CS244694B2 - Production 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.

The novel compounds prepared according to the process of the invention correspond to the general formula I

in which

R also represents a straight or branched group

(C 2 -C 5) alkyl or a morpholine or piperidine group optionally substituted with 1 to 4 methyl groups; n is 2 or 3;

R ₃ and R ₄ each independently represent a methyl or ethyl group, or R ₃ and R ₄ together represent a (CH ₂ ) _{m group} , wherein m represents 4 or 5, wherein the piperidinedione substitutes the pyridyl group at the 2 ', 3' or 4 'position .

It is an object of the present invention to provide a process for the preparation of said compounds of formula I by reacting a carbonyl derivative of the formula

O = CH-C-COOC _n H _c 2 □ with pyridylacetonitrile, whereupon the product thus obtained is catalytically hydrogenated to convert the unsaturated derivative to a saturated derivative and reacted with the haloalkylamine of formula

wherein Hal is a halogen atom and R and n are as defined above, then the product so 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.

The compounds of the formula I each have one asymmetric carbon, which is the carbon atom in the 3-position of the piperidinedione radical. In addition, if the substituents R1 and R2 are different from each other, then there is another asymmetric carbon in the molecule. As a result, the compounds of formula I may exist in the form of diastereoisomers and in the form of optically active isomers, all of which isomers and mixtures thereof form an integral part of the invention.

The compounds of formula (I) are obtained, which may be illustrated by this reaction scheme of pyridylacetonitrile by the following method.

ch ₂ prices

R ₃ Η I ³

O = CC-COOC ₂ H ₆ r ₄

CEN «3

Γ -j — C = C - C-COOC, H,

IV

C = N

I c <CH ₂ ) _n

N / \

R R

C = N ^R 3 ch ₂ -c-cooc ₂ h ₅ -CH ₂ -C ₄ r ₄

Hal (CH ₂ ) _n N 4

-CH.-C-COOC.Hr —— ‘| * ”Cyclization (I)

VI

Pyridylacetonitrile 1 is treated with a carbonyl derivative of the general formula

H

0-C <OOC ₂ H ₅ to give the unsaturated ester fourth operation is carried out in an inert solvent such as benzene, usually at the boiling point of the solvent, wherein the catalyst is added either as para-toluenesulphonic acid or acetic acid and piperidine. The derivative 4 is converted to the corresponding saturated derivative. The solution is worked up in ethanol in the presence of a hydrogenation catalyst such as palladium on activated carbon at ambient temperature and atmospheric pressure.

Compound 5 is substituted on the carbon at the alpha position of the nitrile by the action of a compound of formula

Hal- (CH ₂₎

in the presence of sodium an agent such as sodium hydride in a solvent such as dimethylformamide. Most commonly, the temperature is 20 to 50 ° C. Finally, compound 5 is cyclized to the product of formula I by heating to 80-120 ° C with a strong mineral acid.

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

If and R 6 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 made it possible to determine 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. In these examples, the IUPAC nomenclature (section E, in particular E-5.3) is used to label diastereoisomers.

Example 1

3- (2-Diisopropylaminoethyl) -5,5-dimethyl-3- (2-pyridyl) -2,6-piperidinedione, dichlorohydrate (SR 41298) Formula I:

R = -CH n = 2

Step a)

Ethyl 4-cyano-2,2-dimethyl-4- (2-pyridyl) -3-butenate

A flask equipped with a water separator was charged with 12.8 g of 2-pyridyl acetonitrile, 22 g of ethyl 2-formyl-2-methylpropionate, 500 ml of benzene, 1 ml of acetic acid and 0.2 piperidine. The mixture is heated to reflux until water is released (after about 69 hours), after which the organic solution is washed with sodium bicarbonate solution after cooling. then the solvent is evaporated to dryness. This product was used as such in the next step.

Step b)

Ethyl 4-cyano-2,2-dimethyl-4- (2-pyridyl) butyrate

The product obtained in the preceding step is dissolved in 600 ml of ethanol and 15 g of palladium on charcoal are added to the obtained solution. The weight of palladium, based on the weight of activated carbon, is 5%. the resulting mixture is then hydrogenated at ambient temperature and at 1 bar. The catalyst was filtered off and the solvent was evaporated. to dryness. The residue was distilled under high vacuum. Boiling point at 0.133 Pa: 117-120 ° C, product weight: 20.8 g.

