IL31679A

IL31679A - Thiazole derivatives

Info

Publication number: IL31679A
Application number: IL31679A
Authority: IL
Original assignee: Ici Ltd
Priority date: 1968-03-22
Filing date: 1969-02-23
Publication date: 1972-08-30
Also published as: CH553209A; NL6903963A; CH513907A; ES365089A1; IE32967L; AT284841B; GB1192701A; CS154267B2; BR6807374D0; CS154268B2; IE32967B1; CS154266B2; DK125251B; CA948199A; FR2004544A1; BE730284A; US3661920A; DE1913472A1; DK122393B; DK125326B

Description

THIAZOLE DERIVATIVES >iT8*n rm>in This invention relates to new heterocyclic compounds and more particularly it relates to new thiazole derivatives which have antiinflammatory! analgesic and antipyretic activity.

According to the invention vie provide compounds which in one of their tautomeric forms are thiazole derivatives of the formula:- wherein Y or Z is linked to the 2-position of the thiazole nucleus, X stands for hydrogen or an alkyl radical of not more than 3 carbon atoms, Y stands for the phenyl radical or a phenyl radical which is substituted by not more than two halogen atoms selected from fluorine, chlorine and bromine atoms, and Z stands for a group of the formula:- R1 wherein R stands for hydrogen, an alkali metal atom, an alkyl radical of not more than 3 carbon atoms, a dialkylaminomethyl radical of not more than 5 carbon atoms, the N-piperidinomethyl or -morpholinomethyl 2 3 radical, or a chlorine or bromine atom, and R and R , which may be the same or different, stand for hydrogen or an alkyl radical of not more 2 3 than 3 carbon atoms, provided t;hat when R and R stand for hydrogen, R^" stands for hydrogen or an alkyl radical of not more than 3 carbon atoms, and non-toxic, pharmaceutically-acceptable salts thereof.

The thiazole nucleus is numbered as follows :- 1 It is to be understood that, in the thiazole derivatives of this invention, either Y is linked to position 2 and Z is linked to position 4 or 5» or Z is linked to position 2 and Y is linked to position 4 or 5· This general situation also obtains throughout this specification, thus, it obtains in the case of the intermediates used in making the thiazole derivatives of the invention. It is also to be understood that, in the case where Z is in the 2-position of the thiazole nucleus and R stands for hydrogen, the compounds of the invention may exist predominantly in the tautomeric Δ^-thiazoline form. However, for convenience, in this specification all the compounds of the invention will be named as thiazole derivatives.

As a suitable value for X there may be mentioned, for example, hydrogen or the methyl radical.

As a suitable value for R1 there may be mentioned, for example, hydrogen, the sodium or bromine atom, or the methyl, dimethyl-aminomethyl, N-piperidinomethyl or N-morpholinomethyl radical. 2 3 As a suitable value for R or R there may be mentioned, for example, hydrogen or the methyl or ethyl radical.

As suitable salts in the case where R and/or R stands for hydrogen there may be mentioned, for example, a salt formed from that carboxylic acid and a non-toxic, phar aceutically-acceptable oation, for example an alkali metal salt, an alkaline earth metal salt, or an aluminium or ammonium salt, or a salt with a non-toxic, pharmaceutically-acceptable organic base. In cases where the thiazole derivative of the invention is sufficiently basic, suitable salts are non-toxic pharmaceutically-acceptable acid-addition salts.

Preferred specific compounds of the invention are dimethyl a-[4-(4-bromophenyl)thiazol-2-yl]-a-methylmalonate, dimethyl 2-(4- chlorophenyl)thiazol-4-ylmalonate, the cc-sodium derivative of dimethyl 2-(4-chlorophenyl)thiazol-4-ylmalonate, and dimethyl o-[2-(4-ohloro- phenyl)thiazol-4-yl]-a-methylmalonate· According to a further feature of the invention we provide a process for the manufacture of compounds which in one of their tautomeric forms have the formula:- wherein Y or -CH(C02R4).C02Ir is linked to the 2-position of the thiazole nucleus, and X stands for hydrogen or an alkyl radical of not 4 5 more than 3 carbon atoms, Y has the meaning stated above, and IT and R which may be the same or different, stand for an alkyl radical of not more than 3 oarbon atoms, and non-toxic pliarmaceutically-acceptable acid-addition salts thereof, which comprises reacting a compound of the formula:- H wherein Y or -GH_R is linked to the 2-position of the thiazole nucleus, and, when R stands for hydrogen, -CHg is linked to the 2-position of the thiazole nucleus, and X and Ύ have the meanings stated above, and 5 stands for hydrogen or a -GQ^B. group wherein R has the meaning stated above, with a carbonate of the formula R^O.CO.OR^ wherein R^ has the meaning stated above, and sodium or potassium or a hydride, amide or j alkoxide thereof, 4 5 Suitable values for R and Ήτ are those stated above in 2 3 respect of R and R , but excluding hydrogen. The reaction may be carried out in an excess of the carbonate used as reaotant and/or in an inert solvent, for example ether. The reaction may optionally be carried out under the influence of heat, for example at a temperature of 70°-150°G.

