KR0168979B1 - Thiazolyl triazolothiazole derivatives - Google Patents

Abstract

The present invention relates to novel thiazolyl triazolothiazole derivatives represented by general formula (I) having excellent anti-ulcer effect, pharmaceutically acceptable acid addition salts thereof, and methods for preparing the same.

Wherein R is hydrogen, hydroxy, C ₁ -C ₆ lower alkyl, C ₁ -C ₆ lower alkoxy, phenyl or pyridine, guanidino group, or NR ₄ R ₅ (R ₄ and R ₅ are the same as each other) Or alternatively hydrogen, C ₁ -C ₆ lower alkyl, C ₃ -C ₆ cycloalkyl, phenyl or pyridine, C ₁ -C ₆ alkoxy C ₂ -C ₆ alkyl, phenylalkyl); R ₂ and R ₃ , which are the same as or different from each other, are hydrogen or a C ₁ -C ₄ loweralkyl group; X and Y are different and consist of N and CR ₆ (R ₆ is hydrogen, C ₁ -C ₆ loweralkyl, phenyl).

Description

[Name of invention]

Thiazolyl triazolothiazole derivatives

Detailed description of the invention

The present invention relates to a novel thiazolyl triazolothiazole derivative represented by the following general formula (I) having excellent anti-ulcer effect, a pharmaceutically acceptable acid addition salt thereof, and a preparation method thereof.

Wherein R is hydrogen, hydroxy, C ₁ -C ₆ lower alkyl, C ₁ -C ₆ lower alkoxy, phenyl or pyridine, guanidino group, or NR ₄ R ₅ (R ₄ and R ₅ are Amine groups represented by the same or different hydrogen, C ₁ -C ₆ lower alkyl, C ₃ -C ₆ cycloalkyl, phenyl or pyridine, C ₁ -C ₆ alkoxyC ₂ -C ₆ alkyl or phenylalkyl) ego; R ₂ and R ₃ are the same or different and are hydrogen or a C ₁ -C ₄ lower alkyl group; X and Y are different and N and CR ₆ (R ₆ is hydrogen, C ₁ -C ₆ lower alkyl, phenyl It is composed of

In general, inflammatory diseases of the gastrointestinal tract are known to be caused by various causes such as excessive secretion of gastric acid, toxic chemicals, anti-inflammatory drugs such as indomethacin, pathogenic viruses, and mycotoxins. Therefore, a new drug having a protective effect of enhancing the secretion of gastric acid secretion as well as the various pathogens mentioned above has attracted attention in the treatment of ulcers.

The present inventors have conducted studies on the synthesis of various heterocyclic compounds and their physiological effects. As a result, the thiazolyl triazolothiazole derivatives of the present invention not only have a strong gastric acid secretion inhibitory effect but also a protective effect enhancer (cell protective effect) It has been found that the present invention has been completed.

Known phrases related to the present invention include Japanese Patent Publication Nos. 82-134417 and Korean Patent No. 92-6396 (Tiazolyl Amidazopyridine Derivatives) and Korean Patent Publication No. 91-11861 (Tiazolyl Thiazolobenzimidazole Derivatives ), And the like. However, the compounds of the present invention are completely new compounds that are not structurally similar to the compounds described in these documents and are novel ones that can be used very effectively in the treatment of ulcers.

It is an object of the present invention to provide novel thiazolyl triazolothiazole derivatives represented by the general formula (I), and pharmaceutically acceptable acid addition salts thereof.

The present invention also comprises the steps of reacting a compound of formula (II) with a compound of formula (III) to obtain a compound of formula (IV) or a salt thereof;

Halogenating the compound of formula (IV) or a salt thereof obtained in the above step to obtain a compound of formula (V) or a salt thereof; And

The compound of formula (V) or a salt thereof obtained in the above step is reacted with a thio compound of formula (VI) to obtain a compound of formula (I) or a salt thereof. To provide a novel thiazolyl triazolo thiazole derivative represented by I) and a pharmaceutically acceptable acid addition salt thereof.

