CS215046B2 - Method of making the new 1-benzyl-1,2,5,6-tetrahydropiridine-3-carboxyl acids - Google Patents

Description

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

Various derivatives of N-benzyl-4,5,6,7-tetrahydrothieno [3,2-c], pyridine and N-benzyl-4,5,6,7-tetrahydrofuro [3,2-c] are already known. pyridine exhibits anti-inflammatory activity and inhibits platelet aggregation (see M. Podesta et al., European J. Med. Chem., Chim. Therapeutica, 1974, 9, 487-490). Various esters of 1-benzyl- 1,2,5,6-tetrahydropyridine-4-carboxylic acids are chemical intermediates (see DOS No. 2 221 770 and Annalen, 1972, 7B4, 21 to 27). It has now been found that certain novel 1-benzyl-1 Unexpectedly, 2,5,6-tetrahydropyridine-3-carboxylic acids 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. Ohhhh. Chim. 1957, 27, 3162-3170 (Chemical Abstracts, 1958, 52, 9162C-1 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 the novel 1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylic acids of the formula I

Wherein the 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 hydroxyl groups, and pharmaceutically acceptable salts thereof.

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-Brophenyl group

4-methylphenyl,

2-trifluoromethylphenyl,

A 3-cyanophenyl group,

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. .

In addition, the compounds of formula I may form base addition salts. Suitable base addition salts of the 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, 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) benzene ring A carries one or two halogen substituents and (ii) benzene ring A carries a cyano or carbamoyl group, salts of these substances.

A preferred group of compounds of the invention. are those compounds of formula (I) wherein the benzene ring A is substituted in the 2-position with chloro, carbamoyl or cyano, and their pharmaceutically acceptable salts.

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-carboxylic acid, and pharmaceutically acceptable salts thereof.

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

Ul) in which

R ² represents amino, alkylamino having 1 to 4 carbon atoms, containing dialkylaminoskuplnu in each alkyl moiety has 1 to 4 carbon atoms, benzyloxyskuipinu optionally substituted by halogen or alkoxy having 1-6 carbon atoms.

Particularly suitable radicals represented by R ² as methoxy, ethoxy, benzyloxy or chlorobenzyloxy.

Hydrolysis may 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 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.

It should be noted that if the benzene ring A carries a cyano group, further hydrolysis of this substituent to the carbamoyl residue may occur as well as hydrolysis of the ester moiety. When the benzene ring A carries a cyano group or a carbamoyl group, shorter reaction times are generally used and R ² is preferably a C 1 -C 6 alkoxy group such as a methoxy or ethoxy group.

The required starting materials of formula II in which the benzene ring A is as defined above, with the exception of the 2-hydroxy, 2-carbamoyl and 4-hydroxyphenyl groups, may be obtained by reacting a compound of formula III (III) with a benzyl halide of formula IV nv) in which:

Hal represents a chlorine or bromine atom, conveniently in the presence of a base such as potassium carbonate, sodium acetate or triethylamine, in a solvent such as methanol or ethanol at a temperature of 20 to 120 ° C.

The compound of formula III, those in which R ² is replaced by a hydroxyl radical is known and the remaining compounds of formula III can be obtained from the known compounds in a conventional manner.

The starting materials of formula II in which the benzene ring A is as defined above, with the exception of the 2-carbamoylphenyl group, can also be obtained by reductive alkylation of the compound of the above formula III with an aldehyde of the formula V

(V) in the presence of a reducing agent such as sodium cyanoborohydride, suitably in a solvent such as methanol or ethanol at a temperature of 15 to 30 ° C.

The remaining starting materials of formula II in which the benzene ring A is a 2-carbamoylphenyl radical can be obtained in a conventional manner, for example by substituting a compound of formula V in the above-described reductive alkylation with phthaldehyde acid followed by conventional amidation of the resulting compound of formula II the benzene ring A represents a 2-carboxyphenyl group.

The above-defined pharmaceutically acceptable salts can be prepared in a conventional manner by reaction with a suitable acid or base to provide a pharmaceutically acceptable anion and a pharmaceutically acceptable salt. 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 test in rabbits.

Blood samples are taken from rabbits from the central ear artery by standard means, which are introduced into a 3.8% (w / v) 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 measuring device (transmittance J) and thereby determine the degree of platelet aggregation. The extent of platelet aggregation after adenosine-5'-d-phosphate addition (final concentration 0.5, 1.0) is determined. , 2,0, 4,0 or 8,0 μπιοί to the platelet-rich plasma fraction and record the maximum aggregation value in response to each adenosine-5'-diphosphate concentration.

