IE49402B1 - Blood platelet aggregation inhibitory 1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid derivatives and salts thereof;pharmaceutical compositions thereof;and analogy processes for the manufacture thereof - Google Patents

Description

This inventicn relates to novel carboxylic acid derivatives and, more particularly, it relates to novel 1benzyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid derivatives which inhibit the aggregation of blood platelets in vivo and, therefore, may be of application in the treatment or prophylaxis of thrombosis or occlusive vascular disease.

It is known that various N-benzyl 4,5,6,7tetrahydrothieno[3,2-c]pyridine and N-benzyl-4,5,6,710 .tetrahydrofuro [3,2-c]pyridine derivatives possess antiinflammatory and blood platelet aggregation inhibitory properties (M Podesta et alia, European J.Med.Chem., Chim.Therapeutica, 1974, 2, 487-490). It is also known that various 1-benzyl-1,2,5,6-tetrah.ydropyridine15 M-carboxylic acid esters are chemical intermediates (West German Offenlegungsschrift No.2221770 and Annalen, 1972, 764, 21-27). We have now discovered that certain novel l-benzyl-1,2 ,5 ,6-tetrahydropyridine-3~carboxylic acid derivatives unexpectedly also possess the property of inhibiting the aggregation of blood platelets in vivo, and this is the basis for our invention. Two related compounds , 1-benzy1-1,2,5,6-tetrahydropyridine-3~ carboxylic acid methyl and ethyl esters, are known [Zhur.0bschei.Khim.1957, 27, 3162-3170 (Chemical Abstracts, 1958, 52, 9l62c-i) and J.Chem.Soc.Chemical Communications , 1975, 682, respectively] but no useful pharmacological properties have been ascribed to them.

According to the invention there is provided a l-benzyl-1,2,5,6-tetrahydropyridine-3-earboxylie acid 70 derivative of the formula:- I ‘ 49403 wherein R1 is a hydroxy, amino, (l-4C)alkylamino, or di-[(1-4C)alkyl]amino radical, a benzyloxy radical optionally bearing a halogeno substituent, or a (1-60alkoxy radical optionally bearing a (l-4c)alkoxy, morpholino or di-[(1-40alkyl]amino substituent; and benzene ring A bears one or two substituents independently selected from halogeno, (1-4C) alkyl, cyano, caibatcyl, trifluoromethyl and hydroxy radicals; or a pharmaceutically acceptable salt thereof.

Particular values for R^ are, by way of example only swhen it is a (1-40alkylamino radical, a msthylamino or ethylamino radical; when it is a di-[(1-4C)alkyl]amino radical, a dimethylamino or diethylamino radical; when it is a (l-6C)alkoxy radical, a methoxy, ethoxy, propoxy, butoxy or amyloxy radical; and when it is a substituted (1-6C)alkoxy radical, an ethoxy, propoxy, butoxy or amyloxy radical bearing a methoxy, ethoxy, morpholino, dimethylamino or diethylamino substituent.

Particular values for a substituent on benzene ring A are, by way of example only :when it is a halogeno radical, a fluoro, chloro· or bromo radical; and when it is a (1-4C)alkyl radical,a methyl, ethyl, n-propyl or isopropyl radical.

Particular values for benzene ring A are, for example, when it is a 2-chlorophenyl, 2-cyanophenyl, 2carbamoylphenyl, 4-chlorophenyl, 4-bromophenyl, 4methylphenyl, 2-trifluoromethylphenyl, 3-cyanophenyl, 4cyanophenyl, 4-hydroxyphenyl, 3,4-di chlorophenyl or 3,5dichlorophenyl radical,of which values, 2-cyanophenyl and 2-ehlorophenyl are preferred.

The compounds of formula I are sufficiently basic to form addition salts with acids. Particular pharmaceutically acceptable acid-addition sails of compounds of formula I are, for example, salts with inorganic acids, for example with hydrogen chloride, hydrogen bromide, sulphuric acid or phosphoric acid, or salts with organic acids, for example oxalic or citric acid.

In addition, compounds of formula I wherein R1 is a hydroxy radical can form addition salts with bases. Particular base-addition salts of such compounds of formula I are, for example, alkali or alkaline earth metal salts, for example sodium, potassium, calcium or magnesium salts, aluminium or ammonium salts, or salts with organic bases affording a pharmaceutically acceptable cation, for exanple with triethanolamine.

