Fluoroalkyl indoline derivatives for pharmaceutical use

Claim 2

A trifluoromethyl spiro[imidazolidine-4,3'- indoline]-2,2',5-trione of the formula I wherein the trifluoromethyl substituent in benzene ring A is located at the 5', 6' or 7' position; and benzene ring B is dihalogenophenyl wherein Ra is fluoro or chloro, Rb is hydrogen and Rc is chloro, bromo or iodo; or Ra is hydrogen and Rb and Rc are independently chloro or bromo; or a salt with a base affording a pharmaceutically acceptable cation; or a non-toxic, biodegradable precursor thereof.

Claim 3

A compound as claimed in claim 1 wherein benzene ring B is selected from 3,4-dichloro-, 3,4-dibromo-, 3-bromo-4-chloro-, 4-bromo-3-chloro-, 4-chloro-2-fluoro-, 4-bromo-2-fluoro- and 2-fluoro-4-iodo-phenyl.

Claim 4

A trifluoromethyl spiro[imidazolidine-4,3'- indoline]-2,2',5-trione of the formula III wherein benzene ring B is selected from 4-bromo-2-chloro-, 4-bromo-2-fluoro- and 2-fluoro-4-iodo-phenyl; and one of Rd and Re is trifluoromethyl and the other is hydrogen; or a salt with a base affording a pharmaceutically acceptable cation; or a non-toxic, biodegradable precursor thereof.

Claim 5

A trifluoromethyl spiro[imidazolidine-4,3'- indoline]-2,2',5-trione of the formula III wherein benzene ring B is selected from 4-bromo-2-chloro-, 4-bromo-2-fluoro- and 2-fluoro-4-iodo-phenyl; and one of Rd and Re is trifluoromethyl and the other is hydrogen; or a salt with a base affording a pharmaceutically acceptable cation; or a non-toxic, biodegradable precursor thereof.

Claim 6

A compound selected from 1'-(4-bromo-2-fluorobenzyl)-5'-trifluoromethyl-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione, 1'-(4-bromo-2-fluorobenzyl)-7'-trifluoromethyl-spiroCimidazolidine-4,3'-indoline]-2,2',5-trione, the salts thereof with bases affording a pharmaceutically acceptable cation, and the non-toxic, biodegradable precursors thereof.

Claim 7

A compound selected from 1'-(4-bromo-2-fluorobenzyl)-5'-trifluoromethyl-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione, 1'-(4-bromo-2-fluorobenzyl)-7'-trifluoromethyl-spiroCimidazolidine-4,3'-indoline]-2,2',5-trione, the salts thereof with bases affording a pharmaceutically acceptable cation, and the non-toxic, biodegradable precursors thereof.

Claim 8

(d)-1'-(4-bromo-2-fluorobenzyl)-7'-trifluoromethyl-spiro[imidazolidine-4,3'-indolinel-2,2',5-trione, or a salt thereof with a base affording a pharmaceutically acceptable cation, or a non-toxic, biodegradable precursor thereof.

Claim 9

(d)-1'-(4-bromo-2-fluorobenzyl)-7'-trifluoromethyl-spiro[imidazolidine-4,3'-indolinel-2,2',5-trione, or a salt thereof with a base affording a pharmaceutically acceptable cation, or a non-toxic, biodegradable precursor thereof.

Claim 10

A salt as claimed in any one of claims 1-5 which is an alkali metal, alkaline earth metal, aluminium, or ammonium salt, or a salt with an organic base affording a pharmaceutically acceptable cation.

Claim 11

A biodegradable precursor as claimed in any one of claims 1-5 which is an alkoxycarbonyl, aralkoxycarbonyl, alkoxyoxalyl or l-(alkanoyloxy)alkyl derivative of a compound of formula I.

Claim 12

A pharmaceutical composition which comprises a compound of formula I or III, or a salt or a biodegradable precursor thereof, as claimed in any one preceding claim in admixture or conjunction with a pharmaceutically acceptable diluent or carrier.

Claim 13

A composition as claimed in claim 8 which is in a form suitable for topical administration to the eye.

