NO800449L - ANALOGY PROCEDURE FOR PREPARING PHARMASOYYTIC ACTIVE TETRAHYDROPYRIDINE CARBOXYLIC ACID DERIVATIVES - Google Patents

Description

This invention relates to the production of new carboxylic acid derivatives, in particular new 1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid derivatives which inhibit the aggregation of blood platelets in vivo and which can therefore be used in the treatment or prevention of thrombosis or occlusive vascular diseases .

It is known that various N-benzy1-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine and N-benzy1-4,5,6,7-tetrahydrofuro[3,2-c] -pyridine derivatives have anti-inflammatory and antiplatelet properties (M. Podesta et al., European J. Med. Chem., Chim. Therapeutica, 1974, 9, 487-490). It is

also known that various 1-benzy1-1,2,5,6-tetrahydropyridine-4-carboxylic acid esters are chemical intermediates (West German off.skrift 2,221,770 and Annalen, 1972, 764, 21-27). We have now found that certain new 1-benzy1-1,2,5,6-tetrahydropyridine-3-carboxylic acid derivatives surprisingly also possess the property of inhibiting the aggregation of blood platelets in vivo, and this is the basis of the present invention . Two related compounds, 1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl and ethyl esters, are known [respectively Zhur. Obschei. Kim. 1957, 27, 3162-3170 (Chemical Abstracts , 1958, 5_2, 9162c-i) and J. Chem.. Soc. Chemical Communications, 1975 , 682)],

but they are not indicated to have any useful pharmacological properties.

According to the invention, a 1-benzy1-1,2,5,6-tetrahydropyridine-3-carboxylic acid derivative is prepared with the formula:

where R"<*>" is a hydroxy-, amino-, (1-4C) alkylamino- or di-[(1-4C)alkyl]amino radical, a benzyloxy radical which optionally carries a halogen substituent, or a (1- 6C) alkoxy radical which optionally carries a (1-4C) alkoxy, morpholino or di-[(1-4C) alkyl] amino substituent; and the benzene ring A carries one or two substituents selected from halogen, (1-4C)alkyl, cyano, carboxamido, trifluoromethyl and hydroxy radicals;

or pharmaceutically acceptable salts thereof.

Special values for R are e.g.:

when it is a (1-4C)alkylamino radical, a methylamino or ethylamino radical;

when it is a di-[(1-4C) alkyl] amino radical, a dimethylamino or diethylamino radical;

when it is a (1-6C) 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.

Special meanings for a substituent on the benzene ring A are, for example: when it is a halogen radical, a fluorine, chlorine or bromine radical; and

when it is a (1-4C)alkyl radical, a methyl, ethyl, n-propyl or isopropyl radical.,

Special meanings, for the benzene ring A are e.g.

a 2-chlorophenyl-, 2-cyanophenyl-, 2-carboxamidophenyl-, 4-chlorophenyl-, 4-bromophenyl-, 4-methylphenyl-, 2-trifluoromethylphenyl-, 3-cyanophenyl-, 4-cyanophenyl-, 4-hydroxyphenyl- , 3,4-dichlorophenyl or 3,5-dichlorophenyl radical, of which meanings 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 e.g. salts with inorganic acids, e.g. with hydrogen chloride, hydrogen bromide, sulfuric acid or phosphoric acid, or salts with organic acids, e.g. oxalic or citric acid.

Moreover, compounds of formula I where R"<*>" is a hydroxy radical can form addition salts with bases. Special base addition salts of such compounds with formula I. are e.g. alkali and alkaline earth metal salts, e.g. sodium, potassium, calcium or magnesium salts, aluminum or ammonium salts, or salts with organic bases which provide a pharmaceutically acceptable cation, e.g. with triethanolamine.

Special groups of compounds of formula I which are of particular interest include the above defined compounds of formula I where:

(i) R"1" is a hydroxy radical; (ii) R 1 is an amino radical; 1 (iii) R is a (1-6C) alkoxy radical, especially a methoxy, ethoxy or butoxy radical; (iv) the benzene ring A carries one or two halogen substituents; and (v) the benzene ring A bears a cyano or carboxamido radical; and in each case the pharmaceutically acceptable salts thereof when appropriate.

