Patent GB-1195628-A (GB)
Title: Aroyl-Substituted Pyrroles
IPC: C07D207/337
Filed: 1968-07-24
Abstract: 1,195,628. Substituted pyrroles; oximes; acid chlorides. McNEIL LABORATORIES Inc. 24 July, 1968 [26 July, 1967; 1 July, 1968], No. 35277/68. Heading C2C. Novel 5-aroyl-pyrrole derivatives of the formulµ Ia, Ib, Ic and Id and the therapeutically acceptable basic salts of the acis thereof, wherein: Ar represents a phenyl, monosubstituted phenyl or polysubstituted phenyl group, each substituent being a halogen, lower alkyl, lower alkoxy, nitro, amino, methylthio or cyano group; Ar 1  represents a phenyl, monosubstituted phenyl or polysubstituted phenyl group, each substituent being a halogen, lower alkyl or lower alkoxy group; R represents a hydrogen or lower alkyl group; R 1  represents a hydrogen, lower alkyl or benzyl group; R 2  represents a CN, COOH, COO-(lower alkyl), CONH 2 , CONH (lower alkyl) or CON (lower alkyl) 2  group; and R 3  represents a COOH, COO-(lower alkyl), CONH 2 , CONH (lower alkyl) or CON (lower alkyl) 2  group; provided that: (i) when Ar is nitrophenyl or aminophenyl, then R is hydrogen, R 1  is lower alkyl and R 2  is CN 1 , COOH or COO-(lower alkyl); (ii) when Ar is cyanophenyl or methylthiophenyl, then R 1  is lower alkyl and R 2  is COOH or COO-(lower alkyl) ; and (iii) when R 1  is hydrogen, R is hydrogen, are prepared by (a) reacting a compound of the Formula II with a compound of the formula in the presence of a Lewis acid and a solvent, wherein R<SP>1</SP> is cyano or lower alkoxycarbonyl, whereafter the product may be converted to the corresponding carboxylic acid by hydrolysis, and in the instance of compounds of the Formula (Ia) wherein R is lower alkyl and R 2  is -CN, COOH or COO-(lower alkyl), C- alkylating a compound of the formula wherein R<SP>11</SP> is lower alkyl or benzyl and Ar<SP>1</SP> is phenyl or phenyl substituted with halogen, lower alkyl, lower alkoxy or cyano, with a lower alkyl halide in the presence of a strong base, the product may then be hydrolysed to the free acid; and in the instance wherein it is desired to obtain compounds wherein R 1  is lower alkyl, Ar is the same as Ar<SP>1</SP>, R is lower alkyl and R 2  is CN or COOH, N-alkylating a compound of the formula followed by C-alkylation of the product, if desired, followed by hydrolysis to the corresponding free acid; and in the instance wherein Ar is nitrophenyl, and R 2  is equal to R<SP>1</SP>, the nitro function may be catalytically hydrogenated to yield the corresponding aminophenyl product, if desired, followed by hydrolysis to the corresponding free acid; when R 2  is COOH esterification with a lower alkanol yields the corresponding esters, and when R 2  is CN partial hydrolysis gives the corresponding amides; conversion of the COOH group to an acid chloride followed by reaction with a lower alkyl amine (mono- or di-alkyl) yields the corresponding amides; or (b) reacting a compound of the Formula II above, wherein Ar is other than aminophenyl, with a compound of the formula in the presence of a Lewis acid and a solvent, hydrolysis yields the free acid of Formula (Ib), catalytic hydrogenation of the nitrophenyl will give the corresponding aminophenyl, if desired, followed by hydrolysis of the ester function to give the free acid; the free acids of Formula (Ib) may be converted to their amides with ammonia or a lower (mono- or di-) alkyl amine; (c) and (d) decarboxylating a compound of the formulµ by heating in a basic organic solvent to give compounds XVI and XXIII of the respective formulµ hydrolysis of (XVI) will give the free acid, (XXIII) may be esterified with a lower alkanol, the compounds may be converted to their amides by treatment of the acid with ammonia or a lower (mono- or di-) alkyl amine; and, if desired, preparing therapeutically acceptable salts of acids prepared by the above processes by treatment with an appropriate base. The pyrrole-2-acetate starting materials may be prepared by the action of diazomethane on the acid. The pyrrole-2-propionates may be prepared from the pyrrole-2-aldehydes and ethoxycarbonyl methylene triphenylphosphorane, followed by hydrogenation of the resulting pyrrole-2-acrylates. The aroyl chloride starting materials may be obtained by the action of thionyl chloride on the corresponding acids. The pyrrole-2-acetonitriles may be formed from corresponding pyrrole, dimethylamine and formalin, followed by the addition of methyl iodide to the resulting 2-dimethylaminomethyl-1-benzyl-pyrrole to form the corresponding quaternary salt and then treatment with sodium cyanide. 1-Aryl- 1,2,3 - butanetrione - 2 - oximes may be prepared by treating the 1-aryl-1,3-butanedione with nitrous acid, cyclization of the oxime with diethyl acetone dicarboxylate gives the ethyl- 5 - aroyl - 3 - ethoxy - carbonyl - 4 - methyl pyrrole-2-acetate which upon hydrolysis yields the corresponding acids, treatment with ethanolic hydrogen chloride gives the ethyl 5-aroyl-3- carboxy - 4 - methyl - pyrrole - 2 - acetate. The ethyl 5 - aroyl - 2,4 - dimethyl pyrrole - 3 - acetates are prepared from ethyl 2,4-dimethyl-pyrrole-3- acetates and an aroyl chloride, treatment with sulphuryl chloride yields the ethyl-5-aroyl-4- methyl - 2 - trichloromethyl - pyrazole - 3 - acetates, refluxing with water in dioxan gives the corresponding 3-acetic acids. Methyl pyrrole-2- acetate and methyl 1-methyl-pyrrole-2-acetate by esterifying required acids with diazomethane. Ethyl 2 - (1 - methyl - 2 - pyrrolyl) - propionate is prepared by hydrogenating the corresponding acrylate. Pharmaceutical compositions contain the compounds Ia, Ib, Ic and Id above and a carrier. The compositions have anti-inflammatory activity and may be administered orally.