GB2183234A

GB2183234A - Pharmaceutically active sulphonamidoalkyl substituted phenoxyalkylcarboxylic acids and esters

Info

Publication number: GB2183234A
Application number: GB08627512A
Authority: GB
Inventors: Peter Hallett
Original assignee: Glaxo Group Ltd
Current assignee: Glaxo Group Ltd
Priority date: 1985-11-19
Filing date: 1986-11-18
Publication date: 1987-06-03
Also published as: EP0223593B1; GB2183234B; AU6550586A; GB8627512D0; EP0223593A2; NO864599D0; AU593039B2; JPS62155250A; NO864599L; EP0223593A3; DK550186D0; PT83762A; PT83762B; DK550186A; FI864692A; FI864692A0; GB8528398D0; PH23837A; KR870004950A; IL80701A0

Abstract

Novel compounds of the general formula (1> <IMAGE> wherein R<1> is a hydrogen atom or a C1-4 alkyl group; R<2> is a naphthyl, thienyl or beta -styryl group or a group Ar(CH2)p- where p is zero or an integer from 1 to 3 and Ar is phenyl or phenyl substituted by one or more halogen atoms of C1-4 alkyl, C1-4 alkoxy, hydroxyl, trifluoromethyl, nitro or amino groups; m is an integer 1 or 2; n is an integer from 1 to 4; and the physiologically acceptable salts thereof inhibit blood platelet aggregation, bronchoconstriction and vasoconstriction and thus of interest in the treatment of occlusive vascular diseases and asthma and are useful in renal dialysis and organ transplantation.

Description

1 GB2183234A 1

SPECIFICATION

Phenoxyalkylcarboxylic acids and esters and their preparation and pharmaceutical formulation This invention relates to phenoxyalkylcarboxylic acid and ester compounds, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine.

The compounds of the invention have good thromboxane A2 as well as prostaglandin G2 and H, antagonist activity and in particular inhibit blood platelet aggregation, bronchoconstriction and vasoconstriction. The new compounds are thus of special interest in the treatment of asthma 10 and occlusive vascular diseases.

Thus the present invention provides compounds of the general formula (1) R2SE) NKCH 2 2)n-\ - \O(CH2).COCRI wherein R' is a hydrogen atom or a C,-, alkyl group; R2 is a naphthyl, thienyl or P-styryl group or a group Ar(CH,'),- where p is zero or an integer from 1 to 3 and Ar is phenyl or phenyl substituted by one or more halogen atoms or C,-, alkyl, C,-, alkoxy, hydroxyl, trifluoromethyl, nitro or amino groups; m is an integer 1 or 2; n is an integer from 1 to 4; and the physiologically acceptable salts thereof.

Suitable physiologically acceptable salts of the compounds of general formula (1) include salts formed with bases when R' is a hydrogen atom. Examples of such salts are alkali metal (e.g. sodium or potassium), alkaline earth metal (e.g. calcium or magnesium), ammonium and substituted ammonium (e.g. triethylammonium and piperidine). When R2 is phenyl substituted by amino, salts may also be formed with inorganic or organic acids, e.g. hydrochlorides.

In general formula (1) the group R' may be for example a methyl or ethyl group. R' is preferably however a hydrogen atom or a methyl group, particularly a hydrogen atom.

The chain (CH2),- in compounds of formula (1) may be -CH2, (CH2)2-, (CH2)3, or -(CH2),1-. in general, compounds of formula (1) in which (CH2),- is -(CH2), or -(CH2)3- are preferred. In a particular general preference -(CH2),- is -(CH2)3-.

In general compounds of formula (1) in which the chain (CH2).- 'S -CH2are preferred.

When R2 in compounds of formula (1) represents a group Ar(CHA', p may represent an integer 1, 2 or 3, but is preferably zero. The group Ar may be for example phenyl or phenyl substitued by one, two or three substituents, particularly one substituent. It will be appreciated that when Ar is a substituted phenyl group the substituent(s) may be present in positions ortho, meta or 40 para to the position linking the group to the rest of the molecule. In general, however, when just one substituent is present this is preferably in the para position.

Examples of the substituents which may be present on phenyl groups represented by Ar include fluorine, chlorine, bromine or iodine atoms or methyl, ethyl, methoxy, ethoxy, hydroxyl, trifluoromethyl, nitro or amino groups.

Particular examples of substituted phenyl groups represented by Ar include phenyl substituted by a bromine, chlorine or iodine atom, or a methyl, methoxy, hydroxyl, trifluoromethyl, nitro or amino group. In another example, Ar may be 2, 4, 6-trimethylphenyl.

When R2 in the compounds of formula (1) is a naphthyl group it may be 1or 2-naphthyl.

In one general preference the group R2 in compounds of formula (1) is a phenyl group. 50 According to a further general preference, the group R2 in compounds of formula (1) is a 2 naphthyl group.

Particularly useful compounds according to the invention are:

[3-[3-[(phenyisulphonyl)aminolpropyl]phenoxylacetic acid; [3-[3-[(2-naphthalenyisulphonyi)amino]propyllphenoxyjacetic acid; and their physiologically acceptable salts.

Compounds of formula (1) inhibit blood platelet aggregation, bronchoconstriction and vasoconstriction. A test to determine inhibition of blood platelet aggregation is as described by Lumley and Humphrey (J. Pharmacol. Methods, 1981, 6, 153-166) using Collagen as the pro-aggregatory agent.

The ability of the compounds of the invention to inhibit vasoconstriction or bronchoconstriction is determined using the relevant isolated tissue (e.g. spirally cut rat aortic strip or guinea-pig lung parenchymal strip) by measuring the effect of the compound to be tested on the contraction of the tissue to [1R-[1a,4a,5,6(Z),6a(1E,3S)11-7-[6-(3-hydroxy-l-octenyl)2-axabicycio[2,2,1]hept5- yt]-5-heptenoic acid (U-46619).

1 2 GB2183234A 2 The compounds are thus of interest in the treatment of asthma, and in the treatment and prophylaxis of occlusive vascular disease, including myocardial infarction, cardiac fatalities, an gina, transient ischaemic attacks and cerebral infraction, atherosclerosis and vessel wall disease, peripheral vascular disease, diabetic nephropathy and retinopathy, postoperative thrombosis and pulmonary embolism, and for use in renal dialysis. In addition, the compounds of the invention 5 are considered to be useful in the prophylaxis of peri- and postoperative complications following organ transplantation (partic ularly cardiac and renal), coronary artery bypass, angioplasty, throm bolysis and endarterectomy._ The compounds are also of potential use in the treatment of adult respiratory distress syn drome and the prevention of relapse of healed peptic ulcers.

