GB2098212A - Process for preparing 1'-substituted- spiro imidazolidine-4,3'- indoline-2,2',5-triones - Google Patents

Abstract

The invention provides an analogy process for the manufacture of novel, aldose reductase inhibitory 1'-substituted-spiro[imidazolidine- 4,3'-indoline]-2,2',5-triones of the formula:- <IMAGE> in which Ra is alkyl, phenyl, naphthylmethyl or cinnamyl the aromatic moiety of which may bear one or two halogeno substituents, or Ra is a benzyl optionally bearing up to 3 substituents, and benzene ring A optionally bears one or two substituents, or a pharmaceutically acceptable salt thereof. The compounds of formula I may be used in the treatment or prophylaxis of certain complications of diabetes and/or galactosemia.

Description

SPECIFICATION Chemical process The invention concerns a chemical process for the manufacture of novel 1 '-substituted-spirn- imidazolidine-4, 3'-indoline]-2, 2', 5-triones, which inhibit the enzyme aldose reductase in vivo and are of use in the treatment or prophylaxis of certain complications of protracted diabetes or galactosemia.

The enzyme aldose reductase is responsible for the catalytic conversion of aldoses, for example glucose and galactose, to the corresponding alditols, for example sorbitol and galactitol respectively. Alditols penetrate cell membranes poorly and, once formed, tend to be removed only by further metabolism. As a consequence alditols tend to accumulate within cells where they are formed, causing a rise in internal osmotic pressure which may in turn be sufficient to destroy or impair the function of the cells themselves. In addition, raised alditol levels may result in abnormal levels of their metabolities which may themselves impair or damage cellular function.

However, the enzyme aldose reductase has a relatively low substrate affinity, that is, it is only effective in the presence of relatively large concentrations of aldose. Such large concentrations of aldose are present in the clinical conditions of diabetes (excessive glucose) and galactosemia (excessive galactose).

As a consquence, inhibitors of the enzyme aldose reductase are useful in the reduction or prevention of the development of those complications of protracted diabetes or galactosemia which may be due in part to the accumulation of sorbitol or galactitol respectively.

Such complications are, for example, macular oedema, cataract, retinopathy or impaired neural conduction.

According to the invention there is provided a process for the manufacture of a 1 '-subti tuted-spiro[imidazolidine-4,3'-indoline]-2,2', 5- trione of the formula:

wherein Ra is a (1-12C) alkyl radical, a phenyl, naphthyl-methyl or cinnamyl radical the aromatic rings of which optionally bear one or two halogeno radicals, or Ra is a benzyl radical optionally bearing one, two or three substituents independently selected from halogeno, trifluoromethyl, (1 -4C)alkyl, (1-4 C)alkoxy, nitro, cyano and hydroxy radicals; and benzene ring A optionally bears one substituent selected from halogeno, (1 -4C)alkyl, (1-4)alkoxy, nitro and hydroxy radicals, or bears two substituents indepently selected from halogeno, (1 -4C)alkyl and nitro radicals; or a pharmaceutically acceptable salt thereof; but not excluding those compounds wherein R1 is a methyl, ethyl, n-propyl or unsubstituted benzyl radical, and benzene ring A is unsubstituted; which is characterised by reacting a compound of the formula:

wherein Rb is an alkoxy, aryloxy, aralkoxy or amino radical: (a) with cyanic acid, a urethane of the formula H2N.CO2Rc wherein Rc is an alkyl or aryl radical, or with urea or nitrourea; followed by cyclisation of the intermediate of the formula:

wherein Rb has the meaning defined above, thereby obtained; or (b) with phosgene, an alkyl or aryl haloformate, or an alkyl or aryl carbonate; followed, when Rb is other than amino, by reaction with ammonia; and then cyclising the intermediate obtained; whereafter, 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, when an optically active form of a compound of formula I is required, either the above process is performed with an optically active form of the starting material of formula 11, or a racemic form of the said compound of formula I is reacted with an optically active form of a suitable organic base, for example brucine, an optically active form of coniine, 2-pipercoline or of an N,N,N-trialkyl (1-phenylethyl)ammonium hydroxide such as N,N,N-trimethyl(1-phe- nylethyl)ammonium hydroxide, followed by conventional separation of the diastereoisomeric mixture of salts or complexes thus obtained, for example by fractional crystallisation from a suitable solvent such as a (1 -4C)alka- nol or acetonitrile, and then liberation of the optically active form of said compound by a conventional acidification procedure, for ex ample using an aqueous mineral acid such as dilute hydrochloric acid.

