CS244695B2 - Preparation method of 2,6-piperidindione derivatives - Google Patents

Description

The invention relates to a process for the preparation of novel 2,6-piperidinedione derivatives which exhibit antiarrhythmic activity and serve as a myocardial preservative.

in accordance with the method of the invention, they correspond to the general formula I

These new compounds are being prepared

R is a straight or branched (C 2 -C 5) alkyl group,

R 1 and R 2 independently represent a hydrogen atom or a C 1 -C 4 alkyl group, and R 2 independently represent a C 1 -C 4 alkyl group.

The present invention provides a process for the preparation of 2,6-piperidinedione derivatives of formula (I) as well as salts of these derivatives with pharmaceutically acceptable acids by reacting an unsaturated nitrile of formula (I-C-C-N 1 C).

OF \

wherein R _L and R ₂ have the abovementioned meaning, nitrilera formula wherein R and R are as defined above, in the presence of diisopropylamide at -10 to -80 ° C in a solvent such as tetrahydrofuran, followed by the product thus obtained is reacted with a haloalkylamine of the general formula

Hal-CH ₂ -CH ₂ -N

wherein Hal is a halogen atom and R is as defined above, in the presence of a sodium reagent such as sodium hydride in an inert solvent such as diemtylformamide and the product obtained is cyclized by heating with a strong mineral acid such as hydrochloric acid, sulfuric acid or polyphosphoric acid, to a temperature of 80 to 120 ° C, followed by optionally converting the obtained salt by reaction with a pharmaceutically acceptable acid.

The compounds of the formula I each have one asymmetric carbon, which is the carbon atom in the 3-position of the piperidinedione ring. If also the substituents R, and R ₂ and / or R g and R mutually different, then there exists in the molecule, one or even two additional asymmetric carbons. As a result, the compounds of formula (I) may be in the form of diastereoisomers and in the form of optically active isomers. All these isomers as well as mixtures thereof form an integral part of the invention.

Compounds of formula I are obtained from pyridylacetonitrile by the following method, which may be illustrated by the following reaction scheme:

<.t

Condensation of the nitrile 8 to the unsaturated nitrile 7 results in dinitrile 9. This condensation is carried out in the presence of lithium diisopropyamide (prepared in situ by the action of diisopropyamine on a butyllithium solution) at low temperature and in solution in a solvent such as tetrahydrofuran. Subsequently, dinitrile 9 is substituted with a halogenated derivative of the general formula

Hal-CH ₂

10. Sodium, in an inert solvent, is treated in the presence of sodium with a reagent such as a hydride such as dimethylformamide.

Finally, dinitrile 10 is cyclized by treatment with a concentrated mineral acid such as sulfuric acid at 80 to 120 ° C.

Salts of the compounds of formula (I) are obtained by conventional methods used for conversion to salts.

If, on the one hand, R ₂ and R ₄ and R ₄ are different, then the products of formula I exist in the form of diastereoisomers which can be separated by conventional methods, in particular by chromatography.

For each of the stereoisomers, the study of the nuclear-magnetic resonance spectrum enabled the determination of the spatial configuration.

The following examples serve to illustrate the process of the invention in more detail and do not limit the scope of the invention in any way.

Example

3- (2-Diisopropylaminoethyl) -3- (2-pyridyl) -4,4,5,5-tetramethyl-2,6-piperidinedione (SR 42436)

General formula I:

R = -CH

= CH, = CH,

R = CH,

R. = CH,

Step a)

Λ

4- (2-pyridyl) -2,2,3,3-tetramethylpentane-1,5-dinitrile

To 68 ml of a 1.6 M solution of n-butyllithium in hexane cooled to -20 ° C was added, under stirring and under a nitrogen atmosphere, 11.1 g of diisopropylamine in 100 ml of tetrahydrofuran. The mixture is then cooled to -70 ° C and a solution of 6.9 g of isobutyronitrile in 100 ml of tetrahydrofuran is added to the cooled mixture.

After stirring at -70 ° C for 15 minutes, a solution of 17.4 g of 3-methyl-2- (2-pyridyl) -2-butenenitrile in 120 ml of tetrahydrofuran was added to the mixture.

After the addition was complete, the temperature of the reaction mixture was allowed to rise to ambient temperature and the solvent was evaporated to dryness. The residue was taken up in water and extracted three times with ether. The organic extracts were then dried over sodium sulfate and the solvent was evaporated. The residue was distilled under reduced pressure to give the desired product. It is in the form of a red liquid. Product weight: 11.3 g, boiling point at 199 Pa: 160-170 ° C.

Step b)

6-Diisopropylamino-4- (2-pyridyl) -4-cyano-2,2,3,3-tetramethyl hexanenitrile

2.4 g of a 55% suspension of sodium hydride in oil are added to 50 ml of dimethylformamide under a nitrogen atmosphere. A solution of 11.3 g of dinitrile obtained as described above in 50 ml of dimethylformamide is then added dropwise to the mixture thus obtained. The mixture was stirred at ambient temperature for 30 minutes, then a solution of 9 g of 1-chloro-2-diisopropylaminoethane in 50 ml of dimethylformamide was added.

