Patent GB-1446084-A (GB)
Title: Substituted acylanilides
IPC: C07C231/12
Filed: 1973-11-20
Abstract: 1446084 Substituted acylanilides SCHERICO Ltd 20 Nov 1973 [24 Nov 1972 19 June 1973] 53790/73 Heading C2C Novel compounds of the Formula I wherein R is H or C 1-4  alkyl; R<SP>1</SP> and R<SP>2</SP>, which are the same or different, are C 1-8  alkyl, cylcopropyl or cyclobutyl or R<SP>1</SP> and R<SP>2</SP> together with the carbon to which they are attached form cyclopropyl or cyclobutyl; X is nitro, amino, CF 3 , chlorine, bromine or iodine; Y is H, halogen, nitro, amino lower alkylamino, diloweralkylamino, loweralkyl, loweralkoxy, loweralkanoyl, polyfluoroloweralkyl, polyfluoro loweralkoxy, polyfluoroloweralkylthio, where R 3  is H or loweralkyl and R<SP>4</SP> is H, loweralkyl, aralkyl or alkyl, except that X and Y are not amino simultaneously; Q is hydroxy, loweralkoxy, arylloweralkoxy, loweralkanoyloxy, arylloweralkanoyloxy or a group of the Formula XXI wherein X, Y, R, R<SP>1</SP> and R<SP>2</SP> are as defined above and E is oxygen or sulphur; wherein all loweralkyl, loweralkoxy, and loweralkanoyl groups have up to 6 carbon atoms; with the proviso that Y is not H or Cl when X is Cl, R is H, R<SP>1</SP> and R<SP>2</SP> are CH 3  and Q is OH and that R<SP>1</SP> and R<SP>2</SP> do not form a cyclopropyl ring with the carbon to which they are attached when X and Y are Cl, R is H and Q is CH 3 O; and the pharmaceutically acceptable acid addition salts of those compounds having various amino groups may be prepared by (1) forming the acylamino groups by (2) acylating an aniline, (b) hydrolysing an imido halide or an ester of an N-phenyl imidic acid, (c) subjecting an oxime, O-acyl oxime or hydrazone to a Beckmann rearrangement, (d) subjecting a ketone X to a Schmidt reaction with hydrazoic acid, (e) subjecting an X-, Y-substituted phenylisocyanide to a Passerini-type reaction with a ketone in the presence of an acid QH or a mineral acid, (f) reductively acylating an X-, Y-substituted nitrobenzene, (f) subjecting an X,Y-substituted anilide to an amide exchange, (h) rearranging an N-haloanilide to introduce the halide at the X-position in the ring (i) rearranging an N- nitrosoanilide in the presence of an oxidizing agent to introduce a nitro group at the X position and H at R, (j) rearranging an N-haloanilide in the presence of a HX<SP>1</SP> where X<SP>1</SP> is a halogen of lower electronegativity to introduce X<SP>1</SP> at the X position and H at R; (2) enzymatically hydroxylating an anilide XIV on the α-carbon atom; (3) eliminating an amino substituent on the benzene ring by diazotization and reduction; (4) introducing an X substituent by halogenation or nitration (5) hydrolysing a compound of the Formula I wherein Q is an acyloxy group to give a compound I in in which Q is OH; (6) reacting a compound I in which Q is OH with carbonylchloride or thiocarbonylchloride to form the compounds I in which Q is a Group XXI; (7) removal of protective groups on the nitrogen of the acylamino group; (8) N-alkylating compounds I in which R is hydrogen; (9) acylating compounds I in which Q is OH; (10) hydrolysing a compound in which Q is loweralkanoyloxy or aryl-loweralkanoyloxy; (11) formation of pharmaceutically acceptable salts where appropriate. m - Difluoromethylaniline and m - (α,α - difluoroethyl)aniline are prepared by treating mnitrobenzaldehyde and m-nitroacetophenone with sulphur tetrafluoride to yield m-difluoromethylnitrobenzene and m - (α,α - difluoro ethyl)nitrobenzene respectively followed by reduction of the nitro groups. Pharmaceutical compositions of the compounds I with the usual excipients show anti-androgenic activity when administered orally, parenterally or topically.