IL31991A

IL31991A - Furan and thiophene derivatives

Info

Publication number: IL31991A
Application number: IL31991A
Authority: IL
Original assignee: Ici Ltd
Priority date: 1968-04-16
Filing date: 1969-04-10
Publication date: 1971-12-29
Also published as: NL6905846A; IL31991A0; IE33054L; DE1919381C3; SE366038B; DE1919381B2; CH515231A; FR2007466A1; JPS4913789B1; BE731549A; IE33054B1; DE1919381A1

Description

FUR AN AND THIOPHENE DERIVATIVES This invention relates to new heterocyclic compounds, and more particularly it relates to new ¾¾¾¾¾ir)¾jid furan derivatives which have an i-inflammatory, hypocholesterolaemic, analgesic and antipyretic activity^ According to the invention there are provided heterocyclic compounds of the formula:- rherein X stands for hydrogen, a methyl or ethyl radical, or a chlorine or bromine atom, Y stands for a phenyl radical, optionally substituted by one or two fluorine, chlorine or bromine atom(s), and Z stands for a 12 3 1 group of the formula -CR R R , wherein R stands for hydrogen or a 2 methyl or ethyl radical, R stands for hydrogen or a methyl, ethyl, carboxy (-COgH), Cg g alkoxycarbonyl, benzyloxycarbonyl or phenoxy-carbonyl radical, and -COHHR^ or -CONR^, wherein R^ stands for hydrogen or a alkyl, benzyl or phenyl radical, and R stands for hydrogen or a hydroxy, amino (-NH2) or N-piperidi stands for a carboxy radical ^ stands for a carboxy radical, 'and wherein B stands for an oxygen or sulphur atom, and wherein Y and Z are linked to non-adjacent carbon atoms of the heterocyclic nucleus, and non—toxic pharmaceutically-acceptable salts thereof.

As stated above, in the compounds of this invention Y and Z are linked to non-adjacent carbon atoms of the heterocyclic nucleus. It is to be understood that this situation obtains generally throughout this specification; thus, in the heterocyclic compounds used as starting materials in the processes disclosed below Y and Z, or groups corresponding thereto, are linked to non-adjacent oarbon atoms of the 2 heterocyclic nucleus. As indicated above, when R stands for a carboxy radical, R^ likewise stands for a carboxy radical. It is to be 3 2 understood, however, that R can stand for a carboxy radical when R 2 does not stand for a carboxy radical, for example when R stands for hydrogen or a methyl or ethyl radical.

Compounds wherein Y contains one or two halogeno substituent(s), as described above, constitute a preferred embodiment of the invention because, generally speaking, they are more active than the corresponding unsubstituted derivatives. 2 As a suitable value for R there may be mentioned, for example, hydrogen, or a methyl, carboxy, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl or phenoxycarbonyl radical.

As a suitable value for ^ there may be mentioned, for example, hydrogen,- or a methyl, ethyl, propyl, butyl, benzyl or phenyl radical.

As a suitable value for R there may be mentioned, for example, hydrogen, or a hydroxy, amino or 2-diethylaminoethyl radical.

Suitable salts in the case where the heterocyclic compound is sufficiently basic, are non-toxic pharmaceutically-acceptable acid— 2 3 addition salts. Suitable salts of the compounds wherein R and/or R stands for a carboxy radical are salts containing a non-toxic pharmaceutically-acceptable cationi examples of such salts are salts with alkali metals or alkaline earth metals, or aluminium or ammonium salts, or salts with non-toxic pharmaceutically-acceptable organic bases, for example triethanolamine.

Preferred heterocyclic compounds of the invention are ethyl 5-£-chlorophenylthien-2-ylacetate, dimethyl a-(5-£-chlorophenylthien-2-yl)-a-methylmalonate, methyl 5-j^chlorophenylfur-2-ylacetate, dimethyl a-(5-£-chlorophenylfur-2-yl)- According to a further feature of the invention there is provided a process for the manufacture of compounds of the formula.- wherein B, X, Ύ and R have the meanings stated above, R stands f hydrogen or a methyl or ethyl radical, and R^" stands for a all radical, which comprises reacting a compound of the formula:- wherein B, X, Y, R and R have the meanings stated immediately above, with an alkanol of the formula R^OH, wherein R^ has the meaning stated immediately above, in the presence of sulphuric or hydrochloric acid, provided that when B stands for an oxygen atom the acid is hydrochloric acid.

When B stands for an oxygen atom the reaction should not be carried out under the influence of heat. On the other hand, when B stands for a sulphur atom, the reaction may optionally be carried out under the influence of heat.

According to a further feature of the invention there i provided a process for Vhe manufacture of compounds of the formulai- wherein B, X and Ύ have the meanings stated above and R stands for hydrogen or a C-^_^ alkyl radical, and pharmaceu ically-accep able salts thereof, which comprises carrying out the Arndt-Eistert reaction on an acid halide of the formula:- wherein B, X and Y have the meanings stated above, and Hal stands for a chlorine or bromine atom? The Arndt-Eistert reaction may be carried out by first reacting the acid halide with diazomethane to obtain the corresponding diazoacetyl derivative, which is then reacted with silver oxide and a compound of the formula R^OH, wherein R^" has the meaning stated immediately above. The seoond half of the reaction may be accelerated or completed by the application of heat.

According to a further feature of the invention there is provided a process for the manufacture of amides of the formula:- wherein B, X; Y and R have the meanings stated above and R stands for hydrogen or a methyl or ethyl radical, which comprises hydrolysing a 1 7 mtrile of the formula III above, wherein B, X, Yf R and R1 have the meanings stated immediately above* As a suitable hydrolytic agent there may be mentioned, for example, aqueous hydrogen peroxide.

According to a further feature of the invention there is provided a process for the manufacture of compounds of the formula:- wherein B, X, Y, R and R have the meanings stated above, and non-toxic pharmaceutically-acceptable salts thereof, which comprises hydrolysing a compound of the formul :- wherein B, X, Y, R and R have the meanings stated above, and Cy stands for a cyano, carbamoyl (-COUHg), thiocarbamoyl (-CSHHg), g alkoxy-carbonyl, benzyloxycarbonyl or phenoxycarbonyl radical. Δ suitable hydrolytic agent in the case where Cy stands for a cyano, carbamoyl or thiocarbamoyl radical is an alkali metal hydroxide.

A suitable hydrolytic agent in the case where Cy stands for a C^ g alkoxycarbonyl, benzyloxycarbonyl or phenoxycarbonyl radical is an alkali metal hydroxide, or (only in the case where B stands for a sulphur atom) an inorganic acid.

