Thiazole derivatives and medical compositions thereof

A thiazole derivative represented by the formula I, pharmaceutically acceptable acid addition salt thereof, and a process for preparation thereof ##STR1## wherein R.sub.1 represents --COOR.sub.4, ##STR2## or cyano wherein R.sub.4 represents hydrogen or lower alkyl, and PA1 R.sub.5 and R.sub.6 may be the same or different and represent hydrogen, lower alkyl, aryl, amino-lower alkyl, N-lower alkylamino-lower alkyl, N,N-di-lower alkylamino-lower alkyl or R.sub.5 and R.sub.6 are joined to form a N-containing heterocyclic group; PA0 R.sub.2 represents hydrogen or lower alkyl; and PA0 R.sub.3 represents N-containing heterocyclic group. These compounds are useful as cardiotonic agents.

BACKGROUND OF THE INVENTION 
The present invention relates to a thiazole derivative represented by the 
formula I, pharmaceutically acceptable acid addition salt thereof, and a 
process for preparation thereof 
##STR3## 
wherein R.sub.1 represents --COOR.sub.4, 
##STR4## 
or cyano wherein R.sub.4 represents hydrogen or lower alkyl, and 
R.sub.5 and R.sub.6 may be same or different and represent hydrogen, lower 
alkyl, aryl, amino-lower alkyl, N-lower alkylamino-lower alkyl, 
N,N-di-lower alkylamino-lower alkyl or R.sub.5 and R.sub.6 are joined to 
form N-containing heterocyclic group; 
R.sub.2 represents hydrogen or lower alkyl; and 
R.sub.3 represents N-containing heterocyclic group. 
Some thiazole derivatives having a cardiotonic activity are known as 
described in Japanese Patent Applications laid open under Nos. 
134417/1982, 16889/1984 and 193878/1984 and so on. Meanwhile, thiazole 
derivatives in general are prepared by a method as described in Japanese 
Patent Applications laid open under Nos. 34241/1982, 49969/1974 and so on. 
That is, a thioamide is reacted with an .alpha.-halocarbonyl compound to 
form a compound of thiazole derivative. The known thiazole derivatives 
having a cardiotonic activity is prepared by this well known method. 
However, there is no teaching in the prior art of any cardiotonically 
active compounds having any chemical structure comparable to or suggestive 
of instantly claimed compound. 
Further, such known technique is unsuitable for synthesizing the compound 
of the formula I. 
SUMMARY OF THE INVENTION 
As the result of researches, we, the inventors succeeded in synthesizing 
new thiazole derivatives which are useful as cardiotonic agents. More 
specifically, one aspect of this invention is to provide thiazole 
derivatives having carbonyl, unsubstituted or substituted aminocarbonyl or 
cyano at position 2 and having nitrogen-containing heterocyclic group at 
position 5 and and pharmaceutically acceptable acid addition salt thereof. 
Another aspect of this invention is to provide a cardiotonic agent 
comprising said thiazole derivatives and pharmaceutically acceptable acid 
addition salt thereof as effective component. A further aspect of this 
invention is to provide a process for preparation of said thiazole 
derivatives and pharmaceutically acceptable acid addition salt thereof. 
DETAILED DESCRIPTION 
The thiazole derivative of the present invention is represented by the 
following formula I 
##STR5## 
wherein R.sub.1 represents --COOR.sub.4, 
##STR6## 
or cyano wherein R.sub.4 represents hydrogen or lower alkyl, and 
R.sub.5 and R.sub.6 may be same or different and represent hydrogen, lower 
alkyl, aryl, amino-lower alkyl, N-lower alkylamino-lower alkyl, 
N,N-di-lower alkylamino-lower alkyl or R.sub.5 and R.sub.6 are joined to 
form N-containing heterocyclic group; 
R.sub.2 represents hydrogen or lower alkyl; and 
R.sub.3 represents N-containing heterocyclic group. 
The term "lower" as used herein refers to from 1 to 6 carbon atoms unless 
otherwise indicated. 
The term "lower alkyl" as used herein means alkyl group having from 1 to 6 
carbon atoms which may be arranged as straight or branched chains. The 
"lower alkyl" may be methyl, ethyl, n-propyl, iso-propyl, n-butyl, 
iso-butyl, tert-butyl, n-pentyl, n-hexyl or the like. 
The term "aryl" as used herein means aryl group which may be unsubstituted 
or may bear one or two substituents selected from lower alkyl, lower 
alkoxy (e.g. methoxy, ethoxy), halogeno (e.g. chloro, bromo), cyano, 
nitro, hydroxy and so on. The "aryl" may be phenyl, tolyl, xylyl, mesityl, 
cumenyl, biphenyl, hydroxyphenyl or the like. 
The term "amino-lower alkyl" as used herein means lower alkyl group 
substituted with one or two of amino groups. The "amino-lower alkyl" may 
be aminomethyl, diaminomethyl, aminoethyl, diaminoethyl, amino-n-hexyl or 
the like. 
The term "N-lower alkylamino-lower alkyl" as used herein means amino-lower 
alkyl group substituted with one lower alkyl group. The "N-lower 
alkylamino-lower alkyl" may be N-methylaminomethyl, N-methylaminoethyl, 
N-ethylaminoethyl, N-n-hexylaminoethyl or the like. 
The term "N,N-di-lower alkylamino-lower alkyl" as used herein means amino 
lower alkyl group substituted with two lower alkyl groups. The 
"N,N-di-lower alkyl amino-lower alkyl" may be N,N-dimethylaminomethyl, 
N,N-dimethylaminoethyl, N-methyl-N-n-hexylaminomethyl or the like. 
The term "N-containing heterocyclic group" as used herein means 
nitrogen-containing, 5 or 6 membered mono or condensed heterocyclic ring 
group which may be unsubstituted or may bear one or two substituents 
selected from lower alkyl, lower alkoxy, halogeno, cyano, nitro, aldehyde, 
acyl (e.g. formyl, acetyl), hydroxy and so on. The "N-containg 
heterocyclic group" may be pyridinil, pyridazinyl, pyrimidinyl, pyrazinyl, 
quinolinyl, isoquinolinyl, cinnolinyl, quanazolinyl, quinoxalinyl, 
phthalazinyl, acridinyl, methylpyridinyl, methoxypyrizinyl, 
chloropyridinyl, formylpyridinyl, cyanopyridinyl, nitropyridinyl, 
acetylpyridinyl, hydroxypyridinyl, methoxyquinolinyl, methylpyridazinyl, 
piperidino, morpholino or the like. 
As to the formula I, it is to be noted that some of the compounds may be 
alternatively represented by its tautomers, e.g., "2-hydroxypyridinyl" and 
"2-oxo-pyridinyl". Both of said moieties are in the state of tautomeric 
equilibrium as represented by the following equilibriums. 
##STR7## 
Accordingly it is to be understood that both of such isomers are included 
within the same category of the formula I. 
In the present specification, the formula I includes the group of such 
tautomeric isomers which is however represented by one of the expressions. 
