KR910009958B1 - Novel 2-guanidino-4-(5-thiazolyl) thiazol derivatives - Google Patents

Abstract

2-Guanidino-4-(5-thiazolyl) thiazole derivs. of formula (I) are new. In (I), R1 = H or CH3; R2 = H, C1-4 lower alkyl or - NR3R4; R3 = H or C1-3 lower alkyl or aryl; R4 = H or CH3. Also claimed is the prepn. of (I) which comprises reacting a cpd. of formula (II) with amidinothiourea, and treating it with NaHCO3. Cpds. (I) and their pharmaceutically acceptable acid addn. salts are useful in the treatment of peptic ulcer and gastritis.

Description

[Name of invention]

Novel 2-guanidino-4- (5-thiazolyl) thiazole derivatives

Detailed description of the invention

The present invention relates to a novel 2-guanidino-4- (5-thiazolyl) thiazole derivative useful as an ulcer therapeutic agent.

이다. R₃는 수소원자 또는 메틸, 에틸, 프로필등의 C₁-C₄의 저급알킬기 또는 아릴기이고, R₄는 수소원자 또는 메틸이다.Wherein R ₁ is a hydrogen atom or methyl, R ₂ is a hydrogen atom or a lower alkyl group of C ₁ -C ₄ or

to be. R ₃ is a hydrogen atom or a C ₁ -C ₄ lower alkyl group or an aryl group such as methyl, ethyl or propyl, and R ₄ is a hydrogen atom or methyl.

Inflammatory diseases of the stomach are known to be caused by bacterial toxins, microorganisms, anti-inflammatory drugs and toxic chemicals, and gastric acid itself is also known to cause inflammation.

The novel compounds and acid addition salts of the present invention are useful for the prevention and treatment of gastrointestinal inflammatory diseases, including gastritis, gastric ulcer and duodenal ulcer, in mammals and humans, and particularly for treating peptic ulcers.

Related to the present invention are thiazole derivatives having an anti-ulcer therapeutic effect by gastric acid secretion function. (See Japanese Patent Application Laid-Open Nos. 81-55383, 4,283,408, 4,374,843).

The compounds of the present invention were examined by one or several standard tests showing gastric acid secretion activity. That is, by measuring the acid secretion inhibitory effect by Shay's method, 47% of 2-guanidino-4- (2-amino-4-methyl-5-thiazolyl) thiazole was administered at 30 mg / kg Inhibitory effect was observed, and 2-guanidino-4- (2-methyl-amino-4-methyl-5-thiazolyl) thiazole showed an inhibitory effect of 52% at 30 mg / kg administration. In addition, the compounds of the present invention have been tested by a number of standard laboratory tests for ulcer inhibitory effects on ulcers derived from various ulcer triggers. In other words, by measuring the ulcer inhibitory effect on ulcers derived from indomethacin, 2-guanidino-4- (2-amino-4-methyl-5-thiazolyl) thiazole showed 92% inhibitory effect. 2-guanidino-4- (2-methylamino-4-methyl-5-thiazolyl) thiazole showed an inhibitory effect of 87%. In addition, when the inhibitory effect on the ulcer derived from hydrochloric acid-ethanol was measured, 98% of 2-guanidino-4- (2-amino-4-methyl-5-thiazolyl) thiazole and 2-guani Dino-4- (2-methylamino-4-methyl-5-thiazolyl) thiazole showed an effect of 97%.

The compound of general formula (I) of the present invention is prepared as follows.

(In the above scheme, R ₁ , R ₂ are as described above.)

The preparation scheme is described in detail as follows.

The 5-acetylthiazole derivative of formula (II) was added to the concentrated aqueous bromic acid solution and added dropwise with an equivalent amount of bromine while stirring at about 70 ° C. to give the 5- (bromoacetyl) thiazole derivative of formula (III). Hydrobromide is obtained. This acid addition salt is dissolved in a small amount of ice-cold water and neutralized with an aqueous sodium bicarbonate solution to give 60-80% of 5- (bromoacetyl) thiazole derivative of the general formula (III).

In addition, the thiazole derivative of general formula (III) reacts mildly with amidinothiourea to provide 2-guanidino thiazole derivatives and hydrobromide of general formula (I). Acetone, dimethyl formamide and ethanol are suitable solvents for this reaction, and the reaction temperature is suitably between 50 and 80 ° C. The acid addition salt of formula (I) thus prepared is dissolved in ice-cold water and basified with sodium bicarbonate to give formula (I) as a solid.

