JP3410479B2 - Polycyclic fused thiazole derivative - Google Patents

Description

Detailed Description of the Invention

[0001]

The present invention relates to a polycyclic fused thiazole derivative or a salt thereof and an excellent hepatocyte-denaturing agent containing the same.
Liver disease prevention with necrosis inhibitory action and liver disorder amelioration action
Regarding therapeutic agents.

[0002]

2. Description of the Related Art Conventionally, the problems to be solved by the invention
For the treatment of liver diseases, resting, high protein, high calorie diet, general therapy such as abstinence, other vitamins, general drug treatment such as strong liver drugs, corticosteroids such as prednisolone, glycyrrhizin preparation, immunity such as interferon, etc. Activators have been used extensively.

However, the reality is that there is still no satisfactory therapeutic agent, especially for prolonged or chronic liver damage. In addition, clinically widely used glycyrrhizin preparations and interferons are injections and are not suitable for long-term administration, and further, these drugs and steroids have a problem of serious side effects. Therefore, a prophylactic / therapeutic agent for liver disease, which can be orally administered, can be administered for a long time, and has few side effects, has been desired.

[0004]

[Means for Solving the Problems] In view of the above situation, the present inventors have conducted diligent research to obtain a novel substance that can be used as a prophylactic / therapeutic agent for liver diseases, and as a result, a condensed thiazole derivative represented by the following general formula (1) However, they have found that it can be an excellent prophylactic / therapeutic agent for liver disease that overcomes the above-mentioned problems, and completed the present invention.

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

[0006]

[Chemical 4] [In the formula, Represents a double bond or a single bond, R ¹ represents a hydrogen atom; a halogen atom; a hydroxyl group; a cyano group; a halogen atom, a hydroxyl group,
An alkyl group which may have one or more substituents selected from an amino group, an alkoxy group, a cycloalkyl group, an aryl group, an aryloxy group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group and a mono- or dialkylamino group. A halogen atom, a hydroxyl group, an amino group,
A cycloalkyl group which may have one or more substituents selected from an alkoxy group, a cycloalkyl group, an aryl group, an aryloxy group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group and a mono- or dialkylamino group; halogen One selected from atom, alkyl group, alkoxy group, hydrogen group, halogenoalkyl group, hydroxyalkyl group, alkoxyalkyl group, amino group, mono- or dialkylamino group, amino group, cyano group, carboxyl group and alkyloxycarbonyl group An aryl group or heteroaryl group which may have the above substituents; a halogen atom, an alkyl group, an alkoxy group, a hydrogen group, a halogenoalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, or amino in the aryl part or the heteroaryl part. Basis Aralkyl or heteroaralkyl groups which may have one or more substituents selected from mono- or dialkylamino groups, cyano groups, carboxyl groups and alkyloxycarbonyl groups; carboxyl groups; sulfamoyl groups; alkoxycarbonyl groups; cyclo Alkyloxycarbonyl group; Alkenyloxycarbonyl group; Alxyloxycarbonyl group; Halogen atom, alkyl group, alkoxy group, hydrogen group, halogenoalkyl group, hydroxyalkyl group, alkoxyalkyl group, amino group, mono- or dialkylamino group, cyano Group, carboxyl group and alkyloxycarbonyl group, which may have one or more substituents, aryloxycarbonyl group or heteroaryloxycarbonyl group; formyloxy group; formyl Alkylcarbonyl group; cycloalkylcarbonyl group; halogen atom, alkyl group, alkoxy group, hydrogen group, halogenoalkyl group, hydroxyalkyl group, alkoxyalkyl group, amino group, mono- or dialkylamino group, cyano group, carboxyl group and alkyl An arylcarbonyl group or a heteroarylcarbonyl group which may have one or more substituents selected from oxycarbonyl groups; a halogen atom, an alkyl group, an alkoxy group, a hydrogen group or a halogenoalkyl group in the aryl part or the heteroaryl part. An aralkylcarbo group which may have one or more substituents selected from the group consisting of a hydroxyalkyl group, an alkoxyalkyl group, an amino group, a mono- or dialkylamino group, a cyano group, a carboxyl group and an alkyloxycarbonyl group. A nyl group or a heteroaralkylcarbonyl group;

[Chemical 5] (R ⁷ and R ⁸ are the same or different and each is a hydrogen atom;
10 alkyl groups; cyclic alkyl groups having 3 to 7 carbon atoms;
Alkenyl group; alkynyl group; halogen atom, alkyl group, alkoxy group, hydrogen group, halogenoalkyl group, hydroxyalkyl group, alkoxyalkyl group, amino group,
An aryl group or a heteroaryl group which may have one or more substituents selected from a mono- or dialkylamino group, a cyano group, a carboxyl group and an alkyloxycarbonyl group; , An alkoxy group, a hydrogen group, a halogenoalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an amino group, a mono- or dialkylamino group, a cyano group, a carboxyl group and an alkyloxycarbonyl group. Optionally substituted aralkyl group or heteroaralkyl group; cyclic alkyl-alkyl group; hydroxyl group; alkoxy group; amino group; mono- or dialkylamino group; alkylaminoalkyl group; hydroxyalkyl group; mono-, di- or trihalogenoalkyl group; Alkoxycarbonyl group; an alkoxycarbonylalkyl group; 2-oxo tetrahydrothienyl group; or R ⁷ and R ⁸ may form a five to seven-membered heterocyclic ring together with the nitrogen atom to which they are attached)
R ² is a cyano group, a carboxyl group, an alkoxycarbonyl group or

[Chemical 6] (R ⁷ and R ⁸ are the same or different and each is a hydrogen atom or a carbon number of 1 to
10 alkyl groups, or R ⁷ and R ⁸ may form a 5-membered to 7-membered heterocyclic ring together with the nitrogen atom to which they are attached, R ³ , R ⁴ , R ⁵ and R ⁶ Are the same or different and are a hydrogen atom; a halogen atom; a hydroxyl group; a cyano group;
Halogen atom, hydroxyl group, amino group, alkoxy group, cycloalkyl group, aryl group, aryloxy group, carboxyl group, alkoxycarbonyl group, carbamoyl group,
An alkyl group which may have one or more substituents selected from mono- or dialkylamino groups; a halogen atom, a hydroxyl group, an amino group, an alkoxy group, a cycloalkyl group, an aryl group, an aryloxy group, a carboxyl group,
A cycloalkyl group which may have one or more substituents selected from an alkoxycarbonyl group, a carbamoyl group, a mono- or dialkylamino group; an alkenyl group; an alkynyl group; a halogen atom, an alkyl group, an alkoxy group, a hydrogen group, An aryl group which may have one or more substituents selected from a halogenoalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an amino group, a mono- or dialkylamino group, a cyano group, a carboxyl group and an alkyloxycarbonyl group, or A heteroaryl group;
A halogen atom in the aryl or heteroaryl moiety,
Alkyl group, alkoxy group, hydrogen group, halogenoalkyl group, hydroxyalkyl group, alkoxyalkyl group, amino group, mono- or dialkylamino group, amino group,
Aralkyl group or heteroaralkyl group which may have one or more substituents selected from cyano group, carboxyl group and alkyloxycarbonyl group; carboxyl group; carbamoyl group; monoalkylaminocarbonyl group; alkoxycarbonyl group; cyclo Alkyloxycarbonyl group; alkenyloxycarbonyl group; halogen atom, alkyl group, alkoxy group, hydrogen group, halogenoalkyl group, hydroxyalkyl group, alkoxyalkyl group, amino group, mono- or dialkylamino group, cyano group, carboxyl group and alkyl An aryloxycarbonyl group or a heteroaryloxycarbonyl group which may have one or more substituents selected from oxycarbonyl groups; a formyloxy group; a formyl group; an alkylcarbonyl group; Killcarbonyl group: selected from a halogen atom, an alkyl group, an alkoxy group, a hydrogen group, a halogenoalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an amino group, a mono- or dialkylamino group, a cyano group, a carboxyl group and an alkyloxycarbonyl group. An arylcarbonyl group or a heteroarylcarbonyl group which may have one or more substituents, a halogen atom, an alkyl group, an alkoxy group, a hydrogen group, a halogenoalkyl group, a hydroxyalkyl group, an alkoxy in the aryl moiety or the heteroaryl moiety. Alkyl group, amino group, mono- or dialkylamino group, cyano group,
Does it represent an aralkylcarbonyl group or a heteroaralkylcarbonyl group which may have one or more substituents selected from a carboxyl group and an alkyloxycarbonyl group (provided that the bond between the 5th and 6th positions is a double bond) In this case, one of R ³ and R ⁴ and one of R ⁵ and R ⁶ does not exist), or one of R ³ and R ⁴ and one of R ⁵ and R ⁶ are combined. It may have one or more substituents selected from an alkyl group, an alkoxy group, a cycloalkyl, a cycloalkoxy, a hydroxyl group, a halogen atom, an amino group, a mono- or dialkylamino group, a cyano group, a carboxyl group and an alkoxycarbonyl group. A good alkylene group having 3 to 5 carbon atoms may be formed. R ³ and R ⁴ may combine with the adjacent carbon atom to form a carbonyl group or a thiocarbonyl group. Z is a single bond,
Methylene group, ethylene group, oxygen atom, sulfur atom, SO,
SO ₂ or NR ⁹ (R ⁹ is a hydrogen atom or a carbon number of 1 to 10)
The present invention provides a polycyclic fused thiazole derivative or a salt thereof.

