CS252843B2 - Method of 3-phenyl-2-propenamine's new derivatives production - Google Patents

Description

Hal represents a halogen atom such as a chlorine or bromine atom;

the compound is in the E or z configuration.

The process is usually carried out in an organic solvent, for example methylene chloride, in the presence of a substance which binds an acid such as triethylamine at a temperature of 0 to 20 ° C.

Compounds of formula (IV) may be obtained by application or adaptation of the method described by H. Meerwein, W. Florian, N. Schon, and G. Stoop, Ann. Chem., 641 (1961).

In the process of the present invention, compounds of formula I may be obtained wherein Y is a sulfinyl radical and the other symbols are as defined above, followed by oxidation of a compound of formula IA as described above.

The oxidation may be carried out using a reagent conventionally used to convert sulfide to sulfoxide or sulfone, in a suitable solvent without affecting the rest of the molecule. For example, hydrogen peroxide in acetone or acetic acid, an alkali metal periodate in alcohol or acetonitrile, a carboxylic acid containing peroxyacid (peracetic, perbenzoic, m-chloroperbenzoic, p-nitroperbenzoic or perfthalic) in an ether (e.g. dioxane or tetrahydrofuran) or in ether a chlorinated solvent (e.g. methylene chloride or dichloroethane), acetic acid, or a mixture of the above solvents.

If the sulfoxide, i.e. the compound of formula I in which Y is a sulfinyl radical, is to be recovered, it is particularly preferred to carry out the process in methylene chloride in the presence of two equivalents of an oxidizing agent, preferably m-chloroperbenzoic acid at about 0 ° C, preferably in the presence of one equivalent of an inorganic acid.

The novel compounds of formula (I) may be purified by conventional means, for example, crystallization by chromatography or sequential extraction in acidic and basic media.

When the compounds of formula I and their intermediates exist in the form of E or Z, they can be isolated from the reaction mixture separately, for example by chromatography.

The novel compounds of the formula I can optionally be converted into acid addition salts in an organic solvent, for example an alcohol, a ketone, an ester or a chlorinated solvent. The resulting salt precipitates upon optional concentration of the solution and is then separated by filtration or decantation.

The novel compounds of the formula I and their salts have interesting pharmacological properties which allow their use as antidepressants.

These compounds are effective, for example, as antagonist compounds in the case of depression induced by tetrabenazine in mice at doses of 1 to 100 mg / kg orally.

The dose of DL 40 for the compounds of the present invention is generally in the range of 50 to 900 mg / kg when administered orally.

Belgian Patent No. 781,105 discloses 2-propenamine derivatives and antidepressant properties. However, none of the resulting products contains a -CHOH- group in the molecule and no other known publications suggest that this group has ever been incorporated into the compounds.

The compounds of the invention may be used in medicine as such or in the form of their pharmaceutically acceptable salts, i.e., non-toxic, at the dosages administered.

Examples of pharmaceutically useful salts include salts with inorganic acids such as hydrochlorides, sulfates, nitrates, phosphates, or salts with organic acids such as acetates, propionates, succinates, benzoates, fumarates, maleates, methanesulfonates, isothionates, theophyllinacetates, salioylates, phenolphthaleinates, methylene-bis-naphthoates or substitution derivatives of the above compounds.

In the following examples, a practical embodiment of the method according to the invention will be explained.

In some examples, the resulting products were purified by flash column short column chromatography at about 50 kPa pressure using silica with a particle size of 40-63 µm as described by WC Still, M. Kahn and A. Mitra, J. Org. . Chem. 43,

2923, 1978.

Example 1

To a stirred solution of 40.5 g of 3-phenyl-3-phenylthio-2-propanol (Z) in 370 mL of methanol was added 139 g of dimethylamine hydrochloride and 2 g of molecular sieve with a 3.10 mesh ³⁰ mesh aperture under argon. Sodium cyanoborohydride (10.7 g) was added and the mixture stirred for 18 hours. Concentrated hydrochloric acid (26 ml) was added and the mixture was evaporated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

The residue was mixed with water and washed with ethyl ether. The aqueous phase is then basified to pH 10 by addition of 35% aqueous sodium hydroxide solution and then mixed with methylene chloride. The organic phase is decanted and filtered through diatomaceous earth, washed with 100 ml of water and then dried over sodium sulfate. After filtration, the organic phase is evaporated to dryness under reduced pressure of 2.7 kPa at 40 ° C,

An oily liquid is obtained which is purified by chromatography on silica gel, eluting with a methylene chloride / methanol (90:10 by volume) mixture, collecting 50 ml fractions. Fractions 20 to 30 are evaporated to dryness to give a residue which is dissolved in 10 ml of ethanol and 70 ml of ethyl ether. To this solution is added 17 ml of a 3.5N solution of hydrogen chloride in ethyl ether. A precipitate is formed which is collected by filtration and recrystallized from a mixture of 38 ml of ethanol and 50 ml of ethyl ether.

8.9 g of 1-dimethylamine-3-phenyl-3-phenylthio-2-propene (Z) hydrochloride (Z) are obtained in the form of a white crystalline solid, m.p.

3-Phenyl-3-phenylthio-2-propenal (Z) is obtained as follows:

To a solution of 9.4 g of 3-chloro-3-phenyl-2-propenal (Z) in 50 ml of dichloromethane is added at 0 ° C 9.66 ml of triethylamine and 5.7 ml of thiophenol. After stirring at 20 ° C for 14 hours, the mixture was poured into 50 ml of water. The solution was adjusted to pH 7 by addition of concentrated aqueous hydrochloric acid solution and then mixed with methylene chloride.