Rabbits are then orally administered the test compound and arterial blood samples are taken at intervals after administration. A platelet-rich fraction is prepared and adenosine-5-8 is added as above

diphosphate and measuring the optical permeability of the sample to determine the extent of platelet aggregation. The value determined 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‘-diphosphate.

For example, 1- (2-chlorobenzyl) -1,2,5,6-tetrahydropyridine-3-carboxylic acid exhibits marked inhibition of platelet aggregation at 2 hours after oral administration (as hydrochloride) at 25 mg / kg. In general, the compounds of formula (I) exhibit significant inhibitory potency after oral administration at doses of 100 mg / kg or much lower doses, without any 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.

At. for use in inhibiting 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. 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 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 evaporations were carried out in a vacuum, where possible to dryness, using a rotary evaporator and the melting point was determined in sealed glass capillaries.

Example 1

A solution of 0.45 g of methyl 1- (2-chlorobenzyl) -1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride. in 10 ml of concentrated hydrochloric acid was heated at 95-100 ° C for 2 hours, then cooled and evaporated. To remove the remaining traces of water, the residue was re-evaporated several times with acetone and toluene. The resulting solid was stirred with acetone and then filtered to yield

0.4 g of 1- (2-chlorobenzyl) -1,2,5,6-tetrahydro-pyridine-3-carboxylic acid hydrochloride melting at 208 DEG-210 DEG C. with decomposition.

Example 2

Analogous to Example 1, hydrolysis of methyl 1- (3,4-dichlorobenzyl) -1 + SB-tetrahydropyridine-S-carboxylate hydride chloride afforded 1- (3,4-dichlorobenzyl) -1,2,5,6- 240 DEG-245 DEG C .; tetrahydropyridine-3-carboxylic acid.

Examples 3 and 4

The following compounds were obtained in an analogous manner to that described in Example 1 using the appropriate methyl ester in each case:

EXAMPLE 3 1- (4-Methylbenzyl) -1,2,5,6-tetrahydropyridine-3-carbonyl-xylic acid hydrochloride in 71% yield, m.p. 230 DEG-236 DEG C. (after recrystallization from ethanol / acetone) );

Example 4 1- (4-Bromobenzyl) -1,2,5,6-tetrahydropyridine-3-carboxylic acid hydrochloride in 94% yield, mp 248-253 ° C. Example 5 A mixture of 0.5 g of methyl 1- (2-cyanobenzyl) -1,2,56-tetrahydropyridine-3-carboxylate and 5 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-carbamoylbenzyl) -1,2,5,6-tetrahydropyridine-3-carboxylic acid hydrochloride, m.p. decomposition at 219-222 ° C.

Example 6

By analogy to Example 1, 1- (4-hydroxybenzyl) -1,2,5,6-tetrahydropyridine-3-carboxylic acid hydrochloride can be obtained as a solid by hydrolysis of the corresponding methyl ester with a satisfactory microanalysis.

Example 7

By analogy to Example 2, replacing methyl 1- (3,4-dichlorobenzyl) -1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride with the hydrochloride of the corresponding ethyl, butyl or benzyl ester or the corresponding amide or N 1- (3,4-dichlorobenzyl) -1,2,5,6-tetrahydropyridine-3-carboxylic acid hydrochloride, m.p. 240-245 ° C.

Example 8

To a mixture of 2.9 g of methyl 1- (2-cyanobenzyl) -1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride and 50 ml of methanol is added, with stirring, a solution of 0.48 g of sodium hydronide in 10 ml of water. After stirring at room temperature for 24 hours, the pH of the mixture was adjusted to 7 with 2M hydrochloric acid and evaporated. The residue is suspended in 50 ml and the suspension is evaporated. The solid residue is dissolved in 15 ml of dry ethanol, the solid material consisting mainly of sodium chloride is discarded, to the ethanolic solution is added ethereal hydrogen chloride and the mixture is evaporated. Recrystallization of the residue from methanol gave 1- (2-cyanobenzyl) -1,2,5,6-tetrahydropyridine-3-carboxylic acid hydrochloride in 30% yield, m.p. 217-222 ° C (dec., 0.25 HaO). ).

The necessary starting materials can be prepared as follows:

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 was allowed to react at 20-25 ° C for 24 hours, then evaporated, and 20 ml of water and 10% (w / v) sodium carbonate solution were added to the mixture to give a mixture of pH 10. It is extracted twice with 20 ml of ether each time, the combined extracts are washed with water, dried over magnesium sulphate 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 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. .