The compounds may be formulated in a conventional manner for use with one or more pharmaceutical carriers.

For oral administration, the pharmaceutical composition may take the form of, for example, tablets, capsules, powders, solutions, syrups or suspensions prepared by conventional means with acceptable excipients.

The compounds may be formulated for parenteral administration by continuous infusion. For mulations for injections may be presented in unit dosage form in ampoules, or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oil or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in 20 powder form for reconstitution before use with a suitable vehicle e.g. sterile pyrogen-free water.

For administration by inhalation the compounds are conveniently delivered in the form of an aerosol spray presentation from pressurised packs or a nebuliser, or as a cartridge from which the powdered composition may be inhaled with the aid of a suitable device. In the case of a pressurised aerosol the dosage unit may be determined by providing a valve to deliver a metered amount.

For use as antithrombotic agents, the compounds are preferably administered orally, for example in amounts of 0.05 to 1Orrig/kg body weight, 1 to 4 times daily, or intravenously, for example in amounts of 0.01 to 25 mg/kg body weight, 1 to 4 times daily.

For use in the treatment of asthma, the compounds may also be administered orally in amounts of 0.05 to 1Orrig/kg body weight, 1 to 4 times daily; preferably however they are administered by inhafation at doses varying from 0.02 to 30rrig, preferably 0.02 to 3.Omg, 1 to 4 times daily. The compounds may used in combination with other antiasthmatic agents.

The precise dose administered will of course depend on the age and condition of the patient.

Suitable methods for preparing compounds of formula (1) are described below, the groups W, 35 112, -(CH,),,- and -(CH2),,- being as defined above except where otherwise indicated. It will be appreciated that the following reactions might require the use of, or conveniently might be applied to, starting materials having protected functional groups, and deprotection might thus be required as a final step to yield a compound of the invention. Protection and deprotection of functional groups may be effected using conventional techniques. Thus, for example, amino groups may be protected by acylation, subsequent deacylation being effected when desired by hydrolysis using for example an acid such as hydrochloric acid. (a) Compounds of formula (1) may be prepared by alkylation of a phenol of formula (2) 17.._ % R S02NH(CH2)n-0,, 1.

\ ON (2) using an alkylating agent L(C1-12),C0OR1 [where L is a leaving group, for example a halogen atom 50 such as chlorine, bromine or iodine, or a hydrocarbyisulphonyloxy group such as methanesulpho nyloxy or p-toluenesulphonyloxyl and followed where necessary by hydrolysis as described in section (c) below.

The alkylation is preferably effected in the presence of a base, for example an inorganic base such as potassium carbonate in a solvent such as an alcohol e.g. ethanol or an aqueous alcohol, e.g. aqueous ethanol, or sodium hydride in a solvent such as dimethylformamide. The reaction may be performed at a temperature up to and including reflux.

The alkylation is particularly suitable for the preparation of compounds of formula (1) wherein m is 1 and R2 is other than phenyl substituted by a hydroxyl group.

The alkylating agents L(CH2) COOR' used in this process are either known compounds or may 60 be prepared by methods analogous to those used for the preparation of the known compounds.

(b) In another process, compounds of formula (1) in which R' is C,-, alkyl may be prepared by sulphonylation of an amine of formula (3) 3 GB2183234A 3 H2WCH2)n-O\ (3) O(CH2) (wherein R, is C,, alkyl) with a reactive derivative of a sulphonic acid R2SO3H such as a sulphonyl halide for example a chloride R2SO2Ci.

The sulphonylation is preferably effected in the presence of a suitable acid scavenger, for example an organic base such as triethylamine or pyridine, either neat or in an appropriate solvent such as acetonitrile. (c) Compounds of formula (1) in which R' is -H may be prepared by hydrolysis of a corre- sponding ester (e.g. in which R' is a C,-, alkyl).

The hydrolysis can in general be effected by conventional methods, under acidic or basic conditions, as appropriate, in a polar solvent such as water, or an alcohol e.g. methanol or ethanol, or ketone e.g. acetone, at any suitable temperature up to and including reflux. Suitable bases include inorganic bases (e.g. alkali metal hydroxides such as sodium hydroxide or potassium hydroxide). Alternatively the ester may be cleaved using an acid such as an inorganic acid e.g. hydrochloric acid.

(d) Compounds of formula (1) in which R' is C,, alkyl may be prepared by esterification of the 20 corresponding carboxylic acid (in which R' is H).

Conventional esterification techniques may be used, for example by reaction with an appropriate alcohol in the presence of a mineral acid such as hydrochloric acid or sulphuric acid. (e) In a further process, compounds of formula (1) in which -(CH2)n- is -(CH2)._ or (CH,)4- and R2 is other than thienyl, phenyl substituted by nitro, or fl-styryl may be prepared by reduction of a compound of formula (4) % R250 NH(CH v- 2 2)q \ 1 30:-- \0 (CH 2)-COOR 1 (4) 30 (wherein q is an integer 1 or 2, Y is -CH=CH or -Ca.--C- and R2 is as just defined) using for example hydrogen in the presence of a metal catalyst e.g. palladium on a support such as carbon in a suitable solvent such as an ester, e.g. ethyl acetate. 35 The intermediates of formula (4) are novel compounds and form a further aspect of the invention.

(f) Compounds of formula (1) in which R2 is phenyl substituted by a hydroxyl group may be prepared by demethylation of a corresponding compound of formula (1) in which R2 is phenyl substituted by a methoxy group. The reaction may be performed using for example boron 40 tribromide in a solvent such as dichforomethane at a temperature of O'C to ambient.

(9) Where salts of compounds of the invention are desired, such salts may be formed by conventional methods. For example salts of bases may be prepared by treatment of a compound of the invention with a base in a suitable solvent, e.g. ether or an alcohol such as ethanol. Salts of acids may be prepared by adding the acid (e.g. hydrogen chloride) to a solution of the 45 compound of formula (1) in an organic solvent such as ether.

Salts may also be formed by conversion of one salt of a compound of the invention into another, e.g. by ion exchange using conventional methods.

The intermediate compounds of formula (2) may be prepared by demethylation of compounds of formula (5) 50 / -\X R2502M(CH2)n-X 1 0 (5) X OCH 3 55 using for example boron tribromide as described in process M above.

The intermediates of formula (5) may be prepared by sulphonylation of amines of formula (6) 11 - \\ H2N(CH2)rro \ 1 0 (6) CH 3 using an appropriate sulphony chloride R2So,CJ in the presence of an organic base such as 65 i 4 GB2183234A 4 triethylamine and an inert solvent such as acetonitrile.

