JP3000295B2 - Pyrrolo [2,1-b] thiazole derivatives and agents for preventing / treating liver diseases containing the same - Google Patents

Description

The present invention relates to a pyrrolo [2,1-b] thiazole derivative or a salt thereof and an excellent hepatocellular degeneration / necrosis inhibitory action and liver damage improving action containing the same. A prophylactic / therapeutic agent for liver disease having

[Problems to be solved by conventional technology and invention]

Conventionally, treatment of liver disease includes rest therapy, high protein and high calorie diet, general therapy such as abstinence, general drug therapy such as vitamins, strong hepatic drugs, corticosteroids such as prednisolone, glycyrrhizin preparations, interferon, etc. Immunostimulants have been widely used.

However, clinically used glycyrrhizin preparations and interferons 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.

[Means for solving the problem]

In view of the above situation, the present inventors have conducted intensive studies to obtain a novel substance that can be a prophylactic / therapeutic agent for liver disease.
The present inventors have found that a compound having a specific substituent at the 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 (In the formula, Represents a double bond or a single bond; R ¹ represents an alkyloxycarbonyl group; R ⁶ represents a hydrogen atom or a lower alkyl group; A represents ＝ CH—COR ⁹ (R ⁹ represents a hydroxyl group, a lower alkyl group, A phenyloxy group or a phenylthio group which may be substituted by an atom or a nitro group), (R ¹⁰ is a hydrogen atom, R ¹¹ is a cycloalkyl group, a phenyl group, a benzyl group, or indicates a pyridyl group, R ¹⁰ and R ¹¹ together, other nitrogen atom, contain an oxygen atom or a sulfur atom May form a heterocyclic ring), (R ⁸ is a hydrogen atom or an alkoxycarbonyl group) or -CH
_2- COR ¹⁹ (R ¹⁹ represents a hydroxyl group, an alkoxy group, an amino group, an alkylamino group, a morpholino group or a piperazinyl group)] or a salt thereof, or a salt thereof, And a prophylactic / therapeutic agent for liver disease.

In the case of 一般 A, the compound represented by the general formula (I) includes geometric isomers of E-form and Z-form, and any of these isomers is included in the present invention.

Specific examples of the compound of the present invention can be selected from the compounds shown in Tables 1 to 10 below.

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

Production Method A XC (R ² ) (R ³ ) COCH (R ⁸ ) COR ⁹ or XC (R ² ) (R ³ ) CH = C (R ⁸ ) COR ⁹ (Wherein, X represents a halogen atom, and R ¹ , R ⁶ , R ⁸ , R ⁹ and Have the same meanings as defined ^{above, R 2, R 3, R} 4, R 5, the compounds of the R ⁷ is a hydrogen atom) Formula ^{(II) XC (R 2)} (R 3) COCH (R 8) COR ⁹ or XC (R ² ) (R ³ ) CH ＝ C (R ⁸ ) COR ⁹ is reacted with a compound represented by the formula (Ia) in a suitable organic solvent in the presence or absence of a deoxidizing agent. ) Can be produced.

XC (R ² ) (R ³ ) COCH (R ⁸ ) COR ⁹ or XC (R ² ) (R ³ ) CH
= C Examples of (R ⁶⁾ COR ^9, the 4-Harogenoaseto acid lower alkyl ester, 4- 4- Harogenoaseto acetate
Nitrophenyl S-L, 4-halogenoacetoacetic acid-2,
4,6-trichlorophenyl ester, 4-halogenoacetothioacetic acid phenyl ester, 4-halogenoacetoacetic acid
2,2,2-trichloroethyl ester, 4-halogenocrotonic acid lower alkyl ester, halogenoacetylmalonic acid di-lower alkyl ester, α-cyano-γ-halogenoacetoacetic acid lower alkyl ester, halogenoacetylacetone, N-ethoxycarbonyl-4- Halogeno-3-
Oxobutanamide, N-aryl-4-halogeno-3
-Oxobutanamide and lower alkyl-substituted derivatives thereof.

Examples of the solvent include alcohol solvents such as methanol, ethanol and isopropyl alcohol; ether solvents such as ether and tetrahydrofuran; and benzene solvents such as benzene, toluene and xylene. Potassium carbonate, sodium carbonate,
An inorganic base such as sodium bicarbonate or sodium acetate,
Organic bases such as potassium acetate and triethylamine can be given. The reaction is usually performed at room temperature to 100 ° C for several hours to one day and night.

Manufacturing method B (Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ¹⁰ , R ¹¹ and Is the same as described above, and R ²¹ has a lower alkoxy group having 1 to 10 carbon atoms, a cyclic alkoxy group having 3 to 7 carbon atoms, a mono-, di- or trihalogeno lower alkoxy group, and one or more substituents. Or an arylthio group which may have one or more substituents). The compound of formula (Ib) is prepared by reacting a compound of formula (Ib) with or without a metal salt. By reacting with an amine represented by the formula (I)
The compound of c) can be produced.

Examples of the metal salt include a silver salt such as silver trifluoroacetate and a copper salt such as cuprous iodide. A solvent need not be used, but water, an alcohol solvent such as methanol, ethanol, or isopropyl alcohol, an ether solvent such as dioxane or tetrahydrofuran, dichloromethane, chloroform or the like can also be used. The reaction is carried out at 0 ° C to 80 ° C for 1 hour to 1 day and night. Preferably, the reaction is carried out for several hours at about room temperature in the presence of a metal salt using an active ester of the formula (Ib) wherein R ²¹ is 4-nitrophenoxy, 2,4,6-trichlorophenoxy or phenylthio.

Manufacturing method C (Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ²¹ are the same as above). (I
The compound of d) can be produced. The hydrolysis is preferably performed using zinc dust in water or an 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. The reaction is carried out at room temperature to 80 ° C for several hours.

Manufacturing method D (Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and Is the same as described above, and R ³¹ is (R ¹⁰ and R ¹¹ are the same as described above) or an aryloxy group or an arylthio group which may have one or more substituents. Or an aromatic compound having a mercapto group or a formula By reacting the compound represented by the formula (Ie)
Can be produced.

When directly reacting the compound of the formula (Id), 4-N, N- in a solvent such as tetrahydrofuran or dichloromethane is used.
Dimethylaminopyridine, 1-hydroxybenztriazole or N, N'-dicyclohexylcarbodiimide,
The reaction is carried out in the presence of a carbodiimide such as N, N'-diisopropylcarbodiimide or in the presence of 1,1'-carbodiimidazole. The mixed acid anhydride of the compound of the formula (Id) can be obtained by reacting with an alkyl carbonate, pivalic acid or a derivative thereof in a solvent such as tetrahydrofuran in the presence of a base such as triethylamine.
The reaction is usually performed at about room temperature for 1 hour to 24 hours.

Manufacturing method E (Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and A is the same as described above.) The compound of the formula (Ig) can be produced by reacting the compound of the formula (If) with a dehydrogenating agent in a suitable organic solvent.

Examples of the dehydrogenating agent include palladium black, manganese dioxide, chloranil, and 2,3-dichloro-5,6-dicyanoparabenzoquinone. Solvents include dichloromethane, dichloroethane, chloroform, dioxane,
Examples thereof include tetrahydrofuran or a mixed solvent thereof. The reaction is usually performed at a temperature of -10 ° C to 80 ° C for several hours. Preferably, the reaction is carried out at room temperature for about 1 hour using 2,3-dichloro-5,6-dicyanoparabenzoquinone in a mixed solvent of tetrahydrofuran and dichloromethane.

Manufacturing method F (Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and Is the same as described above.) The compound of the formula (Ih) is reacted with pyridine and trifluoroacetic anhydride in dioxane, chloroform, dichloromethane or a mixed solvent thereof to obtain a compound of the formula (Ih).
The compound of i) can be produced. Reaction is 0 ° C ~ 30
It is carried out at about ° C for several hours.

Manufacturing method G (Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and Is the same as described above, and R ⁴¹ represents a lower alkoxy group having 1 to 10 carbon atoms.) Reduction of the compound of the formula (I j) with a reducing agent such as lithium aluminum hydride in an organic solvent such as tetrahydrofuran. Can produce the compound of the formula (Ik). The reaction is usually carried out at a temperature of from ice cooling to room temperature for 0.5 hours to several hours.

The starting compound of the formula (II) can be prepared by a known method (Pharmaceutical Journal Vol. 92, pp. 465-470, 1972; Pharmaceutical Journal Vol. 95, p. 889 1
975 FARM, ED SCI 30 917-926 1976, Agr. Biol.
Chem. 37, 649 pages, 1973, Journal of the American
Chemical Society 66 1883, Bull.Soc..Chim.Fr.5
93-603 1962, Synthesis 138 1957 Nouv.
J. Chim. 4, pp. 47-51 (1980)), and can be produced by an appropriate combination. More specifically, it can be produced by the method described in Reference Examples described later.

When the compound (I) of the present invention obtained as described above is used as a medicament, its administration method may be either 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 symptoms, age, body weight, etc. of the patient.In general, in the case of oral administration, 1 mg to 300 mg / day per adult, preferably 10 mg to 200 mg
/ Day is appropriate.

Examples of the dosage form include tablets, capsules, powders, granules, and the like, which can be produced by a known pharmaceutical injection together with additives such as ordinary excipients, lubricants, and binders.

〔The invention's effect〕

The compound of the present invention showed an excellent hepatic injury ameliorating effect in an experimental liver injury (hepatitis) model induced by D-galactosamine. Furthermore, the compound of the present invention also exhibited an excellent liver injury-ameliorating effect in a rat complement-dependent liver injury model (iv. Ayumi, 146, 3, 179-180 (1988)) by intravenous administration of an anti-hepatic cell membrane monoclonal antibody. .

Therefore, the compound of the present invention is useful as a prophylactic and therapeutic agent for liver diseases, for example, liver disorders involving necrosis of hepatic parenchymal cells, chronic hepatitis, liver cirrhosis and the like.

〔Example〕

Hereinafter, the present invention will be further described with reference examples, examples, and test examples, but the present invention is not limited thereto.

Reference Example 1 tert-butyl 2-oxopyridine-3-carboxylate 3.3 g of potassium hydroxide was dissolved in 200 ml of ethanol, 8.6 g of isopropyl-2-oxopyrrolidine-3-carboxylate was added, and the mixture was stirred at 50 ° C. for 0.5 hour. After ethanol was distilled off under reduced pressure, 30 ml of water and 4 ml of concentrated hydrochloric acid were added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. To the residue obtained by distilling off the solvent, tetrahydrofuran 100 ml, tert-butyl alcohol 1.7 g, 4-dimethylaminopyridine 0.3 g and N,
4.8 g of N'-dicyclohexylcarbodiimide is added and stirred at room temperature for 1 hour. After 2 ml of acetic acid is added to the reaction solution, insolubles are removed by filtration and extracted with chloroform. The chloroform layer is washed with a saturated aqueous solution of sodium hydrogencarbonate and further with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography to obtain 3.4 g of the title compound.

Melting point 66-67 ° C NMR spectrum δ (CDCl ₃ ): 1.49 (9H, s), 2.2-2.6 (2H, m), 3.1-3.7 (3H, m). Reference Example 2 The compound of Reference Example 2 was produced in the same manner as in Reference Example 1.

2,4,6-Trichlorophenyl 4-methyl-2-oxopyrrolidine-3-carboxylate Oil NMR spectrum δ (CDCl ₃ ): 1.31 (3H, d), 2.9-3.3 (2H, m), 3.3-3.5 (1H, m),
3.5-3.9 (1H, m), 7.38 (2H, s). Reference Example 3 2,4,6-Trichlorophenyl 4-methyl-2-thioxopyrrolidine-3-carboxylate 6.4 g of 2,4,6-trichlorophenyl 4-methyl-2-oxopyrrolidine-3-carboxylate and 4.4 g of phosphorus sulfide is added to 50 ml of benzene and stirred at 50 ° C. for 2 hours.
The insoluble material was removed by filtration, and the residue obtained by evaporating the solvent was purified by silica gel column chromatography to obtain the title compound.
3.9 g was obtained.

Melting point 158-160 ° C NMR spectrum δ (CDCl ₃ ): 1.33 (3H, d), 3.0-3.5 (2H, m), 3.7-4.3 (2H, m),
7.37 (2H, s). Reference Example 4 N-methyl-4-methyl-2-thioxopyrrolidine-3
-Carboxamide 2,4,6-Trichlorophenyl 4-methyl-2-thioxopyrrolidine-3-carboxylate 0.75 g is dissolved in tetrahydrofuran 5 ml, and a 40% monomethylamine aqueous solution 0.3
Add 0 g and stir at room temperature for 0.5 hour. 30 ml of water and 1 ml of acetic acid are added to the reaction solution, and the mixture is extracted with chloroform. The chloroform layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue obtained was purified by silica gel column chromatography to obtain 0.22 g of the title compound.

Melting point 181-183 ° C NMR spectrum δ (CDCl ₃ -DMSO-d ⁶ ): 1.18 (3H, d), 2.83 (3H, d), 3.0-3.4 (3H, m), 3.4-
4.0 (1H, m). Reference Example 5 Phenacyl 2-oxopyrrolidine-3-carboxylate 7.0 g of potassium hydroxide was dissolved in 400 ml of ethanol, and isopropyl 2-oxopyrrolidine-3-carboxylate was dissolved.
Add 17.2 g and stir at 50 ° C. for 1 hour. After ethanol was distilled off under reduced pressure, 20 ml of water and 8.8 ml of concentrated hydrochloric acid were added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. 20 ml of chloroform, 5 ml of triethylamine and 6.7 g of phenacyl bromide are added to the residue obtained by distilling off the solvent, and the mixture is stirred at room temperature for 1 hour. Chloroform is added to the reaction solution, washed with water, and dried over anhydrous sodium sulfate. Then, the residue obtained by distilling off the solvent was purified by silica gel column chromatography, and then crystallized from ether to obtain 8.0 g of the title compound.

NMR spectrum δ (CDCl ₃ ): 2.1 to 2.8 (2H, m), 3.3 to 3.7 (3H, m), 5.36 (1H, d),
5.52 (1H, d), 7.3 to 8.1 (5H, m). Reference Example 6 tert-butyl 2-thiopyrrolidine-3-carboxylate 1.7 g of tert-butyl 2-oxopyrrolidine 3-carboxylate and 1.8 g of Lawesson's reagent were added to 20 ml of benzene, and the mixture was stirred at 50 to 60 ° C for 1 hour. After filtering off the insoluble matter, the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography to obtain 1.0 g of the title compound.

110-111 ° C NMR spectrum δ (CDCl ₃ ): 1.50 (9H, s), 2.3-2.7 (2H, m), 3.4-4.0 (3H, m). The compounds of Reference Examples 7 to 14 were produced in the same manner as in Reference Example 6.

