CS244693B2 - Preparation method of the 3-(2-piperidineethyl)-3-(pyridil)il)-2-hexahydrobenzofuranone - Google Patents

Description

(54) Preparation of 3- (2-piperidinoethyl) -3- (2-pyridyl) -2-hexahydrobenzofuranone derivatives

The present invention relates to a process for the preparation of novel 3- (2-piperidinoethyl) -3- (2-pyridyl) -2-hexahydrobenzofuranone derivatives which exhibit an antiarrhythmic effect.

The present invention provides a process for the preparation of 3- (2-piperidinoethyl) -3- (2-pyridyl) -2- (hexahydrobenzofuranone) derivatives of the general formula I

(I) in which the group -N 'represents a piperidine group substituted by 2 methyl groups, as well as salts, isomers and mixtures of isomers of said derivatives, characterized in that a pyridylacetonitrile anion which is reacted in an inert reaction is used as starting material a solvent such as tetrahydrofuran at -60 to -80 ° C with epoxycyclohexane, followed by acid hydrolysis of the obtained hydroxylated product and reacting the obtained product in a solvent such as tetrahydrofuran and in the presence of sodium. for example sodium hydride, with a compound of the formula _R in which Hal represents a halogen atom and a group

-N

R is as defined above, whereupon the product is optionally converted into a salt by reaction with a mineral or organic acid.

The compounds of formula I have an asymmetric carbon at the 3-position of gamma-butyrolactone. circuit. They also include two hydrogenated rings that are fused, wherein the spherical relation of the carbon atoms at the 4 and 5 positions which are common to both rings can be termed the cis-trans isomerism relative to the position of the hydrogen atoms bound to the carbon atoms at the 4 position; 5. Accordingly, the compounds of formula I may exist in the form of diastereoisomers and optically active isomers.

The process for the preparation of the compounds of the formula I according to the invention can be illustrated by the following reaction scheme:

(6)

product I

The opening of the epoxy ring 5 with the pyridylacetonitrile anion 1 leads to the hydroxynitrile 6.

In order to obtain the pyridylaminoacetonitrile anion, it is convenient to use lithium diisopropylamide (prepared in situ by treatment of butyllithium with diisopropylamine) in an inert solvent such as tetrahydrofuran at a low temperature of -60 to -80 ° C. From hydroxynitrile 6, lactone 7 is obtained by acid hydrolysis. A concentrated mineral acid such as 85% phosphoric acid is used. Finally, a compound of formula I is obtained by substituting compound 7 for a derivative

Hal-CH ₂ -CH ₂ -N

in the presence of sodium an agent such as sodium hydride and in a solvent environment such as tetrahydrofuran.

Salts of compounds of formula I are obtained by known methods for the corresponding conversion to salts.

The invention will be further elucidated by way of example only, without limiting the scope of the invention to illustrative purposes.

Example

3- [2- (2,6-cis-dimethylpiperidino) ethyl] -3- (2-pyridyl) -2- (3H) -hexahydrotransbenzofuranone (SR 42455)

General formula I:

-N

<? ^H 3 cis ch ₃

Step a)

2- [alpha] - (2-traris-hydroxycyclohexyl) pyridylacetonitrile

To a mixture of 45.54 g of diisopropylamine and 200 ml of anhydrous tetrahydrofuran cooled to -20 ° C was added under a nitrogen atmosphere and with stirring, 300 ml of a solution of 1.6 M butyllithium in hexane. The mixture was then cooled to -70 ° C and a solution of 53.1 g of 2-pyridylacetonitrile in 200 ml of anhydrous tetrahydrofuran was added.

The reaction mixture is stirred for 15 minutes at or below -70 ° C and then a solution of 48.5 g of epoxycyclohexane in 200 ml of anhydrous tetrahydrofuran is added at the same temperature. The temperature is then allowed to rise to room temperature (approximately 20 ° C) and the mixture is stirred at this temperature for 15 hours.

The mixture was cooled in an ice bath and then 300 mL of water was added. The organic phase was decanted and the aqueous phase was re-extracted twice with ether.

The combined organic phases are washed twice with saturated sodium chloride solution and dried over sodium sulphate solution. The solvent was evaporated to dryness and the residue was crystallized from isopropanol.

74.6 g of the expected product are obtained.

Melting point: 110-112 ° C.

