Pharmaceutical spiro-succinimide derivatives

Claim 2

A pharmaceutical composition comprising as active ingredient a 1'-substituted-spior[pyrrolidine-3,3'-indoline]-2,2',5-trione of the formula:- wherein Ra is (2-7C)alkyl or (3-7C)alkenyl, naphthylmethyl or cinnamyl optionally bearing one or two halogeno nuclear substituents, or Ra is benzyl optionally bearing one or two substituents independently selected from halogeno, (l-4C)alkyl, (l-4C)alkoxy, cyano, nitro and trifluoromethyl, located in the 2, 3, 4 or 5 position; and benzene ring A optionally bears one or two substituents independently selected from halogeno, (l-4C)alkyl, trifluoromethyl and nitro;or a salt thereof with a base affording a pharmaceutically acceptable cation; or a non-toxic, biodegradable precursor thereof; together with a pharmaceutically acceptable diluent or carrier.

Claim 3

A composition as claimed in claim 1 wherein Ra is ethyl, propyl, butyl, pentyl, hexyl, heptyl, allyl, 2-methylallyl or 3-butenyl, naphthylmethyl or cinnamyl optionally bearing one or two fluoro, chloro, bromo or iodo nuclear substituents, or Ra is benzyl optionally bearing one or two substituents independently selected from fluoro, chloro, iodo, methyl, ethyl, methoxy, ethoxy, cyano, nitro and trifluoromethyl, located in the 2, 3, 4 or 5 position; and benzene ring A optionally bears one or two substitutents independently selected from fluoro, chloro, bromo, iodo, methyl, ethyl, trifluoromethyl and nitro substituents.

Claim 4

A composition as claimed in claim 1 wherein Ra is propyl, butyl, hexyl, heptyl, 1-naphthylmethyl, 2-naphthylmethyl, cinnamyl, halogenocinnamyl, dihalogenocinnamyl, benzyl, (1-4C)alkylbenzyl, halogenobenzyl, trifluoromethylbenzyl or dihalogenobenzyl; and benzene ring A is unsubstituted or bears a fluoro, chloro, bromo methyl or trifluoromethyl substituent located in the 5', 6' or 7'-position.

Claim 5

A composition as claimed in claim 1 wherein the active ingredient is selected from 1"-(4-chlorobenzyl)-spiro[pyrrolidine-3,3'-indoline]-2,2,5-trione, l'-(3,4-dimethoxybenzyl)-spiro[pyrrolidine-3,3'-indoline]-2,2',5- trione, and the salts thereof with bases affording a pharmaceutically acceptable cation.

Claim 6

A composition as claimed in any of claims 1-4 which is in a form suitable for oral, parenteral, rectal or topical opthalmic administration.

Claim 7

A composition for oral administration as claimed in claim 5 which is in the form of a tablet, capsule, granule, dispersible powder, syrup, elixir, emulsion, suspension or gel.

Claim 8

A composition for topical opthalmic administration as claimed in claim 5 which is in the form of an ointment, gel or sterile solution.

Claim 9

A novel l'-substituted-spiro[pyrrolidine-3,3'- indoline]-2,2',5-trione of the formula:- wherein Ra is (2-7C)alkyl or (3-7C)alkenyl, naphthylmethyl or cinnamyl optionally bearing one or two halogeno nuclear substituents, or Ra is benzyl optionally bearing one or two substituents independently selected from halogeno, (l-4Clalkyl, (1-4C)alkoxy, cyano, nitro and trifluoromethyl, located in the 2, 3, 4 or 5 position; and benzene ring A optionally bears one or two substituents independently selected from halogeno, (l-4C)alkyl, trifluoromethyl and nitro; or a salt thereof with a base affording a pharmaceutically acceptable cation; or a non-toxic biodegradable precursor thereof; but excluding 1'benzyl-, 1'-(4-chlorobenzyl)- and l'-(3,4-dimethoxybenzyl)-spiro[pyrrolidine-3,3'-indoline]-2,2',5-trione and 1'-benzyl-5'-chloro-spiro[pyrrolidine-3,3'-indoline]-2,2',5-trione.