The mixture was stirred at ambient temperature for 4 hours, the solvent was evaporated in vacuo, the residue was taken up in water and extracted with ethyl acetate. The solution was dried over sodium sulfate and the solvent was evaporated in vacuo.

The residue is chromatographed on a column of alumina using a 90:10 mixture of pentane and ethyl acetate as the eluent to give a viscous liquid. The product weight was 16 g. This product was used as such in the next cyclization.

Step c)

The product SR 42436

The compound obtained in the preceding step is heated to 100 ° C for one hour, together with 150 ml of concentrated sulfuric acid. The density of the sulfuric acid used is 1.83. 300 ml of water are added to the mixture and the mixture is heated under reflux for 12 hours.

After cooling, the reaction mixture is rendered alkaline by the addition of a 40% sodium carbonate solution while the reaction mixture is externally cooled to a temperature below 30 ° C,

The reaction mixture was then extracted three times with ethyl acetate and the organic extracts were dried over sodium sulfate. The solvent was evaporated and the residue was chromatographed on an alumina column using a 80:20 mixture of pentane and ethyl acetate as the chromatographic system. As a final product a thick liquid is obtained which crystallizes in the presence of isopropyl ether.

After recrystallization from isopropyl ether, colorless crystals are obtained. Weight of the product obtained: 4.1 g: melting point: 89-90 ° C.

If the same procedure is followed, but in step a), 3-methyl-2- (2-pyridyl) -2-butenenitrile is replaced with an equivalent amount of 2- (2-pyridyl) -2-butenenitrile, then 3- ( 2-diisopropylaminoethyl) -3- (2-pyridyl) -4,5,5-trimethyl-2,6-piperidinedione as colorless crystals. Melting point: 93-94 ° C (isopropyl ether). This product is coded SR 42480.

The above compounds obtained by the process of the invention have been subjected to pharmacological tests which demonstrate in particular their antiarrhythmic effect.

This antiarrhythmic effect of compounds of formula I has been shown to be a model ventricular arrhythmia in experimental animals.

Anesthetized dogs were introduced into the coronary bed by a metallic spiral through the catheterization mechanism. At the same time, a micro-transmitter operating with frequency modulation was mounted on the back of the test animals: this micro-transmitter was connected to two precordial electrodes.

The test animal was then returned to its box for progressive thrombosis of the anterial interventricular artery. In this way, localized myocardial infarction is stimulated, a source of abnormal but repeated electrical activity that is typical of ventricular tachycardia.

In this state, 16-24 hours after the introduction of the metallic spiral, the test products are orally administered to the animals, with the telemetry system allowing the actual time evolution of the waking dog to be observed.

The number of sinusoidal and pathological systolic complexes is then permanently detected by the electronic system. In this way, it is possible to evaluate the quality and duration of the effect of the test product and to observe the behavior of the animal.

A product is considered to be effective if it suppresses at least 60% of the abnormal complexes and when the sinus rhythm is restored.

The results of the testing of the individual products produced by the method according to the invention showed an antiarrhythmic efficacy of the test products at an oral dose of 50 mg / kg.

The results obtained show that the compounds of the formula I have a potent effect on disrhythmia, some of which have a very prolonged antiarrhythmic effect. The compounds SR 42 436 and -SR 42 480 re-establish a sinus rhythm within 1 hour.

In addition, the compounds of the invention are of limited toxicity, and at doses effective to suppress disrythmia, the compounds have no toxicity.

Accordingly, the compounds of formula (I) may be used in human therapy as protectors of the myocardium to correct ischemic ventricular rhythm disorders. of origin.

These products can be used in galenic forms corresponding to oral administration (tablets, gelatin capsules and the like) and parenteral administration (injection ampoules).

The dose necessary for reastauration of sinus rhythm in humans is 50 to 150 mg for intravenous administration and 400 to 800 mg for oral administration daily.

Claims (1)

A process for the preparation of 2,6-piperidinedione derivatives of the general formula X ## STR6 ## in which straight or independently represents independently a branched alkyl group having 2 to 5 carbon atoms, a hydrogen atom or an alkyl group having 1 to 4 carbon atoms and an alkyl group having 1 to 4 carbon atoms as well as the salts of these derivatives with pharmaceutically acceptable acids, characterized in that an unsaturated nitrile of the general formula C-CSN ^Λ 12 in which a R ₂ is as defined above, with a nitrile of the general formula CH-CT-N wherein and R 6 are as defined above, in the presence of diisopropyamide at a temperature -10 to -80 ° C and in a solvent such as tetrahydrofuran, whereupon the product is reacted with a haloalkylamine of formula Hal-CH ₂ -CH ₂ -N wherein Hal represents a halogen atom and R is as defined above, in the presence of a sodium reagent such as sodium hydride in an inert solvent such as dimethylformamide, and the product obtained is cyclized by heating with a strong mineral acid such as hydrochloric acid, sulfuric acid and polyphosphoric acid at a temperature of 80 to 120 ° C, whereupon the product obtained is optionally converted into a salt by reaction with a pharmaceutically acceptable acid.