In the above formula (1), examples of the substituents of R ^{1 to} R ⁶ include the groups shown below. That is, as R ¹ and R ² , a halogen atom, a hydroxyl group, a cyano group, an alkyl group which may have one or more substituents, a cycloalkyl group which may have one or more substituents, An aryl or heteroaryl group which may have one or more substituents, an aralkyl group or heteroaralkyl group which may have one or more substituents on the aryl part or the heteroaryl part, a carboxyl group, a substituent A sulfamoyl group which may have a group, an alkoxycarbonyl group, a cycloalkyloxycarbonyl group, an alkenyloxycarbonyl group, an alkoxyloxycarbonyl group, an aryloxycarbonyl group which may have one or more substituents, A heteroaryloxycarbonyl group optionally having one or more substituents, a formyloxy group, a formyl group, an alkyl group Group, a cycloalkylcarbonyl group, an arylcarbonyl group optionally having one or more substituents, a heteroarylcarbonyl group optionally having one or more substituents, an aryl moiety or a heteroaryl moiety An aralkylcarbonyl group optionally having one or more substituents, a heteroaralkylcarbonyl group,

[Chemical 3] (R ⁷ and R ⁸ are the same or different and each is a hydrogen atom or a carbon number of 1 to
10 alkyl groups, cyclic alkyl groups having 3 to 7 carbon atoms, alkenyl groups, alkynyl groups, aryl groups that may have one or more substituents, and hetero groups that may have one or more substituents. Aryl group, an aralkyl group in which the aryl portion may have one or more substituents, a heteroaralkyl group that may have one or more substituents in the heteroaryl portion, a cyclic alkyl-alkyl group, a hydroxyl group, Alkoxy group, amino group, mono- or dialkylamino group, alkylaminoalkyl group, hydroxyalkyl group, mono,
A di- or trihalogenoalkyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, a 2-oxotetrahydrothienyl group, or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocycle. The heterocycle may have 1 or 2 heteroatoms such as a nitrogen atom, a sulfur atom and an oxygen atom which may have a substituent other than the nitrogen atom, or The heterocycle may have one or more substituents such as an alkyl group, a halogen atom, a lower alkoxy group, a carbonyl group, a formyl group, a lower alkoxycarbonyl group, an amino group and a hydroxyl group, and further has a double bond. One or more may be included) and the like.

As R ^{3 to} R ⁶ , a halogen atom, a hydroxyl group,
A cyano group, an alkyl group that may have one or more substituents, a cycloalkyl group that may have one or more substituents, an alkenyl group, an alkynyl group, and one or more substituents. Optionally substituted aryl group, heteroaryl group optionally having one or more substituents, aralkyl group or heteroaralkyl optionally having one or more substituents on the aryl moiety or heteroaryl moiety Group, carboxyl group, carbamoyl group, monoalkylaminocarbonyl group, diaminocarbonyl group, lower alkoxycarbonyl group, cycloalkyloxycarbonyl group, alkenyloxycarbonyl group, alkyloxycarbonyl group, having one or more substituents Optionally aryloxycarbonyl group, heteroaryloxycarbyl optionally having one or more substituents Nyl group, formyloxy group, formyl group, alkylcarbonyl group, cycloalkylcarbonyl group, arylcarbonyl group optionally having one or more substituents, hetero optionally having one or more substituents Examples thereof include an arylcarbonyl group, an aralkylcarbonyl group or a heteroaralkylcarbonyl group which may have one or more substituents on the aryl moiety or the heteroaryl moiety. Further, one of R ³ or R ⁴ and one of R ⁵ or R ⁶ together may have a substituent having 3 carbon atoms.
5 to 5 alkylene groups may be formed, and further, R ³ and R
⁴ may combine with the adjacent carbon atom to form a carbonyl group or a thiocarbonyl group. Z is a single bond, a methylene group, an ethylene group, an oxygen atom, a sulfur atom,
SO, SO ₂ or NR ⁹ (R ⁹ represents a hydrogen atom or a lower alkyl group having 1 to 10 carbon atoms) can be mentioned.

In the above, examples of the alkyl group include linear or branched ones having 1 to 10 carbon atoms, specifically, methyl group, ethyl group, propyl group, isopropyl group, butyl group. , Isobutyl group, sec-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-dimethyl Butyl group, 2,2-dimethylbutyl group, 1,
Examples thereof include a 3-dimethylbutyl group, a 2,3-dimethylbutyl group, a 3,3-dimethylbutyl group, a 1,1,2-trimethylpropyl group, an octyl group and a decyl group.

The cycloalkyl group is preferably one having 3 to 7 carbon atoms, and specific examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group.

When the alkyl group or cycloalkyl group has a substituent, the number thereof is preferably 1 to 3, and specific examples of the substituent include a halogen atom, a hydroxyl group, an amino group, a lower alkoxy group and a cycloalkyl group. , Aryl groups and aryloxy groups, carboxyl groups, lower alkoxycarbonyl groups, carbamoyl groups, mono- and di-lower alkylamino groups, and the like.

Examples of the alkenyl group include linear or branched ones having 1 to 10 carbon atoms, and specific examples thereof include vinyl, propenyl, isopropenyl, butenyl and 2,3-dimethylbutenyl. , 1,3-butadienyl, 2-methylbutenyl, allyl, decenyl and the like.

Examples of the alkynyl group include linear or branched ones having 1 to 10 carbon atoms, and specific examples thereof include ethyl, propynyl, butynyl, decynyl and the like.

As the aryl group, phenyl, naphthyl,
Biphenyl, anthracenyl, a phenanthrenyl group etc. can be mentioned.

The aralkyl group is preferably a group in which any hydrogen atom of the alkyl group is substituted with the aryl group, and specific examples thereof include a benzyl group, a phenethyl group, a 3-phenylpropyl group and a naphthylmethyl group. .

Examples of the heteroaryl group include mono-hetero 5-membered rings such as furan, thiophene and pyrrole; di-hetero 5-membered rings such as pyrazole, imidazole and thiazole; mono-hetero 6-membered rings such as pyridine; and di-hetero 6-membered rings such as pyrimidine. , And groups formed from two or more heterocycles including these monocyclic heterocycles.

The heteroaralkyl group is preferably a group in which any hydrogen atom of the above alkyl group is substituted with the above heteroaryl group, and specific examples include thiophenylmethyl,
Examples thereof include thiazolylethyl, pyridinylmethyl and pyrimidinylmethyl.

When the aryl group, aralkyl group, heteroaryl group or heteroaralkyl group has a substituent, the number thereof is preferably 1 to 3, and specific examples of the substituent include a halogen atom, an alkyl group, an alkoxy group, Examples thereof include a hydrogen group, a halogenoalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an amino group, a mono- and dialkylamino group, an amino group, a cyano group, a carboxyl group and an alkyloxycarbonyl group.

Specific examples of the alkoxy group include linear or branched alkoxy groups having 1 to 3 carbon atoms such as a methoxy group, an ethoxy group, a propoxy group and an isopropoxy group.

The alkoxycarbonyl group includes, for example, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxy group. Carbonyl group, isopentyloxycarbonyl group, neopentyloxycarbonyl group, hexyloxycarbonyl group, octyloxycarbonyl group, decyloxycarbonyl group, cyclopropoxycarbonyl group, cyclobutoxycarbonyl group, cyclopentyloxycarbonyl group, cyclohexyloxycarbonyl group,
Examples include groups in which an ester is formed from a carboxyl group such as a cycloheptyloxycarbonyl group and a 2-methylpentenyloxycarbonyl group, and a linear, branched or cyclic lower alcohol having 1 to 10 carbon atoms. it can.

Examples of the alkylcarbonyl group include an acetyl group, a propionyl group, a butyryl group, a hexanoyl group and a decanoyl group. Examples of the cycloalkylcarbonyl group include a cyclopropanoyl group, a cyclopentanoyl group, a cyclohexanoyl group and the like.

Preferred examples of the arylcarbonyl group include unsubstituted or substituted arylcarbonyl groups such as benzoyl group, naphthoyl group, o, m or p-chlorobenzoyl group, o, m or p-fluorobenzoyl group and the like. Can be mentioned.

Examples of the hydroxyalkyl include a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group and the like.

Examples of the mono-, di- or trihalogenoalkyl group include a 2,2,2-trifluoroethyl group, a 2-fluoroethyl group and a 2-chloroethyl group.

Examples of the mono- or dialkylaminoalkyl group include N-methylamino group, N-ethylamino group and N-
Propylamino group, N, N-dimethylaminoethyl group, N, N-
Examples thereof include a dimethylaminopropyl group, N, N-diethylaminoethyl group, N, N-diethylaminopropyl group and the like.

