CS232348B1 - 1-phenyl-3- (3,4-dimethoxyphenyl) -2-propylamines and their hydrochlorides - Google Patents

Abstract

The invention belongs to the field of synthetic drugs. Its main compounds are 1-phenyl-3-(3,4-diethoxyphenyl)-2-propylamines of the general formula I CH3O ch3o ch2chch2- NHR (I), in which R denotes hydrogen or methyl, and their hydrochlorides. These substances have therapeutically useful local anesthetic and antiarrhythmic activity and are therefore considered as drugs for local anesthesia in minor surgical interventions and as drugs against cardiac arrhythmias. They also show some antimicrobial activity in vitro and are intermediates in the preparation of drugs with dopemnomimetic and antiparkinsonian effects. They can be prepared from i-phenyl-3-(13,4-diethoxyphenyl)prepan-2-one in two stages. In the first step, the ketone is converted by the Leuckert reaction, i.e. by heating with formaldehyde and formic acid to 180°C, to N-(1-phenyl-3-(3,4-dimethoxyphenyl)-2-propyl)formaldehyde, which in the second step is either hydrolyzed alkaline to give substance I, R = H, or reduced with a complex hydride to give substance I, R = CH,. The hydride compounds of substances I are prepared by neutralization reactions with bases or hydrochloric acid.

Description

(54) 1-phenyl-3- (3,4-dimethoxyphenyl) -2-propylamines and their hydrochlorides

The invention is in the field of gynthetic drugs. Its 1-phenyl-3- (3,4-diaethoxyphenyl) -2-propylamines of formula I

CH ₃ OCH ₃ CH ₂ CH ₂ NHR (I), in which R is hydrogen etone or methyl, and their hydrochlorides. These substances do not have therapeutically useful locally anesthetic and anti-erythmic efficacy and are contemplated as drugs for some numbness in minor surgical interventions, and as drugs for cardiac arrhythmias. They also exhibit some anti-microbial activity in vitro and are intermediates for the preparation of dopemlimetallic and antiparkinsonian drugs. They can be prepared from i-phenyl-3-13,4-dinethoxyphenyl) prepan-2-one in two steps. In the first, the ketone is converted by Leuckert reaction, i.e. by heating e formemide and formic acid to 180 ° C, to N- (1-phenyl-3- (3,4-dimethoxyphenyl) -2-propyl) fomeeid which in the second step either alkaline hydrolyses to the substance I, R = H, or reduces coaplexin by hydride to the substance I, R = CH. Ifydrohlerides of compounds Ie are prepared by neutralizing reactions with bases with hydrochloric acid or hydrochloric acid.

(AND).

The invention relates to 1-phenyl-3- (3,4-dimethoxyphenyl) -2-propylaines of the general formula I

CH ₃ O ch ₃ o

CH ₂ CHCH ₂

NHR wherein R is hydrogen or methyl, and their hydrochloride.

The compounds of the invention of formula I and their hydrochlorides have therapeutically useful local anesthetic and antiarrhythmic efficacy and are therefore suitable as medicaments for local anesthesia in minor surgical interventions, and also as medicaments for cardiac arrhythmias. In addition, they also exhibit some antimicrobial activity in in vitro assays, as they are also potential chemotherapeutic agents. They are further intermediates for the preparation of drugs with dopaminomimetic and antiperkinsonic activity.

1-Phenyl-3- (3,4-dimethoxyphenyl) -2-propylamine was tested by phermacology as hydrochloride. When administered intravenously, its acute toxicity in mice is LD50 = 37.5 mg / kg. At doses higher than 7 mg / kg i.v. the compound exhibits a centrally stimulating effect seen to increase the activity and reactivity of the mice in the experiment.

At an intravenous dose of 7 mg / kg it has an antiarrhythmic effect in rats using an aconitine arrhythmia model; the intensity of this effect is similar to that of quinidine, which is a known antiarrhythmic drug. At the following minimum inhibitory concentrations, the agent acts against said microorganisms in vitro: Saccharomyces pasterianus 100, Trichophyton mentagro phytes 50, Candide elbicans 100, Aspergillus niger 100. Concentrations are vjug / ml.

N-methyl-1-phenyl-3- (3,4-dimethoxyphenyl) -2-propylamine was also tested as hydrochloride. Its acute toxicity in mice by intravenous administration, LDg ₀ = 35 mg / kg. At doses greater than 7 mg / kg iv, the compound exerts a central stimulatory effect in mice, resulting in increased activity and reactivity. In the form of a 1% solution, the substance acts locally anesthetically in the rabbit eye anesthesia test. At an intravenous dose of 7 mg / kg iv, similarly to the substance, it has a previous antiarrhythmic effect against aconitine arrhythmias in rats, although somewhat lower in intensity. Similar to the foregoing, it has an antimicrobial effect against some microorganisms in vitro (minimum inhibitory concentrations in µg / ml given): Mycobacterlum tuberculosis H37Rv 100, Saccharomyces pasterianus 100, Trichophyton mentagrophytes 50, Candida albicana 50, Aspergillus niger i 00,

Compounds of the Invention of Formula I can be prepared from 1-phenyl-3- (3,4-dimethoxyphenyl) propan-2-one of Formula II

in two stages. In the first, said ketone of formula II is converted by the Leuckart reaction, i.e. by heating with formamide and formic acid to 180 ° C, to the N- / 1-phenyl-3- (3,4-dimethoxyphenyl) -2-propyl / formamide of the formula III,

ΟΗ ₃ Ο- <Γ ^ - <: Η ₂ ΟΗ <: Η ₂ ^ θ ch / ^{NHCHO (iii)} which in the second stage of the cell is alkaline hydrolyzed to substance I, R = H, or reduced with a complex hydride, preferably lithium aluminum hydride, to compound I, R = CHy Details of the syntheses of compounds of formula I will be apparent from the examples. The starting ketone of formula II is a novel material, the preparation of which is also described in the example. All of the novel compounds disclosed in this invention have been identified both analytically and by spectral methods.

