CS216166B2 - Method of making the new n-substituted n-2-+l2-furyl-ethyl+p-amines,the salts thereof and optical active isomeres - 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 invention relates to a process for the preparation of the novel N-substituted N-2- (2-furylethyl) amines of the formula I

R ¹ R ² (I) wherein each of R ¹ and R ² is hydrogen or C 1 -C 4 alkyl,

R ³ represents C 2 -C 4 haloalkenyl or propynyl as well as their salts and optically active isomers.

The compounds of formula (I) and their salts or optically active isomers are obtained according to the invention by:

R ¹ and R ² are as defined above, reacted with a propargyl halide or C 2 -C 4 -dihaloalkene, preferably in the presence of a solvent, and an acid binding agent at a temperature in the range of 20 to 120 ° C, from the haloalkenyl formed of the derivative is optionally cleaved by hydrogen halide, and the final product is isolated in the form of a free base or a salt or an optically active isomer.

As acid binding agents, inorganic or organic bases, for example alkali and alkaline earth metal hydroxides or carbonates, as well as tertiary amines, can be used. Excess N-2- (2-furylethyl) -amine can also be used as acid binding agents. In this case, it is preferably operated without a solvent, and the excess of the amine component serves simultaneously as a solvent. As solvents, aliphatic and aromatic hydrocarbons such as gasoline, benzene and its homologues, alcohols such as methanol, ethanol, butanol and the like, ketones such as methyl ethyl ketone, cycloliexanone and the like can be used.

In a particularly preferred embodiment of the process according to the invention, the amine component of formula II is dissolved in toluene and propargyl bromide is added dropwise while stirring.

216168

CH-CH-NH (II) and aqueous sodium hydroxide. If necessary, the reaction is completed by heating. The reaction mixture obtained is worked up by adding caustic followed by solvent extraction. If a water-miscible solvent is used in the reaction, it is expedient to distil the solvent off before treatment and add aqueous caustic to the residue. The biphasic mixture obtained in this way is extracted with a water-immiscible solvent such as ether or benzene, the extract obtained is dried, evaporated and the residue purified by fractional distillation.

If the product to be made of a tertiary base (R ² = alkyl), it is possible to perform purification, particularly preferably 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, they can be acylated while hot with acetic anhydride or benzoyl chloride and lye. 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 according to the invention starts from a compound in which the triple bond already exists. However, the triple bond can also be formed in the secondary (R ² = H) or tertiary (R ² = alkyl) amines obtained, additionally. The triple bond can be formed, for example, from dihaloalkylamines or haloalkenylamines by cleavage of hydrogen halide. 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 may be reacted with biologically preferred or indifferent acids to form salts thereof, or may be liberated from their salts when purification of the compounds is accomplished by conversion to 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, dibenzoyl-d-tartaric 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 may 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. 72, p. 265 [1941]). The N-substituted 2- (2-furylethyl) -amines of formula I produced by the process of the invention, but do not have an undesired amphetamine effect, surprisingly, it selectively inhibits 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, p. 1447 [1969]; Br. J. Pharmacology, 45, p. 490 [1972]). However, the compounds described therein mainly inhibit the oxidation of 5-hydroxytryptamine, only Na-dimethyl-N-4-phenylethyl-N-propynylamine, described in earlier 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) are distinguished by their advantageous pharmacological action.

For example, benzylamine oxidation in the liver is inhibited, for example, by N-methyl-N-propynyl-N- (2-furylethyl) amine in vivo at 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 at a dose of 5 mg / kg inhibits 53% oxidation of benzylamine in the brain, 5% hydroxytryptamine oxidation by only 2%. At the same dose, 1-N-methyl-N-propynyl-N- (2-phenyl-1-methylethyl) -amine shows inhibition of benzylamine oxidation at 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 antagonistic effect of reserpine, is stronger than that of similar phenyl compounds. Furan derivatives are less toxic than the corresponding phenyl derivatives

The compounds produced according to the invention or their salts can be formulated in a known manner into medicaments. For the preparation of medicinal preparations, the compounds produced according to the invention are mixed with, for example, liquid or solid fillers, carriers and auxiliaries such as glidants, aromatic substances, preservatives, etc., and formulated in a manner known per se in the form of tablets, dragees, capsules, microcapsules, suppositories, powder mixtures, aqueous suspensions, solutions, etc. in a known manner. In particular, the pharmaceutical preparations are administered orally and parenterally.

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

Example 1

7.9 g (0.0568 mol) of N, α-dimethyl-2- (2-furylethyl) -amine are dissolved in 142 ml of toluene. 6.7 g (0.0568 mol) of propargyl bromide and 11.4 ml of 5 normal sodium hydroxide solution were added dropwise to the solution with stirring at 45-50 ° C. The resulting mixture was heated to reflux for 3 hours with stirring. After cooling, 14.8 ml of 10 normal sodium hydroxide solution are added and the phases are separated. The aqueous phase is shaken twice with benzene. The benzene phases are combined with the toluene solution, dried over anhydrous potassium carbonate and the solvent is distilled off. The residue is taken up in 50 ml of benzene, 6 g of acetic anhydride are added to the solution, and the mixture is heated under reflux for 1 hour. After cooling, the resulting solution was washed with 5% sodium carbonate solution until carbon dioxide evolution began. The solution was washed with water and finally extracted at 0 ° C with 5% hydrochloric acid. The acidic extracts, the temperature of which must not exceed 10 ° C, are combined and made alkaline. The precipitated oil was extracted with ether, the ether extract was dried over potassium carbonate and evaporated. The residue was distilled under reduced pressure. 6.5 g of N-methyl-N- [1-methyl-2- (2-furyl) -ethyl] -propinylamine are obtained.

n _D 22 = 1.4922.

