Patent GB-1206814-A (GB)
Title: Azacycloaliphatic compounds, process for their manufacture and compositions containing them
IPC: C07D231/12
Filed: 1968-02-19
Abstract: 1,206,814. Azacycloaliphatic compounds. CIBA Ltd. 19 Feb., 1968 [1 March, 1967; 24 Jan., 1968], No. 7909/68. Heading C2C. Novel compounds of the formula in which N = Z denotes an N-azacycloaliphatic radical containing 5 to 8 ring members and in the ring at most one carbon-carbon double bond; Pyr denotes a 4-pyrazolyl radical; X- represents an oxygen atom; Alk represents a 1 : 1-lower alkylidene radical, and R denotes a hydrogen atom or a lower alkyl group (the term 'lower' denoting the presence of up to 7 carbon atoms) or salts thereof are prepared by a process which comprises reacting a compound of the formula Pyr-C(=O)-Alk-H with a lower alkanol (e.g. formaldehyde, or an acetal, an acylate or a polymerization product e.g. paraformaldehyde as a lower alkanol-furnishing agent) and an azacycloaliphatic compound of the formula H-N = Z or a salt thereof and if desired removing from a resulting compound, from a N-azacycloaliphatic radical, a hydroxy group and a hydrogen atom, thereby introducing a carbon to carbon double bond or reducing in a resulting compound a double bond in a N- azacycloaliphatic radical. A great number of the compounds as defined above are exemplified in the specification together with their preparations. 4 - Acetyl - 5 - methyl - 1 - (1 - methyl - 4 - piperidyl) - pyrazole monohydrochloride is prepared by adding a solution of 1 -methyl-4- hydrazinopiperidine in dioxane dropwise to a solution of ethoxymethylene-acetylacetone in dioxane at 0‹ C. and finally treating the resulting liquid with a solution of HCl gas in isopropanol. 4 - Acetyl - 1 - carbethoxy - 5 - methyl - pyrazole (and its thiosemicarbazone and guanylhydrazone hydrochloride) is prepared by treating a mixture of ethoxymethylene-acetyl-acetone in ether at 0‹ C. with an ether solution of 1-carbethoxy-hydrazine, and heating the resulting hydrazone in nitrogen for 3 hours at 160‹ C. 1 - (4 - Carbethoxyphenyl) - 4 - acetyl - 5 - methylpyrazole is prepared by adding dropwise an ether solution of 4-hydrazino-benzoic acid ethyl ester to an ether solution of ethoxymethylene-acetylacetone at 0‹ C. Using the corresponding hydrazines 1-(3-chloro-4-methylphenyl) - 4 - acetyl - 5 - methylpyrazole, 1 - (4 - methylmercaptophenyl) - 4 - acetyl - 5 - methylpyrazole, 4 - acetyl - 1 - (3 - methylmercaptophenyl) - 5 - methyl - pyrazole, 4 - acetyl - 1 - (3,5 - bis - carbomethoxyphenyl)- 5 - methyl - pyrazole, 4 - acetyl - 1 - (3,5 - bis - trifluoromethylphenyl) - 5 - - methylpyrazole, 4 - acetyl - 5 - methyl - 1 - (3,4,5 - trimethoxyphenyl) - pyrazole, 4 - acetyl - 1,5 - dimethylpyrazole, 4 - acetyl - 1 - (3 -fluoro - 4 - methylphenyl) - 5 - methylpyrazole, 4 - acetyl - (4 - fluoro - 3 - methylphenyl) - 5 - methylpyrazole, 4 - acetyl - 1 - (2 - dimethylaminoethyl) - 5 - methylpyrazole maleate (final treatment with maleic acid in isopropanol), 4-acetyl- 1 - (2 - diethylaminoethyl) - 5 - methylpyrazole hydrochloride (final treatment with HCl gas in isopropanol), and 4-acetyl-1-(2-piperidinoethyl)- 5-methylpyrazole are similarly prepared. 4- Acetyl - 1 - (7 - chloro - 4 - quinolinyl) - 5 - methylpyrazole is prepared using the corresponding hydrazine and followed by heating the resulting hydrazone for 6 hours at 190‹ C. in nitrogen. 4 - Acetyl - 1 - {2 - [4 - (4 - fluorophenyl) - 1 - piperazino] - ethyl} 5 - methyl - pyrazole monohydrochloride dihydrate is prepared by treating a dioxane solution of 4-acetyl-1- [2 - (4 - bromophenyl - sulphonyloxy) - ethyl] - 5- methylpyrazole with 4-(4-fluorophenyl)-piperazine and heating for 8 hours in a steel tube under pressure at 160‹ C., and eventually treating with HCl gas in isopropanol. Ethoxymethylene-benzoylacetone is prepared by refluxing benzoylacetone, triethyl orthoformate and acetic anhydride and collecting the fraction boiling at 165-174‹ C./5 mm. Hg. 4-Benzoyl-1-(4- fluorophenyl)-5-methylpyrazole is prepared by treating an ether solution of ethoxymethylenebenzoylacetone at 0‹ C. dropwise with an ether solution of 4-fluorophenylhydrazine, and recrystallizing in isopropanol. The mother liquor is evaporated to dryness and a solution of the residue filtered through an aluminium oxide column to give 4-acetyl-1-(4-fluorophenyl) - 5 - phenylpyrazole. 4 - Benzoyl - 1 - (4 - bromophenyl) - 5 - methylpyrazole and its 4- acetyl analogue are prepared similarly using 4- bromophenylhydrazine. 4 - Acetyl - 1 - acetyl - 1 - [2 - (4 - bromophenyl - sulphonyloxy) - ethyl] - 5 - methylpyrazole is prepared from 4-acetyl-1- (2-hydroxyethyl)-5-methylpyrazole and 4-bromobenzene sulphonyl chloride. 3-Fluoro-4- methylphenylhydrazine hydrochloride is prepared by diazotization of 3-fluoro-4-methylaniline followed by treatment with stannous chloride dihydrate in concentrated hydrochloric acid at 0‹ C. 4 - Fluoro - 3 - methylphenylhydrazine hydrochloride is prepared similarly. 4 - Acetyl - 1 - [2 - (4 - fluorophenylsulphonyloxy)- ethyl] - 5 - methylpyrazole is prepared from 4 - acetyl - 1 - (2 - hydroxyethyl) - 5 - methylpyrazole, triethylamine and 4-fluorophenylsulphonyl chloride. 4-Acetyl-1-[2-(4-chloro phenylsulphonyloxy) - ethyl] - 5 - methylpyrazole is prepared similarly. 3 - Ethoxymethylene - 1 - methoxy - 2,4 - pentanedione is prepared by refluxing 1-methoxy - 2,4 - pentanedione, triethyl orthoformate and acetic anhydride. 4 - Acetyl - 5 - methoxymethyl - 1 - phenylpyrazole is prepared from 3-ethoxymethylene- 1 -methoxy-2,4-pentane-dione and phenylhydrazine. Pharmaceutical compositions having antihypertensive properties, tranquillizing, sedative and anticonvulsive properties, as well as antitussive, antiinflammatory, adrenolytic, or barbiturate-potentiating effects and containing compounds of the formula defined above are administered orally or parenterally in association with a suitable pharmaceutical carrier, such compositions being exemplified in examples 15 and 53.