tricarboxylate Melting point: 106-107 ° C. Elemental analysis (as C ₁₅ H ₁₉ NO ₆ S ₂ ) Calculated (%): C 48.24 H 5.13 N 3.75 Found (%): C 48.05 H 4.98 N 3.79 NMR spectrum δ (CDCl ₃ ): 1.2-1.9 (9H, m), 2.9-3.2 ( 2H, m), 3.0 to 3.3 (2H, m), 4.1 to 4.6 (6H, m).

Example 36 Isopropyl 2-acetyl-3-methyl-6,7-dihydro-5H-thiazolo [3,2-a] pyridine-8-
Carboxylate Melting point 214-215 ° C Elemental analysis (as C ₁₄ H ₁₉ NO ₃ S) Calculated (%): C 59.76 H 6.81 N 4.98 Found (%): C 59.81 H 6 .84 N 5.05 NMR spectrum δ (CDCl ₃ ): 1.28 (6H, d), 1.98 (2H, m), 2.32 (3H, s), 2.52 (3H, s), 2.4 to 2.6 (2H, m), 3.6 to 3.9 (2H, m), 5.06 (1H, sept).

Example 37 Ethyl 2-acetyl-3,6,6-trimethyl-6
7-dihydro-5H-thiazolo [3,2-a] pyridine-8-carboxylate Melting point 153-155 ° C Elemental analysis (as C ₁₅ H ₂₁ NO ₃ S) Calculated (%): C 60.99 H 7 .17 N 4.74 Found (%): C 60.69 H 7.03 N 4.84 NMR spectrum δ (CDCl ₃ ): 1.04 (6H, s), 1.31 (3H, t), 2.30 (2H, s), 2.35 (3H, s), 2.52 (3H, s), 3.34 (2H, s), 4.24 (2H, q).

Example 38 Ethyl 2-acetyl-3-methyl-5,6-dihydrothiazolo [2,3-c] [1,4] thiazine-8-carboxylate Melting point: 184-185 ° C. Elemental analysis (C ₁₂ H ₁₅ NO ₃ S ₂ ) Calculated (%): C 50.51 H 5.30 N 4.91 Found (%): C 50.03 H 5.31 N 5.16 NMR spectrum δ (CDCl ₃ ): 1.36 (3H, t), 2.37 (3H, s), 2.58 (3H, s), 2.9 to 3.2 (2H, m), 3.0 to 3.3. (2H, m), 4.30 (2H, q).

Example 39 Ethyl 2-acetyl-1-methylthiazolo [2,3-
c] [1,4] benzothiazine-4-carboxylate Melting point 166-167 ° C Elemental analysis (as C ₁₆ H ₁₅ NO ₃ S ₂ ) Calculated (%): C 57.63 H 4.53 N 4.20 Found (%): C 57.33 H 4.45 N 4.37 NMR spectrum δ (CDCl ₃ ): 1.35 (3H, t), 2.41 (3H, s), 2.68 (3H, s), 4.29 (2H, q), 6.7-7.4 (4H, m).

Example 40 Ethyl 3-acetyl-5,6-dihydro-5H-thiazolo [3,2-a] pyridine-8-carboxylate Melting point 135-136 ° C. Elemental analysis (as C ₁₂ H ₁₅ NO ₃ S) ) calculated (%): C 56.90 H 5.97 N 5.53 Found (%): C 56.83 H 5.84 N 5.61 NMR spectrum _{δ (CDCl 3): 1.30 (} 3H , T), 1.7 to 2.1 (2H, m), 2.44 (3H, s), 2.48 (2H, br t), 4.22 (2H, q), 4.28 (2H , Brt), 7.17 (1H, s).

Example 41 Ethyl 3-acetyl-5,6-dihydrothiazolo [2,3-c] [1,4] thiazine-8-carboxylate Melting point: 158 to 159 ° C. Elemental analysis (C ₁₁ H ₁₃ NO ₃ as S ₂₎ calculated (%): C 48.69 H 4.83 N 5.16 Found (%): C 48.70 H 4.77 N 5.33 NMR spectrum δ (CDCl _3): 1 .35 (3H, t), 2.48 (3H, s), 2.6 to 3.2 (2H, m), 4.24 (2H, q), 4.4 to 4.8 (2H, m ), 7.30 (1H, brs).

Example 42 Ethyl 1-acetylthiazolo [2,3-c] [1,
4] Benzothiazine-4-carboxylate Melting point 167-170 ° C Elemental analysis (as C ₁₅ H ₁₃ NO ₃ S ₂ ) Calculated (%): C 56.40 H 4.10 N 4.39 Actual (%) : C 56.21 H 4.07 N 4.35 NMR spectrum δ (CDCl ₃ ): 1.36 (3H, t), 2.47 (3H, s), 4.29 (2H, q), 6. 48 (1H, m), 7.0 to 7.3 (3H, m), 7.47 (1H, s).

Example 43 Ethyl 2- (2-acetoxyethyl) -3-methyl-
5,6-Dihydrothiazolo [2,3-c] [1,4] thiazine-8-carboxylate Melting point 118-119 ° C Elemental analysis (as C ₁₄ H ₁₉ NO ₄ S ₂ ) Calculated (%): C 51.04 H 5.81 N 4.25 Found (%): C 51.14 H 5.91 N 4.42 NMR spectrum δ (CDCl ₃ ): 1.35 (3H, t), 2.08 (3H, s), 2.12 (3H, s), 2.6-3.2 (4H, m), 4.0-4.5 (6H, m).

Example 44 Ethyl (8-ethoxycarbonyl-2,3,5,6-
Tetrahydronaphthalene thiazolo [2,3-c] [1,4] thiazin-3-ylidene) cyanoacetate mp 183-185 ° C. Elemental analysis _{(C 14 H 16 N 2 O} 4 as S ₂₎ Calculated (%): C 49.40 H 4.74 N 8.23 Found (%): C 49.27 H 4.70 N 8.24 NMR spectrum δ (CDCl ₃ ): 1.36 (6H, t), 3.0 -3.2 (2H, m), 4.30 (2H, q), 4.32 (2H, q), 4.5-4.7 (2H, m), 4.57 (2H, s).

Example 45 Ethyl (8-isopropoxycarbonyl-2,3,
6,7-tetrahydro-5H-thiazolo [3,2-a]
Pyridine-3-ylidene) cyanoacetate Melting point 142-143 ° C Elemental analysis (as C ₁₆ H ₂₀ N ₂ O ₄ S) Calculated (%): C 57.12 H 5.99 N 8.33 Actual (%) ): C 57.17 H 6.04 N 8.32 NMR spectrum δ (CDCl ₃ ): 1.29 (6H, α), 1.36 (3H, t), 1.8-2.1 (2H, m), 2.3-2.6 (2H, m), 4.1-4.4 (4H, m), 4.51 (2H, s), 5.11 (1H, sept).

Example 46 Ethyl (8-ethoxycarbonyl-5,6-dihydrothiazolo [2,3-c] [1,4] thiazin-3-yl) acetate Melting point 95-97 ° C. Elemental analysis (C ₁₃ (As H ₁₇ NO ₄ S ₂ ) Calculated (%): C 49.51 H 5.43 N 4.44 Observed (%): C 49.51 H 5.39 N 4.47

Example 47 Ethyl 2- (8-ethoxycarbonyl-5,6-dihydrothiazolo [2,3-c] [1,4] thiazine-3-
Yl) Propionate Melting point 100-102 ° C Elemental analysis (as C ₁₄ H ₁₉ NO ₄ S ₂ ) Calculated (%): C 51.04 H 5.81 N 4.25 Actual (%): C 50.82 H 5.94 N 4.30 NMR spectrum δ (CDCl ₃ ): 1.26 (3H, t), 1.32 (3H, t), 2.54 (3H, d), 2.9-3.1 (2H, m), 3.60 (1H, q), 4.0 to 4.2 (2H, m), 4.18 (2H, q), 4.26 (2H, q), 6.16 ( 1H, s).

Example 48 N-phenyl- (8-ethoxycarbonyl-5,6-dihydrothiazolo [2,3-c] [1,4] thiazine-3
- yl) acetamide melting one hundred ninety-four to one hundred ninety-five ° C. Elemental analysis _{(C 17 H 18 N 2 O} 3 as S ₂₎ Calculated (%): C 56.33 H 5.01 N 7.73 Found (%): C 56.30 H 5.18 N 7.70 NMR spectrum δ (CDCl ₃ ): 1.29 (3H, t), 2.9 to 3.1 (2H, m), 3.72 (2H, s), 4.1 to 4.4 (4H, m), 6.40 (1H, s), 7.0 to 7.8 (5H, m).

Example 49 Ethyl 3-methyl-2-octylcarbamoyl-6
7-dihydro -5H- thiazolo [3,2-a] pyridine-8-carboxylate melting point one hundred and forty-six to one hundred and forty-seven ° C. Elemental analysis _{(C 20 H 32 N 2 O} 3 as S) Calculated (%): C 63.13 H 8.48 N 7.36 Actual value (%): C 63.03 H 8.52 N 7.52 NMR spectrum δ (CDCl ₃ ): 0.7-1.6 (18H, m), 1.8 -2.2 (2H, m), 2.51 (2H, brt), 2.51 (3H, s), 3.32 (2H, q), 3.74 (2H, brt), 4. 22 (2H, q).

Example 50 Isopropyl 2-cyclohexylcarbamoyl-3-
Methyl-6,7-dihydro-5H-thiazolo [3,2-
a] Pyridine-8-carboxylate Melting point 231 to 233 ° C Elemental analysis value (as C ₁₉ H ₂₈ N ₂ O ₃ S) Calculated value (%): C 62.61 H 7.74 N 7.69 Actual value (%) ): C 62.53 H 7.90 N 7.72 NMR spectrum δ (CDCl ₃ ): 1.28 (6H, d), 1.4-2.2 (12H, m), 2.51 (2H, brt), 2.51 (3H, s), 3.6-4.1 (3H, m), 5.10 (1H, sept).