Reference Example 7 Isopropyl 5-methyl-2-thioxopyrrolidine-3
-Carboxylate Melting point 123-125 ° C NMR spectrum δ (CDCl ₃ ): 1.37 (6H, d), 1.42 (3H, d), 1.9-2.4 (1H, m), 2.4-
2.9 (1H, m), 3.7 ~ 4.0 (1H, m), 4.0 ~ 4.5 (1H, m), 5.0
5.45.4 (1H, m). Reference Example 8 Ethyl 5-methyl-2-thioxopyrrolidine-3-carboxylate Melting point 124-125 ° C NMR spectrum δ (CDCl ₃ ): 1.35 (3H, t), 1.38 (3H, d), 2.0-2.3 (1H , m), 2.6 ~
2.8 (2H, m), 3.81 (1H, t), 4.28 (1H, t). Reference Example 9 ethyl 4,5-dimethyl-2-thioxopyrrolidine-3-
Carboxylate Melting point 81-83 ° C NMR spectrum δ (CDCl ₃ ): 1.0-1.5 (9H, m), 2.3-3.2 (1H, m), 3.3-3.6 (1H,
m), 3.6-4.1 (1H, m), 4.1-4.5 (2H, m). Reference Example 10 Isopropyl 4,4-dimethyl-2-thioxopyrrolidine-3-carboxylate Melting point 94-96 ° C NMR spectrum δ (CDCl ₃ ): 1.20 (6H, d), 1.25 (3H, d), 1.32 (3H , d), 3.28 (1H,
dd), 3.38 (1H, s), 3.67 (1H, d), 5.09 (1H, sept). Reference Example 11 diethyl 2-thioxopyrrolidine-3,5-dicarboxylate Melting point 57 ° C. NMR spectrum δ (CDCl ₃ ): 1.33 (6H, t), 2.78 (2H, t), 4.28 (4H, m), 4.55 (1H,
m). Reference Example 12 Isopropyl 2-thioxopyrrolidine-3-carboxylate Melting point 67-68 ° C NMR spectrum δ (CDCl ₃ ): 1.27 (3H, d), 1.30 (3H, d), 5.10 (1H, m). Reference Example 13 2-thioxopyrrolidine-3-carbonitrile, melting point: 126 to 130 ° C. Reference Example 14: Phenacyl 2-thioxopyrrolidine- ₃ -carboxylate, melting point: 126 to 127 ° C. NMR spectrum δ (CDCl ₃ ): 2.4 to 3.0 (2H) , m), 3.5-4.2 (3H, m), 4.45 (1H, d),
4.57 (1H, d), 7.4 to 8.2 (5H, m). Reference Example 15 Isobutyl 2-thioxopyrrolidine-3-carboxylate 10.0 g of isopropyl 2-thioxopyrrolidine-3-carboxylate was dissolved in 500 ml of isobutyl alcohol, and 22 ml of titanium tetraisopropoxide was added, followed by heating under reflux for 3 days. Excess isobutyl alcohol is distilled off under reduced pressure, water and benzene are added to the residue, and insolubles are removed by filtration.
The benzene layer is washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The residue obtained by distilling off benzene was purified by silica gel column chromatography to obtain 7.0 g of the title compound.

Melting point 97-98 ° C NMR spectrum δ (CDCl ₃ ): 0.97 (6H, d), 2.01 (1H, m), 2.3-2.7 (2H, m) 2.6-
3.0 (3H, m), 3.97 (2H, dd). The compounds of Reference Examples 16 to 23 were produced in the same manner as in Reference Example 15.

Reference Example 16 n-propyl 2-thioxopyrrolidine-3-carboxylate Melting point 64-65 ° C. NMR spectrum δ (CDCl ₃ ): 1.02 (3H, t), 1.72 (2H, tq), 2.3-2.7 (2H, m ), 3.5
~ 4.0 (3H, m), 4.02 (2H, td). Reference Example 17 n-butyl 2-thioxopyrrolidine-3-carboxylate Melting point 68-69 ° C NMR spectrum δ (CDCl ₃ ): 0.94 (3H, t), 1.1-1.8 (4H, m), 2.3-2.6 (2H , m),
3.5-3.9 (3H, m), 4.19 (2H, t). Reference Example 18 sec-butyl 2-thioxopyrrolidine-3-carboxylate Melting point 44-45 ° C NMR spectrum δ (CDCl ₃ ): 0.9-1.4 (6H, m), 1.65 (2H, m), 2.55 (2H, m ), 3.5〜
3.9 (3H, m), 4.84 (1H, m). Reference Example 19 3-Methyl-butyl 2-thioxopyrrolidine-3-carboxylate Melting point 84-86 ° C. Reference Example 20 3-Methyl-2-butenyl 2-thioxopyrrolidine-3
-Carboxylate Melting point 112-114 ° C NMR spectrum δ (CDCl ₃ ): 1.74 (3H, s), 1.78 (3H, s), 2.55 (2H, m), 3.6-4.0
(3H, m), 4.70 (2H, d), 5.40 (1H, t). Reference Example 21 isobutyl 4-methyl-2-thioxopyrrolidine-3-
Carboxylate Melting point 59-60 ° C NMR spectrum δ (CDCl ₃ ): 0.95 (6H, d), 1.21 (3H, d), 2.01 (1H, sept), 2.8-
3.6 (3H, m), 3.7 to 4.1 (1H, m), 3.99 (2H, d). Reference Example 22 Diisopropyl 2-thioxopyrrolidine-3,5-dicarboxylate Melting point 108-110 ° C NMR spectrum δ (CDCl ₃ ): 1.27 (6H, d), 1.30 (6H, d), 2.74 (2H, t) , 3.76 (1H,
t), 4.49 (1H, t), 5.07 (1H, m) 5.12 (1H, m). Reference Example 23 Isopropyl 4,5-dimethyl-2-thioxopyrrolidine-3-carboxylate Melting point 90-92 ° C NMR spectrum δ (CDCl ₃ ): 1.0-1.5 (12H, m), 2.2-3.2 (1H, m) , 3.3 to 3.6 (1H,
m), 3.6-4.4 (1H, m), 4.9-5.4 (1H, m). Reference Example 24 Isopropyl 5-hydroxymethyl-2-thioxopyrrolidine-3-carboxylate 47.9 g of diisopropyl 2-thioxopyrrolidine-3,5-dicarboxylate was dissolved in a mixed solvent of 400 ml of chloroform and 200 ml of isopropyl alcohol, and hydrogen Add 9.7 g of sodium borohydride and stir at room temperature for 5 days. The reaction solution is acidified by adding 10% hydrochloric acid, and then made weakly alkaline with a saturated aqueous solution of sodium hydrogen carbonate, and the solvent is distilled off.
The residue is dissolved in chloroform, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent is purified by silica gel column chromatography to obtain 27.1 g of the title compound.

Melting point 108-110 ° C NMR spectrum δ (CDCl ₃ ): 1.29 (3H, d), 1.33 (3H, d), 2.0-2.8 (2H, m), 3.0-
4.4 (4H, m), 5.09 (1H, m). Example 1 Ethyl (7-n-propoxycarbonyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetate n-Prohill 2-thioxopyrrolidine-3-carboxylate 3.5 g, anhydrous sodium acetate 3.3 g and 4-bromoacetoacetic acid ethyl ester 6.6 g are added to ethanol 60 ml and stirred at room temperature for 1 hour. Water is added to the reaction solution, and the precipitated crystals are collected by filtration. Dissolve the crude crystals in chloroform,
After washing with water, it is dried over anhydrous sodium sulfate. After the chloroform was distilled off, the crystals were collected by filtration with ether to obtain 2.9 g of the title compound.

122-124 ° C NMR spectrum δ (CDCl ₃ ): 0.99 (3H, t), 1.28 (3H, t), 1.65 (2H, qt), 3.0-3.3
(2H, m), 3.5-3.8 (2H, m), 4.11 (2H, t), 4.16 (2H, m
q), 4.7-4.9 (3H, m). In the same manner as in Example 1, the following compounds of Examples 2 to 21 were produced.

Example 2 Ethyl (7-isobutoxycarbonyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetate Melting point 165-168 ° C NMR spectrum δ (CDCl ₃ ): 0.97 ( 6H, d), 1.27 (3H, t), 2.00 (1H, m), 3.1 ~ 3.4
(2H, m), 3.6 to 3.9 (2H, m), 3.93 (2H, d), 4.14 (2H, m
q), 4.83 (3H, m). Example 3 Ethyl (7-tert-butoxycarbonyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazole-3-ylidene) acetate Melting point 178-180 ° C. NMR spectrum δ (CDCl ₃ ): 1.30 (3H, t), 1.50 (9H, s), 3.0 ~ 3.3 (2H, m), 3.5 ~
3.9 (2H, m), 4.18 (2H, q), 4.87 (3H, s). Example 4 Ethyl (7-sec-butoxycarbonyl) -2,3,5,6-tetrahydropyrrolo [2,1-b] thiazole-3-ylidene) acetate Melting point 97-98 ° C. NMR spectrum δ (CDCl ₃ ): 0.94 (3H, t), 1.26 (3H, d), 1.28 (3H, t), 1.62 (2H,
m), 3.19 (2H, t), 3.69 (2H, t), 4.16 (2H, q), 4.84 (3
H, m), 4.95 (1H, m). Example 5 Ethyl [7- (3-methylbutoxycarbonyl) -2,3,
5,6-tetrahydropyrrolo [2,1-b] thiazole-3-
[Ilidene] acetate Melting point 133-135 ° C NMR spectrum δ (CDCl ₃ ): 0.95 (6H, d), 1.29 (3H, t), 1.4-1.9 (3H, m), 3.19
(2H, t), 3.68 (2H, t), 4.15 (2H, q), 4.18 (1H, t), 4.
83 (3H, s). Example 6 Ethyl [7- (3-methyl-2-butenyloxycarbonyl) -2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetate Melting point 149-150 ° C NMR Spectrum δ (CDCl ₃ ): 1.30 (3H, t), 1.76 (3H, s), 1.78 (3H, s), 3.20 (2H,
t), 3.69 (2H, t), 4.16 (2H, q), 4.66 (2H, d), 4.83 (3
H, s), 5.40 (1H, t). Example 7 Ethyl (7-n-butoxycarbonyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetate Melting point 131-132 ° C. NMR spectrum δ (CDCl ₃ ): 0.94 (3H, t), 1.27 (3H, t), 1.1 ~ 1.8 (4H, m), 3.0 ~
3.3 (2H, m), 3.5-3.8 (2H, m), 4.14 (2H, q), 4.14 (2
H, t), 4.81 (3H, s). Example 8 Ethyl (7-phenacyloxycarbonyl-2,3,5,6-
Tetrahydropyrrolo [2,1-b] thiazole-3-ylidene) acetate Melting point 192-194 ° C NMR spectrum δ (CDCl ₃ ): 1.23 (3H, t), 3.0-3.3 (2H, m), 3.6-4.0 (2H , m),
4.10 (2H, q), 4.88 (2H, s), 5.00 (1H, s), 5.51 (2H,
s), 7.5-8.2 (5H, m). Example 9 Ethyl (7-isobutoxycarbonyl-6-methyl-2,
3,5,6-tetrahydropyrrolo [2,1-b] thiazole-3
-Ilidene) acetate Melting point 122-124 ° C NMR spectrum δ (CDCl ₃ ): 0.99 (6H, d), 1.27 (3H, t), 1.34 (3H, d), 1.99 (1H,
sept), 3.1 ~ 3.3 (1H, m), 3.4 ~ 4.0 (4H, m), 4.14 (2H, m
q), 4.78 (2H, d), 4.84 (1H, t). Example 10 Ethyl (7-methoxycarbonyl-6-methyl-2,3,5,
6-tetrahydropyrrolo [2,1-b] thiazole-3-ylidene) acetate Melting point 154-156 ° C NMR spectrum δ (CDCl ₃ ): 1.27 (3H, t), 1.31 (3H, d), 3.1-3.3 (1H , m), 3.4〜
3.9 (2H, m), 3.73 (3H, s), 4.14 (2H, q), 4.77 (2H,
d), 4.85 (1H, t). Example 11 Ethyl [7- (N-methylcarbamoyl) -6-methyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazole-3-ylidene] acetate Melting point 228-230 ° C Elemental analysis (As C ₁₃ H ₁₈ N ₂ O ₃ S) Calculated value (%): C55.30 H6.43 N9.92 Actual value (%): C55.23 H6.43 N9.89 NMR spectrum δ (CDCl ₃ ): 1.25 (3H, t), 1.28 (3H, d), 2.80 (3H, d), 3.28 (1H,
dd), 3.2-3.8 (1H, m), 3.84 (1H, dd), 4.10 (2H, q),
4.71 (2H, d), 4.78 (1H, t). Example 12 Ethyl [5,7-bis (ethoxycarbonyl) -2,3,5,6-
Tetrahydropyrrolo [2,1-b] thiazole-3-ylidene] acetate Melting point 121-122 ° C Elemental analysis (as C ₁₆ H ₂₁ NO ₆ S) Calculated (%): C54.07 H5.96 N3.94 Actual measurement Value (%): C54.13 H5.99 N3.93 NMR spectrum δ (CDCl ₃ ): 1.26 (3H, t), 1.29 (3H, t), 1.31 (3H, t), 3.16 (1H,
dd), 3.58 (1H, dd), 4.13 (2H, q), 4.19 (2H, q), 4.28
(2H, q), 4.53 (1H, dd), 4.83 (3H, brs). Example 13 Ethyl (7-ethoxycarbonyl-5-hydroxymethyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetate Melting point 187-189 ° C. Elemental analysis value (C ₁₄ H ₁₉ NO ₅ as S) calculated (%): C53.66 H6.11 N4.47 Found (%): C53.38 H5.90 N4.27 NMR spectrum _{δ (CDCl 3): 1.28 (} 3H, t ), 1.31 (3H, t), 3.09 (1H, dd), 3.37 (1
H, dd), 3.78 (2H, m), 3.9 ~ 4.4 (5H, m), 4.82 (2H, br
s), 5.16 (1H, br s). Example 14 Ethyl (7-isopropoxycarbonyl-6,6-dimethyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetate Melting point 132-133 ° C Elemental analysis ( (Calculated as C ₁₆ H ₂₃ NO ₄ S) Calculated value (%): C59.05 H7.12 N4.30 Observed value (%): C59.15 H7.07 N4.23 NMR spectrum δ (CDCl ₃ ): 1.27 (3H) , t), 1.28 (6H, d), 1.40 (6H, s), 3.38 (2H,
s), 4.14 (2H, q), 4.76 (2H, d), 4.86 (1H, d), 5.07 (1
H, m). Example 15 Ethyl (6-ethyl-7-isopropoxycarbonyl-
2,3,5,6-tetrahydropyrrolo [2,1-b] thiazole-
3-ylidene) acetate Melting point 97-98 ° C Elemental analysis (as C ₁₆ H ₂₃ NO ₄ S) Calculated (%): C59.05 H7.12 N4.30 Observed (%): C59.03 H7.10 N4.24 NMR spectrum δ (CDCl ₃ ): 0.88 (3H, t), 1.27 (3H, t), 1.27 (6H, d), 1.3 to 2.1
(2H, m), 3.0-3.9 (3H, m), 4.14 (2H, q), 4.75 (2H,
d), 4.87 (1H, t), 5.01 (1H, sept). Example 16 Ethyl [7-ethoxycarbonyl-6- (3,4,5-trimethoxyphenyl) -2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene] acetate Melting point 202 204204 ° C. Elemental analysis value (as C ₂₂ H ₂₇ NO ₇ S) Calculated value (%): C58.78 H6.05 N3.12 Actual value (%): C58.63 H6.13 N3.03 NMR spectrum δ ( CDCl ₃ ): 1.17 (3H, t), 1.25 (3H, t), 3.53 (1H, dd), 3.81 (3
H, s), 3.83 (6H, s), 3.9 ~ 4.1 (5H, m), 4.61 (1H, dd),
4.85 (3H, brs), 6.41 (2H, s). Example 17 ethyl (7-ethoxycarbonyl-5-methyl-2,3,5,
6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetate Melting point 138-139 ° C Elemental analysis (as C ₁₄ H ₁₉ NO ₄ S) Calculated (%): C56.55 H6.44 N4. 71 Observed value (%): C56.63 H6.71 N4.60 NMR spectrum δ (CDCl ₃ ): 1.27 (3H, t), 1.29 (3H, t), 1.36 (3H, d), 2.72 (1H,
q), 3.45 (1H, q), 3.9 to 4.3 (5H, m), 4.78 (2H, d), 4.9
9 (1H, t). Example 18 Ethyl (5-hydroxymethyl-7-isopropoxycarbonyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazole-3-ylidene) acetate Melting point 140-141 ° C Elemental analysis (C ₁₅ H ₂₁ NO ₅ S) Calculated value (%): C55.03 H6.47 N4.28 Observed value (%): C55.04 H6.44 N4.38 NMR spectrum δ (CDCl ₃ ): 1.26 (6H, d), 1.26 (3H, t), 2.62 (1H, t), 3.06 (1H,
dd), 3.38 (1H, dd), 3.7-4.3 (2H, m), 4.12 (2H, q),
4.78 (2H, s), 5.04 (1H, m), 5.12 (1H, s). Example 19 Ethyl (7-isopropoxycarbonyl-5,6-dimethyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetate Oil NMR spectrum δ (CDCl ₃ ) : 1.1 to 1.5 (15H, m), 2.8 to 3.2 (1H, m), 3.5 to 3.9 (1H,
m), 4.14 (2H, q), 4.76 (2H, d), 4.98 (1H, t), 5.06 (1
H, sept). Example 20 Ethyl (7-cyano-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetate Melting point 173-174 ° C. NMR spectrum δ (CDCl ₃ ): 1.29 (3H, t), 3.24 (2H, t), 3.69 (2H, t), 4.17 (2H,
q), 4.86 (1H, s), 4.92 (2H, s). Example 21 (±) ethyl (9-ethoxycarbonyl-2,3,4aα, 5,
6,7,8,8aβ-octahydrothiazolo [3,2-a] indole-3-ylidene) acetate Melting point 115-116 ° C Elemental analysis (as C ₁₇ H ₂₃ NO ₄ S) Calculated (%): C60.51 H6.87 N4.15 Observed value (%): C60.37 H6.77 N4.03 NMR spectrum δ (CDCl ₃ ): 1.28 (3H, t), 1.30 (3H, t), 1.4 to 3.5 ( 10H, m), 4.14
(2H, q), 4.21 (2H, q), 4.74 (2H, dd), 5.30 (1H, d). Example 22 isopropyl 3-acetonylidene-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazole-7-carboxylate 2.9 g of isopropyl 2-thioxopyrrolidone-3-carboxylate and 6.1 g of anhydrous sodium acetate The benzene
Add 80 ml and add bromoacetylacetone 5.
A solution of 5 g of benzene in 20 ml is added. After stirring at 50 ° C. for 1.5 hours, the benzene layer is washed with water and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography, and then recrystallized from a mixed solvent of ether and n-hexane to give 2.7 g of the title compound.
I got