The following examples are merely illustrative of the possibility of preparing the compounds of the invention, but are not intended to fully describe these possibilities. The hydrochlorides of the compounds I according to the invention are prepared by the usual neutralization reaction with hydrogen chloride or hydrochloric acid. These hydrochlorides are crystalline and well characterized

He did

1-phenyl-3- (3,4-dimethoxyphenyl) -2-propylamine

A mixture of 15.5 g of 1-phenyl-3- (3,4-dimethoxyphenyl) propan-2-one, 43 g of the balance forum and 9.0 g of acid ^! the form is stirred and slowly heated to 180 ° C. It is maintained at this temperature for 12 h. After cooling to 90 DEG C., 150 ml of water are added and the mixture is extracted with chloroform. The extract was washed with water, filtered with charcoal, dried over sodium sulfate and evaporated in vacuo. The oily residue (16.4 g, 100%) is crude N- [1-phenyl-3- (3,4-dimethoxyphenyl) -2-propyl] formamide which is used for further work without purification and characterization.

A mixture of 15.5 g of aurochloroformamide, 20 ml of ethanol and 20 g of potassium hydroxide is stirred and refluxed for 2.5 hours. It is then diluted with 100 ml of water and, after cooling, extracted with ether. The extract was dried over potassium carbonate and evaporated. 12.1 g of crude oily base 1-phenyl-3- (3,4-dimethoxyphenyl) -2-propylamine are obtained, which is dissolved in 25 ml of ethanol and a slight excess of a solution of hydrogen chloride in ether is added to the solution. By addition of additional ether, ee is complete by exclusion of the desired hydrochloride, which is obtained in a yield of 11.5 g (72%) mp 180-181 ° C. Krystalizscl from ethanol-ether gave the analytical product melting at 184 DEG-185.5 DEG C. ^e

The starting 1-phenyl-3- (3,4-dimethoxyphonyl) propan-2-one used is a novel compound which can be prepared as follows:

Sodium (9.2 g) is dissolved in 150 ml of ethanol, and 35.4 g of 3,4-dimethoxyphenylacetonitrile are added to the resulting ethoxide solution (7th), followed by 40.0 g of ethyl phenylacetate.

The resulting mixture was stirred and refluxed for 3.5 h, allowed to stand overnight at room temperature and then poured into 600 g of ice / water. Stir 15 min and wash with ether. The aqueous alkaline layer containing the enol sodium salt was separated and acidified with 75 mL of 5M-HCl. The resulting 2- (3,4-dimethoxyphenyl) -3-oxo-4-phenylbutyronitrile was isolated by extraction with ether, dried over sodium sulfate and evaporated. The oily residue (60 g) is said crude nitrile, which is dissolved in 600 ml of acetic acid, 400 µl of hydrochloric acid is added to the solution, and the mixture is heated to 35-50 ° C. It is then allowed to stand for 48 hours at matt temperature. It is poured into 6 L of water at 10 ° C, stirred for 30 min, the precipitated product is filtered off with suction, washed with water and dried. 40.4 g (64%) of 2- (3,4-dimethoxyphenyl) -3-oxo-4-phenylbutyramide melting at 137-143 ° C are obtained. An analytical sample was obtained by recrystallization ₉ from ethanol, mp 15 ° -159 ° C.

A suspension of 15.7 g of the above amide in 550 ml of 10% hydrochloric acid was stirred and refluxed for 6 hours. After cooling, the mixture was extracted with ether, the extract was washed with 10% sodium bicarbonate solution and water, dried over calcium chloride and evaporated. The residue was dissolved in 35 of ethanol, filtered with charcoal, and the filtrate evaporated in vacuo. The residue crystallizes on standing overnight. 10.8 g (80%) of 1-phenyl-3- (3,4-dimethoxyphenyl) propen-2-one melting at 32-35 ° C is obtained. Crystallization from benzene / petroleum ether gave an analytical sample melting at 38-41 ° C.

Example 2

N-methyl-1-phenyl-3- (3,4-dimethoxyphenyl) -2-propylamine

A solution of 14.9 g of crude N- [1-phenyl-3- (3,4-dimethoxyphenyl) -2-propyl] formamide (prepared as described in Example 1) in 150 ml of ether was added dropwise to a stirred suspension of 10.0 g. lithium232348 aluminium hydride in 200 L of ether. The mixture is refluxed for 8 h, cooled, decomposed and slowly added 10 ml of science, 10 and 20% sodium hydroxide solution and 25 ml of water, stirred for 1 h, 10 g of potassium carbonate are added and after a further 30 min. with stirring, the solid was filtered off with suction and washed with ether. The filtrate was evaporated under reduced pressure and 8.4 g of N-ethyl-1-phenyl-3- (3,4-diaethoxyphenyl) -2-propylamine, oily base, was sieved. This crude base and e was purified by ohromatografil to 150 g neutral alumina (activity II). Elution with bensene ae removes less polar compounds and the product then elutes with chloroform (5.4 g). Dissolve in 6 [mu] l of 2-propanol, add a slight excess of the solution of hydrogen chloride in ether and dilute with ether. 3.15 g of the desired hydrochloride are obtained, m.p. 119 DEG-120 DEG C. (2-propanol-ether).

Claims (1)

SUBJECT OF THE INVENTION 1-Phenyl-3- (3,4-dimethoxyphenyl) -2-propylemines of the general formula I (I), in which B is a hydrogen atom or methyl, and their hydrochlorides Severography, n. P., MOST Price 2,40 Kčs