Example 51 1.48 g of sodium isopropyl 2-phenyl-5,6-dihydropyrrolo [2,1-b] thiazole-7-carboxylate (60% oil) was added to ethanol 4
Dissolved in 0 ml and 3.4 g of α-dichloromethylbenzyl alcohol and isopropyl 2-thioxopyrrolidine-
Add 3.0 g of 3-carboxylate, return to room temperature at 0 ° C. for 0.5 hour, and stir for 1 hour. The residue obtained by distilling off the solvent was mixed with 30 ml of chloroform and 10 ml of acetic acid.
And stirred at room temperature for 0.5 hour. The residue obtained by distilling off the solvent is dissolved in chloroform, and washed with an aqueous sodium hydrogen carbonate solution and further with water. After drying the chloroform layer with anhydrous sodium sulfate, the solvent is distilled off. The residue was purified by silica gel column chromatography and recrystallized from isopropyl ether to give the title compound (2.4 g).
I got Melting point 118 ° C Elemental analysis (as C ₁₆ H ₁₇ NO ₂ S) Calculated (%): C 66.87 H 5.96 N 4.87 Found (%): C 67.02 H 5.91 N 4 .87 NMR spectrum δ (CDCl ₃ ): 1.29 (6H, d), 3.20 (2H, t), 4.10 (2H, t), 5.10 (1H, m), 6.89 ( 1H, s), 7.31 (5H, br s). The compounds of Examples 52 and 53 were produced in the same manner as in Example 51.

Example 52 Isopropyl 2-phenyl-6,7-dihydro-5H
-Thiazolo [3,2-a] pyridine-8-carboxylate Melting point 142-144 ° C Elemental analysis (as C ₁₇ H ₁₉ NO ₂ S) Calculated (%): C 67.75 H 6.35 N 65 Actual value (%): C 67.97 H 6.37 N 4.73 NMR spectrum δ (CDCl ₃ ): 1.29 (6H, d), 1.8 to 2.1 (2H, m), 2 .53 (2H, brt), 3.84 (2H, brt), 5.13 (1H, sept), 6.82 (1H, s), 7.2-7.6 (5H, m).

Example 53 2-phenyl-5,6,7,8-tetrahydrothiazolo [3,2-a] azepine-9-carbonitrile Melting point: 153 ° -155 ° C. Elemental analysis (C ₁₅ H ₁₄ N ₂ S) Calculated value (%): C 70.83 H 5.55 N 11.01 Actual value (%): C 70.89 H 5.64 N 10.98 NMR spectrum δ (CDCl ₃ ): 1.8 to 2.1 (4H, m), 2.3 to 2.6 (2H, m), 3.7 to 3.9 (2H, m), 6.56 (1H, s), 7.1 to 7. 4 (5H, m).

Example 54 Isopropyl 2,3,5,6-tetrahydro-3-oxopyrrolo [2,1-b] thiazole-7-carboxylate 10.0 g of isopropyl 2-thioxopyrrolidine-3-carboxylate and bromoacetic acid Ethyl ester6.
Dissolve 5 ml in 100 ml of acetic acid and stir at 70-80 ° C. for 3 hours. The residue obtained by evaporating acetic acid under reduced pressure is dissolved in chloroform, washed with aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent is purified by silica gel column chromatography, and then recrystallized from isopropyl ether to obtain 8.5 g of the title compound. Melting point: 113 ° C. Elemental analysis (as C ₁₀ H ₁₃ NO ₃ S) Calculated value (%): C 52.84 H 5.77 N 6.16 Observed value (%): C 52.64 H 5.62 N 6.19 NMR spectrum δ (CDCl ₃ ): 1.27 (6H, d) , 3.12 (2H, t), 3.84 (2H, t), 4.02 (2H, s), 5.07 (1H, sept). The compounds of Examples 55 to 56 were produced in the same manner as in Example 54.

Example 55 Isopropyl 2,3,6,7-tetrahydro-5H-
3- Okisochiazoro [3,2-a] pyridine-8-carboxylate mp 94 to 96 ° C. Elemental analysis (C ₁₁ H ₁₅ NO ₃ as S) Calculated (%): C 54.75 H 6.27 N 5 .80 found (%): C 54.62 H 6.33 N 5.75 NMR spectrum δ (CDCl ₃ ): 1.29 (6H, d), 1.7-2.1 (2H, m), 2.47 (2H, t), 3.5 to 3.8 (2H, m), 3.65 (2H, s), 5.08 (1H, sept).

Example 56 Diethyl 2,3,5,6-tetrahydro-3-oxothiazolo [2,3-c] [1,4] thiazine-5,8-
Dicarboxylate Melting point 97 ° C Elemental analysis (as C ₁₂ H ₁₅ NO ₅ S ₂ ) Calculated (%): C 45.41 H 4.76 N 4.41 Actual (%): C 45.28 H 4 .83 N 4.36 NMR spectrum δ (CDCl ₃ ): 1.30 (3H, t), 1.36 (3H, t), 3.24 (2H, ddd), 3.81 (1H, s), 3.83 (1H, s), 4.28 (2H, q), 4.31 (2H, q), 5.44 (1H, t).

Example 57 Ethyl 2-isopropyl-3-oxo-2,3,5
Dissolve 3.0 g of 6-tetrahydrothiazolo [2,3-c] [1,4] thiazine-8-carboxylate ethyl 2-thioxothiomorpholine-3-carboxylate in 60 ml of dichloromethane,
30 ml of 0.5N aqueous sodium hydroxide solution is added.
Under ice-cooling and stirring, a solution of 3.2 g of α-bromo-isovaleryl chloride in 30 ml of dichloromethane is added. After 15 minutes, 30 ml of a 0.5 N aqueous sodium hydroxide solution is further added, and the mixture is stirred for 15 minutes. 200 ml of dichloromethane is added to the reaction solution, and the dichloromethane layer is washed with water and a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The crystals obtained by evaporating the solvent were washed with ethyl ether to obtain 3.7 g of the title compound. Melting point 115-116 ° C NMR spectrum δ (CDCl ₃ ): 0.97 (3H, d), 1.08 (3H, d), 1.36 (3H, t), 2.3-2.7 (1H, m), 2.9-3.1 (2H, m), 3.9-4.1 (3H, m), 4.30 (2H, q). The compounds of Examples 58 to 68 were produced in the same manner as in Example 57.

Example 58 Ethyl 2-cyclohexyl-3-oxo-2,3,
5,6-tetrahydrothiazolo [2,3-c] [1,
4] Thiazine-8-carboxylate Melting point 144-145 ° C NMR spectrum δ (CDCl ₃ ): 1.1-2.2 (14H, m), 2.9-3.1 (2H, m), 3.9 -4.2 (3H, m), 4.34 (2H, q).

Example 59 Ethyl 2-cyclohexylmethyl-3-oxo-2,
3,5,6-tetrahydrothiazolo [2,3-c]
[1,4] thiazine-8-carboxylate Melting point 156-157 ° C NMR spectrum δ (CDCl ₃ ): 0.8-2.3 (16H, m), 2.9-3.1 (2H, m), 3.95 (1H, dd), 4.0-4.2 (2H, m), 4.34 (2H, q).

Example 60 Ethyl 2- (2-cyclohexylethyl) -3-oxo-2,3,5,6-tetrahydrothiazolo [2,3-
c] [1,4] thiazine-8-carboxylate Melting point 107-109 ° C NMR spectrum δ (CDCl ₃ ): 0.7-2.4 (18H, m), 2.9-3.1 (2H, m ), 3.90 (1H, dd), 4.0-4.2 (2H, m), 4.33 (2H, q).

Example 61 Isopropyl 2-benzyl-3-oxo-2,3,
5,6-tetrahydro-5H-thiazolo [3,2-a]
Pyridine-8-carboxylate Melting point 78-82 ° C NMR spectrum δ (CDCl ₃ ): 1.26 (6H, d), 1.7-2.0 (2H, m), 2.43 (2H, brt) , 2.8-3.7 (4H, m), 4.10 (1H, dd), 5.08 (1H, sept), 7.27 (5H, s).

Example 62 Ethyl 2-benzyl-3-oxo-2,3,5,6-
Tetrahydro-5H-thiazolo [3,2-a] pyridine-8-carboxylate Melting point 83-85 ° C Elemental analysis (as C ₁₇ H ₁₉ NO ₃ S) Calculated (%): C 64.33 H 6.03 N 4.41 actual value (%): C 64.08 H 6.27 N 4.60 NMR spectrum δ (CDCl ₃ ): 1.27 (3H, t), 1.6 to 2.0 (2H, m) ), 2.44 (2H, brt), 2.98 (1H, dd), 3.3-3.7 (3H, m), 4.20 (2H, q), 4.0-4.4. (1H, m), 7.30 (5H, s).

Example 63 Ethyl 2-benzyl-3-oxo-2,3,5,6-
Tetrahydrothiazolo [2,3-c] [1,4] thiazine-8-carboxylate Melting point 117-118 ° C NMR spectrum δ (CDCl ₃ ): 1.32 (3H, t), 2.7-3.0 (2H, m), 3.04 (1H, dd), 3.54 (1H, dd), 3.9-4.1 (2H, m), 4.1-4.5 (3H, m), 7.36 (5H, s).

Example 64 Ethyl 2- (2-chlorobenzyl) -3-oxo-
2,3,5,6-tetrahydrothiazolo [2,3-c]
[1,4] thiazine-8-carboxylate Melting point 156-158 ° C NMR spectrum δ (CDCl ₃ ): 1.32 (3H, t), 2.8-3.2 (3H, m), 3.86 ( 1H, dd), 4.0 to 4.5 (5H, m), 7.2 to 7.6 (4H, m).