The compounds according to the present invention are for example as 
follows: 
methyl 4-methyl-5-(4-pyridinyl)-thiazole-2-carboxylate; 
4-methyl-5-(4-pyridinyl)-thiazole-2-carboxamide; 
N,4-dimethyl-5-(4-pyridinyl)-thiazole-2-carboxamide; 
4-methyl-5-(4-pyridinyl)-thiazole-2-carboxanilide; 
4-methyl-N-aminomethyl-5-(4-pyridinyl)-thiazole-2-carboxamide; 
4-methyl-N-(2-methylaminoethyl)-5-(4-pyridinyl)-thiazole-2-carboxamide; 
4-methyl-N-(2-dimethylaminoethyl)-5-(4-pyridinyl)-thiazole-2-carboxamide; 
N,N-diethyl-4-methyl-5-(4-pyridinyl)-thiazone-2-carboxamide; 
2',6'-dimethyl-4-methyl-5-(4-pyridinyl)-thiazole-2-carboxamide; 
1-[4-methyl-5-(4-pyridinyl)-2-thiazolylcarbonyl]-piperidine; 
2-cyano-4-methyl-5-(4-piperidinyl)-thiazole; 
methyl 4-methyl-5-(4-pyridazinyl)-thiazole-2-carboxylate; 
4-methyl-5-(4-pyridazinyl)-thiazole-2-carboxamide; 
1-[4-methyl-5-(4-pyridazinyl)-2-thiazolylcarbonyl]-piperazine; 
2-cyano-4-methyl-5-(4-pyridazinyl)-thiazole; 
methyl 4-methyl-5-(4-quinolinyl)-thiazole-2-carboxylate; 
4-methyl-5-(4-quinolinyl)-thiazole-2-carboxamide; 
2-cyano-4-methyl-5-(4-quinolinyl)-thiazole; 
methyl 4-methyl-5-(3-methyl-4-pyridinyl)-thiazole-2-carboxylate; 
4-methyl-5-(3-methyl-4-pyridinyl)-thiazole-2-carboxamide; 
2-cyano-4-methyl-5-(3-methyl-4-pyridinyl)-thiazole; 
methyl 4-methyl-5-(3-acetyl-4-pyridinyl)-thiazole-2-carboxylate; 
4-methyl-5-(3-acetyl-4-pyridinyl)-thiazole-2-carboxamide; 
2-cyano-4-methyl-5-(3-acetyl-4-pyridinyl)-thiazole; 
methyl 4-methyl-5-(3-chloro-4-pyridinyl)-thiazole-2-carboxylate; 
4-methyl-5-(3-chloro-4-pyridinyl)-thiazole-2-carboxamide; 
2-cyano-4-methyl-5-(3-chloro-4-pyridinyl)-thiazole; 
methyl 4-methyl-5-(3-formyl-4-pyridinyl)-2-carboxylate; 
4-methyl-5-(3-formyl-4-pyridinyl)-thiazole-2-carboxamide; 
2-cyano-4-methyl-5-(3-formyl-4-pyridinyl)-thiazole; 
methyl 4-methyl-5-(3-cyano-4-pyridinyl)-thiazole-2-carboxylate; 
4-methyl-5-(3-cyano-4-pyridinyl)-thiazole-2-carboxamide; 
2-cyano-4-methyl-5-(3-cyano-4-pyridinyl)-thiazole; 
methyl 4-methyl-5-(6-methoxy-4-quinolinyl)-thiazole-2-carboxylate; 
4-methyl-5-(6-methoxy-4-quinolinyl)-thiazole-2-carboxamide; 
2-cyano-4-methyl-5-(6-methoxy-4-quinolinyl)-thiazole; 
methyl 4-methyl-5-(2-thiazolyl)-thiazole-2-carboxylate; 
4-methyl-5-(2-thiazolyl)-thiazole-2-carboxamide; 
2-cyano-4-methyl-5-(2-thiazolyl)-thiazole; 
and the like. 
The thiazole derivative of the formula I is prepared according to the 
following process. 
As to the following process, the pressure is under atmospheric pressure 
unless otherwise indicated. 
First of all, the 2,2-di-lower alkoxy-1,4-thiazine derivative of the 
formula II is prepared 
##STR8## 
wherein R.sub.2, R.sub.3 and R.sub.4 are as defined above. 
The compound of the formula II is prepared according to the following 
process. 
When a known 1,4-thiazine derivative of the formula VI 
##STR9## 
wherein R.sub.2 is as defined above, is reacted with a known compound of 
the formula A--X' (in which A represents a residue 
##STR10## 
in which X represents a halogen atom and n is a number of 0 to 3, and X' 
represents a halogen atom which may be the same as or different from X) 
and a known compound of the formula R.sub.3 --H (in which R.sub.3 is as 
defined above), a 1,4-thiazine derivative of the formula V is obtained. 
##STR11## 
wherein R.sub.2, R.sub.3 and A are as defined above and R.sub.3 ' 
represents dihydro form residue of N-containing heterocyclic group. 
This reaction is completed by merely stirring the compound of the formula 
VI, more than equal mole concentration of the compound A--X' and more than 
equal mole concentration of the compound of the formula R.sub.3 --H at 
room temperature for 1 to 7 hours. 
The solvent, which is used in this reaction, may be nitrile such as 
acetonitrile, ether such as tetrahydrofran, or halogenated hydrocarbon 
such as dichloromethan or the like. Incidentally, the compound having 
N-containing heterocyclic group may also be used as a solvent. 
The compound having N-containing heterocyclic group may be unsubstituted or 
may bear one or two substituents selected from lower alkyl, lower alkoxy, 
halogeno, cyano, nitro, aldehyde, acyl, hydroxy, alkoxycarbonyl and so on. 
The compound may be pyridine, pyridazine, pyrimidine, pyrazine, quinoline, 
isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, acridine, 
phenazine, piperidine, piperazine, morpholine, 3-methoxypyridine, 
3-chloropyridine, pyridine-3-aldehyde, nicotinonitrile, 3-acetylpyridine, 
methyl nicotinate, 3-nitropyridine, 3-hydroxypyridine, 6-methoxyquinoline, 
3-methylpyridazine or the like. 
Then the compound of the formula IV is obtained by aromatization of the 
compound of the formula V. This may be effected in various processes; a 
preferred process is as follows. 
The compound of the formula V is reacted with sulfur at elevated 
temperature to obtain the 1,4-thiazine derivative of the formula IV. 
##STR12## 
wherein R.sub.2, R.sub.3, A and R.sub.3 ' are as defined above. 
This reaction proceeds well by stirring the compound of the formula V with 
from half to 5 fold amount of sulfur and heating the mixture at 
120.degree. to 200.degree. C. for 0.5 to 8 hours. Generally, no solvent is 
needed in this reaction; however, N,N-dimethylformamide, dimethyl 
sulfoxide, xylene, (o-, m-, p-) dichlorobenzene, diglime, etc. may be 
employed. 
Alternatively, the compound of the formula IV may be prepared according to 
a process that the compound of the formula V is reacted with zinc at room 
temperature or elevated temperature. Some of the compound of the formula V 
is reacted with zinc to obtain thiazole derivative having dihydro form 
residue of N-containing heterocyclic group at position 6. In this case, it 
is necessary to oxidize a reaction intermediate by an oxidizing agent. 
This process is represented by the following formula 
##STR13## 
wherein R.sub.2, R.sub.3, A and R.sub.3 ' are as defined above. 
This reaction proceeds well by stirring the compound of the formula V with 
excessive amount of zinc and stirring the mixture at room temperature or 
elevated temperature up to 80.degree. C. for 1 to 4 hours. A solvent used 
in this reaction may be an organic solvent in the form of mixture with 
water; the organic solvent may be carboxylic acid such as formic acid, 
nitrile such as acetonitrile, ether such as tetrahydrofuran, sulfoxide 
such as dimethylsulfoxide or amide such as methylformamide or the like. 
The oxidizing agent used in this reaction may be 
2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) or the like. 
Purification of the compounds of the formula V and VI may be accomplished 
by recrystallization from lower alcohol such as methanol, ethanol or 
isopropanol, ketone such as acetone, halogenated hydrocarbon such as 
chloroform, carboxylic acid ester such as ethyl acetate, aromatic 
hydrocarbon such as benzene, ether such as diethylether or nitrile such as 
acetonitrile or the like. 
