CS252845B2 - Process for preparing novel 3-phenyl-2-propenamine derivatives - Google Patents

Abstract

A method for the production of new derivatives of 3-phenyl-2-propenamine of the general formula I where the individual symbols have the meaning given in the definition, as well as pharmacologically acceptable salts of these compounds and geometric and optical isomers and mixtures thereof, characterized in that ammonia, an amine precursor or an amine of the general formula III (III) where and R2 have the meaning given above are reacted with a compound of the general formula IV where the individual symbols have the meaning given in the definition. The compounds of the general formula I can be used in medicine as antidepressants.

Description

The invention relates to a process for the production of novel 3-phenyl-2-propenamine derivatives of general formula X:

(I) where

R represents a hydrogen atom, a halogen atom, an alkyl radical or an alkoxy group,

R3 represents a hydrogen atom or a methyl radical,

R1 and R2, the same or different, represent a hydrogen atom or an alkyl radical, optionally substituted by an alkenyl radical of 2 to 4 carbon atoms, or together with the nitrogen atom to which they are attached, these substituents form a 1-pyrrolidinyl or piperidine radical,

A represents an alkyl radical or a phenyl radical, optionally substituted with 1 or more substituents from the group consisting of a halogen atom, an alkyl radical, an alkoxy group or a trifluoromethyl group, or A represents pyridyl, benzyl or cycloalkyl of 3 to 6 carbon atoms and

Y represents a sulfur atom, a sulfinyl or sulfonyl radical or a radical of the general formula II

R _g “ C - 0R _? (II), where

R^ represents a hydrogen atom or a methyl radical and

R? represents a hydrogen atom, acetyl, ethoxycarbonyl, methylaminocarbonyl or benzoyl, wherein in the above definition all alkyl radicals and alkyl parts of other radicals contain 1 to 4 carbon atoms and have a straight or branched chain, as well as all geometric isomers and optical isomers and mixtures thereof and salts of the above compounds.

The above substances can be processed into pharmaceutical compositions.

The process according to the invention allows the compounds of general formula I, in which Y represents a sulfur atom or a residue of general formula II as defined above, and the other symbols have the meanings defined above, the compound being in the E or Z configuration, to be obtained by the action of ammonia, an amine precursor or an amine of general formula III.

HN

where and R ₂ have the meaning given above.

on the s.i.tuition of the general formula IV (III)

where

A, R and Rj are as defined above and (a) X represents a chlorine atom and

Y' represents a sulfur atom or a residue of the general formula II, in which the individual symbols have the above-mentioned meaning with the exception of the hydrogen atom for R? or (fc>) X represents a bromine atom and

Y' represents a sulfur atom, the compound having the E or Z configuration, followed by optional hydrolysis in the case where a compound of general formula I is to be obtained, in which Y represents a residue of general formula II, in which R' represents a hydrogen atom and the other symbols have the meanings given above.

The process is usually carried out in an organic solvent, for example in an alcohol, such as ethanol, or in dimethylformamide, optionally under elevated pressure at a temperature of 0 to 100°C.

The subsequent hydrolysis is optionally carried out by any method which can remove the acetyl, ethoxycarbonyl, benzoyl or methylaminocarbonyl group which is introduced as a protecting group on the alcohol function. The process can be carried out in a solvent, for example an alcohol, in the presence of a base, for example sodium hydroxide or an alkali metal carbonate.

The amine precursor used in carrying out the above process is understood to mean compounds, for example sodium azide, which, upon condensation with a compound of general formula IV, can lead to the formation of an amine by a conventional subsequent reaction.

In the case of sodium azide, the condensation product with the compound of general formula IV is treated with 1,3-propanedithiol in the presence of an acid-binding compound, for example triethylamine.

Compounds of general formula IV, which are defined above in paragraph a), can be obtained by the action of an alkyl chloroformate on a compound of general formula I _ft :

where

R, R^, R ₂ , Rj and A are as defined above, and

Y represents a sulfur atom or a residue of the general formula II, in which Rg and R? have the above-mentioned meaning, the compound being in the E or Z configuration.

The process is usually carried out in an inert organic solvent, for example an aromatic hydrocarbon such as benzene or toluene, or in a chlorinated solvent, for example carbon tetrachloride, at a temperature of 60°C to the reflux temperature of the reaction mixture.

Compounds of general formula IV, mentioned above in paragraph b), can be obtained by the action of cyanogen bromide on a compound of general formula I^, in which R, R^, R^, R^ and A have the corresponding meaning and Y represents a sulfur atom, the compound being in the E or Z configuration.

The process is usually carried out in a chlorinated solvent, for example methylene chloride or chloroform, at a temperature in the range of 0 to 60°C.

Compounds of general formula _I can be obtained by any of the following methods;

Compounds of general formula IA, in which Y represents a radical of general formula II, in which Rg has the above meaning and R^ represents a hydrogen atom and A, R, R^ and _R2 have the above meaning with the exception of the hydrogen atom for R^ and/or _R2 , these substances occurring in the E and Z configuration can be obtained by treating with a compound of general formula V

A - CO - Rg (V) where

A and Rg have the meanings given above, on the carbanion of general formula VI

R, (VI) where the individual symbols have the above meaning except for the hydrogen atom for R^ and/or R ₂ ·

The reaction is carried out in an inert organic solvent, for example hexane, pentane, diethyl ether, 1,2-dimethoxyethane or tetrahydrofuran, or in a mixture of these solvents, at a temperature of about -30°C.

The carbanion of general formula VI can be obtained by any of the following methods, depending on the nature of the individual residues.

A) In the case where R has the above meaning except for the halogen atom and the trifluoromethyl residue and R ₃ and R ₂ have the above meaning except for the hydrogen atom for R 1 and/or R ₂ , it is possible to treat the compound of formula VII with an organometallic base

C = NNHSO ₂ - tris(VII)

R CH ₂ -R ₃ where

R ₃ has the above meaning,

R has the above meaning except for the halogen atom and tris means 2,4,6-tris-isopropylphenyl, (VIII) followed by the action of a compound of general formula VIII

where the individual symbols have the above meanings, except for the hydrogen atom for R^ and/or

R.

to form an intermediate of general formula IX where

R--CH-CH _e - N 3 5

Θ

N - N - SO ₂ tris

the individual symbols have the above meaning & with the exception of the halogen atom for R and the hydrogen atom for and/or R ₂ , and tris has the above meaning, whereupon the said intermediate of general formula IX is treated with an organometallic base, whereby after fragmentation the corresponding carbanion of general formula is obtained More

In practice, this process is preferably carried out by dissolving the compound of general formula VII in an inert solvent, for example 1,2-dimethoxyethane, then treating the solution obtained with two equivalents of butyllithium in hexane solution at a temperature in the range of -70 to -78 °C, then condensing the product of general formula VIII at a temperature of -50 °C and treating the intermediate of general formula IX with butyllithium in hexane solution at a temperature of -70 to -78 °C, then allowing the temperature to rise to approximately 0 ^° C. In this way, the carbanion of general formula VI is obtained in solution in a mixture of 1,2-dimethoxyethane and hexane _.

Compounds of general formula VII can be obtained by treating a compound of general formula X with tris-2,4,6-isopropylbenzenesulfonylhydrazine.

R where

R and R have the above meanings except for the halogen atom in the case of R, the process is carried out according to the method described in the publication by M. Ru Lipfcon. and R. H, Shapiro, J. Org. Chem., 43, 1409 (1978).

B. In the case where the symbols R, R1, _R2 and R3 are dothioic, as in formula VI, the cabanion can be obtained by the action of an organometallic base on the compound of general formula XI.

.. c =

Br ?3

C - CH.N (XI) where the individual symbols have the meaning given for the carbanion of general formula VI.

In practice, it is preferred to use butyllithium as the organometallic base in solution in hexane and to carry out the reaction in an inert organic solvent, for example in a hydrocarbon such as pentane or in an ether, for example in diethyl ether, at a temperature range of -78 to -10°C.