The compounds of the formula I are derivatives of spiro[imidazolidine-4,3'-indoline] which is numbered as follows:

This- numbering system will be used throughout the specification. In addition, the symbols Ra, and Rb are used to depict generic radicals in this specification and have no other significance.

The compounds of formula I possess at least one asymmetric carbon atom, namely the spiro-linked carbon atom. They therefore exist, and may be isolated, in racemic and optically-active forms. This invention concerns a process for the manufacture of the racemic form of a compound of formula I or of an optically active form which possesses aldose reductase inhibitory properties, it being well known in the art how to prepare the optically active forms, for example by synthesis from optically-active starting materials or by resolution of the racemic form, and how to determine the aldose reductase inhibitory properties by the standard tests described herein be low.

A particular value for a Ra when it is a (1-12C) alkyl radical is, for example, a methyl, ethyl, propyl, butyl, pentyl, hexyl, nonyl or decyl radical.

Particular values for substituents which may be present on benzene ring A on an aryl moiety in Ra as defined above are, by way of example oniy: for a halogeno, a fluoro, chloro, bromo or iodo radical; for a (1 -4C)alkyl, a methyl or ethyl radical; and for a (1 -4C)alkoxy radical, a methoxy or ethoxy radical.

Particular values for ring A are when it is unsubstituted or bears 4'-chloro, 5'-fluoro, 5'chloro, 5'-bromo, 5'-methyl, 5'-methoxy, 5'hydroxy, 5'-nitro, 6 '-chloro, 7'-fluoro, 7'chloro, 7'-methyl, 7'-ethyl, 5',6'-difluoro, 5',6'-dichloro, 4',5'-dichloro, 5',6'-dimethyl, 5'-bromo-7'-nitro or 5'-chloro-7'-methyl substituents.

A preferred value for ring A is when it is unsubstituted or bears a halogeno substituent, for example a chloro substituent and especially such a substituent located at position 5', 6' or 7'.

A preferred value for Ra is when it is a benzyl radical bearing one or two halogeno radicals, for example when it is a 4-halogeno, 2,4-dihalogeno-, 3,4-dihalogeno- or 3,5-dihalogeno-benzyl radical, such as a 4-bromo-, 2fluoro-4-bromo, 2-fluoro-4-iodo-, 3,4-dichloro 3-chloro-4-bromo-or 3,5-dichloro-benzyl radical.

Particular groups of compounds obtainable by the invention are comprised by the following compounds of formula I defined hereinbefore wherein: (a) Ra is a (1-12C)alkyl or an unsubstituted benzyl radical; and benzene ring A bears at least one halogeno substituent; (b) Ra is a phenyl, cinnamyl or naphthylmethyl radical the aromatic ring of which optionally bear one or two halogeno radicals; and benzene ring A is unsubstituted or bears at least one halogeno substituent; and (c) Ra is a benzyl radical bearing one, two or three substituents independently selected from halogeno, trifluoromethyl, cyano, hydroxy, nitro, methyl and methoxy radicals; and benzene ring A is unsubstituted or bears one or two substituents as defined herein be fore; and, in each group, together with the pharmaceutically acceptable salts thereof.

One preferred group of compounds comprises those compounds of formula I wherein Ra and benzene ring A have any of the preferred values specifically defined hereinbefore, together with the pharmaceutically acceptable salts thereof.

A further group of preferred compounds comprises those compounds of formula I wherein Ra is a 3,4-dichlorobenzyl, 4-bromo2-fluorobenzyl, 4-bromo-3-chlorobenzyl or 2fluoro-4-iodobenzyl radical and benzene ring A is unsubstituted or bears 5'-fluoro, 5'-chloro, 5'-bromo, 5',6'-difluoro or 5',6'-dichloro substituents; together with the pharmaceutically acceptable salts thereof.

The following compounds of formula I are of special interest: 1 '-(3,4-dichlornbenzyl)-spirnmidazolidine- 4,3'-indoline]-2',2',5-trione, m.p.

269-271 'C., 1 '-(4-bromo-2-flurobenzylo)-spiro[imidazoli- dine-4,3'-indoline2,2',5-trione, m.p.

298-300"C., 1 '-(3,4-dichlorobenzyl)-5'-fluorospiro[imida- zolidine-4,3'-indoline]-2,2t,5-trione, m.p.