Alternatively, such purification may also be accomplished by column 
chromatography or thin layer chromatography. In this operation, silica gel 
having particles size of 100-200 mesh such as Wakogel C-200 (manufactured 
by Wako Junyaku Kabushiki Kaisha in Japan), silica gel having particle's 
average porous diameter of 40-63 .mu.m such as silica gel 650 Lichloprep 
60 (manufactured by Merck & Co. Inc. in USA) or fluoresces a light blue 
color in the region of 254 nm such as Merch TCL plate silica gel 
60F.sub.254 (manufactured by Merck & Co. Inc. in USA) is preferable to 
use. 
Incidentally, the compound of the formula C may be directly used in the 
subsequent reaction without purification. 
The known starting material 1,4-thiazine derivative of the formula VI may 
be prepared according to the processes proposed by H. Sokol et al. in J. 
Am. Chem. Soc., 70, 3517 (1948), C. R. Johnson et al. in J. Heterocycl. 
Chem., 6, 247-249 (1969), and G. V. Rao et al. in Synthesis, 136 (1972). 
Then, the thiazine derivative having substituent group such as lower 
alkoxy, halogeno, acyloxy or hydroxy or the like at position 2 may be 
prepared according to the process by M. Hojo et al. in Synthesis 312, 426 
(1982). 
Thus, the compound of the formula IV is reacted with the compound of the 
formula A'--COOOH (in which A' represent lower alkyl, alicyclic residue 
or aryl), i.e. peroxycarboxylic acid to obtain the compound of the formula 
III. 
##STR14## 
wherein R.sub.2, R.sub.3 and A' are as defined above. 
This reaction is completed by merely stirring the compound of the formula 
IV and more than equal mole concentration of the compound of the formula 
A'--COOOH under ice-cooling for a few minutes. 
The solvent, which is used in this reaction, may be halogenated hydrocarbon 
such as dichloromethane, nitrile such as acetonitrile, ether such as 
tetrahydrofuran, sulfoxide such as dimethylsulfoxide or amide such as 
dimethylformamide or the like. 
As for the peroxycarboxylic acid, aliphatic peroxycarboxylic acid such as 
performic acid or peracetic acid, alicyclic peroxycarboxylic acid such as 
cyclohexaneperoxycarboxylic acid, or aromatic peroxycarboxylic acid such 
as perbenzoic acid or monoperoxyphthalic acid may be employed. The 
peroxycarboxylic acid having substituent such as lower alkyl, lower 
alkoxy, halogeno, cyano, nitro, aldehdye, acyl, hydroxy or the like may 
also be employed. In view of the state of the reaction system (the 
reactivity and degree of dissociation) and the easy availability, 
m-chloroperbenzoic acid is especially preferred. 
Then, the compound of the formula III is reacted with the nucleophilic 
reagent of the formula R.sub.4 --OH (in which R.sub.4 is as defined above) 
to obtain the compound of the formula II'. 
##STR15## 
wherein R.sub.2, R.sub.3, R.sub.4 and A' are as defined above. 
This reaction is completed by merely stirring the compound of the formula 
III and more than equal mole concentration of the compound of the formula 
R.sub.4 --H at room temperature for more than 1 day. Alternatively, the 
reaction may be carried out at 50.degree.-70.degree. C. 
In this raection, the compound of the formula R.sub.4 --H may be used as a 
solvent. 
Incidentally, amide such as dimethylformamide, nitrile such as 
acetonitrile, ether such as tetrahydrofuran, sulfoxide such as 
dimethylsulfoxide or halogenated hydrocarbon such as dichloromethane or 
the like may be used as a solvent. 
As for the compound of the formula R.sub.4 --OH, lower alcohol such as 
methanol, ethanol, iso-propanol or the like may be employed. 
Then, the compound of the formula II' is reacted with more than equal mole 
concentration of the formula A'--COOOH and more than two mole 
concentration of the formula R.sub.4 --OH to obtain the compound of the 
formula II. 
##STR16## 
wherein R.sub.2, R.sub.3, R.sub.4 and A' are as defined above. 
The compound of the formula III, the compound of the formula II' and the 
compound of the formula II may be used in the subsequent reaction without 
purification. 
Incidentally, purification of these compounds may be accomplished by 
recrystallization from lower alcohol such as methanol, ethanol or 
isopropanol, halogenated hydrocarbon such as chloroform or carboxylic acid 
ester such as ethyl acetate or the like. 
Alternatively, such purification may also be accomplished by alumina column 
chromatography. In this operation, alumina having 300 mesh is preferable 
to use. And, halogenated hydrocarbon such as chloroform or carboxylic acid 
ester such as ethyl acetate or the like may be used as an eluent. 
The thiazine derivative having substituent at position 2, i.e. the compound 
of the formula II, may be also obtained by the following process. One mole 
concentration of the compound of the formula IV is reacted with more than 
two mole concentration of the compound of the formula A'--COOOH and more 
than two mole concentration of the compound of R.sub.4 --OH in a similar 
manner as above. 
Alternatively, the compound of the formula II may be obtained by 
introduction of --OR.sub.4 group position at 2 in the same manner as 
above, then introduction of --R.sub.3 group position at 6 in the same 
manner as above. 
##STR17## 
wherein, R.sub.2, R.sub.3, R.sub.4 are as defined above. 
The compound of the formula II is reacted with an acid to obtain the 
compound of the formula I' i.e. thiazole derivative having lower 
alkoxycarbonyl group at position 2. 
##STR18## 
where R.sub.2, R.sub.3 and R.sub.4 are as defined above. 
This reaction is completed by merely allowing the compound of the formula 
II with more than equal mole concentration of the acid and the mixture to 
stand at room temperature for more than 10 minutes. The acid used in this 
reaction may be inorganic acid such as hydrochloric acid, sulfuric acid, 
etc. or organic acid such as acetic acid, etc. In view of the state of the 
reaction system (the reactivity and degree of dissociation) and the easy 
availability, hydrochloric acid is especially preferred. 
This reaction is proceeded by adding the compound of the formula II into 
the acid which is diluted with water. 
The solvent used in this reaction is water. 
Purification of the compound of the formula I' may be accomplished by 
recrystallization from aromatic hydrocarbon such as benzene or alicyclic 
hydrocarbon such as cyclopentane, cyclohexane or the like or a mixture of 
two or more of these solvents. 
Alternatively, such purification may be accomplished by column 
chromatography or thin layer chromatography. 
Optionally, the --COOR.sub.4 group (in which R.sub.4 is as defined above) 
of the compound of the formula I' may be converted into 
##STR19## 
group (in which R.sub.5 and R.sub.6 are as defined above) or cyano group 
by methods known in the art. Thus the compound of the formula I", i.e. 
thiazole derivative having unsubstituted or substituted aminocarbonyl 
group at position 2, is prepared by reacting the compound of the formula 
I' with the compound of the formula 
##STR20## 
(in which R.sub.5 and R.sub.6 are as defined above). 
##STR21## 
wherein R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are as defined 
above. 
This reaction is completed by merely stirring the compound of the formula 
I' and more than equal mole concentration of the compound of the formula 
##STR22## 
at room temperature for more than 1 hour, preferably about 10 hours. 