According to a further feature of the invention we provide a process for the manufacture of oompounds which in one of their tautomeric forms have the formula:- wherein X, Y, R4" and R^ have the meanings stated above, and R stands for hydrogen or an alkyl radical of not more than 3 carbon atoms, and non-toxic pharmaceutically-acceptable acid-addition salts thereof, which comprises reacting a compound of the formulai- wherein X and Y have the meanings stated above and Hal stands for a chlorine, bromine or iodine atom, with a compound of the formula:- „1 M-C-COglT wherein R , R and R^ have the meanings stated above, and K stands for an alkali metal atom.

The reaction may be carried out in an excess of the appropriate malonato derivative and/or in an inert solvent, for example dimethyl ormamide. The reaction may optionally be accelerated or completed by the application of heat.

According to a further feature of the invention we provide a process for the manufacture of compounds of the formula:- wherein Y or -C lk(C02R4).C02I is linked to the 2-position of the A 5 thiazole nucleus, and X, Y, R and R have the meanings stated above, and Alk stands for an alkyl radical of not more than 3 carbon atoms, and non-toxic pharmaceutioally-accept ble acid-addition salts thereof, which comprises alkylating a compound which in one of its tautomeric forms has the formula wherein Y or -CH(C02R ).C02Ir is linked to the 2-position of the thiazole A 5 nucleus, and X, Y, ϊτ and Ir have the meanings etated above, so as to introduce an alkyl radical of not more than 3 carbon atoms into the a-position.

The alkylation may be carried out by the interaction of an alkali metal derivative of the appropriate thiazole derivative with an alkyl halide of not more than 3 carbon atoms, for example methyl iodide. An organic solvent, for example dimethylformamide, may optionally be present .

According to a further feature of the invention we provide a process for the manufacture of compounds of the formula:- wherein Y or the 2-position of the thiazole nucleus, and have the meanings stated above and M stands for an alkali metal atom, which comprises reacting a compound of the formula:-^ C-C02R wherein Y or -CH(C02R4).C02R5 is linked to the 2-position of the A thiazole nucleus, and X, Y, IT" and Br have the meanings stated above t with an alkali metal or a hydride, amide or C-^ alkoxide thereof.

The reaction is conveniently carried out in an organic solvent, or example ether* According to a further feature of the invention we provide a process for the manufacture of compounds which have the formula:- wherein Y or -CR (C02R4).C02I is linked to the 2-position of the thiazole nucleus, and R^ stands for a dialkylaminomethyl radical of not more than 5 carbon atoms or the N-piperidinomethyl or N-morpholinomethyl radical, and X, Y, R^ and R have the meanings stated above, and nontoxic pharmaceutically-acoeptable acid-addition salts thereof, which comprises reacting a compound which in one of its tautomeric forms has the formula:- wherein Y or -CH(C02R4).C02R^ is linked to the 2-position of the thiazole nucleus, and X, Y, ^ and R-' have the meanings stated above, with formaldehyde and either a dialkylamine of not more than 4 carbon atoms or piperidine or morpholine.

The formaldehyde is conveniently used in the form of an aqueous solution, and an organic solvent, for example methanol, may optionally also "be present.

According to a further feature of the invention we provide process for the manufacture of compounds of the formula:- wherein Y or o the 2-posi ion of the thiazole nucleus, and X, Y, IT A" and R5 have the meanings stated above, and Hal stands for a chlorine or bromine atom, which comprises reacting a compound which in one of its tautomeric forms has the formula:- H wherein Y or the 2-position of the A 5 thiazole nucleus, and X, Y, R^ and R^ have the meanings stated above, with chlorine, bromine, N-bromosuccinimide or phenyltrimethylammonium perbromide.

The last-named reaction may be carried out in an inert solvent, for example ether or tetrahydrofuran. The reaction involving chlorine or bromine itself may be carried out in glacial acetic acid in the presence of an alkali metal acetate.

According to a further feature of the invention we provide a process for the manufacture of compounds of the formula:- 1 wherein X and Y have the meanings stated above, and R stands for hydrogen or an alkyl radical of not more than 3 carbon atoms, which comprises reacting a corresponding alkali metal salt, alkaline earth metal salt, aluminium salt or ammonium salt with an acid at a relatively low temperature.