Melting point 138-142 ° C Elemental analysis value (as C ₁₃ H ₁₇ NO ₃ S · 0.2H ₂ O) Calculated value (%): C57.63 H6.47 N5.17 Actual value (%): C57.77 H6.72 N5.35 NMR spectrum δ (CDCl ₃ ): 1.30 (6H, d), 2.20 (3H, s), 3.1 to 3.4 (2H, m), 3.6 to
3.9 (2H, m), 4.90 (2H, s), 5.12 (1H, sept), 5.37 (1H,
s). Example 23 4-nitrophenyl (7-isopropoxycarbonyl-
6-methyl-2,3,5,6-tetrahydropyrrolo [2,1-b]
Thiazole-3-ylidene) acetate isopropyl 4-methyl-2-thioxopyrrolidine-
Dissolve 8.9 g of 3-carboxylate in 200 ml of benzene,
To this are added 5.1 g of anhydrous sodium acetate and 16.7 g of 4-bromoacetoacetic acid 4-nitrophenyl ester, and the mixture is stirred at room temperature for 8 hours. The reaction solution is added with 500 ml of chloroform, washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was subjected to silica gel column chromatography.
Crystallization from a mixed solvent of -hexane gave 11.9 g of the title compound.

Melting point 182-183 ° C Elemental analysis value (as C ₁₉ H ₂₀ N ₂ O ₆ S) Calculated value (%): C56.43 H4.98 N6.93 Actual value (%): C56.41 H4.96 N6.85 NMR spectrum δ (CDCl ₃ ): 1.30 (6H, d), 1.38 (3H, d), 3.2 to 3.4 (1H, m), 3.5 to
4.1 (2H, m), 4.81 (2H, s), 5.05 (1H, s), 5.10 (1H, sep
t), 7.30 (2H, d), 8.28 (2H, d). The compounds of Examples 24 to 28 were produced in the same manner as in Example 23.

Example 24 (2,4,6-Trichlorophenyl) (7-isopropoxycarbonyl-6-methyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetate Melting point 164 166166 ° C. NMR spectrum δ (CDCl ₃ ): 1.28 (6H, d), 1.35 (3H, d), 3.33 (1H, dd), 3.5 to 3.9
(1H, m), 3.94 (1H, dd), 4.80 (2H, d), 5.10 (1H, sep
t), 5.12 (1H, t), 7.36 (2H, s). Example 25 S-phenyl (7-isopropoxycarbonyl-2,3,5,
6-tetrahydropyrrolo [2,1-b] thiazole-3-ylidene) thioacetate Melting point 216-220 ° C Elemental analysis (as C ₁₈ H ₁₉ NO ₃ S ₂ ) Calculated (%): C59.81 H5.30 N3.88 Observed value (%): C60.00 H5.44 N3.97 NMR spectrum δ (CDCl ₃ ): 1.28 (6H, d), 3.20 (2H, t), 3.72 (2H, t), 4.78 (2H) ,
s), 5.06 (1H, sept), 5.30 (1H, s), 7.44 (5H, s). Example 26 S-phenyl (7-isopropoxycarbonyl-6-methyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) thioacetate Melting point 153-154 ° C Elemental analysis (As C ₁₉ H ₂₁ NO ₃ S ₂ ) Calculated value (%): C60.77 H5.64 N3.73 Observed value (%): C60.67 H5.70 N3.71 NMR spectrum δ (CDCl ₃ ): 1.29 (6H, d), 1.35 (3H, d), 3.2 ~ 4.0 (3H, m), 4.74
(2H, d), 5.08 (1H, sept), 5.32 (1H, t), 7.44 (5H,
s). Example 27 Methyl (7-isopropoxycarbonyl-2-methyl-
2,3,5,6-tetrahydropyrrolo [2,1-b] thiazole-
3-ylidene) acetate mp 85-86 ° C. Elemental analysis (C ₁₄ H ₁₉ NO ₄ as S) Calculated (%): C56.55 H6.44 N4.71 Found (%): C56.68 H6.23 N4.75 NMR spectrum δ (CDCl ₃ ): 1.28 (6H, d), 1.72 (3H, d), 3.0 to 3.3 (2H, m), 3.4 to
3.8 (5H, m), 4.82 (1H, s), 5.10 (1H, sept), 5.47 (1H,
q). Example 28 Ethyl (7-isopropoxycarbonyl-2-methyl-
2,3,5,6-tetrahydropyrrolo [2,1-b] thiazole-
3-ylidene) acetate Melting point 88-89 ° C Elemental analysis (as C ₁₅ H ₂₁ NO ₄ S) Calculated (%): C57.86 H6.80 N4.50 Actual (%): C57.90 H6.73 N4.74 NMR spectrum δ (CDCl ₃ ): 1.27 (3H, t), 2.28 (6H, d), 1.70 (3H, d), 3.0 to 3.3
(2H, m), 3.5-3.8 (2H, m), 4.14 (2H, q), 4.77 (1H,
d), 5.05 (1H, sept), 5.41 (1H, br q). Example 29 Methyl (7-isopropoxycarbonyl-2,2-dimethyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetate isopropyl 2-thioxopyrrolidine-3- 2.5 g of alkoxylate, 1.6 g of anhydrous sodium acetate and methyl 4
-Bromo-4-methyl-3-oxopentanoate 4.2 g
Is added to 50 ml of toluene, and the mixture is refluxed for 24 hours. The reaction solution is poured into water and extracted with benzene. The benzene layer is washed with 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, and recrystallized from petroleum ether to obtain 1.9 g of the title compound.

Melting point 89-90 ° C Elemental analysis value (as C ₁₅ H ₂₁ NO ₄ S) Calculated value (%): C57.85 H6.80 N4.50 Actual value (%): C57.74 H6.89 N4.24 NMR spectrum δ (CDCl ₃ ): 1.27 (6H, d), 2.00 (6H, brs), 3.11 (2H, brt), 3.6
6 (3H, s), 3.68 (2H, m), 4.68 (1H, br s), 5.05 (1H,
m). The compounds of Examples 30 to 36 were produced in the same manner as in Example 29.

Example 30 Methyl (7-methoxycarbonyl-2,2-dimethyl-2,
3,5,6-tetrahydropyrrolo [2,1-b] thiazole-3
−ylidene) acetate Melting point 142 to 144 ° C. Elemental analysis (as C ₁₃ H ₁₇ NO ₄ S) Calculated (%): C55.11 H6.05 N4.94 Observed (%): C55.13 H6.08 N5 .03 NMR spectrum δ (CDCl ₃ ): 1.94 (6H, s), 2.8 to 3.2 (2H, m), 3.56 (3H, s), 3.60
(3H, s), 3.5-3.9 (2H, m), 4.76 (1H, s). Example 31 Methyl (7-ethoxycarbonyl-2,2-dimethyl-2,
3,5,6-tetrahydropyrrolo [2,1-b] thiazole-3
−Ilidene) acetate Melting point 130-131 ° C. Elemental analysis (as C ₁₄ H ₁₉ NO ₄ S) Calculated (%): C56.55 H6.44 N4.71 Observed (%): C56.56 H6.18 N4 .74 NMR spectrum δ (CDCl ₃ ): 1.30 (3H, t), 2.02 (6H, s), 3.0 to 3.3 (2H, m), 3.5 to
3.8 (2H, m), 3.68 (3H, s), 4.22 (2H, q), 4.72 (1H,
s). Example 32 Methyl (7-ethoxycarbonyl-2,2,6-trimethyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetate Melting point 84-87 ° C. NMR spectrum δ (CDCl ₃ ): 1.19 (3H, t), 1.22 (3H, d), 1.93 (3H, s), 1.94 (3H,
s), 3.56 (3H, s), 3.1 to 3.9 (3H, m), 4.06 (2H, q), 4.7
6 (1H, s). Example 33 Ethyl (7-isopropoxycarbonyl-2,2-dimethyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetate Melting point 93-94 ° C Elemental analysis ( (Calculated as C ₁₆ H ₂₃ NO ₄ S) Calculated value (%): C59.05 H7.12 N4.30 Observed value (%): C59.29 H7.13 N4.23 NMR spectrum δ (CDCl ₃ ): 1.27 (6H) , d), 1.28 (3H, t), 2.02 (6H, s), 3.11 (2H,
br t), 3.67 (2H, br t), 4.12 (2H, q), 4.68 (1H, s),
5.06 (1H, m). Example 34 2,2,2-Trichloroethyl (7-isopropoxycarbonyl-2,2-dimethyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetate Melting point 127 128128 ° C. NMR spectrum δ (CDCl ₃ ): 1.29 (6H, d), 2.04 (6H, s), 3.13 (2H, brt), 3.75
(2H, brt), 4.76 (2H, s), 4.78 (1H, s), 5.07 (1H,
m). Example 35 2,2,2-Trichloroethyl (7-isopropoxycarbonyl-2,2,6-trimethyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetate 130-132 ° C NMR spectrum δ (CDCl ₃ ): 1.27 (6H, d), 1.34 (3H, d), 2.01 (3H, s), 2.02 (3H,
s), 3.28 (1H, dd), 3.4 to 3.8 (1H, m), 3.91 (1H, dd),
4.73 (2H, s), 4.78 (1H, s), 5.06 (1H, sept). Example 36 (±) methyl (9-ethoxycarbonyl-2,2-dimethyl-2,3,4aα, 5,6,7,8,8aβ-octahydrothiazolo [3,2-a] indole-3- ylidene) acetate mp 145-147 ° C. elemental analysis (C ₁₈ H ₂₅ NO ₄ as S) calculated (%): C61.51 H7.17 N3.99 Found (%): C61.54 H7.33 N4. 01 NMR spectrum δ (CDCl ₃ ): 1.30 (3H, t), 1.2 to 3.5 (10H, m), 1.97 (3H, s), 1.99
(3H, s), 3.67 (3H, s), 4.18 (2H, q), 5.21 (1H, s). Example 37 Diethyl (7-isopropoxycarbonyl-6,6-dimethyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) malonate isopropyl 4,4-dimethyl-2- 2.6 g of thioxopyrrolidine-3-carboxylate and 5.7 g of diethylchloroacetylmalonate are dissolved in 60 ml of acetic acid, and the mixture is heated and stirred at 60 to 70 ° C for 5 hours. Acetic acid was distilled off under reduced pressure, and the residue was made alkaline with a saturated aqueous solution of sodium hydrogencarbonate and extracted with chloroform. The chloroform layer is washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography to obtain 1.0 g of the title compound.

Melting point 118-119 ° C Elemental analysis (as C ₁₉ H ₂₇ NO ₆ S) Calculated value (%): C57.41 H6.85 N3.52 Actual value (%): C57.54 H6.51 N3.55 NMR spectrum δ (CDCl ₃ ): 1.1 to 1.4 (6H, m), 1.28 (6H, d), 1.36 (6H, s), 3.49
(2H, s), 4.17 (2H, q), 4.29 (2H, q), 4.77 (2H, s), 5.
08 (1H, sept). Example 38 Ethyl (7-isopropoxycarbonyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) cyanoacetate isopropyl 2-thioxopyrrolidine-3-carboxylate 5.58 g and 5.67 g of α-cyano-γ-chloroacetoacetate is added to 20 ml of acetic acid, and the mixture is heated and stirred at 60 to 70 ° C. for 5 hours. After cooling, the precipitated crystals are collected by filtration, washed with water and dried. Recrystallization from a mixed solvent of chloroform and ethanol gave 3.57 g of the title compound.

Melting point 152-154 ° C Elemental analysis value (as C ₁₅ H ₁₈ N ₂ O ₄ S) Calculated value (%): C55.90 H5.59 N8.70 Actual value (%): C56.15 H5.41 N8.52 NMR spectrum δ (CDCl ₃ ): 1.28 (6H, d), 1.32 (3H, t), 3.22 (2H, t), 4.23 (2H,
q), 4.49 (2H, t), 4.96 (2H, s), 5.08 (1H, m). Example 39: Methyl (7-isopropoxycarbonyl-6-methyl-
2,3,5,6-tetrahydropyrrolo [2,1-b] thiazole-
3-yl) acetate isopropyl 4-methyl-2-thioxopyrrolidine-
4.0 g of 3-carboxylate, 4.7 g of methyl 4-bromocrotonate and 2.1 g of anhydrous sodium acetate were added to ethanol 10
Add to 0 ml and stir at 60-70 ° C for 3 hours. The solvent is distilled off under reduced pressure, the residue is dissolved in ethyl acetate, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography to give 4.5 g of the title compound.
As a pale yellow oil.

NMR spectrum δ (CDCl ₃ ): 1.1 to 1.3 (3H, m), 1.25 (6H, d), 2.2 to 3.8 (8H, m),
3.72 (3H, s), 5.03 (1H, sept). The compounds of Examples 40 to 42 were produced in the same manner as in Example 39.

Example 40 Methyl (7-isopropoxycarbonyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-yl)
Acetate Elemental analysis (as C ₁₃ H ₁₉ NO ₄ S) Calculated (%): C54.72 H6.71 N4.91 Actual (%): C54.71 H6.64 N4.74 NMR spectrum δ (CDCl ₃ ): 1.25 (6H, d), 2.5-3.8 (9H, m), 3.72 (3H, s), 5.03
(1H, sept). Example 41 Methyl (7-isopropoxycarbonyl-6,6-dimethyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-yl) acetate Melting point 115-115.5 ° C. Elemental analysis ( C ₁₅ H ₂₃ NO ₄ as S) calculated (%): C57.48 H7.40 N4.47 Found (%): C57.48 H7.44 N4.39 NMR spectrum _{δ (CDCl 3): 1.25 (} 6H , d), 1.27 (3H, s), 1.34 (3H, s), 2.5 ~ 3.7
(7H, m), 3.72 (3H, s), 5.04 (1H, sept). Example 42 Ethyl (7-isopropoxycarbonyl-2,2-dimethyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-yl) acetate Oil NMR spectrum δ (CDCl ₃ ) : 1.25 (6H, d), 1.29 (3H, t), 1.44 (3H, s), 1.50 (3H,
s), 2.46 (2H, d), 2.8-3.2 (3H, m), 3.3-3.6 (2H,
m), 4.18 (2H, q), 5.01 (1H, sept). Example 43 N-methyl- (7-n-propoxycarbonyl-2,3,5,
6-tetrahydropyrrolo [2,1-b] thiazole-3-ylidene) acetamidoethyl (7-n-propoxycarbonyl-2,3,5,6-
2.6 g of tetrahydropyrrolo [2,1-b] thiazole-3-ylidene) acetate is added to a 40% aqueous solution of monomethylamine 70
and stirred at room temperature for 96 hours. The precipitated crystals are collected by filtration, dissolved in chloroform, washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate.
The crude crystals obtained by distilling off the solvent were recrystallized from ethanol to obtain 1.9 g of the title compound.