Examples of the alkoxycarbonylalkyl group include ethoxycarbonylmethyl group and ethoxycarbonylethyl group.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

The substituted carbamoyl group means a group in which the lower alkyl group is mono- or di-substituted on the amino group of the carbamoyl group, and specifically, methylaminocarbonyl group, ethylaminocarbonyl group, propylaminocarbonyl group,
Examples thereof include an isopropylaminocarbonyl group, a dimethylaminocarbonyl group, a diethylaminocarbonyl group, a dipropylaminocarbonyl group, a diisopropylaminocarbonyl group and a cyclohexylaminocarbonyl group.

When R ⁷ and R ⁸ together with the nitrogen atom to which they are bound form a heterocycle, the ring is a substituent (preferably 1
3 to 3) may further have a double bond (preferably 1 to 2), and preferred examples thereof include pyrrole, pyrroline, pyrrolidine, piperidine, piperazine, homopiperazine, pyrazolidine, isoxazole, isoxazoline, Oxazole, oxazolidine, pyridine, 1,2-dihydropyridine, 1,2,3,4-tetrahydropyridine, thiazoline, thiazolidine, pyridine, pyramidine, 1,2,3,
4-tetrahydropyrimidine, 1,2,5,6-tetrahydropyrimidine, 1,4-thiazine, 1,4-oxazine, 2,3-dihydro
5, such as -1,4-oxazine, 1,3,5-triazi, azepine, 1,2-dihydroazepine, 1,2,3,4-tetrahydroazepine
To 7-membered N-containing heterocycles. The heterocycle may preferably have 1 to 3 substituents, and examples thereof include an alkyl group, an alkoxy group, a halogen atom, a hydroxyl group, an amino group and a carboxyl group.

When the alkylene group has a substituent,
The number thereof is preferably 1 to 3, and specific examples of the substituent include lower alkyl, lower alkoxy, cycloalkyl,
Cycloalkoxy, hydroxyl group, halogen atom, amino group,
A mono- or di-lower alkylamino group, a cyano group, a carboxyl group, a lower alkoxycarbonyl group and the like can be mentioned.
The compound of the present invention has optical isomers or geometrical isomers derived from the 5-position, 6-position and 2-position or 3-position of the general formula (1), and further derived from a lower alkyl group or a lower alkenyl group. Inventive compounds also include these optical isomers, geometric isomers and mixtures thereof.

Further, Table 1 below shows specific examples of the present invention.
~ The compounds listed in Table 7 can be mentioned.

[0032]

[Table 1]

[0033]

[Table 2]

[0034]

[Table 3]

[0035]

[Table 4]

[0036]

[Table 5]

[0037]

[Table 6]

[0038]

[Table 7]

The compound of the formula (1) of the present invention can be produced by various methods, and representative production methods thereof are shown below.

Manufacturing method A

[Chemical 4] For example, by reacting 2-haloacrylonitrile, 2-haloacrylic acid alkyl ester, 2,3-halomopropionic acid alkyl ester, 2,3-halomopropionamide, etc. in the presence of a base in a suitable organic solvent, the formula ( The compounds of 1a) can be prepared. As the solvent used here, methanol, ethanol, isopropyl alcohol,
Dichloromethane, dichloroethane, chloroform, etc.
Examples of the base include sodium hydrogen carbonate, potassium carbonate, sodium carbonate, triethylamine, 1,1,3,3-tetramethylguanidine, 1,8-diazabicyclo [5.4.0] -7-undecene and the like. The reaction is usually carried out at −10 ° C. to 50 ° C. for several hours, but preferably in dichloromethane, 1,1,3,3-tetramethylguanidine or 1,8-diazabicyclo [5.4.
0] -7-Undecene is carried out under ice cooling for 0.5 to 1 hour.

Production method B

[Chemical 5] The compound of formula (2) is treated with an alkyl ester of halopyruvic acid or an alkyl ester of 2-halo-2-formylacetic acid in a suitable organic solvent, preferably an organic acid such as acetic acid, at room temperature to 100 ° C.
The compound of formula (1b) can be produced by reacting at the temperature of several hours.

Production Method C

[Chemical 6] The compound of formula (1c) can be produced by reacting the compound of formula (1c) with a dehydrogenating agent in a suitable organic solvent and then treating with water. As a dehydrogenating agent, palladium black, manganese dioxide, chloranil or 2,3-dichloro-5,6
-Dicyanoparabenzoquinone etc. can be mentioned.
Examples of the solvent include dichloromethane, dichloroethane, chloroform, dioxane, tetrahydrofuran and a mixed solvent thereof. Reaction is usually -10 ℃ to 80 ℃
It is carried out at a temperature of ° C for several hours. Preferably, in a mixed solvent of tetrahydrofuran and dichloromethane, 2,3-dichloro-
It is carried out for about 1 hour at room temperature using 5,6-dicyanoparabenzoquinone.

Production Method D

[Chemical 7] A compound of formula (1f) can be prepared by reacting a compound of formula (1e) with an alcohol containing hydrogen chloride and then treating with water. Examples of alcohol include methanol, ethanol, propanol, isopropyl alcohol and the like. The reaction is usually performed at 0 ° C to room temperature for 1 hour to 24 hours.

Production Method E

[Chemical 8] A compound of formula (1g) by reacting the compound of formula (1g) with R ⁷ -NH-R ⁸ without solvent or in an organic solvent such as methanol, ethanol, isopropyl alcohol, dioxane, tetrahydrofuran, dichloromethane, dimethylformamide, etc. The compound can be prepared. The reaction is carried out at 0 ° C to 100 ° C for 1 hour to 1 day.

Manufacturing method F

[Chemical 9] Formula (1i) is obtained by hydrolyzing the compound of formula (1g) with alkali such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate in water or hydrous alcohol.
Compounds of can be prepared. Reaction is usually room temperature to 80
It is carried out at ℃ for several hours.

Manufacturing Method G

[Chemical 10] The compound of formula (1i) is reacted with alkyl carbonic acid, pivalic acid or the like in an organic solvent such as tetrahydrofuran in the presence of a base such as triethylamine to give a mixed acid anhydride, and then R ⁷ -N
The compound of formula (1h) can be prepared by reacting with HR ⁸ . The reaction is usually performed at room temperature for 1 hour to 1 day and night. In addition, the compound of formula (1i) in an organic solvent such as tetrahydrofuran or dichloromethane, 4-N, N-dimethylaminopyridine, 1-hydroxybenzotriazole and carbodiimide such as N, N'-dicyclohexylcarbodiimide, N, N'-diisopropyl The compound of formula (1h) can also be produced by reacting with R ⁷ —NH—R ^{8 in} the presence of carbodiimide or the like or in the presence of 1,1′-carbonyldiimidazole.

Production Method H

[Chemical 11] The compound of formula (1j) can be produced by reacting the compound of formula (3) with a haloacetaldehyde dialkyl acetal, a nitroolefin which may have a substituent, or nitrostyrene in a suitable organic solvent.
Examples of the solvent include dimethylformamide, dimethylsulfoxide and the like. The reaction is at 50 ℃ ~ 150 ℃
It is carried out for 10 minutes to several hours, preferably using dimethylformamide at 100 ° C. for about 10 minutes.

Production Method I

[Chemical 12] A compound of formula (1k) can be prepared by reacting a compound of formula (3) with an alkyl acrylate in the presence of a base in a suitable organic solvent. Examples of the solvent include alcohol solvents such as methanol, ethanol and isopropanol. As the base, triethylamine and the like are suitable, and the reaction is usually carried out at reflux temperature for several hours to one day.

Manufacturing Method J

[Chemical 13] The compound of formula (1k) can be produced by reacting the compound of formula (1k) with Lawesson's reagent or phosphorus pentasulfide in a suitable organic solvent. Examples of the solvent include benzene, toluene, xylene, acetonitrile and the like. The reaction is usually at a temperature of 50 ° C to 100 ° C for 1 hour
It takes 10 hours.

Manufacturing method K

[Chemical 14] The compound of the formula (1m) can be produced by desulfurizing the compound of the formula (1l) with Raney nickel or the like in an organic solvent such as benzene. The reaction is usually performed using an excess amount of Raney nickel at 0 ° C to 50 ° C for several minutes to several hours.

The method of administering the compound of the present invention may be oral or parenteral, but oral administration is generally preferred. Further, the dose of the compound of the present invention depends on the age of the patient,
The dose may be adjusted according to the body weight, etc. Generally, in the case of oral administration, 1 mg to 300 mg / day, preferably 10 per adult
~ 200 mg / day is appropriate. Examples of the dosage form 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.

[0052]

INDUSTRIAL APPLICABILITY The compound of the present invention showed an excellent hepatic disorder-improving effect in the D-galactosamine-induced experimental liver disorder (hepatitis) model. Furthermore, the compound of the present invention is a rat complement-dependent liver injury model by intravenous administration of an anti-hepatic cell membrane monoclonal antibody (Medical Ayumi 146, 3, p179-180).
(1988)) also showed an excellent action to improve liver damage. Therefore, the compound of the present invention is useful for liver diseases such as degeneration of liver parenchymal cells
It is an excellent preventive and therapeutic agent for liver diseases such as hepatic disorder accompanied by necrosis, chronic hepatitis and cirrhosis.

[0053]

EXAMPLES The present invention will now be described in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto.