As a suitable acid there may be mentioned an inorganic acid, for example hydrochloric acid, or a sufficiently strong organic acid, for example acetic acid. The reaction should be carried out at a relatively low temperature, for example at or below 0eC., in order to prevent decomposition of the product.

It is to be understood that the non-toxic, pharmaceutically-acceptable salts of the invention may be obtained by means of conventional procedures.

It is also to be understood that the starting materials used in the above processes can be obtained by known general methods.

Aooording to a further feature of the invention we provide pharmaceutical compositions comprising at least one compound which in one of its tautomeric forms is a thiazole derivative of the formula wherein Y or Z is linked to the 2-position of the thiazole nucleus, and X, Y and Z have the meanings stated above, or a non-toxic pharmaceutically-acceptable salt thereof, and a non-toxio pharmaceutically-acceptable diluent or carrier.

The pharmaceutical compositions may, for example, be in the form of tablets, pills, oapsules, suppositories, non-sterile aqueous or non-aqueous solutions 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 compounds which characterise this invention, at least one known agent having anti-inflammatory or analgesic activity, for example aspirin, paracetamol, codeine, chloroquine, phenylbutazone, oxyphenbutazone , indomethacin, mefenamic acid, flufenamic acid, ibufenac, or an anti-inflammatory steroid, for example prednisolone. Those compositions intended for oral administration may, in addition, optionally contain an anti-cholinergic agent, for example homatropine methyl bromide, and/or an antacid, for example aluminium hydroxide, or a uricosuric agent, for example probenecid. Those compositions suitable 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, a counter-irritant, for example capsicum; and/or at least one agent chosen from the following classes of substancee: anti-baoterial agents, which includes sulphonamides and antibiotics having antibacterial action, for example neomycin; anti-fungal agents, for example hydroxyquinoline 5 anti- histaminio agents, for example promethazine; and rubefacient agents, for example methyl nicotinate.

The invention is illustrated but not limited by the following Examples Example 1 A mixture of sodium hydride (4.8g. , - weighed as a $Oo dispersion in oil, and subsequently washed free from oil by decantation with light petroleum), diethyl carbonate (36ml.), and 4-(4-bromophenyl)-2-methylthiazole (5.1g. ) was stirred under reflux for 3 hours in an oil-bath at 13 -140°C The mass, which was then of a thick consistency, was treated with sufficient ethanol to destroy the excess of sodium hydride. Water (50ml.) was added, and the solid present was extracted with ohloroform (3 x ^Ol,), the extract being washed in turn with dilute hydrochloric acid (40ml.), aqueous sodium carbonate (l0$ w/v, 40ml.), and water (40ml.). The chloroform solution was dried with anhydrous sodium sulphate, and evaporated down to give a residue which was crystallised from ethanol and yielded diethyl 4-(4-bromophenyl)thiazol-2-ylmalonate, m.p.130-1 leC, Example 2 A mixture of sodium hydride (7.2g. , - see Example 1 for procedural details), dimethyl carbonate (52ml.), and 4-(4-bromophenyl)-2-methylthiazole (7»6g. ) was stirred under reflux for 6 hours in an oil-bath at 105-115°C. The resulting thick suspension wes cooled, and any excess of sodium hydride was destroyed by addition of methanol. Water (80ml.), and sufficient hydrochloric acid to give a pH of 7f were added. The solid present was extracted into methylene dichloride (3 x 80ml.). The extract was washed with dilute aqueous sodium carbonate (10 w/v, 50ml.) and then with water (50ml.), It was dried with anhydrous sodium sulphate, and evaporated down to leave a solid, which was triturated with ethyl acetate (50ml.) to remove unchanged starting material.

Crystallisation of the residue from chlorobenzene , in the presence of decolourising carbon, gave dimethyl 4-(4-hromophenyl)thiazol-2-yl-malonate, m.p.l73-174°C.

Example 3 Dimethyl 4-(4-bromophenyl)thiazol-2-ylmalonate (l,85g. ) was added to a suspension of sodium hydride (0.24g«, see Example 1 for procedural details) in dry dimethylformamide (l5ml.), and stirred for 30 minutes at 35eC. Methyl iodide (1.25ml.) was then added, and stirring at 35°C« was continued for a further 1 hour. The mixture was cooled to 10°C. and diluted carefully with water (30ml.). Traces of methyl iodide were distilled off under reduced pressure, and the solid was collected by filtration, washed with water, and dried in vacuo over phosphorus pentoxide. Crystallisation from light petroleum (b.p.60-80eC.) gave dimethyl a-[4-(4-bromophenyl)thiazol-2-yl]-a-methylmalonate, m.p.64-65.5eC.