Step b)

3- (2-pyridyl) -2- (3H) -hexahydro-trans-benzofuranone

A mixture of 32.4 g of the product obtained above and 160 ml of 85% phosphoric acid is heated at 90 ° C for 30 minutes. The reaction mixture is poured onto ice and the mixture is made alkaline by addition of 30% sodium hydroxide solution, maintaining the temperature below 25 ° C.

Extraction is then carried out with ethyl acetate and dried over sodium sulfate. The solvent is dried to dryness and the residue is taken up in isopropyl ether. The solid is centrifuged. Weight of product obtained: 31 g; mp 124-125 ° C.

Step c)

Product SR 42455

100 ml of anhydrous tetrahydrofuran and 2.5 g of a 55% sodium hydride in oil suspension were introduced into the flask under a nitrogen atmosphere. The mixture was heated to reflux and a solution of 250 ml of anhydrous tetrahydrofuran containing 10.85 g of tetrahydrofuran as described above containing 10.85 g of the above product and 917 g of 1- [12-] - was added dropwise. chloroethyl-2,6-cisdimethylpiperidine. After the addition was complete, the reaction mixture was refluxed for one hour, then the tetrahydrofuran was evaporated.

The residue was taken up in water and extracted with ether. The solution is dried over sodium sulfate, the solvent is evaporated and the oily residue is chromatographed on an alumina column.

Elution with 95: 5 pentane: ethyl acetate gave the desired product as an oil.

Weight of the oil obtained: 6.7 g.

Pentane was added to the oil obtained above and the mixture was allowed to crystallize slowly at 0 ° C. The solid residue is centrifuged and washed with a small amount of pentane cooled to 0 ° C. The final product is in the form of crystals.

Product Weight: 3.5 g; mp 81-82 ° C.

The compounds of formula (I) prepared by the process of the invention have been subjected to pharmacological tests to demonstrate in particular their antiarrhythmic properties.

The antiarrhythmic effect of the compounds of formula (I) of the invention has been demonstrated in a ventricular arrhythmia model of an experimental animal.

A group of anesthetized dogs are introduced into the coronary bed by means of back catheterization. Simultaneously, micro-transmitters operating with frequency modulation and connected to two precordial electrodes are fixed on the back of the experimental animals.

The animal housed in the box shows progressive thrombosis of the anterior interventricular artery. This stimulates a localized myocardial infarction which results in an abnormal but repeated electrical activity typical of ventricular tachycardia.

In this state, the active compounds of the invention are administered to the test animals 24 hours after the introduction of the metal loop, and the telemetry system allows real-time tracking of the evolution of the waking dog disrythmia.

The electronic system provides a permanent evaluation of the number of sinus and pathological systolic complexes. In this way, the quality and potency of the test compound can be evaluated.

The results obtained in this test showed that the compounds of the formula I according to the invention show a strong activity against disrhythmia.

At a dose of the product of the invention of 50 mg / kg orally, the sinus rhythm is restored for more than 24 hours. At a dose of the product of the invention of 30 mg / kg, the sinus rhythm is re-established for 1 hour and 30 minutes.

In addition, the compounds produced by the process of the invention are of low toxicity and in particular show no toxicity at doses at which they are antiarrhythmic.

Accordingly, the compounds produced by the process of the invention and their pharmaceutically acceptable salts can be used in human therapy as myocardial protectors to correct the ventricular rhythm of ischemic origin.

The compounds of formula (I) may be administered in galenic forms corresponding to oral administration (these in particular include tablets and gelatin capsules) or parenteral administration (these in particular in injectable ampoules).

The dose required in humans for the reastauration of sinus rhythm is 5 to 150 mg for intravenous administration and 40 to 800 mg for oral administration daily.

Claims (1)

OBJECT OF THE INVENTION A process for the preparation of 3- (2-piperidinoethyl) -3- (2-pyridyl) -2-hexahydrobenzofuranone of the general formula I in which group (I) as well as the salts of said derivatives, characterized in that pyridylacetonitrile anion is used as starting material. reacted in an inert solvent such as tetrahydrofuran at -60 to -80 ° C with epoxycyclohexane, followed by acid hydrolysis of the obtained hydroxylated product and reacting the obtained product in a solvent such as tetrahydrofuran and in the presence of of a sodium compound such as sodium hydride with a compound of the formula wherein Hal is a halogen atom and the -N 'group is as defined above, whereupon the product is optionally converted into a salt by reaction with a mineral or organic acid.