According to a further feature of the invention there provided a process for the manufacture of amides of the formula; wherein B, X, Y, R and R have the meanings stated above , and — NW 6 5 6 stands for -NHR or - R , wherein R and R have the meanings stated above , which comprises reacting a compound of the formulas- wherein B, X, Y, R and R have the meanings stated above, and Q stands for a chlorine or bromine atom or a . alkoxy, benzyloxy or phenoxy radical, with a compound of the formula HNW, wherein -M has the meaning stated above.

According to a further feature of the invention there is provided a process for the manufacture of esters of the formula:- wherein B, X, Y, R and R have the meanings stated above, and R^ stands for a C-_-. alkyl , benzyl or phenyl radical, which comprises esterifying the corresponding carboxylic acid, carboxylic acid halide or carboxylic acid anhydride.

The esterification may be carried out by known general methods it is to be understood that when B stands for an oxygen atom and the esterification is carried out under acidic conditions , the conditions must be mild ones.

According to a further feature of the invention there is provided a process for the manufacture of compounds of the formula:— glT XII wherein B, X and Y have the meanings stated above , stands for a comprises reacting an alkali metal derivative of a compound of the formula:- wherein B, X, Y, R and R4 have the meanings stated immediately above , with a methyl or ethyl halide selected from chlorides, bromides and iodides.

The la3t-named process is conveniently carried out in an organic solvent, for example dimethyl sulphoxide or dioxan. By means of this process there may be obtained mono-alkyl derivatives [i.e.

-CHR2.C02R4 is converted into -CR 2.COgR^] and dialkyl derivatives [i.e. -CH2C02R4 is converted into -CRgCOgR^, or -CH( lkyl).C02R4 is converted into -CR1(alkyl)lC02R^] .

According to a further feature of the invention there is provided a process for the manufacture of compounds of the formula:- wherein B, X and Y have the meanings stated above, R stands for or a methyl or ethyl radical, and R A 4* hydrogen and ^" , which may be the same or different, stand for a C]_,cj alkyl, benzyl or phenyl radical, which comprises reacting sodium or potassium or a hydride, amide or ^ alkoxide thereof, with a carbonate of the formula C0.(0R^)2, wherein ^ has the meaning stated above, and a compound of the formul :- wherein B, X, Y, R and R^" have the meanings stated immediately above. The reaction may be carried out in an excess of the carbonate used as reactant, and it may be accelerated or completed by the application of heat , According to a further feature of the invention there is provided a process for the manufacture of compounds of the formula: wherein B, X, Y and R have the meanings stated above, and pharmaceutically-acceptable salts thereof, which comprises reacting a compound of the formula XIV, wherein B, X, Ύ and R have the meanings A A* stated immediately above and R^" and R^" , which may be the same or different, stand for a ^ alkyl, benzyl or phenyl radical, with an inorganic base in the presence of water and under the influence of heat, or (in the case where B stands for a sulphur atom) xiith an inorganic acid in the presence of water and under the influence of heat. Δ suitable inorganic base is, for example, an alkali metal hydroxide. The reaction may optionally be carried out in the presence of an organic solvent, for example ethanol.

According to a further feature of the invention there is provided a process for the manufacture of compounds of the formula XII, wherein B, Y and R"*" have the meanings stated above, X stands £>r a 2 chlorine or bromine atom, R stands for hydrogen. or a methyl, ethyl, C2__g alkoxycarbonyl, benzyloxycarbonyl or phenoxycarbonyl radical, and R^ stands for a C]_cj alkyl, benzyl or phenyl radical, which comprises reacting a compound of the formula XII, wherein B, Y, and have the meanings stated immediately above, and X stands for hydrogen, in the presence of an alkali metal acetate, with a solution of chlorine or bromine in an organic solvent, for example acetic acid.

According to a further feature of the invention there is provided a process for the manufacture of esters of the formula XII, 1 2 wherein B, X, Y and R have the meanings stated above, R stands for hydrogen or a methyl, ethyl, g alkoxyoarbony1, benzyloxycarbonyl or phenoxycarbonyl radical, and R^ stands for a ^ alkyl, benzyl or phenyl radical, which comprises reacting a methyl or ethyl ester of the formula XII, wherein B, X, Y and R^" have the meanings stated above, and 2 R stands for hydrogen or a methyl, ethyl, methoxycarbonyl or ethoxy-carbonyl radical, and R^ stands for a methyl or ethyl radical, with a [- alkanol, benzyl alcohol or phenol, in the presence of a known metallic transesterification catalyst at a temperature in the range 25" to 200UC.

As a suitable transesterification catalyst there may be mentioned, for example dibutyl tin dilaurate. The reaction may optionally be carried out in the presence of an aromatic hydrocarbon solvent, for example toluene.

According to a further feature of the invention there is provided a process for the manufacture of compounds of the formula:- wherein B, X and Y have the meanings stated above, which comprises first carrying out the Willgerodt reaction on a compound of the formula COCH3 XVIII wherein B, X and Y have the meanings stated above, and then hydrolysing the product by means of an inorganic base, and then converting the resulting salt into the corresponding carboxylic acid of formula XVII in a manner known per se.

The Willgerodt reaction is a well-known organic reaction. It can be carried out, for example, by reacting said compound of formula XVIII with ammonium polysulphide in the presence of an organic solvent, for example pyridine or dioxan, at a temperature of 25° to 200°C. A suitable base for use as hydrolytic agent is an alkali metal hydroxide. The hydrolysis is carried out in the presence of water and at a temperature of 20° to 100°C.

It is to be understood that the starting materials used in all the above processes are obtainable by methods known per sc. Also, the non—toxic pharmaceutically-acceptable salts of the invention are obtainable by methods known per se.

According to a further feature of the invention there ere provided pharmaceutical compositions comprising a heterocyclic compound of the formula I, wherein B, X, Y and Z have the meanings stated above, or a non-toxic pharmaceutically-acceptable salt thereof, and a non-toxic pharmaceutically-acceptable diluent or carrier.

The pharmaceutical composition may, for example, be in the form of tablets, pills, capsules, suppositories, non-sterile aqueous or non-aqueous solu ions or suspensions, sterile injectable aqueous or non-aqueous solutions or suspensions, creams, lotions, or ointments. These compositions may be obtained in conventional manner using conventional excipients. The compositions may optionally contain, in addition to at least one of the heterocyclic compounds which characterise this invention, at least one known agent having antiinflammatory and/or analgesic activity, for example aspirin, paracetamol, codeine, chloroquine, phenylbutazone, oxyphenbutazone , indomethacin, mefenamic acid, flufenamic aoid, ibufenac, or an anti-inflammatory steroid, for example prednisolone. Those compositions intended for oral administration may, in addition, optionally contain at least one anti-cholinergic agent, for example homatropine methyl bromide, and/or an antacid, for example aluminium hydroxide; and/or a uricosuric agent, for example probenecid. Those compositions designed for topical application may, in addition, optionally contain a vasodilating agent, for example tolazoline, or a vasoconstricting agent, for example adrenaline? a local anaesthetic, for example amethocaine, or a counter—irritan , for example capsicum; and/or at least one agent chosen from the following classes! antibacterial agents, which include sulphonamides and antibiotics having antibacterial action, for example neomycin; antifungal agents, for example hydroxyquinoline ; anti— histaminic agents, for example promethazine; and rubefacient agents, for example methyl nicotinate.