Step c)

Ethyl 4-cyano-2,2-dimethyl-4- (2-diisopropylaminoethyl) -4- (2-pyridyl) butyrate

1.4 g of sodium hydride and 20 ml of dimethylformamide are added to a flask under a nitrogen atmosphere. To this mixture is added dropwise a solution of 9.8 g of the compound obtained in step b in 20 ml of dimethylformamide. The mixture was stirred at ambient temperature for one hour, a solution of 7.2 g of 1-chloro-2-diisopropylaminomethane in 20 ml of dimethylformamide was added thereto, and the mixture was stirred at ambient temperature for 2 hours. The solvent was evaporated to dryness and the residue was taken up in ether. The solution was washed with water, dried over sodium sulfate and the solvent was evaporated to dryness. The product thus obtained is used as such in the next step.

Step d)

The product SR 41298

The compound obtained in the previous reaction step was dissolved in 130 ml of concentrated sulfuric acid (d = 1.83) and the reaction mixture was heated at 100 to 110 ° C for one hour. The reaction mixture was then poured onto ice and the solution basified by the addition of aqueous potassium carbonate solution. This solution was then extracted with ethyl acetate and dried over sodium sulfate. The solvent was evaporated to dryness and the residue was chromatographed on an alumina column. As the chromatographic system, a mixture of ethyl acetate and pentane (50:50 by volume) and then ethyl acetate alone are used to obtain the desired product. Weight of product obtained: 11.7 g.

Step e)

Dichlorohydrate g of the base obtained above was dissolved in 100 ml of ethanol, and 5.8 g of concentrated hydrochloric acid (d - 1.18) was added. The solution was evaporated to dryness and ether was added to the residue. The residue crystallizes. The obtained crystals are recrystallized from absolute alcohol to give colorless crystals.

Product weight: 7.3 g, melting point: 203-204 ° C. The chlorohydrate obtained crystallizes with one molecule of water.

Examples 2 to 15

If the procedure of Example 1 is followed, alternating the carbonyl derivative used in the reaction step and / or the halogenated derivative used in the reaction step o, the compounds of the general formula I summarized in the following Table 1 are obtained in the same manner.

Even you

Α!

Λ ti

Η

(0 Ό > φ Μ 4J Αί > ΙΛ Φ 3 0 -χ. 04 / μ + J Ν φ ti Μ 0 4J 0 G Μ 'φ ι — I Μΰ r-l > 1 4J Μ > 1 m + J β 04- 04 * 3 * γ — 1 φ ti > υ co 0 ο- μ ti Μ C > Ν 0 0 Ν > Ν 04 > Ν ti ti ti (~ Ι • Η ti 0 ti X + J 04 / ι — 1 •with η φ σι υ Φ ti 0 VO «Η σι χ: ιη 0 Ε-4 4J ι—) 00 - ·· -. θ '- ·· .- · - »

> 1 ''WITH. + J μ μ ti * ·% » φ φ 0 Η • μ +) γ— ( 0 νφ HU > η 0 Η Ο Η <0 4J 04 ti 04>, «Η φ Ή 04 m 04 • Η 04 ο σι 0 0 Μ 0 ) Ν μ μ > ν μ ti ti ti 04 «4 04 ti 04 44 0 ti ο 0 <η ο * 3 · ω ΙΛ σι φ νο 0 04 · Η * 3 · · Η i — 1 · Η r-i -V. ι — 1 σι r-l 'χ.

ΙΛ> Ν ti «η οο ti

X

Φ

Λ

»0 .Μ

R ti rd

Αί

0> 0

Μ ti

X!

Ή «

Ή

X) Η

Τ3

Ο)

04 04 04

04 /

ΓΟ r-l fO LO · 3 *

Ο

OJ <β ι — Ι «ύ ¹ σ>

σι \ ο i — I σι ο ο Γι — I ο οι> Γ ~ I

Μ ·

Ο ΓΓ ι — I

Οί σι

Μ · ιη ςο Ροο σι

P 0 - ·> 04 / P > P P N Φ Φ Φ M 0 P P P G P XI) XI) P Ml) Nfl r> rd rd σι σι vd vo rd P Ή ω ►, what > 1 σι σι ρ > 1 G r- rd CL | rd 04 / rd rd Q) rd 04 / 3 XJ vo 0 0 at 0 P 3 G > N P > N P > N G > N 3 > N P 0 N > N 3 3 04 3 04 / 3 3 3 rd 3 Ol r-i Ή 3 X 0 0 X 0 0. rd Φ vo w CM ω WHAT Φ co -p m w 0) 3 0 m Λ co -H WHAT • H σι Λ σι o ’Φ • rl Em P rd in - · -. rd rd rd * ·· » rd rd

