FI58331B - FOERFARANDE FOER FRAMSTAELLNING AV NYA TERAPEUTISKT ANVAENDBARA ACYLERADE 2-AMINO-4-PYRIDYLTIAZOLDERIVAT - Google Patents

Description

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Patent- OCh r «riat« rftyrtlNn 'AnetUan uttagd och utl. «KrlfUn puMInrad 30.09 · o0 (32) (33) (31) Pyydetty« tuolkuu * —Begird prior * t «t (71) Egyt Gyogyszervegyeszeti Gyär, Kereszturi u. 30, Budapest X, Hungary

Hungary (HU) (72) Lajos Farkas, Budapest, Endre Kasztreiner, Budapest, Ferenc Andräsi,

Budapest, Jozsef Borsi, Budapest, Istvan Elekes, Budapest, Istvan Polgäri, Budapest, Hungary-Hungary (HU) (7 ^ +) Oy Kolster Ab (5 ^) Method for the preparation of new therapeutically useful acylated 2-amino-k-pyridylthiazole derivatives - The present invention relates to a process for the preparation of novel acylated 2-amino-U-pyridyl-thiazole derivatives, R1 ^ __ ^ R2 (!) I ^, the present invention relates to novel acylated 2-amino-U-pyridyl-thiazole derivatives.

HN-CO-CH -NQ

d \ 5 R? 12 1 wherein R is a pyridyl group, R is hydrogen or a methyl group, R is an alkyl group having 1 to 8 carbon atoms, a lower hydroxyalkyl group, a cyclopropyl group, a benzyl group or a phenyl group. k. 5 and R is hydrogen or a lower alkyl group, or R and R together with an adjacent nitrogen atom form a polymethyleneimino group or a morpholino group containing 5 to 7 methylene groups.

Certain 2-aminothiazole derivatives having an amino acid residue attached to the nitrogen atom of the amino group are known to have valuable therapeutic effect. For example, acylation of the 2-amino group of 2-amino-5 “chlorothiazole with glycine derivatives in 2,533,331 women gives compounds having anti-inflammatory, sedative and analgesic activity (DE-A-2 128 9 ^ 1) · Some 2-arylglycylamidodiazole derivatives are tested as anti-tuberculosis agents (Yakugaku Zasshi JJ_, 61 + 9 »1957) · These compounds were prepared by reacting the corresponding 2-chloroacetamidothiazole derivative with an aliphatic or aromatic amine or by acylating the corresponding 2-aminothiazole with a substituted glycyl chloride.

Novel compounds with valuable pharmaceutical effects have been found to be obtained by acylation of the amino group of 2-aminothiazole with an amino acid derivative such as glycine, alanine, phenylalanine, etc., and by positioning the phenyl or pyridyl group at position U, and the longer alkyl groups at position 5.

The process according to the invention is characterized in that the thiazole derivative of the general formula (II), R1> s \ ^ R2 P f (II)

NH-CO-CH2-X

. 1.2. .

wherein R and R are as defined above and X is halogen, reacting the amine compound N - H (H1) U 5 of the general formula (lii). .

with wherein R and R are as defined above and, if desired, the free base of general formula (i) is converted into a pharmaceutically acceptable acid addition salt, or the salt is converted into the free base.

The reaction according to the invention is preferably carried out in the presence of an inert solvent or diluent. As the solvent or diluent, water, lower alcohols such as methanol, ethanol or isomeric propanols, ketones such as acetone or butanone, ether-type solvents such as diethyl ether, diisopropyl ether or di-n-butyl ether, tetrahydrofuran, dioxane, dioxane can be preferably used. , acidic amide-type solvents such as formamide, methylformamide, dimethylformamide, N-methylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphoric acid triamide, and further, dimethyl sulfoxide or mixtures of such solvents can be used.

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The most preferred solvents are low alcohols and dimethylformamide.

. . . . »O. The process of this invention is preferably carried out at temperatures between -20 ° C and + 150 ° C. However, the use of temperatures below + 80 ° C is preferred because 2-haloacylthiazoles tend to have side reactions higher than this. at what temperatures. Such side reactions include, for example, ring formation. . . ..... „. . . 1 nitrogen atom of a thiazole atomic group, or quaternization of compounds containing a pyridine ring.