Specific groups of compounds of formula I which are of particular interest comprise those compounds of formula I defined above wherein in addition:(i) R1 is a hydroxy radical; (ii) R1 is an amino radical; (iii) R1 is a (l-6c)alkoxy radical, and in particular a methoxy, ethoxy or butoxy radical; (iv) benzene ring A bears one or two halogeno substituents; and (v) benzene ring A bears a cyano or carbamoyl radical; together in each case with the pharmaceutically acceptable salts thereof as appropriate.

A preferred group of compounds of the invention comprises those compounds of formula I wherein R3- is a hydroxy, amino or (l-4C)alkoxy radical, and benzene ring A bears a 2-chloro or 2-cyano substituent; or a pharmaceutically acceptable salt thereof.

Specific compounds of formula I are described in the accompanying Exanples and, of these, l-(2-chlorobenzyl)-1,2,5,6-tetrahydropyridine-3-earboxylie acid, 1-(2-cyanobenzy1)-1,2,5,6-tetrahydropyridine-3-carboxylie acid and the respective methyl esters thereof, or pharmaceutically acceptable salts thereof, are of special interest.

The compounds of formula I may be manufactured by any general process of organic chemistry known to be applicable to the synthesis of analogous pyridine derivatives. Such processes are provided as a further feature of the invention and are illustrated by the following procedures, in which R'*' and benzene ring A have any of the meanings defined hereinbefore:5 a) For a compound of formula I wherein benzene ring A is other than a 2-carbamoylphenyl radical, reacting a compound of the formula:R .CO NH II with a benzyl halide of the formula :10 Hal.CH.

Ill wherein Hal, is a halogeno radical, for example a chloro, bromo or iodo radical.

The process may be conveniently carried out in the presence of a base, for example an alkali metal carbonate or acetate, such as potassium carbonate or sodium acetate, preferably in a suitable solvent or diluent, for example methanol or ethanol, and at a temperature of, for example 2O-120°C.

The compound of formula II wherein R1 is a hydroxy radical is known and the remaining starting materials of formula II may be obtained therefrom in conventional manner, b) For a compound of formula I wherein benzene ring A is other than a 2-carbamoylphenyl radical, reacting a compound of formula II with an aldehyde of the formula :25 IV in the presence of a reducing agent.

A particularly suitable reducing agent is, for example, an inorganic hydride, for example sodium or potassium borohydride, or lithium or sodium cyanoborohydride.

The process is preferably carried out in a solvent or diluent, for example a C^-alkanol, for example ethanol and,conveniently,at or near room temperature, for example at 15-30°C.

Process (b) is of the reaction type known as reductive amination and as such may proceed wholly or in part via an intermediate of the formula: OH formed in situ and which is subsequently reduced. It is to be understood that this invention also embraces the separate reduction of an intermediate of formula V produced, fir example, by reacting a compound of formula II with an aldehyde of formula IV in the absence of a reducing agent.

The aldehydes of formula IV may be obtained by standard procedures of organic chemistry, c) For a compound of formula I wherein R1 is a hydroxy radical , hydrolysing a ccaipound of the formula:- VI 1 wherein R has the same value as R other than a hydroxy radical.

A particularly suitable value for R is for example, a methoxy, ethoxy, benzyloxy or chlorobenzyloxy radical.

The hydrolysis may be carried out in the presence of aqeuous acid or base, for example an aqueous mineral acid, such as hydrochloric or sulphuric acid, or an aqueous strong base, such as sodium or potassium hydroxide, may be used. A solvent or diluent, for example ethanol or acetic acid, may be conveniently used, and the process may be performed at a temperature of, for example, 20-120°C. d) For a compound of formula I wherein R1 is a hydroxy or amino radical and benzene ring A bears a carbamoyl substituert hydrolysing a compound of the formula:- ring C has one of the values defined for ring A which 20 is a cyanophenyl radical.

The hydrolysis may be carried out using conventional conditions for the production of amides from nitriles for example using similar reagents and solvents to those described in process (c) hereinabove.

However in general shorter reaction times are preferred to minimise further hydrolysis of the amide linkage when formed. It will be mderstood that when R is a (1-60alkoxy radical in the conpound of formula VII, the final product from the process is nevertheless a conpound of formula I wherein jo R1 is a hydroxy radical.

