CS215045B2 - Method of making the new derivatives of 1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxyl acid - Google Patents

Description

The invention relates to a process for the production of novel 1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid derivatives which inhibit platelet aggregation in vivo and can therefore be used for the treatment or prophylaxis of thrombosis or occlusive vascular diseases.

It is already known that various derivatives of N-benzyl-4,5,6,7,7-tetrahydrothieno [3,2-c] pyridine and N-benzy 1-4,5,6,7-tetrahydrofuro [3,2-c] Pyridine exhibits anti-inflammatory activity and inhibits platelet aggregation (see M. Podesta et al., European J. Med. Chem., Chim. Therapeutica, 1974 9, 487-490). It is also known that various 1-benzyl-1,2,5,6-tetrahydropyridine-4-carboxylic acid esters are chemical intermediates (see DOS No. 2,221,770 and Annalen, 1972,764, 21-27). It has now been found that certain new 1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid derivatives also unexpectedly also inhibit platelet aggregation in vivo, on which the invention is based.

Two related compounds are known, namely 1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester and ethyl ester [cf. Obščej. Chim. 1957, 27, 3162-3170 (Chemical Abstracts, 1958, 52, 9162c-i and J. Chem. Soc. Chemical Communications, 1975, 682), but to which no useful pharmacological properties have been attributed.

The present invention provides a process for the preparation of novel 1-benzyl-1,2,5,6-terahydropyridine-3-carboxylic acid derivatives of the general formula I

U) in which

R ¹ represents hydroxyl, amino, C 1 -C 4 alkylamino, C 1 -C 4 alkylamino, benzyloxy optionally substituted by halogen, or C 1 -C 6 alkoxy optionally substituted by C 1 -C 4 alkoxy C 4 or C 1-4 dialkylamino groups each having 1 to 4 carbon atoms in each alkyl moiety, and benzene ring A carries one or two substituents selected from the group consisting of halogen atoms, C 1 -C 4 alkyl, cyano, carbamoyl, trifluoromethyl and a hydroxy group, and pharmaceutically acceptable salts thereof.

Examples of particular residues in the meaning of the symbol R ¹ include:

for (C 1 -C 4) alkylamino, methylamino or ethylamino, for (C 1 -C 4) dialkylamino in each alkyl moiety, dimethylamino or diethylamino, for (C 1 -C 6) alkoxy, ethoxy, propoxy, butoxy or butoxy; C 1 to C 6 ethoxy, prppoxy, butoxy or amyloxy bearing a substituent selected from the group consisting of methoxy, ethoxy, dimethylamino and diethylamino.

Examples of particular substituents on benzene ring A include:

for halogen atoms, fluorine, chlorine or bromine atoms; and for C1 -C4 alkyl, methyl, ethyl, n-propyl or isopropyl.

Examples of suitable benzene ring A radicals include 2-chlorophenyl, 2-cyanophenyl, 2-carbamoyl phenyl, 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 2-trifluoromethyl, 3- cyanophenyl, 4-cyanophenyl, 4-hydroxyphenyl, 3,4-dichlorophenyl and 3,5-dichlorophenyl, of which 2-cyanophenyl, 2-carbamoylphenyl and 2-chlorophenyl are preferred.

The compounds of formula (I) are basic enough to form acid addition salts. Examples of suitable pharmaceutically acceptable acid addition salts of the compounds of formula (I) include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, or salts with organic acids such as oxalic acid or citric acid.

Furthermore, those compounds may · formula I wherein R ¹ represents a hydroxyl group, form acid addition salts. Suitable base addition salts of such compounds of formula I are, for example, alkali metal or alkaline earth metal salts such as sodium, potassium, calcium or magnesium salts, aluminum or ammonium salts, or salts with organic bases providing a pharmaceutically acceptable cation, e.g. triethanolamine.

Particular groups of particularly interesting compounds of the invention are those compounds of formula (I) as defined above wherein: (i)

R ¹ represents a hydroxyl group, (ii)

R ¹ is amino, (iilj

R ¹ represents an alkoxy group having 1 to 6 carbon atoms, especially methoxy, ethoxy or butoxy, (IVJ benzene ring A bears one or two halogen substituents, and (v) benzene ring A bears a cyano or carbamoyl group, together with appropriate pharmaceutically acceptable salts of these · substances.