Depending on the amount of reagents used, the compounds of general formula (i); are formed either as free bases or as acid addition salts. General formula (III) depending on the amount of amine according to the invention, a free base or hydrohalide is obtained. 1

The preparation of a compound of general formula (i) can be proceeded by adding a basic substance in the reaction mixture, after which the free base thus obtained is isolated by known methods. Alternatively, the product obtained can first be isolated as a hydrohalide salt and then converted to the free form as a separate step. Alkali and alkaline earth metal hydroxides, carbonates or bicarbonates can be used as the basic substances, further aqueous ammonia solution can be used.

As mentioned above, the compounds of general formula (i) are basic and form acid addition salts with various organic or mineral acids. Of the salts, mention may be made, in particular, of hydrochlorides, hydrobromides, sulphates, phosphates, maleates, fumarates and D-tartrates.

The novel acylated 2-aminothiazole derivatives of general formula (i) are valuable therapeutic agents. They strongly inhibit the secretion of gastrointestinal fluids, and thus can be used to prevent excessive secretion of digestive fluids as well as for the prophylactic treatment of gastric ulcer. The novel compounds of the invention have no parasympatholytic (anticholinergic) side effects at all, nor do anticholinergic phenomena such as oral thickening and renal dilatation occur with the use of the novel compounds.

An effective daily dose of the compounds of general formula (i) is 10 to 500 mg.

The effects of the new compounds are on gastric acid secretion and Shay gastric ulcer was studied by H. Shay et. ai. (Gastroenterology 5, 1 * 3 (19 ^ 5)) while their effect on immobilization and insulin-stomach ulcer prevention was tested according to the method of Borsi et al (Acta Pharm. Hung. 38, 151 (1968)). . The renal dilating effect of the new compounds was studied in P.

According to the method of Pulewka (Arch. F. Exp. Path, u Pharm. 168, 306 (1932)) in order to determine whether or not they have anticholinergic side effects. All experiments were performed on rats. Methanteline bromide (diethyl- (2-hydroxyethyl) -methylammonium bromidexanthene-9 'carboxylate) was used as a reference. The results of the above experiments are shown in Table 1.

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The compounds of general formula (i) or their pharmaceutically acceptable acid addition salts may be administered to humans or animals in the form of pharmaceutical compositions such as tablets, coated tablets, pills, capsules, solutions, suspensions, injectables, suppositories, etc. These pharmaceutical compositions are prepared by known methods, using conventional pharmaceutical carriers, diluents and / or additives. The pharmaceutical preparations can be sterilized if necessary.

The invention is illustrated in detail by the following non-limiting examples.

Example 1 Preparation of 2-cyclopropylamino-acetamido-It- (3'-pyridyl) -thiazole 18 ml of cyclopropylamine are added to a mixture of 10.2 g of 2-chloroacetamido-1- (3'-pyridyl) -thiazole and 120 ml of ml of dimethylformamide, and the mixture is heated to 55 ° C to obtain a clear solution. After 1+ hours, 50% of the solvent is evaporated off under reduced pressure, and isopropanol saturated with dry hydrogen chloride gas is added to the residue. The separated solid is filtered off. 12.9 g (93%) of 2-cyclopropylamino-U- (3'-pyridyl) -thiazole dihydrochloride are obtained; melting point 2k6 - 2l + 7 ° C (when the product is recrystallized from a mixture of methanol and acetone).

1 g of the salt thus obtained is dissolved in 10 ml of water, and the solution is made alkaline with 8% aqueous ammonia solution. The separated crystalline material is filtered off and recrystallized from isopropanol. 0.1+ g of 2-cyclopropylamino-acetamido-1 + - (3'-pyridyl) -thiazole is thus obtained; melting point 189-192 ° C.

Example 2 Preparation of 2-C8-hydroxyethylamino-acetamido) -1- (3 * -pyridyl) -thiazole 20 ml of ethanolamine are added to a mixture of 15.2 g of 2-chloroacetamido-1- (3'-pyridyl) -thiazole and 80 ml of dimethylformamide. A red solution forms, from which a crystalline substance separates after one hour. The crystalline material is collected by filtration, and the mother liquor is concentrated to half its volume under reduced pressure to obtain more final product. In this way, a total amount of 15-5 g (96%) of 2-O-hydroxyethylaminoacetamido) -1- (3'-pyridyl) thiazole is obtained; melting point 186-189 ° C (after recrystallization from ethanol).