The invention is illustrated but not limited by the following Examples :-Example 1 2-Cyanomethyl-5-p-chlorophenyli¾o¾¾¾ (3g« ) was refluxed in ethanol (85ml. ) , water ( lml. ) and concentrated sulphuric acid (30ml. ) for 17 hours . The mixture was then diluted with water (200ml. ) and extracted with ether (3 x 100ml. ). The combined extracts were washed with aqueous sodium bicarbonate ( 10 w/v, 25ml. ) , dried over anhydrous calcium sulphate and evaporated in vacuo. Crystallisation of the residue from petroleum ether (b. p.80-100° C. ) gave ethyl 5- j-chlorophenyl-thien-2-ylace ate , m.p.66-68°C.

The cyanomethyl compound used as starting material was obtained as follows -£-Chlorophenyl-2-f ormylthiophent(36g, , m.p.82-83°C. , prepared similarly to known m-chloro analogue ) was stirred and refluxed with sodium borohydride (24.6g. ) in dioxan (250ml. ) for 2¾- hours. The solvent was distilled in vacuo and the residue was shaken with 2N-hydrochlorio acid ( 1200ml. ) and ether ( 1200ml. ). The ether layer was separated and the aqueous layer was re-extracted with ether (1200ml. ). The combined ether layers were d ried over anhydrous sodium sulphate and evaporated in vacuo. The residual solid was crystallised from petroleum ether (b.p.l00-120°C. ) t o give 2-hydroxymethyl-5-p--chlorophenyl-thiophen, m. p.125-130° C. This material (l5g» ) was dissolved in benzene (250ml. ) , and thionyl chloride (20ml. ) was added. After 15 minutes at ambient temperature , volatile material was distilled in vacuo and the residue was crystallised from n-hexane at -^0°0, to give 2-chloromethyl- thiophene -5-£-chlorophen l a/v iie , m. p.81.5 °-83.5° C .

Potassium cyanide (20g. ) was dissolved in water (50ml. ) and a thiophene solution of 2-chloromethyl-5- -chlorophenyl^l(ipp 3ii/ ( lOg. ) in dioxan ( 150ml. ) was added. The mixture was stirred for 22 hours and the upper layer was evaporated t o a solid which was extracted with boiling ethanol (300ml. ). The extract was decolourised with carbon, evaporated to half volume and cooled, and the precipitated solid was filtered off. There was thus obtained impure 2-cyanomethyl-5-£-chlorophenylthiophen. Example 2 thiophene 3-Chlorocarbonyl^Hmethyl--5-Phenylt i^l5h'eW (53g. ) in dio a ' ( 100ml. ) was added to a solution of diazomethane (prepared from 83g. of N-nitroso-methylurea in the usual way) in ether (500ml. ) . After 18 hours volatile material was distilled jin vacuo and the residue was stirred at 20°C. with silver oxide (24, 5g. ) » sodium bisulphite (71.5g« ) and water (2 1. ) , More silver oxide (24.5g. ) was added. The mixture was heated at 70°C. for 2 hours and then filtered. The filtrate was cooled and acidified with concentrated nitric acid. The resulting solid was reorystallised txfice from petroleum ether (b.p.80-100eC. ) to give 2-methyl-5-Phenylthien-3-ylacetio acid, m.p. H7#5-119«5°C» The chlorocarbonyl compound used as starting material was obtained as follows To a slurry of oil-free sodium hydride (6g. ) in sodium-dried ether (200ml. ) t ethyl acetoacetate (32.5g. ) was added with vigorous agitation at 5*-10°C. W en evolution of hydrogen had ceased, phenacyl bromide (5%· ) in dry ether (250ml.) was added. The mixture was stirred for l8 hours , and then diluted with water (500ml. ). The aqueous layer was discarded, the ether layer was washed with water (2 x 120ml. ) , dried (Na2S0^) and evaporated at 0*5mm./50°C. to an oil (47«5g» )» The °il was dissolved in ethanol ( 100ml. ) , and hydrogen sulphide gas and hydrogen chloride gas were passed through the solution at -10°C. for 1 hours. The mixture was slowly (over 18 hours ) warmed to 20eC , diluted with water (500ml. ) , and extracted with petroleum ether (3 x 250ml, ; b.p.40-60°C. ) . The combined extracts were dried (anhydrous sodium sulphate ) and distilled in vacuo. The fraction boiling at 140"-.150°C./0.2mm. was refractiona ed on a spinning band column of 30 theoretical plates. The higher boiling fractions solidified (m.p.44.5°-45.5°C. ) and were shown to be ethyl 2-methyl-5-phenylthien-3-ylcarboxylate, free of the corresponding furan which collected in the lower boiling fractions. The above ester (lg. ) was refluxed in ethanol (5ml.) and 2N-sodium hydroxide (2ml.) for 10 minutes. After cooling, the mixture was acidified with 2N-hydrochloric acid and the resulting precipitate was crystallised from aqueous ethanol to afford 3-carboxy-2-methyl-5-phenylthiophen<- m.p.l85°-l87eC. The above acid (7g«) was refluxed in dry benzene ( 100ml.) with thionyl chloride (6ml.) for 2 hours. Volatile material was distilled in vacuo and the residue was crystallised from 60°-80°C. petroleum ether to give 3-chlorocarbonyl-2-methyl-5-phenyl-thiophen†" m.p.77°-78cC.

Example 3 2-(a-C anoe h l)-5-jD^chlorophen l|l-i?^h¾^ (2g. ) was refluxed with methanol (lOOml,), concentrated sulphuric acid (40ml.) and water (lml.) for 5 hours. The resulting solution was poured into water (500ml.) and extracted with ether (3 x 250ml.). The ethereal extract was dried (anhydrous sodium sulphate) and evaporated in vacuo o an oil, which was purified by chromatography on a column of magnesium silicate eluted with benzene. The solvent was evaporated from the eluate, and there was thus obtained methyl a—(5-i£-chlorophenylthien-2-yl)propionate. This ester was hydrolysed by heating it with ethanol (50ml.) and N-sodium hydroxide (50ml.) for 30 minutes. The mixture was cooled, diluted :with water (300ml.), and washed with ether (2 x 100ml.). The aqueous layer was acidified with hydrochloric acid and the precipitated solid was collected by filtration and crystallised from chloroform.