Example 1 Isopropyl 2-cyano-2,3,5,6-tetrahydropyrrolo
[2,1-b] Thiazole-7-carboxylate Isopropyl 2-thioxopyrrolidine-3-carboxylate 4.97 g and 2-chloroacrylonitrile 2.80 g were dissolved in 80 ml of dichloromethane and ice-cooled with stirring 1,8- Add 4.85 g of diazabicyclo [5.4.0] -7-undecene. After 15 minutes, 0.56 g of 2-chloroacrylonitrile and 0.95 g of 1,8-diazabicyclo [5.4.0] -7-undecene are further added, and the mixture is stirred for 10 minutes. Dichloromethane is added to the reaction solution, which is washed with water and a saturated aqueous sodium chloride solution, 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 n-hexane to obtain 2.67 g of the title compound. Melting point 86 to 90 ° C Elemental analysis value (as C ₁₁ H ₁₄ N ₂ O ₂ S) Calculated value (%): C55.44 H5.92 N11.76 Measured value (%): C55.53 H5.75 N11.62 NMR spectrum δ (CDCl ₃ ): 1.26 (6H, d), 2.8-3.6 (6H, m), 4.54 (1H, dd), 4.97 (1H, se
pt). In the same manner as in Example 1, the compounds of Examples 2 to 11 were produced.

Example 2 Isopropyl 2-cyano-6-methyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazole-7-carboxylate oil MMR spectrum δ (CDCl ₃ ): 1.26 ( 9H, d), 2.7-3.8 (5H, m), 4.5-4.7 (1H, m), 5.03 (1H,
sept).

Example 3 Isopropyl 2-cyano-6,6-dimethyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazole-7-carboxylate Melting point 97-99 ° C. Elemental analysis value (C ₁₃ H ₁₈ N ₂ O ₂ S) Calculated value (%): C58.62 H6.81 N10.52 Measured value (%): C58.48 H6.86 N10.50 NMR spectrum δ (CDCl ₃ ): 1.26 ( 6H, d), 1.34 (6H, s), 2.9-3.7 (4H, m), 4.50 (1H, d
d), 5.04 (1H, sept).

Example 4 Ethyl 2-cyano-6,6-dimethyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazole-7-carboxylate Melting point 84-85 ° C. Elemental analysis value (C ₁₂ H ₁₆ N ₂ O ₂ S) Calculated value (%): C57.12 H6.39 N11.10 Measured value (%): C57.12 H6.46 N11.15 NMR spectrum δ (CDCl ₃ ): 1.31 ( 3H, t), 1.37 (3H, s), 1.38 (3H, s), 3.02 (1H, d), 3.2
3 (1H, d), 3.37 (1H, q), 3.57 (1H, q), 4.21 (2H, q), 4.34 (1
H, q).

Example 5 Ethyl 2-cyano-6-isopropyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazole-7-carboxylate Melting point 82 ° C. Elemental analysis value (C ₁₃ H ₁₈ N ₂ O ₂ as S) calculated (%): C58.62 H6.81 N10.52 Found (%): C58.75 H6.88 N10.50 NMR spectrum _{δ (CDCl 3): 0.85 (} 3H, d) , 0.87 (3H, d), 1.23 (3H, t), 2.11 (1H, m), 3.0
-3.7 (5H, m), 4.12 (2H, q), 4.45 (1H, dd).

Example 6 Ethyl 2-cyano-2,3,6,7-tetrahydro-5H-thiazolo
[3,2-a] Pyridine-8-carboxylate Melting point 130-131 ° C Elemental analysis value (as C ₁₁ H ₁₄ N ₂ O ₂ S) Calculated value (%): C55.44 H5.92 N11.75 Measured value (%): C55.58 H5.96 N11.84 NMR spectrum δ (CDCl ₃ ): 1.27 (3H, t), 1.8-2.0 (2H, m), 2.32 (1H, dt), 2.46 (1H, d)
t), 3.0-3.2 (1H, m), 3.2-3.4 (1H, m), 3.65 (1H, dd), 3.8
(1H, dd), 4.11 (1H, dd), 4.0-4.2 (2H, m).

Example 7 Isopropyl 2-cyano-2,3,6,7-tetrahydro-5H-thiazolo [3,2-a] pyridine-8-carboxylate Melting point 117-118 ° C. Elemental analysis value (C ₁₂ H ₁₆ N ₂ O ₂ as S) calculated (%): C57.12 H6.39 N11.10 Found (%): C57.13 H6.36 N11.15 NMR spectrum _{δ (CDCl 3): 1.23 (} 6H, d ), 1.9-2.2 (2H, m), 2.2-2.6 (2H, m), 2.9-3.6
(2H, m), 3.6-3.9 (2H, m), 4.0-4.2 (1H, dd), 5.09 (1H, sep
t).

Example 8 Ethyl 2-cyano-6,6-dimethyl-2,3,6,7-tetrahydro-5H-thiazolo [3,2-a] pyridine-8-carboxylate Melting point 156-158 ° C Elemental analysis Value (as C ₁₃ H ₁₈ N ₂ O ₂ S) Calculated value (%): C58.62 H6.81 N10.52 Measured value (%): C58.44 H6.78 N10.52 NMR spectrum δ (CDCl ₃ ). : 1.03 (3H, s), 1.05 (3H, s), 1.28 (3H, t), 2.15 (2H, s), 2.8
0 (1H, d), 2.96 (1H, d), 3.5-3.8 (2H, m), 4.08 (1H, dd), 4.
18 (2H, q).

Example 9 2,3,6,7-Tetrahydro-5H-thiazolo [3,2-a] pyridine-
3,8-Dicarbonitrile Melting point 126-128 ℃ Elemental analysis value (as C ₉ H ₉ N ₃ S) Calculated value (%): C56.52 H4.74 N21.97 Measured value (%): C56.45 H4 .51 N21.96 NMR spectrum δ (CDCl ₃ ): 1.3-2.1 (3H, m), 2.23 (1H, dd), 2.4-2.6 (1H, m), 3.06 (1
H, dd), 3.4-4.2 (2H, m), 4.52 (1H, dd).

Example 10 6,6-Dimethyl-2,3,5,6-tetrahydro-5H-thiazolo [3,2
-a] Pyridine-3,8-dicarbonitrile Melting point 110-112 ℃ Elemental analysis value (as C ₁₁ H ₁₃ N ₃ S) Calculated value (%): C60.24 H5.97 N19.16 Measured value (%) : C59.96 H5.97 N18.96 NMR spectrum δ (CDCl ₃ ): 1.02 (3H, s), 1.22 (3H, s), 1.57 (1H, d), 2.2-2.3 (2H, m),
3.0-3.1 (1H, q), 3.6-3.7 (1H, d), 3.4-3.5 (1H, d), 4.6-
4.7 (1H, q).

Example 11 Ethyl 3-cyano-2,3,5,6-tetrahydrothiazolo [2,3
-c] [1,4] thiazine-8-carboxylate melting point 119 to 122 ° C. Elemental analysis _{(C 10 H 12 N 2 O} 2 as S ₂₎ Calculated (%): C46.85 H4.72 N10.93 Actual value (%): C46.86 H4.58 N10.98 NMR spectrum δ (CDCl ₃ ): 1.34 (3H, t), 2.8-3.2 (2H, m), 3.2-3.4 (1H, m), 3.4- 4.0
(3H, m), 4.0-4.2 (1H, m), 4.28 (2H, q).

Example 12 Diethyl 2,3,5,6-tetrahydrothiazolo [2,3, -c] [1,
4] Thiazine-3,8-dicarboxylate ethyl 3-thioxothiomorpholine-2-carboxylate 0.48 g and 2,3-dibromopropionic acid ethyl ester
Dissolve 0.80 g in 15 ml of dichloromethane, cool with ice, and stir
0.94 g of 1,8-diazabicyclo [5.4.0] -7-undecene is added. After 10 minutes, add water to the reaction solution and extract with dichloromethane. The dichloromethane layer is washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography to obtain 0.40 g of the title compound. Melting point 116 to 117 ° C Elemental analysis value (as C ₁₂ H ₁₇ NO ₄ S ₂ ) Calculated value (%): C47.50 H5.65 N4.62 Measured value (%): C47.37 H5.67 N4.73 NMR Spectrum δ (CDCl ₃ ): 1.30 (6H, t), 2.7-3.1 (2H, m), 3.1-3.4 (2H, m), 3.6-4.0
(3H, m), 4.22 (2H, q), 4.25 (2H, q). In the same manner as in Example 12, the compound of Example 13 was produced.

Example 13 2-Ethyl 8-isopropyl 2,3,6,7-tetrahydro-5H-
Thiazolo [3,2-a] pyridine-2,8-dicarboxylate oil NMR spectrum δ (CDCl ₃ ): 1.23 (6H, d), 1.29 (3H, t), 1.8-2.1 (2H, m), 2.2-2.5 (2H,
m), 3.1-3.4 (2H, m), 3.5-4.2 (3H, m), 4.19 (2H, q), 5.04
(1H, sept).

