CS238371B2 - Pyrrole derivatives production method - Google Patents

Abstract

Process for producing pyrrole derivatives of Formula I / R H C - (¾ CQNHf, ΑΊΙ) Ν \ T R where the general symbols have the meanings given in the main point of the invention. These compounds are protective effect on myocardium, an anti-arrhythmic effect and antiplatelet effect.

Description

(54) Method for producing pyrrole derivatives

2

Process for the preparation of pyrrole derivatives of the general formula I

C - (¾ CQNHf,

ΑΊΙ) where the general symbols have the meaning given in the main point of the invention.

These compounds are characterized by a myocardial protective effect, an anti-arrhythmic effect and an anti-platelet effect.

The present invention relates to a process for the preparation of novel pyrrole derivatives having, in particular, an antiarrhythmic and platelet-clotting action.

The derivatives obtainable by the process according to the invention can be described by the general formula I

R is a radical of formula - _(CH2) "- N

R ³

R ⁴ _ / H (= \ _ 'c (CHJ,

Z CONHrj,

or a group from which this residue can be prepared, wherein R ³ , R ⁴ and n are as defined above, with a compound from the group consisting of a diketone of formula III wherein:

R ² represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms in a straight or branched chain, each of R ³ and R ^4, which are identical or different, represents an alkyl group having 1 to 6 carbon atoms in straight or branched chain, or a (C 3 -C 6) cycloalkyl group;

R ³

R ⁴ represents a five or six-membered ring having 1 nitrogen atom and optionally 1 oxygen atom, which is optionally substituted by up to 2 methyl groups such as pyrrolidine, piperidine, morpholine or 2,6-dimethylpiperidine or 1,4-diazabicyclo A 3,0) -nonyl-4-group of formula

^{R2__c-CH-CH-C-R2}

II II o o (ΙΠ) where

R ² is as defined above, with 2,5-dimethoxytetrahydrofuran and then the resulting compound of formula I, optionally converting its salts with mineral or organic acids.

The individual phases of this procedure are illustrated by the reaction scheme:

COOC 2 H 5 R ³

Z Z

CH3CONH — C— (CHajn — N \ \ _A

COOC2H5 R ⁴ • CD

H2N — CH— (CHa) _n —N

COOH r3

R ⁴ (2)

OF

HaN — CH- (CH2) 2 —N

R ³ and n are 2 or 3.

The compounds of formula I provide soluble salts with mineral or organic acids. The preparation of these salts with pharmaceutically acceptable acids is also within the scope of the invention.

The process according to the invention for the preparation of the compounds of the formula I and their salts consists in reacting a compound of the formula II

COOCH3

(3)

R ³

H2N — CH— (CHa) and —N

CONHa

R ⁴ (4)

H

AND

H2N-C — R

AND

Ac (II) wherein

Ac is an acid residue or an acid derivative residue a

R *

V • (I)

Compound (1) is prepared by alkylation of ethyl acetamidomalonic acid by known methods. By saponification of compound (1) in an alkaline medium, the corresponding malonic acid is obtained which is readily decarboxylated in an acidic medium with heating to give the substituted butyric acid (2). This is esterified in a known manner to the methyl ester (3), which is converted to the corresponding amide (4) by treatment with ammonia according to the known procedure. Thereafter, the amide (4) is converted to the compound of formula I by heating with the γ-dlketone of formula R2-CH2-CH2-CH2-C10 in acetic acid.

Where the symbol R ² represents hydrogen, it is possible to obtain a compound of formula I by heating the amide (4) with 2,5-dimethoxytetrahydrofuran in anhydrous alcohol in the presence of acetic acid.

The following examples illustrate the invention in greater detail, without restricting it thereto.

Example 1

The 2- (2,5-dimethylpyrrol-1-yl) -4-diisopropyleminobutyric acid amide (CM 7753) of formula I wherein R ² is methyl, each of R ³ and R ⁴ is isopropyl and n is 2.

1. 2-Amino-4 diisopropylaminobutyric acid ··

A mixture of ¹ 17.3 g of ethyl 2- (2-diisopropylaminoeíhyl) -acetamidomalonové 4.4 g of sodium hydroxide was heated for 3 hours under reflux in a mixture of 300 ml water 150 ml eíhanolu at 96 ° C. The reaction mixture is then evaporated to dryness and the residue is dissolved in 200 ml of 2 N hydrochloric acid. The resulting solution was heated to reflux for 5 hours.

After cooling, the reaction mixture was neutralized to pH 7 by addition of sodium hydroxide solution, evaporated to dryness and the residue dissolved in chloroform. The insoluble sodium chloride was filtered off, the filtrate was dried over sodium sulfate and evaporated to dryness.

11.3 g of a brownish solid are obtained, which is used as is in the following stage.