Wherein R, R1, R ₂ , X and Y have the same meaning as defined above and Z is a halogen atom such as chlorine or bromine as reactor.

Other objects, features and applications of the present invention will become apparent to those skilled in the art by the following detailed description.

Hereinafter, the present invention will be described in more detail.

The novel thiazolyl triazolo thiazole derivatives represented by formula (I) provided according to the invention are useful as therapeutic agents for ulcers such as gastritis, gastric ulcer and duodenal ulcer.

Compounds of the present invention represented by formula (I) may form acid addition salts which are pharmaceutically acceptable, wherein representative organic or inorganic acids used are citric acid, formic acid, acetic acid, fumaric acid, maleic acid, oxalic acid, malonic acid, Tartaric acid, metalsulfonic acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, and the like.

The compound of general formula (I) of the present invention can be prepared by the same process as in the following preparation scheme.

Manufacture Scheme

Wherein R, R ₁ , R ₂ , R ₃ , X, Y and Z have the same meaning as defined above.

Compounds of formula (IV) and salts thereof can be obtained by reacting a compound of formula (II) with a compound of formula (III) to form a thiazole ring, wherein reaction solvents include methanol, ethanol and propanol. Alcohol solvents such as butanol are suitable and the reaction temperature is suitable from room temperature to the boiling point temperature of the solvent. In this case, the compound of formula (IV) may be obtained as hydrochloric acid or bromate, and in this case, the compound of formula (IV) may be obtained as an alkaline solution such as sodium carbonate, potassium carbonate, caustic soda and caustic in an aqueous solution.

The compound of formula (V) may be prepared by halogenating the compound of formula (VI), preferably in a concentrated aqueous bromic acid solution or acetic acid solution at a temperature ranging from room temperature to 100 캜 and the equivalent of halogen (especially bromine) Injection may yield the halogenated compound of formula (V) as a hydrochloride halide. When this acid addition salt is neutralized by aqueous alkali solution in a water phase, the compound of General formula (V) can be obtained.

The compound of formula (I) of the present invention can be obtained by reacting a compound of formula (V) or a salt thereof with substituted or unsubstituted thiourea, amidinothiourea, thiamide, and the like. As the solvent for this reaction, methanol, ethanol, propanol, butanol, dimethylformamide, and the like are suitable, and the reaction temperature is appropriate between normal temperature and the boiling point temperature of the solvent.

In this case, the compound of the present invention represented by the general formula (I) as a result of the reaction may be obtained as a halogenated salt, and the salt is neutralized with an aqueous alkali solution in an aqueous phase to obtain a compound of the general formula (I), and the obtained general Compounds of formula (I) may react with inorganic or organic acids to form pharmaceutically acceptable acid addition salts. In this case, the inorganic acid or organic acid used has the same meaning as defined above.

Inventive compound (I) or a salt thereof prepared as described above has been shown to exhibit a strong anti-acid secretion effect as well as an excellent anti-ulcer effect, these can be used as a ulcer therapeutic agent in mammals or humans or as a component of an ulcer therapeutic agent.

Gastric acid secretion inhibitory activity and anti-ulcerative activity were measured for the compound of Example 1 as a representative compound of the present invention and omeprazole as a reference substance by the following experimental method, and the results are summarized in Table I.

[Stomach acid secretion inhibitory effect]

Gastric acid secretion inhibitory effect was measured according to Shay method (Gastroenterology, 1954, 26, 903). Spraque-Dawla male rats (130-180 g body weight) are fasted for 24 hours, ligation of the pyloric gland and the test drug administered in the duodenum. After 4 hours, the stomach is removed and the acidity and amount of gastric juice are measured. The inhibitory effect of gastric acid secretion was determined by comparing the gastric acidity and amount of the control group which did not receive the test drug. The concentration of the test drug (IC ₅₀ ) which inhibits gastric acid secretion by 50% is calculated and shown in Table II.