The amines of formula (6) are either known compounds (see for example D.S. Kashdan et al, J. Org. Chem. 1982, 47, 2638) or may be prepared by methods analogous to those used for the preparation of the known compounds.

The intermediate amines of formula (3) may be prepared from the amines of formula (6) by the 5 following sequence of reactions:

(6);o ZNH(CH2)1-0 11 0 (3) X 1 (7) = \ 10 OH (wherein Z is a protecting group, for example an acetyl or benzoyl group).

Protection of an amine (6), for example by reaction with acetyl or benzoyl chloride, followed by demethylation (using e.g. boron tribromide as described above or a nucleophile such as -SC2HJ yields a phenol of formula (7). Alkylation of a phenol (7) with an alkylating agent L(C1-1J, C0OR1 as described in process (a) above yields a compound of formula (3) in which the amino function is protected. Subsequent deprotection, in accordance with conventional practice, followed, if necessary, by esterification to reform the carboxylic ester group yields a common of 20 formula (3).

Intermediate acids of formula (4) where R' is a hydrogen atom may be prepared by hydrolysis of the corresponding ester of formula (4), where R' is C,-, alky], using the techniques described in process (c) above.

Intermediate esters of formula (4) may be prepared by sulphonylation of an amine of formula (8) H2 N(CH2)qY-,, \ 0 (CH 2),Co OR 30 (wherein R' is a C,, alkyl group) having the procedures described in process (b) above.

The amines of formula (8) may be prepared by reaction of a phenyl halide of formula (9) 35 Hal- D(CH2),CDGR' (wherein Hal is a halogen atom such as a bromine or iodine atom) with a protected amine 40 W(CH2),YH (where W is a protected amino group such as phthalimido group) followed where necessary by removal of any protecting group. The reaction is performed in the presence of a metal catalyst (e.g. palladium acetate), a phosphine such as tri(o- tolyi)phosphine or a complex of a metal catalyst and phosphine such as bis(triphenylphosphino)pailadium 11 chloride, and a base such as an organic amine e.g. triethylamine. In reactions of this type in which Y is -C-=C-, it is 45 preferable to additionally include a copper halide, e.g. copper iodide.

Where desired, intermediate ester of formula (4) may be prepared directly using a halide of formula (9), and a sulphonamide R2S02NH(CH.)qYH. Thus, for example, an intermediate ester of formula (4) in which R2 is phenyl may be conveniently prepared using a halide of formula (9) and sulphonamide R2SOM(CH2)qYH (where R2 is phenyl) using the reaction conditions just described. 50 Halides of formula (9) may be prepared by alkylation of the corresponding known phenols using for example a method described in process (a) above.

The protected amines W(CH2),YH and the sulphonamides R2S02NH(CH2)qY1-1 are either known compounds or may be prepared by methods analogous to those used for the preparation of the known compounds.

The following compounds illustrate the invention.

Temperatures are in 'C. ---Dried-refers to drying with M9SO, Chromatography and thin layer chromatography (t.l.c.) refer to the use of silica gel.---Hyflo- is a filtration aid.

The following abbreviations are used ER-ether, EA-ethyl acetate, PE-petroleum ether (b.p. 40-60% DMF-dimethyiformamide, THF-tetrahydrofuran, NaH-sodium hydride dispersed in oil, Et,N-triethyla mine.

Intermediate 1 6 55 GB2183234A 5 N-[2-(3-Hydroxyphenyi)ethyllbenzamide A solution of N-[2-(3-methoxyphenyi)ethyi]benzamide (19) in dry DIVIF (20mi) was added dropwise to a stirred suspension of 60% NaH (48Orng) in DIVIF (20mi) containing ethanethiol (0.9mi) under nitrogen and the mixture was heated at 120 for 5h. The cooled mixture was diluted with water, adjusted to pH2 using 2N HCI and extracted with EA. The combined extracts were washed with water, dried and evaporated and the residue was crystallised from ethanolER-cyclohexane to give the title compound (0.69g). A recrystallised portion had m.p. 123.5-1250.

Intermediate 2 [3-[2-[(Benzoyl)aminolethyllphenoxylacetic acid A mixture of Intermediate 1 (23Orng), ethylbromoacetate (0.12mi) and K2CO, (238mg) in 19:1 ethanol-water (4mi) was heated at reflux under nitrogen for 20h. After following the mixture to cool, water was added and the pH of the solution was adjusted to 2 with 2N HCL The solution was extracted with ER and the combined extracts were extracted with 8% Nal-IC03. The combined Nal-IC03 extracts were adjusted to pH2 with 2N HO and extracted with ER. The combined extracts were dried and evaporated to give a solid which was purified by crystallisation from ethanol-ER-cyclohexane to give the title compound (18Orng) m.p. 141.5-142 Intermediate 3 [3-(2-Aminoethyl)phenoxylacetic acid, hydrochloride Intermediate 2 (3.959) was suspended in 6N HCI (125mi) and heated at 110' with stirring for 17h. The solution was cooled and extracted with EA (2 x 75mi). The aqueous layer was evaporated to dryness in vacuo to afford the title compound as a colourless solid (2.979) m.p. 212-2180.

Intermediate 4 Methyl [3-(2-Aminoethyl)phenoxylacetate, hydrochloride Acetyl chloride (5mi) was added dropwise to stirred methanol (50mi) under nitrogen. After the mixture had cooled to ambient temperature, Intermediate 3 (1.0499) was added and stirring 30 continued for 6h. Evaporation of the solvent in vacuo gave a solid which was triturated with ER to give the title compound as a powder (1.052g).

A portion was crystallised from EA-methanol m.p. 117-122'.

Intermediate 5 (5a) Methyl 3-lodophenoxyacetate A vigorously stirred mixture of 3-iodophenol (14.79), K2C03 (12.929) and methylbromoacetate (7.6mi) in DIVIF (100mi) was kept at 20 for 2h. The mixture was diluted with EA (250mi) and washed with water (3 x 1 00mi), 2N HCI (1 00mi) dried and evaporated. The residue was triturated with PE to give the title compound (16.259) m.p. 50-52'.

The following compound was prepared in a similar manner:(5b) Methyl 3Bromophenoxyacetate, m.p. 39-42' from3-bromophenol.

Purification by distillation b.p. 130'/0.3torr. (air bath temperature).