In this case, the carbanion of general formula VI is obtained in solution in a mixture of pentane and hexane or in a mixture of dimethyl ether and hexane.

Compounds of general formula XI can be obtained from compounds of general formula XII

ÍXII) where

R, R1, R2 and _R3 have the meanings given above for the carbanion of general formula VI, by successive treatment with phosphorus oxybromide, wiethunol, and an alkali metal borohydride, for example sodium cyanoborohydride.

Typically, the process is carried out in an organic solvent, for example methylene chloride, at a temperature of 0 to 110°C.

Compounds of formula XII can be obtained by applying or adapting the method described in H. Meerwein, W. Florian, N. Sohon and G. Stopp, Ann. Chem. 641, 1 (1961).

C) In the case where R has the above meaning except for the halogen atom and R^ and/or R? have the above meaning except for the hydrogen atom, the carbanion can be obtained by the action of an organometallic base on the compound of general formula XIII:

,_, N-NHSO-~triÍS n ^R )

R, (XIII) where

R, Rp _R2 and Rj have the meanings given above, except for the halogen atom in the case of R and in the case of the hydrogen atom for Rj and/or Rj and tris has the meaning given in general formula VII, to form an intermediate of general formula XIV

where

R, R1, _R2 , R3 and tris are as defined above, after which this intermediate is subjected to fragmentation to form the corresponding carbanion of general formula VI.

In practical implementation, the organometallic base is N-butyllithium or tert-butyllithium in solution in an aliphatic hydrocarbon, for example hexane or pentane, and the reaction is carried out in an inert organic solvent, for example 1,2-dimethoxyethane at a temperature

In this case, the corresponding carbanion of general formula IV is obtained in a mixture of 1,2-dimethoxyethane and hexane or 1,2-dimethoxyethane and pentane.

Compounds of general formula XIII can be obtained by treating a compound of general formula XV with tris-2,4,6-isopropylbenzenesulfonylhydrazine

COCH(XIII) where

R, _R2 , R3 have the above meanings, except for the halogen atom in the case of R3 and the hydrogen atom in the case of R4 and/or _R2 .

The process is usually carried out in an organic solvent, such as alcohol, in which hydrogen chloride gas is dissolved.

Compounds of general formula XV can be obtained by applying or adapting the method described in C. E. Mexwell, Org. Syntheses, Coll., Vol. III, ed. John Willey and Sons, London (1955), p. 305.

The process according to the invention makes it possible to obtain a compound of the general formula IA, in which Y*' represents a radical of the general formula II, in which R^ and R? represent a hydrogen atom, A has the meaning given above, represents a hydrogen atom, R ₂ represents a hydrogen atom or an alkyl radical, optionally substituted by an alkenyl radical of 2 to 4 carbon atoms, R represents a hydrogen atom, has the meaning given above, the compound being in the Z configuration, by opening the dihydrofuran ring in the compound of the general formula XVI

NHRj (XVI) where it has the meaning given above.

R' represents an alkyl radical, optionally substituted by an alkenyl radical of 2 to carbon atoms and

Rj has the above meaning.

Opening of the dihydrofuran ring is usually carried out by treatment with an alkali metal borohydride, for example sodium borohydride in a mixture of water and an alcohol, for example methanol and water, at a temperature in the range of 0 to 20°C, preferably at a temperature of 5°C.

In the event that the resulting product of the general formula I is to be obtained in this way, in which Y represents a residue of the general formula II, in which Rg and R^ represent hydrogen atoms, A has the meaning given above, R, R^, R ₂ represent hydrogen atoms and R^ has the meaning given above, and the resulting substance is to be in the Z configuration, it is necessary to start from a compound of the general formula XVI, in which R^ represents an alkyl residue, optionally substituted by an alkenyl residue, and then remove this residue in a known manner, for example in the manner described in the publication D. Picq, M. Cottin, D. Anker and H. Pacheco, Tet. Letters (1983), 1399.

Compounds of general formula XVI can be obtained by treating a compound of general formula XVII, which is in equilibrium with its tautomeric form:

^{0 p} -í II i ³ (RO) ₂ P - CH - CH

NR, (XVII)

About R„

II l ^J (RO) ₂ P - C = CH - NHR ₂ where

It ₃ has the above meaning,

R' represents an alkyl radical, optionally substituted by an alkenyl radical, and

R' represents an alkyl radical, preferably an ethyl radical, in a compound of general formula XVIII:

(XVIII) where 0.1 g of potassium carbonate is added. The suspension obtained is stirred for 70 hours at a temperature of approximately 20°C. The reaction mixture is filtered and then evaporated to dryness under reduced pressure of 2.7 kPa at a temperature of 40°C.

The residue obtained is dissolved in 0.2 ml of methanol. The solution is poured onto 1 g of silica gel in a column with a diameter of 5 ml. The column is washed with 3 ml of methanol, the eluate is discarded and then the column is washed with 2 ml of methanol. The corresponding eluate is evaporated to dryness under reduced pressure of 2.7 kPa at a temperature of 40 °C.

In this way, 0.006 g of 4-amino-1,2-diphenyl-2-buten-1-ol (E) is obtained in the form of a white powdery solid.

The NMR spectrum (250 MHz) of CDCl has the following maxima:

3.20 ppm (d, 2H: -CH,N . 1 ² 5.40 ppm (with, 1H : -CHON) ,1 6 ppm (t, 1H: 1' : -CH=C)

AND

6.9 ppm Ί _ Z (m, 10H: aromatic protons)

7.30 ppm J 1-Amino-4-ethoxycarbonyloxy-3,4-diphenyl-2-butene (E) can be obtained by the method described in Example 4.

Example 6

To a solution of 9.5 g of 4-chloro-1-ethoxycarbonyloxy-1-(3-fluorophenyl)-2-phenyl-2-butene (Z) in 50 ml of ethanol is added 100 ml of 33% ethanolic methylamine solution. After stirring for two hours in the absence of light, the reaction mixture is evaporated under reduced pressure of 2.7 kPa at a temperature of '30 °C, thereby obtaining an oily liquid.

This oily liquid is dissolved in 50 ml of distilled water and the solution obtained is basified to pH 11 by adding 4N sodium hydroxide solution and then extracted three times with 100 ml of ethyl ether. The organic phases are combined, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure of 2.7 kPa at 30°C to give an orange oily liquid.

This liquid is dissolved in 40 ml of ethyl acetate and then 5 ml of a 5.7 N solution of hydrogen chloride gas in ethyl ether are added. A solid is formed which is separated by filtration and recrystallized from 20 ml of acetonitrile. In this way 3 g of 1-(3-fluorophenyl)-4-methylamino-2-phenyl-2-buten-1-ol hydrochloride (Z) are obtained as a white solid with a melting point of 167 °C.

4-Chloro-1-ethoxycarbonyl-1-(3-fluorophenyl)-2-phenyl-2-butene (Z) can be obtained by the method described in Example 3 for the preparation of 4-chloro-1,2-diphenyl-1-ethoxycarbonyloxy-2-butene, but starting from 26.2 g of 1-dimethylamino-4-ethoxycarbonyloxy-4-(3-fluorophenyl)-3-phenyl-2-butene (Z) and 10.6 ml of ethyl chloroformate.

The product is chromatographed by flash chromatography using a mixture of cyclohexane and ethyl acetate in a volume ratio of 90:10 and fractions 12 to 18 are evaporated to dryness under reduced pressure of 2.7 kPa at a temperature of 30 °C, thereby obtaining 21.1 g of 4-chloro-1-ethoxycarbonyloxy-1-(3-fluorophenyl)-2-phenyl-2-butene (Z) in the form of a pale yellow oily liquid with Rf 0.5 when chromatographed using a mixture of cyclohexane and ethyl acetate in a volume ratio of 50:50.