Claim 10

A novel l'-substituted-spiro[pyrrolidine-3,3'- indoline]-2,2',5-trione of the formula:- wherein Ra is (2-7C)alkyl or (3-7C)alkenyl, naphthylmethyl or cinnamyl optionally bearing one or two halogeno nuclear substituents, or Ra is benzyl optionally bearing one or two substituents independently selected from halogeno, (l-4Clalkyl, (1-4C)alkoxy, cyano, nitro and trifluoromethyl, located in the 2, 3, 4 or 5 position; and benzene ring A optionally bears one or two substituents independently selected from halogeno, (l-4C)alkyl, trifluoromethyl and nitro; or a salt thereof with a base affording a pharmaceutically acceptable cation; or a non-toxic biodegradable precursor thereof; but excluding 1'benzyl-, 1'-(4-chlorobenzyl)- and l'-(3,4-dimethoxybenzyl)-spiro[pyrrolidine-3,3'-indoline]-2,2',5-trione and 1'-benzyl-5'-chloro-spiro[pyrrolidine-3,3'-indoline]-2,2',5-trione.

Claim 11

A compound as claimed in claim 8 wherein Ra is ethyl, propyl, butyl, pentyl, hexyl, heptyl, allyl, 2-methylallyl or 3-butenyl, naphthylmethyl or cinnamyl optionally bearing one or two fluoro, chloro, bromo or iodo nuclear substituents, or Ra is benzyl optionally bearing one or two substituents independently selected from fluoro, chloro, bromo, iodo, methyl, ethyl, methoxy, ethoxy, cyano, nitro and trifluoromethyl located in the 2,3,4 or 5 position; and benzene ring A optionally bears one or two substituents independently selected from fluoro, bromo, iodo, methyl, ethyl, trifluoromethyl and nitro substituents.

Claim 12

A compound as claimed in claim 8 wherein Ra is propyl, butyl, pentyl, hexyl, heptyl, 1-naphthylmethyl, 2-naphthylmethyl, cinnamyl, 4-chlorocinnamyl, 3,4-dichlorocinnamyl, benzyl, 4-methylbenzyl, 4-chlorobenzyl, 4-bromobenzyl, 3-trifluoromethylbenzyl, 4-trtfluoromethyl- benzyl, 2,4-dichlorobenzyl, 4-chloro-2-fluorobenzyl, 4-bromo-2-fluorobenzyl, 2-fluoro-4-iodobenzyl, 3,4-dichlorobenzyl, 3-bromo-4-chlorobenzyl or 4-bromo-3-chlorobenzyl; and benzene ring A is unsubstituted or bears a fluoro, chloro, bromo, methyl or trifluoromethyl substituent located in the 5', 6' or 7' position. ll. A compound as claimed in claim 8 wherein Ra is benzyl as defined in claim 8 but bears at least one halogeno or trifluoromethyl substituent, and benzene ring A optionally bears one or two substituents as defined in claim 8 located in the 5',6' or 7' position; but excluding 1'-(4-chlorobenzyl)-spiro[pyrrolidine-3,3'-indoline]-2,2',5-trione.

Claim 13

A compound of the formula I set out in claim 8 wherein Ra is benzyl bearing two independently selected halogeno substituents located at positions 2 and 4, or 3 and 4, or is benzyl bearing bromo or trifluoromethyl substituents located at position 3 or 4; and benzene ring A is unsubstituted or bears one or two substituents independently selected from halogeno, (l-4C)alkyl, trifluoromethyl and nitro; or a salt thereof with a base affording a pharmaceutically acceptable eation; or a non-toxic biodegradable precursor thereof.

Claim 14

A compound of formula I set out in claim 8 wherein Ra is 3,4-dichlorobenzyl, 2-fluoro-4-iodobenzyl or 4-bromo-2-fluorobenzyl; and benzene ring A is unsubstituted or bears a 5'-fluoro, 5'-chloro, 7'-fluoro or 7'-methyl substituent; or a salt thereof with a base affording a pharmaceutically acceptable cation; or a non-toxic biodegradable precursor thereof.