Example 65 Ethyl 2- (3-chlorobenzyl) -3-oxo-
2,3,5,6-tetrahydrothiazolo [2,3-c]
[1,4] thiazine-8-carboxylate Melting point 139-140 ° C NMR spectrum δ (CDCl ₃ ): 1.32 (3H, t), 2.8-3.0 (2H, m), 3.02 ( 1H, dd), 3.46 (1H, dd), 3.9 to 4.4 (5H, m), 7.1 to 7.5 (4H, m).

Example 66 Ethyl 2- (4-chlorobenzyl) -3-oxo-
2,3,5,6-tetrahydrothiazolo [2,3-c]
[1,4] thiazine-8-carboxylate Melting point 143 ° C NMR spectrum δ (CDCl ₃ ): 1.32 (3H, t), 3.15 (1H, dd), 3.63 (1H, dd), 4 .30 (2H, q), 4.42 (1H, dd), 7.1-7.4 (3H, m), 8.08 (1H, m).

Example 67 Ethyl 2-benzyl-1-oxothiazolo [2,3-
c] [1,4] benzothiazine-4-carboxylate Melting point 119-120 ° C NMR spectrum δ (CDCl ₃ ): 1.35 (3H, t), 3.15 (1H, dd), 3.63 (1H, dd), 4.30 (2H, q), 4.42 (1H, dd), 7.1-7.4 (3H, m), 8.08 (1H, m).

Example 68 Ethyl 3-oxo-2-phenethyl-2,3,5,6
-Tetrahydrothiazolo [2,3-c] [1,4] thiazine-8-carboxylate Melting point 75-76 ° C NMR spectrum δ (CDCl ₃ ): 1.36 (3H, t), 2.0-2. 7 (2H, m), 2.7 to 2.9 (2H, m), 2.8 to 3.1 (2H, m), 3.86 (1H, dd), 3.9 to 4.1 ( 2H, m), 4.21 (2H, q), 7.1 to 7.5 (5H, m).

Example 69 Ethyl 2-chloro-3-oxo-2,3,6,7-tetrahydro-5H-thiazolo [3,2-a] pyridine-
Dissolve 6.0 g of ethyl 8-carboxylate 2-thioxopiperidine-3-carboxylate in 150 ml of dichloromethane and add 80 ml of an aqueous solution of 5.9 g of sodium hydrogen carbonate. Under ice cooling and stirring, 5.2 g of dichloroacetyl chloride is added dropwise thereto. Return to room temperature and stir for another 2 hours. The dichloromethane layer is washed with water and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent is n
-Hexane was added for crystallization to obtain 8.2 g of the title compound. 87-90 ° C. NMR spectrum δ (CDCl ₃ ): 1.32 (3H, t), 1.95 (2H, m), 2.55 (2H, t), 3.72 (2H, m), 4 .26 (2H, q), 5.65 (1H, s).

Example 70 Isopropyl 2- (3,5-di-tert-butyl-)
4-hydroxyphenyl) -3-oxo-2,3,6
7-tetrahydro-5H-thiazolo [3,2-a] pyridine-8-carboxylate isopropyl 2-chloro-3-oxo-2,3,6
8.0 g of 7-tetrahydro-5H-thiazolo [3,2-a] pyridine-8-carboxylate and 2,6-di-
6.6 g of tert-butylphenol are dissolved in 300 ml of dichloromethane, and the mixture is cooled with ice and stirred with 3.7 g of stannic chloride.
Add ml. Subsequently, it heats and refluxes for 40 minutes. The reaction solution is poured into water and extracted with dichloromethane. The dichloromethane layer is washed with water and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography, and then recrystallized from a mixed solvent of isopropyl alcohol and n-hexane to give the title compound 5.2.
g. Melting point 146-149 ° C Elemental analysis (as C ₂₅ H ₃₅ NO ₄ S) Calculated (%): C 67.38 H 7.92 N 3.14 Found (%): C 67.50 H 8.11 N 3.02 NMR spectrum δ (CDCl ₃ ): 1.30 (6H, d), 1.42 (18H, s), 1.7 to 2.1 (2H, m), 2.52 (2H, br) t), 3.70 (2H, brt), 4.92 (1H, s), 5.14 (1H, sept), 7.11 (2H, s).

Example 71 Isopropyl 2- (3,5-di-tert-butyl-)
4-hydroxyphenyl) -2,3,5,6-tetrahydro-3-oxopyrrolo [2,1-b] thiazole-7
-Carboxylate isopropyl 2,3,5,6-tetrahydro-3-oxopyrrolo [2,1-b] thiazole-7-carboxylate 1.0 g and N-bromosuccinimide 0.78
g is added to 30 ml of carbon tetrachloride and stirred at 50 ° C. for 10 minutes. The reaction solution is washed with water and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent is dissolved in 30 ml of dichloromethane, 1.0 g of 2,6-di-tert-butylphenol is added, and 0.57 ml of stannic chloride is added under ice cooling and stirring. After stirring at the same temperature for 0.5 hour, the mixture is refluxed for 3 hours. The reaction solution is poured into ice water and extracted with dichloromethane. After drying over anhydrous sodium sulfate, the solvent is distilled off, and the residue obtained is purified by silica gel column chromatography to obtain 1.5 g of the title compound. Melting point 158 ° C Elemental analysis (as C ₂₄ H ₃₃ NO ₄ S) Calculated (%): C 66.79 H 7.71 N 3.25 Found (%): C 66.66 H 8.03 N 3 .21 NMR spectrum δ (CDCl ₃ ): 1.28 (6H, d), 1.45 (18H, s), 3.19 (2H, t), 3.95 (2H, t), 5.12 ( 1H, sept), 5.39 (1H, s), 7.20 (2H, s).

Example 72 Ethyl 2-cyclohexyl-5,6-dihydrothiazolo [2,3-c] [1,4] thiazine-8-carboxylate 0.43 g of lithium aluminum hydride was suspended in 50 ml of tetrahydrofuran and iced. Under cooling and stirring, 2.50 g of ethyl 2-cyclohexyl-3-oxo-2,3,5,6-tetrahydrothiazolo [2,3-c] [1,4] thiazine-8-carboxylate are added. After 0.5 hour, water and an aqueous solution of sodium hydroxide are added thereto and stirred. After filtering off the insoluble matter, the mixture is extracted with chloroform, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent has benzene 10
0 ml and 0.2 g of paratoluenesulfonic acid are added, and the mixture is stirred at room temperature for 1 hour. The benzene layer is washed with water and a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Then, the residue obtained by distilling off the solvent was purified by silica gel column chromatography to give the title compound (1.25).
g was obtained. Melting point 100-101 ° C Elemental analysis (as C ₁₅ H ₂₁ NO ₂ S ₂ ) Calculated (%): C 57.85 H 6.80 N 4.50 Found (%): C 57.70 H 95 N 4.61 NMR spectrum δ (CDCl ₃ ): 1.1 to 2.1 (13H, m), 2.3 to 2.7 (1H, m), 2.8 to 3.0 (2H, m ), 4.1-4.3 (2H, m), 4.24 (2H, q), 6.35 (1H, d). The compounds of Examples 73 to 86 were produced in the same manner as in Example 72.

Example 73 Ethyl 2-cyclohexylmethyl-5,6-dihydrothiazolo [2,3-c] [1,4] thiazine-8-carboxylate Melting point: 96-97 ° C. Elemental analysis (C ₁₆ H ₂₃₎ (As NO ₂ S ₂ ) Calculated (%): C 59.04 H 7.12 N 4.30 Found (%): C 59.15 H 7.17 N 4.40 NMR spectrum δ (CDCl ₃ ): 3. 0.9 to 1.9 (14H, m), 2.38 (2H, d), 2.8 to 3.1 (2H, m), 4.0 to 4.2 (2H, m), 24 (2H, q), 6.30 (1H, s).

Example 74 Ethyl 2- (2-cyclohexylethyl) -5,6-
Dihydrothiazolo [2,3-c] [1,4] thiazine-
8-Carboxylate Melting point 106-107 ° C Elemental analysis (as C ₁₇ H ₂₅ NO ₂ S ₂ ) Calculated (%): C 60.14 H 7.42 N 4.13 Found (%): C 59. 86 H 7.44 N 4.37

Example 75 Ethyl 5-hydroxymethyl-5,6-dihydrothiazolo [2,3-c] [1,4] thiazine-8-carboxylate Melting point: 149-150 ° C. Elemental analysis (C ₁₀ H ₁₃₎ (As NO ₃ S ₂ ) Calculated (%): C 46.31 H 5.05 N 5.40 Found (%): C 46.18 H 5.10 N 5.11 NMR spectrum δ (CDCl ₃ ): 1.33 (3H, t), 2.8 to 3.2 (2H, m), 3.93 (2H, d), 4.25 (2H, q), 4.4 to 4.7 (1H, m), 6.40 (1H, brs), 6.78 (1H, d).

Example 76 Ethyl 2-ethyl-5,6-dihydrothiazolo [2
3-c] [1,4] thiazine-8-carboxylate melting point one hundred and twenty-seven to one hundred twenty-eight ° C. Elemental analysis (C ₁₁ H ₁₅ NO ₂ as S ₂₎ Calculated (%): C 51.34 H 5.87 N 5 .44 actual value (%): C 51.44 H 5.93 N 5.52 NMR spectrum δ (CDCl ₃ ): 1.22 (3H, t), 1.32 (3H, t), 2.3 to 2.7 (2H, m), 2.7 to 3.1 (2H, m), 3.9 to 4.2 (2H, m), 4.26 (2H, q), 6.30 (1H, s).

