CS215044B2 - 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 N-benzyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine and N-benzyl-4,5,6,7-tetrahydrofuro [3,2-c] pyridine derivatives exhibit anti-inflammatory activity and inhibit platelet aggregation (see M. Podesta et al., European J. Med. Chem., Chimi. Therapeutica, 1974, 9, 487-490). It is also known that various esters of 1-benzyl-1,2,5,6-tetrahydropyridine-4-carboxylic acid are chemical intermediates [see DOS No. 2,221,770 and Annalen, 1972,764, 21-27]. It has now been found that certain novel 1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid derivatives unexpectedly also inhibit platelet aggregation in vivo, on which the invention is based.

Two related compounds are known, 1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester and ethyl ester [see Zur. Obščej. Chim. 1957, 27, 3162-2170 (Chemical Abstracts, 1958, 52, 9162.C-1 and J. Chem. Soc. Chemical Communications, 1975, 6 | 82), 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-tetrahydropyridine-3-carboxylic acid derivatives of the general formula I

in in which,

R ¹ represents hydroxyl, amino, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, benzyloxy optionally substituted by halogen, or C 1 -C 6 alkoxy optionally substituted by C 1 -C 4 alkoxy C 4 or C 1 -C 4 dialkylamine and each benzene ring A carries one or two substituents selected from the group consisting of halogen atoms, C 1 -C 4 alkyl, cyano, carbamoyl and trifluoromethyl 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, amine, or alkoxy having 1 to 6 carbon atoms of ethoxy-, propoxy-, butoxyne-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-carbamoylphenyl, 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 2-trifluoromethylphenyl, 3-cyanophenyl 4-cyanophenyl, 3,4-dichlorophenyl, and 3,5-dichlorophenyl, of which 2-cyanophenyl, 2i-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 citric acid.

In addition, those compounds of formula I in which R @ ¹ is hydroxyl may form base addition salts. Suitable base addition salts of such compounds of the 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, for example 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, (iii)

R ¹ is C 1 -C 6 alkoxy, especially methoxy, C 4 thoxy or butoxy; (iv) benzene ring A carries one or two halogen substituents; 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 benzene ring A is substituted at the 2-position with chloro, carbamoyl or cyano, and pharmaceutically acceptable salts thereof. salts.

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

The compounds of formula (I) may be prepared by any of the general methods known in the art of organic chemistry for the synthesis of analogous pyridine derivatives. The present invention provides a process for the preparation of the aforementioned compounds, characterized in that the compound of formula (II) is used

R ^c0 (I) wherein ^R] is as defined above, is reacted with a benzyl halide of the formula III

in which

Hal represents a halogen atom such as chlorine, bromine or iodine and the benzene ring B has the same meaning as the benzene ring A except for the 2-carbamoylphenyl radical.

The reaction may conveniently be carried out in the presence of a base such as an alkali metal carbonate or acetate such as potassium carbonate or sodium acetate, preferably in a suitable solvent or diluent, such as methanol or ethanol, at a temperature of, for example, 20 to 120 ° C. C.

A compound of formula II wherein R ¹ is a hydroxy group is known and the remaining starting materials of formula II may be obtained from the known compounds in a conventional manner.

In order to obtain a compound of formula 215044 ce I in which the benzene ring A is substituted in the 2-position by a carbamoyl group, the corresponding compound of formula I in which the benzene ring A bears 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 nitriles. Thus, the hydrolysis can be carried out in the presence of an aqueous acid or 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, for example 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 in order to minimize further hydrolysis of the resulting amide bond.

To prepare compounds of formula I in which R ¹ represents a radical other than a hydroxyl group, a corresponding compound of formula I in which R ¹ is hydroxyl or a reactive derivative thereof, e.g., the corresponding chloride, bromide or anhydride, reacting under known esterification or amidation conditions and procedures with a corresponding compound of formula

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

The above-defined pharmaceutically acceptable salts may be prepared in a conventional manner by reaction with a suitable acid or base to provide a pharmaceutically acceptable anion or a pharmaceutically acceptable salt thereof. cation.