Intermediate 6 Methyl 2-(3-lodophenoxy)propionate A stirred mixture of 3-iodophenol (4.259), methyl acrylate (10mi) and benzyitriethylammonium hydroxide (0.5mi; 40% solution in methanol) was heated under reflux for 40h. Fresh benzyitri ethylammonium hydroxide (0.5mi) was added and heated continued for a further 24h. The excess of methyl acrylate was removed in vacuo and the residue in CH2C12 (50mi) was washed 50 with water (2 x 20mi), dried and evaporated. The residue was purified by chromatography on silica deactivated with Et3N eluting with 1:1 PE-ER to give the title compound as an oil (2.729).

I.r. (CHBr3) 1730cm-1.

Intermediate 7 N-(2-Propynyl)benzenesulphonamide Benzenesulphonyl chloride (5.6mi) in CHC13 (10M1) was added to a cooled (5"), stirred slurry of propargylamine hydrochloride (2.676g) in pyridine (20mi) under nitrogen. The resulting solution was stirred at ambient temperature for 18h then diluted with EA (150mi), washed with 2N HCI (2 x 75mi) and 8% NaHCO, (75m]), dried and evaporated. The title compound was obtained as an oil which slowly solidified on storage (5.196g) m.p. 52-57'.

Intermediate 8 (8a) (E)-Methyl[3-[3-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)-1propenyllphenoxyl acetate A solution of 1,3-Dihydro-1,3-dioxo-2-(2-propenyi)-2H-isoindole (7.6g) Intermediate 5a 1 1 i i 1 1 i 1 i 1 r i 6 GB2183234A 6 (11.879), palladium acetate (84mg) and tri(o-toiyi)phosphine (244mg) in CH,CN (1 8mi) and Et.,N (1 8mi) was heated under reflux for 2h. The cooled mixture in CHC13 (300mi) was washed with 2N H0 (2)< 150mi), 8% Nal- IC03 (150mf) and brine (100mi). The organic layer was dried and evaporated and the residue was triturated with ER-PE to give the title compound (12.1 g) m.p. 5 127-1300.

The following compounds were prepared in a similar manner:- Methyl [3-[3-[(Phenyisulphonyl)aminol-1-propyny henoxylacetate, (8b) m.p. 56-600, from Intermediates 5b and 7. Purification by chromatography using 3:1 ER-PE as eluant followed by chromatography on silica deactivated with Et3N eluting with 3:1 ER-PE. 10 (8c) (E)-Methyl 2-[3-[3-[(Phenyisulphonyi)amino]-1- propenyl]phenoxy]propionate, from Intermediate 6 and N-(2- propenyl)benzenesulphonamide. Purification by chromatography using 4:1 ER- PE as eluant. 15 I.r. (film) 3280, 1735, 1328, 1160, 970cm-1.

(8d) (E)-Methyl [3-[4-[(Phenyisulphonyl)aminoj- 1-butenyllphenoxylacetate, from Intermediate 5a and N-(3-butenyi)benzenesulphonamide. Purification by chromatography using 3:2 ERPE as eluant. 20 I.r. (film) 3280, 1750, 1325, 1160, 970cm1.

Intermediate 9 (E)-Methyl [3-(3-Amino- 1-propenyl)phenoxylacetate, hydrochloride Hydrazine hydrate (2.29) was added to a hot (60') stirred suspension of Intermediate 8a (1 1.76g) in methanol (500mi). The mixture was allowed to cool to ambient temperature over 19h then acidified with concentrated HCI and evaporated to dryness. The residue was stirred with water (500mi), filtered and the filtrate was evaporated to dryness. The residue in methanol (100mi) containing acetyl chloride (4m]) was kept at ambient temperature for 24h. The mixture was filtered and evaporated in vacuo to give the title compound (4.69). A portion crystallised from isopropanol had m.p. 145-155.

Intermediate 10 (10a) N-[2-(3-Methoxyphenyl)ethyllbenzenesulphonamide A solution of benzenesulphonyl chloride (12.76mi) in dry CH3Cl\1 (10mi) was added to a solution of 3-methoxy(2-phenethylamine) (15.129) and Et,N (14.04mi) in dry CH3Cl\1 (90mi) at 35 20'. After stirring the resulting suspension for 4h, some of the CH3CH (- 50mi) was removed by evaporation. ER (400mi) was added and the mixture washed successively with 2N HCI (2x50mi) and brine (2x50m1). The ethereal solution was dried and evaporated to give an oil which was purified by chromatography eluting with 1:1 PE-ER to provide the title compound as an oil (25.88g).

Analysis Found: C, 61.9; H, 5.9; N, 4.8.

C,r,H17NO,S requires C, 61.8; H, 5.9; N, 4.8%.

The following compounds were prepared in a similar manner:- so (10b) Methyl [3-[2-[[[4(Acetylamino)phenyllsulphonyllaminolethyllphenoxylacetate, m.p. 117-127' from Intermediate 4 and 4-(Acetylamino)benzenesulphonyl chloride in pyridine. Purification by chromatography using EA as eluant.

(10c) N-[(3-Methoxyphenyl)methyllbenzenesulphonamide, m.p. 76.5-78' from 3-methoxybenzylamine and benzenesulphonyl chloride. Purification by chromatography using 1:1 PE-ER followed by ER as eluant and then by crystallisation from EA-PE.

(10d) N-[(3-Methoxyphenyl)methyll-4-(trifluoromethyl)benzenesulphonamide, m.p. 89-91', from 55 3-methoxybenzyiamine and 4-(trifluoromethyi)benzenesulphonyI chloride.

(10e) (E)-Methyl[3-[3-[[[4-(Trifluoromethyl)phenyllsulphonyllaminol-1propenyilphe noxylacetate, m.p. 90-92' from Intermediate 9 and 4-(trifluoromethyi)benzenesulphonyI chloride. Purification by chromatography using 2:1 ERPE as eluant.

(1 Of) (E)-Methyl [3-[3-[[(1-Naphthalenyl)sulphonyllaminol- 1propenyllphenoxylacetate, from Intermediate 9 and l-napthalenesulphonyl chloride. Purification by chromatography using 2:1 ER-PE as eluant. T.I.c. 2:1 ER-PE Rf 0.3.

7 GB2183234A 7 (109) (E)-Methyl[3-[3-[[(2-Naphthalenyl)sulphonyllaminol-1propenyllphenoxylacetat e, m.p. 78.5-79.5', from Intermediate 9 and 2naphthalenesulphonyl chloride. Purification by chromatography using 2:1 ER-PE as eluant.

(1 Oh) (E)-Methyl [3-[3-[[(4-Clorophenyl)sulphonyllaminol- 1propenyllphenoxylacetate, from Inter- 5 mediate 9 and4-chlorobenzenesulphonyl chloride. Purification by chromatography using 3:2 ER-PE as eluant. T.I.c. ER Rf 0.42.