There was thus obtained a-(5-j chlorophenylthien-2-yl)propionic acid, as starting material m.p.74-75°C. ) was obtained from 2-acetyl~5-£-c^l°rophenylthiophen by an analogous method to that described in Example 1 for the preparation of -c anometh l-5-^^l°roPhe^l^^i¾:¾^-Example 4 Methyl oc-(5-£-chlorophenylthien-2-yl)acetate [lOg.; m.p„78-80°C. ; prepared by a similar procedure to that described in Example l] was heated under reflux with sodium hydride (3g. ; washed free from mineral oil with petroleum ether of b»p.60-80°C. ) and dimethyl carbonate (l50ml.) for 3 hours. The mixture was cooled, poured into an ice-water mixture (800ml.), and extracted with ether (4 x 200ml.). The combined extracts were washed with water (2 x 100ml.), dried (anhydrous sodium sulphate), and the solvent evaporated. The residue was crystallised from methanol to give dimethyl o-(5-£-chlorophenylthien-2-yl)malonate, m.p.74-75°C.

Example 5 Dimethyl a-(5-P-chlorophenylthien~2-yl)malonate (2.2g. ) was dissolved in dry dimethylsulphoxide (40ml.). A dispersion of sodium hydride (0.2g. ) in mineral oil (0.2ml.) was added, and the mixture was stirred for 1 hour. Methyl iodide (4ml.) was added to the resulting pale yellow solution and, after it had been stirred overnight, the mixture was poured into an ice-water mixture (400ml.). The precipitated solid was separated by filtration and purified by chroma ography on a column of magnesium silicate (l" diameter x 12" long) which was eluted with benzene in 25ml. portions. Fractions Nos. 7-28 were combined, and the solvent evaporated. The residue was crystallised from methanol to give dimethyl a-(5-£-chlorophenylthien-2- yl)-oc-methylmalonate, m.p.70*C.

Example 6 -£-Chlorophenylfur-2-ylaoetic acid (3g«) was dissolved in methanol ( 100ml.), and dry HC1 gas was passed through the solution for 5 minutes. The solution was kept at ambient temperature for 18 hours, evaporated in vacuo to small volume, triturated with 10$ w/v sodium bicarbonate solution (30ml.) and extracted with ether (2 x 20ml.). The combined ethereal extracts were washed with water (2 x 5ml*)i dried over anhydrous sodium sulphate and evaporated to give a crystalline solid whioh was methyl 5-Pj-chlorophenylfur--2-ylacetate, m.p.64-66°C.

Example 7 Methyl 5-p_-chlorophenylfur-2-ylacetate (2.8g. ) was refluxed with a suspension of sodium hydride (l.6g») in dimethyl carbonate (85ml.) for 1 hour. After 17 hours at ambient temperature the mixture was poured into ice/water (350ml») and extracted with ether (3 x 100ml.). The combined ethereal extracts were dried over anhydrous sodium sulphate and evaporated to dryness. The residual, low melting solid was crystallised from methanol, and there was thus obtained dimethyl -(5-£-chlorophenylfur-2-yl)malonate , m.p.58-59eC.

Example 8 Dimethyl a-(5-_£-chlorophenylf r-2-yl)malonate (l.2g. ) was added to a suspension of sodium hydride (lg. ) in dry dimethylsulphoxide (l0ml«). The mixture was stirred for 30 minutes, and methyl iodide (20ml.) was then added. The mixture was stirred for a further 2 days, poured into ice/water (70ml.) and extracted with ether (3 x 20ml.). The combined ethereal extracts were washed with water (2 x 20ml.), dried over anhydrous sodium sulphate, and evaporated in vacuo. The residual yellow oil solidified and was crystallised from methanol to give dimethyl -(5-p_-chlorophen lfur-2-yl)- -inethylmalonate, m.p.50-54°C.

Example 9 Methyl 5-p_-chlorophenylthien-2-ylacetate (5»32g. ) was stirred with a mixture of glacial acetic acid ( 100ml.) and sodium acetate (4.8g. )„ Δ solution of bromine (l l.) in glacial acetic acid (15ml, ) was added. The mixture was stirred for two hours and then poured into ice/water (l 1·). After days at ambient temperature the mixture was extracted with ether (4 x 200ml,), the combined ethereal extracts were successively washed with water (3 x 200ml.), 10$ w/v aqueous sodium bicarbonate (2 x 200ml.), and water (200mle), dried over anhydrous sodium sulphate, and evaporated to give a pale yellow oil. Part of this oil (l.75g«) was refluxed with ethanol (15ml,), water (40ml,) and llN-sodium hydroxide (l5.nl·) for 3 hours. The mixture was added to ice/water (100ml.) and extracted with ether (3 x 20ml,), The aqueous layer was acidified with 2N-acetic acid and extracted with ether (33 20ml,), The combined ethereal extracts were washed with water (2 x 30ml,), dried over anhydrous sodium sulphate and evaporated in a relatively high vacuum (0,5mm,), The residual solid was dissolved in the minimum volume of ether, and after the addition of 4 volumes of petroleum ether (b.p.60-80°C. ), gave crystals of oc-(4-bromo-5- -chloro-phenylthien-2-yl)acetic acid, m,p.l36-137°C, (2g, ) was refluxed with a solution of sodium hydroxide (lOg, ) in water ( 100ml,) for 5 hours, On cooling, the sodium salt of 5-£-chlorophenylthien-2-yl acetic acid separated. The salt was filtered off, triturated with a mixture of equal volumes of methanol and water (total volume 50ml.) and the crude acid was precipitated from the supernatant liquor with glacial acetic acid (3ml,). The acid was purified by extraction with 2N-ammonium hydroxide (120ml,), filtration of the extract, and acidification of the filtrate with 2N-acetic acid at 0°C, There was thus obtained 5-£-cnloroPhenylthien-2-ylacetic acid hemihydrate, m.p.l 0-l43 C.