2. 2-Amino-diisipropylaminobutyric acid methyl ester

To 30 ml of methanol was added 22 g of thiouyl chloride while maintaining the temperature of the mixture below -5 ° C, followed by the portion-wise addition of -37.7 g of the acid prepared according to paragraph 1. while maintaining the temperature below -5 ° C. . After the addition the mixture was allowed to rise to room temperature and the mixture was heated for 2 hours at 40 DEG C. ^r Methanol was evaporated and the residue dissolved in the minimum amount of water ... To the solution was added 500 ml of ether and stirring the aqueous phase is saturated with potassium carbonate. The ether phase is separated and the aqueous phase is extracted again with ether. The combined ether extracts were dried over sodium sulfate and evaporated to dryness. ·

13 g of a yellow liquid are obtained, which product is used as is in the following stage.

3. 2-Amino-4-diisopropylaminobutyric acid amide

A solution of 3 g of the ester obtained in paragraph 2 in 20 ml of anhydrous ethanol is introduced into an autoclave of a cooled ice bath. A stream of ammonia was then bubbled through the solution for 1 hour. The autoclave is then sealed and heated at 150 ° C for 36 hours.

The alcohol was evaporated and the residue dissolved in a mixture of water and chloroform. The organic phase was separated and washed with water. The aqueous phases are evaporated to dryness and the residue is extracted with chloroform. The combined chloroform extracts were dried over sodium sulfate and evaporated to dryness.

1.54 g of an oily colored liquid are obtained, which product is used as is in the following stage.

4. 2- (2,5-Dimethylpyrrol-1-yl) -4-diisopropylaminobutyric acid amide (CM 77-53)

Dissolve 1.54 g of the oily liquid obtained in paragraph 3 and 0.98 g of hexane-2,5-dione in 4Ω ml of acetic acid and heat at 100 ^° C for 3 hours. and the reaction mixture was basified with dilute sodium hydroxide solution. After alkalization, the reaction mixture is extracted with ether, the ether phase is dried over sodium sulphate and evaporated to dryness. A viscous blackish liquid is obtained which is chromatographed on an alumina column; hexane / ethyl acetate (70/30 by volume) was used as eluent.

1 g of a yellowish substance is obtained, which is recrystallized from isopropyl ether. Recrystallization gave colorless crystals having a melting point of 71-72 ^° C.

Examples 2 to 11

Using the procedure of Example 1, however, using the various starting compounds, the compounds listed in Table I were obtained.

y

For each of the compounds of Formula I, the table shows the code number, the nature of the substituents and the melting point, as well as the solvent used for crystallization.

Example Code R ² n number number

TABLE I

R ³ R ⁴

Melting point ° C (crystallization solvent)

40,017 - CH3 2

40 002 —CH 2

7,921 H 2

40 020 — C2H5 2

-z2-C2H5

CH3

Z —CH

CH3

CH3

From —CH \

CH3 — C2H5

CH3

From —CH \

CH3

CHs

Z —CH

124 to 125 (ethyl acetate) 88 to 89 (isopropyl ether) to 69 (hexane)

105 —CH3 2

169 —CH3 2

176 —CH3 2

40178 —CH3 2

201 —CH3 3

261 —CH3 2 \

isolated as hydrochloride 122 to 124 (methylethylketone)

Isolated in the form of tosylate

O —CH2CH2CH3

CH 3 - CH - CH 2 CH 3

CH3

From —CH \

CH3

-Ό

CH3

From —CH \

CH 3 - CH 2 CH 2 CH 3

CH3 —CH — CH2CH3 isolated as fumarate 165 to 166 (ethanol) isolated as hydrochloride 198 to 199 (isopropanol)

CH3

From —CH \

CH3

Ό isolated as fumarate 147 to 148 (acetone) to 81 (isopropyl ether) to 97 (pentane)

The compounds produced by the process of the invention have been tested in the veterinary pharmacology field to demonstrate their advantageous properties.

Arrhythmical properties

Method

The antiarrhythmic effect of these compounds was tested in the case of dog ventricular arrhythmias.

Dogs serving as test animals are anesthetized and a metal spiral is introduced into the coronary circulatory system by re-catheterization. At the same time, a frequency modulating micro-transmitter is attached to the dog's back and connected to two precordial electrodes.

The dog, once again placed in the cubicle, develop gradual thrombosis of the anterior interventricular artery. This will result in a localized transmural myocardial infarction, causing anomalous but recurrent electrical activity: ventricular tachycardia.

In this state, the test compounds are administered orally and the telemetry system allows the progressive development of disrythmia to be monitored.

Permanent measurement of sinusal systolic and pathological complexes is possible electronically.

Thus, the degree of action and duration of the test compound can be quantitatively evaluated.

Results

The results obtained with the application of the individual compounds produced by the process according to the invention are shown in Table II.