Intermediate 11 (1 l a) N-[2-(3-Hydroxyphenyl)ethyllbenzenesulphonamide A solution of BBr. (25g) in dry CH2C12 (80mi) was added dropwise to a cold (5) solution of Intermediate 10a (14.45g) in dry CH2C12 (200mi). The cooling bath was removed and the solution stirred for 2h. Methanol (200mi) was added cautiously and after a further 1h the solvents were evaporated and the residue was purified by chromatography eluting with ER to give the title compound as an oil (14.019).

Analysis Found: Cl^.N03S requires C, 60.3; H, 5.4; N, 5.0.

C, 60.6; H, 5.45; N, 5.05%.

The following compounds were prepared in a similar manner:- (11 b) N-[(3-Hydroxyphenyl)methyllbenzenesulphonamide, m.p. 107-110 from Intermediate 1 Oc. Purification by chromatography using 1:1 PE-ER followed by ER as eluants.

i C i i (11 c) N-[(3-Hydroxyphenyl)methyll-4-(trifluoromethyl)benzenesulphonamide, m.p. 132-134, from 25 Intermediate 10d. Purification by chromatography using ER as eluant.

Intermediate 12 (12a) (E)-[3-[3-[[(1-Naphthatenyl)sulphonyllaminol-1propenyllphenoxyllacetic acid A solution of Intermediate 10f (0.7g) in methanol (1 1.5mi), THF (5mi) and 5N NaOH (1 1.5mi) 30 was kept at ambient temperature for 3h. The mixture was diluted with water (150mi) and extracted with ER (150mi). The aqueous layer was diluted with 2N HCI (100mi) and extracted with CH.Cl, (2x50mi). The combined extracts were dried and evaporated to give the title compound (0.379) m.p. 101.5-102.5'.

The following compounds were prepared in a similar manner:

(12b) (E)-[3-[3-[[(2-Naphthalenyl)sulphonyllaminol-1-propenyllphenoxy acetic acid, m.p. 121-122', from Intermediate 109.

(12c) (E)-2-[3-[3-[(Phenyisulphonyl)aminol- 1-propenyllphenoxylpropionic acid, m.p. 117-12 1 40 from Intermediate 8c using 5N NaOH and ethanol. Purification by chromatography using ER followed by 99:1 ER-AcOH as eluants.

(1 2d) (E)-[3-[4-[(Phenyisulphonyl)aminol- 1-butenyllphenoxylacetic acid, dicyclohexylamine salt, m.p. 1391430, from Intermediate 8d using KOH in methanol-water. A portion of the acid was 45 converted into the dicyclohexylamine salt in ER.

Intermediate 13 (E)-Methyl 13-[3-1(Phenyisulphonyl)aminol1-propenyllphenoxylacetate A solution of N-(2-propenyi)benzenesulphonamide (19.39), Intermediate 5a (28.0g), palladium acetate (217mg), and tri(o-tolyi)phosphine (620rng) in CH,Cl\1 (30mi) and Et3N (30mi) was heated at reflux under nitrogen for 3.5h. The mixture was cooled, filtered through hyflo and evaporated.

The residue was redissolved in CH2C12 (300mi) and washed with 2M HCI (2x75mi), then 8% Nal-IC03 (75mi), dried and evaporated to give an orange gum (36.09), a portion (2.1g) of this gum was purified by chromatography on silica eluting with 9:1 CHP2-ER to give the title 55 compound as a pale yellow solid (95Orng).

Analysis Found: C, 59.7; H, 5.2; N, 3.8.

C181-1119NO5S requires C, 59.8; H, 5.3; N, 3.9%.

Intermediate 14 2-[N-(2-Propynyl)lnaphthalenesulphonamide A solution of 2-naphthalenesulphonyl chloride in CH2C12 (30mi) was added dropwise to a cooled (O'C), stirred solution of propargylamine (3.7mi) in dry pyridine (20mi) under nitrogen. The mixture was stirred for 1 h, then diluted with CH2C12 (70mi) and washed with 2M HCI (2 x 125mi),65 i i i 1 1 i i 1 i 1 h 1 1 8 GB2183234A 8 then 8% NaHCO, (75mi), dried and evaporated to give the title compound as a pale brown solid (10. 1 g).

Analysis Found: 5 C,3H,,N02S requires C, 63.65; H, 4.5; N, 5.4. C, 63.65; H, 4.5; N, 5.7%.

Intermediate 15 Methyl [3-[3-[(2-Naphthalenyisulphonyl)aminol- 1propynyllphenoxylacetate A solution of Intermediate 14 (60Orng), Intermediate 5a (550m9), bis(triphenylphosphine) palla- dium dichloride, and copper (1) iodide in dry THF (1 mi) and diethylamine (6mf) was stirred at room temperature under nitrogen for 18h then poured into 2M HG (30mi)and extracted with CHIC12 (3x20mi). The combined organic extracts were washed with 2M HO (10mi) and then 8% NaHC03 (10mi), dried, and evaporated to give an orange gum which was purified by chromatography on silica eluting with 2:1 hexane-EA, then 1: 1 hexane-EA to give the title compound as a pale brown solid (495mg).

Analysis Found: C221-1,No5S requires C, 64.5; H, 43; N, 3.5. C, 64.5; H, 43; N, 3.4%.

Example 1 (1a) [3-[2-[(Phenylsulphonyl)aminolethyllphenoxylacetic acid A mixture of Intermediate 11 a (4. 1 g), ethyl bromoacetate (1.8mi) and K2C03 (3.79) in 19: 1 ethanol-water (60mi) was heated at reflux under nitrogen for 20h. After allowing the mixture to cool, the solvent was evaporated, water (20mi) was added and the pH of the solution was adjusted to 2 with 2N HCI. The solution was extracted with ER (3x50mi) and the combined extracts were extracted with 8% NaHC03 (3x20mi). The combined Nal-IC03 extracts were adjusted to pH2 with 2N HCI and extracted with ER (3x40mi). The combined extracts were dried and evaporated to give an oil which was purified by chromatography eluting with 40:10:1 30 ER-PE- AcOH to give an oil (3.049).

A portion of the oil was dissolved in EA-toluene, decolourised with charcoal and the solvents removed in vacuo. The residue was triturated with ER to give the title compound as a powder m.p. 92-95'.

Analysis Found: C, 5 7.3; H, 5.15; N, 4. 1.

C,H,NO,S requires C, 57.21; H, 5. 1; N, 4.2%.

The following compound was prepared in a similar manner:- (1b) [3-[[(Phenylsulphonyl)aminolmethyllphenoxylacetic acid, m.p. 128-131 from Intermediate 40 1 lb. Purification initially by chromatography using 10:5A PE-EA-AcOH as eluant and then by crystallisation from EA.