240-242"C., 1 '-(4-bromo-3-chlorobenzyl)-spiro[imidazoli- dine-4, 3'-indolinel-2,2', 5-trione, m p.

272-273"C., 5'-chloro- 1 '-(3,4-dichlorobenzyl)-spiro(imi- dazolidine-4,3'-indoline]-2,2',5-trione, m.p.

270-272"C., 1 '-(4-bromo-2-fIuornbenzyl)-5'-chlornspirn imidazolidine-4,3'-indoline]-2,2',5-trione, m.p.

262-264"C., 5'-bromo-1 '-(3,4-dichlorobenzyl-spiro[imida zolidine-4,3'-indoline]-2,2',5-trione, m.p.

208-210"C., 1 '-(4-brnmo-24luorobenzyI)-5'4luornspirn imidazolidine-4, 3'-indolinel-2,2', Strione, m.p.

262-264"C., 1 '-(3,4-dichlorobenzyl)-5',6'-dichlorospiro[- imidazolidine-4,3'-indoline]-2,2',5-trione, m.p.

255-256 C., 1 '-(3-4-dichlorobenzyl)-5', 6'-difiuornspiro imidazolidine-4,3'-indoline]-2,2',5-trione, m.p.

244-245"C. and 1 '-(24luoro-4-iodobenzyl)-spiro[imidazoli- dine-4,3'-indoline]-2,2',5-trione, m.p.

288-289"C.; and may be obtained by the process of the invention.

Particular pharmaceutically acceptable salts of formula I are, for example, alkali metal or alkaline earth metal salts, such a sodium, potassium, calcium or magnesium salts, aluminium or ammonium salts, or salts with organic bases, such as triethanolamine, which form pharmaceutically acceptable cations.

A particular value for Rb when it is an alkoxy radical is, for example, a (1-4C)alkoxy radical such as a methoxy or ethoxy radical; when it is an aryloxy radical is, for example, a phenoxy or chlorophenoxy radical; and when it is an aralkoxy radical is, for example, a benzyloxy radical.

A particular value for Rc when it is an alkyl radical is, for example, a (1 -4C)alkyl radical such as a methyl or ethyl radical; and when it is an aryl radical is, for example, a phenyl or chlorophenyl radical.

A suitable alkyl or aryl haloformate is, for example, a (1-4C)alkyl (such as methyl or ethyl), phenyl or chlorophenyl chloroformate or bromoformate; and a suitable alkyl or aryl carbonate is, for example, a di-(1 -4C)alkyl carbonate (such as dimethyl or diethyl carbonate) or diphenyl carbonate.

It will be appreciated that the process of the invention is analogous to well known hydantoin syntheses which are described in the chemical literature, for example by E Ware in Chemical Reviews, 1950, 46, 403-421. Accordingly, the process may be performed using analogous conditions to those known in the art.

By way of example, the process may be performed at a temperature in the general range 20 to 140do. and a suitable diluent or solvent such as a (1 -4C)alkanol (such as methanol or ethanol), acetic acid, acetonitrile, ethylene glycol or diethylene glycol, optionally together with water may conveniently be used.

The cyclisation steps in the above process may generally be performed at elevated temperatures, for example in the range, for example, 60 to 140"C. and an acid catalyst, for example a hydrogen halide (such as hydrogen chloride or bromide) or sulphuric acid, may conveniently be present. By contrast, the reaction with phosgene or a haloformate and the amination step of alternative (b) may generally be performed at or near ambient temperature, for example in the range 20 to 40"C.

In general the intermediate of formula Ill is not isolated and is cyclised in situ.

It will be appreciated that in the above process, where Ra and/or benzene ring A bears a hydroxy radical and alternative (b) is used, such a hydroxy radical is esterified during the process of the invention. In such cases a further mild hydrolysis step is required using a conventional procedure, for example aqueous ethanolic sodium hydroxide, following the process of the invention in order to regenerate the free hydroxy radical.

The starting materials of formula Il may be obtained by conventional procedures of organic chemistry for example from the appropriate indoline-2,3-dione (isatin) of the formula:

Thus those compounds of formula II wherein Rb is an alkoxy, aralkoxy or aryloxy radical may be obtained by reaction of a compound of formula IV with ammonia, hydrogen cyanide and the appropriate phenol, alkanol or aralkanol at a temperature in the range, for example 20 to 40"C. Alternatively thay may be formed by conventional acid-catalysed ester exchange from the compound of formula IV wherein Rb is a methoxy or ethoxy radical itself made by the above procedure.

