CA1144545A - Carboxylic acid derivatives - Google Patents

Abstract

ABSTRACT

The invention concerns novel 1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid derivatives of the formula:- I

wherein R1 is hydroxy, amino, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, benzyloxy optionally substituted by halogeno, or (1-6C)alkoxy optionally substituted by (1-4C)alkoxy, morpholino or di-{(1-4C)alkyl]amino;
and benzene ring A bears one or two substituents selected from halogeno, (1-4C)alkyl, cyano, carboxamido, trifluoromethyl and hydroxy; and their pharmaceutically acceptable salts; together with pharmaceutical compositions thereof; and analogy processes for their manufacture.
The compounds of formula I are inhibitors of the aggregation of blood platelets and may be or application in the treatment or prophylaxis of thrombosis or occlusive vascular disease. A repres-entative compound of the invention is 1-(2-chloro-benzyl)-1,2,5,6-tetrahydropyridine-3-carboxylic acid.

Description

11~4545 CARBOXYLIC ACID DERIVATIVES

Ihis inventicn relates to novel carboxy~c acid deriv-atives and, more particularly, it relates to novel l-benzyl-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 4,5,6,7-tetrahydrothieno~3,2-c]pyridine and N-benzyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridine derivatives possess anti-inflammatory 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 l-benzyl-1,2,5,6-tetrahydropyridine-4-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, l-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl and ethyl esters, are known [Zhur.Obschei.Khim.1957, 27, 3162-3170 (Chemical Abstracts, 1958, 52, 9162c-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-carboxylic acid derivative of the formula:-11~4S45 wherein Rl is a hydroxy, amino, (1-4C)alkylamino, or di-[(1-4C)alkyl]amino radical, a benzyloxy radical optionally bearing a halogeno substituent, or a (1-6C)-alkoxy radical optionally bearing a (1-4C)alkoxy, morpholino or di-[(1-4C)alkyl]amino substituent; and benzene ring A bears one or two substituents selected B from halogeno, (1-4C)al~yl, cyano, ca~ ox~mi~o, tri-fluoromethyl and hydroxy radicals; or a pharmaceutically acceptable salt thereof.
Particular values for Rl are, by way of example only ~
wh.en it is a (l-4C~alkylamino radical, a m~hylamino or ethylamino radical;
when it is a di-[(1-4C)alkyl]amino radical, a dimethylamino or diethylamîno radical;
when it is a (l-6C)alkoxy radical, a methoxy, ethoxy, propoxy, butoxy or am~loxy 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 diethyl-amino substituent, Particular values for a substituent on benzene ring A are, by way oP example only:-when it is a halogeno radical, a fluoro, chloro or bromo radical; and when it i8 a (1-4C~alkyl radical~a methyl, ethyl, n-propyl or isopropyl radical.
Partîcular values for benzene ring A are, for example, wh~en it is a 2-chlorophenyl, 2-cyanophenyl, 2-aar~ox.~ ~ ~oph ~ yl, 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 2-trifluoromethylphenyl, 3-cyanophenyl, 4-cyanophenyl, 4-hydroxyph.enyl, 3,4-dichlorophenyl or 3,5-dichloroph.enyl radical70f which values, 2-cyanophenyl and 2-chlorophenyl are preferred.
The compounds of formula I are sufficiently basic to form addition salts with acids. Particular pharmaceutically acceptable acid-addition salts of compounds of formula I are, for example, salts wi.th inorganic acids, for example with hydrogen chloride, 114~545 hydrogen bromide, sulphuric acid or phosphoric acid, or salts with organic acids, for example oxalic or citric acîd.
In addition, compounds of formula I wherein Rl 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 example with triethanolamine.
Specific groups of compounds of formula I
which are of particular interest comprise those compounds of formula I defined abo~e wherein in addition:-(i) Rl is a hydroxy radical;
(ii) R1 is an amino radical;
(iii~ Rl is a (1-6C~aIkoxy 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 JL~ Car~ox ~ do radical;
together in each case with the pharmaceutieally acceptable salts thereof as appropriate.
A preferred group of compounds of the invention comprises those compounds of formula I wherein R1 is a hydroxy, amino or (1-4C~alkoxy radical, and benzene ring A bears a 2-chloro or 2-cyano substituent; or a pharmaceutîcally acceptable salt thereof.
Specific compounds of formula I are described in the accompanying Examples and, of these, 1-(2-chloro-benzyl)-1,2,5,6-tetrahydropyridine-3-carboxylic acid, 1-(2-cyanobenzyl~-1,2,5,6-tetrahydropyridine-,-carboxylic acid and the respective methyl esters thereof, or pharmaceutically acceptable salts thercof, are of . special interest.
The compounds of formula I may be manufactured by any general process of organic che~istry known to be applicable to the synthesis of analogous 11~454~