[Anti-ulcer effect]

치료) The ulcer treatment effect caused by ethanol was measured using Spraque-Dawley male rats (130-180 g body weight). That is, mice are fasted 24 hours and intraperitoneally administered the test compound suspended in 0.1% CMC. Anhydrous ethanol (5 ml / kg) was orally administered 30 minutes after the test compound was administered, and after 1 hour, the rat was lethal and the concentration of the test compound (ED ₅₀ ) that inhibits the ulceration of each rat by 50% was obtained. .

Ii) The concentration of the compound of the present invention (ED ₅ ) which inhibits 50% of the induced ulcer by administering indomethacin (30 mg / kg) as a substance causing ulcer was determined.

The results of Table 1 demonstrate that the compounds of the present invention not only exhibit gastric acid secretion inhibitory effect comparable to omeprazole, which is a typical representative antiulcer drug, but also are useful new compounds whose action is much stronger in antiulcer effect.

Hereinafter, the present invention will be clearly described based on the following examples, but the present invention is not limited only to these examples.

Example 1

4- (2-aminothiazol-4-yl) -3-methyl [1,2,4] triazolo [3,2-b] thiazole

A) 2-acetyl-3-methyl [1,2,4] triazolo [3,2-b] thiazole

1H-1, 2,4-triazole-3-thiol (2 g) was suspended in ethanol (20 mL) and 3-chloro-2, 4-pentadione (3.19 g) was added with stirring, followed by heating under reflux for 2 hours. I was. After cooling to room temperature, the resulting solids were filtered and suspended in hot water (80 ° C. to 90 ° C.), the pH was adjusted to 8-9 with 5% sodium bicarbonate solution, and the resulting solids were filtered, washed with water and dried to give white crystals. (2.92 g) of the title compound were obtained.

Yield: 82%

Melting Point: 144 ~ 145 ℃

H-NMR (DMSO-d): δ 2.68 (s, 3H), 2.91 (s, 3H), 8.52 (s, 1H)

B) 2-bromoacetyl-3-methyl [1,2,4] triazolo [3,2-b] thiazole bromate

2-acetyl-3-methyl [1,2,4] triazolo [3,2-b] thiazole (2.72 g) prepared in a) was added to an aqueous 47% bromic acid solution, and heated to 70 ° C to dissolve it. Dubromine (2.4 g) was added dropwise and reacted at 70-80 ° C. for 20 minutes. After cooling to room temperature, the mixture was stirred for 3 hours, and the resulting solid was filtered and washed with cold distilled water to obtain a white solid (3.28 g) of the title compound.

Yield: 64%

Melting Point: Decomposes above 175 ℃

H-NMR (DMSO-d): δ 2.91 (s, 3H), 4.98 (s, 2H), 5.7 (br.s, 1H), 8.55 (s, 1H)

C) 4- (2-aminothiazol-4-yl) -3-methyl [1,2,4] triazolo [3, 2-b] thiazole

2-bromoacetyl-3-methyl [1,2,4] triazolo [3,2-b] thiazole bromate (24 g) and thiourea (6.43 g) prepared in b) were anhydrous ethanol (300 mL). After heating under reflux for 2 hours, the resulting solids were filtered, suspended in distilled water (300 ml), neutralized with a 2N aqueous potassium hydroxide solution, and the obtained solid was mixed with dimethylformamide and ethanol (1/1, 500 Recrystallized in mL) to give the title compound as a gray crystal (16 g).

Yield rule: 96%

Melting Point: 266-268 ℃

H-NMR (DMSO-d): δ 2.80 (s, 3H), 6.94 (s, 1H), 7.38 (s, 2H), 8.32 (s, 1H)

Example 2

4- (2-guanidinothiazol-4-yl) -3-methyl [1,2,4] triazolo [3, 2-b] thiazole

2-bromoacetyl-3-methyl [1,2,4] triazolo [3,2-b] thiazole bromate (1.71 g) and amidinothiourea (0.71 g) prepared in Example 1 b). Was reacted in the same manner as in Example 1 c) in anhydrous ethanol (20 mL) to give the title compound (1.11 g).