Claim 15

A non-toxic biodegradable precursor of a compound of formula I as defined in any of claims 1-4 and 8-13 in which the imino hydrogen atom in the pyrrolidine ring is replaced by alkoxycarbonyl, 1-(alkanoyloxy lalkyl, aralkoxycarbonyl or alkoxyoxalyl.

Claim 16

A salt of a compound of formula I as claimed in any of claims 8-13, with a base affording a pharmaceutically acceptable cation, in which the cation is an alkali metal, alkaline earth metal, aluminium, ammonium or triethanolammonium cation.

Claim 17

A process for the manufacture of a compound of formula 1, or a salt or non-toxic biodegradable precursor thereof, as claimed in claim 8 characterised by:- (a) decarboxylating an acid of the formula:- under the influence of heat; (b) deprotecting a compound of the formula:- wherein Rc is a protecting group; (c) alkylating a salt of the formula:- wherein M is an alkali metal cation by reaction with an alkylating agent of the formula Ra.Q wherein Q is a suitable leaving group; (d) for a compound of formula I wherein benzene ring A bears a nitro substituent and/or Ra is benzyl bearing a nitro substituent, nitrating the corresponding compound of formula I wherein benzene ring A is unsubstituted or monosubstituted and/or Ra is unsubstituted benzyl or monosubstituted benzyl; (e) for a compound of formula I wherein benzene ring A bears a chloro or bromo substitutent, chlorinating or brominating the corresponding compound of formula I wherein benzene ring A is unsubstituted or monosubstituted; therein Ra and benzene ring A have the meanings defined in any of claims 8-13; Whereafter, when a non-toxic biodegradable precursor is required, a compound of formula I is reacted with an alkoxycarbonyl, 1-(alkanoyloxy)-alkyl, aralkoxycarbonyl or alkoxyoxalyl halide; when a salt is required, a compound of formula I in free base form is reacted with a base affording a pharmaceutically acceptable cation; and 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 or complexes obtained, and liberation of the optically active form of the compound of formula I by acidification of the appropriate diastereoisomeric salt.

Claim 18

A compound of the formula:- wherein Ra is (2-7C)alkyl or (3-7C)alkenyl, naphthylmethyl or cinnamyl optionally bearing one or two halogeno nuclear substituents, or Ra is benzyl optionally bearing one or two substituents-independently selected from halogeno, (1-4C)alkyl, (l-4C)alkoxy, cyano, nitro and trifluoromethyl, located in the 2, 3, 4 or 5 position; Rb is alkoxycarbonyl, aralkoxycarbonyl, cyano or carbamoyl; and benzene ring A optionally bears one or two-substituents independently selected from halogeno, (1-4C)alkyl, trifluoromethyl and nitro; or a salt thereof; but excluding those compounds wherein Ra is benzyl, 4-chlorobenzyl or 3,4-dimethoxybenzyl, benzene ring A is unsubstituted and Rb is methoxycarbonyl or ethoxycarbonyl, and excluding l'-benzyl-5'-chloro-4- ethoxycarbonyl-spiro[pyrrolidine-3,3'-indolinel-2,2',5- trione.

Claim 19

A compound of the formula:- wherein Ra is (2-7C)alkyl or (3-7C)alkenyl, naphthylmethyl or cinnamyl optionally bearing one or two halogeno nuclear substituents, or Ra is benzyl optionally bearing one or two substituents-independently selected from halogeno, (1-4C)alkyl, (l-4C)alkoxy, cyano, nitro and trifluoromethyl, located in the 2, 3, 4 or 5 position; Rb is alkoxycarbonyl, aralkoxycarbonyl, cyano or carbamoyl; and benzene ring A optionally bears one or two-substituents independently selected from halogeno, (1-4C)alkyl, trifluoromethyl and nitro; or a salt thereof; but excluding those compounds wherein Ra is benzyl, 4-chlorobenzyl or 3,4-dimethoxybenzyl, benzene ring A is unsubstituted and Rb is methoxycarbonyl or ethoxycarbonyl, and excluding l'-benzyl-5'-chloro-4- ethoxycarbonyl-spiro[pyrrolidine-3,3'-indolinel-2,2',5- trione.