Example 4 Diethyl malonate (6.1ml.) was added to a suspension of sodium hydride (l.9g. | see Example 1 for procedural details) in dry dimethyl-formamide (25ml,) and stirred for 30 minutes. 2-Bromo-4-(4-bromophenyl)-thiazole (5·4δ») was then added. The mixture was stirred and heated under reflux for 4 hours in an oil-bath at 145-155°C. Water (50ml.), and sufficient hydrochloric acid to give a pH of 7, were added to the cooled mixture, and the precipitated solid was collected by filtration, and washed successively with water (40ml.) and ether (50ml.) to remove ooloured contaminants. The solid was dissolved in methylene dichloride (lOOml.), and the solution was successively washed with aqueous sodium carbonate (10$ w/v, 30ml.) and *ater (30ml.). The solution was dried over anhydrous sodium sulphate, treated with decolourising carbon, filtered and evaporated to dryness. Two crystallisations from ethanol gave diethyl 4-(4-bromophenyl)thiazol-2-ylmalonate, identical in physical properties with material prepared by the procedure described in Example 1.

Example 5 Sodium hydride (0.26g. ) was suspended in dry ether (60ml.) and a solution of methyl 2-(4~chlorophenyl)thiazol-4-ylacetate (2.6g. ) in dry ether (60ml.) was added dropwise with stirring over 30 minutes. A solution of dimethyl carbonate (l.8g. ) in dry ether (10ml.) was added over 15 minutes, and the resulting mixture was stirred under nitrogen for 16 hours at room temperature. A further quantity of sodium hydride (0.26g.) was then added and the mixture was stirred for a further 3 hours. The mixture was filtered, and the residue was washed with ether, and then stirred with 2N-aqueous sodium hydroxide (30ml.) and filtered. There was thus obtained as solid residue the a-sodium derivative of dimethyl 2-(4-chlorophenyl)thiazol-4-ylmalonate dihydrate, m.p, 133°C.

This sodium derivative (2g.) was suspended in a mixture of water (50ml.) and ether (50ml.), and N-aqueous hydrochloric acid (50ml.) was added with vigorous stirring. The ether layer was separated, washed well with water, dried with anhydrous magnesium sulphate, and evaporated to dryness. The residue was crystallised from n-hexane to give dimethyl 2-(4-chlorophenyl)thiazol-4-ylmalonate, m.p.46°C.

Example 6 A solution of bromine (0.8g. ) in glacial acetic acid (lOml. ) was added over 10 minutes to a stirred mixture of dimethyl 2-(4-chloro-phenyl)thiazol-4-ylmalonate (l.6g. ) and anhydrous sodium acetate (0.82g. ) in glacial acetic acid (20ml. ) at room temperature. After 30 minutes, the mixture was poured into water (lOOml. ) , and the product was extracted into ether (50ml. ) . The ethereal extract was dried over anhydrous magnesium sulphate , the solvent was evaporated in vacuo , and the residue was orystallised from cyclohexane . There was thus obtained dimethyl a-bromo-a-[2-(4-chlorophenyl)thiazol-4-yl]malonate , m.p.llO-llleC.

Example 7 An aqueous solution of 40 dimethylamine (2.84ml, ) was added to a stirred solution of dimethyl 2-(4-chlorophenyl)thiazol-4-yl-malonate (8g. ) in methanol ( l6ml* ) . To the resulting suspension there was added dropviise a 36$ w/v aqueous solution of formaldehyde (2.16ml. ) over 5 minutes at room temperature. After stirring the mixture for one hour, the product was collected by filtration and washed with 50 aqueous ethanol. There was thus obtained dimethyl oc-[2-(4-chlorophenyl)-thiazol-4-yl]-a-dimethylaminomethylmalonate, m. p. 5-96° C.

Example 8 A mixture of sodium hydride (3.4g» t 50$ dispersion - see Example 1 for procedural details) , dimethyl oarbonate (21ml, ) , and 5-(4-chlorophenyl)-2-methylthiazole (2.9g. ) was stirred under reflux in an oil-bath at 105-115*0. for 4½- hours. The mixture, which had become very thick, was cooled, diluted with ether (25ml. ) , treated with sufficient methanol to destroy any remaining sodium hydride, and mixed with water (50ml. ) . Sufficient acetic acid was added to give a pH of 7» and the solid present was collected by filtration, washed well with water and dried. Crystallisation from chlorobenzene in the presence of decolourising carbon gave dimethyl 5-(4-chlorophenyl)thiazol-2-ylmalonate, m.p.212.5-214°C.

