WO1988009785A1

WO1988009785A1 - Butenoic acid amides, their salts, pharmaceutical compositions containing them and process for preparing same

Info

Publication number: WO1988009785A1
Application number: PCT/HU1988/000041
Authority: WO
Inventors: János Fischer; László Dobay; György FEKETE; Elemér Ezer; Judit Matuz; László Szporny
Original assignee: Richter Gedeon Vegyészeti Gyár RT
Priority date: 1987-06-10
Filing date: 1988-06-10
Publication date: 1988-12-15
Also published as: HU198294B; HUT47899A; CN1030229A

Abstract

The present invention relates to novel compounds of general formula (I), wherein R stands for hydrogen, halogen, C1-4alkyl, C1-4 alkoxy or (C1-4acyl)amino group; R1 means straight or branched chain C1-6 alkylene group optionally substituted by a mercapto, hydroxyl, C1-3 alkylthio or phenyl or indolyl group, wherein the phenyl group optionally may in itself be substituted by halogen or hydroxyl group and the indolyl group optionally may in itself be substituted by halogen; and R2 stands for hydrogen or C1-4 alkyl group of E and/or Z configuration as well as their salts. The compounds according to the invention show a cytoprotective effect and their toxicity is low.

Description

BUTENOIC ACID AMIDES, THEIR SALTS, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND PROCESS FOR PREPARING SAME

The invention relates to novel 4-oxo-4-

-(substituted phenyl)butenoic acid amides of E and/or Z configuration having a cytoprotective action.

Several compounds, standing near to these compounds concerning both their type of activity and chemical structure, have been described in the

British patent specification No. 2,096,999. One of the most effective compounds claimed in this cited patent specification was found to be 4-oxo-4-(3,4,5-tri- methoxyphenyl)butenoic acid prepared by dehydrating the product obtained from the aldol condensation of

3,4,5-trimethoxyacetophenone with glyoxylic acid. The yield of the aldol reaction amounted to 28%, that of the dehydration to 71%, which means a total yield of only 20%. The aim of the present invention is to find novel, therapeutically useful compounds which can be prepared in a good yield from simple, commercially available starting substances.

Thus, the present invention relates to novel compounds of the general formula (I),

wherein R stands for hydrogen, halogen, C_1-4alkyl, C_1-4- alkoxy or (C_1-4acyl)amino group; R₁ means straight or branched chain C_1-6 alkylene group optionally substituted by a mercapto, hydroxyl, C_1-3 alkylthio or phenyl or indolyl group, wherein the phenyl group optionally may in itself be substituted by halogen or hydroxyl group and the indolyl group optionally may in itself be substituted by halogen; and

R₂ stands for hydrogen or C_1-4 alkyl group of E and/or Z configuration as well as their salts and pharmaceutical compositions containing these compounds The compounds of the general formula (I) contain a double bond thus, they can exist in the form of the E or Z geometrical isomer.

When a chiral centre is present in the amino acid moiety of the compounds of general formula (I), the general formula (I) may represent any of the enantiomers or a mixture containing these enantiomers in an optional ratio.

According to an other aspect of the invention, there is provided a process for the preparation of the new compounds of the general formula (I) of E and/or Z configuration, wherein

R stands for hydrogen, halogen, C_1-4alkyl, C_1-4- alkoxy or (C_1-4 acyl)amino group; R₁ means straight or branched chain C_1-6 alkylene group optionally substituted by a mercapto, hydroxyl, C_1-3 alkylthio or phenyl or indolyl group, wherein. the phenyl group optionally may in itself be substituted by halogen or hydroxyl group and the indolyl group optionally may in itself be substituted by halogen; R₂ stands for hydrogen or C_1-4 alkyl group and salts thereof, which comprises reacting a compound of the general formula (II)

H₂N- R₁-COOR₃ ( I I ) wherein R ¹ is as def ined above and R ³ means a C_1-4 alkyl group or an acid addition salt thereof, with a substituted butenoic acid of the general formula (III)

(III)

wherein R is as defined above, or with a carboxylic group-activated derivative thereof and, if desired, removing any optionally present protective group in a known manner and/or, if desired, changing in the obtained compound of the general formula (I) the configuration, determined by the double bond, in a known way.

The compounds of the general formula (I), wherein R₂ is hydrogen, can be converted to salts by using pharmaceutically acceptable organic or inorganic bases.