1-Dimethylamino-4-ethoxycarbonyloxy-4-(3-fluorophenyl)-3-phenyl-2-butene hydrochloride (Z) can be obtained by the method described in Example 3 for the preparation of 4-dimethylamino-1-ethoxycarbonyloxy-1,2-diphenyl-2-butene hydrochloride (Z), but starting from 12.6 g of 4-dimethylamino-4-(3-fluorophenyl)-3-phenyl-2-buten-1-ol (Z) and 5.1 ml of ethyl chloroformate. In this way, 7.7 g of 1-dimethylamino-4-ethoxycarbonyloxy-4-(3-fluorophenyl)-3-phenyl-2-butene hydrochloride (Z) are obtained as a beige solid with a melting point of 160 °C.

Example 7

The procedure is similar to that in Example 1, but starting from 45 g of 3-chloro-1-phenyl-1-phenylthio-1-propene (Z) and 143 ml of a 33% methanol solution of methylamine, whereby, after evaporation of the reaction mixture to dryness under reduced pressure of 2.7 kPa at a temperature of 30 °C, an orange oily liquid is obtained, which is dissolved in 150 ml of ethyl acetate.

To the solution is added 18.5 ml of a 5.6 N solution of gaseous hydrogen chloride in ethyl ether. A precipitate is formed, which is separated by filtration and recrystallized from 70 ml of isopropanol. In this way, 12.8 g of 1-methylamino-3-phenyl-3-phenylthio-2-propene hydrochloride (Z) is obtained as a white solid with a melting point of 141 °C.

Example 8

To a solution of 5.1 g of 3-bromo-3-(3-chlorophenyl)-1-dimethylamino-2-propene (Z) in 50 ml of pentane, a 1.5 N solution of n-diethyllithium in hexane (20 ml) is added under a nitrogen atmosphere at a temperature of approximately -78 °C and the mixture is stirred for 25 minutes at a temperature of -50 °C. Then 4 ml of benzaldehyde in solution in 6 ml of pentane is added and the mixture is stirred for a further 30 minutes while the temperature is allowed to rise to 25 °C.

Then 80 ml of distilled water and 30 ml of 2 N aqueous hydrochloric acid are added. The aqueous phase is separated by decantation, washed three times with 25 ml of ethyl ether, neutralized with saturated aqueous sodium bicarbonate solution and then extracted three times with 50 ml of ethyl ether.

The organic phases are combined, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure of 2.7 kPa at 40 °C. The oily liquid obtained is dissolved in 30 ml of ethanol. 5.7 ml of a 5.7 N solution of gaseous hydrogen chloride in ethyl ether is added to the solution.

A solid is formed which is collected by filtration and recrystallized from 80 ml of isopropanol. In this way 3.7 g of 2-(3-chlorophenyl)-4-dimethylamino-1-phenyl-2-buten-1-ol hydrochloride (Z) are obtained as a white solid with a melting point of 199°C.

3-Bromo-3-(3-chlorophenyl)-1-dimethylamino-2-propene (Z) can be obtained in a similar manner to Example 1, but starting from 44 g of 1-(3-chlorophenyl)-3-dimethylamino-2-propen-1-one, g of phosphorus oxybromide and 7.9 g of sodium cyanoborohydride. The reaction mixture is evaporated to dryness under reduced pressure of 2.7 kPa at 30 °C to give a beige solid, which is mixed with 400 ml of chloroform.

The resulting suspension is filtered and the filtrate is evaporated to dryness under reduced pressure of 2.7 kPa at 30 °C. The product is washed with 75 ml of isopropanol, thereby obtaining 46 g of 3-bromo-3-(3-chlorophenyl)-1-dimethylamine-2-propene hydrobromide (Z) in the form of a white solid with a melting point of 146 °C.

1-(3-Chlorophenyl)-3-dimethylamino-2-propen-2-one can be obtained by the method described in U.S. Patent No. 4,209,621.

C = C - CHO (XXIV)

Where is the hall?

R and Rj have the meanings given above and

Hal means a halogen atom, for example a chlorine or bromine atom, wherein 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 an acid-binding agent, for example triethylamine, at a temperature of 0 to 20°C.

The compound of formula XXIV can be obtained by applying or adapting the method described in C. M. Beaton, N. B. Chapman and K. Klarke, J. Chem. Soc. Perkin i, 2355 (1976).

The process according to the invention makes it possible to obtain compounds of general formula IA, in which Y represents a residue of general formula II, in which R? represents a hydrogen atom, and the other symbols have the meanings given above, the compound being in the E configuration, by the action of an organomagnesium derivative of general formula XXV

MgX ₀ (XXV) where it has the above meaning and represents a halogen atom, preferably a bromine atom, to a compound of the general formula XXVI

ACC = C- C- N z' ¹ (XXVI)

OH where the individual symbols have the meanings given above.

The procedure is carried out by any method for reacting an organomagnesium derivative with an acetylene derivative without affecting the rest of the molecules.

Compounds of general formula XXVI can be obtained by treating a compound of general formula XXVII.

CO (XXVII) where

A and Rj have the meanings given above, to a propargylamine of general formula XXVIII:

where

R^ and R ₂ have the above meanings except for the hydrogen atom in the case of R^ and R _2. The reaction is usually carried out in an inert organic solvent, for example 1,2-dimethoxyethane at a temperature of -40 to 0 ° C. This reaction can be carried out, for example, by the action of an organometallic base, for example n-butyllithium in solution in hexane at a temperature of about -70 ° C.

Compounds of general formula XXVIII can be obtained by the action of an amine of general formula XXII on propargyl bromide, for example by the method described in the publication M. Gaudemar, Ann. Chim. (France) 13, 161 (1956).

By the process according to the invention, it is possible to obtain compounds of the general formula IA, in which Y represents a radical of the general formula II, in which 1<~, represents nityl, ethoxycarbonyl or benzoyl, and the other symbols have the meanings given above, by the action of a compound of the general formula XXIX

R' - Χ _Σ (XXIX) where

R 1 represents acetyl, ethoxycarbonyl or benzoyl and

X^ represents a reactive ester residue, for example halogen, in a compound of the general formula I, in which Y represents a residue of the general formula II, in which Y represents a hydrogen atom and the other symbols have the meanings given above, i.e. in a compound of the general formula xxx

(XXX).

The process is carried out by any known method for the acylation of a secondary or tertiary alcohol, for example in pyridine at a temperature in the range of 0 to 50°C or in an inert solvent, for example in a chlorinated solvent in the presence of a substance which binds the acid in the case where Xi represents a halogen atom.

It is clear that in the case where R, and/or R., represent hydrogen atoms, it is necessary to protect the amino group before the reaction of the compounds of general formula XXIX with the compound of general formula XXX. After the reaction is completed, the protected amino group is then released again. The amino group can be protected, for example, by a carbonyl group, which can be easily removed without damaging the residue Ky.

By the method according to the invention, it is possible to obtain compounds of the general formula IA, in which Y represents a residue of the general formula II, in which R 1 represents methylaminocarbonyl and the other symbols have the meanings given above, by the action of methyl isocyanate on compounds of the general formula IA, in which Y represents a residue of the general formula II, in which R 2 represents a hydrogen atom and the other symbols have the meanings given above, i.e. on compounds of the general formula XXX.

The process is carried out by any known method for preparing a carbamate from an isocyanate and an alcohol, for example the process is carried out in a chlorinated solvent, for example chloroform, at a temperature of 0°C to the reflux temperature of the reaction mixture.

It is clear that in the case where R1 and/or _R2 represent a hydrogen atom, it is necessary to protect the corresponding amino group before carrying out the reaction of methyl isocyanate with the compound of the general formula XXX. The protected amino group is then released after carrying out the basic reaction. The protection of the amino group is carried out, for example, by introducing a tert-butoxycarbonyl radical, which can be easily cleaved in a known manner without damaging the radical R2, which is introduced into the molecule during the process according to the invention.