In a similar fashion, but using diethyl carbonate instead of dimethyl carbonate , and a reaction time of !¾· hours at 13 -140°0· ι there was obtained diethyl 5-(4-chlorophenyl)thiazol-2-ylmalonate , m. p.161-161.5eC. (crystallised from n-propanol) , The 5-(4-c^lorophenyl)-2-methylthiazole used as starting material was obtained as follows :- 5-(4-Chlorophenyl)-2-methyloxazole (7.75g» - »η·ρ.74·5-75·5βΟ· 5 prepared by the action of sodium azide and sulphuric acid on 4-°hlor°-benzoylacetone by an adaptation of a known procedure for the preparation of 2-methyl-5-phenyloxazole) was intimately mixed with finely-powdered phosphorus pentasulphide (8.9g. ) and heated directly over a flame to give a dark, viscous melt. After minutes, the melt was allowed to cool, and the mixture was boiled with aqueous 4N-hydrochloric acid ( 150ml. ) for 20 minutes. The resultant suspension was cooled and filtered, and the filtrate was clarified by addition of kieselguhr, and then filtered again. Aqueous sodium hydroxide was added slowly to the filtrate, which was cooled to 10-20°C. and stirred during the addition. When the pH had reached 7» the resulting precipitate was collected by filtration, and was washed well with water. It was crystallised from a 4:1 mixture of methanol and water to give 5-(4-chlorophenyl)-2-methylthiazole , m.p.83.5-S4.5°C.

V-' Example 9 Dimethyl 5-(4-chlorophenyl)thiazol-2-ylmalonate (3.9g» ) was added to a suspension of sodium hydride (0.6g. , dispersion, treated as in Example l) in dry dimethylf ormamide (35nl« ) » a d the mixture was stirred at 30-35eC. for 30 minutes. Methyl iodide (7»lg» ) was added, and stirring at 30-35cC. was continued for a further hour. The liquid was then cooled to 15eC , and diluted with water (50ml. ) .

Extraction with ether (3 x 50ml, ) gave a solution which was washed with water (3 x 40ml. ), dried over anhydrous sodium sulphate, and evaporated to dryness. The residual solid was a mixture which was separated into its two components by passing a solution of the material in benzene down an alumina column (200g. of alumina). One compound passed through readily, and was recovered by evaporation of the eluate and crystallised from acetonitrile to give dimethyl a-[5-(4-chlorophenyl)-thiazol-2-yl]-a-methylmalonate, m,p.l29-130°C. The second component , eluted from the oolumn with chloroform, was 5-(4-chlorophenyl)-2-[di-( methoxycarbonyl )methy lene] -1-methy Ι-Δ^-t hiazoline .

Example 10 The oc-sodium derivative of dimethyl 2-(4-chlorophenyl)thiazol-4-yimalonate (2.5g. ) was suspended in dry dimethylf ormamide (20ml. ) , and methyl iodide (lml. ) was added. The mixture was stood at 15-20* C. for 16 hours. Water (200ml. ) was added, and the mixture was extracted with ether (lOOml. ) . The ethereal layer was washed with water, dried over anhydrous magnesium sulphate , filtered and evaporated to dryness, giving dimethyl a-[2-(4-chlorophenyl)thiazol-4-yl]-a-methylmalonate was obtained as a yellow oil, examination by N. .R. shows a methyl signal at 6 3.7ppra« and methyl ester signal at l,65ppm.

Example 11 A mixture of methyl 2-(4-chlorophenyl)-4-methylthiazol-5-ylacetate (14.6g» ) , sodium hydride (2.5g. ) and dimethylcarbonate (50ml. ) was stirred at a hath temperature of lOO-llCfor ½- hours. Methanol (lOml. ) was added to destroy the excess of sodium hydride , and immediately afterwards 10$ v/v aqueous acetic acid (200ml. ) was added. The resultant mixture was extracted with 3 separate portions of chloroform (50mli, each). The combined chloroform extracts were washed with water (3 x 100ml. ) , dried over anhydrous magnesium sulphate , filtered and evaporated to dryness. The resultant solid residue was crystallised from cyclohexane to give dimethyl 2-(4-chlorophenyl)-4-methylthiazol-5-ylnialonate , m, p.140-141" C.

Example 12 A solution of dimethyl 2-(4-chlorophenyl)thiazol-4-ylmalonate (3«25g. ) and piperidine (lml. ) in methanol (15ml. ) was stirred at 15°C. , and a $&fo w/v aqueous solution of formaldehyde ( lml. ) was added over 5 minutes. After 10 hours , water (5^1. ) was added, and after a further 12 hours a solid had precipitated. This solid was collected by filtration and washed with 5° aqueous methanol ( lOml.-). There was thus obtained dimethyl a-[2-(4-chlorophenyl)thiazol-4-yl]-a-(N--piperidinomethyl)malonate, m,p.90~91°C.