Those starting materials of formula II wherein Rb is an amino radical may be obtained by reaction of a compound of formula II with hydrogen cyanide and an excess of ammonia at a temperature in the range, for example 20 to 40"C, or by reaction of the compound of formula II wherein Rb is a methoxy or ethoxy radical with an excess of ammonia.

The starting materials of formula II may be obtained in their separate optically active forms by conventional resolution procedures, for example by reaction with an optically active acid, and may then be used to form the corresponding optically active form of a compound of formula I.

The starting materials of formula IV may be obtained by conventional procedures of indole chemistry. For example, those compounds of formula IV wherein Ra is other than a phenyl radical may be obtained by reacting an indoline-2,3-dione of formula IV wherein Ra is replaced by hydrogen with the appropraite alkyl or aralkyl halide, for example a chloride, bromide or iodide, in the presence of a base such as sodium or potassium hydroxide in dimethyl sulphoxide at a temperature of 20-40'C.

Those starting materials of formula IV wherein Ra is a phenyl radical may be made, for example, by condensation of the appropriate diphenylamine with oxalyl chloride and aluminium chloride, as described in US Patent Serial No. 3,509,149.

The starting mateials of formula II are believed to be novel and in some cases, possess useful biological properties in addition to their utility as chemical intermediates. The invention accordingly provides as a further feature a novel compound of formula II as defined hereinbefore or a salt thereof as appropriate.

The compounds of formula I are inhibitors of the enzyme aldose reductase, as demonstrated by the following standard laboratory test. Thus, rats are made diabetic (as evidenced by severe glucosuria being present) by dosing with streptozotocin. The animals are then dosed daily with the test compound for 5 days. The animals are then killed and the eye lenses and sciatic nerves are removed. After a standard work-up prcedure the residual sorbitol levels in each tissue are determined by gas liquid chromatography after conversion to the poly-trimethylsilyl derivatives. Inhibition of aldose reductase in vivo is then assessed by comparing the residual sorbitol levels in tissues from the dosed diabetic group of rats with those of an undosed group of diabetic rats and an undosed, normal group of rats.

Alternatively, a modified test may be used in which the streptozotocin induced diabetic rats are dosed daily with test compound for two days. After 2-4 hours from the final dose the animals are killed and the sciatic nerves are removed and assessed for residual sorbitol levels as described above.

In general compounds of formula I produce significant inhibition of aldose reductase (as measured by the reduction of residual sorbitol levels in either of these tests) when dosed orally at 100 mg/kg. of much less, without overt toxic or other undesirable effects. Thus, by way of illustration, 1 '-(3,4-dichlorobenzyl) spiro-[imidazolidine-4, 3'-indolinej-2,2', 5- trione and 1 '-(4-bromo-2-fluorobenzyl)-spiro[- imidazolidine-4, 3'-indoline]-2, 2', 5-trione both produce a residual sorbitol level in the sciatic nerve which is approximately 20% of that obtained in control undosed diabetic rats, following oral dosing at 10 mg./kg. for 5 days.

The property of inhibiting the enzyme aldose reductase may also be demonstrated in vitro. Thus, purified aldose reductase is isolated in known manner from bovine lenses.

The percentage inhibition of this enzyme's ability in vitro to reduce aldoses to polyhydric alcohols, and particularly to reduce glucose to sorbitol, caused by a test compound is then determined using standard spectrophotometric methods. In this test the compounds of formula I in general show significant inhibition of the enzyme aldose reductase at a concentration of about 10-6M or much less.

When a compound of formula I is used to produce an effect on the enzyme aldose reductase in warm-blooded animals, it may be administered primarily orally at a daily dose of 0.5 to 25 mg./kg., which is equivalent in man to a total daily dose in the range 10 to 750 mg. per man, given in divided doses if necessary.

The broad outline of the invention will now be illustrated by the following Examples in which, unless otherwise stated: (i) all evaporations were carried out by rotary evaporation in vacuo; (ii) all operations were carried out at room temperature, that is in the range 18-26"C.; (iii) petroleum ether (b.p. 60-80"C) is referred to as "petrol 60-80"; and other petroleum ether fractions accordingly; (iv) all compounds of formula I were fully charcterised on the basis of microanalysis and NMR and IR spectroscopy; and (v) yields (where given) are for illustration and are not necessarily the maximum attainable.