Yield: 83%

H-NMR (DMSO-d): δ 2.75 (s, 3H), 7.73 (s, 1H), 8.28 (s, 4H), 8.40 (s, 1H)

Example 3

4- (2-N-methylaminothiazol-4-yl) -3-methyl [1,2,4] triazolo [3, 2-b] thiazole

2-bromoacetyl-3-methyl [1,2,4] triazolo [3,2-b] thiazole bromate (1.71 g) and methylthiourea (496 mL) prepared in Example 1 b) were prepared. It was heated to reflux in anhydrous ethanol (20 mL) for 1 hour. After cooling slowly to room temperature, the mixture was stirred at 0 ° C. for 30 minutes, filtered and washed with anhydrous ethanol to obtain the bromate of the title compound. The solid was suspended in distilled water at 80-90 ° C., neutralized with 5% aqueous sodium bicarbonate solution, filtered, washed with acetone and dried to prepare the title compound as a yellow solid (1.1 g).

Yield: 88%

Melting Point: 200-202 ℃

H-NMR (DMSO-d): δ 2.71 (s, 3H), 2.88 (d, 3H), 6.99 (s, 1H), 7.87 (q, 2H), 8.30 (s, 1H)

Example 4

4- (4-N, N-dimethylaminothiazol-4-yl) -3-methyl [1,2,4] triazolo [3,2-b] thiazole

2-bromoacetyl-3-methyl [1,2,4] triazolo [3,2-b] thiazole bromate (1.71 g) and N, N-dimethyl urea prepared in Example 1 b) 573 mg) and anhydrous ethanol (20 mL) were reacted in the same manner as in Example 3 to obtain the title compound (1.15 g) as a white solid.

Yield: 87%

Melting Point: 188 ℃

H-NMR (DMSO-d): δ 2.74 (s, 3H), 3.11 (s, 6H), 7.11 (s, 1H), 8.32 (s, 1H), 8.32 (s, 1H)

Example 5

4- (2-N-ethylaminothiazol-4-yl) -3-methyl [1,2,4] triazolo [3,2-b] thiazole

2-bromoacetyl-3-methyl [1,2,4] triazolo [3,2-b] thiazole bromate (1.71 g) and ethylthiourea (573 mg) prepared in Example 1 b) were prepared. It was heated to reflux for 2 hours in anhydrous ethanol (20 mL) and treated in the same manner as in Example 3 to give the title compound (1.04 g) of an orange solid.

Yield: 78%

Melting Point: 217-218 ℃

H-NMR (DMSO-d): δ 1.20 (t, 3H), 2.70 (s, 3H), 3.28 (q, 2H), 6.96 (s, 1H), 7.90 (br.s, 1H), 8.30 (s , 1H)

Example 6

4- (2-N-cyclopropylaminothiazol-4-yl) -3-methyl [1,2,4] triazolo [3,2-b] thiazole

2-bromoacetyl-3-methyl [1,2,4] triazolo [3,2-b] thiazole bromate (1.71 g) and N-cyclopropylthiourea (639) prepared in Example 1 b). Mg) was used to prepare the title compound (1.16 g) as a yellow solid, in the same manner as in Example 5.

Yield: 84%

Melting Point: 191-192 ℃

H-NMR (DMSO-d): δ 0.55 (m, 2H), 0.76 (m, 2H), 2.71 (s, 3H), 7.05 (s, 1H), 8.30 (s, 1H), 7.90 (br.s , 1H)

Example 7

4- [2- (2-methoxyethyl) aminothiazol-4-yl) -3-methyl [1,2,4] triazolo [3,2-b] thiazole

2-bromoacetyl-3-methyl [1,2,4] triazolo [3,2-b] thiazole bromate (1.71 g) and 2-methoxyethylthiourea prepared in Example 1 b) 738 mg) was prepared in the same manner as in Example 3 to obtain the title compound (1.28 g) as a yellow solid.

