CS216167B2 - Method of making the derivatives of the n-substituted n-+l2-+l2-furyl+p-ethyl-p-propinylamine and the salts thereof - Google Patents

Abstract

The novel N-2-(2-furylethyl)amines of the formula I, in which the symbols R<1>, R<2> and R<3> have the meaning given in Claim 1, have an inhibitory effect on the monoamide oxidases without having any unwanted amphetamine effect. They are prepared by reacting a compound of the formula II with a compound of the formula III, in which compounds one of the radicals A or B corresponds to the group <IMAGE> , in which R<2> has the above meaning, while the other represents halogen or a sulphonic acid ester group. <IMAGE>

Description

The present invention provides a process for the preparation of N-substituted N- [2- (2-furyl) -ethyl) -propinylamine derivatives of the general formula I _n 1 n ₂ R ₂ с ₂ н 4) is hydrogen or (C1-C4) -alkyl, and salts thereof.

The compound of formula (1) and its salts are obtained according to the invention by providing an N-substituted N- [2- [2-furyl) -ethyl] -amine derivative of formula (II):

R1 and R2 are as defined above, condensed with formaldehyde and acetylene, whereupon the compound of formula I obtained is optionally converted into or released from its salt.

In the process of the invention, the compound of formula II is reacted with acetylene in a high-boiling ether such as butyl ether or dioxane in the presence of copper acetylide. The reaction temperature is conveniently in the range of 80 to 150 ° C. The reaction can be carried out, for example, by dissolving the N-substituted N- [2- (2-furyl) -ethyl] -amine of formula II in dioxane, adding copper acetylide or a compound to form acetylide to the resulting solution. copper, and acetylene is introduced into the reaction mixture while stirring and heating. The compound of formula (I) obtained is isolated in a conventional manner.

The compound produced by the process of the invention can be reacted with biologically preferred or indifferent acids to form their salts, or - when the compound is purified by conversion to a salt - can be released from its salts. Inorganic acids such as hydrochloric, sulfuric or phosphoric acid and organic acids such as maleic, lactic, ascorbic, citric, etc. are suitable for salt formation.

The compounds of formula I contain a chiral carbon atom and are optically active. Optically active isomers can be obtained when the racemic compound of formula I is decomposed into its optical antipodes or starting from an optically active compound of formula II.

The compounds of formula I are novel. Their pharmacological activity is similar to that of phenylethylamine [J. Pharmacol. 72, 265 (1941)]. The N-substituted N- [2- (2-furyl) -ethyl-propynylamines of formula (I) produced by the process of the invention, however, do not have an undesired amphetamine effect but surprisingly selectively inhibit the monoamine oxidase. Such an inhibitory effect has already been demonstrated for several compounds structurally similar to those produced by the method of the invention [Biochemical Pharmacology, 18, 1447 (1969); Br. J. Pharmacology, 45, 490 (1972)]. However, the compounds described therein mainly inhibit the oxidation of 5-hydroxytryptamine, only N-α-dimethyl-N- (3-phenylethyl-N-propynylamine) disclosed in British Patent No. 1,031,425, has a similar inhibitory effect on benzylamine oxidation [Br. J. Pharmacology, 45, 490 (1972)]. The novel compounds of formula (I) have a more advantageous pharmacological action.

Benzylamine oxidation in the liver is inhibited, for example, by N-methyl-N-propynyl-N- (2-furylethyl) amine in vivo at a dose of 6.25 mg / kg of 79%, while at the same dose the inhibition of tyramine oxidation is only 44% . N-methyl-N-propynyl-N- (2-furyl-1-methylethyl) -amine inhibits 53% oxidation of benzylamine in the brain at 5 mg / kg, 5% hydroxytryptamine only by 2%. At the same dose, 1-N-methyl-N-propynyl-N- (2-phenyl-1-methylethyl) -amine shows inhibition of benzylamine oxidation by 80%, inhibition of 5-hydroxytryptamine oxidation by 15%. At a dose of 10 mg / kg, the phenyl derivative inhibits the oxidation of benzylamine in the liver by 78%, and the oxidation of 5-hydroxytryptamine by 56%.

These data show that furan derivatives have a more selective effect than known phenyl derivatives in inhibiting monoamine oxidase. Selectivity is even more pronounced in in vitro experiments. Even the antidepressant effect of furan derivatives, the antagonist effect of reserpine, is stronger than that of similar phenyl compounds. Furan derivatives are less toxic than the corresponding phenyl derivatives.

The compounds produced by the process according to the invention or their salts can be formulated in a known manner into medicaments. For the manufacture of medicaments, the compounds produced by the process according to the invention are mixed with, for example, liquid or solid fillers, carriers and auxiliaries such as glidants, flavoring agents, preservatives, etc., and formulated in a known manner in the form of tablets. , dragees, capsules, microcapsules, suppositories, powder mixtures, aqueous suspensions, solutions, etc. Medicaments are preferably administered orally and parenterally.

The process according to the invention is illustrated by the following example.

Example 1

13.9 g (0.1 mol) of N-methyl-N- [1-methyl-2- (2-furyl) -ethyl] -amine are dissolved in 80 ml of dioxane. 6 g of paraformaldehyde and 1 g of cuprous chloride were added. Acetylene is then added to the reaction mixture with stirring for 30 hours, the solution is filtered and the filtrate is concentrated. The residue was dissolved in benzene, the benzene solution was washed with water, dried over potassium carbonate and evaporated. The residue was distilled under reduced pressure. 6.8 g of N-methyl-N- [1-methyl-2- (2-furyl) -ethyl] -propinylamine are obtained, boiling in the range of 114-116 [deg.] Celsius at a pressure of 2.67 kPa; n _D ²⁰ = 1.4910.

Example 2

12.5 g (0.1 mol) of 1-methyl-2- (2-furyl) -ethylamine are dissolved in 70 ml of dioxane. 6 g of paraformaldehyde and 1 g of cuprous chloride are added thereto, followed by the introduction of acetylene as described in Example 1, and the solution is treated as in Example 1. 6.3 g of N- [1-methyl] are thus obtained. -2- (2-furyl) -ethyl] -propinylamine, m.p. 55-60 ° C / 0.666 kPa. n _D ²⁰ = 1.4895.

The melting point of the hydrochloride is in the range of 107 to 111 ° C.

Pro CioHisNO. HCl calculated:

H, 7.06; N, 7.01; Cl, 17.75; found:

% H, 7.03;% N, 6.04;% Cl, 18.27.

WITH

Claims (1)

OBJECT OF THE INVENTION Process for the preparation of N-substituted N- [2- (2-furyl) -ethyl] -propinylamine derivatives of the general formula I R <2>. (Wherein each of R 1 and R 2 is hydrogen or C 1 -C 4 alkyl as well as a salt thereof, characterized in that the N-substituted N- [2- (2-furyl) ethyl] - of an amine of formula II O-C ^ C-7 ···. <111 where R1 and R2 are as defined above, condensed with formaldehyde and acetylene, whereupon the compound of formula I obtained is optionally converted into or released from its salts.