The starting materials are commercially available or can be prepared by methods described in the literature. Thus, the preparation of 4-oxo- -4-phenyl-2(E)-butenoic acid was described in Org. Synth. Coll. Vol. 3 , 109 (1955); 4-(4-methylphenyl)-4- -oxo-2(E)-butenoic acid was prepared according to Pechman [Berichte 15, 888 (1982)] whereas 4-(4- -methoxy-phenyl)-4-oxo-2(E)-butenoic acid was synthetized according to Papa et al. [3. Am. Chem. Soc, 70, 3356 (1948)]. The aminoesters of the general formula (II) were prepared as described in: Houben-Weyl: "Methoden der organischen Chemie", Vol. 15/1, pp. 316-340, G. Thieme Verlag, Stuttgart 1974. It has been found in the course of our investigations that the reaction of the starting substances could be carried out in a yield of 40 to 70%.

In the process of the present invention, a substituted butenoic acid of the general formula (III) or a carboxylic group-activated derivative thereof, which may have E or Z configuration on basis of the geometry of the double bond, is reacted with an amino acid derivative of the general formula (II) in an inert organic solvent. Activated derivatives of the compounds of general formula (III) are their esters, acid halides or acid anhydrides or a derivative formed with an activating reagent each of which can be prepared in a manner known per se. Carbodiimides such as dicyclohexylcarbodiimide may preferably be used as activating reagents. When dicyclohexylcarbodiimide is used, the reaction is preferably carried out in anhydrous dichloromethane as inert organic solvent at a temperature between 0 °C and 20 °C. Diphenylphospinyl chloride may also be employed as activating agent preferably in ethyl acetate as an inert organic solvent at -10 °C as described in the literature (Houben-Weyl as cited above, Vol. E5, p. 949, 1985) by adding a stoichiometric amount of a base, preferably triethylamine or N-methylmorpholine to the reaction mixture for binding the hydrogen chloride formed.

If desired, the E and Z isomers of the compounds of the general formula (I) can be converted into each other under the effect of e.g. UV light in the presence of an inert organic solvent. The compounds of the general formula (I) contain ing hydrogen as R₂ are prepared in such a way that any group, which is bound in the carboxylic group and is different from hydrogen, is removed in a known way, e.g. by using trifluorocacetic acid. In the course of our pharmacological study, ethyl N-(4-oxo-4-phenyl-2(E)-butenoyl)- β -alaninate and related compounds proved to possess cytoprotective action which could be demonstrated by using the method of A. Robert [Gastroenterology 77, 761 ( 1919)] as follows.

Starved rats were given absolute ethanol containing concentrated hydrochloric acid which induced longitudinal bleedings, in the glandular part of the stomach within a short time. This damaging effect is prevented by cytoprotective substances. The oral

ED₅₀ values of the compounds according to the invention proved to be 2 to 3 mg/kg. In addition, their toxicity values were also very favourable since no toxic symptoms were observed after the single oral administration of 1000 mg/kg of body-weight.

The invention is illustrated in detail by the following non-limiting Examples. Example 1

Preparation of ethyl N-[4-oxo-4-phenyl-2(E)- -butenoyl]- β -alaninate

A suspension containing 3.0 g (17 mmol) of 4-oxo-4-phenyl-2(E)-butenoic acid and 2.61 g (17 mmol) of ethyl β -alaninate hydrochloride in 50 ml of abs. dichloromethane is cooled to 0 °C, 1.72 g (17 mmol) of N-methylmorpholine are added and after stirring for 5 minutes, 3.50 g (17 mmol) of dicyclohexylcarbodiimide are added to the reaction mixture. The heterogeneous mixture is stirred at 0 °C for 30 minutes, then at room temperature for one hour. The precipitated dicyclohexylurea is filtered and the solution is extract ed twice with 15 ml of 1N hydrochloric acid each, then with 15 ml of water and twice with 15 ml of 10% aqueous sodium carbonate solution each and finally with 15 ml of water. The organic phase is dried over anhydrous magnesium sulfate and evaporated . After crystallizing the residue from ethyl ether, a yield of 2.20 g (47%) of the title compound is obtained, m.p.: 69-70 °C. Example 2