Φ Φ <D Φ Φ Φ Φ N rd N N N N N N * 3 »3 * 3 * 3 MXf MTJ χΰ ff) w X5 Λ Λ Λ Ό Λ

what WITH ro W what E what E WHAT E what E O O AT O AT AT 04 / 1 1 1 1 1 1

what E ro E what E what with what E ro E what AT O O O O O

cm cm

CM CM CM

CM

CM

CM

CM 'CM ‘CO

Μ

G * 3>

O> o

P .X a

M

G> 0

P • H

P

M a

ω

P> 1

Λ o

G • «d t3

CM

CM 'CO CM

CM rd

X)

Em

0 '0> * * 3

Λί

M> P to &

tn oo rd «Φ

CM CO i — I -Φ

O

CO Lf) rd rd

CM CM sj · «Φ m

rd

CM • Φ r — 1 «Φ CM CM

M

TO)

O rd fM rd

WHAT 'R — I — 4

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 the compounds produced by the method of the invention has been demonstrated in a model animal ventricular arrhythmia.

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 animals. The micro transmitter was connected to two precordial electrodes.

The animal was returned to its box for progressive thrombosis of the anterial interventicular 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, the test products are orally administered to animals 16-24 hours after the introduction of the metallic coil, and the telemetry system allows the actual time evolution of the waking dog to be observed.

The number of sinus and pathological systolic complexes is then permanently measured by the electronic system. In this way, it is possible to evaluate the quality and duration of action of the test product and 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 testing the various products made by the method of the invention for oral administration of a dose of 50 mg / kg are shown in Table 2 below. For each of these cases, the number of experiments and duration of action of the test product are also shown.

These results show that the compounds prepared by the process of the invention have a potent effect on disrhythmia, some of which have a markedly prolonged effect.

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

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

Table 2

Product code number Number of animals Duration of the effect on the ventricular tachycardia SR 41298 3 3 times longer than 24 hours SR 41338 2 8 h and more than 24 h SR 41612 1 longer than 24 h SR 41620 2 2 times longer than 24 h SR 41639 1 1 h 40 min SR 41700 2 2 times longer than 24 h SR 41770 1 5 h SR 41811 1 9 h

An example of a useful galenic form is a tablet having the following composition:

product SR 41298 microcrystalline cellulose lactose magnesium stearate

0.200 g 0.140 g 0.140 g 0.020 g

0.500 g.

Claims (2)

A process for the preparation of 2,6-piperidinedione derivatives of the general formula I (I) represents a straight or branched alkyl group having 2 to 5 carbon atoms or also a morpholine or piperidine group optionally substituted by 1 to 4 methyl groups means 2 or 3, each independently represents a methyl group or an ethyl group or the like R 3 and R 6 together represent a group (CH 2) wherein m represents 4 or 5, and piperidinedione substitutes the pyridyl group at the 2 ', 3' or 4 'position, as well as salts of these derivatives with pharmaceutically acceptable acids, characterized in that reacts the carbonyl derivative of the general formula O = CH cooc ₂ h ₅ wherein R 6a are as defined above, with pyridylacetonitrile, whereupon the product obtained is catalytically hydrogenated and the resulting saturated derivative is then reacted with a haloalkylamine of formula Hal- (CH ₂ ) _n -N in which Hal is a halogen atom and R and _n are as defined above, after which the obtained product is cyclized by heating with a strong mineral acid such as hydrochloric acid, sulfuric acid or polyphosphoric acid to a temperature of 80- 120 ° C, and the product obtained is optionally converted into a salt by reaction with a pharmaceutically acceptable acid. 2. The process of item 1 for preparing 2,6-piperidinedione derivatives of the general formula X wherein: R is a straight or branched (C 2 -C 5) alkyl group; or R is also an -N 'group is a morpholine or piperidine group optionally substituted by 1 or 2 methyl groups, n is 2 or 3, and R 6 is each independently methyl or ethyl R ^ and R ^ together represent a group _{(CH2) m} wherein m represents 4 or 5, wherein piperidinedione is attached to the pyridyl ring at the 2 ', 3' or 4 ', and salts of these derivatives with pharmaceutically acceptable acids, characterized by reacting a carbonyl derivative of the general formula O = CH 3 --Co ₂ h ₅ , in which and R 6 are as defined above, with pyridylacetonitrile, whereupon the product obtained is catalytically hydrogenated and the resulting saturated derivative is reacted with a haloalkylamine of formula Hal- (CH ₂ ) in which Hal is a halogen atom and R is as defined above, then 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 , and optionally obtaining the product obtained by treatment with a pharmaceutically acceptable acid.