Example 2

12.5 g of 2- (2-furyl) -ethyl-methylamine are dissolved in 70 ml of toluene and reacted as described in Example 1 with 11.9 g (0.1 mol) of propargyl bromide and 20 ml of 5 normal sodium hydroxide solution. . 11.2 g of N-methyl-N- [2- (2-furyl) -ethyl] -propinylamine are obtained, b.p. 105-106 ° C at 20 mm Hg; n _D 22 = 1.4891. The melting point of the hydrochloride after recrystallization from an alcohol / ether mixture is in the range of 106 to 108 ° C.

Example 3

To 13.9 g (0.1 mol) of N-methyl 1-N- [1-methyl-2- (2-furyl)] -ethylamine was added dropwise 10 grams (0.05 mol) of 1,2-dibromopropenes. The mixture was kept at 100 ° C for 7 hours, then cooled to room temperature and dissolved in 5% hydrochloric acid. The acidic solution was extracted with ether and basified with 40% sodium hydroxide solution. An oil is formed which is taken up in ether. The ether solution was dried and evaporated. 60 ml of 40% sodium hydroxide solution and 35 ml of benzoyl chloride are added dropwise to the brown oil. This reaction, which lasts 30 to 45 minutes, benzoylates unreacted N-methyl-N- [1-methyl-2- (2-furyl)] -ethylamine. During the addition, the temperature is raised to 50-60 ° C. At this temperature, the reaction mixture was stirred for an hour, then cooled to room temperature and benzene was added. After shaking, the benzene phase is separated.

The separated benzene phase is extracted with 5% hydrochloric acid, whereby N-methyl-N- (1-methyl-2- (2-furyl) -ethyl] -N-2-bromopropenylamine goes into the acid phase while N-methyl-N- (1-methyl-2- (2-furyl) -ethyl pN-benzoylamine remains in the benzene phase.

The acidic phase is basified and the precipitated N-methyl-N- [1-methyl-2- (2-furyl) -ethyl] -N-2-bromo-propenylamine is extracted with benzene. After drying and evaporating the solution and distilling off the residue under reduced pressure, 7.1 g of N-methyl-N- [1-methyl-2- (2-furyl) -ethyl] -N-2-bromopropenylamine is obtained.

This compound is dissolved in 100 ml of ethanol and 14 ml of 50% potassium hydroxide solution are added. The resulting mixture was heated under reflux for 16 hours. The alcohol was then distilled off, water was added to the residue, and the solution was extracted with benzene. The benzene extract is dried over anhydrous potassium carbonate and then concentrated. Distillation under reduced pressure yielded 4.9 g of N-methyl-N- [1-methyl-2- (2-furyl) -ethyl] -propinylamine having a boiling point of 114-116 [deg.] C at 20 mm Hg; n ₂₀ = 1.4915.

Example 4

12.5 g (0.1 mol) of 2- (2-furyl) -ethynyl-ethylamine were reacted with 10 g (0.05 mol) of 1,2-dibromopropene as described in Example 3. 7.6 g of (N-methyl-N - [(4-furyl) -ethyl] -N-2-bromo-propenylamine are obtained, which is heated as described in Example 3) in 100 ml of ethanol with 14 ml of 50% KOH under reflux. This yields 5.1 g of N-methyl-N- [2- (2-furanyl] -ethyl ^ -propinylaminu b.p. 105-106 ° C, n _D ²⁰ = 1.4890. The hydrochloride, recrystallized from ethanol and of ether, melts at 107-108 ° C.

Claims (4)

A process for the preparation of N-substituted N-2- (2-furylethyl) -amines of formula I R ⁴ R ^2, QLc = CH-NR ³ (I) wherein each of R ¹ and R ² is hydrogen or C 1 -C 4 alkyl, and R ³ is a haloalkenyl radical with 2-4 carbon atoms, or a propynyl radical, and their salts and optically active isomers, characterized in that a compound of formula II (II) wherein R ¹ and R ² has the abovementioned meaning, is reacted with propargylhalogenldem or 1,2-dihalogenalkenem with 2-4 carbon atoms, preferably in the presence of a solvent and an acid acceptor at a temperature ranging from 20 to 120 ^C C, the obtained derivative halogenalkenylového optionally, the hydrogen halide is cleaved off and the final product is isolated in the form of a free base or a salt or an optically active isomer. Process according to claim 1, characterized in that petrol, benzene and its homologues, alcohols, preferably methanol, ethanol or butanol, or ketones, preferably methyl ethyl ketone or cyclohexanone, are used as solvents. 3. The process of claim 1 wherein the acid binding agent is an alkali metal or alkaline earth metal hydroxide or carbonate or an excess of N-2- (furylethyl) amine. 4. A process according to claim 1 for the preparation of optically active isomers of compounds of formula (I), characterized in that it is used in the crystallization of dibenzoyl-d-tartaric acid.