Formula (I) of the present invention readily acts with an equivalent inorganic or organic acid to form an acid addition salt. The inorganic acids used to prepare this acid addition salt are hydrochloric acid, sulfuric acid, phosphoric acid, sulfurous acid and organic acids are acetic acid, maleic acid, citric acid, succinic acid, aspartic acid, fumaric acid, tartaric acid and methanesulfonic acid.

The compounds of the present invention can be used orally, subcutaneously, or intravenously to treat gastrointestinal inflammatory diseases and peptic ulcers. Oral administration is used in the form of a pharmaceutical composition in the form of a stagnation, capsule, powder or syrup in combination with a pharmacologically suitable carrier to increase the drug efficacy and stability. For example, when orally administered 2-guanidino-4- (2-methylamino-4-methyl-5-thiazolyl) thiazole, the LD ₅₀ value was 3,000 mg / kg or more, which was very stable.

In addition, the compounds of the present invention can be parenterally administered in preparation with pharmacologically acceptable acid addition salts. In this case, acceptable acid addition salts include inorganic acid salts such as hydrochloride, sulfate, sulfite and phosphate, and organic acid salts such as acetate, maleate, fumarate, citrate, tartarate, succinate, aspartate and methanesulfonate. have.

The dosage of the drug prepared with the compound of the present invention is 0.1 mg / kg to 100 mg / kg, but the daily commercial dosage is 0.2 mg / kg to 2.0 mg / kg.

Example 1

a) Production of 5-acetyl-2-amino-4-methylthiazole hydrochloride

Thiourea (31.6 g) is suspended in anhydrous ethanol (300 ml) at room temperature, and 3-chloro-2, 4-pentadione (62.2 g) is slowly added dropwise thereto. After completion of the dropwise addition, the reaction mixture was heated to reflux for 4 hours and cooled to yield a white crystalline solid. The solids were collected by filtration, washed with anhydrous ethanol (30 ml) and dried to yield 69.8 g of the desired product.

b) Preparation of 2-amino-5-bromoacetyl-4-methylthiazole

5-Acetyl-2-amino-4-methylthiazole hydrochloride (21.1 g) is added to concentrated hydrobromic acid (300 ml), and an equivalent amount of bromine is slowly added dropwise. The temperature of the reaction was raised to 70 ° C. and stirred for 2 hours and then concentrated under reduced pressure. Water is added to the concentrate to dissolve and neutralized with saturated aqueous sodium bicarbonate solution to form a precipitate. The resulting solids were collected by filtration, washed with water and dried to afford 26.8 g of the desired product.

c) Preparation of 2-guanidino-4- (2-amino-4-methyl-5-thiazolyl) thiazole

2-amino-5-bromoacetyl-4-methyl-thiazole (11.9 g) and amidino thiourea (6.0 g) were dissolved in anhydrous ethanol (180 ml), heated to reflux for 5 hours, and cooled to obtain a crystalline solid. Obtained. Filtration of this solid yields about 11 g of 2-guanidino-4- (2-amino-4-methyl-5-thiazolyl) thiazole hydrobromic acid salt. The solid is dissolved in water and converted to basic by adding saturated aqueous sodium carbonate solution to precipitate a solid. The solid was collected by filtration, washed with water and dried to yield 8.8 g of the desired product.

Acid addition salts of 2-guanidino-4- (2-amino-4-methyl-5-thiazolyl) thiazole suspend the thiazole compound in ethanol anhydride and add an equivalent of the corresponding acid, i.e. hydrochloric acid, sulfuric acid, Inorganic acids such as phosphoric acid and sulfurous acid or organic acids such as acetic acid, maleic acid, succinic acid and fumaric acid were added and stirred to prepare corresponding acid addition salts.

Example 2

a) Preparation of 2-methylamino-5-bromoacetyl-4-methylthiazole

5-acetyl-2-methylamino-4-methylthiazole hydrochloride (40.0 g) prepared by reacting 1-methylthiourea with 3-chloro-2, 4-pentadione in the same manner as in Example 1 a) ) Is dissolved in concentrated hydrobromic acid (250 ml) and 1.05 equivalent of bromine is added dropwise. Bromine is added dropwise while maintaining the temperature of the reaction mixture at 70 ° C., and stirring is continued for another hour at the same temperature when the dropping is complete. The reaction mixture was concentrated under reduced pressure, neutralized with saturated aqueous sodium bicarbonate solution and the resulting solid collected to yield 34 g of 2-methylamino-5-bromoacetyl-4-methylthiazole.

b) Preparation of 2-guanidino-4- (2-methylamino-4-methyl-5-thiazolyl) -thiazole

2-methylamino-5-bromoacetyl-4-methylthiazole (31 g) and amidinothiourea (14.3 g) obtained in Example 2 a) are dissolved in ethanol (300 ml) and heated to reflux. After refluxing for 5 hours, it is cooled and concentrated under reduced pressure. The residue is dissolved in distilled water, the insolubles are filtered off and treated with 10% aqueous sodium hydroxide solution to give a solid. The solid was collected by filtration, washed with water and dried under reduced pressure to yield 25.2 g of the desired product.