pyridine derivatives. Such processes are provided as a further feature of the invention and are illustrated by t~e following procedures, in which and benzene ring A have any of the meanings defined hereinbefore:-a) Reacting a compound of the formula:-~1.C ~ ~ NR II
~J .

with a benzyl halide of the formula:-Hal.CH2 ~ III
~ A J

lO wherein Hal. is a halogeno radical, for examplea chloro, bromo or `odo 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 15 carbonate or sodium acetate, preferably in a suitable sol~ent or diluent, for example methanol or ethanol, and at a temperature of, for example 20-120C.
The compound of formula II wherein Rl is a hydroxy radical is known and the remaining 20 starting materials of formula II may be obtained therefrom in conventional manner.
b) Reacting a compound of formula II with an aldehyde of the formula:-¦¦ A ¦ I~
.. ' \~

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.
~ he process is preferably carried out in a solvent or diluent, for example a Cl_4-alkanol, for example ethanol and,conveniently,at or near room temperat~re, for example at 15-30C.
Process (b) i5 of the reaction type known as reductive amination and as 6uch may proceed wholly or in part via an intermediate of the formula:-0~
Rl. CO ~ V

formed in situ and which is subsequently reduced. It 15 is to be understood that this invention also embraces the separate reduction of an intermediate of formula V produced, ~r example, by reacting a compound of formula II ~ith 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 Rl i8 a hydroxy r,adical shydr~lysing a ca~ound of the fo~a:-R2.CC ~ ~ ~2 ~ ~ VI

11~4~4 wherein R has the same value as Rl other than a hydroxy radical.

A particularly suitable value for R2 is for example, a methoxy, ethoxy, benzyloxy or chloro-benzyloxy radical.
The hydrolysis may be carried out in thepresence 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 ma~ ~e performed at a temperature of, for example, 20-120C.
d) For a compound of formula I wherein Rl is a hydroxy or amino radical and benzene ring A bears a ~ c; a r6~ Y/
e~o~ D s~stitue~ hydrolysing a compound of the formula:-~ N ~C~2 ~ VII

wherein R3 is ahy~y, (1-6C)a~o~ or-~ino radical andbenzene ring C has one of the values defined for ring A which is a cyanophenyl radîcal.
The hydrolysis may be carried out using conventional conditions for the production of amides from nitriles for example using similar reagent3 and solvents to those described in process (c) hereinabove.
However in general shorter reaction times are preferred to minimise further hydrolysis of the amide lin~age when formed. It willbe ~derstood that when R3 is a (l-~C)-a~oxy ra~cal in the compound of fo~a VII, the ~nal product from the prc~oess is nevertheless a conpound of formulaI wherein 3o Rlis a;~c~oxy radical.