Yield: 87%

Melting Point: 153-155 ℃

H-NMR (DMSO-d): δ 2.70 (s, 3H), 3.30 (s, 3H), 3.46 (t, 2H), 3.52 (t, 2H), 6.95 (s, 1H), 7.96 (t, 1H ), 8.30 (s, 1H)

Example 8

4- (2-N-phenylaminothiazol-4-yl) -3-methyl [1,2,4] triazolo [3,2-b] thiazole

2-bromoacetyl-3-methyl [1,2,4] triazolo [3,2-b] thiazole bromate (1.71 g) and 1-phenyl-2-thiourea prepared in Example 1 b). (0.84 g) was used to prepare the title compound (1.5 g) as a yellow solid, in the same manner as in Example 3.

Yield: 95%

Melting Point: 242-244 ℃

H-NMR (DMSO-d): δ 2.77 (s, 3H), 7.02 (t, 1H), 7.24 (s, 1H), 7.37 (t, 2H) 7.67 (d, 2H), 8.36 (s, 1H) , 10.48 (s, 1H)

Example 9

4- (2-phenylmethylaminothiazol-4-yl) -3-methyl [1,2,4] triazolo [3,2-b] thiazole

2-bromoacetyl-3-methyl [1,2,4] triazolo [3,2-b] thiazole bromate (1.71 g) and 1-phenylmethyl-2-thio prepared in Example 1 b). Using the urea (0.92g) was prepared in the same manner as in Example 3 to obtain the title compound (1.3g) as a white solid.

Yield: 80%

Melting Point: 188-190 ℃

H-NMR (DMSO-d): δ 2.70 (s, 3H), 4.50 (d, 2H), 7.00 (s, 1H), 7.24-7.46 (m, 5H), 8.32 (s, 1H), 8.50 (t , 1H)

Example 10

4- (2- (1-piperazino) thiazol-4-yl) -3-methyl [1,2,4] triazolo [3,2-b] thiazole

2-bromoacetyl-3-methyl [1,2,4] triazolo [3,2-b] thiazole bromate (1.71 g) and 1-thiocarboxamidopiperazine prepared in Example 1 b) (0.80 g) was used to prepare the title compound (1.15 g) as a white solid, in the same manner as in Example 3.

Yield: 84%

Melting Point: 165-167 ℃

H-NMR (CDCl): δ 2.78 (s, 3H), 3.04 (m, 4H), 3.54 (m, 4H), 4.14 (br.s, 1H), 6.74 (br, 1H), 8.15 (s, 1H )

Example 11

4- (2-N-allylaminothiazol-4-yl) -3-methyl [1,2,4] triazolo [3,2-b] thiazole

2-bromoacetyl-3-methyl [1,2,4] triazolo [3,2-b] thiazole bromate (1.71 g) and 1-allyl-2-thiourea prepared in Example 1 b) (0.64 g) was used to prepare the title compound (1.41 g) as yellow crystals in the same manner as in Example 3.

Yield: 82%

Melting Point: 213-215 ℃

H-NMR (DMSO-d): δ 2.73 (s, 3H), 3.92 (br.s, 2H), 5.14-5.34 (m, 2H), 5.94 (m, 1H), 7.01 (s, 1H), 8.10 (br.s, 1H), 8.32 (s, 1H)

Example 12

4- (2- (3-pyridyl) thiazol-4-yl) -3-methyl [1,2,4] triazolo [3,2-b] thiazole 2 prepared in Example 1) -Bromoacetyl-3-methyl [1,2,4] triazolo [3,2-b] thiazole bromate (1.71 g) and thionicotinamide (0.76 g) in the same manner as in Example 3 The title compound (1.71 g) in yellow solid was prepared.