Example 77 Ethyl 2-isopropyl-5,6-dihydrothiazolo [2,3-c] [1,4] thiazine-8-carboxylate Melting point: 77-78 ° C. Elemental analysis (C ₁₂ H ₁₇ NO (Calculated as ₂ S ₂ ) Calculated value (%): C 53.11 H 6.31 N 5.16 Actual value (%): C 53.30 H 6.25 N 5.24 NMR spectrum δ (CDCl ₃ ): 1 0.1 to 1.5 (9H, m), 2.4 to 3.1 (3H, m), 4.0 to 4.3 (2H, m), 4.12 (2H, q), 6.28 (1H, d).

Example 78 Isopropyl 2- (3,5-di-tert-butyl-
4-hydroxyphenyl) -6,7-dihydro-5H-
Thiazolo [3,2-a] pyridine-3,8-dicarboxylate Melting point 216-219 ° C. Elemental analysis (as C ₂₅ H ₃₅ NO ₃ S) Calculated (%): C 69.89 H 8.21 N 3.26 found (%): C 69.80 H 8.44 N 3.27 NMR spectrum δ (CDCl ₃ ): 1.29 (6H, d), 1.45 (18H, s), 1.8. ~ 2.2 (2H, m), 2.54 (2H, brt), 3.83 (2H, brt), 5.13 (1H, sept), 6.70 (1H, brs), 7 .20 (2H, s).

Example 79 Ethyl 2-benzyl-6,7-dihydro-5H-thiazolo [3,2-a] pyridine-8-carboxylate Melting point: 122-124 ° C. Elemental analysis (as C ₁₇ H ₁₉ NO ₂ S) ) Calculated value (%): C 67.75 H 6.35 N 4.65 Observed value (%): C 67.45 H 6.35 N 4.39 NMR spectrum δ (CDCl ₃ ): 1.27 (3H) , T), 1.7 to 2.1 (2H, m), 2.49 (2H, t), 3.69 (2H, brt), 3.75 (2H, s), 4.18 (2H). , Q), 6.18 (1H, s), 7.26 (5H, s).

Example 80 2-Benzyl-5,6,7,8-tetrahydrothiazolo [3,2-a] azepine-9-carbonitrile Melting point 94-97 ° C. Elemental analysis (C ₁₆ H ₁₆ N ₂ S) Calculated value (%): C 71.60 H 6.01 N 10.44 Actual value (%): C 71.65 H 6.06 N 10.14 NMR spectrum δ (CDCl ₃ ): 1.7 to 2.0 (4H, m), 2.3 to 2.5 (2H, m), 3.5 to 3.8 (2H, m), 3.63 (2H, s), 5.88 (1H, s), 7.0-7.3 (5H, br s).

Example 81 Ethyl 2-benzyl-5,6-dihydrothiazolo [2,3-c] [1,4] thiazine-8-carboxylate Melting point 109-110 ° C. Elemental analysis (C ₁₆ H ₁₇ NO (Calculated as ₂ S ₂ ) Calculated value (%): C 60.16 H 5.36 N 4.38 Actual value (%): C 60.39 H 5.52 N 4.39 NMR spectrum δ (CDCl ₃ ): 1 .30 (3H, t), 2.9 to 3.1 (2H, m), 3.7 to 3.9 (2H, m), 4.0 to 4.2 (2H, m), 4.22 (2H, q), 6.24 (1H, s), 7.1 to 7.4 (5H, m).

Example 82 Ethyl 2- (2-chlorobenzyl) -5,6-dihydrothiazolo [2,3-c] [1,4] thiazine-8-carboxylate Melting point: 103-104 ° C. Elemental analysis ( (As C ₁₆ H ₁₆ ClNO ₂ S ₂ ) Calculated (%): C 54.31 H 4.56 N 3.96 Found (%): C 54.30 H 4.62 N 4.04 NMR spectrum δ ( CDCl ₃ ): 1.30 (3H, t), 2.8-3.0 (2H, m), 3.92 (2H, s), 4.0-4.4 (4H, m), 6. 30 (1H, s), 7.1 to 7.5 (4H, m).

Example 83 Ethyl 2- (3-chlorobenzyl) -5,6-dihydrothiazolo [2,3-c] [1,4] thiazine-8-carboxylate Melting point: 120-121 ° C. Elemental analysis ( (As C ₁₆ H ₁₆ ClNO ₂ S ₂ ) Calculated (%): C 54.31 H 4.56 N 3.96 Found (%): C 54.20 H 4.64 N 4.09 NMR spectrum δ ( CDCl ₃ ): 1.32 (3H, t), 2.8-3.1 (2H, m), 3.79 (2H, s), 4.1-4.3 (2H, m), 4. 25 (2H, q), 6.34 (1H, s), 7.1-7.4 (4H, m).

Example 84 Ethyl 2- (4-chlorobenzyl) -5,6-dihydrothiazolo [2,3-c] [1,4] thiazine-8-carboxylate Melting point 125 ° C. Elemental analysis (C ₁₆ H ₁₆ ClNO ₂ S ₂ ) Calculated (%): C 54.31 H 4.56 N 3.96 Found (%): C 54.07 H 4.56 N 4.10 NMR spectrum δ (CDCl ₃₎ ): 1.30 (3H, t), 2.8-3.0 (2H, m), 3.77 (2H, d), 4.1-4.2 (2H, m), 4.33 ( 2H, q), 6.25 (1H, t), 7.1 to 7.4 (4H, m).

Example 85 Ethyl 2-benzylthiazolo [2,3-c] [1,
4] benzothiazine-4-carboxylate melting one hundred twenty-three to one hundred twenty-four ° C. Elemental analysis (C ₂₀ H ₁₇ NO ₂ as S ₂₎ Calculated (%): C 65.36 H 4.66 N 3.81 Found (%) : C 64.98 H 4.65 N 3.79 NMR spectrum δ (CDCl ₃ ): 1.31 (3H, t), 3.88 (2H, brs), 4.23 (2H, q), 6 0.6-7.4 (10H, m).

Example 86 Ethyl 2-phenethyl-5,6-dihydrothiazolo [2,3-c] [1,4] thiazine-8-carboxylate Melting point: 88-89 ° C. NMR spectrum δ (CDCl ₃ ): 1 0.32 (3H, t), 2.7 to 3.1 (6H, m), 3.9 to 4.1 (2H, m), 4.25 (2H, q), 6.20 (1H, s) ), 7.0-7.4 (5H, m).

Example 87 Ethyl 3-hydroxymethyl-5,6-dihydrothiazolo [2,3-c] [1,4] thiazine-8-carboxylate 1.55 g of lithium aluminum hydride was suspended in 30 ml of tetrahydrofuran. , Ice-cooled, diethyl under stirring
A solution of 2.20 g of 5,6-dihydrothiazolo [2,3-c] [1,4] thiazine-3,8-dicarboxylate in 20 ml of tetrahydrofuran is added. Return to room temperature 1
After stirring for an hour, the mixture is cooled again, and 5 ml of water and 5 ml of a 20% aqueous sodium hydroxide solution are added. After filtering off the water-soluble matter, chloroform is added and the mixture is washed with a saturated aqueous solution of sodium chloride. After drying over anhydrous sodium sulfate, the solvent was distilled off, and the resulting crude crystals were recrystallized from methanol to obtain 1.18 g of the title compound. Melting point 169-170 ° C Elemental analysis (as C ₁₀ H ₁₃ NO ₃ S ₂ ) Calculated (%): C 46.31 H 5.05 N 5.40 Found (%): C 46.33 H 5. 14 N 5.54 NMR spectrum δ (CDCl ₃ ): 1.28 (3H, t), 2.8 to 3.1 (2H, brs), 4.17 (2H, q), 4.1 to 4 .4 (2H, m), 4.40 (2H, s), 6.35 (1H, s). The compounds of Examples 88 to 92 were produced in the same manner as in Example 87.

Example 88 Isopropyl 3-hydroxymethyl-6,7-dihydro-5H-thiazolo [3,2-a] pyridine-8-carboxylate Melting point: 164 ° -165 ° C. Elemental analysis (C ₁₂ H ₁₇ NO ₃ S) Calculated value (%): C 56.45 H 6.71 N 5.49 Actual value (%): C 56.40 H 6.73 N 5.51 NMR spectrum δ (CDCl ₃ ): 1.27 ( 6H, d), 1.8 to 2.1 (2H, m), 2.49 (2H, t), 3.88 (2H, t), 4.41 (2H, d), 5.09 (1H) , Sept), 6.00 (1H, s).

Example 89 Ethyl 3-hydroxymethyl-5,6,7,8-tetrahydrothiazolo [3,2-a] azepine-9-carboxylate Melting point: 132-133 ° C. Elemental analysis (C ₁₂ H ₁₇ NO ₃ as S) calculated (%): C 56.48 H 6.66 N 5.49 Found (%): C 56.43 H 6.91 N 5.52 NMR spectrum δ (CDCl _3): 1. 28 (3H, t), 1.8 to 2.2 (4H, m), 2.6 to 2.9 (2H, m), 3.9 to 4.3 (2H, m), 4.13 ( 2H, q), 4.32 (2H, br s), 6.02 (1H, s).

Example 90 Ethyl 3- (2-hydroxyethyl) -5,6-dihydrothiazolo [2,3-c] [1,4] thiazine-8-
Carboxylate Melting point 134-136 ° C Elemental analysis (as C ₁₁ H ₁₅ NO ₃ S ₂ ) Calculated (%): C 48.33 H 5.53 N 5.12 Actual (%): C 48.15 H 5.39 N 5.14 NMR spectrum δ (CDCl ₃ ): 1.34 (3H, t), 2.76 (2H, t), 2.9 to 3.1 (2H, m), 3.92 ( 2H, t), 4.1 to 4.3 (2H, m), 4.29 (2H, q), 6.15 (1H, s).