The organic phase is decanted, dried over sodium sulphate, filtered and evaporated to dryness under reduced pressure of 2.7 kPa at 40 ° C. The residue is purified by chromatography on silica, eluting with hexane and then with ethyl acetate. First, non-polar impurities are eluted with 400 ml of hexane, fractions 8 to 15, which are eluted with 400 ml of ethyl acetate, are combined and evaporated under reduced pressure of 2.7 kPa at 40 ° C.

7.8 g of 3-phenyl-3-phenylthio-2-propenol (Z) are obtained in the form of a red oil, Rf0.9, on silica gel thin-layer chromatography (ethyl acetate / hexane, 50% by volume): 50 as eluent.

3-chloro-3-phenyl-2-propenal (Z) can be obtained according to the method of C.M. Beaton, N. B. Chapman, K. Clarke, J. Chem. Soc. Perkin I, 2355 (1976).

In a similar manner to Example 1, the following compounds were obtained using the appropriate starting materials:

1-dimethylamino-3-phenyl-3-phenylthio-2-propene (Z), the hydrochloride of which is in the form of white crystals, m.p. 176 DEG C., 1-dimethylamino-3-phenyl-3-phenylthio-2-propene (E) whose hydrochloride is in the form of a white solid, m.p. 146-147 ° C,

3- (4-chloro-phenylthio) -1-dimethylamino-3-phenyl-2-propene (Z), the hydrochloride of which is in the form of a white powder, m.p. 226 DEG C., 1-dimethylamino-3-phenyl -3- (4-pyridyl-2-propene) (Z), the sesquioxalate of which is in the form of white crystals, m.p. 173 ° C;

3- (4-chlorophenyl) -1-dimethylamino-3-phenylthio-2-propene (Z), the oxalate of which is in the form of white crystals, m.p. 183 DEG C., 1-di-diethylamino-3- (4-fluorophenyl) -3- Phenylthio-2-propene (E), the hydrochloride of which is in the form of a white solid, m.p. 160 ° C; 1-dimethylamino-3- (4-fluorophenylthio) -3-phenyl-2-propene (Z), the oxalate of which is in the form of a white solid with a melting point of J63 ° C,

3- (4-bromophenyl) -1-dimethylamino-3-phenylthio-2-propene (E), the hydrochloride of which is in the form of white crystals, m.p.

3- (4-bromophenylthio) -1-dimethylamino-3-phenyl-2-propene (Z), the hydrochloride of which is in the form of a white solid, m.p.

3- (2-chlorophenylthio) -1-dimethylamino-3-phenyl-2-propene (Z), the hydrochloride of which is a white solid, m.p. 162 ° C;

3- (3-chlorophenylthio) -1-dimethylamino-3-phenyl-2-propene (Z), the hydrochloride of which is in the form of a white solid, m.p. 156-157 ° C; 1-dimethylamino-3- (4-methylphenylthio) -3-phenyl-2-propene (Z), the hydrochloride of which is a white solid, m.p. 197-198 ° C;

1-methylamino-3-phenyl-3-phenylthio-2-propene (Z), the hydrochloride of which is in the form of a white solid, m.p.

Example 2

To a solution of 6 g of 1-dimethylamino-3-phenyl-3-phenylthio-2-propane (Z) hydrochloride in 68 ml of dichloromethane is added a total of 4.7 g of m-chloroperbenzoic acid at 0 ° C. After stirring at 20 [deg.] C. for 24 hours, 4.7 g of m-chloroperbenzoic acid are added, followed by stirring for 3 hours. The reaction mixture was then poured into 100 ml of water. The solution was adjusted to pH 10 by addition of 35% aqueous sodium hydroxide solution and then extracted with methylene chloride. The organic phase is decanted, dried over sodium sulphate, filtered and then evaporated to dryness under reduced pressure of 2.7 kPa at 40 ° C. The residue is dissolved in 10 ml of ethanol. 6 ml of a 3 N solution of hydrogen chloride in ethyl ether are added to the solution and the precipitated solid is collected by filtration and recrystallized from a mixture of 60 ml of ethanol and 5 ml of acetonitrile. 2 g of 1-dimethylamino-3-phenyl-3-phenylsulphinyl-2-propene hydrochloride (Z2) are obtained as a white crystalline solid, m.p. 268 DEG C. with decomposition.

1-Dimethylamino-3-phenyl-3-phenylthio-2-propene hydrochloride (1) can be obtained by the method of Example 1.

SUBJECT OF THE INVENTION

Claims (1)

SUBJECT OF THE INVENTION Process for the preparation of the novel 3-phenyl-2-propenamine derivatives of the general formula I CH-, C = CH-CH ₀ -N. I ² in (i) where R is hydrogen or halogen, is hydrogen or methyl, A is phenyl optionally substituted by a halogen atom or a straight or branched chain alkyl radical of 1 to 4 carbon atoms or pyridyl, and Y represents a sulfur atom or a sulfinyl radical, as well as the pharmaceutically acceptable salts of these compounds, the geometric and optical isomers and mixtures thereof, characterized in that an aldehyde of the formula II is treated with an amine selected from methylamine and dimethylamine R S-A (II) wherein A and R are as defined above in the E or Z configuration to form a compound of formula I wherein Y is sulfur and the other symbols are as defined above, i.e. to form a compound of formula IA CH _O (IA) Whereupon the resulting product is isolated and optionally converted into a therapeutically effective salt or converted by oxidation to another compound of formula I wherein Y is a sulfinyl radical and the other substituents are as defined above and the product is optionally isolated and optionally is converted into a pharmaceutically acceptable salt thereof, or optionally, the product is always converted into a geometric or optical isomer or a mixture of isomers.