As mentioned above, the compounds of formula I inhibit platelet aggregation.

Their ability can be demonstrated in vivo using standard tests in laboratory animals, for example using the following rabbit test.

Blood samples are taken from rabbits from the central ear artery in a standard manner and placed in a 3.8% (w / v) solution of trinotrate citrate as an anticoagulant and then centrifuged, first at 150 g and then at 1000 g, thereby prepare platelet-rich and platelet-rich plasma fractions. These fractions are used to calibrate the optical transmittance measuring device and thereby determine the degree of platelet aggregation. The extent of platelet aggregation after addition of adenosine 5'-diphosphate (0.5, 1.0, 2.0, 4.0, or 8.0 µmol concentration to platelet-rich plasma fraction) is determined and the maximum aggression value is recorded. in response to each adenosine-5'-diphosphate concentration.

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

For example, 1- (2-chlorobenzyl) -1,2,5,6-tetrahydropyridine-3-carboxylic acid exhibits a significant inhibition of platelet aggregation 2 hours after oral administration (in the form of the hydrochloride) at a dose of 25 mg / / kg. The compounds of formula (I) in the test described above exhibit significant inhibitory potency after oral administration at doses of 100 mg / kg or much lower, with no apparent signs 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 in warm-blooded animals, including humans, 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, using a pharmaceutically acceptable salt. an equivalent amount is applied. The above total daily dosage 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

(a) the yields are given by way of example only and in no way represent the maximum achievable yields;

(b) the evaporation is carried out in a vacuum where possible to dryness using a rotary evaporator; and

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

Example 1

To a solution of 1.63 g of methyl 1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride in 10 ml of methanol was added 2.2 g of triethylamine and 1.63 g of 2-chlorobenzyl chloride. The resulting solution is allowed to react at 20-25 ° C for 24 hours, then evaporated, and 20 ml of water and 10% (w / v) sodium carbonate solution are added to the residue to give a mixture of pH 10. This · mixture The combined extracts were washed with water, dried (MgSO4) and evaporated. The oily residue was dissolved in acetone and a slight excess of ethereal hydrogen chloride was added to the solution. The precipitated solid was filtered off and washed with acetone to give 1.5 g of methyl 1- (2-chlorobenzyl) -1,2,5,6-tetrahydropyridine-3-carboxylate, m.p. 171-175 ° C. Examples 2 to 5

The following compounds can be prepared in analogy to Example 1 using the corresponding benzyl halide (III) and the corresponding ester (II) as starting material:

EXAMPLE 2 Methyl 1- (2-cyanobenzyl) -1,2,5,6-terahydropyrldine-3-carboxylate hydrochloride, m.p. 183-184 [deg.] C, yield 54% (after recrystallization from methanol / acetone);

EXAMPLE 3 Ethyl 1- (3,4-dichlorobenzyl) -1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride, m.p. 192-199 ° C, yield 76%; EXAMPLE 4 Methyl 1- (4-methylbenzyl) -1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride, m.p. 183-184 [deg.] C, in a yield of 81% (after recrystallization from methanol / methanol). ethyl acetate);

EXAMPLE 5 Methyl 1- (3,4-dichlorobenzyl) -1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride, m.p. 185-188 [deg.] C, 71% yield. Example 6

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 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, whereupon the 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 7 to 11

The following esters or carboxamides of the general formula (I) in which the ring A represents a 3,4-dichlorophenyl group are obtained in the form of the hydrochloride (unless otherwise stated) using the appropriate alcohol or amine in analogy to Example 6:

example number R ¹ yield (%) melting point (° C) crystallization solvent | 7 C6H5GH2O 86 166 to 169 dimethylketone / ethyl acetate 8 (C2H5) CH2O ₂ anch 21 208 to 211 *) 9 HaN 18 145 to 150 *) isopropanol 10 C2H5NH 61 224 to 228 11 (CaH5) 2'N 72 200 to 202 ethanol / dimethylketone Legend: chého eth anol and insoluble material (

*) dihydrochloride. 1¾ H2O, *) free base. 1/4 H2O.