Example 7 3-Amino- 1 -(3,4-dichlorobenzyl)-3-ethoxy- carbonylindoline-2-one (0.1 g.) and potassium cyanate (0.025 g.) were heated together in acetic acid (2.0 ml.) at 95-100C.for 1 hour.

The mixture was poured into water (10 ml.).

The solid which formed was collected and washed with water (2 ml.) to give 1-(3,4 d ichloro-benzyl)-3-ethoxycarbonyl-3-ureidoin- doline-2-one as a solid which was not characterised. This solid was heated under reflux with 20% v/v hydrochloric acid for 2 hours.

The mixture was cooled and the solid which formed was collected by filtration washed with water, air-dried and recrystallised from ethyl acetate/petrol 60-80 (4:1 v/v) to give 1' (3,4-dichlorobenzyl)-spiro[imidazolidine-4,3'- indoline]-2,2',5-trione, m.p. 269-271"C.

Example 2 1 -(3,4-Dichlorobenzyl)indoline-2,3-dione (3.4 g.) was added to a stirred suspension of sodium cyanide (3.0 g.) in ethanol (50 ml.).

Ammonia gas was bubbled through this mixture until no more was absorbed. The mixture was then stirred for 2 days and added to 2M hydrochloric acid (200 ml.). The aqueous mixture was extracted with ether (3 X 200 ml.).

The aqueous phase was basified with concentrated ammonia solution and then extracted with ether (3 x 100 ml.). The combined ether extracts were washed with water (100 ml.), dried (Na2SO4) and evaporated. The solid residue obtained was recrystallised from ethyl acetate/petrol 60-80 (4:1 v/v) to give 3amino-1 -(3,4-dichlorobenzyl)-3-ethoxycarbonylindoline-2-one, m.p. 120-121"C., in 63% yield [based on reacted 1-(3,4-dichlorobenzyl)- indoline-2,3-dione].

Example 3 Potassium cyanide (1.3 g.) was added to a stirred suspension of 1 -(3,4-dichlorobenzyl)in- doline-2,3-dione (5.2 g.) and ammonium chloride (1.07 g.) in a mixture of ethanol (30 ml.) and water (20 ml.). The mixture was stirred for 18 hours, then poured into water (200 ml.) and acidified with concentrated hydrochloric acid to pH2. The mixture obtained was extracted with ether (3 X 100 ml.) and the extracts were discarded. The aqueous phase was basified with concentrated ammonia solution to pH 11 and then extracted with ether (2 X 100 ml.). These extracts were combined, washed with water (50 ml.), dried (Na2SO4) and evaporated. The residue was recrystallised from ethyl acetate/petrol 60-80 (4: 1 v/v) to give 3-amino-3-carbamoyl-1 -(3,4dichlorobenzyl)indoline-2-one m.p.

201 -203'C.

Example 4 An ethanol solution of potassium hydroxide (100 m. of a 1 M solution) was added to a stirred solution of indoline-2,3-dione (isatin) (14.7 g.) in dimethyl sulphoxide (200 ml.).

After 10 minutes a solution of 3,4-dichlorbenzyl chloride (21.5 g.) in dimethyl sulphoxide (10 ml.) was added. The mixture was stirred for 72 hours, and then poured into water (600 ml.) The solid which formed was collected, washed with water, air-dried and recrystallised from ethyl acetate/petrol 60-80 (3:2 v/v). There was thus obtained 1-(3,4dichlorobenzyl)-indoline-2,3-dione (13.8 g.), m.p. 183-184"C.

Example 5 ( + )-1 '-(3,4-Dichlorobenzyl)-spiro[imidazoli- dine-4, 3'-indoline]-2,2', 5-trione (4.4 g.) was added to 61.5 ml of a 0.19M solution of (- )-N,N, N-trimethyl(1 -phenylethyl)ammonium hydroxide. The mixture was warmed to facilitate solution and then evaporated. The residue was disssolved in warm propan-2-ol (11 ml.).

The solution obtained was cooled to 0 C. for 48 hours. The crystalline solid which formed was collected by filtration, washed with cold propan-2-ol (5 ml.), then with petrol 40-60 (20 ml.) and recrystallised twice from propan2-ol to give the (+ )-diasteroisomeric salt or (- )-N,N, N-trimethyl-( 1 -phenylethyl)am mon- ium hydroxide and ( + )-1 '-(3,4-dichlorobenzyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5- trione (1.6 g.), m.p. 148-150"C., [a]23+ 32.8" (c, 1.4; MeOH).