Preparation of ethyl N -4[-oxo-4-phenyl-2(E)- -butenoyl]-γ-aminobutyrate

A suspension containing 3.0 g (17 mmol) of 4- -oxo-4-phenyl-2(E)-butenoic acid and 2.85 g (17 mmol) of ethyl γ-aminobutyrate hydrochloride in 50 ml of dichloromethane is cooled to 0 °C, 1.72 g (17 mmol) of N-methylmorpholine are added and after stirring for 5 minutes a solution of 3.50 g (17 mmol) of dicyclohexyl carbodlimide in 10 ml of dichloromethane is added to the reaction mixture. After stirring at 0 °C for 30 minutes and at room temperature for one hour, the precipitated dicyclohexylurea is filtered and the filtrate is extracted twice with 15 ml of 1N hydrochloric acid each, with 15 ml of water, then twice with 15 ml of saturated aqueous sodium carbonate solution each and finally with 15 ml of water. The organic phase is dried over anhydrous magnesium sulfate. then the solvent is evaporated. The residue is crystallized from ethyl ether to give 2.05 g (42%) of the title compound, m.p.: 56-57 ºC.

Analysis: calculated: C 66.42; H 6.62; N 4.84%; found: C 66.56; H 6.75; N 5.04%.

Example 3

Preparation of ethyl N-[4-oxo-4-phenyl-2(E)- -butenoyl]-(S)-alaninate

To the solution containing 3.52 g (20 mmol) of 4-oxo-4-phenyl-2(E)-butenoic acid In 50 ml of dichloromethane 3.07 g (20 mmol) of ethyl (S)-alaninate hydrochloride are added. After cooling this suspension to 0 ºC, 2.02 g (20 mmol) of N-methylmorpholine are added and after stirring for 5 minutes, a solution of 4.12 g (20 mmol) of dicyclohexylcarbodiimide in 10 ml of dichloromethane are added dropwise. The mixture is stirred at 0 ºC for 30 minutes and then at room temperature for one hour. After filtering the precipitated dicyclohexylurea, the filtrate is extracted twice with 15 ml of 1N hydrochloric acid each, twice with 15 ml of water each, then twice with 15 ml of 10% aqueous sodium carbonate solution each and finally with 15 ml of water. After drying the organic phase over anhydrous magnesium sulf ate and evaporating the solvent, the residue is crystallized from ethyl ether to give 2.20 g (40%) of the title compound, m.p.: 84-85 °C, [ α ]p -49.9° (C=2, methanol).

Analysis: calculated: C 65.44; H 6.22; N 5.08%; found: C 65.39; H 6.50; N 5.10%. Example 4

Preparation of N-[4-oxo-4-phenyl-2(E)-butenoyl]- (S)-alanine

1.64 gg (11.3 mmol) of tert-butyl (S)-alaninate are added to the solution of 2.0 g (11.3 mmol) of 4-oxo-4-phenyl-2(E)-butenoic acid in 20 ml of anhydrous dichloromethane and the solution is cooled to 0 °C. After dropwise adding 2.34 g (11.3 mmol) of dicyclohexylcarbodiimide dissolved in 10 ml of abs. dichloromethane, the reaction mixture is stirred at 0 ºC for 30 minutes and at room temperature for one hour. After filtering the precipitated dicyclohexylurea, the filtrate is extracted twice with 15 ml of IN hydrochloric acid each, then with 15 ml of water, twice with 15 ml of saturated aqueous sodium carbonate solution each and finally with 15 ml of water. The organic phase is dried over anhydrous magnesium sulfate and the solvent is evaporated. The oily residue is dissolved in 20 ml of dichloromethane and 20 ml of trifluoroacetic acid are added dropwise to the solution while cooling. After allowing to warm the solution to room temperature (about 2 hours), the solvent Is evaporated and the oily residue is crystallized by using ethyl acetate to give 1.30 g (47%) of the title compound, m.p.: 165-167 ºC, [ α ] -32° (c=2, methanol).

Example 5

Preparation of methyl N-[4-oxo-4-phenyl-2(E)- -butenoyl]-(S)-methioninate

3.99 g (20 mmol) of methyl (S)-methioninate hydrochloride are added to the solution of 3.52 g (20 mmol) of 4-oxo-4-phenyl-2(E)-butenoic acid in 40 ml of anhydrous dichloromethane. After cooling the solution to 0 °C, 2.02 g (20 mmol) of N-methylmorpholine and then 4.12 g (20 mmol) of dicyclohexylcarbodiimide dissolved in 15 ml of dichloromethane are added drop- wise, then the mixture is stirred at 0 °C for 30 minutes and at room temperature for one hour. After filtering the precipitated dicyclohexylurea, the filtrate is extracted twice with 15 ml of 1N hydrochloric acid each, then with 15 ml of water, twice with 15 ml of 10% aqueous sodium carbonate solution each and finally with 15 ml of water. After drying the organic phase over anhydrous magnesium sulfate and evaporating the solvent, the oily residue is crystallized with ethyl ether to yield 3.60 g (56%) of the title compound, m.p.: 77-79 °C, [ α ] -36.8° (c=2,

methanol).