Yield: 82%

Melting Point: 228-229 ℃

1H-NMR (DMSO-d + TFA-d): δ 2.88 (s, 3H), 8.22 (m, 1H), 8.25 (s, 1H), 8.36 (s, 1H), 9.06 (d, 1H) , 9.14 (q, 1H), 9.58 (m, 1H)

Example 13

4- (2-aminothiazol-4-yl) -3,6-dimethyl [1,2,4] triazolo [3,2-b] thiazole

A) 2-acetyl-3, 6-dimethyl [1,2,4] triazolo [3,2-b] thiazole

1H-3-methyl-1,2,4-triazole-5-thiol (1.15 g) was suspended in anhydrous ethanol (15 mL), 3-chloro-2, 5-pentadione was added, and then heated for 2 hours 30 minutes. It was refluxed. After cooling to room temperature, the mixture was stirred for 30 minutes, and the resulting solid was filtered and washed with anhydrous ethanol. The resulting solid was suspended in water at 80 ° C. and treated with 5% aqueous sodium bicarbonate solution while heating to adjust the pH to 8-9 and then filtered to give the title compound (1.7 g) as white crystals.

Yield: 87%

Melting Point: 154-155 ℃

H-NMR (DMSO-d): δ 2.58 (s, 3H), 2.60 (s, 3H), 2.90 (s, 1H)

B) 2-bromoacetyl-3, 6-dimethyl [1,2,4] triazolo [3,2-b] thiazole bromate

2-acetyl-3, 6-dimethyl [1,2,4] triazolo [3,2-b] thiazole (1 g) prepared in a) was added to a 48% -bromic acid solution and heated to 70 ° C. Bromine (0.72 g) was then added dropwise and stirred for 30 minutes while maintaining 70-80 ° C. The solvent was removed by evaporation under reduced pressure, ethanol was added, and the resultant solid was filtered by stirring at 0 ° C. to obtain the title compound (1.45 g) as a yellow solid.

Yield: 95%

Melting Point: Decomposes above 170 ℃

H-NMR (DMSO-d): δ 2.48 (s, 3H), 2.89 (s, 3H), 4.87 (s, 2H), 10.08 (br, 1H)

C) 4- (2-aminothiazol-4-yl) -3, 6-dimethyl [1,2,4] triazolo [3,2-b] thiazole

2-bromoacetyl-3, 6-dimethyl [1,2,4] triazolo [3,2-b] thiazole bromate (1.78 g) and thiourea (0.46 g) prepared in b) 20 ml) was heated to reflux for 1 hour. After cooling to room temperature, the filtered solid was suspended in 80 ° C. water (50 mL), and then the pH was adjusted to 8-9 with 5% aqueous sodium bicarbonate solution, filtered and washed with ethanol to give the title compound as a white crystal ( 1.16 g) was obtained.

Yield: 92%

Melting Point: Decomposes above 248 ℃

H-NMR (DMSO-d): δ 2.43 (s, 3H), 2.66 (s, 3H), 6.88 (s, 1H), 7.32 (s, 2H)

Example 14

4- (2-amidinothiazol-4-yl) -3, 6-dimethyl [1,2,4] triazolo [3,2-b] thiazole

2-bromoacetyl-3, 6-dimethyl [1,2,4] triazolo [3,2-b] thiazole bromate (1.78 g) and amidinothiourea (0.71) prepared in Example 13 b) g) was reacted in anhydrous ethanol (20 mL) under heating to reflux, and the title compound (1.14 g) was prepared in the same manner as in Example 13C).

Yield: 78%

Melting Point: Decomposes above 260 ℃

H-NMR (DMSO-d): δ 2.43 (s, 3H), 2.66 (s, 3H), 6.94 (br, 4H), 7.03 (s, 1H)

Example 15

4- (2-N-methylaminothiazol-4-yl) -3, 6-dimethyl [1,2,4] triazolo [3,2-b] thiazole

2-bromoacetyl-3, 6-dimethyl [1,2,4] triazolo [3,2-b] thiazole bromate (1.07 g) and 1-methyl-2- prepared in Example 13 b) Thiourea (0.3 g) was heated and refluxed in anhydrous ethanol (20 mL) for 1 hour, and the same method as in Example 13) was performed. The resultant was washed with ethanol to give the title compound (0.67 g) as a red solid.