Example 14 Isopropyl 2-carbamoyl-6,6-dimethyl-2,3,5,6
-Tetrahydropyrrolo [2,1-b] thiazole-7-carboxylate isopropyl 4,4-dimethyl-2-thioxopyrrolidine-3
-1.02 g of carboxylate and 1.42 g of 2,3-dibromopropionamide were dissolved in 30 ml of dichloromethane, and while cooling with ice, stirring 1,8-diazabicyclo [5.4.0] -7-undecene 2.82 g
Add. After returning to room temperature and stirring for 3 hours, water is added to the reaction solution and the mixture is extracted with dichloromethane. The dichloromethane layer is washed with a saturated aqueous sodium chloride solution and then 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 dichloromethane and ether to give the title compound.
64 g was obtained. Mp one hundred fifty-seven to one hundred fifty-eight ° C. Elemental analysis _{(C 13 H 20 N 2 O} 3 as S) Calculated (%): C54.91 H7.09 N9.85 Found (%): C54.94 H6.97 N9.87 NMR spectrum δ (CDCl ₃ ): 1.27 (6H, d), 1.30 (3H, s), 1.34 (3H, s), 2.89 (1H, d), 3.1
7 (1H, d), 3.24 (1H, dd), 3.71 (1H, dd), 4.33 (1H, dd), 5.0
5 (1H, sept), 5.92 (1H, brs), 6.68 (1H, brs). In the same manner as in Example 14, the compound of Example 15 was produced.

Example 15 Isopropyl 2-carbamoyl-2,3,6,7-tetrahydro
-5H-thiazolo [3,2-a] pyridine-8-carboxylate Melting point 121-123 ° C Elemental analysis value (as C ₁₂ H ₁₈ N ₂ O ₃ S) Calculated value (%): C53.31 H6.71 N10 .36 Found (%): C53.23 H6.67 N10.41 NMR spectrum δ (CDCl ₃ ): 1.25 (6H, d), 1.7-2.1 (2H, m), 2.1-2.4 (2H, m), 2.9-3.5
(2H, m), 3.5-4.2 (3H, m), 5.05 (1H, sept), 6.12 (2H, brs).

Example 16 2-Ethyl 7-isopropyl 5,6-dihydropyrrolo [2,1-
b] Thiazole-2,7-dicarboxylate isopropyl 2-thioxopyrrolidine-3-carboxylate 2.05 g and ethyl 2-chloro-2-formyl acetate
5.0 g of acetic acid was added to 30 ml of acetic acid, and the mixture was heated with stirring at 70 to 80 ° C. for 3 hours. The residue obtained by distilling off acetic acid under reduced pressure is poured into saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The dichloromethane layer is washed with water and a saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. The crystals obtained by distilling off the solvent were washed with n-hexane-ether to obtain 2.57 g of the title compound. Melting point 148 to 149 ° C NMR spectrum δ (CDCl ₃ ): 1.28 (6H, d), 1.31 (3H, t), 3.0-3.3 (2H, m), 3.9-4.2 (2H,
m), 4.26 (2H, q), 5.07 (1H, sept), 7.38 (1H, s). In the same manner as in Example 16, the compounds of Examples 17 to 18 were produced.

Example 17 3-Ethyl 7-isopropyl 5,6-dihydropyrrolo [2,1-
b] Thiazole-3,7-dicarboxylate Melting point 93 ° C Elemental analysis value (as C ₁₃ H ₁₇ NO ₄ S) Calculated value (%): C55.10 H6.05 N4.94 Measured value (%): C55. 02 H6.00 N4.95 NMR spectrum δ (CDCl ₃ ): 1.26 (6H, d), 1.34 (3H, t), 3.16 (2H, t), 4.30 (2H, q), 4.3
1 (2H, t), 5.06 (1H, m), 6.87 (1H, s).

Example 18 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 (%): C47.82 H5.02 N4.65 Found (%): C47. 61 H4.83 N4.66 NMR spectrum δ (CDCl ₃ ): 1.36 (6H, t), 2.8-3.0 (2H, m), 4.26 (2H, q), 4.30 (2H, q),
4.5-4.7 (2H, m), 7.30 (1H, s).

Example 19 Isopropyl 2-cyano-2,3-dihydropyrrolo [2,1-b]
Thiazole-7-carboxylate isopropyl 2-cyano-2,3,5,6-tetrahydropyrrolo
4.0 g of [2,1-b] thiazole-7-carboxylate was dissolved in a mixed solvent of 100 ml of chloroform and 40 ml of tetrahydrofuran, and 3.0 g of 2,3-dichloro-5,6-dicyanoparabenzoquinone was added with stirring under ice cooling. Add and stir for 30 minutes. The reaction mixture is made alkaline with saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The chloroform layer is washed with water and a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography and then recrystallized from a mixed solvent of ether and n-hexane to obtain 1.7 g of the title compound. Melting point 88-89 ° C Elemental analysis value (as C ₁₁ H ₁₂ N ₂ O ₂ S) Calculated value (%): C55.91 H5.12 N11.86 Measured value (%): C55.94 H5.12 N11.87 NMR spectrum δ (CDCl ₃ ): 1.32 (6H, d), 4.2-4.6 (2H, m), 4.81 (1H, dd), 5.13 (1H, se
pt), 6.61 (1H, d), 6.68 (1H, d). In the same manner as in Example 19, the compounds of Examples 20 to 22 were produced.

Example 20 Isopropyl 2-cyano-6-methyl-2,3-dihydropyrrolo [2,1-b] thiazole-7-carboxylate Melting point 124-125 ° C. Elemental analysis value (C ₁₂ H ₁₄ N ₂ O ₂ as S) calculated (%): C57.58 H5.64 N11.19 Found (%): C57.59 H5.69 N11.24 NMR spectrum _{δ (CDCl 3): 1.32 (} 6H, d), 2.24 (3H, d), 4.1-4.5 (2H, m), 4.74 (1H, d
d), 5.13 (1H, sept), 6.47 (1H, q).

Example 21 3-Ethyl 7-isopropyl pyrrolo [2,1-b] thiazole
3,7-dicarboxylate mp 79 ° C. Elemental analysis (C ₁₃ H ₁₅ NO ₄ as S) Calculated (%): C55.50 H5.37 N4.98 Found (%): C55.56 H5. 61 N5.09 NMR spectrum δ (CDCl ₃ ): 1.37 (6H, d), 1.43 (3H, t), 4.44 (2H, q), 5.22 (1H, sept),
6.98 (1H, dd), 7.79 (1H, d), 7.82 (1H, d).

Example 22 Isopropyl 3-N-methylcarbamoylpyrrolo [2,1-b]
Thiazole-7-carboxylate Melting point 163 to 165 ° C Elemental analysis value (as C ₁₂ H ₁₄ N ₂ O ₃ S) Calculated value (%): C54.12 H5.30 N10.52 Measured value (%): C53.91 H5.04 N10.46 NMR spectrum δ (CDCl ₃ ): 1.36 (6H, d), 2.99 (3H, d), 5.19 (1H, sept), 6.5-6.9 (1H,
br), 6.95 (1H, dd), 7.38 (1H, d), 7.86 (1H, d).

Example 23 2-Ethyl 7-isopropyl pyrrolo [2,1-b] thiazole
-2,7-Dicarboxylate 2-ethyl 7-isopropyl 2,3-dihydropyrrolo [2,1-
b] thiazole-2,7-dicarboxylate 1.94 g and 2,3
-3.12 g of dicyano-5,6-dichlorobenzoquinone is added to 150 ml of toluene and heated under reflux for 3 hours. After cooling, saturated aqueous sodium hydrogen carbonate solution is added and the mixture is stirred for 10 minutes. The insoluble matter is filtered off and extracted with toluene. The toluene layer is washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography to obtain 0.48 g of the title compound. Melting point 101 to 102 ° C Elemental analysis value (as C ₁₃ H ₁₅ NO ₄ S) Calculated value (%): C55.50 H5.37 N4.98 Measured value (%): C55.32 H5.34 N4.97 NMR spectrum δ (CDCl ₃ ): 1.37 (6H, d), 1.39 (3H, t), 4.39 (2H, q), 5.22 (1H, sept),
7.03 (1H, d), 7.17 (1H, d), 8.12 (1H, s).

Example 24 2-Ethyl 7-isopropyl 2,3-dihydropyrrolo [2,1-
b] thiazole-2,7-dicarboxylate isopropyl 2-cyano-2,3-dihydropyrrolo [2,1-b]
20 ml of ethanol saturated with hydrochloric acid is added to 1.15 g of thiazole-7-carboxylate and stirred at room temperature for 24 hours. Water in the reaction solution 20
Add ml and distill off ethanol under reduced pressure. The residue is made alkaline with sodium carbonate and extracted with chloroform. The chloroform layer is washed with water and a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography to obtain 1.25 g of the title compound. Oil NMR spectrum δ (CDCl ₃ ): 1.29 (3H, t), 1.31 (6H, d), 4.22 (1H, dd), 4.24 (2H, q),
4.61 (1H, dd), 4.81 (1H, dd), 5.12 (1H, sept), 6.55 (1H,
d), 6.61 (1H, d). In the same manner as in Example 24, the compounds of Examples 25 to 29 were produced.