Whereafter, for a compound of formula I wherein R1 is other than a hydroxy radical, the corresponding compound of formula I wherein R^ is a hydroxy radical, or a reactive derivative thereof, for example the corresponding acid chloride, bromide or anhydride, is reacted using well known esterification or amidification procedures and conditions with the appropriate compound of the formula R .H 1 wherein R has the same value as R other than a 10 hydroxy radical.

The pharmaceutically acceptable salts as defined hereinbefore may be made by conventional procedures, by reaction with the appropriate acid or base affording a pharmaceutically acceptable anion or cation respectively.

As stated above the compounds of formula I possess the property of inhibiting the aggregation of blood platelets. This property may be demonstrated in vivo, using standard tests in laboratory animals, for example, in the following test in rabbits.

In this test blood samples are taken by a standard open flow technique from the central ear artery of rabbits. The samples are taken into a 3.8? w/v solution of trisodium citrate as anti25 coagulant and then centrifuged at first 150 g , and then at 1000 g , to prepare platelet rich and platelet poor plasma fractions, which are used to calibrate an instrument for measuring light transmittance and •thus the amount of platelet aggregation. The extent ° of platelet aggregation following addition of adenosine 5'-diphosphate (ADP) (final concentration 0.5, 1.0, 2.0, 4.0 or 8.0 uM) to the platelet rich 48402 plasma fraction is then determined, and the value of maximum aggregation in response to each concentration of ADP is recorded. The rabbits are then dosed orally with test compound, and arterial blood samples are withdrawn at intervals after dosing. The platelet rich plasma fraction is prepared and ADP is added as above, and the extent of aggregation assessed by measuring the light transmittance of the sample. This value is compared with that obtained from the same rabbit before dosing, so that a measure of the extent of inhibition of ADP induced blood platelet aggregation is obtained. By way of example only, the compound l-(2-chlorobenzyl)l,2,5,6-tetrahydropyridine-3-carboxylic acid showed significant inhibition of the aggregation of blood platelets two hours after an oral dose (as its hydrochloride) of 25 mg./kg. However, in general, compounds of formula I produce significant inhibition in the above test following oral doses of 100 mg./kg., or much less,without any signs of overt toxicity at the active dose.

Compounds which inhibit the aggregation of blood platelets, for example acetylsalicylic acid, have been used in the treatment or prophylaxis of thrombosis or occlusive vascular disease, and it is envisaged that the compounds of the present invention will be used in a generally similar manner, and for the same clinical indications.

When used to inhibit the aggregation of blood platelets in warm-blooded animals including man, a compound of formula I may be administered at a daily oral dose in the range 1-30 mg./kg. and preferably in the range 1-10 mg./kg., or an equivalent amount of a pharmaceutically acceptable salt thereof. In man these doses are equivalent to daily oral doses of approximately 0.07-2.1 g. and 0.07-0.7 g. respectively, or an equivalent amount of a pharmaceutically acceptable salt, given in divided doses if necessary.

The compounds of formula I are preferably administered in the form of pharmaceutical compositions, and according to a further feature of the invention there is provided a pharmaceutical composition which comprises a compound of formula I, or a pharmaceutically acceptable salt thereof as defined hereinbefore, together with a pharmaceutically acceptable diluent or carrier. Such a composition is conveniently in a form suitable for oral administration, for example as a tablet, capsule, aqueous or oily suspension, syrup or' elixir. Alternatively it may be in a form suitable for parenteral administration by infusion or injection, for example as a sterile injectable solution or suspension, or in a form suitable for rectal administration, for example as a suppository.

Such compositions may be obtained by conventional procedures and using conventional excipients. A composition for oral administration should preferably contain from 5-500 mg. of active ingredient per unit dose, a composition for parenteral administration, 0.5-20 mg./ml. of active ingredient, and a composition for rectal administration, SO25 500 mg. of active ingredient.

A composition of the invention may also conveniently contain one or more agents which can have a beneficial effect on thrombosis or occlusive vascular disease, or on associated conditions, selected from, for example, clofibrate, sulfinpyrazone, and dipyridamole.