Melting point 209-210 ° C Elemental analysis value (as C ₁₃ H ₁₈ N ₂ O ₃ S) Calculated value (%): C55.30 H6.43 N9.92 Observed value (%): C55.39 H6.38 N9.83 NMR spectrum δ (CDCl ₃ ): 1.00 (3H, t), 1.74 (2H, m), 2.88 (3H, d), 3.0 to 3.4
(2H, m), 3.5-3.9 (2H, m), 4.14 (2H, t), 4.79 (1H,
s), 4.95 (2H, s). The compounds of Examples 44 to 69 were produced in the same manner as in Example 43.

Example 44 N-methyl- (7-isobutoxycarbonyl-2,3,5,6
- tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetamide mp 192-195 ° C. Elemental analysis _{(C 14 H 20 N 2 O} 3 as S) Calculated (%): C56.71 H6.80 N9 .49 actual value (%): C56.71 H6.76 N9.32 NMR spectrum δ (CDCl ₃ ): 0.97 (6H, d), 1.96 (1H, m), 2.83 (3H, d), 3.1 to 3.4
(2H, m), 3.5-3.8 (2H, m), 3.92 (2H, d), 4.74 (1H,
t), 4.89 (2H, d). Example 45 N-methyl (7-tert-butoxycarbonyl-2,3,5,6
- tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetamide mp 200 to 203 ° C. Elemental analysis _{(C 14 H 20 N 2 O} 3 as S) Calculated (%): C56.71 H6.80 N9 .49 actual value (%): C56.65 H6.86 N9.40 NMR spectrum δ (CDCl ₃ ): 1.50 (9H, s), 2.83 (3H, d), 3.0 to 3.3 (2H, m), 3.5 to
3.8 (2H, m), 4.70 (1H, t), 4.87 (2H, d). Example 46 N-methyl- (7-sec-butoxycarbonyl-2,3,5,6
- tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetamide melting one hundred eighty-seven to one hundred eighty-eight ° C. Elemental analysis _{(C 14 H 20 N 2 O} 3 S · 0.5H as ₂ O) Calculated (%): C55. 06 H6.93 N9.17 Observed value (%): C55.00 H6.76 N9.20 NMR spectrum δ (CDCl ₃ ): 0.93 (3H, t), 1.23 (3H, d), 1.60 (2H, m) , 2.83 (3H,
d), 3.17 (2H, t), 3.62 (2H, t), 4.72 (1H, br), 4.89
(2H, br), 4.91 (1H, m). Example 47 N-methyl- [7- (3-methylbutoxycarbonyl)
2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene] acetamide mp one hundred eighty-eight to one hundred eighty-nine ° C. Elemental analysis _{(C 15 H 22 N 2 O} 3 as S) Calculated (%) : C58.04 H7.14 N9.30 Actual value (%): C58.15 H7.06 N9.01 NMR spectrum δ (CDCl ₃ ): 0.95 (6H, d), 1.4 to 1.9 (3H, m), 2.86 (3H, d), 3.18
(2H, t), 3.64 (2H, t), 4.18 (2H, t), 4.73 (1H, s), 4.
90 (2H, s). Example 48 N-methyl- [7- (3-methyl-2-butenyloxycarbonyl) -2,3,5,6-tetrahydropyrrolo [2,1-
b] thiazol-3-ylidene] acetamide mp 184-186 ° C. Elemental analysis _{(C 15 H 20 N 2 O} 3 as S) Calculated (%): C58.42 H6.54 N9.08 Found (%): C58.22 H6.67 N8.89 NMR spectrum δ (CDCl ₃ ): 1.74 (6H, s), 2.85 (3H, d), 3.18 (2H, t), 3.64 (2H,
t), 4.64 (2H, d), 4.74 (1H, s), 4.90 (2H, s), 5.40 (1
H, t). Example 49 N-methyl- (7-n-butoxycarbonyl-2,3,5,6
- tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetamide mp 184-186 ° C. Elemental analysis _{(C 14 H 20 N 2 O} 3 as S) Calculated (%): C57.12 H6.16 N9 .52 actual value (%): C57.10 H6.06 N9.37 NMR spectrum δ (CDCl ₃ ): 0.94 (3H, t), 1.2 to 1.8 (4H, m), 2.83 (3H, d), 3.0 to
3.3 (2H, m), 3.4 to 3.8 (2H, m), 4.13 (2H, t), 4.78 (1
H, t), 4.89 (2H, s). Example 50 N-methyl- (7-methoxycarbonyl-6-methyl-
2,3,5,6-tetrahydropyrrolo [2,1-b] thiazole-
3-ylidene) acetamide Melting point 170-172 ° C Elemental analysis (as C ₁₂ H ₁₆ N ₂ O ₃ S) Calculated (%): C53.71 H6.01 N10.44 Actual (%): C53.46 H5 .99 N10.16 NMR spectrum δ (CDCl ₃ ): 1.31 (3H, d), 2.83 (3H, d), 3.0 to 3.2 (1H, m), 3.4 to
3.9 (2H, m), 3.72 (3H, s), 4.76 (1H, t), 4.87 (2H,
d). Example 51 N-methyl- (7-isobutoxycarbonyl-6-methyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetamide Melting point 149-152 ° C Elemental analysis (As C ₁₅ H ₂₂ N ₂ O ₃ S) Calculated value (%): C58.04 H7.14 N9.02 Actual value (%): C58.08 H7.23 N8.77 NMR spectrum δ (CDCl ₃ ): 0.98 (6H, d), 1.33 (3H, d), 1.98 (1H, m), 2.83 (3H,
d), 3.0-3.3 (1H, m), 3.4-3.9 (2H, m), 3.95 (2H, m
d), 4.7-5.0 (3H, m). Example 52 N-methyl- (7-cyclohexyloxycarbonyl-
6-methyl-2,3,5,6-tetrahydropyrrolo [2,1-b]
Thiazol-3-ylidene) acetamide mp 178-180 ° C. Elemental analysis _{(C 17 H 24 N 2 O} 3 as S) Calculated (%): C60.69 H7.19 N8.33 Found (%): C60. 62 H7.19 N8.22 NMR spectrum δ (CDCl ₃ ): 1.1 to 2.1 (13H, m), 2.85 (3H, d), 2.1 to 2.3 (1H, m),
2.4 ~ 3.0 (2H, m), 4.75 (1H, s), 4.87 (2H, s), 4.8 ~ 5.
0 (1H, m). Example 53 N-methyl- (7-n-octyloxycarbonyl-6
-Methyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazole-3-ylidene) acetamide Melting point 144-145 ° C Elemental analysis (as C ₁₉ H ₃₀ N ₂ O ₃ S) Calculated ( %): C62.26 H8.25 N7.64 Actual value (%): C62.23 H8.24 N7.61 NMR spectrum δ (CDCl ₃ ): 0.7 to 1.9 (18H, m), 1.86 (3H, d) , 3.0-3.3 (1H, m),
3.3 to 3.9 (2H, m), 4.16 (2H, t), 4.7 to 5.0 (3H, m). Example 54 N-ethyl- (7-isopropoxycarbonyl-6-phenyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetamide Melting point 159-160 ° C Elemental analysis value (As C ₂₀ H ₂₄ N ₂ O ₃ S) Calculated value (%): C64.49 H6.50 N7.52 Observed value (%): C64.28 H6.53 N7.48 NMR spectrum δ (CDCl ₃ ): 1.05 (3H, t), 1.16 (6H, d), 3.1 to 3.6 (3H, m), 3.98
(1H, t), 4.4 ~ 5.1 (3H, m), 4.90 (2H, s), 5.24 (5H,
s). Example 55 N-methyl- [7-ethoxycarbonyl-6- (3,4,5
- As trimethoxyphenyl) -2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene] acetamide mp one hundred ninety-three to one hundred ninety-four ° C. Elemental analysis _{(C 21 H 26 N 2 O} 6 S) Calculated value (%): C58.05 H6.03 N6.45 Actual value (%): C58.09 H6.20 N6.21 NMR spectrum δ (CDCl ₃ ): 1.18 (3H, t), 2.83 (3H, d) ), 3.82 (3H, s), 3.84 (6H,
s), 3.48 (1H, m), 4.60 (1H, m), 3.9 to 4.1 (3H, m), 4.7
4 (1H, s), 4.94 (2H, s), 6.42 (2H, s). Example 56 N-methyl- (6-ethyl-7-isopropoxycarbonyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazole-3-ylidene) acetamide Melting point 196-198 ° C Elemental analysis (As C ₁₅ H ₂₂ N ₂ O ₃ S) Calculated value (%): C58.04 H7.14 N9.03 Actual value (%): C58.09 H7.14 N8.95 NMR spectrum δ (CDCl ₃ ): 0.88 (3H, t), 1.27 (6H, d), 1.4 ~ 2.0 (2H, m), 2.83
(3H, d), 3.1 to 3.8 (3H, m), 4.76 (1H, brs), 4.84 (2
H, brs), 5.05 (1H, sept). Example 57 N-methyl- (7-isopropoxycarbonyl-5-methyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetamide Melting point 159-161 ° C Elemental analysis (As C ₁₄ H ₂₀ N ₂ O ₃ S) Calculated value (%): C56.74 H6.80 N9.45 Observed value (%): C56.46 H7.06 N9.16 NMR spectrum δ (CDCl ₃ ): 1.26 (6H, d), 1.30 (3H, d), 2.68 (1H, dd), 2.83 (3
H, d), 3.40 (1H, dd), 4.0 ~ 4.4 (1H, m), 4.88 (3H, s),
5.04 (1H, sept). Example 58 N-methyl- (7-ethoxycarbonyl-5-methyl-
2,3,5,6-tetrahydropyrrolo [2,1-b] thiazole-
3-ylidene) acetamide mp 153 to 155 ° C. Elemental analysis _{(C 13 H 18 N 2 O} 3 as S) Calculated (%): C55.30 H6.43 N9.92 Found (%): C55.24 H6 .40 N9.76 NMR spectrum δ (CDCl ₃ ): 1.30 (3H, t), 1.33 (3H, d), 2.69 (1H, dd), 2.83 (3
H, d), 3.42 (1H, dd), 4.0 ~ 4.4 (3H, m), 4.88 (3H,
s). Example 59 N-methyl- (5-ethyl-7-isopropoxycarbonyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetamide Melting point 169-172 ° C NMR spectrum δ _{(CDCl 3): 0.91 (3H} , t), 1.27 (6H, d), 1.5~2.0 (2H, m), 2.80
(1H, dd), 2.83 (3H, d), 3.33 (1H, dd), 3.8 ~ 4.2 (1H,
m), 4.86 (3H, s), 5.04 (1H, m). Example 60 N-methyl- (7-isopropoxycarbonyl-5,6-
Dimethyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetamide Oil NMR spectrum δ (CDCl ₃ ): 1.24 (3H, d), 1.28 (6H, d), 1.30 (3H, d), 2.83 (3H,
d), 2.9-3.3 (1H, m), 3.4-4.0 (1H, m), 4.86 (3H,
s), 5.05 (1H, sept). Example 61 N-methyl- (7-ethoxycarbonyl-5,6-dimethyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetamide Oil NMR spectrum δ (CDCl ₃ ): 1.1 ~ 1.5 (9H, m), 2.83 (3H, d), 2.9 ~ 3.2 (1H, m),
3.4-4.0 (1H, m), 4.18 (2H, q), 4.8-5.1 (3H, m). EXAMPLE 62 N-Methyl - (7-cyano-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene (acetamido) mp two hundred and thirty-five to two hundred and thirty-seven ° C. Elemental analysis (C ₁₀ H ₁₁ N ₃ OS) Calculated value (%): C54.28 H5.01 N18.99 Actual value (%): C54.10 H4.92 N18.78 NMR spectrum δ (CDCl ₃ ): 2.80 (3H, d), 3.20 (2H, t), 3.65 (2H, t), 4.91 (1H,
s), 4.98 (2H, s). Example 63 N-methyl- (7-ethoxycarbonyl-5-hydroxymethyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazole-3-ylidene) acetamide Melting point 209-211 ° C. Elemental analysis (As C ₁₃ H ₁₈ N ₂ O ₄ S) Calculated value (%): C52.33 H6.08 N9.39 Actual value (%): C52.23 H6.16 N9.28 NMR spectrum δ (CDCl ₃ ): 1.27 (3H, t), 2.76 (3H, d), 3.02 (1H, dd), 3.35 (1
H, dd), 3.71 (2H, t) 4.14 (2H, q), 4.55 (1H, br t), 4.
84 (2H, dd), 5.20 (1H, d), 6.50 (1H, brs). Example 64 N-methyl- (7-isopropoxycarbonyl-6,6-
Dimethyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazole-3-ylidene) acetamide Melting point 180-189 ° C Elemental analysis (as C ₁₅ H ₂₂ N ₂ O ₃ S) Calculated (%) ): C58.04 H7.14 N9.03 Actual value (%): C57.94 H7.28 N8.96 NMR spectrum δ (CDCl ₃ ): 1.28 (6H, d), 1.40 (6H, s), 2.83 ( 3H, d), 3.32 (2H,
s), 4.81 (3H, br s), 5.06 (1H, m). Example 65 N-ethyl- (7-isopropoxycarbonyl-6,6-
Dimethyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazole-3-ylidene) acetamide Melting point 162-165 ° C Elemental analysis (as C ₁₆ H ₂₄ N ₂ O ₃ S) Calculated (%) ): C59.23 H7.46 N8.63 Observed value (%): C59.51 H7.72 N8.73 NMR spectrum δ (CDCl ₃ ): 1.16 (3H, t), 1.28 (6H, d), 1.40 ( 6H, s), 3.1 ~ 3.5
(2H, m), 3.36 (2H, s), 4.74 (1H, br s), 4.86 (2H, d)
5.10 (1H, sept). Example 66 (7-isopropoxycarbonyl-6,6-dimethyl-2,
3,5,6-tetrahydropyrrolo [2,1-b] thiazole-3
−ylidene) acetamide Melting point 208 to 211 ° C. Elemental analysis value (as C ₁₄ H ₂₀ N ₂ O ₃ S) Calculated value (%): C56.73 H6.80 N9.45 Actual value (%): C56.68 H7. 08 N9.46 NMR spectrum δ (CDCl ₃ ): 1.20 (6H, d), 1.33 (6H, s), 3.35 (2H, s), 4.68 (2H,
d), 4.90 (1H, sept), 4.98 (1H, brs). Example 67 N- (2-hydroxyethyl)-(7-isopropoxycarbonyl-6,6-dimethyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetamide 225-229 ° C Elemental analysis (as C ₁₆ H ₂₄ N ₂ O ₄ S) Calculated (%): C56.45 H7.11 N8.23 Observed (%): C56.18 H6.96 N8.21 NMR Spectrum δ (CDCl ₃ ): 1.26 (6H, d), 1.43 (6H, s), 3.0 to 3.8 (6H, m), 3.36
(2H, d), 4.73 (2H, d). Example 68 N- (2-hydroxyethyl)-(7-isopropoxycarbonyl-2,3,5,6-tetrahydropyrrolo [2,1-b]
Thiazol-3-ylidene) acetamide mp 198-199 ° C. Elemental analysis _{(C 14 H 20 N 2 O} 4 as S) Calculated (%): C53.83 H6.45 N8.97 Found (%): C53. 65 H6.23 N8.95 NMR spectrum δ (CDCl ₃ ): 1.30 (6H, d), 3.0 to 3.8 (8H, m), 4.88 (2H, d), 5.08
(1H, m), 7.20 (1H, t). Example 69 N- (2-hydroxyethyl)-(7-isopropoxycarbonyl-6-methyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetamide Melting point 168- 174 ° C Elemental analysis value (as C ₁₅ H ₂₂ N ₂ O ₄ S) Calculated value (%): C55.19 H6.79 N8.58 Actual value (%): C55.20 H6.80 N8.44 NMR spectrum δ _{(DMSO-d 6): 1.19} (6H, d), 1.21 (3H, d), 3.0~4.0 (8H, m), 4.74
(2H, brs), 4.90 (1H, sept), 5.02 (1H, brs). Example 70 N-methyl- (7-isopropoxycarbonyl-2,3,5,
6-tetrahydropyrrolo [2,1-b] thiazol-3-yl) acetamide mp 90-95 ° C. Elemental analysis _{(C 13 H 20 N 2 O} 3 as S) Calculated (%): C54.91 H7.09 N9.85 Observed value (%): C54.86 H7.05 N9.91 NMR spectrum δ (CDCl ₃ ): 1.25 (6H, d), 2.3 to 3.8 (9H, m), 2.81 (3H, d), 5.00
(1H, sept). Example 71 N-methyl- (7-isopropoxycarbonyl-6-methyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-yl) acetamide Oil Mass spectrum m / z 298 (M ⁺ ) NMR spectrum δ (CDCl ₃ ): 1.25 (9H, d), 1.8 to 3.9 (8H, m), 2.81 (3H, d), 5.01
(1H, sept). Example 72 N-methyl- (7-isopropoxycarbonyl-6,6-
Dimethyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-yl) acetamide mp 100-101 ° C. Elemental analysis _{(C 15 H 24 N 2 O} 3 as S) Calculated (% ): C57.66 H7.74 N8.97 Actual value (%): C57.66 H7.77 N9.00 NMR spectrum δ (CDCl ₃ ): 1.25 (6H, d), 1.26 (3H, s), 1.32 ( 3H, s), 2.3-2.6
(2H, m), 2.82 (3H, d), 2.9-3.9 (5H, m), 5.01 (1H, se
pt). Example 73 N-methyl- (7-isopropoxycarbonyl-2,2-
Dimethyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-yl) acetamide Melting point 111-112 ° C Elemental analysis (as C ₁₅ H ₂₄ N ₂ O ₃ S) Calculated (%) ): C57.67 H7.74 N8.97 Observed value (%): C57.64 H7.90 N8.94 NMR spectrum δ (CDCl ₃ ): 1.24 (6H, d), 1.42 (3H, s), 1.51 ( 3H, s), 2.2 ~ 2.4
(2H, m), 2.83 (3H, d), 2.8-3.2 (3H, m), 3.2-3.7 (3
H, m), 5.00 (1H, sept). Example 74 N-allyl- (7-isopropoxycarbonyl-2,3,5,
6-tetrahydropyrrolo [2,1-b] thiazole-3-ylidene) acetamide S-phenyl (7-isopropoxycarbonyl-2,3,
5,6-tetrahydropyrrolo [2,1-b] thiazole-3-
Dissolve 1.0 g of (ylidene) thioacetate in 5 ml of allylamine and stir at room temperature for 1 hour. The crude crystals obtained by removing excess allylamine were recrystallized from a mixed solvent of isopropyl alcohol and isopropyl ether to give the title compound 0.1.
9 g were obtained.