Analysis: calculated: C 59.79; H 5.96; N 4.35%; found: C 59.81; H 5.95; N 4.32%. Example 6

Preparation of ethyl N-[4-oxo-4-phenyl-2(E)- -butenoyl]-S-benzyl-(S)-cysteinate

A suspension of 1.97 g (11.2 mmol) of 4-oxo-4- -phenyl-2(E)-butenoic acid and 3.08 g (11.2 mmol) of ethyl S-benzyl-(S)-cysteinate hydrochloride in 50 ml of anhydrous dichloromethane is cooled to 0 ºC, 1.13 g (11.2 mmol) of N-methylmorpholine and then 2.31 g (11.2 mmol) of dicyclohexylcarbodiimide are added. After stirring at 0 °C for 30 minutes, then at room temperature for one hour the precipitated dicyclohexylurea is filtered and the filtrate is extracted first twice with 15 ml of 1N hydrochloric acid each, then with 15 ml of water, twice with 15 ml of saturated aqueous sodium carbonate solution each and finally with 15 ml of water. After drying the organic phase over anhydrous magnesium sulfate and then evaporating the solvent, the residue is crystallized from ethyl ether to yield 2.00 g (45%) of the title product, m.p.: 86-88 °C, [ α ]

p -81.3° (c=2, methanol).

Analysis: calculated: C 66.47; H 5.83; N 3.52%; found: C 66.01; H 5.88; N 3.73%. Example 7

Preparation of ethyl N-[4-(4-methylphenyl)-4- -oxo-2(E)-butenoyl]-(S)-alaninate

A suspension of 3.80 g (20 mmol) of 4-(4-methyl- phenyl)-4-oxo-2(E)-butenoic acid and 3.07 g (20 mmol) of ethyl (S)-alaninate hydrochloride in 60 ml of dichloromethane is cooled to 0 ºC and first 2 .02 g (20 mmol) of N-methylmorpholine and then 4.12 g (20 mmol) of dicyclohexylcarbodiimide are added. After stirring the mixture at 0 ºC for 30 minutes and then at room temperature for one hour, the precipitated dicyclohexylureai is filtered and the filtrate is washed twice with 15 ml of 1N hydrochloric acid each, then with 15 ml of water, twice with 15 ml of saturated aqueous sodium carbonate solution each and finally with 15 ml of water. After drying the organic phase over anhydrous magnesium sulfate and evaporating the solvent, the residue is crystallized from ethyl ether to give 2.30 g (40%) of the title compound, m.p.: 106-108 °C, [ α ]

p -54° (c=1, methanol). Analysis: calculated: C 66.42; H 6.62; N 4.84%; found: C 65,98; H 6,56; N 4.65%. Example 8

Preparation of ethyl N-[4-(4-methoxyphenyl)- -4-oxo-2(E)-butenoyl]-(S)-alaninate

To a solution containing 4.12 g (20 mmol) of 4-(4-methoxyphenyl)-4-oxo-2(E)-butenoic acid in 40 ml of anhydrous dichloromethane, 3.07 g (20 mmol) of ethyl (S)-alaninate hydrochloride are added. After cooling to 0 °C 2.02 g (20 mmol) of N-methylmorpholine and then 4.12 g (20 mmol) of dicyclohexylcarbodiimide dissolved in 15 ml of anhydrous dichloromethane are added. The mixture is stirred at 0 °C for 30 minutes, at room temperature for one hour, then the precipitated dicyclohexylurea is filtered. The filtrate is extracted twice with 15 ml of 1N hydrochloric acid each, then with 15 ml of water, twice with 15 ml of saturated aqueous sodium carbonate solution each and finally with 15 ml of water. After drying the organic phase over anhydrous magnesium sulfate and evaporating the solvent, the residue is crystallized from ethyl ether to yield 2.56 g (42%) of the title compound, m.p.: 103-106 °C, [α ]- £ -56.6° (c=2, methanol).

Analysis: calculated: C 62,94; H 6.27; N 4.58% ; found: C 62.47; H 6.11; N 4.78%.