A preferred group of compounds of formula I are those where R"'" is a hydroxy, amino or (1-4C) alkoxy radical.

and the benzene ring A carries a 2-chloro or 2-cyano substituent; or a pharmaceutically acceptable salt thereof.

Particular compounds of formula I are described in the examples, and of these compounds 1-(2-chlorobenzyl)-1,2,5,6-tetrahydropyridine-3-carboxylic acid, 1-(2-cyanobenzyl)-1,2,5 ,6-tetrahydropyridine-3-carboxylic acid and their methyl esters or their pharmaceutically acceptable salts, of particular interest.

The compounds of formula I can be prepared by known methods which can be used in the synthesis of analogous pyridine derivatives. Such methods are described in the following, where R and the benzene ring A have the meanings given above.

a) Reaction of a compound with the formula:

with a benzyl halide of the formula:

where Hal is a halogen radical, e.g. a chlorine, bromine or iodine radical.

The method can conveniently be carried out in the presence of a base, e.g. an alkali metal carbonate or acetate, such as potassium carbonate or sodium uric acetate, preferably in a suitable solvent or diluent, e.g. methanol ! or ethanol, and at a temperature of e.g. 20-120°C.

The compound with formula II where is a hydroxy radical is known, and the other starting materials with formula II can be prepared from this in the usual way.

b) Reaction of a compound of formula II with an aldehyde of the formula:

in the presence of a reducing agent.

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

The method is preferably carried out in a solvent or diluent, e.g. a C^_^ alkanol such as ethanol, and conveniently at or near room temperature, e.g. at 15-30°C.

Method (b) is of the type of reaction known as reductive amination, and as such it can take place in whole or in part

via an intermediate with the formula:

which is formed in situ and which is then reduced. It should be understood that this method also includes the separate reduction of an intermediate of formula V such as e.g. formed by turnover

of a compound of formula II with an aldehyde of formula IV in the absence of a reducing agent.

The aldehydes of formula IV can be obtained by standard methods in organic chemistry.

c) To prepare a compound of formula I where R"*" is a hydroxy radical, a compound is hydrolyzed with 1

the formula:

2 1

where R has the same meaning as R except for a hydroxy radical.

A particularly suitable meaning for R 2 is e.g. a methoxy, ethoxy, benzyloxy or chlorobenzyloxy radical.

The hydrolysis can be carried out in the presence of aqueous acid or base, - e.g. an aqueous mineral acid such as hydrochloric or sulfuric acid, or an aqueous strong base such as sodium or potassium hydroxide may be used. A solvent or diluent, e.g. ethanol or acetic acid can suitably be used, and the method can be carried out at a temperature of e.g. 20-120°C.

d) For the preparation of a compound of formula I where R is a hydroxy or amino radical, and the benzene ring A carries

a carboxamido substituent, hydrolyzes a compound of the formula:

where R 3 is a hydroxy, (1-6C) alkoxy or amino radical, and the benzene ring C has one of the meanings given for the ring A, namely a cyanophenyl radical.

The hydrolysis can be carried out using usual conditions for the preparation of amides from nitriles, e.g. using similar reagents and solvents as described above in method (c). However, a shorter reaction time is usually preferred in order to reduce the further hydrolysis of the amide bond after it has been formed. It will be understood that when R 3 is a (1-6C) alkoxy radical in the compound of formula VII, the end product will still be a compound of formula I where R is a hydroxy radical.

For the preparation of a compound of formula I where B?~ is . from a hydroxy radical, the corresponding compound of formula I where R<1> is a hydroxy radical, or a reactive derivative thereof, e.g. the corresponding acid chloride,

-bromide or -anhydride, is reacted using well-known esterification or amidation methods and conditions with the 2 2 appropriate compound of formula R H where R has the same meanings as R"<*>" except for a hydroxy radical.

The pharmaceutically acceptable salts as defined above

can be prepared by conventional methods by reaction with the appropriate acid or base which gives a pharmaceutically acceptable anion or cation, respectively.