Wherea~ter, for a compound of formula I
wherein Rl is other than a hydroxy radical, the corresponding compound of fo~l~ula I wherein Rl is a hydroxy radical, or a reactive derivative thereof, ; 5 ~or example the corresponding acid chlor de, bromide or anhydride, is reacted using well known esteri~ic-ation or amidi~ication procedures and conditions with the appropriate compound of the fo~mula R2.H
wherein R2 has the same valuesas Rl other than a 10 hydroXY radical.
The pharmaceutically acceptable salts as defined hereinbefore may be made by conventional procedures, b~ reaction with the appropriate acid or base affording a pharmaceutically acceptable 15 anion or cation respecti~ely.
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, 20 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% I~/v solution of trisodium citrate as anti-25 coagulant and then centrifuged at first 150 g , andthen at 1000 g , to prepare platelet rich and platelet poor plasma fractions, which a~e used to calibrate an instrument for measurin~ light t~ransmittance and thus the amount o~ platelet aggregation. The extent 30 of platelet aggregation following addition of adenosine 5'-diphos~hate ~ADP) (final concentration 0~5, 1.0, 2.0, 4.0 or 8.o ~M) to the platelet rich 11~4545 plasma fraction is then determined, and the value of maximum aggregation in res~onse 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 pre-pared 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, ~o that a measure of the extent of inhlbition of ADP
induced blood platelet aggregation is obtained. By way of example only, the compound l-(2-chlorobenzyl)-1,2,~,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, ~or example acetylsalicylic acid, have been used in the treatment or prophylaxis of ~5 thr~mbosis 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 o~
3 blood platelets ;n ~Jarm-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 pharmaceuticall~ acceptable salt thereof.
3~ In man these doses are equivalent to daily oral doses of approx~mately 0.07-2.1 g. and 0.07-0.7 g. respect-ively, or an equivalent amount of a pharmaceutically 1~4S45 .
g acceptable salt, ~ ~n in divided doses if neoessa~.
The compounds of formula I are preferably administered in the form of pharmaceutical compos-itions, and according to a further feature of the invention there is provided a pharmaceutical composit~on which comprises a compound of formula I, or a pharmaceuticall~ 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 administra~ion, 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 ~-500 mg. of active ingredient per unit dose, a composition for parenteral administration, 0.5-20 mg./ml. of active ingredient, and ~ composition for rectal administration, 50-500 mg. of active ingredient.
A composition of the invention may alsoconveniently contain one or more agents wh~ch can have a beneficial effect on t~rombosis or occlusive vascular disease, or on associated conditions, selected from, ~or example, clofibrate, sulfinpyrazone, and dipyridamole.