Examples 3-22 15.2 g (0.06 mol) of 2-chloroacetamido-1 + - (3'-pyridyl) -thiazole are stirred with stirring in 80 ml of dimethylformamide. A total of 0.29 moles of the amine shown in Table 2 is added to the mixture in several portions. The starting material slowly dissolves in solution. The final product separates from the solution as a crystalline substance. The reaction temperature is 20 to 50 ° C, as in many cases the reaction is associated with poor heat evolution. (Warming of the reaction mixture is a drawback, since above 50 ° C 2-chloroacetamido-1 - (3'-pyridyl) thiazole produces worthless by-products in dimethylformamide). After 6-12 hours, the crystals are filtered and recrystallized from ethanol or isopropanol. Yield 50 ~ 90%. The product name and melting point are shown in Table 2.

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Example 23 Preparation of 2-cyclopropylamino-acetamido-U- (2'-pyridyl) -thiazole dihydrochloride

Step A: Preparation of 2-chloroacetamido-1- * (2'-pyridyl) -thiazole.

A solution of 13.5 ml of chloroacetyl chloride dissolved in 1 * 8 ml of dimethylformamide is added, over a period of three hours, to a suspension of 28.8 g of 2-amino-1 * - (2, -pyridyl) -thiazole ( DE 1 062 21 * 5) suspended in 100 ml of dry dimethylformamide and 10.5 ml of pyridine. During the addition, the mixture is cooled in an ice bath, after which the mixture is placed in a refrigerator. The next day, 1 * 00 ml of water is stirred into the solution, the precipitated crystalline substance is filtered off, washed with ice water and ethanol and dried at 50 ° C. 35 * 38 g (87.0%) of 2-chloroacetamido-1 - - (2'-pyridyl) -thiazole are thus obtained. Melting point: 181 -18U ° C. This compound is used in the next step without further purification.

Step B: Preparation of 2-cyclopropylamino-acetamido-1 - (2'-pyridyl) -thiazochloride.

20 ml of cyclopropylamine are added to a stirred suspension in which 2 * *, 5 g of 2-chloroacetamido-1 * - (2'-pyridyl) -thiazole are suspended in 60 ml of dry dimethylformamide. The mixture warms slightly and the chloroacetyl compound dissolves. The mixture is stirred for 5 hours, after which it is allowed to stand overnight. 50 ml of the liquids are then evaporated off under reduced pressure, and 70 ml of isopropanol containing 7% of hydrogen chloride are added to the residue. The separated crystalline substance is filtered off.

28.0 g of 2-cyclopropylamino-acetamido-1- (2'-pyridyl) -thiazole hydrochloride are obtained. Melting point 185-190 ° C. This product is recrystallized from 90 Icy methane live solution. Yield 16.8 g (1 * 8%) of purified material, m.p. 2lk - 218 ° C. Example 2b Preparation of 2-cyclopropylamino-acetamido-N- (3'-pyridyl) -5-methylthiazolidine hydrochloride

Step A: Preparation of 2-chloroacetamido-1- * (3'-pyridyl) -5-methyl-thiazole 11.6 g of 2-amino-U- (3'-pyridyl) -5-methyl-thiazole (melting point: 191- 19 [deg.] C., prepared by reacting 3-propionylpyridine with bromine and not treating the 3- (OC-bromopropionyl) -pyridine hydrobromide thus obtained with thioure), suspended in a mixture of 61 * ml of dry dimethylformamide and 5 * 5 ml of dry pyridine, and a solution of 5 x 92 ml of chloroacetyl chloride dissolved in 10 ml of dry dimethylformamide is added to the stirred suspension over two hours. During the addition, the mixture is cooled in an ice bath. The mixture is stored in the refrigerator overnight, after which it is poured into 200 any ice water. The separated crystals are filtered off, washed with ice water and dried at 50 ° C. 10.81 g (66.9%) of 2-chloroacetamido-1- (3'-pyridyl) -5-methylthiazole are obtained; melting point 261 * - 266 ° C. This compound is used in the next step without purification.