As indicated above, the compounds..of formula I have the property that. they inhibit the clumping of blood platelets. This property can be illustrated in vivo using standard samples on laboratory animals, e.g. in the following examination on rabbits.

In this examination, blood samples are taken using a standard "open flow" technique from the central ear artery in rabbits. The sample is 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 produce platelet-rich and platelet-poor plasma fractions. which is used to calibrate an instrument for measuring light transmission and thus the amount of platelet aggregation. The degree of platelet aggregation after the addition of adenosine-5'-diphosphate (ADP)

(final concentration 0.5, 1.0, 2.0, 4.0, or 8.0 µM) to the platelet-rich plasma fraction is then determined, and the value of maximal aggregation in response to each concentration of ADP is recorded. The rabbits are then given the test compound orally, and arterial blood samples are taken at intervals after administration. The platelet-rich plasma fraction is prepared and ADP is added as above, and the degree of clumping is assessed by measuring the light transmission of the sample. This value is compared with the one obtained from the same rabbit before administration, so that one obtains a

measures the degree of inhibition of ADP-induced platelet aggregation. As an example, the compound 1-(2-chloro-j benzyl)-1,2,5,6-tetrahydropyridine-3-carboxylic acid showed significant inhibition of platelet aggregation 2 hours after an oral dose (as the hydrochloride) of 25 mg/kg . However, the compounds of formula I generally produce a significant inhibition in the above-described test after an oral dose of 100 mg/kg or much less, without any evidence of obvious toxicity at the active dose.

Compounds that inhibit the aggregation of blood platelets, e.g. acetylsalicylic acid, has been used in the treatment or prevention of thrombosis or occlusive vascular disease, and it is assumed that the compounds produced according to the present invention will be used in generally the same way, and for the same clinical indications.

When used to inhibit the aggregation of blood platelets

in warm-blooded animals, including humans, a compound of formula I can be administered in a daily oral dose in the range of 1-30 mg/kg and preferably in the range of 1-10 mg/kg, or an equivalent amount of a pharmaceutically acceptable salt thereof.

In humans, these doses correspond to daily oral doses, of approx. 0.07-2.1 g and 0.07-0.7 g, or an equivalent amount of a pharmaceutically acceptable salt, optionally administered in divided doses.

The compounds of formula I are preferably administered in the form of pharmaceutical preparations, in which a compound of formula I is mixed with a pharmaceutically acceptable diluent or carrier. Such a preparation is conveniently in a form suitable for oral administration, e.g. 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, e.g. as a sterile injectable solution or suspension, or in a form suitable for rectal administration, e.g. like a suppository.

Such preparations can be prepared by usual methods

using common excipients. A preparation for oral administration should preferably contain 5-500 mg of active ingredient per unit dose, a preparation for parenteral administration, 0.5-20 mg/ml active ingredient, and a preparation for rectal

administration, 50-500 mg active ingredient.

A preparation can also suitably contain one or ■> more agents which can have a beneficial effect on thrombosis or occlusive vascular disease or on associated disorders,

selected from e.g. clofibrate, sulfinpyrazone and dipyridamole.

The invention is illustrated by the following examples where

(i) the yields are to serve as examples only and do not mean the maximum obtainable; (ii) evaporations were carried out in vacuo to dryness when possible, using a rotary evaporator; and (iii) melting points were determined in closed glass capillary tubes.

Example 1

Triethylamine (2.2 g) and 2-chlorobenzyl chloride (1.63 g) were

added to a solution of methyl 1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride (1.63 g) in methanol (10 mL). The resulting solution 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 pH 10 mixture.

This mixture was extracted with ether (2 x 20 mL). The

combined extracts were washed with water, dried (MgSO 4 ) and evaporated. The remaining oil was dissolved in acetone to give a solution which was treated with a small excess of ethereal hydrogen chloride. The solid that precipitated was collected by filtration and washed with acetone to give methyl 1-(2-chlorobenzyl)-1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride (1.5 g), srn.p. 171-175°C.