The invention is illustrated by the following Examples in which (i), yields are by way of example only and are not to be construed as the maximum attainable; (ii), evaporations were carried out in vacuo to dryness where possible, using a 49403 rotary evaporator; and (iii), melting points were determined in sealed glass capillary tubes :Example 1 Triethylamine (2.2 g.) and 2-chlorobenzyl chloride (1.63 g.) were added to a solution of methyl l,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride (1.63 g.) in methanol (10 ml.). The solution obtained was kept for 24 hours at 20-25’C. and then evaporated. Water (20 ml.) and 10% w/v sodium carbonate solution were then added to the residue to give a mixture of pH 10. This mixture was extracted with ether (2 x 20 ml.). The combined extracts were washed with water, dried (MgSOp and evaporated. The residual oil was dissolved in acetone to give a solution which was treated with a slight excess of ethereal hydrogen chloride. The solid which precipitated was collected by filtration and washed with acetone to give methyl l-(2-chlorobenzyl)-l,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride (1.5 g.) m.p. 171-175eC.

Example 2 . A solution of methyl l-(2-chlorobenzyl)l,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride (0.45 g.) in concentrated hydrochloric acid (10 ml.) was heated at 95-100°C. for 2 hours, cooled and evaporated. The residue was evaporated several times with acetone and toluene to remove remaining traces of water. The solid obtained was stirred with acetone and then collected by filtration to give l-(2-chlorobenzy1)-1,2,5,6-tetrahydropyridine3-carboxylic acid hydrochloride (0.4 g.), m.p. 208210°C (dec.).

Example 3 4-Hydroxybenzaldehyde (1.34 g.) and sodium cyanoborohydride (0.7 g.) were added to a solution of methyl l,2,5,S-tetrahydropyridine-3-carboxylate hydrochloride (3-1 g·) in methanol (30 ml.). The mixture was stirred for 3 days at 25°C., evaporated and water (30 ml.) added to the residue followed by concentrated hydrochloric acid to pH 1. This mixture was extracted with ether (2 x 20 ml.) and the extracts discarded. The aqueous phase was basified to pH 9 with 10% w/v sodium carbonate solution and then extracted with ether (2 x 30 ml.).

The combined extracts were dried (MgSOjj) and evaporated. The oil obtained was dissolved in acetone and treated with a slight excess of ethereal hydrogen chloride. The solid which was precipitated was collected by filtration to give methyl 1-(4hydroxybenzyl)-l,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride (2.05 g·)· A portion was recrystallised from methanol and acetone to give pure material of m.p. 212-214’C. (dec.).

Example 4 (Note : all parts are by weight) A mixture of micro-crystalline cellulose (196 parts) and finely divided 1-(2-chlorobenzyl)l,2,5,6-tetrahydropyridine-3-carboxylic aeid hydrochloride (200 parts) was sieved through a 30 mesh screen British Standard No. 410. Magnesium Stearate (60 mesh particle size) (4 parts) was then added and, after thorough mixing, the mixture was compressed into tablets weighing 400 mg. and containing 200 mg. of active ingredient, which may be administered to man for therapeutic purposes , Using a similar procedure, tablets containing 20, 50, 100 and 400 mg, of active ingredient may be obtained.

Similarly the active ingredient may be replaced by another compound of formula I, for example a compound described in any one of Examples 1, 3, or 5--20. 48402 Examples 5-8 Using a similar procedure to that described in Example 1 but starting from the appropriate benzyl halide of formula III and the appropriate ester of formula II there were obtained:- methyl l-(2-cyanobenzyl)-l,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride (Example 5) m.p. 183-4°C., in 54% yield after recrystallisation from methanol/acetone; ethyl 1-(3,4-di chlorobenzyl)-1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride (Example 6) m.p. 192-9 °C., in 76% yield; methyl l(4-methylbenzyl)-l,2,5,6-tetrahydropyridine3-carboxylate hydrochloride (Example 7) m.p. 185-4°C., in 8l% yield after recrystallisation from methanol/ ethyl acetate; and methyl 1-(3,4-dichlorobenzy1)-1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride (Example 8) m.p. 185-188OC., in 71% yield.

Example 9 Using a similar procedure to that described in Example 2, hydrolysis of methyl l-(3,4-dichlorobenzyl)-l,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride gave 1-(3,4-dichlorobenzyl)-1,2,5,6tetrahy dropyri dine-3-cart oxy lie acid, m.p. 240-245’C. Example 10 A mixture of 1-(3,4-dichlorobenzyl)-l,2,5,6tetrahydropyridine-3-carboxylic acid hydrochloride (.2.0 g.) and thionyl chloride (15 ml.) was heated under reflux for 30 minutes. Excess thionyl chloride was removed by evaporation and the residue was mixed with toluere and then evaporated. n-Butyl alcohol (30 ml.) was added to the cooled residual solid and the mixture was stirred at 25°C. for 1 hour, during which time all the solid dissolved. The solution obtained was heated under reflux for 10 minutes and then excess n-butyl alcohol was removed by evaporation. The residue was recrystallised from acetone/ether to give n-butyl 1-(3,4-dichlorobenzyl)-1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride (1.2 g.), m.p. 16O-162°C.