Example 11 Methyl 5~JP"chlorophenylthien-2-ylacetate (6g. ), sodium hydroxide (5g»)i ethanol (20ml,) and water (50ml.) were refluxed for 3 hours. The mixture was diluted with water (100ml,) and ethanol (lOml.) and filtered, and the filtrate was cooled to 5°C. and acidified with 2N-acetic acid to pH 4.5. The resulting precipitate was filtered, and extracted with 2N-ammonium hydroxide ( 100ml,), and the extract was acidified with 2N-acetic acid to pH 4,5· The mixture was filtered to give 5-£-°h] orophenylthien-2-ylacetic acid hemihydrate, m.p.l40-l43eC. Example 12 -£-Chlorophenylthien-2-ylacetic acid (50mg, ) was dissolved in sodium-dried benzene (lOml,), Thionyl chloride (lml.) was added, and after 2 days at ambient temperature volatile material was distilled off in vacuo. The residual oil was taken up in benzene (5ml.), and piperidine (lml.) was added. After 30 minutes the resulting precipitate of piperidine hydrochloride was filtered off, the filtrate was evaporated in vacuo and triturated with dilute hydrochloric acid. There was thus obtained l^-(5-j^chlorophenylthien-2-yl)acetylpiperidine, m.p.74-76eC.

Example 13 By a similar procedure to that described in Example 1, but substituting n-butanol for ethanol, there was obtained n-butyl 5-J-chlorophenylthien-2-ylacetate, m.p.34-35°C.

Example 3 Methyl 5-p chlorophenylthien-2-ylacetate (2g. ) was refluxed in a mixture of benzyl alcohol (5ml. ) , toluene ( 100ml. ) and dibutyl tin dilaurate ( 0.1ml. ). The vapours were passed up a 12" fractionating Dixon column packed with ¾*τπκ¾η gauee rings and fitted with a variable take-off head. Methanol and toluene were slowly distilled for 4 hours. At the end of four hours only toluene distilled. The residue in the flask was passed down a Plorisil column ( l2" long x 1" diameter) which was eluted with toluene. The eluate was evaporated, and the residue triturated with a small volume of ice-cold methanol, and gave crystals of benzyl 5-£-chlorophenylthien-2-ylacetate , m.p.71-72*C« By a similar procedure , substituting dimethyl a-(5-j>-chloro-phenylthien-2-yl)malonate for the above acetate , there was obtained dibenzyl a-(5-£-chlorophenylthien-2-yl)malonate , m.p.94*C.

By a similar procedure , substituting phenol for benzyl alcohol in the first example above and using sodium phenoxide (0.2mole ) as an additional catalyst , there was obtained phenyl 5- -chlorophenylthien-2-ylacetate, m.p.l01-103°C.

Example 15 2-Cya on^ hyl- -^ch oro hen )<¾-: ¾ (lg. ) was dissolved in acetone ( 100ml. ) . 2>Oo w/v aqueous hydrogen peroxide (20ml« ) was added, followed by 10 w/v aqueous sodium carbonate solution. After 4 days at ambient temperature , the mixture was filtered and the filtrate was evaporated in vacuo to a small volume . The crude product which crystallised on cooling was crystallised from methanol to give a-(5-£-chlorophenylthien-2-yl)acetamide , mep.209-210°C.

Example 16 Hydroxy lamine hydrochloride (6«95g« ) was added to a solution of sodium (2.3g.) in methanol (100ml.). A solution of methyl (2-methyl-5-phenylthi»a—3—yl)acetate in methanol was added. The mixture was refluxed for 2 minutes and then stirred at ambient temperature for 2 days. The mixture was filtered, the filtrate was evaporated to dryness in vacuo, and the residue itfas washed with cold water. The residue was N-hydroxy a-^-phenyl-2-methylthien-3-yl)aoetamide mono sodium salt trihydrate, m.p.l34-136°C, Example 17 2-Acetyl-5-£-chlorophenyll{i-¾Dl¾fe]h (7g») was heated in a sealed tube at 165*C for 3 hours with a mixture of sulphur (ll.2g. ), ammonium hydroxide (29»4ml,, S.G. 0.88) and pyridine (15.5^1.)· The resulting mixture was evaporated to dryness in vacuo and refluxed with 2N-sodium hydroxide (50ml.) for 1 hour. The mixture was cooled, and filtered, and the filtrate was acidified with dilute hydrochloric acid to pH 2. The resulting precipitate was filtered off and crystallised from aqueous ethanol to m.p.l40-143eC.

Example 18 Methyl 5-J-chlorophenylthien-2-ylacetate (lg.) was stirred with a solution of hydrazine hydrate (5ml.) in ethanol (50ml.) for 17 hours. The precipitated solid was filtered off and extracted with hot ethyl acetate ( 100ml.). The extract was evaporated to about l/5 volume and on cooling gave a-(5-j-chlorophenylthien-2-yl)acethydrazide, m.p.l66-l68°C.

Example 1 Methyl 5-£-chlorophenylthien-2-ylacetate (2g. ) was heated with ,N-diethylethylenediamine (lOml.) at 130°C. for 3 hours. On cooling, methanol (70ml.) was added, the mixture was filtered, and the filtrate was diluted with, water (250ml.). The resulting mixture was filtered to give a-(5-£-ohlorophenylthien-2-yl)-N-( →iiethylaminoethyl)-acetamide, m.p.l01-103°C.

By a similar procedure, replacing the N,N-diethylethylene-diamine in the above example with piperidine, there was obtained l-[a-(5- -chlorophenylthien-2'-yl)acetyl] piperidine , m.p.74*-76°C.

Example 20 Methyl 5~£-chlorophenylthien-2— lacetate (lg. ) was dissolved in dry dioxan (lOml. ). Sodium hydride (O.lg. ) was added, the mixture was stirred for 30 minutes, and methyl iodide (0.6g, ) was then added. The mixture was refluxed for 30 minutes, cooled, and further sodium hydride (O.lg. ) and methyl iodide ( 1.1ml.) were added. The mixture was refluxed for 2 hours, cooled and evaporated in vacuo to give an oil which lias chroma ographed on a column of Plorisil (column: 9" lo x 1" diameter) which was eluted with a mixture of equal volumes of benzene and petroleum ether (b.p.60-eo0C. ). The first 35°ml. of eluate was evaporated in vacuo to give an oil. This oil, which was mainly methyl a,a-^.imethyl-a-(5-£-chlorophenylthien-2-yl)acetate, was hydrolysed by a similar procedure to that described in Example 12 above, and gave a,a-dimethyl-«-(5-t^chlorophenylthien-2-yl)acetic acid, m.p.l46-148eC.

Example 21 Dimethyl -(5-£-chlorophenylthien-2-yl)-a-methylmalonate (0.05g. ) was heated at 95eC. for 3 hours with 8N-sodium hydroxide (4ml.). After cooling, the mixture was acidified with glacial acetic acid to pH 4.5 and extracted with ether (3 x 10ml.). The ether extracts were dried over anhydrous sodium sulphate and evaporated in •gaouo to give a solid which was a-(5—£-chlorophenylthien-2-yl) ropionic acid, m.p. I5O-I51°C.