Melting point 190-191 ° C Elemental analysis value (as C ₁₅ H ₂₀ N ₂ O ₃ S) Calculated value (%): C58.42 H6.54 N9.08 Actual value (%): C58.28 H6.52 N9.08 NMR spectrum δ (CDCl ₃ ): 1.29 (6H, d), 3.20 (2H, t), 3.67 (2H, t), 3.94 (2H,
t), 4.79 (1H, s), 4.94 (2H, s), 5.0 to 6.2 (4H, m). The compounds of Examples 75 to 84 were produced in the same manner as in Example 74.

Example 75 N, N-dimethyl- (7-isopropoxycarbonyl-2,
3,5,6-tetrahydropyrrolo [2,1-b] thiazole-3
−ylidene) acetamide Melting point 159 to 160 ° C. Elemental analysis value (as C ₁₄ H ₂₀ N ₂ O ₃ S · 0.6H ₂ O) Calculated value (%): C54.73 H6.90 N9.12 Observed value (%): C54.80 H7.05 N8.95 NMR spectrum δ (CDCl ₃ ): 1.30 (6H, d), 3.06 (6H, s), 3.21 (2H, t), 3.72 (2H,
t), 4.95 (2H, s), 5.11 (1H, sept), 5.13 (1H, s). EXAMPLE 76 N-Cyclopropyl - (7-isopropoxycarbonyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetamide mp 98 to 101 ° C. Elemental analysis (C ₁₅ H ₂₀ N ₂ O ₃ as S · H ₂ O) calculated (%): C55.19 H6.79 N8.58 Found (%): C55.26 H6.54 N8.59 NMR spectrum δ (CDCl ₃₎ : 0.5 to 0.9 (4H, m), 1.30 (6H, d), 2.70 (1H, m), 3.20
(2H, t), 3.66 (2H, t), 4.72 (1H, s), 4.95 (2H, s), 5.
11 (1H, m). Example 77 N- (2-N, N-dimethylaminoethyl)-(7-isopropoxycarbonyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetamide Melting point 80 8383 ° C Elemental analysis value (as C ₁₆ H ₂₅ N ₃ O ₃ S.H ₂ O) Calculated value (%): C53.76 H7.61 N11.76 Actual value (%): C53.98 H7.44 N11 .86 NMR spectrum δ (CDCl ₃ ): 1.26 (6H, d), 2.30 (6H, s), 2.52 (2H, m), 3.19 (2H,
m), 3.31 (2H, m), 3.64 (2H, m), 4.82 (1H, brs), 4.88
(2H, brs), 5.06 (1H, m). Example 78 Nn-propyl- (7-isopropoxycarbonyl-
2,3,5,6-tetrahydropyrrolo [2,1-b] thiazole-
3-ylidene) acetamide mp 152-154 ° C. Elemental analysis _{(C 15 H 22 N 2 O} 3 as S) Calculated (%): C58.04 H7.14 N9.03 Found (%): C57.82 H7 .06 N9.02 NMR spectrum δ (CDCl ₃ ): 0.95 (3H, t), 1.29 (6H, d), 1.50 (2H, m), 3.1 to 3.4
(4H, m), 3.64 (2H, t), 4.73 (1H, s), 4.90 (2H, s), 5.
07 (1H, sept). Example 79 N-isopropyl- (7-isopropoxycarbonyl-
2,3,5,6-tetrahydropyrrolo [2,1-b] thiazole-
3-ylidene) acetamide Melting point 131-133 ° C Elemental analysis value (as C ₁₅ H ₂₂ N ₂ O ₃ S.H ₂ O) Calculated value (%): C54.85 H7.37 N8.53 Actual value (%): C54.82 H7.81 N8.53 NMR spectrum δ (CDCl ₃ ): 1.17 (6H, d), 1.27 (6H, d), 3.16 (2H, t), 3.62 (2H,
t), 4.06 (1H, m), 4.69 (1H, s), 4.88 (2H, s), 5.06 (1
H, sept). Example 80: Nn-butyl- (7-isopropoxycarbonyl-2,
3,5,6-tetrahydropyrrolo [2,1-b] thiazole-3
−ylidene) acetamide Melting point 143 to 144 ° C. Elemental analysis value (as C ₁₆ H ₂₄ N ₂ O ₃ S · 0.2H ₂ O) Calculated value (%): C58.58 H7.50 N8.54 Actual measured value (%): C58.40 H7.39 N8.75 NMR spectrum δ (CDCl ₃ ): 0.94 (3H, t), 1.27 (6H, d), 1.42 (4H, m), 3.0 to 3.4
(4H, m), 3.63 (2H, t), 4.72 (1H, t), 4.90 (2H, d), 5.
06 (1H, sept). Example 81 N-isobutyl- (7-isopropoxycarbonyl-2,
3,5,6-tetrahydropyrrolo [2,1-b] thiazole-3
−Ilidene) acetamide Melting point 145 to 147 ° C. Elemental analysis value (as C ₁₆ H ₂₄ N ₂ O ₃ S · 0.5H ₂ O) Calculated value (%): C57.63 H7.56 N8.40 Actual value (%): C57.72 H7.59 N8.51 NMR spectrum δ (CDCl ₃ ): 0.94 (6H, d), 1.30 (6H, d), 1.80 (1H, m), 3.0 to 3.3
(4H, m), 3.68 (2H, t), 4.79 (1H, t), 4.94 (2H, d), 5.
12 (1H, m). EXAMPLE 82 N-cyclohexyl - (7-isopropoxycarbonyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetamide mp 152-153 ° C. Elemental analysis (C ₁₈ H (Calculated as ₂₆ N ₂ O ₃ S) Calculated value (%): C61.68 H7.48 N7.99 Observed value (%): C61.64 H7.62 N7.95 NMR spectrum δ (CDCl ₃ ): 1.1 to 2.1 ( 10H, m), 1.29 (6H, d), 3.30 (2H, brt),
3.5 ~ 4.0 (3H, m), 4.74 (1H, br s), 4.93 (2H, d), 5.10
(1H, m). Example 83 N-isopropyl- (7-isopropoxycarbonyl-
6-methyl-2,3,5,6-tetrahydropyrrolo [2,1-b]
Thiazole-3-ylidene) acetamide Melting point 161-163 ° C Elemental analysis (as C ₁₆ H ₂₄ N ₂ O ₃ S) Calculated (%): C59.23 H7.46 N8.63 Actual (%): C59. 15 H7.51 N8.46 NMR spectrum δ (CDCl ₃ ): 1.16 (6H, d), 1.27 (6H, d), 1.31 (3H, d), 3.1 to 3.3
(1H, m), 3.4-3.9 (2H, m), 4.12 (1H, d sept), 4.70
(1H, s), 4.84 (2H, s), 5.12 (1H, sept). Example 84: N-isobutyl- (7-isopropoxycarbonyl-6
- a methyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetate mp 134-135 ° C. Elemental analysis _{(C 17 H 26 N 2 O} 3 S · H 2 O ) Calculated value (%): C57.28 H7.92 N7.86 Actual value (%): C57.16 H7.87 N7.75 NMR spectrum δ (CDCl ₃ ): 0.92 (6H, d), 1.27 (6H, d), 1.32 (3H, d), 1.6 ~ 2.0
(1H, m), 3.10 (2H, t), 3.3 ~ 3.9 (3H, m), 4.73 (1H,
t), 4.84 (2H, d), 5.06 (1H, sept). Example 85 (7-Isopropoxycarbonyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazole-3-ylidene) acetylpiperidine S-phenyl (7-isopropoxycarbonyl-2,3,
5,6-tetrahydropyrrolo [2,1-b] thiazole-3-
1.0 g of (ylidene) thioacetate and 1.2 g of piperidine are suspended in 40 ml of tetrahydrofuran, and 740 mg of silver trifluoroacetate is added under stirring at room temperature. After 2 hours, the insolubles are removed by filtration and the filtrate is concentrated. The residue was purified by silica gel column chromatography, and recrystallized from ethanol to obtain 0.65 g of the title compound.

Mp 128-130 ° C. Elemental analysis _{(C 17 H 24 N 2 O} 3 as S) Calculated (%): C60.68 H7.19 N8.33 Found (%): C60.39 H7.30 N8.26 NMR spectrum δ (CDCl ₃ ): 1.29 (6H, d), 1.65 (6H, m), 3.18 (2H, t), 3.50 (4H,
m), 3.68 (2H, t), 4.90 (2H, s), 5.09 (1H, sept), 5.13
(1H, s). The compounds of Examples 86 to 100 were produced in the same manner as in Example 85.