Examples 11-15 Using a similar procedure to that described in Example 10 but using the appropriate alcohol or amine , the following esters or amides of formula I (ring A = 3,4-dichlorophenyl) were obtained as their hydrochloride salts (unless otherwise stated)..

Exanple R1 Yield (%) m.p. (°C.) Re crystallisation solvent 11 PhCH2O 86 166-169 IfegCO/EtOAc 12 Et^JCH2CH2O 21 208-211* 13 HgN- 18 145-15O+ iPiOH 14 EtNH- 61 224-228 15 Et^- 72 200-202 EtOH/tfejCO * Dihydrochloride, 1^ H20 + Free base, ; HgO Examples 16-18 Using a similar procedure to that described in Example 2 but starting from the appropriate methyl ester, there were obtained: l-(4-methylbenzyl)-l,2,5,6tetrahydropyri.dine-3-carboxylic acid hydrochloride (Example 16) in 71% yield, m.p. 230-6 °C (after re crystallisation from ethanol/acetone) ; and 1-( 4-bromobenzyl)-l,2 ,5 ,6-tetrahydropyridine-3~ carboxylic acid hydrochloride (Example 17) in 94? yield, m.p. 248-253°C.

The starting material for Example 17 was obtained using a procedure similar to that described in Example 1 but starting from 4-bromobenzy1 chloride to give, methyl 1-( 4-bromobenzyl)-l,2 ,5 ,6-tetrahydropyridine-3-carboxylate hydrochloride,m.p.2OO-2O5eC. (Example 18) Example 19 A mixture of l,2,5,6-<-tetrahydropyridine-3carboxylic acid bydrochloride (4,0 g.), triethylamine (8.2 g.) and 2-cyanobenzylbromide (4.0 g.) in methanol (20 ml.) was heated at 9.5-1θθ’£· for 3 hours. The mixture was evaporated to dryness and an excess of aqueous sodium carbonate solution added. The mixture was again evaporated to dryness and acidified with 2N hydrochloric acid to pH 2-3. Hie subsequent mixture was evaporated to dryness. The residue was suspended in toluene (30 ml.) and evaporated to dryness. The resultant solid was dissolved in dry ethanol (10 ml.) and the residue (largely sodium chloride) was discarded.

The solution was evaporated and the residue recrystallised from ethanol/ether to give l-(2-eyanobenzyl)~l,2,5,6tetrahydropyridine-3-carboxylie acid hydrochloride as a solid, m.p. 206-212’C.

Example 20 A mixture of methyl l-(2-cyanobenzyl)-l,2,5,6tetrahydropyridine-3-carboxylate ( 0.5 g.) and concentrated hydrochloric acid ( 5.0 ml.) was heated at 95-100°C. for 1-2 hours. The mixture was evaporated to dryness and the residue was triturated with acetone to give l-(2-carbamoylbenzyl) 1,2,5,6-tetrahydropyri.dine-3-carboxylic acid hydrochloride, m.p.219-222 °c. (dec.) after recrystallisation from ethanol/acetone.

Claims (12)

Claims

1. A l-benzyl-1,2,5,6-tetrahydropyridine-3carboxylic acid derivative of the formula:- 5 wherein R 1 is a hydroxy, amino, (1-4C)alkylamino, or di-[(1-40alkyl]amino radical, a benzyloxy radical optionally bearing a halogeno substitutent, or a (1-60alkoxy radical optionally bearing a (1-40alkoxy, morpholino or di-[(1-40alkyl]amino substituent; and 10 benzene ring A bears one or two substituents independently selected fran halogeno, (1-4C)alkyl, cyano, carbamoyl, trifluoromethyl and hydroxy radicals, or a pharmaceutically acceptable salt thereof.

