SU1099844A3 - Process for preparing thiazole derivatives or their salts - Google Patents

Abstract

Thiazoles of formula <IMAGE> and salts thereof, wherein R represents hydrogen or an acyl group, possess anti-inflammatory activity and have low toxicity. The compounds may be formulated as pharmaceutical compositions.

Description

UGM1L1IV refers to the method of obtaining new thiaeol derivatives of the formula Tn.soon where R is hydrogen or Cg C is alkanoyl or their salts, which have inflammatory activity and can be used in medicine. There is a known method for the preparation of derivatives of thiazolecarboxylic acid (formula: cn, ooo), which consists in the fact that 3-bromo-3 (p-chlorobenzene) propionic acid is reacted with thiobenzamide in ethanol at the boiling point of the reaction mixture, followed by hydrolysis of the forming potassium hydroxide ethyl ester in aqueous ij. Compound of formula IV has anti-inflammatory activity. The purpose of the invention is the synthesis of new thiazole derivatives that can be used in medicine as anti-inflammatory The goal is achieved by the method of obtaining compounds of general formula 1 or their salts with ib halo-ketone of the general formula CO-CHOHjCOOB Hat where Na is halogen, hydrogen or lower alkyl is reacted by heating in an inert solvent with a thioamide of the general formula fil H;, NSC where - or - lower alkyl, and if 2 is lower alkyl, then dealkylation is carried out, which bark connection, where R is hydrogen, and if RI in the product is lower alkyl, then the hydronic wire to get connection where R, is hydrogen, and, if desired, then received 1 O1: Comm nenie formula 1, in which B - is hydrogen, is acylated to give compound forg-t Do 1, in which R - Cj-C5 apkanoil and the title product is isolated in free form or in salt form. Hat means chlorine or bromine. 2 - C-C4-alkyl. 3-Bromo-J- (, 4-chlorophenyl) propionic acid is reacted with 4-hydroxythiobenzamide to obtain 4- (4-chlorophenyl) -2- (4-hydroxyphenyl) thiazole-5-acetic acid. Example. 4- (4-Chlorophenyl) -2 (4-hydroxyphenyl) thiazole-5-acetic acid. 1.26 g (3.5 mmol of 4- (chlorophenyl) 2- (4-methoxyphenyl) thiazole-5-acetic acid, obtained by the method of example 2 by the interaction of 3-bromo-3 (4-chlorobenzoyl) propionic acid with 4-methoxybenzamide The mixture is heated under reflux in a mixture of glacial acetic acid (10 ml) and 48% hydrobromic acid (20 mp) for 4 hours. Upon cooling, the hydrobromic acid salt of the title compound is isolated as crystals (1.03 g The crystals are collected, washed with water and ether and then dried (mp 293241 C (with decomposition). Found: C 47.7; H 3.1; N 2.4; b ohm ion 19.2., s, n, sevvg Calculated,%: C, 47.8; H, 3.1; N, 3.3; and rh-ion, 18.7. - (4-Chlorophenyl I-2 (4-hydroxyphenyl) thiaz6l-5-acetic acid); 27 g of 3-bromo-3- (4-chlorobenzoyl) propionic acid and 14.6 g of 4-hydroxythiobenzamide are heated to 50 ml of dimethylformamide. The reagents are kept at this temperature for 1 hour, cooled and poured into ice. The resulting mass hardens, it is filtered and washed with water, resulting in 31.6 g of a powder having m.p. 184-194 ° C (with decomposition). This powder was recrystallized from ovage from aqueous isopropanol, resulting in 25.4 g of the title compound as a hemihydrate. M.p. 192-194 ° C (with decomposition). Found,%: C 57.7; H 3, b; M 3.6. C n, 2 1/2 Calculated,%: C 57.55; H 3.7; W 3.9. Froze 2- (4-Lcetoxyphenyl) -4- (4-chlorophenyl) thiazole-5-acetic acid. 7.0 g (0.016 mol) of 4- (1-chlorophenyl) -2- (4-hydroxyphenyl) -thiazole-5-acetic acid is dissolved in 493 ml, 372 mol) of 0.1 N. sodium hydroxide and cooled to before . To this mixture was added 1.5 NUI (0.016 mol) of acetic anhydrile and left for 3 hours at room temperature. Dilute hydrochloric acid is added to the solution and the resulting precipitate is filtered off; washing it with a small amount of water is dried and recrystallized from methyl ethyl ketone to obtain the title compound as a colorless solid (2.4 having a melting point of 177-180 ° C. Found: C 58.94; H 3 , 87; С „Нц NO, S Calculated,%: С 58.84; H 3.64; N 3.61. EXAMPLE 4. 4- (4-Chlorophenyl) 2- (4-valeryloxyphenyl) thiazole-5-uksuu acid; 3.81 g (0.011 mol) of 4- (4-chloroPhenyl) -2- (4-hydroxyphenyl) -thiazole-5 acetic acid is dissolved in 55 ml (0.027 mol) of 0.2 N. hydroxide hydroxide and the solution is cooled to. To the mixture is added 2.0 0.0111 mol) valeryl anhydride and in ensivno reaction vessel was shaken for 4 minutes. To the mixture is added diluted hydrochloric acid, the chloroform is extracted with a thick mass. The chloroform extract was washed with water, decomposed, dried over magnesium sulfate, and a white solid was obtained. This solid is stirred with water for about 1/4 h at 50 ° C, filtered and dried to give the title compound as a colorless solid (3.68 g}, having a mp 197-199 ° C. - Found,%: C 61.16; H4.61; N 3.11. CjjHjoCe N Calculated,%: C 61.46; H 4.69; 3.26. Example 5. 4- ( 4-X. chlorophenyl) 2- (4-hydroxyphenyl) thiazole-5-acetic acid. Analogously to Example 2, the reaction between methyl-3-bromo-3- is carried out (4% inhibition of