Example 2

A solution of methyl 1-(2-chlorobenzyl)-1,2,5,6-tetrahydro-pyridine-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 resulting solid was stirred with acetone and then collected by filtration to give 1-(2-chlorobenzyl)-1,2,5,6 -tetrahydropyridine-3-carboxylic acid hydrochloride (0.4 g), srn.p. 208-210°C (dec.)

Example 3

4-hydroxybenzaldehyde (1.34 g) and sodium cyanoborohydride

(0.7 g) was added to a solution of methyl 1,2,5,6-tetrahydro-pyridine-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) was 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 were 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 (MgSO 4 ) and evaporated. The oil obtained was dissolved in acetone and treated with a small excess of ethereal hydrogen chloride. The precipitated solid was collected by filtration

to give methyl 1-1-(4-hydroxybenzyl)-1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride (2.05 g). A portion was recrystallized from methanol and acetone to give pure material with srn.p. 212-214°C (dec.) .

Example 4 (NB: all parts are by weight)

A mixture of microcrystalline cellulose (196 parts)

and finely divided 1-(2-chlorobenzyl)-1,2,5,6-tetrahydropyridine-3-carboxylic acid hydrochloride (200 parts) was sieved through a 30 mesh sieve. Magnesium stearate (60 mesh particle size) (4 parts) was then added, and after careful mixing, the mixture was pressed into tablets weighing 400 mg and containing 200 mg of active ingredient, which can be administered to humans for therapeutic purposes.

Using a similar method, tablets containing 20, 50, 100 and 400 mg of active ingredient can be prepared.

Likewise, the active ingredient can e.g. replaced with

another compound of formula I, e.g. a compound described in any of Examples 1, 3 or 5-20.

Example 5-8

Using a method similar to that described in example 1, but by starting from the appropriate benzyl halide of formula III and the appropriate ester of formula II gave: methyl-1-(2-cyanobenzyl)-1,2,5 ,6-tetrahydropyridine-3-carboxylate hydrochloride (Example 5), srn.p. 183-4°C in 54% yield after recrystallization from methanol/acetone; ethyl 1-(3,4-dichlorobenzyl)-1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride (Example 6), m.p. 192-9°C in 76% yield; methyl 1-(4-methylbenzyl)-1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride (Example 7), m.p. 183-4°C in 81% yield after recrystallization from methanol/ethyl acetate; and methyl 1-(3,4-dichlorobenzyl)-1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride (Example 8), m.p. 185-188°C in 71% yield.

Example 9

Using a procedure similar to that described in Example 2, methyl 1-(3,4-dichlorobenzyl)-1,2,5,6-tetrahydro-pyridine-3-carboxylate hydrochloride was hydrolyzed to give 1- (3,4-dichlorobenzyl)-1,2,5,6-tetrahydropyridine-3-carboxylic acid,

sm.p. 240-245°C.

Example 10

A mixture of 1-(3,4-dichlorobenzyl)-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid hydrochloride (2.0 g) and thionyl chloride

(15 mL) was heated under reflux for 30 min. Excess thionyl chloride was removed by evaporation, and the residue was mixed with toluene 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 was dissolved. The resulting solution was heated under reflux for 10 minutes, and then excess n-butyl alcohol was removed by evaporation.

The residue was recrystallized from acetone/ether to give n-butyl 1-(3;4-dichlorobenzyl)-1,2,5,e-tetrahydropyridine-S-carboxylate hydrochloride (1.2 g), m.p. 160-162°C.

E xample 11-15

Using a method similar to that described

in Example 10, but using the appropriate alcohol or amine, the following esters or carboxamides of formula I (ring A = 3,4-dichlorophenyl) were prepared as their

.hydrochloride salts (unless otherwise stated) .

Examples 16-18

Using a procedure similar to that described in Example 2, but starting from the appropriate methyl ester, one prepared: i 1-(4-methylbenzyl)-1,2,5,6-tetrahydropyridine-3- carboxylic acid hydrochloride (Example 16) in 71% yield, m.p. 230-6°C (after recrystallization from ethanol/acetone) p and

1-(4-bromobenzyl)-1,2,5,6-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-bromobenzyl chloride to form methyl-1-(4-bromobenzyl)-1,2,5,6-tetrahydropyridine -3-carboxylate hydrochloride, m.p. 200-205°C (Example 18).