The invention is illustrated by the ollow ng Examples in which (i), yields are by way of example only and are not to be construed as the maximum attainable; (ii), eva~orations were carried out in vacuo to dryness ~here possible, using a rotary evaporator; and (iii), melting points were determined in sealed glass capillary tubes:-Example 1 Triethylamine (2.2 g.) and 2-chloro-benzyl chloride (1.63 g.) were added to a solutionof methyl 1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride (1.63 g.) in methanol (10 ml.). The solution obtained was kept for 24 hours at 20-25C.
and then evaporated. Water (20 ml.) and 10% w/v sodium carbonate solution were then added to the re~idue to gi~e a mixture of pH 10. rhis mixture was extracted with ether (2 x 20 ml.). The combined extracts were washed with water, dried (MgS04) and evaporated. The residual oil was dissolved in acetone to give a solution which was treated with a 9 light exces~ of ethereal hydrogen chloride. The solid which precipitated was collected by filtration and washed ~ith acetone to give methyl l-(2-chloro-benzyl)-1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride (1.5 g.) m.p~ 171-175C.
Example 2 A solution o~ methyl 1-(2-chlorobenzyl)-1,2,5,6-tetrahydropyridine-3-carboxvlate h~drochlor-ide (0.45 g.) in concentrated hydrochloric acid (10 ml.) was heated at 95-100C. for 2 hours, cooled and evaporatedt The residue was evaporated several times with acetone and toluene to remove remaining traces of ~ate~. The solid obtained was stirred with acetone and then collected by ~iltration to give 1-(2-chlorobenzyl)-1,2,5,6-tetrahydropyridine-3-carboxylic acid hydrochloride (0.4 g.), m.p. 208-210C (dec,).
Example 3 4-Hydroxybenzaldehyde (1.34 g.) and sodium cyanoborohydride (0.7 g.) were added to a solution o~ methyl 1,2,5,5-tetrah~dro~yridine-3-carboxylate hydrochloride (3.1 g.) in methanol (30 ml.). The 11~4S45 mixture was stirred for 3 days at 25C., evaporated ' and water (30 ml.) added to the residue followed by ~oncentrated hydrochloric acid to pH 1. This mixture was extracted with etAer (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 (MgS04) and evaporated. The oil obtained ~as dissolYed in acetone and treated with a slight excess of ethereal hydrogen chloride. The solid which was precipitated was collected by filtration to give methyl ~-(4-hydroxybenzyl)-1,2,5,6-tetrahydropyridine-3-carboxy-late hydrochloride (2.05 g.). A portion ~as re-crystallised from methanol and acetone to give purematerial o~ m.p. 212-214C. (dec~).
E'x'am'pl'e 4 (Note : all parts are by weight) A mixture of micro-crystalline cellulose (1~6 parts) and finely divided 1-(2-chlorobenzyl)-1,2,5,6-tetrahydropyridine-3-carboxylic acid hydro-chloride (200 parts) was sieved through a 30 me~h screen. 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 contain-ing 20, 50, 100 a~d 400 mg, o~ active ingredient may ~0 be obtained.
Similarly the active ingredient ma~ be replaced by another compound of formula I, for example a compound described in an~ one of Examples 1, 3, or 5-20.' Exan~ les 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:- rr.ethyl 1-(2-cyano-benzyl)-1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride (Example 5) m.p. 183-4C., in 54% yield after recrystallisation from methanol/acetone;
ethyl 1-(3,4-dichlorobenzyl)-1,2 ,5,6-tetrahydro-I0 pyridine-3-carboxylate hydrochloride (Example 6) m.p. 192-9 C., in 76g yield;
methyl 1(4-methylbenzyl)-1,2,5 ,6-tetr~hydropyridine-3-carboxylate hydrochloride (Example 7 ) m.p. 183-4C., in 81% yield after recrystallisation from methanol~
ethyl acetate; and methyl l-(3,4-dichlorobenzyl)-1,2,5 ,6-tetrahydro-pyridine-3-carbo~late hydrochloride (Example 8 ) m.p. 185-188C., in 71% yield.
Examp le 9 Using a 3imilar procedure to that described in Example 2, hydrolysis of methyl 1-(3,4-dichloro-benzyl)-1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride gave l-(3,4-dichlorobenzyl)-1,2,5,6-tetrahydropyridine-3-carboxylic acid, m.p. 240-245C.
Example 10 A mixture of 1-(3,4-dichlorobenzyl)-1,2,5,6-tetrahydropyridine-3-carboxylic acid hydrochloride (2.0 g.) and thionyl chloride (15 ml.) was heated under re flux for 30 minutes. Excess thionyl chloride was removed by evaporation and the residue was mixed with toluer~ and then evaporated. n-Butyl alcohol (30 ml.) was added to the cooled residual solid and the mixture was stirred at 25C. ~or 1 hour, during which time all the solid dissolved. The soluti on obtained was heated under reflux for 10 minutes and then excess n-butyl alcohol was removed by evaporation.
The residue was recrystallised from acetone~et;her to give n-butyl 1-(3~4-dichlorobenzyl)-1,2,5,6-tetra-hydropyridine~3-carboxylate hydrochloride (102 g.), ~1~45~5 m.p. 160-162C.
Examples 11-15 Using a similar procedure to that described in Example 10 but using the appropriate alcohol or B 5 amine, the following esters or aarboxamldcs of formula I (ring A = 3,4-dichlorophenyl) were obtained as their hydrochloride salts (unless otherwise stated).