Analysis Found:

C,1-1,5N05S requires C, 55.9; H, 4.7; N, 4.4.

C, 56. 1; H, 4.7; N, 4.4%.

Example 2

Ethyl [3-[2-[(Phenyisulphonyl)aminolethyllphenoxylacetate A solution of the product of Example la (0.2169) in ethanol (6mi) containing conc. H2S04 (0.2mi) was kept at ambient temperature for 65h. The solution was diluted with 2N Na.C03 to pH7 and extracted with EA (2 x 1 Omi). The combined extracts were dried and evaporated and the residue was purified by chromatography eluting with 1: 1 PE-ER to give the title compound as an oil (0. 1849).

I.r. (film) 3280, 1750, 1325, 1160cm-1 Analysis Found: C, 59.9; H, 5.8; N, 4.0.

C,J-12,1\10,S requires C, 59.5; H, 5.8; N, 3.85%.

Example 3

Methyl[3-[[[[4(Trifluoromethyl)phenyllsulphonyllaminolmethyllphenoxylacetat e A solution of Intermediate 1 lc (344m9) in dry DIVIF (8mi) was stirred under nitrogen for 1.5h with 80% NaH (78mg). Methy[bromoacetate (175m9) in DMF (8m[) was added dropwise over 30 min. and the mixture was stirred at ambient temperature for 2h. The mixture was diluted with 65 9 GB2183234A 9 i i i pH 6.5 phosphate buffer (100mi) and extracted with EA (4x50mi). The combined extracts were washed with brine, dried and evaporated to give an oil which was purified by chromatography on silica, deactivated with Et.N eluting with ER to give the title compound (132m9), m.p. 83-85 Analysis Found: C171-116F3NOr,S requires C, 50.8; N, 3.9; N, 3.4. C, 50.6; H, 4.0; N, 3.5%.

i Examples 4-18

Methyl [3-[2-[(Sulphonyl)aminolethyllphenoxylacetates Table 1 summarises the preparation of the title compounds by the following method.

A mixture of Intermediate 4 and an excess of the sulphonyl chloride was stirred in pyridine under nitrogen until reaction was complete as judged by t.l.c. The mixture was diluted with 2N HCI at 00 and extracted with EA. The extracts were washed with water, dried and evaporated and the residue was purified by chromatography as indicated in the Table.

i 1 r 1 i i i GB2183234A 10 Table 1 /OCH2C02% / OCH P 2He Hel RSO2C1/pyridine RSO 2NHCH 2CH f-0 1r---% 5 H^CH21\ Intermediate 4 Examples 4-18 10 Example' R Chromatography. M.pc I.r. (film) cnri No system (t.l.c. Rf) Oc 4 Ph ER (0.36) 94-97 (Nujol) 3260, 1748, 1318, 1162 Br-0 1:1 PE-ER then ER - 3290, 1760, 1330, (0.48) 1160 6 Me- ER (0.54) 3280, 1760, 1325, 1160 7 Meo-O ER+ (0.21) - 3280, 1755, 1335, 1150 Me 8 Me-@ 2:1 ER-PE (0.26) 80-82 (Nujol) 3280, 1760, / me 1323, 1160 //,\\ 9 - ER+ (0.27) 3320, 1755, 1342, CF3 1160 ER+ (0.31) 3280, 1750, 1325, 1160 (br.) F3C 11 2:1 ER-PE (0.17) 71-74 (NuJol) 3260, 1768, 1320, 1153 12 ER (0.23) 83-85 (Nujol) 3275, 1753, 1320, 1160 11 GB2183234A Table 1 (cont.) is + Silica deactivated with Et3N Example 19

Methyl [3-[2-[[(2-Hydroxyphenyl)sulphonyllaminolethyllphenoxylacetate BBr3 (1.2mi, 1M in CH2C12) was added to a stirred solution of the product of Example 12 (463m9) in CH2C12 (4mi) at 0' under nitrogen. After 16h at ambient temperature methanol (0.7mi) was cautiously added and stirring continued for 0.25h. The mixture was diluted with 8% Nal---1C03 and extracted with EA (3 x 40mi). The combined extracts were dried and evaporated and the residue was purified by chromatography using ER as eluant to give"the title compound as an oil 45 (302mg). T.I.c. ER Rf 0.41, I.r. (film) 3305 (br.), 1750, 1320, 1157cm-1.

Example R Chromatography M.PC (film) cm-1 No system (t.l.c. R0 c 13 PhCH2CH2- 2:1 ER-PE (0.25) 3290, 1750, 1330, then ER 1140 14 02N_\ ER+ (0.28).99 (CHBr,) 3365, 1755, 1530, 1350 1: 1 CH 2C1 rER then 3300, 1700, 1320, ER (0.61) 1160 16 ER+ (0.29) 3280, 1755, 1340, 1130 17 ER+ (0.28) 3270, 1715, 1320, Ph 1150, 973 //\ 18 2:1 ER-PE then ER 94-96 (Nujol) 3250, 1745, % (0.42) 1318, 1158 1 Example 20 (20a) Methyl [3-[3-[(Phenyisulphonyl)aminolpropyllphenoxylacetate A solution of Intermediate 8b (0.39) in EA (10mi) was hydrogenated over 5% Pd/C (50m9) 50 until uptake of hydrogen ceased. The catalyst was removed by filtration (hyflo) and the filtrate evaporated to give the title compound as an oil (0.2989).

T.I.c. ER Rf 0.38, I.r. (film) 3280, 1758, 1325, 1160cm-1.

The following compounds were prepared in a similar manner (20b) Methyl [3-[3-[[[4(Trifluoromethyl)phenyllsulphonyllaminolpropyllphenoxylacetate, m.p. 6971', from Intermediate 10e.

Purification by tituration with 3:1 PE-ER.

I.r. (Nujol) 3255, 1746, 1322, 1162cm-1.

(20c) [3-[3-[(1-Naphthalenylsulphonyl)aminolpropyllphenoxylacetic acid, from Intermediate 12a, t.l.c. 99:1 ER-AcOH Rf 0.33 I.r. (Film) 3290, 1735(br.), 1318, 1160cm-1.

(20d) Methyl [3-[3-[[(4Chforophenyl)sulphonyllaminolpropyllphenoxylacetate, from Intermediate 65 12 GB2183234A 12 10h, t.f.c. ER Rf 0.41, I.r. (Film) 3275, 1750, 1330, 1160cm-1 (20e) 2-[3-[3-[(Phenylsonyl)aminolpropyllphenoxylpropionic acid, m.p. 70- 74, from Intermediate 12c, I.r. (Nujol) 3280, 1710, 1690, 1330, 1160cm-1.