Example 19

A mixture of 1,2,5,6-tetrahydropyridine-3-carboxylic acid hydrochloride (4.0 g), triethylamine (8.2 g) and 2-cyanobenzyl bromide (4.0 g) in methanol (20 ml) was heated at 95-100°C for 3 hours. The mixture was evaporated to dryness and excess aqueous sodium carbonate solution was added. The mixture was again evaporated to dryness and acidified with 2N hydrochloric acid to pH 2-3. The subsequent mixture was evaporated to dryness. The residue was suspended in toluene (30 mL) and evaporated to dryness. The

resulting solid was dissolved in dry ethanol (10 mL)

and the residue (mainly sodium chloride) was discarded. The solution was evaporated and the residue recrystallized from ethanol/ether to give 1-(2-cyanobenzyl)-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid hydrochloride as a solid.

sm.p. 206-212°C.

Example 20

A mixture of methyl 1-(2-cyanobenzyl)-1,2,5,6-tetrahydro-pyridine-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 triturated with acetone to give 1-(2-carboxamidobenzyl)-1,2,5,6-tetrahydropyridine-3-carboxylic acid hydrochloride, m.p. 219-222°C (dec.) after recrystallization from ethanol/acetone.

Claims (3)

1. Analogy method for the preparation of a therapeutic ! active 1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid- . derivative with the formula: where R is a hydroxy-, amino-, (1-4C)alkylamino- or di-[(1-4C)alkyl]amino radical, a benzyloxy radical which optionally carries a halogen substituent, or a (1-6C)alkoxy radical which optionally carries a (1-4C) alkoxy-, morpholino- or di-[ (1-4-C) - . alkyl]amino substituent; and the benzene ring A carries one or two substituents selected from halogen, (1-4C)alkyl, cyano, carboxamido, trifluoromethyl and hydroxy radicals, or a pharmaceutically acceptable salt thereof, characterized in that (a) a compound of the formula: is reacted with a benzyl halide of the formula: where Hal is a halogen radical; (b) a compound of formula II is reacted with an aldehyde of the formula: in the presence of a reducing agent; (c) for the preparation of a compound of formula I where R1 is a hydroxy radical, hydrolyze a compound of the formula: where R<2> has the same meaning as R , except for a hydroxy radical; or (d) for the preparation of a compound of formula I where R"1" is a hydroxy or amino radical and the benzene ring A carries a carboxamido radical. hydrolyzes a compound with the formula: where R 3 is a hydroxy, (1-6C) alkoxy or amino radical, and the benzene ring C has one of the meanings given for ring A which is a cyanophenyl radical; after which, for the preparation of a compound of formula I where R"'" is different from a hydroxy radical, a compound of formula I where R^" is a hydroxy radical, or a reactive derivative thereof, is reacted with a compound of formula R2 H where R 2 has the same meaning as R 1 except for a hydroxy radical, using a known esterification or amidation process; and then, to prepare a pharmaceutically acceptable base addition salt of a compound of formula I wherein R<1> is a hydroxy radical, such compound is reacted with a suitable base to yield a pharmaceutically acceptable cation; and to prepare a pharmaceutically acceptable acid addition salt, a compound of formula I is reacted with a suitable acid which gives a pharmaceutically acceptable anion. 2. Process as stated in claim 1 for the production of 1-(2-chlorobenzyl)-1,2,5,6-tetrahydropyridine-3-carboxylic acid or its methyl ester, characterized in that starting materials are used where A is 2-chlorophenyl and R "*" is hydroxy or methoxy or converted thereto. 3. Process as stated in claim 1 for the production of 1-(2-cyanobenzyl)-1,2,5,6-te trahydropyridine-3-carboxylic acid or the methyl ester thereof, characterized in that starting materials are used where A is 2-cyanophenyl and R"1" is hydroxy or methoxy or is converted thereto.