The salt (1.6 g.) was dissolved in water (10 ml.) and methanol (3 ml.) and the solution acidified with concentrated hydrochloric acid (1 ml.). The precipitated solid was collected, washed with water and recrystallised from ethanol to give ( + )-1 '-(3,4-dichlorobenzyl) spiro[imidazolidine-4, 3'-indoline]-2,2',5- trione, m.p. 1 99-200'C., [a23+ 410 (c, 1.6, MeOH).

The starting quaternary ammonium hydroxide solution was obtained by passing an aque ous solution of (-)-N,N,N,-tri (- )-N,N,N,-trimethyl(1-phe- nylethyl)ammonium iodide (27.8 g.) (I.

Angres and H.E. Zieger, J. Org. Chem. 1975, 40, 1457-1460) down a column of anion exchanging resin ('Amberlite' IRA 401, 200 g.) newly converted into the hydroxide form.

('Amberlite' is a trademark).

Claims (11)

1. A process for the manufacture of a 1 ' substituted-spiro-[imidazolidine-4, 3'-indoline]- 2,2',5-trione of the formula:

wherein Ra 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 Ra 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, (1-4C)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' is a methyl, ethyl, n-propyl or unsubstituted benzyl radical, and benzene ring A is unsubstituted; which is characterised by reacting a compound of the formula:

wherein Rb is an alkoxy, aryloxy, arlkoxy or amino radical: (a) with cyanic acid, a urethane of the formula H2H.CO2Rc wherein Rc is an alkyl or aryl radical, or with urea or nitrourea; followed by cyclisation of the intermediate of the formula:

wherein Rb has the meaning defined above, thereby obtained; or (b) with phosgene, an alkyl or aryl haloformate, or a alkyl or aryl carbonate; followed, when Rb is other than amino, by reaction with ammonia; and then cyclising the intermediate obtained; whereafter, when a pharmaceutically acdeptable salt is required, a compound of formula I is reacted with an appropriate base affording a pharmaceutically acceptable cation, using a conventional procedure; and, when an optically active form of a compound of formula I is required, either the above process is performed with an optically active form of the starting material of formula II, or a racemic form of the said compound of formula I is reacted with an optically active form of a suitable organic base, followed by conventional separation of the diastereoismeric mixtute of salts of complexes thus obtained, and then liberation of the optically active form of said compound by a convention acidification procedure.

2. A process according to claim 1 characterised in that Rb is a (1 -4C)alkoxy, phenoxy, chlorophenoxy, benzyloxy or amino radical.

3. A process according to part (a) of claim 1 characterised in that Rb has the meanings defined in claim 1 or 2 and Rc is a (1-4C)alkyl, phenyl or chlorophenyl radical.

4. A process according to part (b) of claim 1 characterised in that phosgene, a (1-4C)alkyl, phenyl or chlorophenyl chloroformate or bromoformate, di-(1 -4C)alkyl coarbonate or diphenyl carbonate is used.

5. A process according to any of claims 1-4 characterised by carrying it out in a suitable diluent or solvent.

6. A process according to claim 5 characterised in that the solvent is selected from a (1 -4C)alkanol, acetic acid, acentronitrile, ethylene glycol and diethylene glycol, optionally together with water.

7. A process according to any preceding claim characterised by carrying it out at a temperature of 20 to 140'C.

8. A process according to claim 7 characterised in that the cyclisation step is carried out at a temperature of 60 to 140"C.

9. A process according to claim 8 characterised in that the cyclisation step is carried out in the presence of an acid catalyst.

1 0. A process according to any preceding claim characterised in that in the starting materials Ra is a benzyl radical bearing one or two haiogeno radicals and benzene ring A is unsubstituted or bears a halogeno substituent located at position 5', 6' or 7'.

11. A process according to any of claims 1-9 characterised in that in the starting materials Ra is a 3,4-dichlorobenzyl, 4-bromo-2fluorobenzyl, 4-bromo-3-chlorobenzyl or 2fluoro-4-iodobenzyl radical, and benzene ring A is unsubstituted or bears 5'-fluoro, 5'chloro, 5'-bromo, 5',6'-difluoro or 5',6'-dichloro substituents.

1 2. A compound of formula I or a salt thereof as defined in claim 1 whenever prepared by a process according to any of claims 1-11.