(20f) Methyl [3-[4-[(Phenylsulphonyl)aminolbutyllphenoxylacetate, from Intermediate 8d, t.f.c. 1: 1 ERPE Rf 0.09, I.r. (film) 3280, 1758, 1325, 1160cm-1.

(209) [3-[4-[(Phenylsulphonyl)aminolbutyllphenoxylacetic acid, dicyclohexylamine salt, m.p. 10 112-1160, from Intermediate 12d.

Purification by conversion into the dicyclohexylamine salt in ER. - I.r. (Nujol) 3500-2300, 1630(br.), 1328, 1160cm-1.

Examples 21-35 15 [3-[2-[(Sulphonyl)aminolethyllphenoxylacetic acids Table 2 summarises the preparation of the title compounds by the following method:

Each ester (prepared as in Examples 4-19) was dissolved in aqueous NaOH, with the addition of an alcohol, e.g. methanol, if necessary, and allowed to stand at room temperature until hydrolysis was complete as judged by fl.c. The solution was poured into an excess of 2N HCI and extracted with EA or CH2C12. The extracts were washed with water, dried and evaporated. 20 The majority of compounds were obtained analytically pure by this method. If necessary a compound was further purified as indicated in the Table.

13 GB2183234A 13 Table 2

IDCH2C02MC /OCHP24 0He RSO fflCH 2CH R502NHCH2CH2-w\ /o ==19 Examples 4-19 Examples 21-35 10 Example R M.PO Analysis Analysis Purification No OC % Found % Required Method % 21 Br- 121-122.5 C,46.5;H,3.8; C,46.4;%3.9; N,3.3 N,3.4 Crystal 22 Me- 118-122 C,58.4;H,5.4; C,58.4;H,5.5; lisation N,3.9 N,4.0 from EA-PE 23 Meo-O 1 59-62 C,55.9;H,53; C,55.9;H,5.2; N,3.7 N,3.8 Me 24 Me- 154-155 C,60.5;H,6.25; C,603;%6.1; me N,3.7 N,3.7 11,\\ Crystallis 128-130 H,3.8; C,50.6;H,4.0; ation from C,20.0.

I- N,30 N,3.5 CH 2C1 Z-PE CF3 26 109-112 C,50.5;H,44; C,50.6;%4.0; N,3.4 N,3.5 F3C 27 118-120 C941.7;HyM; C,41.7;%3.5; N,34 N,34 28 93-95 C,55.8;M.,.m2j C,5.9 H,5.2; Nj33 N,3.8 0Me 1 14 is GB2183234A 14 Table 2 (cont.) Example R M. p. Analysis Analysis iPurification No OC % Found Required Method 29 PhCH 2CH 116-117 C,59.5;1H1,5.9; C,59.5;1H1,53; Chromato N,3.9 IS1,3.85 graphy using 10:50 PE-EA-AcOH 02IN-W 138-141 C,513.6;1H1,42; C,50.5;1H1,4.2; N,7.11 N,7.4 31 107.5- C,62.2;H,5M C,62.3;H,5.0; % # 109.5 N,3.6 N,3.6 32 106-109 C,48.6;A,4.2; C,493;P1,4.4; N,3.9 N,4.1 33 /0\\ 132-134 C,29.121-,1H1,5.45; C,59.8;1H1,53; Ph N,3.7 N,3.9 34 01 174-176 C,611.9;H,52; C,623;%5.0; N,3.4 N,3.6 Chromato h-97 C,55.0;1H1,54; C,54.5;1H1,54; graphy using CH N,3.7 N,3.5 ER then 199:1 ER-AcOH Sample contains a trace'of CH2C12 by n.m.r. spectroscopy Example 36

The following compounds were prepared according to the procedure described for the compounds of Examples 21-35 in Table 2.

(36a) [3-[[[[4(Trifluoromethyl)phenyllsulphonyllaminolmethyllphenoxylacetic acid, m.p. 143-146' 60 from the product of Example 3.

Analysis Found: C16H,F3NO,S requires C, 49.3; H, 3.6; N, 3.4. C, 49.4; H, 3.6; N, 3.6%.

GB2183234A 15 (36b) [3-[3-[[[4(7'rifluoromethyl)phenyllsulphonyllaminolpropyllphenoxylacetic acid, m.p. 122-125' from the product of Example 20b.

Analysis Found: C, 51.4; H, 4.2; N, 3.4.

C,,HJ3NO.S requires C, 51.8; H, 4.35; N, 3.4%.

(36c) [3-[3-[[(4-Chforophenyl)sulphonyllaminolpropyllphenoxylacetic acid, m.p. 106-110', from the product of Example 20d. Purification by crystallisation from EA-PE.

I.r. (Nujol) 3260, 1710, 1700, 1325, 1160cm-1.

Example 37 Methyl [3-[2-[[(4Aminophenyl)sonyllaminolethyllphenoxylacetate A solution of Intermediate 10b (552rng) in methanol (10mi) and 2N HCI (10mi) was heated under reflux for 6h. The cooled mixture was adjusted to pH8 using 8% NaHC03 and extracted with EA (4x30m1). The combined extracts were dried and evaporated and the residue was purified initially by chromatography using 99:1 ER-AcOH as eluant followed by -crystallisation from EA-PE to give the title compound (246mg) m.p. 82-84.

Analysis Found: 20 CN2,1\1201S requires C, 55.9; H, 5.5; N, 7.5.

C, 56.0; H, 5.5; N, 7.7%.

Example 38 [3-[2-[[(4-Aminophenyl)sulphonyllaminolethyllphenoxylacetic acid The bicarbonate layer described in the preparation of the compounds of Example 37 was adjusted to pH2 using 2N HCI and extracted thoroughly with EA. The combined extracts were 2 5 dried and evaporated and the residue was crystallised from EA to give the title compound (94m9) m.p. 149-152'.

Analysis Found:

C, .,H,N.O.,S requires C, 54.8; H, 5.2; N, 7.9. C, 54.9; H, 5.2; N, 8.0%.

Example 39 [3-[3-[(Phenylsulphonyl)aminolpropyl)phenoxylacetic acid A mixture of the product of Example 20a (185m9) and potassium hydroxide (200mg) in methanol and water 0A, 6mi) was stirred at 20' for 4h. The solution was diluted with water 35 (40mi), washed with ER (25mi), acidified with 2N HCl and extracted with CH2C12 (2x30mi). The organic extracts were dried and evaporated to give a solid (140mg) which on crystallisation from EA-PE gave the title compound (131mg) as a white solid with m.p. 100-103'.