Exan~le ~ Yield (%) m.p. (C.) RecIystallisation solYent .. .. _ . . ..
11 PhCH2086 166-169 Me2a)~EtOAc 12 Et2NC~I2CH20 21 20~2~1*

13 H2N-ap 18 145-150 iPrOH

14 Et~- 61 224-228 Et2N 72 200 202 EtO~ e200 * Dihydrochloride, 13/4 H20 10 ~ Free b ase, ~ H20 Examples 16-18 Using a similar procedure to that described in Example 2 but starting from the appropriate methyl ester, there were obtained: 1-(4-methylbenzyl)-1,2,5,6-15 tetrahydropyridine-3-carboxylic acid hydrochloride (Example 16) in 71% yield, m.p. 230-6 C (after recrystallisation from ethanol~acetone); and 1-(4-b romobenzyl)-1,2,5,6-tetrahydropy ridine-3-carb oxy li c acid hydroch loride (Example 17) in 94%
20 yield, m.p. 248-253C.
The starting material for Example 17 was ob taine d usin g a p rocedure similar tv that described - in Example 1 but starting from 4-bromoben2yl chloride to give, methyl 1-(4-bromobenzyl)-1,2,5,6-tetrahydro-25 py~idine-3-carboxylate hydrochloride,m.p. 200-2û5C.
(Example 18) ~4~5~5 Example 19 A mixture of 1,2,5,6~tetrahydropyridine-3-carboxylic acid bydrochloride C4.0 g.~, triethylamine (8.2 g.) and 2-cy-anobenzylbromide (4.0 g.~ in methanol (20 ml.) was heated at ~5-100C. for 3 hours. me mixture ~as evaporated to dryness and an excess of aqueous sodium carbonate solution added. The mixture was again evaporated to dryness and acidified with 2N
hydrochlori-c acid to pH 2-3. The subsequent mixture was evaporated to dr~ness. m e residue was suspended in toluene (30 ml.~ and evaporated to dryness. The resultant solid was dissolved in dry ethanol (10 ml.) ar.dthe residue (largely sodium chloride) was discarded.
The solution was evaporated and the residue recrystallised from ethanol/ether to give 1-(2-cyanobenzyl)-1,2,5,6-tetrahydropyridine-3-carboxylic acid hydrochloride as a solid, m.p. 206-212C.
Example 20 A mixture of methyl 1-(2-cyanobenzyl)-1,2,5,6-tetrahydropyridine-3-carboxylate ( 0.5 g.) and concen-trated hydrochloric acid ( 5.0 ml.~ was heated at 95-lOO~C. for 1-2 hours. The mixture was evaporated to dryness and the residue was triturated with acetone to give 1-(2- ~ ~o~c~ 1)-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid hydrochloride, m.p.219-222 C.
(dec.) after recrystallisation from ethanol/acetone.

Claims (14)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the manufacture of a 1-benzyl-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid derivative of the formula:- I

wherein R1 is a hydroxy, amino, (1-4C)alkylamino, or di-[(1-4C)alkyl]amino radical, a benzyloxy radical optionally bearing a halogeno substituent, or a (1-6C)alkoxy radical optionally bearing a (1-4C)alkoxy, morpholino or di-1(1-4C)alkyl] amino substituent; and benzene ring A bears one or two sub-stituents selected from halogen, (1-4C)alkyl, cyano, carbamoyl, trifluoro-methyl and hydroxy radicals; or a pharmaceutically acceptable salt thereof;
characterised by:-(a) for a compound of formula I wherein benzene ring A is other than a 2-carbamoylphenyl radical, alkylating a compound of the formula:- II

wherein R1 has the meaning defined above with a benzyl halide of the formula:- III

wherein benzene ring A has the meaning defined above other than a 2-carbamoyl-phenyl radical, and Hal. is a halogeno radical;
(b) for a compound of formula I wherein benzene ring A is other than a 2-carbamoylphenyl radical, reacting a compound of the formula II with an aldehyde of the formula:- IV

wherein benzene ring A has the meaning of formula I other than a 2-carbamoyl-phenyl radical, in the presence of a reducing agent;
(c) for a compound of formula I wherein R1 is a hydroxy radical, hydrolysinga compound of the formula:- VI

wherein R2 has the same value as R1 other than a hydroxy radical and benzene ring A has the meaning of formula I; or (d) for a compound of formula I wherein R1 is a hydroxy or amino radical and benzene ring A bears a carbamoyl radical, hydrolysing a compound of the formula:- VII

wherein R3 is a hydroxy, (1-6C)alkoxy or amino radical and benzene ring C
has one of the values defined for ring A which is a cyanophenyl radical;
whereafter, for a compound of formula I wherein R1 is other than a hydroxy radical, a compound of formula I wherein R1 is a hydroxy radical, or a reactive derivative thereof, is esterified or amidified with a compound of the formula R2.H wherein R2 has the same values as R1 other than a hydroxy radical; and for a pharmaceutically acceptable base addition salt of a compound of formula I wherein R1 is a hydroxy radical, such a compound is reacted with a suitable base affording a pharmaceutically acceptable 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.