The process according to the invention allows obtaining a compound of general formula I, in which Y represents a sulfinyl radical and the other symbols have the meanings given above, by oxidizing a compound of general formula I, in which Y represents a sulfur atom and the other symbols have the meanings given above, i.e. a compound of general formula XXXII

where the individual symbols have the meanings given above.

The oxidation can be carried out with conventional reagents used to convert sulfide to sulfoxide or sulfone, the process being carried out in an appropriate solvent without affecting the rest of the molecules.

For example, hydrogen peroxide in acetone or acetic acid, an alkali metal periodate in alcohol or acetonitrile, a carboxyl-containing peroxyacid, for example peracetic, perbenzoic, m-chloroperbenzoic, p-nitroperbenzoic or perphthalic acid, in an ether, for example dioxane or tetrahydrofuran, or in a chlorinated solvent, for example methylene chloride or dichloroethane, in acetic acid or in a mixture of the above solvents, may be used.

In the case where a sulfoxide, i.e. a compound of general formula I, in which Y represents a sulfinyl group, is to be obtained, it is particularly advantageous to carry out the process in methylene chloride in the presence of two equivalents of an oxidizing agent, preferably m-chloroperbenzoic acid at a temperature of about 0 °C, preferably in the presence of an equivalent of an inorganic acid.

It is obvious that in the case where the starting materials are to be reacted with an organometallic compound and one of these components contains an amino group, it is necessary to protect this amino group before carrying out the relevant process. The amino group is protected in this case by some of the conventional methods, for example, it is possible to react the starting material with a compound containing a cleavable silyl group, which is introduced in this way onto the amino group and is easily cleaved after the reaction.

»

The novel compounds of general formula I can be purified in a conventional manner, for example by crystallization, chromatography or sequential extraction in acidic or basic media.

In the event that the compounds of general formula I or their intermediates, which were mentioned above, exist in ^{the r} configurations E and Z in a mixture in the reaction medium, their separation can be carried out by any known method, for example by chromatography.

The novel compounds of formula I can optionally be converted into acid addition salts by reaction with an acid in an organic solvent, for example an alcohol, ketone, ester or chlorinated solvent. The salt formed precipitates, optionally after concentration of its solution, and can then be separated by filtration or decantation.

The novel compounds of general formula I and their salts have interesting pharmacological properties which allow the use of these compounds as antidepressant agents.

These compounds are particularly effective in the test for antagonism against depression induced by tetrabenazine in mice at doses of 1 to 100 mg/kg when administered ^orally .

The lethal dose of DL _5Q usually ranges from 50 to 900 mg/kg when administered orally.

Particularly valuable resulting products are the following compounds:

- 4-dimethylamino-1,2-diphenyl-2-buten-1-ol (Z)

- 4-methylamino-1,2-diphenyl-2-buten-1-ol (Z)

- 1-(3-fluorophenyl)-4-diamino-2-phenyl-2-buten-1-ol (Z)

- 1-(3-chlorophenyl)-4-dimethylamino-2-enyl-2-buten-1-ol (Z)

- 1-(3-bromophenyl)-4-dimethylamino-2-phenyl-2-buten-1-ol (Z)

- 4-dimethylamino-1-(2-methylphenyl)-2-phenyl-2-buten-1-ol (Z)

- 4-amino-1,2-diphenyl-2-buten-1-ol (Z)

- 3-(2-chlorophenylthio)-1-dimethylamino-3-phenyl-2-propene (Z)

- 2-(3-chlorophenyl)-1-(3-fluorophenyl)-4-dimethylamino-2-buten-1-ol (Z)

- 2-(3-chlorophenyl)-4-dimethylamino-1-phenyl1-2-buten-1-ol (Z)

- 1-(3-fluorophenyl)-4-methylamino-2-phenyl-2-buten-1-ol (Z)

- 3-amino-l-phenyl-l-phenylthio-1-propene (Z)

- 1-(4-chlorophenyl)-4-dimethylamino-2-phenyl-2-buten-1-ol (Z)

- 1-(4-bromophenyl)-4-dimethylamino-2-phenyl-2-buten-1-ol (Z)

- 4-acetoxy-1-dimethylamino-3,4-diphenyl-2-butene (Z)

- 4-allylamino-1,2-diphenyl-2-buten-1-ol (Z)

- 1-(2-chlorophenyl)-4-dimethylamino-2-phenyl-2-buten-1-ol (Z)

- 3-(4-fluorophenylthio)-3-phenyl~2-propene (Z)

- 1-(2-fluorophenyl)-2-phenyl-2-buten-1-ol (Z)

- 1-dimethylamino-5-methyl-3-phenyl-2-hexen-4-ol (Z)

- 1-methylamino-3"phenyl-3-phenylthio-2-propene (Z)

- 1-cyclohexyl-4.'dimethylamino-2-phenyl-2-buten-1-ol (Z)

- 4-dimethylamino-2-phenyl-1-(2-pyridyl)-2-buten-1-ol (Z)

- 4-dimethylamino-1-(4-fluorophenyl)-2-buten-1-ol (Z)

- 1-(2-chloro-6-fluorophenyl)-4-dimethylamino-2-phenyl-2-buten~1-ol (Z).

Derivatives of 2-propenamines with antidepressant activity are known from Belgian patent specification No. 781 105. However, none of the products mentioned contain the radical Y in the above-mentioned meaning in the molecule and there is no mention anywhere of how this radical is introduced into the molecule.

For medical use, the novel compounds of the general formula I are suitable as such or in the form of their pharmaceutically acceptable salts, i.e. salts which are not toxic in the doses used.

Examples of useful pharmaceutical salts may include addition salts with inorganic acids, for example hydrochlorides, sulfates, nitrates or phosphates, as well as with organic acids, for example acetates, propionates, succinates, benzoates, fumarates, maleates, methanesulfonates, isothianates, theophylline acetates, salicylates, phenolphthaleinates, methylene-bis-beta-oxynaphthoates or substituted derivatives of these compounds.

The following examples will illustrate the practical implementation of the method according to the invention.

In some examples, the compounds are purified by flash chromatography. This is a purification carried out on a short chromatographic column at a mean pressure of 50 kPa and using silica with a particle diameter of 40 to 63 µm, as described in W. C. STILL, M. KAHN and A. MITRA, J. Org. Chem. 43, 2923 (1978).,

In NMR spectral data, the letters s = singlet, d = doublet, t - triplet, and m = = multiplet.

Example 1

A total of 10.4 g of 3-chloro-1-phenyl-1-phenylthio-1-propene (Z) in crude form in solution in 40 ml of ethanol is slowly added to a solution of 41.6 ml of tert-butylamine in 100 ml of ethanol at 0 °C and the reaction mixture is then stirred for 14 hours at room temperature of 22 °C. The reaction mixture is then evaporated to dryness under reduced pressure of 2.7 kPa at 30 °C.

In this way, a yellow-orange residue is obtained, which is purified by flash chromatography, using a mixture of methylene chloride and methanol in a volume ratio of 95:5 as the eluent. Fractions 21 to 60 are combined and evaporated to dryness under reduced pressure of 2.7 kPa at a temperature of 30 °C.

In this way, a solid is obtained which is recrystallized from acetonitrile.

1.4 g of 3-phenyl-3-phenylthio-1-tert-butylamino-2-propene (Z) is obtained in the form of a white solid with a melting point of 206°C.

3-Chloro-1-phenyl-1-phenylthio-1-propene (Z) can be obtained as follows:

To a solution of 17.6 g of l-dimethylamino-3-phenyl-3-phenylthio-2-propene (Z) in 230 ml of toluene is added 9.4 ml of ethyl chloroformate. The mixture is heated for two hours and 30 minutes at 90 °C and then evaporated to dryness under reduced pressure of 2.7 kPa at a temperature of 30 °C. In this way 21.8 g of a yellow oily liquid are obtained, which contains l-chloro-3-phenyl-3-phenylthio-2-propane (Z)

21.8 g of a yellow oily liquid containing 1-chloro-3-phenyl-3-phenylthio-2-propane (z) in a mixture with dimethylethyl carbamate formed during the reaction. This pale yellow oily liquid is used for further syntheses without prior purification.