Example 9

Preparation of ethyl N-[4-(4-methoxyphenyl)-4- -oxo-2(E)-butenoyl]- β -alaninate A suspension containing 3.50 g (17 mmol) of 4- -(4-methoxyphenyl)-4-oxo-2(E)-butenoic acid and 2.6 g (17 mmol) of ethyl β-alaninate hydrochloride in 40 ml of anhydrous dichloromethane is cooled to 0 ºC and first 1.72 g (17 mmol) of N-methylmorpholine and then 3.5 g (17 mmol) of dicyclohexylcarbodiimide are added. After stirring the mixture at 0 °C for 30 minutes and then at room temperature for one hour, the precipitated dicyclohexylurea is filtered and the filtrate is extracted twice with 15 ml of IN hydrochloric acid each, then with 15 ml of water, twice with 15 ml of saturated aqueous sodium carbonate solution each and finally with 15 ml of water. After drying the organic phase over anhydrous magnesium sulfate and evaporating the solvent, the residue is crystallized from ethyl ether to give 3.30 g (64%) of the title compound, m.p.: 86-88 °C.

Analysis: calculated: C 62,94; H 6.27; N 4.58%; found: C 62.45; H 6.24; N 4.66%. Example 10

Preparation of ethyl N-[4-(4-chlorophenyl)- -4-oxo-2(E)-butenoyl]- β -alaninate

4.21 g (20 mmol ) of 4-(4-chlorophenyl)-4- -oxo-2(E)-butenoic acid and 3.07 g (20 mmol) of ethyl -β-alaninate hydrochloride is dissolved in 60 ml of anhydrous dichloromethane. The suspension is cooled to 0 °C, 2.02 g (20 mmol) of N-methylmorpholine and after a few minutes 4.12 g (20 mmol) of dicyclohexylcarbodiimide are added. After stirring the mixture at 0 ºC for 30 minutes and then at room temperature for one hour, the precipitated dicyclohexylurea is filtered and the filtrate is extracted twice with 15 ml of 1N hydrochloric acid each, then with 15 ml of water, twice with 15 ml of 10% aqueous sodium carbonate solution each and finally with 15 ml of water. After drying the organic phase over anhydrous magnesium sulfate and evaporating the solvent, the oily residue is crystalized by using ethyl ether to give 3.10 g (50%) of the title compound, m.p.: 112-114 °C. Analysis: calculated: C 58.16; H 5.20; N 4.52; Cl:11.44%; found: C 58.05; H 5.35; N 4.69; Cl: 11.10%. Preparation of the starting material Preparation of 4-(4-chlorαphenyl)-4-oxo-2(E)- -butenoic acid To a solution of 17.0 g (0.172 mol) of maleic anhydride in 100 ml of chlorobenzene, 50.45 g (0.378 mol) of anhydrous aluminium chloride are added in five equal portions. The suspension is heated at 80 °Cfor 8 hours, then poured onto the mixture of 200 g of ice and 25 ml of concentrated hydrochloric acid. After decomposing the complex, the desired product is extracted four times with 50 ml of dichloromethane each, the organic phase is washed with 50 ml of water, filtered through a celite pad and the solvent is evaporated under reduced pressure. After crystallizing the residue from toluene, the title product is obtained in a yield of 21.70 g (60%), m.p.: 159-161 °C. Analysis: calculated: C 57.03; H 3.34; Cl: 16.83%; found: C 56,97; H 3.45; Cl: 16.55%. Example 11

Preparation of ethyl N-[4-(4-methoxyphenyl)- -4-oxo-2(Z)-butenoyl]-(S)-alaninate

To a soltuion containing 4.12 g (20 mmol) of 4- -(4-methoxyphenyl)-4-αxo-2(Z)-butenoic acid in 50 ml o abs. dichloromethane, 3,07 (20 mmol) of ethyl (S)- -alaπiπate hydrochloride are added. The mixture is cooled to 0 °C, 2.02 g (20 mmol) of N-methylmorpholine are added and then 4.12 g (20 mmol) of dicyclohexylcarbodiimide dissolved in 20 ml of anhydrous dichloro- methane are added dropwise. After stirring the reaction mixture at 0 °C for 2 hours and filtering the precipitated dicyclohexylurea, the filtrate is extracted twice with 20 ml of IN hydrochloric acid each, then with 20 ml of water, twice with 20 ml of saturated aqueous sodium carbonate solution each and finally with 20 ml of water. After drying the organic phase over anhydrous magnesium sulfate and evaporating the solvent, the oily residue is crystallized from a mixture of ethyl ether and n-hexane to yield 3.12 g (52%) of the title compound, m.p.: 74-76 °C, [ α -58.6° (c=1,

methanol).