2. A 1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid derivative as defined in claim 1 whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.

3. A process as claimed in claim 1 wherein in the starting materials R1 is a hydroxy, amino, methoxy, ethoxy or butoxy radical.

4. A process as claimed in claim 1 wherein in the starting materials benzene ring A is a 2-chlorophenyl, 2-cyanophenyl, 2-carbamoylphenyl, 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 2-trifluoromethylphenyl, 3-cyanophenyl, 4-cyanophenyl, 4-hydroxyphenyl, 3,4-dichlorophenyl or 3,5-dichlorophenyl radical.

5. A process as claimed in claim 1, 3 or 4 for the manufacture of a compound of formula I wherein benzene ring A is other than a 2-carbamoylphenyl radical in which procedure (a) or (b) is used.

6. A process as claimed in claim 1, 3 or 4 in which procedure (c) or (d) is used.

7. A process for the manufacture of a 1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid derivative of the formula:-I
wherein R1 is a hydroxy radical and benzene ring A is a 2-chlorophenyl, 2-cyanophenyl or 2-carbamoylphenyl radical, or a pharmaceutically acceptable salt thereof; characterised by hydrolysing a compound of the formula:- VI

wherein R2 is methoxy, ethoxy, benzyloxy or chlorobenzyloxy and benzene ring A has the meaning defined above; whereafter, when a pharmaceutically acceptable salt is required, a compound of formula I is reacted with the corresponding base or acid affording a pharmaceutically acceptable cation or anion, respect-ively.

8. A process as claimed in claim 7 in which the hydrolysis is performed in the presence of an aqueous mineral acid or an aqueous strong base, at a temperature in the range 20-120°C.

9. A 1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid derivative as defined in claim 7 whenever prepared by the process of claim 7 or 8, or by an obvious chemical equivalent thereof.

10. A process for the manufacture of a 1-benzyl-1,2,5,6-tetrahydropyridine -3-carboxylic acid derivative of the formula:- I

wherein R1 is a hydroxy or amino radical and benzene ring A is a 2-carbamoyl-phenyl radical, or a pharmaceutically acceptable salt thereof, characterised by hydrolysing a compound of formula I wherein R1 is a hydroxy, methoxy ethoxy or amino radical and benzene ring A is a 2-cyanophenyl radical; whereafter when a pharmaceutically acceptable base-addition salt is required, the compound of formula I wherein R1 is a hydroxy radical is reacted with a base affording a pharmaceutically acceptable cation, and when a pharmaceutically acceptable acid-addition salt is required, the compound of formula I is reacted with an acid affording a pharmaceutically acceptable anion.

11. A process as claimed in claim 10 in which the hydrolysis is performed in the presence of an aqueous mineral acid or an aqueous strong base at a temperature in the range 20-120°C.

12. A 1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid derivative as defined in claim 10 whenever produced by the process of claim 10 or 11 or by an obvious chemical equivalent thereof.

13. A process as claimed in claim 1 wherein in the starting materials R1 is a hydroxy, methoxy, ethoxy, butoxy or amino radical and benzene ring A
is a 2-cyanophenyl radical and procedure (a) or (b) is used.

14. A 1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid derivative of the formula I set out in claim 1, and wherein R1 is a hydroxy, methoxy, ethoxy, butoxy or amino radical and benzene ring A is a 2-cyano-phenyl radical, or a pharmaceutically acceptable acid-addition salt thereof, whenever produced by the process of claim 13, or by an obvious chemical equivalent thereof.