Alternatively, it may be completed by once converting the compound of the 
formula I' into a reaction intermediate having chlorocarbonyl group and 
then reacting the same with the compound of the formula 
##STR23## 
More specifically, first, the compound of the formula I' and a base such 
as sodium hydroxide aqueous solution or potassium hydroxide aqueous 
solution are stirred at room temperature to obtain a thiazole derivative 
having carboxy group at postion 2. Secondly, the compound having carboxy 
group at position 2 and more than equal mole of chlorination agent such as 
thionyl chloride are stirred at room temperature for more than 10 hours to 
obtain a thiazole derivative having chlorocarbonyl group at position 2. 
Thirdly, the compound having chlorocarbonyl group at position 2 is reacted 
with more than equal mole of the compound of the formula 
##STR24## 
at room temperature for more than 10 hours to obtain the compound of the 
formula I'. This process is represented by the following formula 
##STR25## 
wherein R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are as defined 
above. 
As for the compound represented by the formula 
##STR26## 
ammonia water, lower alkyl amine such as methylamine or ethylamine, 
aromatic amine such as aniline, toluidine or xylidine, di-amine such as 
N,N-dimethylaminoethylamine, secondary amine such as N,N-dimethylamine, 
N,N-diethylamine or heterocyclic compound having nitrogen atoms such as 
piperidine, piperazine or morpholine or the like may be used in this 
reaction. As for the solvent, lower alcohol such as methanol or ethanol, 
ether such as tetrahydrofuran, aromatic hydrocarbon such as toluene or 
xylene or water or the like may be used in this reaction. 
Alternatively, the compound of the formula 
##STR27## 
may be used as a solvent. 
Purification of the compound of the formula I" may be accomplished by 
recrystallization from lower alcohol such as methanol, ethanol or 
iso-propanol, aromatic hydrocarbon such as benzene, alicyclic hydrocarbon 
such as cyclopentane or cyclohexane, ether such as tetrahydrofuran or a 
mixture of two or more of these solvents or the like. 
Alternatively, it may be accomplished by silica gel column chromatography 
or silica gel thin layer chromatography. 
The compound of the formula I"', i.e. the thiazole derivative having cyano 
group at position 2, is obtained by treating the compound of the formula 
I", especially 2-carbamoylthiazole derivative in which R.sub.5 and R.sub.6 
are hyrogen atoms, with a dehydrating agent in the usual way. More 
specifically, the reaction is completed by stirring the compound of the 
formula I" and more than equal mole of a dehydrating agent such as 
p-toluenesulfonyl chloride or phosphorus trichloride at 60.degree. to 
120.degree. C. for about 20 hours. It is preferable to conduct this 
reaction in the presence of a base such as pyridine. 
##STR28## 
wherein R.sub.2 and R.sub.3 are as defined above. 
Amide such as N,N-dimethylformamide, ether such as tetrahydrofuran or 
heterocyclic compound having nitrogen atom such as pyridine is employed as 
a solvent. 
Purification of the compound of the formula I"' may be accomplished by 
recrystallization from halogenated hydrocarbon such as chloroform or lower 
alcohol such as methanol, ethanol or iso-propanol. 
Alternatively, it may be accomplished by silica gel column chromatography 
or thin layer chromatography. 
When the known thioamide of the formula VIII (in which R.sub.1 and R.sub.3 
are as defined above) is reacted with the known halocarbonyl compounds of 
the formula VII (in which R.sub.2 is as defined above and X" represents 
halogen atom) according to the process proposed by Richard H. Willey in 
Organic Reaction 6 382 (1951), the compound of the formula I may be also 
obtained. 
##STR29## 
wherein R.sub.1, R.sub.2, R.sub.3 and X" are as defined above. 
However, with this known method, the compound of the formula I is obtained 
in lower yield. This method is unsuitable as industrial process. 
The compound of the formula I may be converted into a pharmaceutically 
acceptable salt by using an appropriate acid. 
The appropriate acids which may be used include, for example, inorganic 
acid such as hydrochloric, hydrobromic, sulfuric, nitric or phosphoric 
acid, or organic acid such as acetic, propionic, glycolic, lactic, 
pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, 
benzoic, cinnomic, manderic, methanesulfonic, hydroxyethanesulfonic, 
benzenesulfamic, p-toluenesulfamic, cyclohexanesulfamic, salicylic, 
p-aminosalicylic, 2-phenoxybenzoic or 2-acetoxybenzoic acid. 
The pharmacological effects of the compound of the formula I will now be 
described; 
##STR30## 
wherein R.sub.1, R.sub.2 and R.sub.3 are as defined above. 
(1) The contractile force of left atrium was tested according to the method 
described in Basic Lectures of Medicine Development, Volume V, 
Pharmacological Test Methods, Part 2, page 535 (1971). A 7-weeks-old male 
Hartley guinea pig (having a bodyweight of about 350 g) was killed by a 
blow on a head. The chest was opened and the heart was removed and placed 
in Krebs-Henseleit solution (prepared by adding distilled water to 6.92 g 
of sodium chloride, 0.35 g of calcium chloride, 0.29 g of magnesium 
sulfate, 0.16 g of mono-basic potassium phosphate, 2.1 g of sodium 
bicarbonate and 1.8 g of glucose so that the total amount was 1 l) which 
sufficiently bubbled with oxygen gas. Threads were tied to each tip of the 
left atrium. One thread was attached to a fixed pin in Magnus's bath and 
the other to a force-displacement transducer connected to an electric 
amplifier and recorder. The atrium was stimulated electrically at 0.5 cps, 
5 msec and a voltage of 20% above threshold. The preparation is mounted in 
Krebs-Henseleit solution through which 95% oxygen gas and 5% carbon 
dioxide was blown. Then the samples were added. The results are shown in 
Table 1. 
TABLE 1 
__________________________________________________________________________ 
Effect on Contractile Force of Isolated Left Atrium 
Corresponding 
Maximum 
Concentration 
Contractile 
The compound of the formula I 
(mol) Force (mg) 
__________________________________________________________________________ 
R.sub.1 = --COOCH.sub.3, R.sub.2 = --CH.sub.3, R.sub.3 = 4-pyridinyl 
1 .times. 10.sup.-4 
446 .+-. 91 
R.sub.1 = --CONH.sub.2, R.sub.2 = --CH.sub.3, R.sub.3 = 4-pyridinyl 
1 .times. 10.sup.-4 
1,325 .+-. 132 
R.sub.1 = --CONHCH.sub.3, R.sub.2 = --CH.sub.3, R.sub.3 
1 .times. 10.sup.-4 
510 .+-. 45 
R.sub.1 = --CN, R.sub.2 = --CH.sub.3, R.sub.3 = 4-pyridinyl 
1 .times. 10.sup.-4 
558 .+-. 123 
__________________________________________________________________________ 
(2) The acute toxicity of the compound of the formula I was determined 
according to the Litchfield-Wilcoxon method, J. Pharm. Exp. Ther., 96, 99 
(1949) using 6-weeks-old male ddY mice (having a bodyweight of 19-24 g) 
while administrating the sample compound in intraperitonial injection. The 
results are shown in Table 2. 
TABLE 2 
______________________________________ 
Acute Toxicity Test Result 
The compound of the formula I 
LD.sub.50 (mg/kg) 
______________________________________ 
R.sub.1 = --CONH.sub.2, R.sub.2 = --CH.sub.3, R.sub.3 = 4-pyridinyl 
230 
______________________________________ 
From the above test results, it was confirmed that the contractile force of 
isolated left atrium was significantly increased by administration of the 
compound of the formula I, and the acute toxicity of the compound of the 
formula I is low. 