Example 3

[Preparation of 2-guanidino-4- (2-dimethylamino-4-methyl-5-thiazolyl) thiazole]

2-dimethylamino-5-bromoacetyl-4-methylthiazole (2.35) prepared by bromination reaction of 5-acetyl-2-dimethylamino-4-methylthiazole hydrochloride in the same manner as in Example a) g) and amidinothiourea (1.3 g) were heated to reflux for 5 hours in ethanol (15 ml), concentrated under reduced pressure, and the residue was dissolved in distilled water (30 ml). After basification with saturated aqueous sodium bicarbonate solution, the resulting solids were collected by filtration and dried to yield 2.1 g of the desired product.

[Examples 4 to 7]

2-alkylamino-5-bromoacetyl-4-methylthiazole and amidinothiourea are reacted in the same manner as in Example 1 c) to give the corresponding 2-guanidino-4- (2-alkylamino- 4-methyl-5-thiazolyl) thiazole was prepared. These results are shown in Table 1 below. The 5-bromoacetyl thiazole derivative used was prepared by the same method as in b) of Example 1 by bromination of the 5-acetylthiazole compound.

TABLE 1

Example 8

[Measurement of gastric acid secretion inhibitory effect]

Gastric acid secretion inhibitory effect was measured by Shay's method. Sprague-Dawlay male rats (130-180 g body weight) are fasted for 24 hours and the test drug is administered in the duodenum while ligating the pyloric region. After 4 hours, the stomach is removed, gastric juice is collected, and the acidity and amount of gastric juice are measured. The gastric acid secretion inhibitory effect was calculated by comparing the acidity of gastric juice of the control group to which no test drug was administered.

TABLE 2

Example 9

[Measurement of Ulcer Inhibition Effect]

Various ulcer inducing factors were used to measure the ulcer inhibition effect of the test drug while inducing ulcers. The results are shown in the following Tables 3 and 4.

TABLE 3

* Indomethacin (30mg / kg) is administered to induce ulcers

TABLE 4

* 0.15M HCl-60% EtOH (5mg / kg, P.O) is administered to induce ulcers

As described above in Example 8 and Example 9, the compound of the present invention has a gastric acid secretion inhibitory effect, it can be seen that particularly excellent ulcer prevention and treatment effect.

Claims (4)

The compound of the following general formula (I) and a pharmacologically acceptable acid addition salt.

Wherein R ₁ is a hydrogen atom or methyl, R ₂ is a hydrogen atom or a lower alkyl group of C ₁ -C ₄ or

to be. R ₃ is a hydrogen atom or a lower alkyl group or an aryl group of C ₁ -C ₄ , and R ₄ is a hydrogen atom or methyl. 2. 2-guanidino-4- (2-amino-4-methyl-5-thiazolyl) thiazole, 2-guanidino-4- (2-methylamino-4-methyl-5 Thiazolyl) thiazole, 2-guanidino-4- (2-dimethylamino-4-methyl-5-thiazolyl) thiazole, 2-guanidino-4- (2-ethylamino-4-methyl -5-thiazolyl) thiazole, 2-guanidino-4- (2-propylamino-4-methyl-5-thiazolyl) thiazole, 2-guanidino-4- (2, 4-dimethyl- 5-thiazolyl) thiazole and a pharmacologically acceptable acid addition salt selected from the group consisting of. A method for preparing the following compound of formula (I), wherein the compound of formula (II) is reacted with amidinothiourea and then basified with sodium bicarbonate.

Wherein R ₁ is a hydrogen atom or methyl, R ₂ is a hydrogen atom or a lower alkyl group of C ₁ -C ₄ or

Is a hydrogen atom or C ₁ -C ₄ lower alkyl group or aryl group, R ₄ is a hydrogen atom or methyl. A composition for preventing and treating peptic ulcer and gastrointestinal inflammatory disease in a mammal consisting of an effective amount of the compound of claim 1 in admixture with a pharmaceutically acceptable carrier or solvent.