CS216168B2 - Method of making the n-substituted-n-2-furylethylamines - Google Patents

Description

The present invention relates to a process for the preparation of N-substituted N-2-furylethylamines of the formula I

CH £CH ”N-CH ^CH (II) wherein each of R ¹ and R ² represents a C 1 -C 4 alkyl group, as well as salts thereof.

The compounds of the formula I and their salts are obtained according to the invention by a compound of the formula II

Rt = 2.

Ul) where

R ¹ and R ² are as defined above, reacted with propargylaldehyde and the resulting compound is reduced, whereupon the resulting product is optionally converted into its salts or released from its salts.

The condensation reaction of the N- [2- (2-furyl) ethyl] amine of formula II with propargylaldehyde is carried out by mixing the reactants, optionally in the presence of a solvent. Solvents which are preferably water-immiscible solvents such as benzene and its homologues, and gasoline, are advantageously used, since in this case the water formed during the reaction is separated as a special phase, thereby shifting the reaction equilibrium in the direction of Schiff base formation. The resulting Schiff base is then reduced to give a compound of formula I. However, condensation and reduction can also be carried out in a single step. Hydrogen is preferably used in the birth state for the reduction.

The compounds produced by the process of the invention may be reacted with biologically preferred or indifferent acids to form salts thereof, or may be liberated from their salts when the compounds are purified by conversion to a salt. Inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid as well as organic acids such as maleic acid, lactic acid, citric acid, ascorbic acid, 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 racemic compounds of formula I are resolved into their optically active antipodes or starting from optically active compounds of formula II.

The compounds of formula I are novel. Their pharmacological activity is similar to that of phenylethylamine (J. Pharmacol, 72, 265 (1941)). However, the N-substituted 2- (2-furylethyl) -amines of the formula I produced by the process of the invention do not have an undesired amphetamine effect Such inhibitory effect has already been demonstrated for several compounds structurally similar to those produced by the method of the invention (Biocheinical Pharmacology, 18, 1447 (1969); Brit. J. Pharmacology, 45, 490 (1972)). However, the compounds disclosed therein mainly inhibit the oxidation of 5-hydroxytryptamine, only Na-dimethyl-N- (3-phenylethyl-N-propynylamine, described in earlier British Patent No. 1,031,425, has a similar inhibitory effect on benzylamine oxidation [Brit. J. Pharmacology, 45, 490 (1972)] The novel compounds of formula I exhibit advantageous pharmacological effects.

Benzylamine oxidation in the liver is inhibited, for example, by N-methyl-N-propynyl-N- (2-furylethyl) amine in vivo at a dose of 6.2-5 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, and 5% hydroxytryptamine only by 2%. At the same dose, 1 N-methyl-N-propynyl-N- (2-phenyl-1-methylethyl) -amine in the brain shows an inhibition of benzylamine oxidation of 80%, inhibition of 5-hydroxytryptamine oxidation of 15%. kg of phenyl derivative inhibits benzylamine oxidation in the liver by 78%, 5-hydroxytryptamine oxidation by 56%.

These data indicate 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 greater 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 of the invention are mixed with, for example, liquid or solid fillers, carriers and auxiliaries such as glidants, flavoring agents, preservatives, etc., and are formed in known manner into ready-to-use tablets 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 explained in more detail below by way of example.

Example

To a solution of 13.9 g (0.1 mol) of N-ethyl-N- [1-methyl-2- (2-furyl) ethyl] -amine in 100 ml of ethanol is added 7 g (0.184 mol) of propargylaldehyde. 5 g of aluminum foil are degreased with alcohol, then 1 g of mercury chloride and 15 g of sodium chloride in 30 ml of water are activated, and after 6 to 8 minutes the activation solution is decanted, the activated aluminum foil is washed with cold water and added to the above The temperature is maintained at 15 to 30 [deg.] C. by cooling, the mixture is stirred for 24 hours, 30 ml of 40% sodium hydroxide solution are added, the phases are separated and the aqueous phase is extracted three times with benzene. The organic phase is extracted with benzene, the benzene solution is dried over potassium carbonate, the benzene is distilled off and the residue is distilled off under reduced pressure. 6.1 g of N-methyl-N- [1-ethyl-2- (2-furyl)] - propynylanine are obtained, boiling in the range of 114-115 [deg.] C. at a pressure of 10 mm Hg; n _D ²⁰ = 1.4910.

Claims (2)

A process for the preparation of N-substituted N-2-furylethylamines of formula I CH-CH-N-CH-C-CH CX (tlf (I i wherein each of R ¹ and R ² is C 1 -C 4 alkyl) characterized in that the compound of formula (II) wherein: R ¹ and R ² are as defined above, is reacted with propargyl aldehyde, and the resulting compound is reduced, whereupon the resulting product is optionally converted in its salt or liberated from its salt. 2. The process according to claim 1, wherein the condensation and reduction are carried out in a single step.