Average weight increase for Average increase

- 100 X EPySOi DE ° i§ffli ° 5BS5 ° Iii G 5§5z for control groups

Average weight gain for control groups

The results obtained for the typical toxicity of the compounds of the general form representatives of the compounds of the general formula I are given in table. one.

All compounds have a marked anti-inflammatory activity of about the same order. JL mules were measured as a result of peroral administration of the test compounds to groups of 3 male-3 and 3 male females (after catching

their feelings of hunger) in the form of progressive increase, and their doses.

The results are in table. 2. yyurbenoyl propioate and 4-gilro1 (sitiobenzamide to give 4- (4-porphenyl) -2- (4-hydroxyphenol) and azog. 5-acetate. The said compound is hydrolyzed using 2 and sodium hydroxide, to give in the result. The title compound. EXAMPLE 6 4- (4-X-11Orphenyl} -2 (4-hydroxyphenyl) thiazole-5-uksunuyu acid. Prepared according to Example 3 2- (4-acetoxyphenyl) -4- (4-chlorophenyl) thiazole-5-acetic acid hydrolyzed with 2N sodium oxide hydrate, resulting in the title compound. Example 7: 2- (4-Lcetoxypheni.n) 4 - 4 lorophenyl) thiazole-5-acetic acid. Analogously to Example 2, 3-bromo-3 (4-chlorobenzoyl) -propionic acid is reacted with 4-acetoxythiobenzamide to obtain the title compound, the hemihydrate of which has mp 192-194 C (decomposed) A compound of general formula 1 was tested for anti-inflammatory activity according to the following procedure: Groups of 10 female rats weighing 60-70 g were used. Eden of the ear is caused by rubbing irritant substances on both surfaces of the ear. This mixture consists of 1% croton oil, 20% pyridine, 5% water and 4% diethyl ether (with or without the test compound, it is used once and only on the right ear of the animal. After 6 hours, the animals are killed, taken 9 mm in diameter from each ear of the animal with a drill for plugs and weighed. The anti-inflammatory activity of the tested compounds is estimated from an expression corresponding to the percentage difference in the average ear weight increase for control groups of animals treated with the corresponding compound. Niemi.

Table

Table 2

Claims (4)

1. The method of producing thiazole derivatives of the general formula where K is hydrogen or C ₂ -C ₅ ~ alkanoyl, or their salts, characterized in that -halo ketone of the general formula p - ^^ - co-snsNgCOOK, _(ίΓ ) Na1 where nab is halogen; - hydrogen or lower alkyl, exposed when heated in an inert solvent with a thioamide of the general formula _ n ₂ ngc - ^^ - ok ₂ (“') where K, - K, or (C is lower alkyl, and if “lower alkyl, then dealkylation is carried out, which gives the compound, where K is hydrogen, and if K, the product has lower alkyl, then hydrolysis is carried out to obtain the compound, where K, is hydrogen, and, if desired, the resulting compound of formula 1, in which I is hydrogen, is acylated, that p gives a compound of formula 1, in which "K - C ₂ -Cd-alkanoyl, and the target product is assigned in free form or in salt form. 2. The method according to π. 1, characterized in that Nab is chlorine p or bromine. 3. The method according to paragraphs. 1 and 2, on the basis of the fact that (? ₂ - C ₁ -C ^ alkyl. 4. The method according to π. 1, characterized in that the 3-bromo-3 (4-chlorophenyl) propionic acid is reacted with 4-hydroxythiobenzamide to obtain 4- (4-chlorophenyl) -2- {4-hydroxyphenyl) thiazole-5 acetic acid. SP with 099844 one 1. υ 9 9 a 4 4 2