Example 12

A mixture of 4.0 g of 1,2,5,6-tetrahydropyridine-3-carboxylic acid hydrochloride, 8.2 g of triethylamine and 4.0 g of 2-cyanobenzyl bromide was heated at 95-100 ° C in 20 ml of methanol for 3 hours. The reaction mixture was evaporated to dryness and excess aqueous sodium carbonate solution was added to the residue. The mixture is again evaporated to dryness and the residue is acidified with 2 N hydrochloric acid to pH 2-3. The mixture is evaporated to dryness, the residue is suspended in 30 ml of toluene and the suspension is evaporated to dryness. The solid residue was dissolved in 10 ml (dry sodium chloride) and discarded. The solution was evaporated and the residue was recrystallized from ethanol-ether to give 1- (2-cyanobenzyl) -1,2,5,6-tetrahydropyridine-3-carboxylic acid hydrochloride solid, m.p. 206-212 ° C.

Example 13

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 was evaporated to dryness and the residue was triturated with acetone to give 1- (2-fearbamoylbenzyl) -1,2,5,6-tetrahydropyridine-3-carboxylic acid hydrochloride, melting after recrystallization from ethanol / acetone. with decomposition at 219-222 ° C.

Example 1 a d 14

Using an analogous procedure to that of Example 12, the following compounds of formula I (in the form of hydrochlorides) can be obtained from the corresponding compounds of formula II and halides of formula III (Hal-Cl or Br) in a yield of 15 to 30%:

merge- nina number Rl circle A 1 OH 2-chlorophenyl 2 OH 3,4-dichlorophenyl 3 OH 4-methylphenyl 4 OH 4-bromophenyl

Example 15

In a manner analogous to Example 1, crystallization (° C) solvent was used as the melting point using 4-bromobenzyl chloride.

208 to 210 - (decomposition)

240 to 245 -

230-236 ethanol / acetone

248-253 - the title compounds are obtained in a yield of 55% of methyl 1- (4-bromobenzyl) -1,2,5,6-tetrahydropyridine-3-carbonyl oxyl hydrochloride, m.p. 200-205 ° C.

Claims (5)

1. A process for the preparation of the novel 1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid derivatives of the general formula I R? CO (s) in which · R @ ¹ is hydroxy, amino, C1 -C4 alkylamino, C1 -C4 dialkylamino, benzyloxy optionally substituted by halogen or C1 -C6 alkoxy optionally substituted by a radical selected from the group 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, cyano, a carbamoyl group and a trifluoromethyl group, and pharmaceutically acceptable salts thereof, characterized in that the compound of formula (II): R ¹ has the above meanings, is reacted with a benzyl halide of the formula III OF THE INVENTION M1) wherein, the benzene benzene ring A, with the exception of the 2-carbamoylphenyl moiety and Hal is a halogen atom and then optionally hydrolyzed to prepare compounds of formula I wherein the benzene ring A is substituted in the 2-position with a carbamoyl group, the corresponding compound of formula I wherein the benzene ring A is substituted in the 2-position with a cyano group 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, with a compound of formula R ² . H, ring B has the same meaning as where R ² is defined as R · ^1, except for hydroxyl group using esterification or amidation procedures, and the obtained compound of formula I in which R < ¹ & gt ^; is a hydroxyl group, optionally by reaction with a base providing a pharmaceutically acceptable cation to its pharmaceutically acceptable base addition salt, or optionally converting the obtained compound of formula I into a pharmaceutically acceptable acid addition salt by reaction with a acid providing a pharmaceutically acceptable anion . 2. The process of claim 1, wherein B is as defined above and Hal is chlorine or bromine, and the reaction is carried out at a temperature of 20 to 120 ° C. A process according to claim 1 or 2, characterized in that the reaction is carried out in the presence of a base such as an alkali metal carbonate or acetate or triethylamine. 4. A process according to claim 1, wherein the benzene ring A is substituted at 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; % of an aqueous solution of a strong base, 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 O is substituted in the 2-position by chlorine, in the 3 and 4 positions, by chlorine atoms or position 2 is cyano; and R ¹ is hydroxyl, methoxy or ethoxy.