Example 22 By a similar procedure tc that described in Example 2, starting from p-chlorophenacyl bromide, there was obtained 2-methyl-5-p-chlorophenylthien-3-ylacetic acid, which was characterised by a peak in the N.M.R. spectrum at 6.4"^ (two-proton singlet due to the methylene hydrogen atoms).

Example 23 3-Cyanomethyl-2-methyl-5-]^bromophenylfuran (2.2g. ) was refluxed for 4 hours with methanol (100ml.) and concentrated sulphuric acid (40ml.). After cooling, the reaction mixture was poured into water (l 1.) and extracted with ether (3 x 250ml.). The ether extracts were dried (anhydrous sodium sulphate) and evaporated in vacuo to give an oil. The required product, which had an Rp value of 0.5 on a silica plate irrigated with 10:90 v/v ethyl acetate/petroleum ether (b.p.40-60°C.), was separated from impurities by chromatography on a Florisil column (column: 16" long x 1" diameter) eluted with the same solvent mixture. It was a solid which melted below 3 *C. and was methyl (5-£-bromophenyl-2-methylfur-3-yl)acetate.

The cyanomethylfuran used in the above Example was prepared as follows Sodium hydride (l7*25g. ) was stirred in dry ether (600ml.), and ethyl aoetoacetate (93·4έ?·) was added over 1 hour, the temperature being kept below 10°C. More ether (300ml.) was added, followed by j>-bromophenacyl bromide (200g. ) slurried in dry ether (800ml. ). The mixture was stirred for l8 hours, and water (l500ml.) was added. The two layers were separated; the aqueous layer was extracted v/ith ether (2 x 300ml.) and the combined ethereal layers were dried (NaJSO ) and evaporated in vacuo to give a solid (215g. )· The solid was dissolved in a mixture of dry dioxan (500ml.) and ethanol (100$ v/v; 250ml.). Hydrogen chloride gas was passed through the mixture at -30°C. for 4 hours, and agitation was continued for l8 hours. The mixture was poured into water (2. 1.) and the resulting oil was triturated with petroleum ether. The resulting crystals were crystallised from ethanol to yield 5-£-¾romophenyl-3-ethoxycarbonyl-2-methylfuran, m.p.73-75°C. This ester (lg. ) was dissolved in dry ether (25ml.), and lithium aluminium hydride (0.123g. ) in dry ether (lOml.) was added. The mixture was refluxed for 1 minutes, excess hydride was destroyed by the addition of water (lml.) followed by 2N-hydrochloric acid (4ml. )« The ether layer was separated, dried (anhydrous sodium sulphate) and evaporated in vacuo to give a solid which, on crystallisation from chloroform/hexane, afforded crystals of 5-£-bromophenyl-3-hydroxymethyl-2-methylfuran, m.p.l40-141°C. This hydroxy-methylfuran (24g. ) was dissolved in benzene (250ml.), and thionyl chloride (24g» ) was added. After 30 minutes, volatile material Mas distilled off in vacuo and the residue was crystallised from hexane to yield 5-£~'bromophenyl-3-chloromethyl-2-methylfuran, m.p.82-84°C. The above 3-chloromethylfuran (lOg. ) was stirred with dioxan ( 100ml.), water ( 100ml.) and potassium cyanide (lOg. ). After 19 hours the upper layer was separated and evaporated in ^acuo to give an oil. The required 5-,2~ romophenyl-3-cyanomethyl-2-methylfuran was obtained by chromatography on a Plorisil column (column: 26" long x lg" diameter) eluted with benzene. Fractions of 200ml, were taken and the product collected in fractions Nos. 10-18.

Example 24 5_ >Chlorophenyl-2-cyanomethylfuran (lg. ) was dissolved in dry methanol (200ml.) containing 1$ w/v of dry hydrogen chloride.

After 8 days at ambient temperature volatile material was distilled in vacuo« the residue was triturated with water (l00ml») and extracted with ether (3 x 60ml. ). The ether extract was washed with water (3 x 20ml. ), dried (anhydrous sodium sulphate), decolourised (carbon) and evaporated in vacuo to a solid which was methyl -j≥-cklorcPhenyl-fur-2-ylace a e , m.p.64-66°C.

Example 25 A mixture of 5° parts of dimethyl a-(5-£-chlorophenylthien-2-yl)-a-methylmalonate and 300parts of maize starch was granulated with a sufficient quantity of 10 w/v starch paste. The granules were passed through a 20-mesh screen and dried at a temperature not exceeding 50°0. The dried granules were blended with 4 parts of magnesium stearate and compressed into tablets which contained from 0 to 250mg. of active ingredient. There were thus obtained tablets suitable for oral use for therapeutic purposes.

Instead of the 0 parts of dimethyl a-(5-]-chlorophenylthien-2-yl)~a-methylmalonate there were used 0 parts of dimethyl a-(5-J>-chlorophenylfur-2-yl)-oc-methylmalonate and in a similar manner there vore obtained tablets suitable for oral administration for therapeutic purposes.

Example 26 0 Parts of micronised ethyl 5-J^hlorophenylthien-2«ylacetate were mixed with 130 parts of lactose and 35 parts of a 10^ w/v aqueous gelatine solution, and the mixture was granulated. 4*5 Parts of maize starch were mixed with the granules, and 2 parts of magnesium stearate were then added. The mixture was compressed into tablets containing 50mg. of active ingredient. There were thus obtained tablets which were suitable f or oral administra ion for therapeutic purposes.

Example 27 To a stirred mixture of 20 parts of stearic acid, 15 parts of arachis oil, 5 parts of liquid paraffin and 0.5 part of cetostearyl alcohol heated at 65°C. there was added a solution at 60°C, prepared from 5 parts of a— (4-bromo-5-pi-chlorophenylthien-2-yl)acetic acid, O.75 part of triethanolamine and 53·75 parts of water, and stirring was continued after mixing while the temperature was allowed to fall to 40eC. The mixture was then homogenised by passage through a colloid mill and there was thus obtained a vanishing oream suitable for topical application for therapeutic purposes.

Claims

1. What we claim iss- 1. A heterocyclic compound of the formula:- wherein X stands for hydrogen, a methyl or ethyl radical, or a chlorine or bromine atom, Y stands for a phenyl radical, optionally substituted by one or two fluorine, chlorine or bromine atom(s), and Z stands for a ½2 3 1 IT wherein R stands for hydrogen or a methyl 2 or ethyl radical, R stands for hydrogen or a methyl, ethyl, carboxy, g alkoxycarbonyl, benzyloxycarbonyl or phenoxycarbonyl radical, and R^ stands for a group of the formula -COgR^, -CONHR^ or -CONR^, wherein ^ stands for hydrogen or a ^ alkyl, benzyl or phenyl radical, and R stands for hydrogen or a hydroxy, amino or C^_g dialkylaminoalkyl , radical, and -KR^ stands for an N-piperidino, N-morpholino or N- 2 pyrrolidine radical, and wherein when R stands for a carboxy radical R^ stands for a carboxy radical, and wherein B stands for an oxygen or sulphur atom, and vrherein Y and Z are linked to non-adjacent carbon atoms of the heterocyclic nucleus, or a non-toxic pharmaceutically- acceptable salt thereof.