Yield: 84%

Melting Point: 211-212 ℃

H-NMR (DMSO-d): δ 2.41 (s, 3H), 2.68 (s, 3H), 2.87 (d, 3H), 6.93 (s, 1H), 7.84 (q, 1H)

Example 16

4- (2-N-phenylaminothiazol-4-yl) -3, 6-dimethyl [1,2,4] triazolo [3,2-b] thiazole

2-bromoacetyl-3, 6-dimethyl [1,2,4] triazolo [3,2-b] thiazole bromate (1.78 g) and 1-phenyl-2- prepared in Example 13 b) Thiourea (0.84 g) was prepared in the same manner as in Example 13 using anhydrous ethanol (30 ml) to give the title compound (1.44 g) as a white solid.

Yield: 88%

Melting Point: 250-253 ℃

H-NMR (DMSO-d): δ 2.43 (s, 3H), 2.73 (s, 3H), 7.20 (s, 1H), 7.00-7.66 (m, 5H), 10.43 (s, 1H)

Claims (3)

Novel thiazolyl triazolothiazole derivatives represented by the following general formula (I) and pharmaceutically acceptable acid addition salts thereof. Wherein R is hydrogen, hydroxy, C ₁ -C ₆ lower alkyl, C ₁ -C ₆ lower alkoxy, phenyl or pyridine, guanidino group, or NR ₄ R ₅ (R ₄ and R ₅ are The same or different and is an amine group represented by hydrogen, C ₁ -C ₆ loweralkyl, C ₃ -C ₆ cycloalkyl, phenyl or pyridine, C ₁ -C ₆ alkoxy C ₂ -C ₆ alkyl, phenylalkyl); R ₂ and R ₃ , which are the same as or different from each other, are hydrogen or a C ₁ -C ₄ loweralkyl group; X and Y are different and consist of N and CR ₆ (R ₆ is hydrogen, C ₁ -C ₆ loweralkyl, phenyl). The compound of claim 1, wherein R is C ₁ -C ₆ lower alkyl, phenyl or pyridine, guanidino group, or amine group represented by NR ₄ R ₅ ; R ₄ and R ₅ , which are the same or different from each other, are hydrogen, C ₁ -C ₆ loweralkyl, C ₃ -C ₆ cycloalkyl, phenyl or pyridine, C ₁ -C ₆ alkoxy C ₂ -C ₆ alkyl, phenyl alkyl group; R ₂ is hydrogen; R ₃ is methyl; X is CH or CCH ₃ ; Y is N. A compound of formula (I) and a pharmaceutically acceptable acid addition salt thereof. Reacting a compound of formula (II) with a compound of formula (III) to obtain a compound of formula (IV) or a salt thereof; Halogenating the compound of formula (IV) or a salt thereof obtained in the above step to obtain a compound of formula (V) or a salt thereof; And reacting a compound of formula (V) or a salt thereof obtained in the step with a thio compound of formula (VI) to obtain a compound of formula (I) or a salt thereof. A method for producing a novel thiazolyl triazolo thiazole derivative represented by (I) and a pharmaceutically acceptable acid addition salt thereof. In which R is hydrogen, hydroxy, C ₁ -C ₆ lower alkyl, C ₁ -C ₆ lower alkoxy, phenyl or pyridine, guanidino group, or NR ₄ R ₅ (R ₄ and R ₅ are the same as each other) Or alternatively hydrogen, C ₁ -C ₆ lower alkyl, C ₃ -C ₆ cycloalkyl, phenyl or pyridine, C ₁ -C ₆ alkoxy C ₂ -C ₆ alkyl, phenylalkyl); R ₂ and R ₃ , which are the same as or different from each other, are hydrogen or a C ₁ -C ₄ lower alkyl group; X and Y are different and consist of N and CR ₆ (R ₆ is hydrogen, C ₁ -C ₆ lower alkyl, phenyl); Z is chlorine or bromine atom as reactor.