Example 91 Ethyl 3- (2-hydroxyethyl) -5,6,7,
8-tetrahydrothiazolo [3,2-a] azepine-9
-Carboxylate Melting point 95-97 ° C Elemental analysis (as C ₁₃ H ₁₉ NO ₃ S) Calculated (%): C 57.96 H 7.11 N 5.20 Found (%): C 57.81 H 7.19 N 5.10 NMR spectrum δ (CDCl ₃ ): 1.27 (3H, t), 1.8 to 2.1 (4H, m), 2.64 (2H, t), 2.6 to 2.8 (2H, m), 3.78 (3H, t), 3.7-4.0 (2H, m), 4.13 (2H, q), 5.88 (1H, s).

Example 92 Isopropyl 3- (2-hydroxy-1-methyl) ethyl-6,7-dihydro-5H-thiazolo [3,2-
a] Pyridine-8-carboxylate Melting point 127-130 ° C Elemental analysis (as C ₁₄ H ₂₁ NO ₃ S) Calculated (%): C 59.33 H 7.47 N 4.94 Found (%): C 59.35 H 7.70 N 4.97 NMR spectrum δ (CDCl ₃ ): 1.22 (3H, d), 1.26 (6H, d), 1.8 to 2.1 (2H, m) , 2.50 (2H, t), 2.6-3.0 (2H, m), 3.5-3.9 (4H, m), 5.07 (1H, sept), 5.83 (1H , D).

Example 93: Ethyl 2- (2-hydroxyethyl) -3-methyl-
5,6-dihydrothiazolo [2,3-c] [1,4] thiazine-8-carboxylate ethyl 2- (2-acetoxyethyl) -3-methyl-
2.0 g of 5,6-dihydrothiazolo [2,3-c] [1,4] thiazine-8-carboxylate is suspended in 40 ml of methanol, and 10 ml of a 2N aqueous potassium carbonate solution is added at room temperature with stirring. After 40 minutes, the methanol is distilled off and extracted with chloroform. Next, the mixture is washed with water and a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The crude crystals obtained by distilling off the solvent were recrystallized from methanol to obtain 2.1 g of the title compound. Mp 139-140 ° C. Elemental analysis (C ₁₂ H ₁₇ NO ₃ as the S ₂₎ Calculated (%): C 50.15 H 5.96 N 4.87 Found (%): C 50.18 H 6 . 02 N 4.87 NMR spectrum δ (CDCl ₃ ): 1.32 (3H, t), 2.12 (3H, s), 2.76 (2H, brt), 2.8 to 3.2 (2H , M), 3.78 (2H, br q), 4.0-4.4 (4H, m).

Example 94 Isopropyl 2-benzyl-3-thioxo-2,3
6,7-tetrahydro-5H-thiazolo [3,2-a]
Pyridine-8-carboxylate isopropyl 2-benzyl-3-oxo-2,3,
6,7-tetrahydro-5H-thiazolo [3,2-a]
6.5 g of pyridine-8-carboxylate and Lawe
4.4 g of sson's reagent in benzene 2
Heat to reflux for 5 hours. The residue obtained by distilling off benzene was purified by silica gel column chromatography to obtain 5.0 g of the title compound. Melting point 100-103 ° C NMR spectrum δ (CDCl ₃ ): 1.27 (6H, d), 1.6-2.0 (2H, m), 2.45 (2H, brt), 2.8-4 4.1 (4H, m), 4.1 to 4.6 (1H, m), 5.09 (1H, sept), 7.2 to 7.4 (5H, m). The compounds of Examples 95 and 96 were prepared in the same manner as in Example 94.

Example 95 Isopropyl 2- (2-chlorobenzyl) -3-thioxo-2,3,6,7-tetrahydro-5H-thiazolo [3,2-a] pyridine-8-carboxylate Melting point 110-112 ° C

Example 96 Ethyl 2-cyclohexylmethyl-3-thioxo-
2,3,5,6-tetrahydrothiazolo [2,3-c]
[1,4] thiazine-8-carboxylate Melting point: 162 to 163 ° C NMR spectrum δ (CDCl ₃ ): 0.8 to 2.0 (15H, m), 2.2 to 2.6 (1H, m), 2.9-3.2 (2H, m), 4.2-4.6 (5H, m).

Example 97 Isopropyl 2-benzyl-3-methylthio-6,7
-Dihydro-5H-thiazolo [3,2-a] pyridine-
0.29 g of 8-carboxylate sodium hydride (60% oil) and 3.4 g of methyl iodide were added to 20 ml of tetrahydrofuran,
Isopropyl 2-benzyl-3-thioxo-2,3,6,7-tetrahydro-5H-thiazolo [3,2-a] pyridine-8-carboxylate 2.1 under ice cooling and stirring
Add g. After one hour, the reaction solution is poured into ice water and stirred. The precipitated crystals were collected by filtration, purified by silica gel column chromatography, and then recrystallized from a mixed solvent of isopropyl alcohol and chloroform to give the title compound (1.2 g).
I got Melting point 137-140 ° C Elemental analysis (as C ₁₉ H ₂₃ NO ₂ S ₂ ) Calculated (%): C 63.13 H 6.41 N 3.87 Found (%): C 62.97 H 6. 45N 3.88 NMR spectrum δ (CDCl ₃ ): 1.24 (6H, d), 2.16 (3H, s), 1.8 to 2.1 (2H, m), 2.51 (2H, brt), 3.93 (2H, brt), 4.02 (2H, s), 5.07 (1H, sept), 7.24 (5H, s). Compounds 98 to 101 were produced in the same manner as in Example 97.

Example 98 Isopropyl 2- (2-chlorobenzyl) -3-methylthio-6,7-dihydro-5H-thiazolo [3,2-
a] Pyridine-8-carboxylate Melting point 130-131 ° C Elemental analysis (as C ₁₉ H ₂₂ ClN ₂ S ₂ ) Calculated (%): C 57.63 H 5.60 N 3.54 Actual (%) : C 57.48 H 5.66 N 3.53 NMR spectrum δ (CDCl ₃ ): 1.23 (6H, d), 1.8 to 2.1 (2H, m), 2.24 (3H, s) ), 2.3 to 2.7 (2H, m), 3.8 to 4.1 (2H, m), 4.16 (2H, s), 5.02 (1H, sept), 7.0 to 7.0. 7.4 (4H, m).

Example 99 Ethyl 2-cyclohexylmethyl-3-methylthio-
5,6-dihydrothiazolo [2,3-c] [1,4] thiazine-8-carboxylate melting point 100-101 ° C. Elemental analysis (C ₁₇ H ₂₅ NO ₂ as S ₃₎ Calculated (%): C 54.95 H 6.78 N 3.77 Found (%): C 55.65 H 6.85 N 3.83.

Example 100 Ethyl 3-benzylthio-2-phenyl-6,7-dihydro-5H-thiazolo [3,2-a] pyridine-8-
Carboxylate Melting point 110-112 ° C Elemental analysis (as C ₂₃ H ₂₃ NO ₂ S ₂ ) Calculated (%): C 67.45 H 5.66 N 3.42 Actual (%): C 67.57 H 5.67 N 3.59 NMR spectrum δ (CDCl ₃ ): 1.30 (3H, t), 1.6-1.9 (2H, m), 2.46 (2H, brt), 3.64 (2H, brt), 3.64 (2H, s), 4.22 (2H, q), 6.9-7.6 (10H, m)

Example 101 Ethyl 2-phenyl-3- (2-phenylethylthio) -6,7-dihydro-5H-thiazolo [3,2-
a] Pyridine-8-carboxylate Melting point 90-92 ° C Elemental analysis (as C ₂₄ H ₂₅ NO ₂ S ₂ ) Calculated (%): C 68.05 H 5.95 N 3.31 Actual (%) : C 68.27 H 6.03 N 3.46 NMR spectrum δ (CDCl ₃ ): 1.31 (3H, t), 1.8 to 2.2 (2H, brt), 2.56 (2H, brt), 2.6-3.0 (4H, m), 3.93 (2H, brt), 4.24 (2H, q), 7.0-7.7 (10H, m).

Example 102 Ethyl 3-carbamoyl-6,7-dihydro-5H-
Thiazolo [3,2-a] pyridine-8-carboxylate diethyl 6,7-dihydro-5H-thiazolo [3,2
-A] pyridine-3,8-dicarboxylate 6.6 g
96 ml of concentrated aqueous ammonia was added to the mixture, and the mixture was stirred at room temperature for 5 days. The precipitated crystals are collected by filtration, washed with water, and dried to obtain 4.3 g of the title compound. Melting point: 216 to 220 ° C. Elemental analysis value (as C ₁₁ H ₁₄ N ₂ O ₃ S) Calculated value (%): C 51.95 H 5.55 N 11.02 Actual value (%): C 52.03 H 5 .50 N 11.01 NMR spectrum δ (CDCl ₃ ): 1.19 (3H, t), 1.6 to 2.1 (2H, m), 2.38 (2H, t), 4.01 (2H) , Brt), 4.05 (2H, q), 6.98 (1H, s). The compounds of Examples 103 to 108 were produced in the same manner as in Example 102.

Example 103 9-Cyano-5,6,7,8-tetrahydrothiazolo [3,2-a] azepine-3-carboxamide Melting point: 208-209 ° C. Elemental analysis (as C ₁₀ H ₁₁ N ₃ OS) ) Calculated value (%): C 54.28 H 5.01 N 18.99 Actual value (%): C 54.12 H 4.97 N 18.78 NMR spectrum δ (CDCl ₃ ): 1.8-2 .1 (4H, m), 2.3 to 2.6 (2H, m), 3.8 to 4.0 (2H, m), 6.84 (1H, s).