A preferred group of compounds of the invention are those compounds of formula I wherein R ¹ is hydroxy, amino or C 1 -C 4 alkoxy and the benzene ring A is substituted at the 2-position with chloro, carbamoyl. or a cyano group, and pharmaceutically acceptable salts thereof.

Specific compounds of Formula I are described in the Examples below. Of these, 1- (2-chlorobenzyl) -1,2,5,6-tetrahydropyridine-3-carboxylic acid and 1- (2-cyanobenzyl) -1,2,5,6-tetrahydropyridine-3- are of particular interest. carboxylic acid and their methyl esters, as well as pharmaceutically acceptable salts thereof.

The compounds of formula (1) may be prepared by any method known in the art of organic chemistry for the synthesis of analogous pyridine derivatives. The present invention is a process for preparing the above compounds, wherein the compound of formula II ^{fi? C} v _w (//) wherein

R ¹ has the above meaning, is reacted with an aldehyde of the formula III

wherein the benzene ring B has the same meaning as the benzene ring A except for the 2-carbamoylphenyl moiety in the presence of a reducing agent.

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

The above reaction is preferably carried out in a solvent or diluent, for example in a C 1 -C 4 alkanol such as ethanol, conveniently at or around room temperature, for example at 15 to 30 ° C.

The above process is a reaction of the type known as reductive amination and which may be carried out wholly or at least in part via the intermediate of formula IV

(IV) which arises in situ and is subsequently reduced. It should be emphasized that the invention also includes the separate reduction of 'the intermediate of formula IV, prepared as example ¹ by reacting a compound of formula II with an aldehyde of formula III in the absence of a reducing agent.

The aldehydes of formula (III) above may be prepared by standard organic chemistry techniques.

In order to obtain a compound of the formula I in which the benzene ring A is substituted in the 2-position by a carbamoyl group, the corresponding compound of the formula I in which the benzene ring A carries in the 2-position a cyano group is subjected to hydrolysis.

This hydrolysis can be carried out using conventional conditions for the preparation of amides from nitrile. Thus, the hydrolysis can be carried out in the presence of an aqueous acid or a base, for example an aqueous mineral acid such as hydrochloric or sulfuric acid, or an aqueous solution of a strong base such as sodium or potassium hydroxide. Conveniently, a solvent or diluent such as ethanol or acetic acid may be used for the hydrolysis, and the reaction may be carried out at a temperature of, for example, from 20 to 120 ° C. Generally, a short reaction time is preferred to minimize further hydrolysis of the resulting amide bond.

For the preparation of compounds of formula I wherein R ¹ is other than hydroxyl. a compound of formula I wherein R ¹ is a hydroxyl group, or a reactive derivative thereof, such as the corresponding acid chloride, bromide or anhydride, is reacted with the corresponding compound of formula I under known esterification or amidation conditions and procedures.

R ² . H, wherein R ² has the same meaning as R ¹ , except for the hydroxy group.

The above-defined pharmacologically acceptable salts can be prepared in a conventional manner by reaction with a suitable acid or base to give a pharmaceutically acceptable anion, respectively. cation.

As mentioned above, the compounds of formula I inhibit platelet aggregation. Their ability can be demonstrated in vivo using standard g

tests in laboratory animals, for example using the following test in rabbits.

Blood samples are taken from rabbits from the central ear artery using a standard method and introduced into a 3.8% [weight / volume] solution of trisodium citrate as an anticoagulant and then centrifuged, first at 150 g and then at 1000 g, to prepare platelet-rich and platelet-poor plasma fractions. These fractions are used to calibrate the optical transmittance device to determine the degree of platelet aggregation, and to determine the extent of platelet aggregation after addition of ademosine-5'-diphosphate (final concentration 0.5, 1.0, 2). 0, 4.0 or 8.0 µmol) to the platelet-rich plasma fraction and the maximum aggregation value is recorded in response to each concentration of adenosine-5-diphosphate.

Rabbits are then orally administered the test compound and arterial blood samples are taken at intervals after administration. A platelet-rich fraction is prepared, adenosine 5‘-diphosphate is added to the same as above and the extent of platelet aggregation is measured by measuring the optical transmittance of the sample. The value obtained is compared to that obtained in the same rabbit prior to administration of the test compound to give a measure of the inhibition of platelet aggregation induced by adenosine-5 ' -difO'fate.