2. Δ heterocyclic compound of the formula:- vfherein X stands for hydrogen or a methyl radical, Y stands for a phenyl radical, optionally substituted by a fluorine, chlorine or bromine atom, and Z stands for a group of the formula -CR R R , 1 2 wherein R stands for hydrogen or a methyl radical, R stands for hydrogen or a methyl, carboxy, g alkoxycarbonyl, benzyloxycarbonyl or phenoxycarbonyl radical, and R^ stands for a group of the formula -COgR^ or -CONHR^, wherein ^ stands for hydrogen or a alkyl, benzyl 5 or phenyl radioal, and R stands for hydrogen or a hydroxy, amino or dialkylaminoalkyl radical of up to 8 carbon atoms, and wherein when 2 3 R stands for a carboxy radical R stands for a carboxy radical, and wherein B stands for an oxygen or sulphur atom, and wherein Y and Z are linked to non-adjacent carbon atoms of the heterocyclic nucleus, or a non-toxic pharmaoeutically-acceptable salt thereof. 3· A heterocyclic compound of the formulai- wherein X stands for hydrogen or a methyl radical, Y stands for a phenyl radical, optionally substituted by a fluorine, chlorine or 12 3 bromine atom, and Z stands for a group of the formula -CR R R , 1 2 wherein R stands for hydrogen or a methyl or ethyl radical, R stands for hydrogen or a methyl, ethyl, carboxy, alkoxycarbonyl, benzyloxycarbonyl or phenoxycarbonyl radical, and R^ stands for a group of the formula stands for hydrogen, or a 5 alkyl, benzyl or phenyl radical, and R^ stands for hydrogen or a hydroxy or amino radical or a dialkylaminoalkyl radical of up to 8 2 3 carbon atoms, and wherein when R stands for a carboxy radical R stands for a carboxy radical, and wherein B stands for an oxygen or sulphur atom, and wherein Y and Z are linked to non-adjacent carbon atoms of the he erocyclic nucleus, or a non-toxic pharmaceutically-acceptable salt thereof* 4, A heterocyclic compound of the formula:- wherein X stands for hydrogen, a methyl radical, or a chlorine or bromine atom, Y stands for a phenyl radical, optionally substituted by a fluorine, chlorine or bromine atom, and Z stands for a group of the formula wherein R1 stands for hydrogen or a methyl or ethyl 2 radical, R stands for hydrogen or a methyl, ethyl, carboxy, ^2-6 alkoxycarbonyl, benzyloxycarbonyl or phenoxycarbonyl radical, and R^ stands for a group of the formula stands 5 for hydrogen or a - alkyl, benzyl or phenyl radical, and R^ stands for hydrogen or a hydroxy, amino or dialkylaminoalkyl radical of up to 2 3 8 carbon atoms, and wherein when R stands for a carboxy radical R stands for a carboxy radical, and wherein B stands for an oxygen or sulphur atom, and wherein Y and Z are linked to non-adjacent carbon atoms of the heterocyclic nucleus, or a non-toxic pharmaceutically-acceptable salt thereof. 5. A compound as claimed in claim 1 wherein X stands for hydrogen, a methyl radical or a bromine atom, Y stands for a phenyl radical optionally substituted by a fluorine, chlorine or bromine atom, Z stands ½2 3 1 R , wherein R stands for hydrogen or 2 a methyl radical, R stands for hydrogen or a methyl, g alkoxycarbonyl or benzyloxycarbonyl radical, and R^ stands for a group of the formula -C0„R^, -CONHR^ or -CONR^, wherein R^ stands for hydrogen or a ,2 ^ alk l, "benzyl or phenyl radical, provided that when R stands for a g alkoxycarbonyl or benzyloxycarbonyl radical R^ stands for the same or a different Cg g alkoxycarbonyl or benzyloxycarbonyl radical, 5 and R stands for hydrogen or a hydroxy, amino or diethylaminoethyl radical, and - R^ stands for an N-piperidino radical, and B stands for an oxygen or sulphur atom, and Y and Z are linked to non-adjac nt carbon atoms of the heterocyclic nucleus, or a non-toxic pharmaceutically- acceptable salt thereof, 6. A salt as claimed in any of claims 1 to 5 which is an alkali metal salt , alkaline earth metal salt , aluminium salt or ammonium salt , or a salt with a non-toxic pharmaceutically-acceptable organic base. (/ 7» Ethyl 5-£-chlorophenylthien-2-ylacetate f l/ 8. Dimethyl -(5-£-chlorophenylthien-2-yl)-a-methylmalonate« ¾ 9· Methyl 5-£-chlorophenylfur-2~ylacetate. ^ 10. Dimethyl a-(5-P -chlorophenylfur-2-yl)-aHTiethylmalonate . ^ll. a-(4-Bromo-5- j-ohl°rophenylthien-2-yl)acetic acid. 12. Δ process for the manufacture of compounds of the formula X 1 wherein B, X, Y and R have the meanings stated in claim 1, R stands for hydrogen or a methyl or ethyl radical, and R^ stands for a ^ alkyl radical, which comprises reacting a compound of the formulai- X wherein B, X, Y, R and R have the meanings stated immediately above, with an aUanol of the formula R^OH, wherein R^ has the aeaning stated immediately above, in the presence of sulphuric or hydrochloric acid, provided that when B stands for an oxygen atom the acid is hydrochloric aeid. 13· A process for the manufacture of compounds of the formula:- wherein B, X and Y have the meanings stated in claim 1 and R stands for hydrogen or a alkyl radical, and pharmaceutically-acceptable salts thereof, which comprises carrying out the Arndt-Eistert reaction on an acid halide of the formula wherein B, X and Y have the meanings stated in claim 1 and Hal stands for a chlorine or bromine atom. 14· A process for the manufacture of amides of the formula:- CR V. CO Hg VI wherein B, X, Y,and R have the moanings stated in claim 1 and R has the meaning stated in claim 12, which comprises hydrolysing a nitrile of the formula III given in claim 12 wherein B, X, Y, R 1 and R7 have the meanings stated immediately above. 15» A process for the manufacture of compounds of the formula: wherein B, X, Y and R have the meanings stated in olaim 1 and R has the meaning stated in claim 12, and non-toxic pharmaceutically-acceptable salts thereof, which comprises hydrolysing a compound of the formula:- wherein B, X, Y, R and R have the meanings stated in claim 1, and stands for a cyano, carbamoyl, thiocarbamoyl, C2-6 a-^oxycar^ony 1 benzyloxycarbonyl or phenoxycarbonyl radical. 16. Δ process for the manufacture of amides of the formula:- wherein B, X, Y and R have the meanings stated in claim 1, R has the 5 6 meaning stated in claim 12, and -UW stands for -NHR or -UR wherein 5 6 R^ and R have the meanings stated in claim 1, which comprises reacting a compound of the formula:- wherein B, X, Y, R and R have the meanings stated immediately above, and Q stands for a chlorine or bromine atom or a - alkoxy, benzyloxy or phenoxy radical} with a compound of the formula HNW wherein -NW has the meaning stated immediately above. 17. A process for the manufacture of esters of the formula:- wherein B, X, Y and R have the meanings stated in claim 1, R has the carboxylic acid halido or carboxylic acid anhydride, l8« Δ process for the manufacture of compounds of the formula:- wherein B, X and Y have the meanings stated in claim 1, R stands for 2 a methyl or ethyl radical, and R stands for hydrogen or a methyl, ethyl, g alkoxycarbonyl, benzyloxycarbonyl or phenoxyoarbonyl radical, and stands for a Ci_i 5 alkyl, benzyl or phenyl, ' ts30£n£& i-x iM^t&W} g$ which comprises reacting an alkali metal derivative of a compound of the formulaj- wherein B, X, Ύ, R and R have the meanings stated immediately above with a methyl or ethyl halide selected from chlorides, bromides and iodides. 19. A process for the manufacture of compounds of the formula:- wherein B, X and Y have the meanings stated in claim 1, R stands for hydrogen or a methyl or ethyl radical, and R 4^" and R 4*, which may be the same or different, stand for a ^ alkyl, benzyl or phenyl radical, which comprises reacting sodium or potassium or a hydride, amide or ^ alkoxide thereof, with a carbonate of the formula C0.(0R^)2, wherein ^ has the meaning stated immediately above, and a compound of the formula:- wherein B, X, Y, R and R have the meanings stated immediately above. 20, A process for the manufacture of compounds of the formula:- wherein B. X, Y and R have the meanings stated in claim 1, and pharmaceutically-acceptable salts thereof, which comprises reacting a compound of the formula XIV given in claim 1 wherein B, X, Y and R A 4* have the meanings stated immediately above and and R have the meanings stated in claim 1 , with an inorganic base in the presence of water and under the influence of heat, or, in the case where B stands for a sulphur atom, with an inorganic acid in the presence of water and under the influence of heat. 21. A process for the manufacture of compounds of the formula XII given in claim 18 wherein B, Y and R^" have the meanings stated in claim 2 1, X stands for a chlorine or bromine atom, R stands for hydrogen or a methyl, ethyl, g alkoxycarbonyl, benzyloxycarbonyl or phenoxy-carbonyl radical, and R^ stands for a C-^- alkyl, benzyl or -phenyl radical, which comprises reacting a compound of the formula XII given in claim 18 wherein B, Y, have the meanings stated immediately above and X stands for hydrogen, in the presence of an alkali metal acetate, with a solution of chlorine or bromine in an organic solvent. 22. A process for the manufacture of esters of the formula XII given in claim l8 wherein B, X, Y and R^ have the meanings stated in 2 claim 1, R stands for hydrogen or a methyl, ethyl, C^_g alkoxycarbonyl, benzyloxycarbonyl or phenoxycarbonyl radical, and ^ stands for a C, alkyl, benzyl or phenyl radical, which comprises reacting a methyl or ethyl ester of the said formula XII wherein B, X, Y and R have the 2 meanings stated above, R stands for hydrogen or a methyl, ethyl, methoxycarbonyl or ethoxycarbonyl radical, and R^ stands for a methyl or ethyl radical, with a ^ alkanol, benzyl alcohol or phenol, in the presence of a known metallic transesterif icatxon catalyst at a temperature in the range 25° to 200°C. 2