Example 86 N- (2,2,2-trifluoroethyl)-(7-isopropoxycarbonyl-2,3,5,6-tetrahydropyrrolo [2,1
-B] thiazol-3-ylidene) acetamide mp 207 to 209 ° C. Elemental analysis _{(C 14 H 17 F 3 N} 2 O 3 S · 0.3H as ₂ O) Calculated (%): C47.26 H4.99 N7 .88 actual value (%): C47.21 H4.78 N7.68 NMR spectrum δ (CDCl ₃ ): 1.28 (6H, d), 3.19 (2H, t), 3.66 (2H, t), 3.94 (2H,
m), 4.75 (1H, s), 4.88 (2H, s), 5.07 (1H, sept). EXAMPLE 87 (7-isopropoxycarbonyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetyl morpholine mp 186-187 ° C. Elemental analysis (C ₁₆ H ₂₂ N ₂ (Calculated as O ₄ S) Calculated value (%): C56.78 H6.55 N8.28 Observed value (%): C56.48 H6.57 N8.14 NMR spectrum δ (CDCl ₃ ): 1.28 (6H, d), 3.19 (2H, t), 3.5 to 3.8 (10H, m), 4.91
(2H, s), 5.06 (1H, s), 5.07 (1H, sept). EXAMPLE 88 (7-isopropoxycarbonyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetyl thiomorpholine mp 183-185 ° C. Elemental analysis (C ₁₆ H ₂₂ N ₂ as O ₃ S ₂₎ calculated (%): C54.21 H6.26 N7.90 Found (%): C53.97 H6.28 N7.74 NMR spectrum _{δ (CDCl 3): 1.29 (} 6H, d ), 2.66 (4H, t), 3.22 (2H, t), 3.72 (2H,
t), 3.88 (4H, t), 4.94 (2H, s), 5.08 (1H, sept), 5.10
(1H, s). Example 89 N- [3- (2-oxo-2,3,4,5-tetrahydro) thienyl]-(7-isopropoxycarbonyl-2,3,5,6
-Tetrahydropyrrolo [2,1-b] thiazole-3-ylidene) acetamide Melting point 179-181 ° C Elemental analysis value (as C ₁₆ H ₂₀ N ₂ O ₄ S ₂ .0.3H ₂ O) Calculated value (%): C51 .40 H5.55 N7.49 actual value (%): C51.12 H5.45 N7.53 NMR spectrum δ (CDCl ₃ ): 1.27 (6H, d), 2.8 to 3.4 (6H, m), 3.64 (2H , br t), 4.
55 (1H, m), 4.80 (1H, d), 4.86 (2H, brs, 5.07 (1H,
m). Example 90 N- (2-chloro-6-methylphenyl)-(7-isopropoxycarbonyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetamide Melting point 194- 197 ° C Elemental analysis value (as C ₁₈ H ₂₁ ClN ₂ O ₃ S) Calculated value (%): C56.76 H5.56 N7.35 Actual value (%): C56.53 H5.62 N7.40 NMR spectrum δ (CDCl ₃ ): 1.38 (6H, d), 2.19 (3H, s), 3.18 (2H, brt), 3.64
(2H, brt), 3.94 (2H, s), 4.86 (1H, s), 5.22 (1H, sep
t), 6.9-7.3 (3H, m). Example 91 N- (2-pyridyl)-(7-isopropoxycarbonyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetamide Melting point 218-220 ° C Elemental analysis value (As C ₁₇ H ₁₉ N ₃ O ₃ S) Calculated value (%): C59.11 H5.54 N12.17 Observed value (%): C59.13 H5.85 N12.22 NMR spectrum δ (CDCl ₃ ): 1.22 (6H, d), 2.9-3.3 (2H, m), 3.5-3.8 (2H, m),
4.85 (2H, s), 4.92 (1H, sept), 5.40 (1H, s), 7.0-8.2
(4H, m). Example 92 N-[(2-pyridyl) -methyl]-(7-isopropoxycarbonyl-2,3,5,6-tetrahydropyrrolo [2,1-
b] Thiazole-3-ylidene) acetamide Melting point 119-121 ° C Elemental analysis (as C ₁₈ H ₂₁ N ₃ O ₃ S) Calculated (%): C60.14 H5.89 N11.69 Actual (%): C60.37 H5.61 N11.67 NMR spectrum δ (CDCl ₃ ): 1.28 (6H, d), 3.17 (2H, t), 3.64 (2H, t), 4.59 (2H,
d), 4.90 (3H, s), 5.06 (1H, m), 7.1 to 7.4 (2H, m), 7.6
8 (1H, m), 8.55 (1H, d). Example 93 N- [2- (3-methoxyphenyl) ethyl]-(7-
Isopropoxycarbonyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetamide Melting point 126-127 ° C Elemental analysis (as C ₂₁ H ₂₆ N ₂ O ₄ S) Calculated (%): C62.66 H6.51 N6.96 Actual value (%): C62.61 H6.54 N6.94 NMR spectrum δ (CDCl ₃ ): 1.29 (6H, d), 2.82 (2H, t), 3.16 (2H, t), 3.52 (2H,
t), 3.60 (2H, t), 3.83 (3H, s), 4.66 (1H, t), 4.80 (2
H, d), 5.17 (1H, sept), 6.8-7.3 (4H, m). EXAMPLE 94 N-ethoxycarbonyl - (7-isopropoxycarbonyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetamide mp 188-190 ° C. Elemental analysis (C ₁₅ H ₂₀ N ₂ O ₅ as S) calculated (%): C52.92 H5.92 N8.23 Found (%): C53.05 H5.74 N8.16 NMR spectrum _{δ (CDCl 3): 1.28 (} 6H , d), 1.30 (3H, t), 3.19 (2H, br t), 3.79
(2H, br t), 4.20 (2H, q), 4.87 (2H, br s), 5.07 (1H,
m), 6.14 (1H, brs). Example 95 N-benzyl-N-methyl- (7-isopropoxycarbonyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazole-3-ylidene) acetamide Melting point 177-178 ° C Elemental analysis value (As C ₂₀ H ₂₄ N ₂ O ₃ S) Calculated value (%): C64.49 H6.49 N7.52 Observed value (%): C64.41 H6.64 N7.44 NMR spectrum δ (CDCl ₃ ): 1.28 (6H, d), 3.00 (3H, s), 3.16 (2H, t), 3.58 (2H,
t), 4.60 (2H, s), 4.94 (2H, d), 5.07 (1H, sept), 5.10
(1H, t), 7.28 (5H, m). Example 96 N-cyclopropyl- (7-isopropoxycarbonyl-6-methyl-2,3,5,6-tetrahydropyrrolo [2,1-
b] Thiazole-3-ylidene) acetamide Oil NMR spectrum δ (CDCl ₃ ): 0.3-0.9 (4H, m), 1.28 (9H, d), 2.5-2.9 (1H, m),
3.0-3.4 (1H, m), 3.4-3.8 (2H, m), 4.83 (3H, s), 5.0
0 (1H, sept). Example 97 N-cyclohexyl- (7-isopropoxycarbonyl-6-methyl-2,3,5,6-tetrahydropyrrolo [2,1-
b] Thiazole-3-ylidene) acetamide Melting point 166-168 ° C Elemental analysis value (as C ₁₉ H ₂₈ N ₂ O ₃ S) Calculated value (%): C62.61 H7.74 N7.69 Observed value (%): C62.55 H7.72 N7.69 NMR spectrum δ (CDCl ₃ ): 1.27 (6H, d), 1.31 (3H, d), 1.5 to 2.1 (10H, m), 3.1
~ 4.0 (4H, m), 4.70 (1H, s), 4.84 (2H, d), 5.06 (1H, s
ept). Example 98 N-benzyl-N-methyl- (7-isopropoxycarbonyl-6-methyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetamide Melting point 126-128 ℃ Elemental analysis value (as C ₂₁ H ₂₆ N ₂ O ₃ S) Calculated value (%): C65.26 H6.78 N7.25 Actual value (%): C65.22 H6.78 N7.19 NMR spectrum δ ( CDCl ₃ ): 1.25 (9H, d), 2.98 (3H, s), 3.0 to 3.9 (3H, m), 4.60
(2H, s), 4.90 (2H, d), 5.10 (1H, sept), 5.10 (1H,
s), 7.1-7.6 (5H, m). Example 99 (7-isopropoxycarbonyl-6-methyl-2,3,5,
6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetyl piperidine mp 155 to 158 ° C. Elemental analysis _{(C 18 H 26 N 2 O} 3 as S) Calculated (%): C61.69 H7. 48 N7.99 Found (%): C61.56 H7.44 N7.80 NMR spectrum _{δ (CDCl 3): 1.27 (} 6H, d), 1.33 (3H, d), 2.5~2.8 (6H, m), 3.2 ~
3.8 (7H, m), 4.85 (2H, d), 5.06 (1H, sept), 5.13 (1H,
t). Example 100 (7-isopropoxycarbonyl-6-methyl-2,3,5,
6-tetrahydropyrrolo [2,1-b] thiazole-3-ylidene) acetylmorpholine Melting point 138-140 ° C Elemental analysis (as C ₁₇ H ₂₄ N ₂ O ₄ S) Calculated (%): C57.93 H6. 86 N7.95 actual value (%): C57.76 H6.90 N7.80 NMR spectrum δ (CDCl ₃ ): 1.27 (6H, d), 1.33 (3H, d), 3.1 to 3.4 (1H, m), 3.4 ~
3.9 (10H, m), 4.85 (2H, d), 5.05 (1H, t), 5.13 (1H, se
pt). Example 101 N, N-dimethyl- (7-isopropoxycarbonyl-6
-Methyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazole-3-ylidene) acetamide 4-nitrophenyl (7-isopropoxycarbonyl-6-methyl-2,3,5,6- Tetrahydropyrrolo [2,1-
b] 25% in 1.5 g of thiazole-3-ylidene) acetate
Add 40 ml of dimethylamine aqueous solution and stir at room temperature for 3 days. To this is added 40 ml of water, and the precipitated crystals are collected by filtration. The crude crystals are dissolved in chloroform, washed with water and dried over anhydrous sodium sulfate. The crude crystals obtained by distilling off the solvent were recrystallized with a mixed solvent of ether and n-hexane to obtain 0.6 g of the title compound.

Melting point 126-128 ° C Elemental analysis value (as C ₁₅ H ₂₂ N ₂ O ₃ S) Calculated value (%): C58.04 H7.14 N9.02 Actual value (%): C58.28 H7.15 N9.08 NMR spectrum δ (CDCl ₃ ): 1.24 (6H, d), 1.33 (3H, d), 3.02 (6H, s), 3.1 to 3.3
(1H, m), 3.5-3.9 (2H, m), 4.85 (2H, d), 5.08 (1H, se
pt), 5.10 (1H, t). The compound of Example 102 was synthesized in the same manner as in Example 101.

Example 102 (7-isopropoxycarbonyl-6-methyl-2,3,5,
6-tetrahydropyrrolo [2,1-b] thiazole-3-ylidene) acetylthiomorpholine Melting point 164-165 ° C Elemental analysis (as C ₁₇ H ₂₄ N ₂ O ₃ S ₂ ) Calculated (%): C55.41 H6.56 N7.60 actual value (%): C55.23 H6.56 N7.38 NMR spectrum δ (CDCl ₃ ): 1.27 (6H, d), 1.33 (3H, d), 2.5 to 2.8 (4H, m ), 3.21
(1H, dd), 3.6-4.0 (6H, m), 4.85 (2H, d), 5.07 (1H,
s), 5.13 (1H, sept). Example 103 4-methyl-1- (7-isopropoxycarbonyl-2,
3,5,6-tetrahydropyrrolo [2,1-b] thiazole-3
-Ylidene) acetylpiperazine ethyl (7-isopropoxycarbonyl-2,3,5,6-
3.5 g of tetrahydropyrrolo [2,1-b] thiazole-3-ylidene) acetate in 13 ml of 0.5 N sodium hydroxide
And 13 ml of ethanol and stirred at room temperature for 2 hours. Thereafter, the solvent is distilled off under reduced pressure to dryness. To this are added 20 ml of tetrahydrofuran and 2.2 ml of triethylamine. Next, the mixture was cooled to 0 ° C., and pivaloyl chloride (1.9 ml) was added.
And stirred for 0.5 hour. 1.5 g of N-methylpiperazine is added to the reaction solution, and the mixture is stirred at room temperature for 1 hour. The reaction solution is poured into water and 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 a mixed solvent of isopropyl alcohol and ether to obtain 1.2 g of the title compound.

Mp 153-156 ° C. Elemental analysis _{(C 17 H 25 N 3 O} 3 as S) Calculated (%): C58.10 H7.17 N11.96 Found (%): C58.32 H7.09 N12.12 NMR spectrum δ (CDCl ₃ ): 1.26 (6H, d), 2.34 (3H, s), 2.42 (4H, m), 3.17 (2H,
t), 3.5-3.8 (6H, m), 4.87 (2H, s), 5.07 (1H, d), 5.1
2H, m). The compounds of Examples 104 to 105 were produced in the same manner as in Example 103.

Example 104 N-benzyl- (7-isopropoxycarbonyl-2,3,
5,6-tetrahydropyrrolo [2,1-b] thiazole-3-
Ylidene) acetamide Melting point 150-152 ° C Elemental analysis (as C ₁₉ H ₂₂ N ₂ O ₃ S) Calculated (%): C63.66 H6.19 N7.81 Observed (%): C63.81 H6.03 N7.84 NMR spectrum δ (CDCl ₃ ): 1.28 (6H, d), 3.18 (2H, t), 3.64 (2H, t), 4.50 (2H,
d), 4.79 (2H, s), 5.90 (1H, sept), 7.36 (5H, s). Example 105 S-phenyl (7-isopropoxycarbonyl-2,3,5,
6-Tetrahydropyrrolo [2,1-b] thiazole-3-ylidene acetate The data of the compound obtained were in accordance with those of the compound of Example 25.

Melting point 216-220 DEG C. Example 106 N- (2-pyridyl)-(7-isopropoxycarbonyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetamide isopropyl 2- 1.5 g of thioxopyrrolidine-3-carboxylate and 2.1 g of N- (2-pyridyl) -4-bromo-3-oxobutanamide are added to 50 ml of benzene,
Heat and stir at 50-60 ° C for 1 hour. After cooling, the precipitated crystals are collected by filtration,
Wash with water and dry. Then, recrystallization from ethanol gave 2.0 g of the title compound. The data of the obtained compound are shown in Example 91.
Of the compound.

Melting point: 218 to 220 ° C. The compounds of Examples 107 to 108 were produced in the same manner as in Example 106.

Example 107 N-Ethoxycarbonyl- (7-isopropoxycarbonyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetamide Matched that of the compound.

Melting point 188 DEG-190 DEG C. Example 108 N-benzylsulfonyl-N-methyl- (7-ethoxycarbonyl-6-methyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetamide mp one hundred eighty-three to one hundred and eighty-four ° C. elemental analysis _{(C 20 H 24 N 2 O} 5 as S ₂₎ calculated (%): C55.02 H5.54 N6.42 Found (%): C54.84 H5.34 N6 .36 NMR spectrum δ (CDCl ₃ ): 1.31 (3H, t), 1.34 (3H, d), 2.99 (3H, s), 3.0 to 3.8
(3H, m), 4.22 (2H, q), 4.56 (2H, s), 4.77 (2H, d), 5.
37 (1H, t), 7.36 (5H, s). Example 109 N-Hydroxymethyl- (7-isopropoxycarbonyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetamide To 50 ml of tetrahydrofuran was added 0.26 g of lithium aluminum hydride. N-ethoxycarbonyl- (7-isopropoxycarbonyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazole-3-ylidene) under ice-cooling and stirring.
1.3 g of acetamide is added and stirred at the same temperature for 0.5 hour. An acetic ester and further water are added thereto and stirred. The ethyl acetate 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 to obtain 0.2 g of the title compound.

Mp 181-182 ° C. Elemental analysis _{(C 13 H 18 N 2 O} 4 as S) Calculated (%): C52.33 H6.08 N9.39 Found (%): C52.15 H6.35 N9.33 NMR spectrum δ (CDCl ₃ ): 1.22 (6H, d), 3.10 (2H, t), 3.66 (2H, t), 4.59 (2H,
q), 4.80 (2H, s), 4.93 (1H, sept), 4.99 (1H, s). Example 110 (7-isopropoxycarbonyl-2,2-dimethyl-2,
3,5,6-tetrahydropyrrolo [2,1-b] thiazole-3
2,2,2-Trichloroethyl (7-isopropoxycarbonyl-2,2-dimethyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazole-3-ylidene) acetate 1.3
5 g is dissolved in 30 ml of tetrahydrofuran, and 1.0 g of ammonium chloride and 1.0 g of zinc dust are added, followed by heating and stirring for 10 minutes. water
5 ml was added, the insolubles were removed by filtration, and the filtrate was extracted with dichloromethane. After the dichloromethane layer was dried over anhydrous sodium sulfate, the solvent was distilled off (7-isopropoxycarbonyl-2,2-dimethyl-2,3,5,6-tetrahydropyrrolo [2,1
-B] Thiazole-3-ylidene) acetic acid 0.75 g was obtained.

NMR spectrum δ (CDCl ₃ ): 1.28 (6H, d), 2.02 (6H, s), 3.12 (2H, brt), 3.70
(2H, brt), 4.70 (1H, s), 5.06 (1H, m). Example 111 (B) -N-methyl- (7-isopropoxycarbonyl-2,2-dimethyl-2,3,5,6-tetrahydropyrrolo [2,1
-B] thiazole-3-ylidene) acetamide (7-isopropoxycarbonyl-2,2-dimethyl-
2,3,5,6-tetrahydropyrrolo [2,1-b] thiazole-
0.75 g of 3-ylidene) acetic acid was dissolved in 30 ml of tetrahydrofuran, and 520 m of 1-hydroxybenzotriazole was added thereto.
g then N, N'-dicyclohexylcarbodiimide 900 mg
And stirred at room temperature for 20 hours. Next, the reaction solution is cooled with ice water, and 3 ml of a 40% aqueous solution of methylamine is added with stirring. After 0.5 hour, the solvent was distilled off, and ethyl acetate was added to the residue to remove insolubles. The residue obtained by evaporating the solvent of the filtrate was purified by silica gel column chromatography, and recrystallized from isopropyl ether to obtain 350 mg of the title compound.

Melting point 172-176 ° C Elemental analysis value (as C ₁₅ H ₂₂ N ₂ O ₃ S) Calculated value (%): C58.04 H7.14 N9.03 Actual value (%): C57.96 H7.23 N9.01 NMR spectrum δ (CDCl ₃ ): 1.26 (6H, d), 2.06 (6H, s), 2.82 (3H, d), 3.10 (2H,
br t), 3.60 (2H, br t), 4.52 (1H, s), 5.04 (1H, m). Example 112 (7-isopropoxycarbonyl-2,3,5,6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetonitrile (7-isopropoxycarbonyl-2,3,5,6-tetrahydro Pyrrolo [2,1-b] thiazole-3-ylidene)
1.0 g of acetamide and 1.0 g of pyridine in 10 ml of dioxane
The mixture is dissolved in a mixed solvent of 10 ml of chloroform and 10 ml of chloroform, and 0.6 ml of trifluoroacetic anhydride is added dropwise with ice cooling and stirring. After stirring at room temperature for 2 hours, water is added to the reaction solution, 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 a mixed solvent of isopropyl alcohol and isopropyl ether to obtain 0.5 g of the title compound.