In similar manner but using morpholine ( lml. ) instead of piperidine there was obtained dimethyl a-[2-(4-chlorophenyl)thiazol-4-yl]-a-(N-morpholinomethyl)malonate , m.p, 124-126°C.

Example 13 A mixture of methyl 2-(2 ,4-dichlorophenyl)thiazol-4-yl-acetate ( l,6g. ) , sodium hydride (0.7g. ) and dimethyl carbonate (lOml, ) was stirred under reflux (bath temperature 100-110*0.) for 3 hours.

The mixture was cooled, and methanol (5ml.) was added to destroy the excess of sodium hydride. An aqueous solution of 10$ v/v acetic acid (50ml.) was added, and the resultant mixture was extracted with ether (3 x 50ml.). The combined ethereal extracts were washed with water (3 x 100ml.), dried over anhydrous magnesium sulphate, filtered, and evaporated to dryness. The residue was crystallised from petroleum ether (b.p.60-80°C.) to give dimethyl 2-(2,4-dichlorophenyl)thiazol-4-ylmalonate, m.p.92-94*C.

Example 14 Diethyl a-methylmalonate (3»5g») w¾s added to a suspension of sodium hydride (0.96g. , 50$ dispersion, treated as in Example l) in dry dimethylformamide (l2ml.), and the mixture was stirred at ambient temperature until evolution of hydrogen had ceased. 2-Bromo-4-(4-bromophenyl)thiazole (3.2g. ) was added, and the mixture was stirred in an oil-bath at llO'C. for !¾■ hours. The solution was cooled, diluted with water (50ml«) and extracted thoroughly with methylene dichloride (3 x 50ml.). The extract was washed with water (3 x 30ml.), dried over anhydrous sodium sulphate, and evaporated to give an oil. This was submitted to thin layer chromatography on silica, with benzene as developing solvent. Elution of the appropriate band with ether and recovery by evaporation gave diethyl a-[4-(4-Dromophenyl)thiazol-2-yl]-oc-methylmalonate which was crystallised from petroleum ether (b.p.40-60ec), and had m.p.45-46°C.

Example 15 A solution of dimethyl 2-(4-chlorophenyl)thiazol-4-ylmalonate (0.65g.) in dimethylformamide (lOml.) was stirred at 0-5°C. and 10N- aqueous sodium hydroxide (0»6ml.) was added. After stirring for 12 hours, dry ether (20ml.) was added. The resulting precipitate was collected "by filtration and washed with dry ether (20ml.) to give disodium 2-(4-ohlorophenyl)thiaaol-4-ylmalonate, m.p.296eC. (decomposition). This salt was dissolved in water (20ml.), and glacial acetio acid was added at a temperature "below 10°C. until precipitation ceased. The mixture was filtered to give 2-(4~chloro-phenyl)thiazol-4-ylmalonic acid. This melted with decomposition over the range 50-70*0. (to give 2-(4-ohlorophenyl)thiazol-4-ylacetic acid, m.p.l54,5"fi.).

Example 16 A mixture of dimethyl a-[4-(4-bromophenyl)thiazol-2-yl]-oc-methylmalonate (lOOg. ) and maize starch (300g. ) was granulated with a sufficient quantity of 10$ w/v starch paste. The granules were passed through a 20-mesh screen, and were dried at a temperature not exceeding 50°C. The dried granules were blended with magnesium stearate (4g») and then compressed into tablets containing from 50 to 250mg. of active ingredient. There were thus obtained tablets suitable for oral use for therapeutic purposes.

Claims

What we claim is:

1. A compound which in one of its tautomeric forms is a thiazole derivative of the formul :- wherein Y or Z is linked to the 2-position of the thiazole nucleus, X stands for hydrogen or an alkyl radical of not more than 3 carbon atoms, Y stands for the phenyl radical or a phenyl radical which is substituted by not more than two halogen atoms selected from fluorine, chlorine and bromine atoms, and Z stands for a group of the formula:- wherein R stands for hydrogen, an alkali metal atom, an alkyl radical of not more than 3 carbon atoms, a dialkylaminomethyl radical of not more than 5 carbon atoms, or the N-piperidinomethyl or -morpholino- 2 3 methyl radical, or a chlorine or bromine atom, and R and R , whxch may be the same or different, stand for hydrogen or an alkyl radical of not 2 3 more than 3 carbon atoms, provided that when R and R stand for hydrogen, R^" stands for hydrogen or an alkyl radical of not more than 3 carbon atoms, or a non-toxic pharmaceutically-acceptable salt thereof. 2. A compound which in one of its tautomeric forms is a thiazole derivative of the formula:- t wherein Y or Z is linked to the 2-position of the thiazole nucleixs, X stands for hydrogen or an alkyl radical of not more than 3 carbon atoms, Y stands for the phenyl radical or a phenyl radical which is substituted by not more than two halogen atoms selected from fluorine, chlorine and bromine atoms, and Z stands for a group of the formul :- 1 wherein R stands for hydrogen, an alkali metal atom, an alkyl radical of not more than 3 carbon atoms, a dialkylaminomethyl radical of not 2 3 10 more than 5 carbon atoms, or a chlorine or bromine atom, and R and R which may be the same or different, stand for hydrogen or an alkyl