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Step B: Preparation of 2-cyclopropylamino-acetamido-14- (3-pyridyl) -5-methylthiazole.

10 ml of cyclopropylamine are added to a stirred suspension in which 10.8 g of 2-chloroacetamido-U- (3-pyridyl) -5-methylthiazole are suspended in 25 ml of dry dimethylformamide. The mixture heats up slightly and a solution forms. The mixture is stirred for 1+ hours, after which it is stirred in 150 ml of cold water. The oily product separates, which solidifies on standing. The crystalline product is filtered off, washed with water and dried at 50 ° C. 10.2 g (87.6%) of 2-cyclopropylamino-acetamido-N- (3'-pyridyl) -5-methylthiazole are obtained; mp. 128-13 ° C.

The product obtained is converted into the dihydrochloride salt in methanol. 11.1 g (76.5%) of hydrochloride are obtained; mp. 22 DEG-228 DEG C. After recrystallization from 75 overnight methanol-water solution, the melting point rises to 235-238 ° C.

Example 25 Preparation of 2- (2, -hydroxyethylaminoacetamido) -U- (3 "-pyridyl) -5-methylthiazole

A mixture of 8.0 g of 2-chloroacetamido-1 + - (3'-pyridyl) -5-methylthiazole, 20 ml of dry dimethylformamide and 12 ml of ethanolamine is kept at room temperature for one hour. The resulting solution is mixed with ice water and allowed to stand in the refrigerator. The separated crystals are filtered the next day, washed with water, and dried at 50 ° C. 5.2 g (59.5%) of 2- (2'-hydroxyethylaminoacetamido) -N- (3 "-pyridyl) -5-methylthiazole are obtained; mp 176-179 ° C. the melting point of ethanol rises to 178-180 ° C.

Example 26 Preparation of 2-cyclopropylamino-acetamido-N- (4'-pyridyl) -thiazole dihydrochloride

Step A; Preparation of 2-chloroacetamido-H- (k'-pyridyl) -thiazole.

The procedure is as described in Example 23, Step A, except that 2-amino-1 + - (H'-pyridyl) -thiazole is used as the starting material (J. Heterocyclic Chem. 7, 1135 (1970)). 22.7 g (52.5%) of the subtitle compound are obtained; mp. 28 DEG-287 DEG C. This material is used in the next step crude.

Step B: Preparation of 2-cyclopropylamino-acetamido-1 - ((β'-pyridyl) -thiazole dihydrochloride).

17.1 g of 2-chloroacetamido-β- (1'-pyridyl) -thiazole and 70 ml of dry dimethylformamide are mixed and 20 ml of cyclopropylamine are added. The mixture is stirred at room temperature for 3 hours, after which the excess amine is evaporated off under reduced pressure. The residue is treated with isopropanol saturated with hydrogen chloride to give 17.6 g (72.7%) of 2-cyclopropylamino-acetamido-β- (1 '' - pyridyl) -thiazole dihydrochloride; mp. 2 ^ 2 - 2U6 ° C. When recrystallization is performed from a mixture of 90 arista aqueous methanol and acetone, the melting point rises to 263-267 ° C.

Claims (2)

A process for the preparation of new therapeutically useful acylated 2-amino-U-pyridyl-thiazole derivatives of the general formula (i) or pharmaceutically acceptable acid addition salts thereof, I (I) Y V hn-co-ch-nC ^ 2 ^ R5 1 P 1+ wherein R is a pyridyl group, R is hydrogen or a methyl group, R is an alkyl group having 1 to 8 carbon atoms, a lower hydroxyalkyl group, a cyclopropyl group, a benzyl group or a phenyl group, and R 1 is hydrogen or a lower alkyl group, or R 1 and R 2 form together with an adjacent nitrogen atom a polymethyleneimino group or a morpholino group containing a 5-T methylene group, characterized in that the thiazole derivative of the general formula (II), R 1 v R 2 (II) NH-CO-CH 2 -X 1.2. wherein R and R are as defined above, and X is halogen, is reacted with the amine compound h 's JY N - H (III) ----- ^ - 5 of the general formula (lii). . with wherein R and R are groups as defined above and, if desired, converting the free base of general formula (I) into a pharmaceutically acceptable acid addition salt, or converting the salt into the free base.