Claim 14

A process for the manufacture of a compound of the formula I or III as claimed in any one of claims 1-7 characterised by:- (a) reacting an indoline-2,3-dione of the formula IV with an alkali metal cyanide and ammonium carbonate or carbamate; or (b) reacting a compound of the formula VII wherein Rf is acyl or tri-[(1-4C)alkyl]silyl with ammonium carbonate or carbamate; whereafter when a non-toxic biodegradable precursor is required a compound of formula I is reacted with a suitable alkoxycarbonyl, aralkoxycarbonyl, alkoxyoxalyl or 1-(alkanoyloxy)alkyl halide; when an optically active form is required, a racemic form of a compound of formula I is reacted with an optically active form of a suitable organic base, followed by separation of the diastereoisomeric mixture of salts thus obtained and liberation of the optically active form of said compound of formula I by treatment with acid; and when a salt is required, a compound of formula I in free base form is reacted with a suitable base affording a pharmaceutically acceptable cation.

Claim 15

A process for the manufacture of a novel trifluoromethyl spiro[imidazolidine-4,3'-indoline]-2,2',5-trione of the formula I wherein the trifluoromethyl substituent in benzene ring A is located at the 5', 6' or 7' position; and benzene ring B is dihalogenophenyl wherein Ra is fluoro or chloro, Rb is hydrogen and Rc is chloro, bromo or iodo; or Ra is hydrogen and Rb and Rc are independently chloro or bromo; or a salt with a base affording a pharmaceutically acceptable cation; or a non-toxic, biodegradable precursor thereof; characterised by:- (a) reacting an indoline-2,3-dione of the formula IV with an alkali metal cyanide and ammonium carbonate or carbamate; or (b) reacting a compound of the formula VII wherein Rf is acyl or tri[(1-4C)alkyl]silyl with ammonium carbonate or carbamate; wherein benzene ring A and B and the substituents thereon have the meanings defined above; whereafter when a non-toxic,biodegradable precursor is required a compound of formula I is reacted with a suitable alkoxycarbonyl, aralkoxycarbonyl, alkoxyoxalyl or 1-(alkanoyloxy)alkyl halide; when an optically active form is required, a racemic form of a compound of formula I is reacted with an optically active form of a suitable organic base, followed by separation of the diastereoisomeric mixture of salts thus obtained and liberation of the optically active form of said compound of formula I by treatment with acid; and when a salt is required, a compound of formula I in free base form is reacted with a suitable base affording a pharmaceutically acceptable cation.

Claim 16

A process for the manufacture of a novel trifluoromethyl spiro[imidazolidine-4,3'-indoline]-2,2',5-trione of the formula I wherein the trifluoromethyl substituent in benzene ring A is located at the 5', 6' or 7' position; and benzene ring B is dihalogenophenyl wherein Ra is fluoro or chloro, Rb is hydrogen and Rc is chloro, bromo or iodo; or Ra is hydrogen and Rb and Rc are independently chloro or bromo; or a salt with a base affording a pharmaceutically acceptable cation; or a non-toxic, biodegradable precursor thereof; characterised by:- (a) reacting an indoline-2,3-dione of the formula IV with an alkali metal cyanide and ammonium carbonate or carbamate; or (b) reacting a compound of the formula VII wherein Rf is acyl or tri[(1-4C)alkyl]silyl with ammonium carbonate or carbamate; wherein benzene ring A and B and the substituents thereon have the meanings defined above; whereafter when a non-toxic,biodegradable precursor is required a compound of formula I is reacted with a suitable alkoxycarbonyl, aralkoxycarbonyl, alkoxyoxalyl or 1-(alkanoyloxy)alkyl halide; when an optically active form is required, a racemic form of a compound of formula I is reacted with an optically active form of a suitable organic base, followed by separation of the diastereoisomeric mixture of salts thus obtained and liberation of the optically active form of said compound of formula I by treatment with acid; and when a salt is required, a compound of formula I in free base form is reacted with a suitable base affording a pharmaceutically acceptable cation.

Claim 17

A process according to part (a) of claim 1 characterised in that the alkali metal cyanide is sodium or potassium cyanide.

Claim 18

A process according to part (b) of claim 1 characterised in that Rf is selected from acetyl, propionyl, phenylsulphonyl, toluene p-sulphonyl, benzoyl benzyloxycarbonyl and trimethylsilyl.

Claim 19

A process according to any of claims 1-3 characterised in that a solvent or diluent selected from a (1-4C)alkanol, ethylene glycol and diethylene glycol, optionally together with water,is present.

Claim 20

A process according to any of claims 1-4 characterised in that it is performed at a temperature in the range 20 to 100°C.

Claim 21

A process according to any one preceding claim characterised in that in the starting materials benzene ring B is selected from 4-bromo-2-fluoro-, 4-bromo-2-chloro-and 2-fluoro-4-iodo-phenyl; and benzene ring A bears a trifluoromethyl substituent at position 5' or 7'.