CS216169B2 - Method of making the new n-substituted n-2-+l2-furylethyl p-amines and the salts thereof - Google Patents

Description

The present invention relates to a process for the preparation of N-substituted N-2- (2-furylethyl) -amines which possess advantageous pharmacological effects.

Said compounds can be represented by the general formula I d R ^z (I) wherein each of R ¹ and R ² represents a hydrogen atom or an alkyl radical of 1 to 4 carbon atoms and

R ³ is a haloalkenyl radical with 2-4 carbon atoms, or a propynyl radical.

According to the invention, the compounds of the formula I or their salts or their optically active isomers are prepared by a compound of the formula II wherein:

R ¹ has the abovementioned meaning and

X is a halogen atom or a sulfonic acid ester residue, reacted with an amine of formula III

R ³

OF

HN \

R2 (III) wherein

R ² and R ³ have the abovementioned meaning, if appropriate in the presence of a solvent and / or acid-binding agent, and the final product is isolated as the free base or salts or optically active isomer.

The acid binders used are alkali metal or alkaline earth metal hydroxides or carbonates or tertiary amines or an excess of N-2- (2-furylethyl) -amine.

Suitable solvents are hydrocarbons, for example, petrol, benzene and its homologues, as well as alcohols, ketones, etc. An excess of the amine reactant can also serve as the solvent.

The reaction is carried out in a pressure tube at temperatures ranging from 20 to 130 ^° C, preferably 50 to 90 ° C.

After isolation, the product is purified in the usual manner by extraction, distillation or crystallization.

If the product to be made of a tertiary base (R ² is an alkyl radical), it is possible to purify particularly preferably be carried out by acylation of the residue. The unreacted secondary base is acylated thereby rendering it insoluble in dilute acids. The tertiary base produced can then be isolated in pure form by extraction with dilute acid.

For example, acylated with acetic anhydride or benzoyl chloride and lye may be acylated. The acylated reaction mixture is extracted cold with dilute hydrochloric acid, the acidic extract is rendered alkaline and the tertiary base is taken up in a solvent. The extract is evaporated, the residue is distilled and the base is optionally converted into an organic or inorganic salt.

The process described herein is based on compounds in which the triple bond already exists. However, a triple bond may be formed in the obtained secondary ^(R2 is hydrogen) or tertiary ^(R2 is alkyl) amino and subsequently, for example by elimination of hydrogen halide halogenalkylenaminů. Cleavage of the hydrogen halide can be achieved with an alkali metal or alkaline earth metal hydroxide or organic bases.

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

Compounds of formula I in which R ¹ represents an alkyl group, contain a chiral carbon atom and is optically active. Optically active isomers can be obtained when racemic compounds of formula I are decomposed into their optical 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. However, the N-substituted 2- (2-furylethyl) -amines of formula (I) produced by the process of the invention do not have an undesired amphetamine effect, but surprisingly inhibit the monoamine oxidase selectively. compounds structurally similar to those produced by the process of the invention [Biochemical Pharmacology, 18, p.

1447 (1969); Br. J. Pharmacology, 45, 490 (1972)]. However, the compounds disclosed therein mainly inhibit the oxidation of 5-hydroxytryptamine, only the N-α-dimethyl-N- (3-phenylethyl-N-propynylamine) disclosed in earlier British Patent No. 1,031,425 is characterized by a similar inhibitory effect on benzylamine oxidation [Br. J. Pharmacology, 45, 490 (1972)]. The novel compounds of the formula I have, as already mentioned, advantageous pharmacological effects.

Oxidation of benzylamine 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 depression of tyramine oxidation is only 44%. N-methyl-N-propynyl-N- (2-furyl-1-methylethyl) -amine at a dose of 5 mg / kg inhibits the oxidation of benzylamine in the brain by 53%, the oxidation of 5-hydroxytryptamine by only 2%. At the same dose, 1-N-methyl-N-propynyl-N- (2-phenyl-1-methylethyl) -amine shows inhibition of benzylamine oxidation by 80% in the brain, inhibition of 5-hydroxytryptamine oxidation is 15%. At a dose of 10 mg / kg, the phenyl derivative inhibits the oxidation of benzylamine in the liver by 78%, 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 medicinal preparations, the compounds produced by the process according to the invention are mixed, for example, with liquid or solid fillers, carriers and auxiliaries such as glidants, flavoring agents, preservatives, etc., and formulated in a known manner into ready-to-use 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 examples.

Example 1

12.8 g (0.1 mol) of 1-methyl-2- (2-furyl) ethyl chloride and 15 g (0.208 mol) of methylpropinylamine are heated at 70-80 ° C for 4 hours in a sealed pressure tube. The mixture was cooled and 30 ml of 40% sodium hydroxide solution was added. After the reaction mixture was extracted with benzene, the benzene solution was dried and evaporated. The residue was distilled under reduced pressure to give 9.8 g of N-methyl-N- [1-methyl-2- (2-fu216169 (0.1 mol) 2-furylethyl chloride) and 15 g (0.208 mol) of methylpropinylamine yielding 8 g. 8 g of N-methyl-N- [2- (2-furyl) -ethyl] -propinylamine boiling in the range of 104 to 105 ° C at a pressure of 2.67 kPa. N _D ²⁰ = 1.4868.

ethyl) -ethyl] -propinylamine, b.p. 113-115 ° C at 20 mm Hg. n _D ²⁰ = 1.49O4.

Example 2

Following the procedure described in Example 1 of 11.45 g

Claims (3)

Subject A process for the preparation of N-substituted N-2- (2-furylethyl) -amines of formula I R ⁴ R ² til wherein each R ¹ and R ² represents a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms and R ³ is a haloalkenyl radical with 2-4 carbon atoms, or a propynyl radical, or salts or optically active isomers, characterized in that a compound of formula II wherein tm R ¹ has the abovementioned meaning and X is a halogen atom or a sulfonic acid ester residue, reacted with an amine of formula III R ³ / HN \ R ² (III) wherein R ² and R ³ have the abovementioned meaning, if appropriate in the presence of a solvent for the subsequent addition of an acid binding agent, and the final product is isolated as the free base or salts or optically active isomer. 2. The process of claim 1, wherein the reaction is carried out in a pressure tube at a temperature in the range of 50-90 ° C. 3. The process of claim 1, wherein the acid binding agent is an alkali or alkaline earth metal hydroxide or carbonate or tertiary amine or an excess of N-2- (2-furylethyl) amine.