Example 104 Ethyl 3-carbamoyl-5,6-dihydrothiazolo [2,3-c] [1,4] thiazine-8-carboxylate Melting point: 206-207 ° C. Elemental analysis (C ₁₀ H ₁₂ N) (Calculated as ₂ O ₃ S ₂ ) Calculated (%): C 44.10 H 4.44 N 10.29 Found (%): C 44.09 H 4.37 N 10.06 NMR spectrum δ (CDCl ₃ ) : 1.30 (3H, t), 2.8 to 3.0 (2H, m), 4.19 (2H, q), 4.4 to 4.6 (2H, m), 7.11 (1H , S).

Example 105 Ethyl 3-methylcarbamoyl-6,7-dihydro-
5H-thiazolo [3,2-a] pyridine-8-carboxylate Melting point 210-212 ° C Elemental analysis (as C ₁₂ H ₁₆ N ₂ O ₃ S) Calculated (%): C 53.71 H 6.01 N 10.44 Observed value (%): C 53.75 H 5.87 N 10.36 NMR spectrum δ (CDCl ₃ ): 1.29 (3H, t), 2.09 (2H, m), 2. 49 (2H, br t), 2.93 (3H, d), 4.05 (2H, br t), 4.20 (2H, q), 6.45 (1H, s).

Example 106 Ethyl 3-methylcarbamoyl-5,6-dihydrothiazolo [2,3-c] [1,4] thiazine-8-carboxylate Melting point: 197 ° -198 ° C. Elemental analysis (C ₁₁ H ₁₄₎ (Calculated as N ₂ O ₃ S ₂ ) Calculated (%): C 46.14 H 4.93 N 9.78 Found (%): C 46.37 H 4.88 N 9.84 NMR spectrum δ (CDCl ₃₎ ): 1.34 (3H, t), 2.8 to 3.1 (5H, m), 4.16 (2H, q), 4.4 to 4.6 (2H, m), 6.68 ( 1H, s).

Example 107 N-methyl- (8-ethoxycarbonyl-5,6-dihydrothiazolo [2,3-c] [1,4] thiazine-3-
Yl) acetamide mp 198-200 ° C. Elemental analysis _{(C 12 H 16 N 2 O} 3 as S) Calculated (%): C 47.98 H 5.37 N 9.33 Found (%): C 47. 66 H 5.52 N 9.27 NMR spectrum δ (CDCl ₃ ): 1.34 (3H, t), 2.85 (3H, d), 2.9-3.1 (2H, m), 47 (2H, s), 4.1-4.3 (2H, m), 4.30 (2H, q), 6.23 (1H, s).

Example 108 N-methyl- (8-isopropoxycarbonyl-6,7
-Dihydro-5H-thiazolo [3,2-a] pyridine-
3-yl) acetamide mp 153 to 155 ° C. Elemental analysis _{(C 14 H 20 N 2 O} 3 as S) Calculated (%): C 56.73 H 6.80 N 9.45 Found (%): C 56.69 H 6.89 N 9.42 NMR spectrum δ (CDCl ₃ ): 1.26 (6H, d), 1.7 to 2.1 (2H, m), 2.49 (2H, brt). , 2.80 (3H, d), 3.67 (2H, brt), 5.08 (1H, sept), 5.99 (1H, s).

Example 109 Ethyl (8-ethoxycarbonyl-2,3,6,7-
Tetrahydro-5H-thiazolo [3,2-a] pyridine-3-ylidene) acetate ethyl 5.0 g of sodium 2-thioxopiperidine-3-carboxylate and 2.9 g of sodium acetate are added to 50 ml of ethanol, and the mixture is stirred at room temperature for 4 hours. 7.3 g of bromoacetoacetic acid ethyl ester are added. After 3 hours, the solvent is distilled off and the residue is extracted with chloroform and washed with a saturated aqueous sodium chloride solution. After drying over anhydrous sodium sulfate, the solvent is distilled off. The obtained crude crystals are purified by silica gel column chromatography to obtain 4.2 g of the title compound. 136-137 ° C Elemental analysis (as C ₁₄ H ₁₉ NO ₄ S) Calculated (%): C 56.55 H 6.44 N 4.71 Found (%): C 56.37 H 6.62 N 4.72 NMR spectrum δ (CDCl ₃ ): 1.27 (3H, t), 1.30 (3H, t), 1.96 (2H, m), 2.48 (2H, t), 3. 45 (2H, t), 4.15 (2H, q), 4.23 (2H, q), 4.40 (2H, d), 5.09 (1H, t). The compound of Example 110 was produced in the same manner as in Example 109.

Example 110 Ethyl (8-ethoxycarbonyl-2,3,5,6-
Tetrahydronaphthalene thiazolo [2,3-c] [1,4] thiazin-3-ylidene) acetate mp 160-161 ° C. Elemental analysis (C ₁₃ H ₁₇ NO ₄ as S ₂₎ Calculated (%): C 49. 51 H 5.43 N 4.41 Found (%): C 49.43 H 5.41 N 4.33 NMR spectrum _{δ (CDCl 3): 1.28 (} 3H, t), 1.33 (3H, t), 2.9-3.2 (2H, m), 3.7-4.0 (2H, m), 4.16 (2H, q), 4.26 (2H, q), 4.43 (2H, d), 5.16 (1H, t).

Example 111 Methyl (8-isopropoxycarbonyl-2,2-dimethyl-2,3,6,7-tetrahydro-5H-thiazolo [3,2-a] pyridin-3-ylidene) acetate isopropyl 2- 2.6 g of thioxopiperidine-3-carboxylate, methyl 4-bromo-4-methyl-3
4.6 g of oxopentanoate and 2.6 g of sodium acetate are added to 40 ml of toluene and heated under reflux for 12 hours. After cooling, add benzene and wash with water and saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the solvent is distilled off. The residue was purified by silica gel column chromatography, and then recrystallized from a mixed solvent of chloroform and n-hexane to obtain 2.0 g of the title compound. Melting point 115-116 ° C Elemental analysis (as C ₁₆ H ₂₃ NO ₄ ) Calculated (%): C 59.05 H 7.12 N 4.30 Found (%): C 59.31 H 6.83 N 4.05 NMR spectrum δ (CDCl ₃ ): 1.27 (6H, d), 1.9 to 2.1 (2H, m), 1.91 (6H, s), 2.3 to 2.6 ( 2H, m), 3.3 to 3.5 (2H, m), 3.66 (3H, s), 5.00 (1H, s), 5.08 (1H, sept). The compounds of Examples 112 to 114 were produced in the same manner as in Example 111.

Example 112 Ethyl (8-isopropoxycarbonyl-2,2-dimethyl-2,3,5,6-tetrahydrothiazolo [2,
3-c] [1,4] thiazine-3-ylidene) acetate Melting point 118-119 ° C Elemental analysis (as C ₁₆ H ₂₃ NO ₄ S ₂ ) Calculated (%): C 53.76 H 6.48 N 3.92 Found (%): C 53.57 H 6.61 N 3.72 NMR spectrum δ (CDCl ₃ ): 1.28 (3H, t), 1.30 (6H, d), 1.89 (6H, s), 2.9 to 3.2 (2H, m), 3.7 to 4.0 (2H, m), 4.13 (2H, q), 5.05 (1H, s), 5.09 (1H, m).

Example 113 2,2,2-Trichloroethyl (8-isopropoxycarbonyl-2,2-dimethyl-2,3,6,7-tetrahydro-5H-thiazolo [3,2-a] pyridine-3
-Ilidene) acetate Melting point 136-138 ° C Elemental analysis (as C ₁₇ H ₂₂ Cl ₃ NO ₄ S) Calculated (%): C 46.11 H 5.01 N 3.16 Observed (%): C 46 .21 H 4.99 N 2.93 NMR spectrum δ (CDCl ₃ ): 1.27 (6H, d), 1.91 (6H, s), 1.7-2.2 (2H, m), 2 .47 (2H, brt), 3.50 (2H, brt), 4.75 (2H, s), 5.09 (1H, s), 5.09 (1H, sept).

Example 114 2,2,2-Trichloroethyl (8-ethoxycarbonyl-2,2-dimethyl-2,3,5,6-tetrahydrothiazolo [2,3-c] [1,4] thiazine -3-ylidene) acetate Melting point 167-168 ° C NMR spectrum δ (CDCl ₃ ): 1.32 (3H, t), 1.90 (6H, s), 3.0-3.2 (2H, m), 3.8-4.1 (2H, m), 4.26 (2H, q), 4.76 (2H, s), 5.15 (1H, s).

Example 115 (8-ethoxycarbonyl-2,2-dimethyl-2,
3,5,6-tetrahydrothiazolo [2,3-c]
[1,4] thiazine-3-ylidene) acetic acid 2,2,2-trichloroethyl (8-ethoxycarbonyl-2,2-dimethyl-2,3,5,6-tetrahydrothiazolo [2,3-c] 1.65 g of [1,4] thiazine-3-ylidene) acetate was added to a mixed solvent of 10 ml of tetrahydrofuran and 3 ml of acetic acid.
While stirring, 2.0 g of zinc powder is added and the mixture is stirred for 0.5 hour. After returning to room temperature and stirring for another 0.5 hour, insoluble materials are removed by filtration. The filtrate is extracted with dichloromethane, washed with dilute hydrochloric acid and water, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the precipitated crystals were collected by filtration with ether to obtain 0.90 g of the title compound. Mp 177-178 ° C. Elemental analysis (C ₁₃ H ₁₇ NO ₄ as S ₂₎ Calculated (%): C 49.51 H 5.43 N 4.44 Found (%): C 49.60 H 5 . 48 N 4.85 NMR spectrum δ (CDCl ₃ ): 1.32 (3H, t), 1.60 (6H, s), 2.9 to 3.1 (2H, m), 3.7 to 3. 9 (2H, m), 4.20 (1H, s), 4.28 (2H, q). The compound of Example 116 was produced in the same manner as in Example 115.