The NMR spectrum (60 MHz, CDCl^) has the following maxima:

4.5 ppm, 2H : -CH ₂ ~

6.5 ppm, 1H: -CH=

6.9 - 75 ppm, 10 H: aromatic l-Bimethylamino-3-phenyl-3-phenylthio-2-propene (Z) can be obtained as follows:

To a solution of 5 g of 3-dimethylaminoacrylophenone in 16 ml of methylene chloride is added dropwise at 0 °C 2.5 ml of phosphorus oxychloride in solution in 6 ml of methylene chloride. The mixture is stirred for 15 minutes at 0 °C and then for 30 minutes at 20 °C, after which the temperature is adjusted to 0 °C again.

The precipitate formed was dissolved by adding 5 ml of methanol. Then 8 ml of triethylamine and 3.15 ml of thiophenol in a solution of 10 ml of methylene chloride were added dropwise. The mixture was stirred for 2 hours and 30 minutes at 20°C, then 30 ml of methanol and 1 g of sodium cyanoborohydride were added at 0°C and the mixture was stirred for a further 3 hours at 20°C.

The mixture is then evaporated under reduced pressure of 2.7 kPa at 40°C. The solid obtained is dissolved in chloroform and the solution is filtered. The organic phase is evaporated to dryness under reduced pressure of 2.6 kPa at 40°C.

The residue obtained is dissolved in water and the solution is basified to pH 10 by adding 35% aqueous sodium hydroxide solution and then extracted with methylene chloride. The organic phase is dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure of 2.7 kPa at a temperature of 40°C.

The residue obtained is dissolved in 10 ml of ethyl ether. To the resulting solution is added 10 ml of a 3 M solution of gaseous hydrogen chloride in ethyl ether. A precipitate is formed, which is separated by filtration and then allowed to recrystallize from a mixture of 15 ml of ethanol and 20 ml of ethyl ether.

In this way, 3 g of 1-dimethylamino-3-phenyl-3-phenylthio-2-propene hydrochloride (Z) are obtained in the form of a white crystalline substance with a melting point of 176°C.

3-Dimethylaminoacrylophenone can be obtained by the method described in the publication by H. Meerwein,

W. Florian, N. Schon, and G. Stopp, Ann. Chem. 641 (1961).

Example 2

A solution of 17.2 g of 3-chloro-1-phenyl-1-phenylthio-1-propene (Z) in 68 ml of ethanol is added dropwise to 150 ml of a 4.2N ammonia solution in ethanol cooled to 0 °C. After stirring for 14 hours at room temperature, the reaction mixture is evaporated to dryness under reduced pressure of 2.7 kPa at 30 °C. In this way, a light yellow pasty product is obtained, which is mixed with 100 ml of ethyl acetate.

A white solid is formed which is collected by filtration and recrystallized from 250 ml of methyl ethyl ketone. In this way 3.5 g of a mixture of 75% 3-amino-1-phenyl-1-phenylthio-1-propene hydrochloride (Z) and 25% 3-amino-1-phenyl-1-phenylthio-1-propene hydrochloride (E) are obtained as a white solid with a melting point of 184 °C.

Example 3

A mixture of 0.6 g of 4-chloro-1,2-diphenyl-1-ethoxycarbonyloxy-2-butene (2) and 6 ml of 4.2 N ethanolic ammonia gas solution is heated in an autoclave for 6 hours at 100 °C and then cooled to room temperature. The reaction mixture is then evaporated to dryness under reduced pressure of 2.6 kPa at 30 °C and the residue obtained is purified by chromatography on a silica gel column using a mixture of methanol and ethyl acetate in a volume ratio of 60:40 as the eluent? 2 ml fractions are collected.

Fractions 7 to 10 are combined and evaporated to dryness under reduced pressure of 2.7 kPa at a temperature of 30 ° C. In this way, 0.1 g of 1-amino-3,4-diphenyl-4-ethoxycarbonyloxy-2-butene (Z) is obtained in the form of a light yellow oily liquid with an R _f of 0.15 using ethyl acetate and methanol in a volume ratio of 40:60.

4-Chloro-1,2-diphenyl-1-ethoxycarbonyl-2-butene can be obtained as follows:

To a solution of 1-dimethylamino-4-ethoxycarbonyloxy-3,4-diphenyl-2-butene (Z) in the form of a free substance in a solution in 30 ml of toluene is added 1.2 ml of ethyl chloroformate. The mixture is stirred for 1 hour and 30 minutes at a temperature of 90 °C and then evaporated to dryness under reduced pressure of 2.7 kPa at a temperature of 30 °C. A residue is obtained, which is chromatographed on a silica gel column using a mixture of cyclohexane and ethyl acetate in a volume ratio of 50:50, 30 ml fractions are collected.

Fractions 3 to 6 are evaporated to dryness under reduced pressure of 2.7 kPa at a temperature of 30 ° C. In this way, 1.56 g of 4-chloro-1,2-diphenyl-1-ethoxycarbonyloxy-2-butene (Z) is obtained in the form of a light yellow oily liquid of 0.5 using a mixture of cyclohexene and ethyl acetate in a volume ratio of 50:50.

1-Dimethylamino~4-ethoxycarbonyloxy-3,4-diphenyl-2-butene (Z) can be obtained from the corresponding hydrochloride prepared as follows:

To a solution of 4.4 g of 4-dimethylamino-1,2-diphenyl-2-buten-1-ol (Z) in free form in 50 ml of toluene was added 1.9 ml of ethyl chloroformate. The mixture was stirred for 3 hours at 90-95 °C and then cooled to room temperature.

A precipitate is formed which is filtered through a glass frit and then washed with isopropyl ether. In this way 3.86 g of 4-dimethylamino-1-ethoxycarbonyloxy-1,2-diphenyl butene hydrochloride (12) are obtained in the form of a white solid with a melting point of 178°C.

T-methyl-V-imino-1,2-diphenyl-2-buten-1-ol (Z) can be obtained by the following reaction.

To a solution of 24 y tris-2,4,6-Isopropylbenzenesulfonylhydrazone-acetophenone in 1,000 ml 1,2 limethoxyethbarium riéí in a nitrogen atmosphere at a temperature of -75 °C is added 83 ml of a solution of n-butyllithium in hexane at a concentration of 1.5 M. To the orange solution thus obtained is added 11.1 g N, N dimethyl hydrazine: ·> v 1 o n a ;n o < 15. um iodide.

The resulting mixture is stirred vigorously for 20 minutes at a temperature of approximately -50 °C. Then, at a temperature of approximately -75 °C, 41.5 ml of a solution of n-butyllithium in hexane with a concentration of

1.5 M. i mnn-'· j ge snovu slowly warms up to a temperature of approximately 0 °C.

From a temperature of -30°C it is possible to observe that gas is formed, the formation of gas ceases at a temperature of 0°C. The reaction mixture is cooled again to a temperature of approximately -30°C. Then 7.7 g of benzaldehyde in solution in 200 ml of 1,2-dimethoxyethane are added and the mixture is stirred for a further 2 hours at a temperature of approximately 20°C.

Then 250 ml of distilled water, 50 ml of concentrated hydrochloric acid and 300 ml of ethyl ether are added successively. The aqueous phase is separated by decantation and the organic phase is extracted with 13 ml of aqueous hydrochloric acid solution of 1 M252845

The aqueous phases are combined, basified with 10 N aqueous sodium hydroxide solution to pH 11, and the aqueous phase is extracted three times with 200 ml of ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure of 2.7 kPa at 40 °C.

A residue is obtained which is dissolved in a mixture of 140 ml of ethyl ether and 70 ml of ethanol.