2. 3 radical of not more than 3 carbon atoms, provided that when R and R stand for hydrogen, ^" stands for hydrogen or an alkyl radical of not more than 3 carbon atoms, or a non-toxic, pharmaceutically-acoeptable salt thereof.

3. » A compound as claimed in claim 1 which in one of its tautomeric forms is a thiazole derivative of the formulas- wherein Y or Z is linked -to the 2-position of the thiazole nucleus, X stands for hydrogen or the methyl radical, Y has the meaning stated in claim 1, and Z stands for a group of the formula;- wherein R stands for hydrogen, the sodium or bromine atom, or the methyl, dimethylaminomethyl, N-piperidinomethyl or N-morpholinomethyl radical, and R 2 and R 3 , which may he the same or different , stand for hydrogen or the methyl or ethyl radical, or an alkali metal salt , alkaline earth metal salt , aluminium or ammonium salt , or a salt with a non-toxic pharmaceutically-aoceptable organio base, or a non-toxic pharmaceut i ca 1 ly-acoe p able acid-addit i on s alt ·

4. * A compound as claimed in claim 2 whioh in one of its tautomeric forms is a thiazole derivative of the formula:- wherein Y or Z is linked to the 2-position of the thiazole nucleus, X stands for hydrogen or the methyl radical, Y has the meaning stated in claim 2 , and Z stands for a group of the formula :- wherein R stands for hydrogen, the sodium or bromine atomt or the 2 3 methyl or dimethylaminomethyl radical, and R and R , which may he the same or different, stand for hydrogen or the methyl or ethyl radical, or an alkali metal salt, alkaline earth metal salt, aluminium or ammonium salt, or a salt with a non-toxio pharmaceutically-acceptable organic base, or a non-toxic pharmaceutically-acceptable acid-addition salt.

5. Dimethyl a-[4-(4-bromophenyl)thiazol-2-yl]-o-methylmalonate.

6. Dimethyl 2-(4-chlorophenyl)thiazol-4-ylntalonate.

7. » The of-sodium derivative of dimethyl 2-(4-chlorophenyl)thiazol- 4-ylmalonate.

8. Dimethyl a-[2-(4-chlorophenyl)thiazol-4-yl]-a-methylmalonate.

9. Δ process for the manufacture of compounds whioh in one of their tautomeric forms have the formula:- wherein Y or -CH(C02 ).C02Rp is linked to the 2-position of the thiazole nucleus, and X stands for hydrogen or an alkyl radical of not more than 3 carbon atoms, Y has the meaning stated in claim 1, and R^ 5 and R , which may be the same or different, stand for an alkyl radical of not more than 3 carbon atoms, and non-toxic pharmaoeutically-acoeptable acid-addition salts thereof, which comprises reacting a compound of the formula:- 6 wherein Y or -CHgR is linked to the 2-position of the thiazole nucle s! and, when R^ stands for hydrogen, -CHgR^ is linked to the 2-position of the thiazole nuoleus, and X and Y have the meanings stated above, 6 5 5 and R stands for hydrogen or a -COg ^ group wherein R has the meaning stated above, with a carbonate of the formula R^O.CO.OR^ wherein ^ has the meaning stated above, and sodium or potassium or a hydride, amide or ^ alkoxide thereof.

10. A process for the manufacture of compounds which in one of their tautomeric forms have the formula:- wherein X and Y have the meanings stated in claim 1, R and Br have the meanings stated in claim 9» and R^" stands for hydrogen or an alkyl radical of not more than 3 carbon atoms, and non-toxic pharmaceutically-acceptable acid-addition salts thereof, which comprises reacting a compound of the formul :- wherein X and Y have the meanings stated above and Hal stands for a chlorine, bromine or iodine atom, with a compound of the formula:- wherein R , IP and Br have the meanings stated above, and M stands for an alkali metal atom.