Example 25 2-Ethyl 7-isopropyl 6-methyl-2,3-dihydropyrrolo [2,1-b] thiazole-2,7-dicarboxylate oil NMR spectrum δ (CDCl ₃ ): 1.30 ( 3H, t), 1.32 (6H, d), 2.23 (3H, s), 4.0-4.5 (2H, m),
4.24 (2H, q), 4.5-4.8 (1H, m), 5.12 (1H, sept), 6.42 (1H, b
rs).

Example 26 2-Ethyl 7-isopropyl 6,6-dimethyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazole-2,7-dicarboxylate oil NMR spectrum δ ( CDCl ₃ ): 1.1-1.4 (15H, m), 3.04 (3H, s), 3.33 (1H, dd), 3.53 (1H, d
d), 4.23 (2H, q), 4.53 (1H, dd), 5.03 (1H, sept).

Example 27 Diethyl 2,3,6,7-tetrahydro-5H-thiazolo [3,2-a]
Pyridine-2,8-dicarboxylate Melting point 31-35 ° C NMR spectrum δ (CDCl ₃ ): 1.26 (3H, t), 1.28 (3H, t), 1.8-2.1 (2H, m), 2.2-2.5 (2H ,
m), 3.1-3.4 (2H, m), 3.5-4.0 (3H, m), 4.16 (2H, q), 4.19
(2H, q).

Example 28 Diethyl 6,6-dimethyl-2,3,6,7-tetrahydro-5H-thiazolo [3,2-a] pyridine-2,8-dicarboxylate oil MS (m / z) : 313 (M ⁺ ) NMR spectrum δ (CDCl ₃ ): 1.00 (6H, s), 1.26 (3H, t), 1.27 (3H, t), 2.13 (2H, s), 2.8
5 (2H, s), 3.5-4.2 (3H, m), 4.16 (2H, q), 4.19 (2H, q).

Example 29 Ethyl 8-cyano-2,3,6,7-tetrahydro-5H-thiazolo
[3,2-a] Pyridine-3-carboxylate Melting point 66-67 ° C Elemental analysis value (as C ₁₁ H ₁₄ N ₂ O ₂ S) Calculated value (%): C55.44 H5.92 N11.76 Measured value (%): C55.29 H5.94 N11.80 NMR spectrum δ (CDCl ₃ ): 1.30 (3H, t), 1.5-2.0 (3H, m), 2.20 (1H, dd), 2.3-2.6 (1
H, m), 2.82 (1H, dd), 3.4-4.0 (2H, m), 4.24 (2H, q), 4.52
(1H, dd).

Example 30 Isopropyl 2-carbamoyl-2,3-dihydropyrrolo
[2,1-b] Thiazole-7-carboxylate 2-ethyl 7-isopropyl 2,3-dihydropyrrolo [2,1-
b] 1.54 g of thiazole-2,7-dicarboxylate is suspended in 50 ml of methanol, 50 ml of concentrated aqueous ammonia is added thereto, and the mixture is stirred at room temperature for 20 hours. The residue obtained by distilling off methanol is dissolved in chloroform, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. The crude crystals obtained by distilling off the solvent were recrystallized from a mixed solvent of ethanol and n-hexane to obtain 0.73 g of the title compound. Melting point 152-153 ° C Elemental analysis value (as C ₁₁ H ₁₄ N ₂ O ₃ S) Calculated value (%): C51.95 H5.55 N11.02 Measured value (%): C51.88 H5.57 N10.91 NMR spectrum δ (CDCl ₃ ): 1.32 (6H, d), 4.24 (1H, dd) 4.64 (2H, dt), 5.14 (1H, sep
t), 5.8-6.1 (1H, br), 6.56 (1H, d), 6.64 (1H, d), 6.6-7.1
(1H, br). The compounds of Examples 31 to 39 were produced in the same manner as in Example 30.

Example 31 Isopropyl 2-carbamoyl-6-methyl-2,3-dihydropyrrolo [2,1-b] thiazole-7-carboxylate Melting point 172 to 173 ° C. Elemental analysis value (C ₁₂ H ₁₆ N ₂ O ₃ as S) calculated (%): C53.71 H6.01 N10.44 Found (%): C53.74 H6.11 N10.46 NMR spectrum _{δ (CDCl 3): 1.33 (} 6H, d), 2.22 (3H, s), 4.0-4.4 (1H, m), 4.4-4.8 (2H,
m), 5.14 (1H, sept), 6.00 (1H, brs), 6.45 (1H, brs), 6.84
(1H, brs).

Example 32 Ethyl 3-carbamoyl-2,3-dihydropyrrolo [2,1-b]
Thiazole-7-carboxylate melting one hundred ninety-three to one hundred ninety-four ° C. Elemental analysis _{(C 10 H 12 N 2 O} 3 as S) Calculated (%): C49.99 H5.03 N11.66 Found (%): C49.99 H4.95 N 11.70 NMR spectrum δ (CDCl ₃ ): 1.32 (3H, t), 3.7-4.2 (2H, m), 4.21 (2H, q), 4.96 (1H, d)
d), 6.52 (1H, d), 6.73 (1H, d), 7.22 (2H, brs).

Example 33 Isopropyl 2- (N-methylcarbamoyl) -2,3-dihydropyrrolo [2,1-b] thiazole-7-carboxylate Melting point 72-74 ° C. Elemental analysis value (C ₁₂ H ₁₆ N ₂ O ₃ as S) calculated (%): C53.71 H6.01 N10.44 Found (%): C53.69 H5.97 N10.43 NMR spectrum _{δ (CDCl 3): 1.32 (} 6H, d), 2.83 (3H, d), 4.1-4.9 (3H, m), 5.14 (1H, sep
t), 6.55 (1H, d), 6.63 (1H, d), 7.18 (1H, brs).

Example 34 Isopropyl 2- (N-methylcarbamoyl) -6,6-dimethyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazole
-7- Carboxylate oil NMR spectrum δ (CDCl ₃ ): 1.26 (6H, d), 1.29 (3H, s), 1.32 (3H, s), 2.84 (3H, d), 2.9
4 (1H, d), 3.14 (1H, d), 3.27 (1H, dd), 3.68 (1H, dd), 4.44
(1H, dd), 5.02 (1H, sept), 6.9-7.3 (1H, br).

Example 35 Isopropyl 3- (N-methylcarbamoyl) -5,6-dihydropyrrolo [2,1-b] thiazole-7-carboxylate Melting point 207-209 ° C. Elemental analysis value (C ₁₂ H ₁₆ N ₂ O ₃ as S) calculated (%): C53.71 H6.01 N10.44 Found (%): C53.71 H5.89 N10.20 NMR spectrum _{δ (CDCl 3): 1.76 (} 6H, d), 2.93 (3H, d), 3.16 (2H, brt), 4.33 (2H, br
t), 5.06 (1H, m), 6.10 (1H, brs), 6.38 (1H, s).

Example 36 Ethyl 2- (N-methylcarbamoyl) -2,3,6,7-tetrahydro-5H-thiazolo [3,2-a] pyridine-8-carboxylate Melting point 169-171 ° C. Elemental analysis value (As C ₁₂ H ₁₈ N ₂ O ₃ S) Calculated value (%): C53.31 H6.71 N10.36 Measured value (%): C53.20 H6.89 N10.31 NMR spectrum δ (CDCl ₃ ): 1.28 (3H, t), 1.7-2.1 (2H, m), 2.2-2.6 (2H, m), 2.82 (3H,
d), 2.9-3.8 (4H, m), 3.90 (1H, dd), 4.18 (1H, m), 6.7-7.1
(1H, br).

Example 37 Isopropyl 2- (N-methylcarbamoyl) -2,3,6,7-
Tetrahydro-5H-thiazolo [3,2-a] pyridine-8-carboxylate Melting point 168-170 ° C Elemental analysis value (as C ₁₃ H ₂₀ N ₂ O ₃ S) Calculated value (%): C54.91 H7.09 N9.85 measured value (%): C54.84 H7.16 N9.77 NMR spectrum δ (CDCl ₃ ): 1.26 (6H, d), 1.8-2.0 (2H, m), 2.2-2.4 (1H, m) , 2.4-2.5
(1H, m), 2.82 (3H, d), 3.0-4.0 (5H, m), 5.07 (1H, sept),
6.93 (1H, br).

Example 38 N-Methyl-8-cyano-2,3,6,7-tetrahydro-5H-thiazolo [3,2-a] pyridine-3-carboxamide Melting point 152-155 ° C. Elemental analysis value (C ₁₀ H ₁₃ N ₃ OS) Calculated value (%): C53.79 H5.87 N18.82 Measured value (%): C53.48 H5.71 N18.54 NMR spectrum δ (CDCl ₃ ): 1.6-3.0 (6H , m), 2.85 (3H, d), 3.4-4.1 (2H, m), 4.39 (1H,
q), 6.4-6.8 (1H, br).

Example 39 Ethyl 3-methylcarbamoyl-2,3,5,6-tetrahydrothiazolo [2,3-c] [1,4] thiazine-8-carboxylate Melting point 236-237 ° C. Elemental analysis value ( C ₁₁ H ₁₆ N ₂ O ₃ S ₂ ) Calculated value (%): C45.81 H5.59 N9.71 Found value (%): C45.86 H5.67 N9.74 NMR spectrum δ (CDCl ₃ ): 1.28 (3H, t), 2.78 (3H, d), 2.9-4.0 (7H, m), 4.16 (2H, q),
7.85 (1H, br).