The compound of the formula I may be administered to human body orally, by 
injection (intravenously, subcutaneously or intramuscularly) or in any 
other manner. When the compound of the formula I is in the form of solid 
preparations for oral administration, the preparations may be tablets, 
granules, powders, capsules or the like. The preparations may contain 
additives, for example, an excipient such as a saccharide or cellulose 
preparation, a binder such as starch paste or methyl cellulose, a filler, 
a disintegrator and so on, all being ones usually used in manufacture of 
medical preparations. 
In case the compound of the formula I is employed as oral liquid 
preparations, they may be of any form selected from aqueous preparations 
for internal use, suspensions, emulsions, syrups, etc., and further they 
may be in the form of dried products which are dissolved prior to the use. 
The compound of the formula I may be injected in the form of aqueous 
solutions, suspensions or oily or aqueous emulsions, but usually the 
injections are prepared by dissolving or suspending them in aqueous liquid 
media such as sterile water of physiological saline solutions. 
If necessary, conventionally used dissolving agents, stabilizers, 
preservatives, additives for preparing isotonic solutions, etc. may be 
added to the injections. 
Further, the above-mentioned tests were carried out by using following 
apparatuses. 
Magnus's bath: supplied by Kabushiki Kaisha Natsume Seisakusho 
Recorder: Model WI-680G supplied by Nippon Koden Kabushiki Kaisha 
Force displacement transducer: supplied by Nippon Koden Kabushiki Kaisha 
Electrical amplifier: Model AP-600G supplied by Nippon Koden Kabushiki 
Kaisha 
Programmed electrosphygmonometer: supplied by Nippon Koden Kabushiki Kaisha 
The invention will be understood more readily with reference to the 
following examples; however these examples are intended to illustrate the 
invention and are not to be constituted to limit the scope of the 
invention. In the examples, the measurements were carried out by using the 
following apparatuses. 
Melting point: Model MP-1 supplied by Yamato Kagaku Kabushiki Kaisha 
Mass analysis: Model M-60 supplied by Kabushiki Kaisha Hitachi Seisakusho 
Infrared absorption spectrum (IR): Model 260-10 supplied by Kabushiki 
Kaisha Hitachi Seisakusho 
Nuclear magnetic resonance (NMR): Model FX-270 supplied by Nippon Denshi 
Kabushiki Kaisha 
Elementary analysis: Model MT-2 supplied by Kabushiki Kaisha Yanagimoto 
Seisakusho

EXAMPLE 1 
Methyl 4-methyl-5-(4-pyridinyl)-thiazole-2-carboxylate 
(i) Preparation of intermediate, 
5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-1,4-dihydro-4-pyridinyl]-2H- 
1,4-thiazin-3(4H)-one 
2,2,2-Trichloroethylchloroformate (64 ml) was added dropwise to a stirred 
suspension of 5-methyl-2H-1,4-thiazin-3(4H)-one (50 g) in a mixture of 
acetonitrile (500 ml)-pyridine (75 ml) under ice-cooling. The mixture was 
stirred at room temperature for 1 hour and then, poured into cold water 
(1.5 l) The resulting precipitates were collected by filtration, 
recrystallized from ethanol to give 
5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-1,4-dihydro-4-pyridinyl]-2H- 
1,4-thiazin-3(4H)-one (120 g, yield 80.7%) as pale yellow prisms. 
Melting point: 158.degree.-160.degree. C. 
Elementary analysis values as: C.sub.13 H.sub.13 N.sub.2 O.sub.3 SCl.sub.3 
; Calculated: C=40.69, H=3.41, N=7.29 (%). Found: C=40.62, H=3.37, N=7.02 
(%). 
Mass spectrum: M.sup.+ 382. 
NMR spectrum (CDCl.sub.3, TMS) .delta.: 1.986 (3H, s), 3.229 (2H, s), 4.161 
(1H, m), 4.800 (4H, m), 6.970 (2H, d), 7.264 (1H, b). 
IR spectrum .nu..sub.max.sup.KBr (cm.sup.-1): 3200, 3100, 1720, 1670, 1630. 
(ii) Preparation of intermediate, 
5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one 
(A) The mixture of 
5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-1,4-dihydro-4-pyridinyl]-2H- 
1,4-thiazin-3(4H)-one (2.14 g) and sulfur (10.7 g) was stirred at 
140.degree. C. for 1.5 hours and then cooled to room temperature. The 
obtained solid was extracted with methanol by using Soxhlet extractor. 
Methanol was evapolated to dryness, and the residue was dissolved in 50 ml 
of 2N hydrochloric acid. The insoluble solid was removed by filtration and 
the filtrate was adjusted to pH 7.2 by addition of 2N sodium hydroxide 
aqueous solution. The precipitates were collected by filtration and the 
filtrate was extracted with chloroform (20 ml.times.5 times) and was 
evaporated to dryness. The combined precipitates and the residue were 
recrystallized from isopropanol to give 
5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one (0.88 g, yield 76.5%) as 
pale yellow plates. 
Melting point: 187.degree.-188.5.degree. C. (decomposition). 
Elementary analysis values as: C.sub.10 H.sub.10 N.sub.2 OS; Calculated: 
C=58.22, H=4.88, N=13.58 (%). Found: C=58.48, H=4.99, N=13.53 (%). 
Mass spectrum: M.sup.+ 206. 
NMR spectrum (CDCl.sub.3, TMS) .delta.: 2.05 (3H, s), 3.43 (2H, s), 7.28 
(2H, d), 8.61 (2H, d), 8.70 (1H, s). 
IR spectrum .nu..sub.max.sup.KBr (cm.sup.-1): 3200, 3050, 1680, 1580. 
(B) Zinc powder (1 g) was added to a stirred solution of 
5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-1,4-dihydro-4-pyridinyl]-2H- 
1,4-thiazin-3(4H)-one (1 g) in formic acid (14 ml), and the reaction 
mixture was stirred at room temperature for 3 hours. The insoluble solid 
was removed by filtration. The filtrate was evaporated to dryness and the 
residue was dissolved in water (30 ml). The solution was adjusted to pH 
7.0 by addition of 1N sodium hydroxide aqueous solution. The precipitates 
were extracted with chloroform (although the solution was converted into 
an emulsion at this extracting step, the operation was facilitated by 
using a filter aid such as "Avicel"). The extract was dried over anhydrous 
magnesium sulfate and was evaporated under reduced pressure. The crude 
product was purified by the preparative thin layer chromatography [Merck 
TLC plate, silica gel 60F.sub.254 t (particles average porous diameter 
60A, Fluorescent substance Zn.sub.2 SiO.sub.4 /Mn), 20.times.20 cm, t=1 
mm, chloroform/methanol= 20/1] to give 200 mg of 
5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one. The physical properties 
were as described above. 
(iii) Preparation of intermediate, 
2,2-dimethoxy-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3-(4H)-one 
m-Chloroperbenzoic acid (5.4 g) was added to a stirred suspension of 
5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one (4.5 g) in methanol (180 
ml) under ice-cooling, and the mixture was stirred at room temperature for 
3 days. The mixture was evaporated to dryness and the residue was 
extracted with ethyl acetate, and was washed with sodium bicarbonate 
aqueous solution and water, dried over magnesium sulfate and concentrated 
under reduced pressure. The residue was chromatographed on activated 
alumina column (100 g, 300 mesh, manufactured by Wako Junyaku Kabushiki 
Kaisha) and eluted with chloroform (30 ml). The eluate was concentrated 
under reduced pressure and the residue was washed with ether (100 ml), and 
was collected by filtration. m-Chloroperbenzoic acid (2.8 g) was added to 
a stirred solution of the resulting precipitates in methanol (100 ml) at 
room temperature, and the reaction mixture was stirred at room temperature 
for 2 hours. The reaction mixture was evaporated to dryness and the 
residue was dissolved in ethyl acetate. The extract was washed with sodium 
bicarbonate aqueous solution and successively with water, dried over 
magnesium sulfate and concentrated under reduced pressure. The residue was 
washed with ether, and the resulting powder was collected by filtration to 
give 2,2-dimethoxy-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-(4H)-one (2 g, 
yield 35.0%) as pale yellow powder. 