The effect of the test compounds on ventricular tachycardia is expressed either by restoring the sinus rhythm or by significantly improving the ratio of the number of anormal complexes to the number of sinusal complexes.

TABLE II

Compound Dose, mg / kg p.o. Number Effect on ventricular (code number of experimental animals tachycardia)

CM 7753 50 4 sinus rhythm or 90% improvement over 1.5 to 5 hours

Effect against platelet aggregation

Method

In vitro and ex vivo anti-platelet aggregation assays were performed by the Borne turbidiuretric method.

In vitro assays were performed with blood plasma containing a large number of platelets prepared from venous human blood.

Solutions of test substances were prepared first; the compounds designated by the code numbers CM 7753, 7921 and 40 020 were dissolved in acetone to a concentration of 2 x 10 ² mol.

For compounds CM 40 169 and 40 178, aqueous solutions were prepared at a concentration of 2 x χ 10 ^-3 moles, followed by 2 microliters of acetone solutions, respectively. 40 .mu.l of aqueous solutions of the above compounds were left in an incubator at 37 DEG C. for 388 min. 350 microliters of blood plasma containing a large number of platelets. After incubation, 10 microliters of 40 pg / ml collagen solution was added. As controls, 2 microliters of acetone, respectively, were used. 40 microlitres of distilled water.

The ex vivo baboon tests were only intended to determine the efficacy of CM 7753 against platelet aggregation. In this orally at 50 mg / kg / day for 5 days.

Blood samples for stopping platelet aggregation were taken before administration of test compound, then 2 hours after 50 mg / kg administration on the first day and 2 hours after the last administration on the fifth day.

Platelet aggregation was quantified by graphically determining the maximum aggregation rate.

Results are expressed as% inhibition of this parameter, as determined by control solutions (100% clustering). Results

In vitro tests

Of the compounds studied, CM 7753 inhibits platelet aggregation by 50% at a concentration of 100 gmoles. Compounds CM 7921 and 40 020 have a lower platelet aggregation inhibitory effect (20 to 30% inhibition at 100 μΐηοΐύ).

Ex vivo test

In an ex vivo assay, CM 7753 inhibits, in particular, collagen-induced platelet aggregation.

The four baboons tested in this manner were 100% inhibited after 5 days of administration of the compound at 50 mg / kg / day. Less pronounced anti-agglomeration activity was also observed in the case of adenosine diphosphoric acid.

These results show that the compounds produced by the process of the invention exhibit potent efficacy on experimental disrhythmia and have potent anti-platelet aggregation activity. Therefore, the compounds of formula I can be used in human medicine for myocardial protection to treat disorders of ventricular rhythm of ischemic origin, as well as to correct platelet aggregation.

The compounds produced by the method of the invention may be administered in galenic formulations for oral administration (tablets, pills, etc.) and for parenteral administration (injection solutions in ampoules).

The daily dose required to produce an anti-platelet aggregation effect or to restore sinusal rhythm in humans is 50 to 150 mg by intravenous administration and 400 to 800 mg by oral administration.

An example is the tablet composition: Tablets

CM 7753 0.200 g microcrystalline cellulose 0.140 g lactose 0.140 g magnesium stearate 0.020 g

Claims (2)

SUBJECT VYNALEZU A process for the preparation of pyrrole derivatives of the general formula I FR ³ -C-CH ₂ -aZ ₂ CONH ₂ Z m where R ² represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms in a straight or branched chain, each of R ³ and R ^4, which are identical or different, represents an alkyl group having 1 to 6 carbon atoms in straight or branched chain, or a (C 3 -C 6) cycloalkyl group; R ³ Z —N \ \ R ⁴ represents a five or six membered ring having 1 nitrogen atom and optionally 1 oxygen atom optionally substituted by up to 2 methyl groups such as pyrrolidine, piperidine, morpholine or 2,6-dimethylpiperidine or 1,4-diazabicyclo ( 4,3,0) -nonyl-4-group of formula a n represents 2 or 3 as well as 1 salts of these compounds with mineral or organic acids, characterized in that the compound of formula II is reacted H HžN — C — R Ac (Π) where Ac is an acid residue or an acid derivative residue a R is a radical of formula R ³ / - (ΟΙ ^ ,, - Ν \) R ⁴ or a group from which this residue can be prepared, wherein R ³ , R ⁴ and n is as defined above, with a compound from the group comprising a diketone of formula III R 2 C 3 _CH 2 -CH 2 _-C -R 2 oo (III) wherein R ² is as defined above, with 2,5-dimethoxytetrahydrofuran and then the resulting compound of formula I, optionally converting its salts with mineral or organic acids. 2. The process according to claim 1, wherein the starting material is a compound of formula IV R ⁵ OF H2N — CH— (CH2-N I \ CONHz R ⁴ (IV), where R ³ , R ⁴ and n are as defined in point 1.