11. A process for the manufacture of compounds of the formula:- Alk wherein Y or -C(Alk)C02R .COgR5 is linked to the 2-position of the thiazole nucleus, and X and Y have the meanings stated in claim 1, and R^ and R- have the meanings stated in claim 9, and Alk stands for an alkyl radical of not more than 3 carbon atoms, and non-toxio pharmaceutically-acceptable acid-addition salts thereof, which comprises alkylating a compound which in one of its tautomeric forms has the formula:- wherein Y or -OH(C02R4).C02R5 is linked to the 2-position of the thiazole nucleus, and X, Y, R^ and R* have the meanings stated above, so as to introduce an alkyl radical of not more than 3 carbon atoms into the a-position.

12. , A process for the manufacture of compounds of the formula:- M wherein Y or■ -(M(CO^ )-,C0^B is linked to the 2-position of the thiazole nucleus, and X and Y have the meanings stated in claim 1, and R^ and "* have the meanings stated in claim , and M stands for an alkali metal atom, which comprises reacting a compound of the formula:- H wherein Y or -CH(C02R4).C02R-> is linked to the 2-position of the thiazole nucleus, and X, Y, R^ and R^ have the meanings stated above with an alkali metal or a hydride, amide or alkoxide thereof.

13. · A process for the manufacture of compounds which have the formula:- wherein Y or -CR (COglrJ.COglr is linked to the 2-position of the thiazole nucleus, and R^" stands for a dialkylaminomethyl radical of not more than 5 oarbon atoms or the N-piperidinomethyl or N-morpholinomethyl A 5 radical, and X and Y have the meanings stated in claim 1, and B7 and Br have the meanings stated in claim | a d non-toxic pharmaceu ically— acceptable acid-addition salts thereof, which comprises reacting a compound which in one of its tautomeric forms has the formula:- H wherein Y or -CH(C02R4).C02R-? is linked to the 2-position of the 5 thiazole nucleus, and X, Y, R A^" and R^ have the meanings stated above, with formaldehyde and either a dialkylamine of not more than 4 carbon atoms or piperidine or morpholine.

14. » Δ process for the manufacture of compounds of the formula wherein Y 6rw-CHal(C02 4).C02R:> is linked to the 2-position of the thiazole nucleus, and X and Y have the meanings stated in claim 1, A 5 and R^ and R-' have the meanings stated in olaim 9» and Hal stands for a chlorine or bromine atom which comprises reacting a compound which in one of its tautomeric forms has the formula:- wherein Y or -CH(C02R4).C02- is linked to the 2-position of the A 5 thiazole nuoleus, and X, Y, R^" and R have the meanings stated above, with chlorine, bromine, N-bromosucciniraide or phenyltrimethylammonium perbromide.

15. · A process for the manufacture of compounds of the formula t- wherein X and Y have the meanings stated in claim 1 and R stands for hydrogen or an alkyl radical of not more than 3 carbon atoms, which comprises reacting a corresponding alkali metal salt, alkaline earth metal salt, aluminium salt or ammonium salt with an acid at a relatively low temperature.

16. A pharmaceu cal composition comprising at least one compound which in one of its tautomeric forms is a thiazole derivative of the formul :- wherein Y or Z is linked to the 2-position of the thiazole nucleus , and X, Y and Z have the meanings stated in claim 1, or a non-t oxic pharmaceutically-aoceptable salt thereof , and a non-toxic pharmaceutically-acceptable diluent or carrier,

17. · Δ composition as claimed in claim 16 xrtiich is in the form of a tablet , pill, capsule , supposit ory, non-sterile aqueous or non-aqueous solution or suspension, sterile injectable aqueous or non-aqueous solution or suspension, cream, lotion or ointment .

18. , A composition as claimed in claim 16 or 17 which contains at least one known agent having anti-inf lammatory or analgesio activity.

19. » A composition as claimed in claim 16 or 17 and intended for oral administration which contains an anticholinergic agent , and/or an antacid, or a uricosuric agent ,

20. , A composition as claimed in claim 16 or 17 and suitable for topical application, which contains a vasodilating or vasooonst rioting agent , a local anaesthetio, a counter-irritant , and/or at least one agent chosen from the following classes of substances : anti-bacterial agents , anti-fungal agents , anti-histaminic agents and rubefacient agents,

21. · A compound, claimed in claim 2, substantially aa described in any of Examples 1 to ·

22. , A compound, claimed in claim 1, substantially as described in any of Examples 10 to 15,

23. A chemical process, claimed in any of claims 9 to 15, substantially as described in any of Examples 1 to 15. 24, A tablet, olaimed in claim 17, substantially as described in Example 16· FH.20915: RA/JLG: 29.I.69