Melting point: 154.degree.-155.degree. C. 
NMR spectrum (CDCl.sub.3, TMS) .delta.: 2.03 (3H, s), 3.59 (6H, s), 7.25 
(2H, dd), 8.43 (1H, s), 8.62 (2H, dx2). 
(iv) Preparation of methyl 4-methyl-5-(4-pyridinyl)-thiazole-2-carboxylate 
2,2-Dimethoxy-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one (200 mg) 
was dissolved in 2N hydrochloric acid (2 ml), and the mixture was allowed 
to stand at room temperature for 30 minutes. Then, the solution was made 
alkaline by addition of 2N aqueous sodium hydroxide under ice-cooling, and 
the resulting precipitates were collected by filtration. The precipitates 
were washed with water, air-dried, and was recrystallized from 
benzene-petroleum ether to give methyl 
4-methyl-5-(4-pyridinyl)-thiazole-2-carboxylate (158 mg, yield 90%) as 
colorless needles. 
Melting point: 121.degree.-123.degree. C. 
Elementary analysis values as: C.sub.11 H.sub.10 N.sub.2 O.sub.2 S; 
Calculated: C=56.39, H=4.30, N=11.95 (%). Found: C=56.33, H=4.29, N=11.62 
(%). 
Mass spectrum: M.sup.+ 234. 
NMR spectrum (CDCl.sub.3, TMS) .delta.: 2.65 (3H, s), 4.04 (3H, s), 7.40 
(2H, dd), 8.72 (2H, dx2). 
IR spectrum .nu..sub.max.sup.KBr (cm.sup.-1): 1750, 1720, 1600. 
In the same manner as described in Example 1 (i)-(iv), the compounds of 
Example 2 to 4 are obtained. 
EXAMPLE 2 
Methyl 4-methyl-5-(3-methyl-4-pyridinyl)-thiazole-2-carboxylate 
5-Methyl-2H-1,4-thiazine-3(4H)-one was treated with 3-methyl-pyridine to 
give methyl 4-methyl-5-(3-methyl-4-pyridinyl)-thiazole-2-carboxylate as 
colorless prisms. 
Melting point: 95.5.degree.-96.3.degree. C. 
NMR spectrum (CDCl.sub.3, TMS) .delta.: 2.24 (3H, s), 2,37 (3H, s), 4,04 
(3H, s), 7,19 (1H, d), 8.54 (1H, d), 8.60 (1H, s). 
IR spectrum .nu..sub.max.sup.KBr (cm.sup.-1): 1735. 
EXAMPLE 3 
Methyl 4-methyl-5-(3-cyano-4-pyridinyl)-thiazole-2-carboxylate 
5-Methyl-2H-1,4-thiazine-3(4H)-one was treated with 3-cyano-pyridine to 
give methyl 4-methyl-5-(3-cyano-4-pyridinyl)-thiazole-2-carboxylate as 
colorless columns. 
Melting point: 193.degree.-194.degree. C. 
NMR spectrum (CDCl.sub.3, TMS) .delta.: 2.55 (3H, s), 4.05 (3H, s), 7.47 
(1H, d), 8.90 (1H, d), 9.03 (1H, s). 
IR spectrum .nu..sub.max.sup.KBr (cm.sup.-1): 2230, 1710. 
EXAMPLE 4 
Methyl 4-methyl-5-(4-quinolinyl)-thiazole-2-carboxylate 
5-Methyl-2H-1,4-thiazine-3(4H)-one was treated with quinoline to give 
methyl 4-methyl-5-(4-quinolinyl)-thiazole-2-carboxylate as colorless 
granules. 
Melting point: 116.degree.-117.degree. C. 
NMR spectrum (CDCl.sub.3, TMS) .delta.: 2.37 (3H, s), 4.07 (3H, s), 7.41 
(1H, d), 7.60-8.23 (4H, m), 9.01 (1H, d). 
IR spectrum .nu..sub.max.sup.KBr (cm.sup.-1): 1730, 1710. 
EXAMPLE 5 
4-Methyl-5-(4-pyridinyl)-thiazole-2-carboxamide 
Methyl 4-methyl-5-(4-pyridinyl)-thiazole-2-carboxylate (3 g) was added to a 
stirred ammonia (28%, 85 ml) at room temperature, and the mixture was 
stirred at room temperature for overnight. The resulting precipitate was 
collected by filtration, washed with water, and air dried. The precipitate 
were recrystallized from ethanol to give 
4-methyl-5-(4-pyridinyl)-thiazole-2-carboxyamide (2.3 g, yield 82%) as 
pale yellow needles. 
Melting point: 222.5.degree.-224.degree. C. 
Elementary analysis values as: C.sub.10 H.sub.9 N.sub.3 OS; Calculated: 
C=54.77, H=4.13, N=19.16 (%). Found: C=54.77, H=4.11, N=18.73 (%). 
Mass spectrum: M.sup.+ 219. 
IR spectrum .nu..sub.max.sup.KBr (cm.sup.-1): 3450, 3200, 1670, 1580. 
EXAMPLE 6 
N,4-Dimethyl-5-(4-pyridinyl)-thiazole-2-carboxamide 
Methyl amine (0.5 ml) was added to a stirred solution of methyl 
4-methyl-5-(4-pyridinyl)-thiazole-2-carboxylate (250 mg) in absolute 
ethanol (10 ml) at room temperature, and the mixture was stirred at room 
temperature for overnight. The mixture was evaporated to dryness and the 
residue was recrystallized from iso-propanol to give 
N,4-dimethyl-5-(4-pyridinyl)-thiazole-2-carboxamide (200 mg, yield 80.0%) 
as pale yellow needles. 
Melting point: 184.degree.-186.degree. C. 
Elementary analysis values as: C.sub.11 H.sub.11 N.sub.3 OS; Calculated: 
C=56.63, H=4.75, N=18.01 (%). Found: C=56.69, H=4.80, N=17.50 (%). 
NMR spectrum (CDCl.sub.3, TMS) .delta.: 2.56 (3H, s), 3.04 (3H, d), 7.26 
(1H, b), 7.40 (2H, dd), 8.70 (2H, dx2). 
IR spectrum .nu..sub.max.sup.KBr (cm.sup.-1): 3200, 3100, 1670, 1600. 
EXAMPLE 7 
4-Methyl-5-(4-pyridinyl)-thiazole-2-carboxanilide 
n-Butyllithium (14-17% in hexane, 1.2ml) was added to dropwise a stirred 
solution of aniline (0.12 ml) in dry tetrahydrofuran (3 ml) at room 
temperature under nitrogen atmosphere. Then, methyl 
4-methyl-5-(4-pyridinyl)-thiazole-2-carboxylate (200 mg) was added to a 
stirred solution at room temperature under nitrogen atmosphere, and the 
mixture was stirred in the same condition for 1 hour. The resulting 
precipitates were collected by filtration, and the precipitates were 
washed with water, and air-dried. The precipitate was recrystallized from 
benzenepetroleum ether to give 
4-methyl-5-(4-pyridinyl)-thiazole-2-carboxanilide (80 mg, yield 33.3%) as 
colorless plates. 
Melting point: 196.degree.-197.degree. C. 