Example 40 7-Isopropoxycarbonylpyrrolo [2,1-b] thiazole
-3-Carboxylic acid 3-ethyl 7-isopropyl pyrrolo [2,1-b] thiazole
4.5 g of -3,7-dicarboxylate was added to a mixed solution of 20 ml of 1N sodium hydroxide and 50 ml of ethanol, and the mixture was stirred at room temperature for 1 hour. The residue obtained by distilling off ethanol is dissolved in water, acidified with hydrochloric acid, and extracted with chloroform. The chloroform layer is washed with saturated sodium chloride and then dried over anhydrous sodium sulfate. The solvent was concentrated and the precipitated crystals were collected by filtration to give the title compound (3.89 g). Melting point 186-187 ° C Elemental analysis value (as C ₁₁ H ₁₁ NO ₄ S) Calculated value (%): C52.16 H4.38 N5.53 Measured value (%): C52.11 H4.35 N5.51 NMR spectrum δ (CDCl ₃ ): 1.38 (6H, d), 5.28 (1H, sept), 7.10 (1H, dd), 7.90 (1H,
d), 8.06 (1H, d).

Example 41 Isopropyl 3- (4-methyl-piperazinecarbonyl)
Pyrrolo [2,1-b] thiazole-7-carboxylate 7-isopropoxycarbonylpyrrolo [2,1-b] thiazole
-3-Carboxylic acid 1.52 g, N-methylpiperazine 2.6 g and catalytic amount of 4-N, N-dimethylaminopyridine are added to dichloromethane.
The mixture is dissolved in 50 ml, N, N-dicyclohexylcarbodiimide (3.0 g) is added under ice-cooling and stirring, the mixture is returned to room temperature and stirred for 3 days. The insoluble material was removed by filtration, the solvent was evaporated, 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 1.34 g of the title compound. . Melting point 146 to 147 ° C Elemental analysis value (as C ₁₆ H ₂₁ N ₃ O ₃ S) Calculated value (%): C57.29 H6.31 N12.53 Measured value (%): C57.31 H6.53 N12.43 NMR spectrum δ (CDCl ₃ ): 1.36 (6H, d), 2.34 (3H, s), 2.46 (4H, t), 3.74 (4H, t), 5.2
1 (1H, sept), 6.97 (1H, dd), 7.04 (1H, d), 7.33 (1H, d).

Example 42 Diethyl 2,3-dihydropyrrolo [2,1-b] thiazole-3,7
-Dicarboxylate 2- (ethoxycarbonyl) -methylene-4-ethoxycarbonylthiazolidine 1.29 g and bromoacetaldehyde diethyl acetal 1.00 g dimethylformamide 10 ml
Dissolve in and heat and stir at 100 ° C for 10 minutes. The solvent is distilled off under reduced pressure and the obtained residue is dissolved in benzene and washed with water and a saturated aqueous sodium chloride solution. After drying over anhydrous sodium sulfate, the solvent was evaporated and the obtained residue was purified by silica gel column chromatography to obtain 0.60 g of the title compound. Oil NMR spectrum δ (CDCl ₃ ): 1.28 (3H, t), 1.32 (3H, t), 3.7-4.1 (2H, m), 4.24 (4H, q),
4.96 (1H, dd), 6.56 (1H, d), 6.74 (1H, d).

Example 43 Diethyl 5-oxo-2,3,6,7-tetrahydro-5H-thiazolo [3,2-a] pyridine-3,8-dicarboxylate 2- (ethoxycarbonyl) methylene-4- Ethoxycarbonyl thiazolidine 2.0g Acrylic acid ethyl ester 2.5ml
And 2.1 ml of triethylamine are added to 100 ml of ethanol, and the mixture is heated under reflux for 30 hours. The crystals obtained by distilling off ethanol were collected by filtration and washed with a mixed solvent of petroleum ether and ether to obtain 0.70 g of the title compound. Melting point 151-152 ° C Elemental analysis value (as C ₁₃ H ₁₇ NO ₅ S) Calculated value (%): C52.16 H5.72 N4.68 Measured value (%): C51.80 H5.58 N4.69 NMR spectrum δ (CDCl ₃ ): 1.26 (3H, t), 1.30 (3H, t), 2.68 (4H, brt), 3.3-3.4 (2H,
m), 4.23 (4H, q), 5.2-5.4 (1H, m).

Example 44 Diethyl 5-thioxo-2,3,6,7-tetrahydro-5H-thiazolo [3,2-a] pyridine-3,8-dicarboxylate diethyl 5-oxo-2,3,6 2.8 g of 7,7-tetrahydro-5H-thiazolo [3,2-a] pyridine-3,8-dicarboxylate
Add 2.0 g of Lawesson's reagent to 100 ml of benzene and heat to reflux for 1 hour. After cooling, the insoluble material was filtered off, the filtrate was concentrated, and the oily substance obtained was purified by silica gel column chromatography to obtain 1.7 g of the title compound. Mp 102 - 103 ° C. Elemental analysis (C ₁₃ H ₁₇ NO ₄ as S ₂₎ Calculated (%): C49.50 H5.43 N4.44 Found (%): C49.21 H5.38 N4.41 NMR Spectrum δ (CDCl ₃ ): 1.27 (3H, t), 1.32 (3H, t), 2.4-3.6 (6H, m), 4.24 (4H, q),
6.04 (1H, dd).

Example 45 Diethyl 2,3,6,7-tetrahydro-5H-thiazolo [3,2-a]
Pyridine-3,8-dicarboxylate diethyl 5-thioxo-2,3,6,7-tetrahydro-5H-thiazolo [3,2-a] pyridine-3,8-dicarboxylate 0.30 g
Is dissolved in 5 ml of benzene, and an excess amount of Raney nickel is added with stirring at room temperature and stirred for 5 minutes. The insoluble material was filtered off, the solvent was evaporated, and the obtained residue was purified by silica gel column chromatography to obtain 0.13 g of the title compound. Melting point 75-76 ° C NMR spectrum δ (CDCl ₃ ): 1.27 (3H, t), 1.30 (3H, t), 1.8-2.0 (1H, m), 1.9-2.0 (1H,
m), 2.4-2.5 (2H, m), 3.1-3.3 (2H, m), 3.2-3.4 (1H, m), 3.
4-3.5 (1H, m), 4.1-4.3 (5H, m) .MS (m / z): 285 (M ⁺ )

Test Example Effect on liver injury (hepatitis) model induced by D-galactosamine Experimental animal: SD male rats (body weight 170 to 200 g) were used. Drug administration: Each of the test drugs was suspended in a 1% aqueous solution of methylcellulose and orally administered at a dose of 200 mg / kg one hour before the onset of liver injury.

Induction of galactosamine liver injury (hepatitis): D-
Galactosamine hydrochloride 800 mg / kg was subcutaneously administered to rats,
Caused liver damage. Fast after D-galactosamine administration,
24 hours later, blood was collected from the descending vena cava under ether anesthesia,
The GPT value, which is an index of liver damage, was measured. Results: The results are shown in Table 8.

[0101]

[Table 8]

As is clear from Table 8, the GPT value of the test compound administration group was significantly lower than that of the pathological control group.
Therefore, it was shown that the compound of the present invention has an improving or preventive effect on liver damage (hepatitis) induced by administration of D-galactosamine hydrochloride.

