1'-Substituted-spiro(imidazolidine-4,3'-indoline)-2,2',5-triones, processes for their manufacture and pharmaceutical compositions thereof

Claim 1

A process for the manufacture of a 1'-substituted -spiro[imidazolidine-4,3'-indoline]-2,2',5-trione of the formula:- wherein R 1 is a (1-12C)alkyl radical, a phenyl, naphthylmethyl or cinnamyl radical the aromatic rings of which optionally bear one or two halogeno radicals, or R 1 is a benzyl radical optionally bearing one, two or three substituents independently selected from halogeno, trifluoromethyl, (1-4C)alkyl, (1-4C)alkoxy, nitro, cyano and hydroxy radicals; and benzene ring A optionally bears one substituent selected from halogeno, (1-4C) alkyl, ( 1 -4 C )alkoxy, nitro and hydroxy radicals, or bears two substituents independently selected from halogeno, (1-4C)-alkyl and nitro radicals; or a pharmaceutically acceptable salt thereof; but excluding those compounds wherein R 1 is a methyl, ethyl, n-propyl or unsubstituted benzyl radical, and benzene ring A is unsubstituted; characterised by:- a) reacting an in cblin-2,3-dione of the formula:- with an alkali metal cyanide, and ammonium carbonate or carbamate; b) reacting a compound of the formula:- with a compound of the formula R 2 .X. wherein R 2 has the same meaning as R 1 other than a phenyl radical and X is a halogeno or an aryl- or alkyl-sulphonyloxy radical, in the presence of a suitable base; c) reacting a compound of the formula:- wherein R 3 is an acyl or tri-[(1-4C)alkyl]silyl radical with ammonium carbonate or carbamate; (d) - for a compound of formula I wherein benzene ring A bears a nitro substituent and/or R 1 is a benzyl radical bearing a nitro substituent, nitrating the corresponding compound of formula I wherein benzene ring A is unsubstituted or bears a single substituent and/or R 1 is an unsubstituted benzyl radical or a benzyl radical bearing one or two substituents; (e) for a compound of formula I wherein benzene ring A bears a chloro or bromo substituent, chlorinating or brominating the corresponding compound of formula I in which benzene ring A is unsubstituted; or ( f ) for a compound of formula I wherein benzene ring A and/or R 1 bears a hydroxy radical, dealkylating the corresponding compound of formula I wherein benzene ring A and/or R 1 bears a (1-4C)alkoxy radical; whereafter, when an optically active form of a compound of formula I is required, a racemic form of the said compound is reacted with an optically active form of a suitable organic base followed by conventional separation of the disastereoisomeric mixture of salts thus obtained, and liberation of the optically active form of the said compound by treatment with acid in a conventional manner; and when a pharmaceutically acceptable salt is required, a compound of formula I is reacted with an appropriate base affording a pharmaceutically acceptable cation, using a conventional procedure; and wherein R l and benzene ring A have the meanings defined above.