Elementary analysis values as: C.sub.16 H.sub.13 N.sub.3 OS; Calculated: 
C=65.06, H=4.43, N=14.22 (%). Found: C=64.98, H=4.43, N=13.82 (%). 
NMR spectrum (CDCl.sub.3, TMS) .delta.: 2.62 (3H, s), 7.18-7.43 (5H, m), 
7.75 (2H, dd), 8.72 (2H, dx2), 9.05 (1H, s). 
IR spectrum .nu..sub.max.sup.KBr (cm.sup.-1): 3220, 3100, 1660, 1590. 
EXAMPLE 8 
4-Methyl-N-(2-dimethylaminoethyl)-5-(4-pyridinyl)-thiazole-2-carboxamide 
hydrochloride 
N,N-Dimethylethylenediamine (1.4 ml) was added to a suspension of methyl 
4-methyl-5-(4-pyridinyl)-thiazole-2-carboxylate (200 mg) in water (2.8 ml) 
at room temperature, and the mixture was stirred at room temperature for 
overnight. The mixture was evaporated to dryness and the residue was 
chromatographed on an activated alumina column and eluted with chloroform 
to give 
4-methyl-N-(2-dimethylaminoethyl)-5-(4-pyridinyl)-thiazole-2-carboxamide 
as yellow oil. 
IR spectrum .nu..sub.max.sup.KBr (cm.sup.-1): 3200, 1650, 1590, 1530. 
4-Methyl-N-(2-dimethylaminoethyl)-5-(4-pyridinyl)-thiazole-4-carboxamide 
was adjusted to pH 1 to 2 by addition of conc. hydrochloric acid, and the 
solution was evaporated to dryness. The residue was washed with ethanol to 
give 
4-methyl-N-(2-dimethylaminoethyl)-5-(4-pyridinyl)-thiazole-2-carboxamide 
hydrochloride as colorless powder. 
Melting point: over 220.degree. C. (decomposition). 
Elementary analysis values as: C.sub.14 H.sub.20 N.sub.4 
OSCl.sub.2.2H.sub.2 O; Calculated: C=43.18, H=6.21, N=14.39 (%). Found: 
C=43.62 H=5.74, N=14.38 (%). 
NMR spectrum (DMSO-d.sub.6, TMS) .delta.: 2.67 (3H, s), 2.81 (3H, s), 2.83 
(3H, s), 3.30 (2H, m), 3.70 (2H, m), 8.15 (2H, dd), 8.95 (2H, dx2), 9.24 
(1H, t). 
EXAMPLE 9 
N,N-diethyl-4-methyl-5-(4-pyridinyl)-thiazole-2-carboxamide 
(i) Preparation of 4-methyl-5-(4-pyridinyl)-thiazole-2-carboxylic acid 
Potasium hydroxide (1 g) was added to a stirred solution of methyl 
4-methyl-5-(4-pyridinyl)-thiazole-2-carboxylate (2 g) in methanol (50 ml) 
at room temperature and the mixture was stirred at room temperature for 
1.5 hours, diluted with water (150 ml), and washed with chloroform. Then 
the solution was adjusted to pH 3 to 4 by addition of 2N hydrochloric acid 
aqueous solution. The resulting precipitate was collected by filtration, 
and air-dried to give 4-methyl-5-(4-pyridinyl)-thiazole-2-carboxylic acid 
(1.8 g, 96%) as colorless powder. 
Melting point: 133.degree.-134.degree. C. (decomposition) 
Elementary analysis values as: C.sub.10 H.sub.8 N.sub.2 O.sub.2 S; 
Calculated: C=54.33, H=3.66, N=12.72 (%). Found: C=53.95, H=3.54, N=12.37 
(%). 
IR spectrum .nu..sub.max.sup.KBr (cm.sup.-1): 1705, 1630, 1610, 1520. 
(ii) Preparation of 
N,N-diethyl-4-methyl-5-(4-pyridinyl)-thiazole-2-carboxamide 
Catalytic amount of N,N-dimethylformamide in thionyl chloride (2 ml) is 
added to a stirred solution of 
4-methyl-5-(4-pyridinyl)-thiazole-2-carboxylic acid (100 mg) at room 
temperature for overnight. The mixture was evaporated to dryness. 
Diethylamine (1 ml) was added to a stirred solution of the mixture in dry 
toluene (2 ml), and the reaction mixture was stirred at room temperature 
for overnight. The reaction mixture was diluted with ethyl acetate, washed 
with water, dried over magnesium sulfate, and evaporated to dryness. The 
residue was washed with petroleum ether, and was chromatographed on a 
flash column and eluted with ethyl acetate-n-hexane=6:4 to give 
N,N-diethyl-4-methyl-5(4-pyridinyl)-thiazole-2-carboxamide (60 mg, yield 
48%) as colorless needles. 
Melting point: 87.5.degree.-89.degree. C. 
Elementary analysis values as: C.sub.14 H.sub.17 N.sub.3 OS; Calculated: 
C=61.06, H=6.22, N=15.26 (%). Found: C=60.68, H=6.25, N=14.62 (%). 
NMR spectrum (CDCl.sub.3, TMS) .delta.: 1.3 (6H, t), 2.6 (3H, s), 3.3-4.4 
(4H, m), 7.5 (2H, dd), 8.8 (2H, dx2). 
IR spectrum .nu..sub.max.sup.KBr (cm.sup.-1): 1610, 1590. 
EXAMPLE 10 
2',6'-dimethyl-4-methyl-5-(4-pyridinyl)-thiazole-2-carboxanilide 
2,6-Dimethyl aniline hydrochloride (230 mg) was added to a stirred 
suspension of 4-methyl-5-(4-pyridinyl)-thiazole-2-carbonylchloride 
hydrochloride (230 mg) in dry toluene (4 ml) at room temperature, and 
triethylamine (1.8 ml) was added to the mixture, and was stirred at room 
temperature for overnight. The mixture was diluted with chloroform, washed 
with water, dried over magnesium sulfate, and evaporated to dryness. The 
residue was recrystallized from iso-propanol to give 
2',6'-dimethyl-4-methyl-5-(4-pyridinyl)-thiazole-2-carboxanilide (180 mg, 
yield 31%) as colorless plates. 
Melting point: 192.degree.-194.degree. C. 
Elementary analysis values as: C.sub.18 H.sub.17 N.sub.3 OS; Calculated: 
C=66.84, H=5.29, N=12.99 (%). Found: C=66.30, H=5.30, N=12.43 (%). 
NMR spectrum (CDCl.sub.3, TMS) .delta.: 2.33 (6H, s), 2.63 (2H, s), 7.17 
(3H, m), 7.42 (2H, dd), 8.59 (1H, s), 8.72 (2H, dx2). 
IR spectrum .nu..sub.max.sup.DBr (cm.sup.-1): 3350, 1680, 1590. 
EXAMPLE 11 
1-[4-methyl-5-(4-pyridinyl)-thiazolyl-2-carbonyl]-piperidine 
Piperidine (1.4 ml) was added to a stirred suspension of 
4-methyl-5-(4-pyridinyl)-thiazole-2-carbonylchloride hydrochloride (400 
mg) in dry toluene (4 ml) at room temperature, and the mixture was stirred 
at room temperature for overnight. The mixture was treated in the same 
manner as described in Example 6, and was recrystallized from ethyl 
acetate-n-hexane to give 
1-[4-methyl-5-(4-pyridinyl)-thiazolyl-2-carbonyl]-piperidine (100 mg, 
yield 24%) as pale yellow granules. 
Melting point: 139.degree.-142.degree. C. (decomposition). 