For example, 1- (2-chlorobenzyl) -1,2,5,6-tetrahydropyridine-3-carboxylic acid exhibits marked inhibition of platelet aggregation 2 hours after oral administration (in the form of the hydrochloride at 25 mg / kg). The compounds of formula I can be said to exhibit a marked inhibitory potency after oral administration at doses of 100 mg / kg or much lower, with no apparent evidence of toxicity at the effective dose.

Platelet aggregation inhibiting compounds, for example acetylsalicylic acid, are used for the treatment or prophylaxis of thrombosis or occlusive vascular diseases. The compounds of the invention are expected to be used in a similar manner and for the same clinical indications.

When used to inhibit platelet aggregation, for example acetylsalicylic acid, the compound of formula I may be administered at a daily dose of between 1 and 30 mg / kg, preferably between 1 and 10 mg / kg, with pharmaceutically acceptable an equivalent amount is applied to the salt. In humans, this dosage corresponds to a daily oral dose of from about 0.07 to 2.1 g, respectively. from 0.07 to 0.7 g, wherein when pharmaceutically acceptable salts are used, an equivalent amount is applied again. The above total daily dose may be administered in divided doses, if desired.

The compounds of formula I are preferably administered in the form of pharmaceutical compositions.

The invention is illustrated by the following non-limiting examples. In these examples, the yields are given by way of example only and in no way represent the maximum achievable yields, i.e. evaporation is carried out in a vacuum where possible to dryness using a rotary evaporator and

(c) melting points were determined in sealed glass capillaries.

Example 1

To a solution of 3.1 g of methyl 1,2,5,6-tetrahydropyridine-3-carboxylate in 30 ml of methanol was added 1.34 g of 4-hydroxybenzaldehyde and 0.7 g of sodium cyanoborohydride. The resulting mixture was stirred at 25 ° C for 3 days, evaporated, 30 ml of water was added to the residue, acidified to pH 1 with concentrated hydrochloric acid, extracted twice with 20 ml of ether each time, and the extracts were discarded. The aqueous phase was basified to pH 9 with 10% (w / v) sodium carbonate solution and extracted twice with 30 ml of ether each time. The combined extracts were dried (MgSO4) and evaporated. The oily residue was dissolved in acetone and a slight excess of ethereal hydrogen chloride was added to the solution. Filtration of the precipitated solid product afforded 2.05 g of methyl 1- (4-hydroxybenzyl) -1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride. Recrystallization of a portion of this material from methanol and acetone gave pure product, mp 212-214 ° C (dec.).

Example 2

A mixture of 1- (3,4-dihlorobenzyl) -1,2,5,6-tetrahydropyridine-3-carboxylic acid hydrochloride (2.0 g) and thionyl chloride (15 ml) was heated at reflux for 30 minutes, then the excess thionyl chloride was evaporated and the residue is mixed with toluene. The mixture was evaporated, 30 ml of n-butyl alcohol was added to the cooled solid residue, and the resulting mixture was stirred at 25 ° C for 1 hour, during which time all solid material dissolved. The resulting solution was heated to reflux for 10 minutes, then excess n-butyl alcohol was evaporated. Recrystallization of the residue from a mixture of acetone and ether gave 1.2 g of n-butyl 1- (3,4-dichlorobenzyl) -1,2,5,6-tetrahydropyridine-3-carboxylate, m.p. 160-162 ° C. .

Examples 3 to 7

The following esters or carboxamides of the general formula I in which ring A represents a 3,4-dichlorophenyl group are obtained in the form of the hydrochloride (unless otherwise indicated) using the corresponding alcohol or amine in analogy to Example 2:

Example R ¹ Number Yield (%) Melting point (° C) Crystallization solvent

3 CeHsCHaO 86 166 to 169 dimethylketone / ethyl acetate 4 (C 2 H 5) 2NCH 2 CH 2 O 21 208 to 211 *} 5 H2N 18 145 to 150 ** j isopropanol 6 C2H5NH 61 224 to 228 7 (C2’H5] 2N 72 200 to 202 ethanol / dimethylketone Legend: chloride 1- (2-carbamoylbenzyl) -1,2,5,6-tetra- hydropyridine-3-carboxylic acid, melting

* J dihydrochloride. 1% H 2 O, **) free base. Vi H2O.

after recrystallization from a mixture of ethanol and acetone with decomposition at 219 to 222 ° C.