Example 12

Preparation of ethyl N-[4-(4-methoxyphenyl)- -4-oxo-2(Z)-butenoyl]-(S)-alaninate A solution containing 1.0 g (3.2 mmol) of ethyl

N-[4-(4-methoxyphenyl)-4-oxo-2(E)-butenoyl]-(S)- -alaninate in 100 ml of acetone is irradiated by UV light at room temperature for 3 hours while stirring. Then the solvent is evaporated and the residue is crystallized from a mixture of ethyl ether and n-hexane to yield 0.82 g (82%) of the title compound, m.p.: 74-76 °C, [ α ] -58.6° (c=1, methanol).

Claims

C L A I M S 1 . 4-oxo-4-( substituted phenyl)butenoic acid amides of the general f ormula ( I )

( I)

wherein R stands for hydrogen, halogen, C_1-4alkyl, C_1-4- alkoxy or (C_1-4acyl)amino group; R₁ means straight or branched chain C_1-6 alkylene group optionally substituted by a mercapto, hydroxyl, C_1-3 alkylthio or phenyl or indolyl group, wherein the phenyl group optionally may in Itself be substituted by halogen or hydroxyl group and the indolyl group optionally may in itself be substituted by halogen; and R₂ stands for hydrogen or C_1-4 alkyl group of E and/or Z configuration as well as their salts.

2. A pharmaceutical composition, which comprises as active ingredient a 4-oxo-4-(substituted phenyl) butenoic acid amide of the general formula (I), wherein R stands for hydrogen, halogen, C_1-4alkyl, C_1-4- alkoxy or (C_1-4acyl)amino group; R₁ means straight or branched chain C_1-6 alkylene group optionally substituted by a mercapto, hydroxyl, C_1-3 alkylthio or phenyl or indolyl group, wherein the phenyl group optionally may in itself be substituted by halogen or hydroxyl group and the indolyl group optionally may in itself be substituted by halogen; and R₂ stands for hydrogen or C_1-4 alkyl group or a pharmaceutically acceptable salt thereof, in admixture with carriers and/or additives commonly used in the pharmaceutical industry.

3. A process for the preparation of 4-oxo-4- (substituted phenyl)butenoic acid amides of the general formula (I),

wherein R stands for hydrogen, halogen, C_1-4alkyl, C_1-4- alkoxy or (C_1-4 acyl)amino group; R₁ means straight or branched chain C_1-6 alkylene group optionally substituted by a mercapto, hydroxyl, C_1-3 alkylthio or phenyl or indolyl group, wherein the phenyl group optionally may in itself be substituted by halogen or hydroxyl group and the indolyl group optionally may in itself be substituted by halogen; and

R₂ stands for hydrogen or C_1-4 alkyl group of E and /or Z configuration as well as their salts, which comprises reacting a compound of the general formula (II), H₂N-R₁-COOR₃ (II)

wherein R¹ is as defined above and R³ means a C_1-4 alkyl group or an acid addition salt thereof, with a substituted butenoic acid of the general formula (III)

(III)

4. A process as claimed in claim 3, which comprises using a substituted butenoic acid of the general formula (III), wherein R is as defined in claim 3, in the form activated by a carbodiimide, preferably by dicyclohexylcarbodiimide.

5. A process as claimed in claim 3, which comprises using a substituted butenoic acid of the general formula (III), where in R is as defined in claim 3, in the form of its ester, acid halid or acid anhydride as activated derivatives formed in a manner known per se.

6. A process as claimed in any of the claims 3 to 5, which comprises changing the configuration determined by the double bond of the compounds of the general formula (I), wherein R, R₁ and R₂ are as defined in claim 3, by using UV light.

7. A process for the preparation of a pharmaceutical composition, which comprises mixing as active ingredient a 4-oxo-4-(substituted phenyl)butenoic acid amide of the general formula (I), wherein R, R₁ and R₂ are as defined in claim 3 or a pharmaceutically acceptable salt thereof, prepared by using a process according to any of the claims 3 to 5, with carriers and/or additives commonly used in the pharmaceutical industry and transforming them to a pharmaceutical composition.