─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Shuichi Yokohama 1-16-13 Kitakasai, Edogawa-ku, Tokyo Inside Daiichi Pharmaceutical Central Research Institute (72) Toru Hosougami 1-1-16 Kitakasai, Edogawa-ku, Tokyo No. 13 Central Research Laboratory of Daiichi Pharmaceutical Co., Ltd. (56) Reference JP-A-60-172977 (JP, A) JP-A-50-10622 (JP, A) JP-A-4-208290 (JP, A) US Patent 4536512 ( US, A) US Patent 4033978 (US, A) US Patent 3920672 (US, A) SYNTHESIS, 1990, No. 2, pp. 162-7 SYBTHESIS, 1989, No. 2, pp. 141-142 Z. Chem. , 1988, Vol. 28, No. 6, pp. 214-215 SYNTHESIS, 1988, No. 4, pp. 284-6 J.I. Med. Chem. , 1988, Vol. 31, No. 7, pp. 1427-9 J.I. Chem. Soc. Parkin Trans. 2, 1987, No. 2, pp. 591-J. Heterocyclic Ch em. , 1986, Vol. 23, No. 6, pp. 1889 J. Chem. Soc. Parkin Trans. 1, 1986, No. 7, pp. 1255 Aust. J. Chem. , 1986, Vol. 39, No. 6, pp. 887-92 Heterocycles, 1985, Vol. 23, No. 12, pp. 2995-8 Aust. J. Chem. , 1984, Vol. 34, No. 7, pp. 1473-81 J. Org. Chem. , 1980, Vol. 45, No. 24, pp. 5008-9 J.I. Chem. Soc. Jpn. , 1980, Vol. 53, No. 11, pp. 3308-1 Chem. Let. , 1980, No. 3, pp. 223-4 J. Chem. Soc. Parkin Trans 1, 1979, No. 10, pp. 2334 Heterocycles, 1977, Vol. 8, pp. 455-9 Acta Crystallog r. , Sect. B, 1975, B31, No. 4, pp. 1217 J. Chem. Soc. Parkin Trans. 1, 1973, No. 6, pp. 657- Tetrahedron, 1972, Vol. 28, No. 16, pp. 4341-52 Tetrahedron, 1971, Vol. 27, No. 17, pp. 4171-78 (58) Fields surveyed (Int.Cl. ⁷ , DB name) C07D 513/04 A61K 31/428 A61K 31/437 A61K 31/542 A61P 1/16 BIOSIS (STN) CAPLUS (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 hydrogen atom; a halogen atom; a hydroxyl group; a cyano group;
It has one or more substituents selected from halogen atom, hydroxyl group, amino group, alkoxy group, cycloalkyl group, aryl group, aryloxy group, carboxyl group, alkoxycarbonyl group, carbamoyl group and mono- or dialkylamino group. Optionally alkyl group; halogen atom, hydroxyl group, amino group, alkoxy group, cycloalkyl group, aryl group, aryloxy group, carboxyl group,
A cycloalkyl group which may have one or more substituents selected from an alkoxycarbonyl group, a carbamoyl group and a mono- or dialkylamino group; a halogen atom,
Alkyl group, alkoxy group, hydrogen group, halogenoalkyl group, hydroxyalkyl group, alkoxyalkyl group, amino group, mono- or dialkylamino group, cyano group,
An aryl group or a heteroaryl group which may have one or more substituents selected from a carboxyl group and an alkyloxycarbonyl group; a halogen atom, an alkyl group, an alkoxy group, a hydrogen group or a halogeno in the aryl part or the heteroaryl part. Aralkyl group or hetero group which may have one or more substituents selected from alkyl group, hydroxyalkyl group, alkoxyalkyl group, amino group, mono- or dialkylamino group, cyano group, carboxyl group and alkyloxycarbonyl group. Aralkyl group; Carboxyl group; Sulfamoyl group; Alkoxycarbonyl group; Cycloalkyloxycarbonyl group; Alkenyloxycarbonyl group; Alxyloxycarbonyl group;
One or more selected from a halogen atom, an alkyl group, an alkoxy group, a hydrogen group, a halogenoalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an amino group, a mono- or dialkylamino group, a cyano group, a carboxyl group and an alkyloxycarbonyl group. Aryloxycarbonyl group or heteroaryloxycarbonyl group which may have a substituent; formyloxy group; formyl group; alkylcarbonyl group; cycloalkylcarbonyl group; halogen atom, alkyl group, alkoxy group, hydrogen group, halogenoalkyl Group, hydroxyalkyl group, alkoxyalkyl group, amino group, mono- or dialkylamino group, cyano group, carboxyl group, and arylcarbo group which may have one or more substituents selected from alkyloxycarbonyl group. Group or heteroarylcarbonyl group; halogen atom, alkyl group, alkoxy group, hydrogen group, halogenoalkyl group, hydroxyalkyl group, alkoxyalkyl group, amino group, mono- or dialkylamino group, cyano group in the aryl or heteroaryl moiety , An aralkylcarbonyl group or a heteroaralkylcarbonyl group optionally having one or more substituents selected from a carboxyl group and an alkyloxycarbonyl group; (R ⁷ and R ⁸ are the same or different and each is a hydrogen atom;
10 alkyl groups; cyclic alkyl groups having 3 to 7 carbon atoms;
Alkenyl group; alkynyl group; halogen atom, alkyl group, alkoxy group, hydrogen group, halogenoalkyl group, hydroxyalkyl group, alkoxyalkyl group, amino group,
An aryl group or a heteroaryl group which may have one or more substituents selected from a mono- or dialkylamino group, a cyano group, a carboxyl group and an alkyloxycarbonyl group; , An alkoxy group, a hydrogen group, a halogenoalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an amino group, a mono- or dialkylamino group, a cyano group, a carboxyl group and an alkyloxycarbonyl group. Optionally substituted aralkyl group or heteroaralkyl group; cyclic alkyl-alkyl group; hydroxyl group; alkoxy group; amino group; mono- or dialkylamino group; alkylaminoalkyl group; hydroxyalkyl group; mono-, di- or trihalogenoalkyl group; Alkoxycarbonyl group; an alkoxycarbonylalkyl group; 2-oxo tetrahydrothienyl group; or R ⁷ and R ⁸ may form a five to seven-membered heterocyclic ring together with the nitrogen atom to which they are attached)
R ² is a cyano group, a carboxyl group, an alkoxycarbonyl group or (R ⁷ and R ⁸ are the same or different and each is a hydrogen atom or a carbon number of 1 to
10 alkyl groups, or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached may form a 5-membered to 7-membered heterocycle), R ³ , R ⁴ , R ⁵ and R ⁶ Are the same or different hydrogen atoms;
Halogen atom; hydroxyl group; cyano group; one selected from halogen atom, hydroxyl group, amino group, alkoxy group, cycloalkyl group, aryl group, aryloxy group, carboxyl group, alkoxycarbonyl group, carbamoyl group, mono- or dialkylamino group Alkyl group which may have the above substituents; halogen atom, hydroxyl group, amino group, alkoxy group, cycloalkyl group, aryl group, aryloxy group, carboxyl group, alkoxycarbonyl group, carbamoyl group, mono- or dialkylamino A cycloalkyl group which may have one or more substituents selected from the group; alkenyl groups; alkynyl groups; halogen atoms, alkyl groups, alkoxy groups, hydrogen groups, halogenoalkyl groups, hydroxyalkyl groups, alkoxyalkyl groups , Amino group, Or an aryl group or a heteroaryl group which may have one or more substituents selected from a dialkylamino group, a cyano group, a carboxyl group and an alkyloxycarbonyl group; a halogen atom or an alkyl group in the aryl part or the heteroaryl part. , An alkoxy group, a hydrogen group, a halogenoalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an amino group, a mono- or dialkylamino group, a cyano group, a carboxyl group and an alkyloxycarbonyl group. Optionally substituted aralkyl group or heteroaralkyl group; carboxyl group; carbamoyl group; monoalkylaminocarbonyl group; alkoxycarbonyl group; cycloalkyloxycarbonyl group; alkenyloxycarbonyl group; halogen atom, alkyl group, It has at least one substituent selected from a lucoxy group, a hydrogen group, a halogenoalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an amino group, a mono- or dialkylamino group, a cyano group, a carboxyl group and an alkyloxycarbonyl group. Optionally aryloxycarbonyl group or heteroaryloxycarbonyl group; formyloxy group; formyl group; alkylcarbonyl group; cycloalkylcarbonyl group; halogen atom, alkyl group, alkoxy group, hydrogen group, halogenoalkyl group, hydroxyalkyl group, An arylcarbonyl group or a heteroarylcarbyl group which may have one or more substituents selected from an alkoxyalkyl group, an amino group, a mono- or dialkylamino group, a cyano group, a carboxyl group and an alkyloxycarbonyl group. Halogen atom, alkyl group, alkoxy group, hydrogen group, halogenoalkyl group, hydroxyalkyl group, alkoxyalkyl group, amino group, mono- or dialkylamino group, cyano group, carboxyl group and alkyl group for the bonyl group, aryl moiety or heteroaryl moiety Is an aralkylcarbonyl group or heteroaralkylcarbonyl group optionally having one or more substituents selected from oxycarbonyl groups (provided that the bond between the 5th and 6th positions is a double bond, One of R ³ and R ⁴ and R ⁵ and R ⁶
Or one of R ³ and R ⁴ and one of R ⁵ and R ⁶ together form an alkyl group, alkoxy group, cycloalkyl, cycloalkoxy, hydroxyl group, halogen atom, amino group. , A mono- or dialkylamino group, a cyano group, a carboxyl group and an alkoxycarbonyl group may form an alkylene group having 3 to 5 carbon atoms, which may have one or more substituents. R ³ and R ⁴ may combine with the adjacent carbon atom to form a carbonyl group or a thiocarbonyl group. Z represents a single bond, a methylene group, an ethylene group, an oxygen atom, a sulfur atom, SO, SO ₂ or NR ⁹ (R ⁹ represents a hydrogen atom or a lower alkyl group having 1 to 10 carbon atoms)] A represented polycyclic fused thiazole derivative or a salt thereof. 2. R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and each is a hydrogen atom or a halogen atom, a hydroxyl group, an amino group, an alkoxy group, a cycloalkyl group, an aryl group, an aryloxy group, a carboxyl group, An alkoxycarbonyl group,
It is an alkyl group optionally having one or more substituents selected from a carbamoyl group and a mono- or dialkylamino group, or R ³ and R ⁴ together with an adjacent carbon atom form a carbonyl group or a thiol group. The polycyclic fused thiazole derivative or a salt thereof according to claim 1, which forms a carbonyl group. 3. The polycyclic fused thiazole derivative or a salt thereof according to claim 1, wherein R ¹ is a cyano group or an alkoxycarbonyl group.