2. A compound as claimed in claim 1 wherein R 1 15 is a hydroxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, methoxy, ethoxy, propoxy, butoxy or amyloxy radical, or an ethoxy, propoxy, butoxy or amyloxy radical bearing a methoxy, ethoxy, morpholino, dimethylamino or diethylamino substituent; and wherein 20 benzene ring A bears 1 or 2 substituents independently selected from fluoro, chloro, bromo, methyl, ethyl, npropyl, isopropyl, cyano, carbamoyl, trifluoromethyl and hydroxy radicals .

3. A compound as claimed in claim 1 or 2 wherein 25 benzene ring A is a 2-chlorophenyl, 2-cyanophenyl, 2-carbamoylphenyl,

4. -chlorophenyl, 4-bromophenyl, 4methylphenyl, 2-trifluoromethylphenyl, 3-cyanophenyl, 4cyanophenyl, 4-hydroxyphenyl, 3,4-dichlorophenyl or 3,5dichloropheny1 radical. 30 4. A compound as claimed in claim 1, 2 or 3 wherein benzene ring A bears one or two halogeno s ubscituents. 48402

5. A compound as claimed in claim 1, 2 or 3 wherein benzene ring A bears a cyano or carbamoyl radical.

6. A compound of the formula I set out in claim 1 wherein R 1 is a hydroxy, amino or (1-4C)alkoxy radical; and benzene ring A bears a 2-chloro or 2-cyano substituent; or a pharmaceutically acceptable salt thereof.

7. l-(2-Chlorobenzy1)-1,2,5,6-tetrahydropyridine3-carboxylic acid, l-(2-cyanobenzyl)-l,2,5,6-tetrahydropyridine-3-carboxylic acid, or the methyl esters thereof, or a pharmaceutically acceptable salt of said acids or esters,

8. A pharmaceutically acceptable base addition salt of a compound of formula I wherein R 1 is a hydroxy radical as claimed in any preceding claim which is an alkali metal, alkaline earth metal, aluminium or ammonium salt, or a salt with an organic base affording a pharmaceutically acceptable cation.

9. A pharmaceutically acceptable acid addition salt of a compound of formula I as claimed in any of claims 1-7 which is a salt with hydrogen chloride, hydrogen brcmide, sulphuric acid, phosphoric acid, oxalic acid or citric acid.

10. A pharmaceutical composition which comprises a compound of formula i or a pharmaceutically acceptable salt thereof as claimed in any preceding claim together with a pharmaceutically acceptable diluent or carrier.

11. A process for the manufacture of a compound of formula I or a pharmaceutically acceptable salt thereof as claimed in any of claims 1-8, wherein R 1 and benzene ring A have any of the meanings specified in any of claims 1-6, characterised by:(a) for a caroound of fannula I wherein benzene ring A is other than a 2-carbampylphenyl radical, reacting a conpound of the formula: - R 1 . CO NH II with a benzyl halide of the formula:Hal.CH 2 III wherein Hal. is a halogeno radical; (b) for a compound of formula I wherein benzene ring A is 5 other than a 2-carbamoylphenyl radical, reacting a compound of formula II with an aldehyde of the formula:H.CO IV in the presence of a reducing agent; (c) for a compound of formula I wherein R^ is a 10 hydroxy radical, hydrolysing a compound of the formula:R 2 .CO CHVI 2 1 wherein R has the same value as R other than a hydroxy radical; or (d) for a compound of formula I wherein R^ is a hydroxy

12. 15 or amino radical and benzene ring A bears a carbamoyl radical, hydrolysing a compound of the formula:CHR 3 .C0 VII 49*0 2 wherein R 3 is a hydroxy, (l“6C)alkoxy, or amino radical and benzene ring C has cne of the values defined for ring A which is a cyanophenyl radical; whereafter, for a compound of formula I 5 wherein R 1 is other than a hydroxy radical, a compound of fonnula I wherein R 1 is a hydroxy radical, or a reactive derivative thereof, is reacted with a compound 2 2 of the formula R ,H wherein R has the sane values as R 1 other than a hydroxy radical using a known 10 esterification or amidification procedure; and whereafter, for a pharmaceutically acceptable base addition salt of a compound of formula I wherein R 3, is a hydroxy radical, such a compound is reacted with a suitable base affording a pharmaceutically acceptable 15 cation; and for a pharmaceutically acceptable acid addition salt, a compound of formula I is reacted with a suitable acid affording a pharmaceutically acceptable anion; in either case, using a conventional procedure. Dated thia the 18th day of February, 1980.