Example 8

Example 9

A mixture of 0.5 g of methyl 1- (2-cyanobenzyl) -1,2,5,6-tetrahydropyridine-3-carboxylate and 5.0 ml of concentrated hydrochloric acid was heated at 95-100 ° C for 1-2 hours. The reaction mixture is evaporated to dryness and the residue is triturated with acetone to give the analogous procedure of Example 1 using the corresponding compound (II) and the aldehyde (III) in a yield of 30 to 55% of the following compound (I). hydrochloride form:

Claims (5)

merge- nina number R ¹ a substituent on ring A melting point (° C) crystallization solvent · 1 methoxy 2-chloro 171 to 175 - 2 hydroxy 2-chloro 208 to 210 - (decomposition] 3 methoxy 2-cyano 183 to 184 acetone / methanol 4 ethoxy 3,4-dichloro 192 to 199 - 5 methoxy 4-methyl 183 to 184 methanol / ethyl acetate 6 methoxy 3,4-dichloro 185 to 188 - OF hydroxy 3,4-dichloro 240 to 245 - 8 hydroxy 4-methyl 230 to 236 ethanol / acetone 9 hydroxy 4-bromo 248 to 253 - 10 methoxy 4-bromo 200 to 205 - 11 hydroxy 2-cyano 206 to 212 ethanol / ether SUBJECT OF THE INVENTION 1. A process for the production of new 1-ben- in which zyl-1,2,5, N-tetrahydropyridine-3-carboxy- benzene ring B has the same meaning of the general formula I Wherein R 1 is hydroxy, amino, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, C 1 -C 4 benzyloxy optionally substituted by halogen, or C 1 -C 6 alkoxy, an optionally substituted radical selected from the group consisting of C 1 -C 4 alkoxy and C 1 -C 4 dialkylamino in each alkyl moiety, and the benzene ring A carries one or two substituents selected from the group consisting of halogen atoms, C 1 -C 4 alkyl groups , a cyano group, a carbamoyl group, a trifluoromethyl group and a hydroxyl group, and pharmaceutically acceptable salts thereof, characterized in that the compound of formula II RÍCO NH (II) wherein R ¹ has the above meaning, is reacted with an aldehyde of the formula III H.CO benzene ring A, with the exception of the 2-carbamoylphenyl radical, in the presence of a reducing agent, and optionally, for the preparation of compounds of formula I wherein the benzene ring A is substituted at the 2-position by carbamoyl, the corresponding compound of formula I wherein the benzene ring A is substituted at the 2-position with cyano, subjected to hydrolysis, and optionally, to prepare compounds of formula I wherein R ¹ is other than hydroxyl, a compound of formula I wherein R ¹ is hydroxyl, or a reactive derivative thereof, is reacted with a compound of formula R ² . H, where R ² is defined as R ^1, with the exception of the hydroxyl group using esterification or amidation procedures, and the obtained compound of formula I wherein R ¹ is hydroxy, optionally reacting with a base affording a pharmaceutically acceptable cation into a pharmaceutically acceptable acid addition a salt with a base, or optionally obtaining a compound of formula (I), by reaction with an acid giving a pharmaceutically acceptable anion to its pharmaceutically acceptable acid addition salt. 2. The process according to claim 1, wherein the reducing agent is an inorganic hydride such as sodium borohydride, potassium borohydride, lithium cyanoborohydride or sodium cyanoborohydride. 3. Process according to claim 1 or 2, characterized in that the reaction is carried out in a solvent or diluent at a temperature of 15 to 30 ° C. (III) 4. A process according to claim 1, wherein the benzene ring A is substituted in the 2-position by a carbamoyl group, characterized in that the hydrolysis of the corresponding 2-cyander derivative is carried out in the presence of an aqueous mineral acid or an aqueous of a strong base solution, at a temperature of 20 to 120 ° C. 5. Process according to claim 1, 2, 3 or 4, characterized in that the starting materials of the formulas II and III are used in which the benzene ring B is substituted in the 2-position by chlorine, in the 3 and 4 positions by chlorine atoms or And R ¹ represents a hydroxyl group, a methoxy group or an ethoxy group.