Analysis Found: C, 57.9; H, 5.5; N, 3.95.

C,H,NO5S requires C, 58.4; H, 5.5; K 4.0%.

Example 40 [3-[3-[(2-Naphthalenylsulphonyl)aminolpropyllphenoxylacetic acid A solution of Intermediate 12b (0.39) in ethyl acetate (30mi), was reduced by hydrogenation 45 over a pre-reduced 10% palladium on charcoal catalyst (0.1g), The catalyst was filtered off through 'hyflo' and the filtrate evaporated in vacuo to give the title compound as a fawn solid (0.309) m.p. 95-97'. I.r. (Nujol) 3700-2500 (br), 1715, (br), 1315, 1160cm-1 Example 41 Methyl [3-[3-[(Phenylsulphonyl)aminolpropyllphenoxylacetate A solution of Intermediate 13 (935mg) in methanol (85mi) was hydrogenated over 10% Pd/C (350rng) until uptake of hydrogen ceased. The catalyst was removed by filtration (hyflo) and the filtrate was evaporated to give a yellow oil (98Orng) which was purified by chromatography on silica eluting with 2:1 hexane-EA to give the title compound as a colorless oil (740mg), fl.c. ER Rf 0.38 1 1 i 1 1 1 i 1 i Analysis Found: C,H.ffl.S requires C, 59.5; H, 6.05; N, 4.0.

C, 5 9.5; H, 5.8; N, 3.85%.

Example 42 Methyl [3-[3-[(2Naphthatenesulphonyl)aminolpropyllphenoxylacetate A solution of Intermediate 15 (470rng) in methanol (35mi) was hydrogenated over 10% Pd/C (20Orng) until uptake of hydrogen ceased. The catalyst was removed by filtration (hyflo) and the 65 filtrate was evaporated to give a yellow solid (40Orng) which was purified by chromatography on 65 1 16 GB2183234A 16 silica eluting with 3:2 hexane-EA to give the title compound as a pale yellow crystalline solid (330mg) m.p. 780.

I.r. (Nujol) v,,.. 1760; 3280cm-1.

Example 43 [3-[3-[(2-Naphthalenylsulphonyl)aminolpropyllphenoxylacetic acid A solution of Example 42 (326m9) in methanol (3mi) and 2M NaOH (18mi) was heated at reflux for 2.5h, then cooled and the methanol evaporated in vacuo. The resulting aqueous suspension was treated with 5M HCI (9m1) and extracted with EA (4x20mi). The combined extracts were dried and evaporated to give the title compound as a white solid (30Orng) m.p. 10 118-1210.

Analysis Found: C, 63.3; H, 5.3; N, 3.5.

C,1-12,1\105S requires C, 63.0; H, 5.5; N, 3.5%.

The following is an example of a pharmaceutical formulation according to the invention. The term 'active ingredient' used in the example means a compound of formula (1) and may be a compound of the Examples, especially the compound of ExamMe 39 or Example 40:

Tabiets-Direct Compression mg/tablet Active Ingredient 100.00 Microcrystalline Cellulose B.P.C. 298.00 Magnesium Stearate 2.00 Compression Weight 400.00 The active ingredient is sieved through a 250pm sieve, blended with the excipients and 30 compressed using 1Omm punches.

Claims

CLAIMS 1. Compounds of the general formula (1)

R 2 so 2NH(CR2)n_ 0 < O(CR2),nCOOR 1 (1) wherein R' is a hydrogen atom or a C, alkyl group; R2 is a naphthyl, thienyl or fl-styryl group or a group Ar(CHAP- where p is zero or an integer from 1 to 3 and Ar is phenyl or phenyl substitued by one or more halogen atoms of C,-, alkyl, C, alkoxy, hydroxyl, trifluorornethyl, nitrof or amino groups; m is an integer 1 or 2; n is an integer from 1 to 4; and the physiologically acceptable salts thereof.
2. Compounds according to claim 1 in which R' is a hydrogen atom or a methyl group.
3. Compounds according to claim 1 or claim 2 in which m is 1.
4. Compounds according to any preceding claim in which n is 2 or 3.
5. Compounds according to any preceding claim in which R2 is a naphthyl, phenyl or substituted phenyl group.
6. Compounds according to any of claims 1 to 4 in which R2 is a 2naphthyl or phenyl group.
7. A compound according to claim 1, said compound being [3-[3(phenyisulphonyl)amino]propyi]phenoxylacetic acid or a physiologically acceptable salt thereof.
8. A compound according to claim 1, said compound being [3-[3[(2naphthalenyisulphonyi)amino]propyllphenoxylacetic acid or a physiologically acceptable salt thereof.
9. A pharmaceutical composition comprising a compound according to any preceding claim 60 together with one or more pharmaceutical carriers.
10. A process for the preparation of a compound according to claim 1 which comprises:

(a) alkylation of a compound of formula (2) 1 17 GB2183234A 17 R 2 so 2NH (CF12) n -p on (2) using an alkylating agent L(CH2) COOR' (where L is a leaving group); (b) in the preparation of a compound in which R' is a C1-4 alkyl group, sulphonylating a 10 compound of formula (3) - R 2N (CH 2)n --Q (3) O(CH 2)m COORI (wherein R' is C,-, alkyl) with a reactive derivative of a sulphonic acid R2SO3H; (c) in the preparation of a compound in which R' is a hydrogen atom, hydrolysing a corresponding ester, (d) in the preparation of a compound in which R' is a C,-, alkyl group, esterifying the 20 corresponding carboxylic acid; (e) in the preparation of a compound in which -(CH2)n- is -(CH2)3- or - (CH2),- and R2 is other than thienyi, phenyl substituted by nitro, or fl-styryl, reducing a compound of formula (4) R2 so 2MCR2)q Y- Q 0 (CEú2)'COOR 1 (4) (wherein q is an integer 1 to 2, Y is -CH=CH- or -CL-=C- and R2 is as just defined):

(f) in the preparation of a compound in which R2 is phenyl substituted by a hydroxyl group, demethylating the corresponding compound in which R2 is phenyl substituted by a methoxy group; or (9) in the preparation of a salt, treating a compound in which R' is a hydrogen atom with a base or treating a compound in which R2 is phenyl substituted by amino with an acid or 35 converting one salt into another.
11. A compound according'to claim 1, said compound being the title compound of any of Examples.143 herein.

Printed for Her Ma,.esty"s Stationery Office by Burgess & Son (Abingdon) Ltd, Od 8991685. 1987. Published at The Patent Office. 25 Southampton Buildings. London. WC2A 'I AY. from which copies may be obtained.

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