In an analogous manner, the corresponding benzyl halide of formula (IV) and the corresponding ester of formula (III) can be prepared in each case:

in a yield of 54% methyl 1- (2-cyanobenzyl) -1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride melting after recrystallization from a mixture of methanol and acetone at 183-184 ° C, in 76% yield. ethyl 1- (3,4-dichlorobenzyl) -1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride, m.p. 192-199 ° C, yield 81% methyl 1- (4- methylbenzyl) -1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride melting after recrystallization from methanol-ethyl acetate at 183-184 ° C, in 71% yield of methyl 1- (3,4-dichlorobenzyl) -1,2 5,6-tetrahydropyridine-3-carboxylate hydrochloride, m.p. 185-188 ° C, in 60% yield n-butyl-1- (3,4-dichlorobenzyl) -1,2,5, 6-Tetrahydropyridine-3-carboxylate hydrochloride, m.p. 160-162 ° C, in about 40% yield benzyl 1- (3,4-dichlorobenzyl) -1,2,5,6-tetrahydropyyridine-3-carboxylate -hydrochloride melting after recrystallization

215 from a mixture of acetone and ethyl acetate at 186-169 ° C, in about 50% yield of 1- (3,4-dichlorobenzyl) -1,2,5,6-tetrahydropyridine-3-carboxamide isolated in the form of the free base melting after recrystallization from 2-propanol at 145 and 150 ° C, and in about 40% yield of N-ethyl-1- (3,4-chlorobenzyl) -1,2,5,6-tetrahydropyridine-3-carboxamide hydrochloride, m.p. 228 ° C.

The remaining starting material can be obtained as follows:

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, then evaporated, to the residue was added 30 mL of vo4S

3.0 dy, a mixture with concentrated hydrochloric acid. acidified to pH 1, extracted twice with 20 ml of ether each time and 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 over magnesium sulphate and evaporated. The oily residue was dissolved in acetone and a slight excess of ether was added. Filtration of the precipitated solid afforded 2.05 g of methyl 1-1- (4-hydroxybenzyl) -1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride, recrystallizing a portion of this material from methanol and acetone to give a pure product of m.p. Mp 212 DEG-214 DEG C. (decomposition).

Claims (7)

1. A process for the preparation of novel 1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylic acids of the general formula (11) in which the benzene ring A carries one or two substituents selected from the group consisting of halogen atoms, alkyl groups having from 1 to 4 carbon atoms, a cyano group, a carbamoyl group, a trifluoromethyl group and a hydroxy group, and pharmaceutically acceptable addition salts thereof, characterized in that a compound of formula II (II) in which: R ² represents amino, alkylamino having 1-4 carbon atoms, dialkylamino radicals in which each alkyl moiety has 1 to 4 carbon atoms, benzyloxy, optionally substituted by halogen or alkoxy having 1-6 carbon atoms, whereafter, if desired, the resulting carboxylic acid of formula I by reaction with a base providing a pharmaceutically acceptable cation to its pharmaceutically acceptable. a base addition salt, or the compound of formula (I) obtained is optionally converted by treatment with an acid to give a pharmaceutically acceptable union to its pharmaceutically acceptable acid addition salt. 2. Method according to claim 1, characterized in that, the starting materials of formula II wherein R ² is methoxy, ethoxy, n-butyloxy or chlorobenzyloxy, and benzene ring A • is as defined in point 1. 3. The method according to claim 1 or 2, ^{characterized:} in that the hydrolysis is effected with aqueous mineral acid such as hydrochloric or sulfuric acid, at 20 to 120 ° C. 4. Process according to claim 1 or 2, characterized in that the hydrolysis is carried out by treatment with an aqueous strong base such as sodium or potassium hydroxide at a temperature of 20 to 120 ° C. 5. A process according to claim 1 for the preparation of a compound of formula I wherein the benzene ring A carries a carbamoyl group, wherein the compound of formula II wherein the benzene ring A carries a cyano group and ² is as hereinbefore defined, hydrolyzes with an aqueous mineral acid such as hydrochloric or sulfuric acid at a temperature of 20 to 120 ° C. 6. The process of item 1, for producing a compound of formula I wherein the benzene ring. A bears as a cyano group substituent, characterized in that a compound of formula ^II in which R2 is C1 -C6 alkoxy and the benzene ring A is as defined above is hydrolyzed with an aqueous inorganic base such as sodium or potassium hydroxide , at a temperature of 20 to 39 ° C. 7. A process according to claim 1, 2, 3 or 4 wherein the starting material is a compound of formula (II) wherein the benzene ring A is substituted with chlorine at the 2-position, chlorine at the 3 and 4-positions, or cyano in position 2, and R ² is as defined above.