To the obtained solution is added 20 ml of a solution of gaseous hydrogen chloride in ethyl ether with a concentration of

3.5 N. A solid is formed which is collected by filtration and recrystallized from acetonitrile. In this way 10 g of 4-dimethylamino-1,2-diphenyl-2-buten-1-ol hydrochloride in the Z configuration are obtained as a white powdery solid with a melting point of 178°C.

Tris-2,4,6-isopropylbenzenesulfonylhydrazone-acetophenone can be obtained by the method described in the publication: M. P. Lipton and R. H. Shapiro, J. Org. Chem., 43, 1409 (1978).

Example 4

To a solution of 0.5 g of 4-azido-1,2-diphenyl-1-ethoxycarbonyloxy-2-butene (Z) in 7.5 ml of methanol were added 1.05 ml of triethylamine and 0.74 ml of 1,3-propanedithiol. The mixture was stirred under nitrogen for 18 hours at room temperature. The reaction mixture was then poured into 10 ml of water.

It is adjusted to pH 12 with 4 N aqueous sodium hydroxide solution and then extracted three times with methylene chloride. The organic phase is dried over magnesium sulfate, filtered and evaporated under reduced pressure of 2.7 kPa at 30 °C.

The residue obtained is purified by chromatography on silica gel, using a mixture of ethyl acetate and methanol in a volume ratio of 40:60 as the eluent and 5 ml fractions are collected. Fractions 15 to 25 are evaporated to dryness under reduced pressure of 2.7 kPa at a temperature of 30 °C.

In this way, 0.168 g of 1-amino-3,4-diphenyl-4-ethoxycarbonyloxy-2-butene (E) is obtained in the form of a pale yellow oily liquid with Rf 0.15 using a mixture of methanol and ethyl acetate in a volume ratio of 60:40 as eluent.

4-Azido-1,2-diphenyl-1-ethoxycarbonyloxy-2-butene (Z) can be obtained as follows:

To a solution of 0.65 g of 4-chloro-1,2-diphenyl-1-ethoxycarbonyloxy-2-butene (Z) in 6.5 ml of N,N-dimethylformamide, cooled to 0 °C, is added 0.2 g of sodium azide and then the mixture is heated with constant stirring for 15 minutes at a temperature of 80 °C. The reaction mixture is then cooled, 10 ml of water is added to it and the mixture is extracted three times with 10 ml of methylene chloride.

The organic phase is dried over magnesium sulfate, filtered and then evaporated to dryness under reduced pressure of 2.7 kPa at 30 °C. In this way, a residue is obtained which is chromatographed on a silica gel column using a mixture of ethyl acetate and cyclohexane in a volume ratio of 30:70 as eluent, 30 ml being taken from each fraction.

Fractions 1 to 5 are combined and evaporated to dryness under reduced pressure of 2.7 kPa at a temperature of 30 °C. In this way, 0.54 g of 4-azido-1,2-diphenyl-1-ethoxycarbonyloxy-2-butenol (Z) is obtained in the form of a pale pink oily liquid with an R _f of 0.7 using a mixture of ethyl acetate and cyclohexane in a volume ratio of 30:70 as the eluent.

4-Chloro-1,2-diphenyl-1-ethoxycarbonyloxy-2-butene (Z) can be obtained by the method described in Example 3.

Example 5

To a solution of 0.02 g of 1-amino-4-ethoxycarbonyloxy-3,4-diphenyl-2-butene (E) in 1 ml of methanol

Y represents a radical of the general formula II in which R _g and R ₇ represent hydrogen atoms and

And it has the meaning given above.

The process is usually carried out in an organic solvent, for example tetrahydrofuran, in the presence of a condensing agent, for example an alkali metal hydride, at a temperature of 20 to 100°C, preferably at a temperature of about 60°C.

Compounds of formula XVII can be obtained by the method described in N. D. Dawson and A. Burger, J. Am. Chem. Soc. 74, 5312 (1952).

Compounds of general formula XVIII can be obtained by applying or adapting the methods described in the publications of L. R. Krepski, S. M. Heilmann and J. K. Rasmussen, Tet. Letters,

4075 (1983) and R.E. Koenigkramer and H. Zimmer, Tet. Letters, 1017 (1980).

The process according to the invention allows the compounds of general formula IA, in which Y represents a sulfur atom, A has the meaning given above, and the other symbols have the meaning given above with the exception of the hydrogen atom in the case of the substituents R^ and/or R ₂ , wherein the compounds occur in the Z or E configuration, by the action of a mercaptan of general formula XIV

A - SH where

A has the meaning given above for the compound of general formula XX:

(xiv)

Hall

X-© (XX) where

R, R1, _R2 and _R3 have the above meanings, except for the hydrogen atom in the case of and/or

Hal means a halogen atom, for example a chlorine or bromine atom, and

Θ

X' represents an anion, for example halide, chlorate, perchlorate, phosphate or fluoroborate.

followed by reduction of the resulting intermediate of general formula XXI:

R

where individual symbols have corresponding meanings.

(XXI)

The reaction of a compound of general formula XXX with a compound of general formula XX is usually carried out in a chlorinated solvent, in an alcohol, ether or in a mixture of these solvents in the presence of an acid-binding agent, such as triethylamine, at a temperature in the range of 0 to 20°C.

The reduction of the intermediate of formula XXI is typically carried out by treatment with an alkali metal borohydride, for example sodium borohydride or sodium cyanoborohydride, in the solvent in which the condensation of the compound of formula XIX with the compound of formula XX was carried out.

Compounds of general formula XX can be obtained by the action of a phosphorus oxyhalide on a compound of general formula XII, in which R, R1 and _R2 have the meanings given above, with the exception of the hydrogen atom for the substituents and/or R2 _. The process is usually carried out in a chlorinated solvent, for example methylene chloride, at a temperature in the range of 0 to 20 °C.

To initiate the reaction of the product of general formula XIX with the compound of general formula XX, it is not necessary to isolate the compound of general formula XX in advance. After preparing the compound of general formula XX in the above-mentioned manner, it is sufficient to add the compound of general formula XIX and the acid-binding agent to the reaction mixture, and then carry out the further reaction at a temperature of 0 to 20 °C and then reduce the intermediate of general formula XXI directly in the reaction mixture in the above-mentioned manner.

By the process according to the invention, it is possible to obtain compounds of general formula IA, in which Y represents a sulfur atom or a residue of general formula II, and the others, by the action of ammonia or an amine of general formula XXII, all have the above-mentioned meaning.

(XXII) where

R1 and _R2 have the meanings given above, for an aldehyde of the general formula XXIII

C = C - CHO ^R S - A (XXIII) where

A, R and R ₃ have the above meanings, the compound being in the Z or E configuration.

The process is typically carried out in an organic solvent, for example an alcohol such as methanol, in the presence of an alkali metal borohydride, for example sodium cyanoborohydride, and a molecular sieve at a temperature of about 20°C.