Example 116 (8-isopropoxycarbonyl-2,2-dimethyl-
2,3,6,7-tetrahydro-5H-thiazolo [3,
2-a] pyridine-3-ylidene) acetic acid melting point 161 to 165 ° C NMR spectrum δ (DMSO-d ₆ ) 1.19 (6H, d), 1.82 (6H, s), 1.6 to 2.1 (2H, m), 2.33 (2H, brt), 3.44 (2H, brt), 4.97 (1H, sept), 5.03 (1H, s).

Example 117 N-methyl- (8-ethoxycarbonyl-2,2-dimethyl-2,3,5,6-tetrahydrothiazolo [2,3
-C] [1,4] thiazine-3-ylidene) acetamide (8-ethoxycarbonyl-2,2-dimethyl-2,
3,5,6-tetrahydrothiazolo [2,3-c]
0.90 g of [1,4] thiazine-3-ylidene) acetic acid and 0.52 g of 1-hydroxybenzotriazole are dissolved in 10 ml of tetrahydrofuran, and 3 ml of a tetrahydrofuran solution of 0.80 g of N, N-dicyclohexylcarbodiimide is stirred at room temperature. Add. 24 hours later,
20 ml of a 40% aqueous methylamine solution was added, and the mixture was treated at the same temperature with 0.1 ml.
Stir for 5 hours. Water is added to the residue obtained by evaporating the solvent, and the mixture is extracted with chloroform. The chloroform layer is washed with water and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography, and then recrystallized from benzene to obtain 0.68 g of the title compound. Elemental analysis (as C ₁₄ H ₂₀ N ₂ O ₃ S ₂ ) Calculated (%): C 51.20 H 6.14 N 8.53 Actual (%): C 51.44 H 6.38 N 8 .59 NMR spectrum δ (CDCl ₃ ): 1.3 (3H, t), 1.88 (6H, s), 2.89 (3H, brd), 2.9 to 3.1 (2H, m) , 3.7-3.9 (2H, m), 4.28 (2H, q), 4.99 (1H, s). The compound of Example 118 was produced in the same manner as in Example 117.

Example 118 N-methyl (8-isopropoxycarbonyl-2,2-
Dimethyl-2,3,5,6-tetrahydro-5H-thiazolo [3,2-a] pyridine-3-ylidene) acetamide Melting point 175-182 ° C Elemental analysis (as C ₁₆ H ₂₄ N ₂ O ₃ S) Calculation Value (%): C 59.23 H 7.46 N 8.63 Actual value (%): C 59.28 H 7.33 N 8.45 NMR spectrum δ (DNSO-d ₆ ) 1.18 (6H, d), 1.81 (6H, s), 1.8 to 2.1 (2H, m), 2.33 (2H, brt), 2.60 (3H, d), 3.36 (2H, s). brt), 4.88 (1H, sept), 5.18 (1H, s).

Example 119 Isopropyl 3- (4-methoxyphenyloxymethyl) -6,7-dihydro-5H-thiazolo [3,2-
a] Pyridine-8-carboxylate isopropyl 3-hydroxymethyl-6,7-dihydro-5H-thiazolo [3,2-a] pyridine-8-carboxylate 5.0 g, triphenylphosphine 5.8
g and 2.5 g of 4-methoxyphenol are dissolved in 70 ml of tetrahydrofuran, and 3.8 g of diethyl azodicarboxylate is added with stirring at room temperature. After 1.5 hours, the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography, and then recrystallized from a mixed solvent of ethyl acetate and n-hexane to obtain 1.58 g of the title compound. Melting point 119-120 ° C Elemental analysis (as C ₁₉ H ₂₃ NO ₄ S) Calculated (%): C 63.13 H 6.41 N 3.88 Found (%): C 63.24 H 6.44 N 3.87 NMR spectrum δ (CDCl ₃ ): 1.26 (6H, d), 1.8 to 2.1 (2H, m), 2.51 (2H, t), 3.76 (3H, s) ), 4.71 (2H, s), 5.11 (1H, sept), 6.13 (1H, s), 6.84 (4H, s).

Example 120 Ethyl 3-cyano-5,6-dihydrothiazolo [2,
3-c] [1,4] thiazine-8-carboxylate ethyl 1.9 g of 3-carbamoyl-5,6-dihydrothiazolo [2,3-c] [1,4] thiazine-8-carboxylate in dioxane 20 ml and pyridine 5 m
Then, 3 ml of acetic anhydride is added under ice-cooling and stirring. After returning to room temperature and further stirring for 1.5 hours, the reaction solution is poured into water, and the precipitated crystals are collected by filtration. The crude crystals were recrystallized from benzene to give the title compound (0.92 g). Mp 190 to 192 ° C. Elemental analysis _{(C 10 H 16 N 2 O} 2 as S ₂₎ Calculated (%): C 47.23 H 3.96 N 11.01 Found (%): C 47.21 H 3.95 N 11.15 NMR spectrum δ (CDCl ₃ ): 1.32 (3H, t), 2.9 to 3.1 (2H, m), 4.1 to 4.5 (4H, m), 7.12 (1H, s).

Test Example The effect on a liver injury (hepatitis) model induced by D-galactosamine was examined. Experimental animal: SD male rat (weight: 170-200 g)
Was used. Drug administration: All test drugs were suspended in a 1% aqueous methylcellulose solution and orally administered at a dose of 300 mg / kg one hour before the induction of liver injury. Induction of galactosamine liver injury and evaluation of drug effect: D-
Rats were subcutaneously administered with 800 mg / kg of gaclatosamine hydrochloride to induce liver damage. After administration of D-galactosamine, fasting is performed, and 24 hours later, blood is collected from the descending vena cava under ether paralysis, which is an index of the degree of liver damage. The GPT value was measured, and the inhibition rate of liver injury was calculated. Results: The results are shown in Table 11.

[0161]

[Table 11] **: P <0.05 (pathological control group) As is clear from Table 11, the GPT value of the test compound administration group was significantly lower than that of the pathological control group. Therefore D-
The compound of the present invention was shown to have an improving or preventing effect on liver damage induced by the administration of galactosamine hydrochloride.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61K 31/437 A61K 31/437 31/542 31/542 31/55 31/55 // A61P 1/16 A61P 1/16 (C07D 513/04 C07D 513/04 277: 00 277: 00 279: 00) 279: 00 (C07D 513/04 C07D 241: 00 241: 00 265: 00 277: 00) (C07D 513/04 265: 00 277: 00 (72) Inventor Masashi Hasegawa 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo Daiichi Pharmaceutical Central Research Laboratory (72) Inventor Shuichi Yokohama 1-1-16-13 Kita-Kasai, Edogawa-ku, Tokyo Daiichi Pharmaceutical Central Research In-house (56) References JP-A-4-208290 (JP, A) Khim. Gesterotsik l. Soedin, 1967, No. 6, pp. 1043-7 Can. J. Chem. , 1968, Vol. 46, No. 23, pp. 3659-63 Ukr. Khim. Zh. , 1966, Vol. 32, No. 9, pp. 991-5 (58) Fields surveyed (Int. Cl. ⁷ , DB name) C07D 513/04 345 A61K 31/437 A61K 31/542 A61K 31/55 A61P 1/16 BIOSIS (STN) CAPPLUS (STN) MEDLINE ( STN) REGISTRY (STN) EMBASE (STN)

Claims (3)