Elementary analysis values as: C.sub.15 H.sub.17 N.sub.3 OS; Calculated: 
C=62.68, H=5.96, N=14.62 (%). Found: C=62.77, H=6.01, N=14.09 (%). 
NMR spectrum (CDCl.sub.3, TMS) .delta.: 1.70 (6H, m), 2.58 (3H, s), 3.75 
(2H, m), 4.25 (2H, m), 7.40 (2H, dd), 8.70 (2H, dx2). 
IR spectrum .nu..sub.max.sup.KBr (cm.sup.-1): 1610, 1590. 
EXAMPLE 12 
2-cyano-4-methyl-5-(4-pyridinyl)-thiazole 
p-Toluenesulfonyl chloride (860 mg) was added to a stirred suspension of 
4-methyl-5-(4-pyridinyl)-thiazole-2-carboxamide (450 mg) in dry pyridine 
(5 ml) under ice-cooling, and the mixture was stirred at 90.degree. C. for 
21 hours. The mixture was evaporated to dryness, and the residue was 
dissolved 2N hydrochloric acid aqueous solution (10-15 ml), washed twice 
with chloroform, and made alkaline by addition of 2N sodium hydroxide 
aqueous solution. The resulting precipitates were extracted with 
chloroform, washed with water, dried over magnesium sulfate, and 
evaporated to dryness. The residue was washed with petroleum ether, and 
was recrystallized from iso-propanol (twice) to give 
2-cyano-4-methyl-5-(4-pyridinyl)-thiazole (220 mg, yield 53%) as pale 
yellow needles. 
Melting point: 169.degree.-170.degree. C. 
Elementary analysis values as: C.sub.10 H.sub.7 N.sub.3 S; Calculated: 
C=59.67, H=3.50, N=20.88 (%). Found: C=59.36, H=3.44, N=20.45 (%). 
NMR spectrum (CDCl.sub.3, TMS) .delta.: 2.63 (3H, s), 7.39 (2H, dd), 8.76 
(2H, dx2). 
IR spectrum .nu..sub.max.sup.KBr (cm.sup.-1): 2240, 1600. 
EXAMPLE 13 
Methyl 4-methyl-5-(2-thiazolyl)-thiazole-2-carboxylate 
(i) Preparation of intermediate, 
2-methoxy-5-methyl-2H-1,4-thiazin-3(4H)-one 
m-Chloroperbenzoic acid (28.8 g) was added dropwise to a stirred solution 
of 5-methyl-2H-1,4-thiazin-3(4H)-one (15 g) in methanol (300 ml) under 
ice-cooling and the mixture was stirred at room temperature for 1 day. 
After the mixture was evaporated to dryness, the residue was extracted 
with ethyl acetate, washed with saturated sodium bicarbonate aqueous 
solution and dried over anhydrous magnesium sulfate. The solvent was 
evaporated to dryness to give 2-methoxy-5-methyl-2H-1,4-thiazin-3(4H)-one 
(11.3 g, yield 61%) as pale yellow powder. 
Melting point: 157.degree.-160.degree. C. 
(ii) Preparation of intermediate, 
2,2-Dimethoxy-5-methyl-2H-1,4-thiazin-3(4H)-one 
m-Chloroperbenzoic acid (25.6 g) was added dropwise to a stirred solution 
of 2-methoxy-5-methyl-2H-1,4-thiazin-3(4H)-one (16 g) in methanol (500 ml) 
under ice-cooling and the mixture was stirred at room temperature for 4 
hours. Then, the reaction mixture was made alkaline by addition of 
anhydrous potassium carbonate and evaporated to dryness. The residue was 
extracted twice with chloroform and the combined extracts were washed with 
water, dried over anhydrous magnesium sulfate and evaporated to dryness. 
The residue was triturated with ethyl ether to give 
2,2-dimethoxy-5-methyl-2H-1,4-thiazin-3(4H)-one (10 g, yield 53%) as pale 
yellow plates. 
Melting point: 86.degree.-88.degree. C. 
(iii) Preparation of intermediate, 
2,2-dimethoxy-5-methyl-6-(3-ethoxycarbonyl-2,3-dihydro-2-thiazolyl)-2H-1,4 
-thiazin-3(4H)-one 
Ethyl chloroformate (1.0 g) was added dropwise to a stirred solution of 
thiazole (0.79 g) in dichloromethane (10 ml) under ice-cooling and the 
mixture was stirred at room temperature for 0.5 hour. Then, 
2,2-dimethoxy-5-methyl-2H-1,4-thiazin-3(4H)-one (1.47 g) was added, and 
the mixture was stirred at room temperature for 3 hours. The solution was 
washed with saturated sodium bicarbonate aqueous solution, dried over 
magnesium sulfate and evaporated to dryness. The residue was 
chromatographed on silica gel (Merck Lobar column size B: Art.10401, 
solvent: ethyl acetate-n-hexane=2:3) to give 
2,2-dimethoxy-5-methyl-6-(3-ethoxycarbonyl-2,3-dihydro-2-thiazolyl)-2H-1,4 
-thiazin-(4H-one (510 mg, yield 19%) as colorless prisms. 
Melting point: 148.degree.-149.degree. C. 
(iv) Preparation of intermediate, 
2,2-dimethoxy-5-methyl-6-(2-thiazolyl)-2H-1,4-thiazine-3-one 
DDQ (206.4 mg) was added dropwise to a stirred solution of 
2,2-dimethoxy-5-methyl-6-(3-ethoxycarbonyl-2,3-dihydro-2-thiazolyl)-2H-1,4 
-thiazine-3(4H)-one (300 mg) in dichloromethane (5 ml) at room temperature, 
and the mixture was stirred at room temperature for 1 hour. Then, the 
insoluble materials were filtered off and the solvent was evaporated to 
dryness. 
The residue was chromatographed on silica gel (Merck Lobar column size B: 
Art.10401, solvent: ethyl acetate-n-hexane=2:3) to give 
2,2-dimethoxy-5-methyl-6-(2-thiazolyl)-2H-1,4-thiazin-3-(4H)-one (144 mg, 
yield 61%) as colorless column. 
Melting point: 127.degree.-128.degree. C. 
(v) Methyl 4-methyl-5-(2-thiazolyl)-thiazole-2-carboxylate 
A mixture of 
2,2-dimethoxy-5-methyl-6-(2-thiazolyl)-2H-1,4-thiazin-3-(4H)-one (80 mg) 
and 2N hydrochloric acid solution (2 ml) was stirred at room temperature 
for 6 hours. Then the mixture was neutralized with saturated sodium 
bicarbonated aqueous solution and the resulting precipitates were 
collected to give methyl 4-methyl-5-(2-thiazolyl)-thiazole-2-carboxylate 
(58 mg, yield 82.2%) as colorless powder. 
Melting point: 129.degree.-129.5.degree. C. 
As is apparent from the foregoing description, the thiazole derivative of 
the present invention is a compound not described in any literature, the 
contractile force of isolated left atrium was significantly increased by 
administration of the thiazole derivative of the present invention, and 
the acute toxicity of the thiazole derivative of the present invention is 
low. Accordingly, the thiazole derivative of the present invention is 
effective in curing and preventing heart diseases, especially cardiac 
insufficiency. 
As for the process of the present invention, it is advantageous from the 
industrial view point since the thiazole derivative of the present 
invention can be prepared from relatively easily available starting 
compounds in high yield by a relatively easy operation. 
While the preferred form of the present invention has been described, it is 
to be understood that modifications will be apparent to those skilled in 
the art without departing from the true spirit of the invention.The scope 
of the invention, therefore, is to be determined solely by the following 
claims.