Compounds of general formula XXIII can be obtained by the action of mercaptan on the product of general formula XXIV

Example 9

By carrying out the process according to Example 1 and using the appropriate starting materials, the following compounds can be obtained:

4-diphenylamino-1,2-diphenyl-2-buten-1-ol (Z), whose hydrochloride is a white powder with a melting point of 178 °C, 1-cyclohexyl-4-dimethylamino-2-phenyl-2-buten-1-ol (Z), whose hydrochloride is a white powder with a melting point of 222 °C,

1-(4-chlorophenyl}-4-dimethylamino-2-phenyl-2-buten-1-ol (Z), the hydrochloride of which is a white powder with a melting point of 170 °C,

4-dimethylamino-1,2-diphenyl-1-methyl-2-buten-1-ol (Z), the hydrochloride of which is a white powder with a melting point of 160 °C,

1-(4-bromophenyl)-4-dimethylamino-2-phenyl-2-buten-1-ol (Z), the hydrochloride of which is a white powder with a melting point of 163 °C,

5-dimethyl-1,3-diphenyl-3-penten-2-ol, the hydrochloride of which is a white powder with a melting point of 220 °C,

4-dimethylamino-2-phenyl-1-(3-trifluoromethylphenyl-2-buten-1-ol (Z), the hydrochloride of which is in the form of white crystals with a melting point of 180 °C,

4-dimethylamino-2-(4-methylphenyl)-1-phenyl-2-buten- ¹ -ol (Z), the hydrochloride of which is in the form of white crystals with a melting point of 185 °C,

4-dimethylamino-2-phenyl-1-(3-pyridyl)-2-buten-1-ol (Z), the sesquioxalate of which is in the form of a white powder with a melting point of 195 °C,

4-dimethylamino-2-phenyl-1-(2-pyridyl)-2-buten-1-ol (Z), the sesquioxalate of which is in the form of white crystals with a melting point of 152 °C,

4-dimethylamino-2-phenyl-1-(4-pyridyl)-2-buten-1-ol (Z), whose oxalate (2.5 moles of oxalic acid per 1 mole of product) is in the form of yellow crystals with a melting point of 158 °C,

4-dimethylamino-1-(4-methoxyphenyl)-2-phenyl-2-buten-1-ol (Z), the hydrogen oxalate of which is in the form of white crystals with a melting point of 110 °C,

4-dimethylamino-2-(4-methoxyphenyl)-1-phenyl-2-buten-1-ol (Z), the hydrogen oxalate of which is in the form of white crystals with a melting point of 98 °C,

4-dimethylamino-1-(4-fluorophenyl)-2-phenyl-2-buten-1-ol (Z), the hydrogen oxalate of which is in the form of white crystals with a melting point of 125 °C,

1-(2Chloro-6-fluorophenyl)-4-dimethylamino-2-phenyl-2-buten-1-ol (Z), the hydrogen oxalate of which is in the form of white crystals with a melting point of 88 °C,

2-(4-chlorophenyl)-4-dimethylamino-1-phenyl-2-buten-1-ol (Z), the hydrochloride of which is a white powder with a melting point of 172 °C,

2-(4-chlorophenyl)-4-dimethylamino-1-(3-pyridyl)-2-buten-1-ol (Z), whose sesquioxalate is a white crystalline substance with a melting point of 187 °C,

4-dimethylamino-2-(4-fluorophenyl)-1-phenyl-2-buten-1-ol (Z), the hydrochloride of which is a white crystalline substance with a melting point of 141 °C,

1,2-diphenyl-4-piperidin-2-buten-1-ol (Z), the hydrochloride of which is a white crystalline substance with a melting point of 195 to 196 °C,

2-(4-bromophenyl)-4-dimethylamino-1-phenyl-2-buten-1-ol (Z), the hydrochloride of which is a white solid with a melting point of 178 °C,

4-dimethylamino-1,2-diphenyl-2-buten-1-ol (Z), the hydrochloride of which is a white crystalline substance with a melting point of 140 °C,

1,2-diphenyl-4-(1-pyrrolidine)-2-buten-1-ol (Z), the hydrochloride of which is a white crystalline substance with a melting point of 106 °C,

1-(3-chlorophenyl)-4-dimethylamino-2-phenyl-2-buten-1-ol (Z), the hydrochloride of which melts at 185 °C,

1-(3-fluorophenyl)-4-dimethylamino-2-phenyl-2-buten-1-ol (Z), the hydrochloride of which melts at 165 °C,

1-(2-chlorophenyl)-4-dimethylamino-2-phenyl-2-buten-1-ol (Z), which melts at 90 °C, ,

1-(3-methoxy)-4-dimethylamino-2-phenyl-2-buten-1-ol (Z), the hydrochloride of which melts at 160 °C,

1-(2,3-dimethoxyphenyl)-4-dimethylamino-2-phenyl-2-buten-1-ol (Z), which melts at 105 °C,

1,2-diphenyl-4-methylamino-2-buten-1-ol (Z) in the form of white crystals with a melting point of 90 °C,

1,2-diphenyl-4-ethylamino-2-buten-1-ol (Z) in the form of a white powder with a melting point of 82 °C,

1,2-diphenyl-4-(2-propylamino-2-buten-1-ol (Z), the hydrochloride of which is white crystals with a melting point of 188 °C,

4-butylamino-1,2-diphenyl-2-buten-1-ol (Z), the hydrochloride of which is white crystals with a melting point of 155 °C,

4-allylamino-1,2-diphenyl-1-buten-1-ol (Z), the hydrochloride of which is a white powder with a melting point of 113 °C, 1-dimethylamino-3-phenyl-3-phenylthio-2-propene (Z), the hydrochloride of which is white crystals with a melting point of 176 °C, 1-dimethylamino-3-phenyl-3-phenylthio-2-propene (E), the hydrochloride of which is a white solid with a melting point of 146 to 147 °C,

3-(4-chlorophenylthio)-1-dimethylamino-3-phenylthio-2-propene, the hydrochloride of which is a white powder with a melting point of 226 °C, 1-dimethylamino-3-phenyl-3-(4-pyridylthio)-2-propene (Z), the sesquioxalate of which is white crystals with a melting point of 173 °C,

3-(4-chlorophenyl)-1-dimethylamino-3-phenylthio-2-propene (Z), the oxalate of which is white crystals with a melting point of 183 °C, 1-dimethyl-3-(4-fluorophenyl)-3-phenylthio-2-propene (E), the hydrochloride of which is a white solid with a melting point of 160 °C, 1-dimethylamino-4-(4-fluorophenylthio)-3-phenyl-2-propene (Z), the oxalate of which is a white solid with a melting point of 163 °C,

3-(4-bromophenyl)-1-dimethylamino-3-phenylthio-2-propene (E), the hydrochloride of which is white crystals with a melting point of 187 °C,

3-(4-bromophenylthio)-1-dimethylamino-3-phenyl-2-propene (Z), the hydrochloride of which is a white solid with a melting point of 252 °C, 1-dimethylamino-3-phenyl-3-phenylthio-2-propene (Z), the hydrochloride of which is white crystals with a melting point of 176 °C,

4-dimethylamino-1,2-diphenyl-2-buten-1-ol (E) as white crystals with a melting point of 113 °C,

4-benzoyl-1-dimethylamino-3,4-diphenyl-2-butene (Z), whose oxalate melts at 170 °C

4-acetoxy-1-dimethylamino-3,4-diphenyl-2-butene (Z), whose oxalate melts at 156 °C

4-dimethylamino-1-ethoxycarbonyloxy-1,2-diphenyl-2-butene (Z), the hydrochloride of which is a white solid with a melting point of 178 °C,

3-phenyl-3-phenylthio-1-tert.butylamino-2-propene (Z) with a melting point of 206 °C, 1-dimethylamino-4-methylcarbamoyloxy-3,4-diphenyl-2-butene (Z), whose oxalate melts at a melting point of 194 °C,

4-amino-1,2-diphenyl-2-buten-1-ol (Z) as a white solid with the following NMR spectrum:

(250 MHz, what ₃ ) 3.35 pp«i 2H ·. -ch ₂ nh ₂ ) 5.75 1H ·. -CHOH-) 5.90 ppm to go, 1H : -CH=) 7.25 7.40 ppiti ppm 10H : aromatic protons)

4-dimethylamino-1-(2-fluorophenyl)-2-phenyl-2-buten-1-ol (Z), the hydrochloride of which is a white powder with a melting point of 175 °C,

1-(3-bromophenyl)-4-dimethylamino-2-phenyl-2-buten-1-ol (Z), the hydrochloride of which is a white solid with a melting point of 188 °C,

4-dimethylamino-1-(2-methylphenyl)-2-phenyl-2-buten-1-ol (Z), the hydrochloride of which is a white powder with a melting point of 204 °C, d-dimethylamino-1-(2-methoxyphenyl)-2-phenyl-2-buten-1-ol (Z) as a white powder with a melting point of 77 °C,