(57) [Claims] 1. The following general formula (1): (In the formula, Represents a double bond or a single bond; R ¹ represents a cyano group or a lower alkoxycarbonyl group; R ² and R ³ are the same or different and are a hydrogen atom; a lower alkyl group; a cyclic group having 3 to 7 carbon atoms Alkyl group; cyclic alkyl lower alkyl group; lower alkyl group, lower alkoxy group, halogen atom, hydroxyl group, amino group, halogenoalkyl group, carboxyl group, and aryl group optionally having one or more substituents selected from carbamoyl groups A 5- or 6-membered heterocyclic residue which may have at least one substituent selected from a halogen atom, a lower alkyl group, a trihalogeno lower alkyl group, a hydroxyl group, a carboxyl group, an amino group and a carbamoyl group; an aryl moiety A lower alkyl group, a lower alkoxy group, a halogen atom, a hydroxyl group, an amino group, a halogenoalkyl group, a carboxyl group and An aralkyl group which may have one or more substituents selected from a moyl group; a lower alkoxycarbonyl group; a carbamoyl group; a mono- or di-lower alkylaminocarbonyl group; a cyclic alkylaminocarbonyl group; a hydroxy-lower alkyl group; An alkyl group; an acyl group having 1 to 5 carbon atoms or a halogen atom, wherein R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different and are a hydrogen atom; a lower alkyl group; A cyclic alkyl group; an alkenyl group; one substituent selected from a lower alkyl group, a lower alkoxy group, a halogen atom, a hydroxyl group, an amino group, a halogenoalkyl group, a carboxyl group and a carbamoyl group.
An aryl group which may have one or more substituents; 5 to 6 members which may have one or more substituents selected from a halogen atom, a lower alkyl group, a trihalogeno lower alkyl group, a hydroxyl group, a carboxyl group, an amino group and a carbamoyl group. Membered heterocyclic residue; the aryl moiety may have at least one substituent selected from a lower alkyl group, a lower alkoxy group, a halogen atom, a hydroxyl group, an amino group, a halogenoalkyl group, a carboxyl group and a carbamoyl group. Aralkyl group; lower alkoxycarbonyl group; hydroxy lower alkyl group; carbamoyl group; mono or di lower alkylaminocarbonyl group; acyl group having 1 to 5 carbon atoms; lower alkyl group, lower alkoxy group, halogen atom, hydroxyl group, amino group , A halogenoalkyl group, a carboxyl group and a carbamoyl group. Aryl-carbonyl group which may have a group 1 or more; or a hydroxyl group, or a halogen atom,
Or a substituent selected from a lower alkyl group, a halogen atom, an amino group, a trihalogeno lower alkyl group, a carboxyl group and a carbamoyl group, together with a carbon atom to which one of R ⁴ and R ⁵ and one of R ⁶ and R ⁷ are bonded. And may form an aliphatic ring, an aromatic ring or a hetero ring which may be used. Is a hydrogen atom; a lower alkyl group having 1 to 10 carbon atoms; one substituent selected from a lower alkyl group, an amino group, a lower alkoxy group, a halogen atom, a hydroxyl group, a carboxyl group, a carbamoyl group and a halogeno lower alkyl group A cyclic alkyl group having 3 to 7 carbon atoms which may have the above; a cyclic alkyl lower alkyl group; selected from a lower alkyl group, a lower alkoxy group, a halogen atom, a hydroxyl group, an amino group, a halogenoalkyl group, a carboxyl group and a carbamoyl group. Aryl group which may have at least one substituent selected from the group consisting of halogen atom, lower alkyl group, trihalogeno lower alkyl group, hydroxyl group, carboxyl group, amino group and carbamoyl group. Good 5- or 6-membered heterocyclic residue; lower alkyl group, lower alkoxy group, halogen Atom, a hydroxyl group, an amino group, a halogenoalkyl group, an aralkyl group which may have one or more substituents selected from a carboxyl group and carbamoyl group;
Hydroxy lower alkyl group; mono, di or trihalogeno lower alkyl group; mono, di or trihalogeno lower alkoxy group; lower alkoxycarbonyl group; carboxyl group; cyano group; carbamoyl group; mono or di lower alkylaminocarbonyl group; 1 to 5 acyl groups; a substituent selected from a lower alkyl group, a lower alkoxy group, a halogen atom, a hydroxyl group, an amino group, a halogenoalkyl group, a carboxyl group and a carbamoyl group;
A lower alkylthio group; a lower alkenylthio group; a substituent selected from a lower alkyl group, a lower alkoxy group, a halogen atom, a hydroxyl group, an amino group, a halogenoalkyl group, a carboxyl group and a carbamoyl group An arylthio group optionally having one or more substituents; the aryl moiety has at least one substituent selected from a lower alkyl group, a lower alkoxy group, a halogen atom, a hydroxyl group, an amino group, a halogenoalkyl group, a carboxyl group and a carbamoyl group. Aralkyloxy or aralkylthio groups which may be substituted; mono, di or trihalogeno lower alkylthio groups; hydroxy lower alkylthio groups; lower alkoxycarbonyl lower alkylthio groups; amino lower alkylthio groups; mono or disubstituted amino lower alkylthio groups; An aryloxy lower alkyl group optionally having at least one substituent selected from a lower alkyl group, a lower alkoxy group, a halogen atom, a hydroxyl group, an amino group, a halogenoalkyl group, a carboxyl group and a carbamoyl group; ; = S; Wherein R ⁸ and R ⁹ are the same or different and are a hydrogen atom; a lower alkyl group having 1 to 10 carbon atoms;
7 cyclic alkyl groups; alkenyl groups; alkynyl groups;
An aryl group optionally having one or more substituents selected from a lower alkyl group, a lower alkoxy group, a halogen atom, a hydroxyl group, an amino group, a halogenoalkyl group, a carboxyl group and a carbamoyl group;
Lower alkoxy group, halogen atom, hydroxyl group, amino group,
An aralkyl group optionally having one or more substituents selected from a halogenoalkyl group, a carboxyl group, and a carbamoyl group; a lower alkyl group, an amino group, a lower alkoxy group, a halogen atom, a hydroxyl group, a carboxyl group, a carbamoyl group, and a halogeno group A cyclic alkyl group optionally having one or more substituents selected from lower alkyl groups; a lower alkyl group, an amino group, a lower alkoxy group, a halogen atom, a hydroxyl group, a carboxyl group, a carbamoyl group and a halogeno lower group in the cyclic alkyl moiety A cyclic alkyl lower alkyl group which may have one or more substituents selected from alkyl groups; a hydroxyl group; a lower alkoxy group; an amino group; a mono- or di-lower alkylamino lower alkyl group; a hydroxy lower alkyl group; Or trihalogeno lower alkyl group; lower alkoxy Or shows a carbonyl-lower alkyl group, or R ⁸ and R ⁹ together with the adjacent nitrogen atom, may contain another hetero atom and further a halogen atom, a lower alkyl group, a trihalogeno lower alkyl group, a hydroxyl group May form a heterocyclic residue which may have a substituent selected from a carboxyl group, an amino group and a carbamoyl group. R ¹⁰ is a hydrogen atom; a lower alkyl group having 1 to 10 carbon atoms;
A lower alkoxycarbonyl group; an aralkyl group which may have at least one substituent selected from a lower alkyl group, a lower alkoxy group, a halogen atom, a hydroxyl group, an amino group, a halogenoalkyl group, a carboxyl group and a carbamoyl group in the aryl moiety An aryl group; a heterocyclic residue or a cyano group; R ¹¹ is a hydroxyl group; a lower alkoxy group; selected from a lower alkyl group, a lower alkoxy group, a halogen atom, a hydroxyl group, an amino group, a halogenoalkyl group, a carboxyl group, and a carbamoyl group. An aryloxy or arylthio group optionally having one or more substituents; a heterocyclic residue; a lower alkyl group, a lower alkoxy group, a halogen atom, a hydroxyl group, an amino group, a halogenoalkyl group, a carboxyl group, Having at least one substituent selected from carbamoyl groups An aralkyl group which may be a lower alkyl group, a lower alkoxy group, a halogen atom, a hydroxyl group,
An aralkyloxy group optionally having one or more substituents selected from an amino group, a halogenoalkyl group, a carboxyl group and a carbamoyl group; a lower alkyl group, a lower alkoxy group, a halogen atom, a hydroxyl group, an amino group, a halogeno An aralkylthio group or a trihalogeno lower alkoxy group which may have one or more substituents selected from an alkyl group, a carboxyl group and a carbamoyl group, wherein R ¹² and R ¹³ are the same or different, and A lower alkyl group of 1 to 10;
Is shown). However, between 2nd and 3rd place Represents a double bond, only R ² is substituted on the 2-position carbon atom and Represents a single bond. Z is a methylene group, an ethylene group, an oxygen atom, a sulfur atom, SO, SO ² , NR ¹⁴ (R ¹⁴ is a hydrogen atom or a halogen atom or a carbon atom having 1 to 10 carbon atoms which may have a hydroxyl group.
Lower alkyl groups). ] The condensed thiazole derivative represented by these, or its salt. 2. Z is a methylene group, an ethylene group or a sulfur atom, and R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different and are each a hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group or a lower alkyl group. 2. The fused thiazole derivative or a salt thereof according to claim 1, which is an alkoxycarbonyl group or forms an aromatic ring together with a carbon atom to which one of R ⁴ and R ⁵ and one of R ⁶ and R ⁷ are bonded. (3) Is a hydrogen atom; a lower alkyl group having 1 to 10 carbon atoms; an aryl group optionally having one or more substituents selected from a lower alkyl group and a hydroxyl group; a hydroxy lower alkyl group;
A lower alkoxycarbonyl group; a cyano group; a carbamoyl group; a mono- or di-lower alkylaminocarbonyl group;
An acyl group having 1 to 5 carbon atoms; a lower alkylthio group; and a substituent selected from a lower alkyl group, a lower alkoxy group, a halogen atom, a hydroxyl group, an amino group, a halogenoalkyl group, a carboxyl group and a carbamoyl group in the aryl portion.
An aralkyloxy or aralkylthio group optionally having at least one (Where R ⁸ and R ⁹ are the same or different and represent a hydrogen atom, a lower alkyl group or an aryl group having 1 to 10 carbon atoms, R ¹¹ represents a lower alkoxy group, and R ¹² and R ¹³ represent A hydrogen atom or a lower alkyl group having 1 to 10 carbon atoms, which may be the same or different, and n represents 0) (where the bond between the 3-position and A represents a single bond); R ² may have one or more substituents selected from a hydrogen atom; a lower alkyl group; a cyclic alkyl group having 3 to 7 carbon atoms; a cyclic alkyl lower alkyl group; a lower alkyl group, a halogen atom and a hydroxyl group. An aryl group; an aralkyl group optionally having one or more halogen atoms in the aryl moiety; a lower alkoxycarbonyl group; a mono- or di-lower alkylaminocarbonyl group; a cyclic alkylaminocarbonyl group; Or acyloxy lower alkyl group or a number 1-5 acyl group carbons, or ## STR4 ## (Where R ⁸ and R ⁹ are the same or different and represent a hydrogen atom or a lower alkyl group having 1 to 10 carbon atoms, R ¹⁰ represents a hydrogen atom or a cyano group, R ¹¹ represents a hydroxyl group, a lower alkoxy group, R ² and R ³ are the same or different and each represents a hydrogen atom; a lower alkyl group; a cyclic alkyl group having 3 to 7 carbon atoms; a cyclic alkyl lower alkyl group; An aryl group optionally having one or more substituents selected from a group and a hydroxyl group; an aralkyl group optionally having one or more halogen atoms in the aryl moiety; a lower alkoxycarbonyl group or a halogen atom. Or the condensed thiazole derivative according to 2 or a salt thereof.