3. A process as claimed in claim 22 in whioh the transesterif ication catalyst is dibutyl tin dilaurate , 2

4. A process for the manufacture of compounds of the formula:- wherein B, X and Y have the meanings stated in claim 1, which comprises first carrying out the Willgerodt reaction on a compound of the f ormula:- C0CH3 XVIII wherein B, X and Y have the meanings stated immediately above , and then hydrolysing the product by means of an inorganic base , and then converting the resulting salt into the corresponding oarboxylic acid of formula XVII in a manner known per se* 25· A heterocyclic compound or a non-toxic pharmaceutically-acceptable salt thereof , whenever obtained by a process claimed in any of claims 12 to 2 · 26» A pharmaceutical composition, comprising a compound claimed in claim 1 and a non-toxic pharmaceutically—acceptable diluent or carrier* 27» Δ pharmaceu ical composition as claimed in claim 26 which is in the form of a tablet, pill, capsule ^ suppository, non-sterile aqueous or non-aqueous solution or suspension, sterile injectable aqueous or non-aqueous solution or suspension, cream, lotion or ointment, 28. A pharmaceutical composition as claimed in claim 26 or 27 which contains, in addition to the compound claimed in claim 1, at least one known agent having an i-inflammatory and/or analgesic activity. 2 · A pharmaceu ical composition as claimed in claim 26, 2 or 28 and suitable for oral administration which contains, in addition to the compound claimed in olaim 1, at least one an i-cholinergic agent, and/or an antacid, and/or a uricosuric agent. 30· pharmaceutical composition as claimed in claim 26, 27 or 28 and suitable for topical application x-jhich contains, in addition to the compound claimed in claim 1, a vasodilating or vasoconstricting agent, a local anaesthetic, or a counter-irritant, and/or at least one agent chosen from the following classes: antibacterial agents, antifungal agents, an histaminic agents, and rubefacient agents. 31. A heterocyclic compound, claimed in claim 2 , substantially as described in Example 1 or 2. 32. A heterocyclic compound,, claimed in claim 3, substantially as described in Example 3, 4 °r 5· 33. A heterocyclic compound, claimed in claim 4 , substantially as described in Example 6, 7 » 8 or 9· 34· A heterocyclic compound, claimed in claim lt substantially as described in any of Examples 10 to 24 · 35 · A pharmaceutical composition, claimed in claim 26, substantially as described in Example 25 , 26 or 27· S. HOROWITZ & CO. Agents for Applicants