4-dimethylamino-2-(3-methoxyphenyl)-1-phenyl-2-buten-1-ol (Z), whose hydrochloride is a white solid with a melting point of 166 °C, /52845 l-cyclopropyl-4-dimethylamino-2-phenyl-2-buten-1-ol (Z), whose oxalate is a white powder with a melting point of 127 °C, l-dimethylamino-5-methyl-3-phenyl-2-hexen-4-ol (Z), whose hydrochloride is a white powder with a melting point of 163 °C,

4-dimethylamino-1,2-diphenyl-3-methyl-2-buten-1-ol (Z), the hydrochloride of which is a white powder with a melting point of 212 °C,

3-(2-chlorophenylthio)-1-dimethylamino-3-phenyl-2-propene (Z), the hydrochloride of which is a white solid with a melting point of 162 °C,

3-(3-chlorophenylthio)-1-dimethylamino-3-phenyl-2-propene (Z), the hydrochloride of which is a white solid with a melting point of 156 to 157 °C,

1-dimethylamino-3-(4-methylphenylthio)-3-phenyl-2-propene (Z), the hydrochloride of which is a white solid with a melting point of 197 to 198 °C,

2-(3-chlorophenyl)-1-(3,5-dichlorophenyl)-4-dimethylamino-2-buten-1-ol (Z), the hydrochloride of which is a white solid with a melting point of 215 °C,

2-(3-chlorophenyl)-4-dimethylamino-1-(3-fluorophenyl)-2-buten-1-ol (Z), the hydrochloride of which is a white solid with a melting point of 200 °C,

2-(2-chlorophenyl)-4-dimethylamino-1-phenyl-2-buten-1-ol (Z), the hydrochloride of which is a white solid with a melting point of 168 °C and

4-amino-1,2-diphenyl-2-buten-1-ol (Z), the hydrochloride of which is a white powder with a melting point of 180 °C.

Example 10

A total of 4.7 g of m-chloroperbenzoic acid was added to a solution of 6 g of l-dimethylamino-3-phenyl-3-phenylthio-2-propene hydrochloride (Z) in 68 ml of dichloromethane at 0 °C. After stirring for 24 hours at 20 °C, another 4.7 g of m-chloroperbenzoic acid was added and the mixture was stirred for a further 3 hours. The reaction mixture was then poured into 100 ml of water.

The solution is adjusted to pH 10 by adding 35% aqueous sodium hydroxide solution and then extracted with methylene chloride. The organic phase is decanted, dried over sodium sulfate, filtered and then evaporated to dryness under reduced pressure of 2.7 kPa at 40 °C. In this way, a residue is obtained which is dissolved in 10 ml of ethanol.

To the solution was added 6 ml of a 3N solution of hydrogen chloride gas in ethyl ether, and the precipitated solid was collected by filtration and recrystallized from a mixture of 60 ml of ethanol and 5 ml of acetonitrile. In this way, 2 g of 1-dimethylamino-3-phenyl-3-phenylsulfinyl-2-propene hydrochloride (Z) were obtained as a white crystalline substance with a melting point of 268 °C with decomposition.

1-Dimethylamino-3-phenyl-3-phenylthio-2-propene hydrochloride (Z) can be obtained by the method of Example 9.

Claims (3)

SUBJECT OF THE INVENTION A process for the preparation of novel 3-phenyl-2-propenamine derivatives of the general formula I (I) wherein R represents a hydrogen atom, a halogen atom, an alkyl radical or an alkoxy group, R ₃ is hydrogen or methyl, and R _{2 is the} same or different is hydrogen or an alkyl radical optionally substituted by a C 2 -C 4 alkenyl radical, or forms R 1 and R ₂ together with the nitrogen atom to which they are attached; -pyrrolidinyl or piperidino residue, A is an alkyl or phenyl radical optionally substituted by one or two substituents selected from the group consisting of halogen, alkyl, alkoxy or trifluoromethyl, or A is pyridyl, benzyl or cycloalkyl of 3 to 6 carbon atoms, Y represents a sulfur atom, a sulfinyl radical or a radical of formula II AND Rg-c-0R _? (II) where R 8 is hydrogen or methyl and is hydrogen, acetyl, ethoxycarbonyl, methylaminocarbonyl or benzoyl, wherein the alkyl groups and the alkyl portions of the other groups have a straight or branched chain and contain 1 to 4 carbon atoms, unless otherwise specified, and salts thereof pharmacologically acceptable compounds and geometric and optical isomers and mixtures thereof, characterized in that they are treated with ammonia, an amine precursor or an amine of the formula (III): R 1 and R ₂ are as defined above for a compound of formula IV wherein A and R are as defined above and (a) X represents a chlorine atom and Y znamená means a sulfur atom or a radical of formula II in which R 8 and R 8? are as defined above except for a hydrogen atom for R 2, or (b) X represents a bromine atom and Y 'is a sulfur atom wherein the compound of formula IV is in the E or Z configuration, then optionally hydrolyzing the resulting product to obtain a compound of formula I wherein γ is a radical of formula II wherein R is is hydrogen and the other symbols are as defined above, then the resulting product is isolated and optionally converted to a pharmaceutically acceptable salt or, when Y is sulfur, optionally oxidized to another compound of formula I wherein Y is sulfinyl and the other symbols are as defined above, then the resulting product is isolated and optionally converted into a pharmaceutically acceptable salt, or the optional compounds are separated into geometric or optical isomers or converted into a mixture thereof. 2. The process according to item 1, for the preparation of 3-phenyl-2-propenamine of the general formula I (I) wherein R represents a hydrogen atom, a halogen atom, an alkyl or alkoxy radical, R 6 represents a hydrogen atom, R 1 and R ₂ , the same or different, are hydrogen or alkyl optionally substituted by C 2 -C 4 alkenyl or form R 1 and R ₂ together with the nitrogen atom to which they are attached a 1-pyrrolidinyl or piperidine radical, A is phenyl optionally substituted by one or two substituents selected from the group consisting of halogen, alkyl, alkoxy or trifluoromethyl or A is pyridyl, benzyl or cycloalkyl of 3 to 6 carbon atoms, Y represents a sulfur atom, a sulfinyl radical or a radical of formula II Rg-c-OR _? where R 8 represents a hydrogen atom or methyl a R _? represents a hydrogen atom, acetyl, ethoxycarbonyl, methylaminocarbonyl or benzoyl, wherein the alkyl radicals and the alkyl portions of the other radicals have a straight or branched chain and contain 1 to 4 carbon atoms, unless otherwise indicated, as well as pharmaceutically acceptable salts, geometric and optical isomers and mixtures thereof, characterized in that they are treated with ammonia, an amine precursor or an amine of formula III HN where R 6 and R 6 are as defined above for a compound of formula IV wherein A and R are as defined above and (a) X represents a chlorine atom and Y 'is a sulfur atom or a radical of formula (II) wherein R R and R? Are hydrogen; are as defined above except for a hydrogen atom for R 2, or (b) X represents a bromine atom and Y is a sulfur atom wherein the compound of formula IV is in the E or Z configuration, then optionally hydrolyzing the resulting product to obtain a compound of formula I wherein Y is a radical of formula II wherein R? is hydrogen and the other symbols are as defined above, then the resulting product is isolated, optionally converted into a pharmaceutically acceptable salt, or, when Y is sulfur, optionally oxidized to another compound of formula (I), wherein Y is a sulfinyl radical and the affinity symbols are as defined above, then isolating the resulting product and optionally leading to a pharmaceutically acceptable salt, or optionally separating the 2-bis compounds into geometric or optical isomers or converting them into mixtures thereof. 3. The process according to claim 1, wherein the J-phenyl-P is prepared using the appropriate starting materials. R is methyl, Znamená represents alkyl having 1 to 4 carbon atoms and the other symbols have the meaning given in 1.