Mp 138-140 ° C. Elemental analysis _{(C 12 H 14 N 2 O} 2 S · 0.2H as ₂ O) Calculated (%): C56.76 H5.72 N11.03 Found (%): C57.02 H5 .92 N10.88 NMR spectrum δ (CDCl ₃ ): 1.29 (6H, d), 3.22 (2H, t), 3.69 (2H, t), 4.14 (1H,
s), 4.60 (2H, s), 5.11 (1H, sept). Example 113 N-methyl- (7-n-butoxycarbonyl-2,3-dihydropyrrolo [2,1-b] thiazole-3-ylidene)
Acetamide N-methyl- (7-n-butoxycarbonyl-2,3,5,
5.9 g of 6-tetrahydropyrrolo [2,1-b] thiazol-3-ylidene) acetamide was dissolved in a mixed solvent of 200 ml of chloroform and 70 ml of tetrahydrofuran, and 2,3-dichloro-5, 5.7 g of 6-dicyanoparabenzoquinone are added. After 0.5 hour, a saturated aqueous solution of sodium hydrogen carbonate was added and the mixture was stirred. The insoluble material was removed by filtration using Celite, and the filtrate was extracted with chloroform. The chloroform layer is washed with water and then with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography to obtain 3.2 g of the title compound.

Melting point 139-141 ° C Elemental analysis value (as C ₁₄ H ₁₈ N ₂ O ₃ S) Calculated value (%): C57.12 H6.16 N9.52 Actual value (%): C57.10 H6.06 N9.37 NMR spectrum δ (CDCl ₃ ): 0.96 (3H, t), 1.2 to 1.9 (4H, m), 2.90 (3H, d), 4.23
(2H, t), 4.98 (2H, d), 5.79 (1H, t), 6.73 (1H, d), 6.
86 (1H, d). The compounds of Examples 114 to 147 were produced in the same manner as in Example 113.

Example 114 N-methyl- (7-isobutoxycarbonyl-2,3-dihydropyrrolo [2,1-b] thiazole-3-ylidene)
Acetamide Melting point 172-174 ° C Elemental analysis value (as C ₁₄ H ₁₈ N ₂ O ₃ S) Calculated value (%): C57.10 H6.17 N9.52 Actual value (%): C57.21 H6.24 N9. 45 NMR spectrum δ (CDCl ₃ ): 1.01 (6H, d), 1.8 to 2.3 (1H, m), 2.90 (3H, d), 4.02
(2H, d), 4.99 (2H, d), 5.77 (1H, t), 6.82 (1H, d), 6.
87 (1H, d). Example 115 N-methyl- (7-isobutoxycarbonyl-6-methyl-2,3-dihydropyrrolo [2,1-b] thiazole-3-
Ylidene) acetamide melting one hundred seventy-two to one hundred seventy-three ° C. Elemental analysis _{(C 15 H 20 N 2 O} 3 as S) Calculated (%): C58.42 H6.54 N9.08 Found (%): C58.50 H6.50 N9.10 NMR spectrum δ (CDCl ₃ ): 1.02 (6H, d), 2.03 (1H, t sept), 2.27 (3H, d), 2.89
(3H, d), 4.03 (2H, d), 4.91 (2H, d), 5.70 (1H, t), 6.
67 (1H, br s). Example 116 N-methyl- (7-cyclohexyloxycarbonyl-
6-methyl-2,3-dihydropyrrolo [2,1-b] thiazol-3-ylidene) acetamide Melting point 179-181 ° C Elemental analysis (as C ₁₇ H ₂₂ N ₂ O ₃ S) Calculated (%): C61.05 H6.63 N8.38 Observed value (%): C61.02 H6.68 N8.20 NMR spectrum δ (CDCl ₃ ): 1.1 to 2.2 (10H, m), 2.27 (3H, d), 2.89 ( 3H, d), 4.91
(2H, d), 4.9 ~ 5.1 (1H, m), 5.69 (1H, t), 6.65 (1H,
q). Example 117 N-methyl- (7-n-octyloxycarbonyl-6
-Methyl-2,3-dihydropyrrolo [2,1-b] thiazol-3-ylidene) acetamide Melting point 142-143 ° C Elemental analysis (as C ₁₉ H ₂₈ N ₂ O ₃ S) Calculated (%): C62 .61 H7.74 N7.69 actual value (%): C62.53 H7.82 N7.52 NMR spectrum δ (CDCl ₃ ): 0.7-2.0 (15H, m), 2.26 (3H, d), 2.89 (3H , d), 4.21
(2H, t), 4.90 (2H, d), 5.70 (1H, t), 6.65 (1H, q). Example 118 N-methyl- (7-methoxycarbonyl-6-methyl-
2,3-dihydro-pyrrolo [2,1-b] thiazol-3-ylidene) acetamide mp 185 through 187 ° C. Elemental analysis _{(C 12 H 14 N 2 O} 3 as S) Calculated (%): C54.12 H5 .30 N10.52 Observed value (%): C53.99 H5.27 N10.31 NMR spectrum δ (CDCl ₃ ): 2.27 (3H, d), 2.89 (3H, d), 3.82 (3H, s), 4.91 (2H,
d), 5.67 (1H, t), 6.66 (1H, q). Example 119 N-ethyl- (7-isopropoxycarbonyl-6-methyl-2,3-dihydropyrrolo [2,1-b] thiazole-3
−ylidene) acetamide Melting point 139 to 140 ° C. Elemental analysis value (as C ₁₅ H ₂₀ N ₂ O ₃ S) Calculated value (%): C58.42 H6.54 N9.08 Actual value (%): C58.30 H6. 63 N9.01 NMR spectrum δ (CDCl ₃ ): 1.15 (3H, t), 1.27 (6H, d), 2.28 (3H, s), 3.1 to 3.6
(2H, m), 4.90 (2H, d), 5.15 (1H, sept), 5.68 (1H,
t), 6.65 (1H, s). Example 120 N-cyclopropyl - (7-isopropoxycarbonyl-6-methyl-2,3-dihydro-pyrrolo [2,1-b] thiazol-3-ylidene) acetamide mp 155 to 157 ° C. Elemental analysis (C ₁₆ H ₂₀ N ₂ O ₃ as S) calculated (%): C59.98 H6.29 N8.74 Found (%): C60.07 H6.30 N8.86 NMR spectrum δ (CDCl _3): 0.5~1.0 (4H, m), 1.33 (6H, d), 2.25 (3H, brs), 2.
5 to 2.9 (1H, br), 4.90 (2H, d), 5.14 (1H, sept), 5.64
(1H, br), 6.62 (1H, brs). Example 121 N-isopropyl- (7-isopropoxycarbonyl-
6-Methyl-2,3-dihydropyrrolo [2,1-b] thiazole-3-ylidene) acetamide Melting point 130-131 ° C. Elemental analysis (as C ₁₆ H ₂₂ N ₂ O ₃ S) Calculated (%): C59.60 H6.88 N8.69 Observed value (%): C59.62 H6.88 N8.46 NMR spectrum δ (CDCl ₃ ): 1.19 (6H, d), 1.33 (6H, d), 2.25 (3H, d), 4.14 (1H,
sept), 4.89 (2H, d), 5.15 (1H, sept), 5.67 (1H, t),
6.63 (1H, q). Example 122 N-isobutyl- (7-isopropoxycarbonyl-6
- methyl-2,3-dihydro-pyrrolo [2,1-b] thiazol-3-ylidene) acetamide mp 138-139 ° C. Elemental analysis _{(C 17 H 24 N 2 O} 3 as S) Calculated (%): C60 .69 H7.19 N8.33 Observed value (%): C60.72 H7.31 N8.10 NMR spectrum δ (CDCl ₃ ): 0.94 (6H, d), 1.33 (6H, d), 1.6 to 2.0 (1H , m), 2.26
(3H, d), 3.15 (2H, t), 4.89 (2H, d), 5.15 (1H, sep
t), 5.72 (1H, t), 6.65 (1H, q). Example 123 (7-isopropoxycarbonyl-6-methyl-2,3-
Dihydropyrrolo [2,1-b] thiazole-3-ylidene) acetylmorpholine Melting point 156-158 ° C Elemental analysis (as C ₁₇ H ₂₂ N ₂ O ₄ S) Calculated (%): C58.27 H6.33 N7 .99 Found (%): C58.45 H6.32 N7.90 NMR spectrum _{δ (CDCl 3): 1.33 (} 6H, d), 2.88 (3H, d), 3.4~3.9 (8H, m), 4.87
(2H, d), 5.15 (1H, sept), 6.06 (1H, t), 6.74 (1H, br
s). Example 124 (7-isopropoxycarbonyl-6-methyl-2,3-
Dihydro-pyrrolo [2,1-b] thiazol-3-ylidene) acetyl thiomorpholine melting one hundred forty-nine to one hundred fifty-five ° C. Elemental analysis _{(C 17 H 22 N 2 O} 3 as S) Calculated (%): C55.71 H6.05 N7.64 Found (%): C55.55 H5.99 N7.48 NMR spectrum _{δ (CDCl 3): 1.33 (} 6H, d), 2.28 (3H, d), 2.6~2.8 (4H, m), 3.7 ~
4.1 (4H, m), 4.86 (2H, d), 5.18 (1H, sept), 6.06 (1H,
t), 6.77 (1H, d). Example 125 (7-isopropoxycarbonyl-6-methyl-2,3-
Dihydropyrrolo [2,1-b] thiazole-3-ylidene) acetylpiperidine Melting point 122-123 ° C Elemental analysis (as C ₁₈ H ₂₄ N ₂ O ₃ S) Calculated (%): C62.04 H6.94 N8 .04 actual value (%): C61.80 H6.98 N7.88 NMR spectrum δ (CDCl ₃ ): 1.33 (6H, d), 1.5 to 1.8 (6H, m), 2.28 (3H, d), 3.4 to
3.7 (4H, m), 4.87 (2H, d), 5.15 (1H, sept), 6.13 (1H,
t), 6.76 (1H, d). Example 126 N-cyclohexyl- (7-isopropoxycarbonyl-6-methyl-2,3-dihydropyrrolo [2,1-b] thiazol-3-ylidene) acetamide Oil NMR spectrum δ (CDCl ₃ ): 1.33 ( 6H, d), 1.4 ~ 2.1 (10H, m), 2.25 (3H, s), 3.6
~ 4.0 (1H, m), 4.89 (2H, d), 5.14 (1H, sept), 5.73 (1
H, t), 6.63 (1H, s). Example 127 N, N-dimethyl- (7-isopropoxycarbonyl-6
- methyl-2,3-dihydro-pyrrolo [2,1-b] thiazol-3-ylidene) acetamide mp 132 to 135 ° C. Elemental analysis _{(C 15 H 20 N 2 O} 3 as S) Calculated (%): C58 .40 H6.54 N9.09 actual value (%): C58.37 H6.50 N8.96 NMR spectrum δ (CDCl ₃ ): 1.33 (6H, d), 2.29 (3H, d), 3.07 (6H, s) ), 4.88 (2H,
d), 5.15 (1H, sept), 6.10 (1H, t), 6.75 (1H, d). Example 128 N-methyl-N-benzyl- (7-isopropoxycarbonyl-6-methyl-2,3-dihydropyrrolo [2,1-b]
Thiazole-3-ylidene) acetamide Oil NMR spectrum δ (CDCl ₃ ): 1.33 (6H, d), 2.25 (3H, s), 3.02 (3H, s), 4.63 (2H,
s), 4.92 (2H, d), 5.14 (1H, sept), 6.12 (1H, br s),
6.5 to 6.9 (1H, br), 7.1 to 7.6 (5H, m). Example 129 N- (2-hydroxyethyl)-(7-isopropoxycarbonyl-6-methyl-2,3-dihydropyrrolo [2,1-
b] Thiazole-3-ylidene) acetamide Melting point 178-180 ° C Elemental analysis value (as C ₁₅ H ₂₀ N ₂ O ₄ S) Calculated value (%): C55.54 H6.21 N8.64 Actual value (%): C55.56 H6.27 N8.66 NMR spectrum _{δ (CDCl 3): 1.25 (} 6H, d), 2.19 (3H, d), 3.0~3.6 (4H, m), 4.83
(2H, d), 4.99 (1H, sept), 6.10 (1H, t), 6.96 (1H,
d). EXAMPLE 130 N-ethoxycarbonyl - (7-isopropoxycarbonyl-6-methyl-2,3-dihydro-pyrrolo [2,1-b] thiazol-3-ylidene) acetamide melting one hundred and sixty-six to one hundred sixty-seven ° C. Elemental analysis (C ₁₆ H ₂₀ N ₂ O ₅ as S) calculated (%): C54.53 H5.72 N7.95 Found (%): C54.52 H5.80 N7.94 NMR spectrum _{δ (CDCl 3): 1.32 (} 3H , t), 1.34 (6H, d), 2.28 (3H, d), 4.24 (2H,
q), 4.85 (2H, d), 5.16 (1H, sept), 6.85 (1H, q), 7.11
(1H, t). Example 131 N-methyl- (7-isopropoxycarbonyl-5-methyl-2,3-dihydropyrrolo [2,1-b] thiazole-3
−ylidene) acetamide Melting point 183 to 187 ° C. Elemental analysis value (as C ₁₄ H ₁₈ N ₂ O ₃ S) Calculated value (%): C57.12 H6.16 N9.52 Observed value (%): C56.95 H5. 97 N9.40 NMR spectrum δ (CDCl ₃ ): 1.31 (6H, d), 2.42 (3H, d), 2.89 (3H, d), 4.99 (2H,
d), 5.13 (1H, sept), 5.95 (1H, t), 6.36 (1H, brs). Example 132 N-methyl- (5-ethyl-7-isopropoxycarbonyl-2,3-dihydropyrrolo [2,1-b] thiazole-3
−ylidene) acetamide Melting point 181 to 183 ° C. Elemental analysis value (as C ₁₅ H ₂₀ N ₂ O ₃ S) Calculated value (%): C58.42 H6.54 N9.08 Actual value (%): C58.24 H6. 57 N8.98 NMR spectrum δ (CDCl ₃ ): 1.27 (3H, t), 1.31 (6H, d), 2.77 (2H, q), 2.89 (3H,
d), 4.99 (2H, d), 5.14 (1H, sept), 5.91 (1H, t), 6.41
(1H, s). Example 133: N-methyl- (6-ethyl-7-isopropoxycarbonyl-2,3-dihydropyrrolo [2,1-b] thiazole-3
−ylidene) acetamide Melting point 179-182 ° C. Elemental analysis value (as C ₁₅ H ₂₀ N ₂ O ₃ S) Calculated value (%): C58.42 H6.54 N9.08 Actual value (%): C58.41 H6. 49 N9.12 NMR spectrum δ (CDCl ₃ ): 1.19 (3H, t), 1.33 (6H, d), 2.73 (2H, q), 2.89 (3H,
d), 4.90 (2H, d), 5.15 (1H, sept), 5.71 (1H, t), 6.60
(1H, s). Example 134 N-methyl- (7-ethoxycarbonyl-5,6-dimethyl-2,3-dihydropyrrolo [2,1-b] thiazole-3-
Ylidene) acetamide Melting point 255-258 ° C Elemental analysis (as C ₁₄ H ₁₈ N ₂ O ₃ S) Calculated (%): C57.12 H6.16 N9.52 Actual (%): C57.32 H6.25 N9.39 NMR spectrum δ (CDCl ₃ ): 1.35 (3H, t), 2.20 (3H, s), 2.35 (3H, s), 2.88 (3H,
d), 4.27 (2H, q), 4.94 (2H, d), 5.95 (1H, t). Example 135 N-methyl- (7-isopropoxycarbonyl-5,6-
Dimethyl-2,3-dihydro-pyrrolo [2,1-b] thiazol-3-ylidene) acetamide mp 184-185 ° C. Elemental analysis _{(C 15 H 20 N 2 O} 3 as S) Calculated (%): C58. 42 H6.54 N9.08 actual value (%): C58.39 H6.65 N9.31 NMR spectrum δ (CDCl ₃ ): 1.25 (6H, d), 2.20 (3H, s), 2.35 (3H, s) , 2.88 (3H,
d), 4.93 (2H, d), 5.14 (1H, sept), 5.94 (1H, t). Example 136 N-ethyl- (7-isopropoxycarbonyl-6-phenyl-2,3-dihydropyrrolo [2,1-b] thiazole-
3-ylidene) acetamide mp 133-135 ° C. Elemental analysis _{(C 20 H 22 N 2 O} 3 as S) Calculated (%): C64.84 H5.99 N7.56 Found (%): C65.03 H6 .20 N7.38 NMR spectrum δ (CDCl ₃ ): 1.17 (3H, t), 1.25 (6H, d), 3.1 to 3.5 (2H, m), 4.91
(2H, d), 5.10 (1H, sept), 5.74 (1H, t), 6.84 (1H,
s), 7.2-7.6 (5H, m). Example 137 ethyl (7-isopropoxycarbonyl-6-methyl-
2,3-Dihydropyrrolo [2,1-b] thiazole-3-ylidene) acetate Melting point 114-116 ° C Elemental analysis (as C ₁₅ H ₁₉ NO ₄ S) Calculated (%): C58.23 H6.19 N4.53 Observed value (%): C58.35 H6.26 N4.38 NMR spectrum δ (CDCl ₃ ): 1.30 (3H, t), 1.33 (6H, d), 2.27 (3H, d), 4.21 (2H ,
q), 4.80 (2H, d), 5.15 (1H, sept), 5.77 (1H, t), 6.71
(1H, d). Example 138 Ethyl (5-formyl-7-isopropoxycarbonyl-2,3-dihydropyrrolo [2,1-b] thiazol-3-ylidene) acetate Melting point 147-150 ° C NMR spectrum δ (CDCl ₃ ): 1.32 ( 3H, t), 1.35 (6H, d), 4.23 (2H, q), 4.93 (2H,
d), 5.19 (1H, sept), 7.52 (1H, t), 7.58 (1H, s), 9.37
(1H, s). Example 139 Ethyl [7- (N-methylcarbamoyl) -6-methyl-2,3-dihydro-pyrrolo [-2,1 b] thiazol-3-ylidene] acetate mp 143 to 146 ° C. Elemental analysis (C ₁₃ H ₁₆ N ₂ O ₃ S) Calculated value (%): C55.70 H5.75 N9.99 Actual value (%): C55.55 H5.80 N9.90 NMR spectrum δ (CDCl ₃ ): 1.31 (3H, t), 2.30 (3H, s), 2.97 (3H, d), 4.22 (2H,
q), 4.80 (2H, d), 5.77 (1H, t), 6.74 (1H, s). Example 140 Methyl (7-ethoxycarbonyl-2,2,6-trimethyl-2,3-dihydropyrrolo [2,1-b] thiazol-3-ylidene) acetate Melting point 83-84 ° C. Elemental analysis (C ₁₅ H) ₁₉ NO ₄ as S) calculated (%): C58.23 H6.19 N4.53 Found (%): C58.26 H6.19 N4.40 NMR spectrum _{δ (CDCl 3): 1.34 (} 3H, t) , 2.04 (6H, s), 2.26 (3H, d), 3.72 (3H,
s), 4.26 (2H, q), 5.73 (1H, s), 6.64 (1H, q). Example 141 2,2,2-Trichloroethyl (7-isopropoxycarbonyl-2,2,6-trimethyl-2,3-dihydropyrrolo [2,1
-B] Thiazole-3-ylidene) acetate Melting point 113-114 ° C NMR spectrum δ (CDCl ₃ ): 1.33 (6H, d), 2.05 (6H, s), 2.27 (3H, d), 4.78 (2H,
s), 5.14 (1H, sept), 5.82 (1H, s), 6.73 (1H, q). Example 142: Methyl (7-isopropoxycarbonyl-6-methyl-
2,3-dihydropyrrolo [2,1-b] thiazol-3-yl) acetate Oil NMR spectrum δ (CDCl ₃ ): 1.31 (6H, d), 2.22 (3H, d), 2.7-2.9 (2H, m), 3.35
(1H, dd), 3.73 (3H, s), 3.91 (1H, dd), 4.5 ~ 4.9 (1H,
m), 5.13 (1H, sept), 6.40 (1H, d). Example 143 Methyl (7-isopropoxycarbonyl-2,3-dihydropyrrolo [2,1-b] thiazol-3-yl) acetate Melting point 42 ° C. Elemental analysis (as C ₁₃ H ₁₇ NO ₄ S) Calculated ( %): C55.11 H6.05 N4.94 Actual value (%): C55.16 H6.13 N4.88 NMR spectrum δ (CDCl ₃ ): 1.31 (6H, d), 2.77 (1H, d), 2.85 (1H, d), 3.42 (1H,
dd), 3.73 (3H, s), 3.99 (1H, dd), 4.7 ~ 5.0 (1H, m),
5.13 (1H, sept), 6.56 (1H, d), 6.60 (1H, d). Example 144: N-methyl- (7-isopropoxycarbonyl-6-methyl-2,3-dihydropyrrolo [2,1-b] thiazole-3
- yl) acetamide mp 108-109 ° C. Elemental analysis _{(C 14 H 20 N 2 O} 3 as S) Calculated (%): C56.73 H6.80 N9.45 Found (%): C56.71 H6. 83 N9.49 NMR spectrum δ (CDCl ₃ ): 1.30 (6H, d), 2.18 (3H, d), 2.3 to 2.7 (2H, m), 2.80
(3H, d), 3.32 (1H, dd), 3.89 (1H, dd), 4.7 ~ 5.0 (1H,
m), 5.08 (1H, sept), 6.38 (1H, d). Example 145 N-methyl- (7-isopropoxycarbonyl-2,3-
Dihydropyrrolo [2,1-b] thiazol-3-yl) acetamide Melting point 117-119 ° C Elemental analysis (as C ₁₃ H ₁₈ N ₂ O ₃ S) Calculated (%): C55.30 H6.43 N9. 92 actual value (%): C55.27 H6.38 N9.86 NMR spectrum δ (CDCl ₃ ): 1.30 (6H, d), 2.57 (1H, s), 2.64 (1H, s), 2.80 (3H,
d), 3.38 (1H, dd), 3.99 (1H, dd), 4.93 (1H, ddt), 5.1
0 (1H, sept), 6.53 (1H, d), 6.56 (1H, d). Example 146 (7-isopropoxycarbonyl-6-methyl-2,3-
Dihydro-pyrrolo [2,1-b] thiazol-3-yl) acetamide mp 143 to 146 ° C. Elemental analysis _{(C 13 H 18 N 2 O} 3 as S) Calculated (%): C55.30 H6.43 N9. 92 actual value (%): C55.20 H6.47 N9.71 NMR spectrum δ (CDCl ₃ ): 1.31 (6H, d), 2.21 (3H, d), 2.6 to 2.8 (2H, m), 3.34
(1H, dd), 3.94 (1H, dd), 4.7 ~ 5.0 (1H, m), 5.12 (1H,
sept), 6.43 (1H, d). Example 147 (7-isopropoxycarbonyl-6-methyl-2,3-
Methyl dihydropyrrolo [2,1-b] thiazol-3-yl) acetate (7-isopropoxycarbonyl-6-methyl-2,3-dihydropyrrolo [2,1-b] thiazol-3-yl) acetate 7.0 g Is dissolved in 70 ml of methanol, 25 ml of a 1 N aqueous sodium hydroxide solution is added, and the mixture is stirred at room temperature for 5 hours. The residue obtained by distilling off the solvent was acidified by adding 40 ml of 1N hydrochloric acid and extracted with chloroform. The chloroform layer is washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Next, the residue obtained by distilling off the solvent was crystallized from a mixed solvent of ether and n-hexane to obtain 5.0 g of the title compound.

Melting point 130-132 ° C Elemental analysis value (as C ₁₃ H ₁₇ NO ₄ S) Calculated value (%): C55.10 H6.05 N4.94 Actual value (%): C55.18 H6.08 N4.89 NMR spectrum δ (CDCl ₃ ): 1.32 (6H, d), 2.22 (3H, s), 2.8 to 3.0 (2H, m), 3.39
(1H, dd), 3.93 (1H, dd), 4.6 ~ 4.9 (1H, m), 5.14 (1H,
sept), 6.43 (1H, s). Example 148 4-methyl-1- (7-isopropoxycarbonyl-6
-Methyl-2,3-dihydropyrrolo [2,1-b] thiazol-3-yl) acetylpiperazine (7-isopropoxycarbonyl-6-methyl-2,3
-Dihydropyrrolo [2,1-b] thiazol-3-yl)
Acetic acid 1.54 g, N-methylpiperazine 0.70 g and 4-N, N
0.12 g of dimethylaminopyridine in 50 ml of dichloromethane
Then, 1.44 g of dicyclohexylcarbodiimide was added under ice-cooling and stirring, and the mixture was returned to room temperature and stirred for 9 days. After filtering off the insoluble matter, the solvent was distilled off, and the oily substance obtained was purified by silica gel column chromatography to obtain 1.1 g of the title compound.

Melting point 103-104 ° C Elemental analysis (as C ₁₈ H ₂₇ N ₃ O ₃ S) Calculated (%): C59.15 H7.45 N11.50 Actual (%): C59.06 H7.56 N11.52 NMR spectrum δ (CDCl ₃ ): 1.32 (6H, d), 2.22 (3H, d), 2.29 (3H, s), 2.5 to 2.8
(2H, m), 3.2 ~ 3.5 (3H, m), 3.5 ~ 3.8 (2H, m), 4.00 (1
H, dd), 4.7-5.1 (1H, m), 5.14 (1H, sept), 6.42 (1H,
d). The compounds of Examples 149 to 150 were produced in the same manner as in Example 148.

Example 149 (7-isopropoxycarbonyl-6-methyl-2,3-
Dihydro-pyrrolo [2,1-b] thiazol-3-yl) acetyl morpholine mp 97 to 99 ° C. Elemental analysis _{(C 17 H 24 N 2 O} 4 as S) Calculated (%): C57.93 H6.86 N7 .95 actual value (%): C57.99 H6.91 N7.90 NMR spectrum δ (CDCl ₃ ): 1.32 (6H, d), 2.22 (3H, s), 2.5 to 2.8 (2H, m), 3.2 to
3.5 (3H, m), 3.4 ~ 3.7 (6H, m), 4.00 (1H, dd), 4.7 ~ 5.
1 (1H, m), 5.13 (1H, sept), 6.42 (1H, s). Example 150 (7-isopropoxycarbonyl-2,3-dihydropyrrolo [2,1-b] thiazol-3-ylidene) acetonitrile Melting point 165-167 ° C Elemental analysis (as C ₁₂ H ₁₂ N ₂ O ₂ S) Calculated value (%): C58.06 H4.83 N11.29 Actual value (%): C58.25 H4.77 N11.45 NMR spectrum δ (CDCl ₃ ): 1.22 (6H, d), 4.67 (2H, d) ), 5.18 (1H, sept), 5.22
(1H, t), 6.76 (1H, d), 6.84 (1H, d). Reference Example 25 N- (7-isopropoxycarbonyl-2,2,6-trimethyl-2,3-dihydropyrrolo [2,1-b] thiazole-3
-Ylidene) acetoxysuccinimide 2,2,2-trichloroethyl (7-isopropoxycarbonyl-2,2,6-trimethyl-2,3-dihydropyrrolo [2,
1-b] Thiazole-3-ylidene) acetate (0.80 g) is added to acetic acid (10 ml), and zinc powder (1.9 g) is added thereto at room temperature under stirring.
After 3 hours, the insolubles were removed by filtration and the filtrate was distilled off under reduced pressure. Water was added to the residue, extracted with dichloromethane, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The solvent is distilled off to obtain 0.46 g of carboxylic acid. The crude carboxylic acid obtained here, N-hydroxysuccinimide 0.
33 g and N, N'-dicyclohexylcarbodiimide 0.51 g
Is added to 5 ml of tetrahydrofuran and stirred at room temperature overnight. 0.5 ml of acetic acid was added to the reaction solution, and the mixture was stirred for 1 hour, and ethyl acetate was added. The filtrate is washed with water and a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography to obtain 0.46 g of the title compound.

Melting point 171-173 ° C NMR spectrum δ (CDCl ₃ ): 1.33 (6H, d), 2.00 (6H, s), 2.27 (3H, s), 2.86 (4H,
s), 5.14 (1H, sept), 5.87 (1H, s), 6.70 (1H, s). Example 151 N-methyl- (7-isopropoxycarbonyl-2,2,6
-Trimethyl-2,3-dihydropyrrolo [2,1-b] thiazole-3-ylidene) acetamide N- (7-isopropoxycarbonyl-2,2,6-trimethyl-2,3-dihydropyrrolo [2,1 -B] thiazole-
0.40 g of 3-ylidene) acetoxysuccinimide is dissolved in 10 ml of tetrahydrofuran, and 1 m of a 40% ethylamine aqueous solution is dissolved.
Add l and stir at room temperature for 0.5 hour to react. Water in the reaction solution
50 ml was added, extracted with 100 ml of chloroform, washed with 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 0.32 g of the title compound.

Melting point 104-105 ° C Elemental analysis value (as C ₁₆ H ₂₂ N ₂ O ₃ S) Calculated value (%): C59.60 H6.88 N8.69 Actual value (%): C59.45 H6.96 N8.58 NMR spectrum δ (CDCl ₃ ): 1.32 (6H, d), 2.05 (6H, s), 2.25 (3H, d), 2.87 (3H,
d), 5.13 (1H, sept), 5.64 (1H, s), 6.57 (1H, q). Test Example Effect on liver injury (hepatitis) model induced by D-galactosamine Experimental animal: An SD male rat (body weight 170 to 200 g) was used.

Drug administration: All test drugs were suspended in a 1% aqueous solution of methylcellulose and orally administered at a dose of 200 mg / kg one hour before induction of liver injury.

Induction of galactosamine hepatic injury (hepatitis) and evaluation of drug effect: D-galactosamine hydrochloride 800 mg / kg was subcutaneously administered to rats to induce liver injury. After administration of D-galactosamine, the animals were fasted, and 24 hours later, blood was collected from the descending vena cava under ether anesthesia, and the GPT value as an index of the degree of liver damage was measured.

Results: The results are shown in Table 1.

As is clear from Table 1, the GPT value of the test compound administration group was significantly lower than that of the disease state 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.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61K 31/496 A61K 31/495 601 31/5377 31/535 606 31/541 31/54 601 (72) Inventor Masashi Hasegawa Tokyo 1-16-13 Kita-Kasai, Edogawa-ku, Daiichi Pharmaceutical Central Research Laboratories (72) Inventor Shuichi Yokohama 1-1-16-13 Kita-Kasai, Edogawa-ku, Tokyo, Japan Daiichi Pharmaceutical Central Research Laboratories (56) References JP 3 -128385 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 513/04 A61K 31/425 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. The compound of the general formula (I) (In the formula, Represents a double bond or a single bond; R ¹ represents an alkyloxycarbonyl group; R ⁶ represents a hydrogen atom or a lower alkyl group; A represents ＝ CH—COR ⁹ (R ⁹ represents a hydroxyl group, a lower alkyl group, A phenyloxy group or a phenylthio group which may be substituted by an atom or a nitro group), (R ¹⁰ is a hydrogen atom, R ¹¹ is a cycloalkyl group, a phenyl group, a benzyl group, or indicates a pyridyl group, R ¹⁰ and R ¹¹ together contain other nitrogen atom, an oxygen atom or a sulfur atom May form a heterocyclic ring), (R ⁸ is a hydrogen atom or an alkoxycarbonyl group) or -CH
_2- COR ¹⁹ (R ¹⁹ represents a hydroxyl group, an alkoxy group, an amino group, an alkylamino group, a morpholino group or a piperazinyl group)] or a pyrrolo [2,1-b] thiazole derivative or a salt thereof. 2. A preventive / therapeutic agent for liver disease, comprising the pyrrolo [2,1-b] thiazole derivative or a salt thereof according to claim 1 as an active ingredient.