Patent EP-0236163-B1 (EP)
IPC: C07K5/06
Filed: 1987-01-22
Granted: 1990-10-03
Abstract: 1. Claims for the Contracting States : BE CH DE FR GB IT LI LU NL SE Compounds of formula (I)   see diagramm : EP0236163,P44,F3   wherein R1 represents hydrogen, a C1-6 alkyl or hydroxyalkyl group, benzyl, a phenyl group or a 4-hydroxyphenyl group ; R2 represents an alkyl, alkenyl or alkynyl group each having up to 6 carbon atoms, a benzyl group, a C1-6 alkoxy, C1-6 carbonylalkyl, C1-6 carboxyalkyl or C1-6 hydroxyalkyl group ; R3 and R4 , which may be identical or different, each represent an alkyl, hydroxyalkyl, alkenyl or alkynyl group each having up to 6 carbon atoms, or form together with the nitrogen to which they are attached a saturated heterocyclic group selected from among morpholino, thiomorpholino, pyrrolidino, either unsubstituted or substituted by a C1-6 alkoxy, carbonyl or carboxy group, piperazino, 4-(C1-6 alkyl)-piperazino, 4-(C1-6 hydroxyalkyl)-piperazino, or piperidino with either unsubstituted or substituted by a C1-6 alkyl group, benzyl, hydroxy, C1-6 hydroxyalkyl, amino, C1-6 aminoalkyl, hydroxyamino, C1-6 alkoxy, carbonyl or carboxy ; Ar represents a phenyl, alpha-naphthyl, beta-naphthyl, methoxycarbonylphenyl group or a heteroaryl group selected from among the pyridyl, quinolinyl, isoquinolinyl or methyl-quinolinyl groups ; and the addition salts thereof with pharmaceutically acceptable organic or inorganic acids and the stereoisomers or mixtures thereof. 1. Claims for the Contracting States : AT GR ES Process for preparing compounds of formula (I)   see diagramm : EP0236163,P48,F1   wherein R1 represents hydrogen, a C1-6 alkyl or hydroxyalkyl group, benzyl, a phenyl group or a 4-hydroxyphenyl group ; R2 represents an alkyl, alkenyl or alkynyl group each having up to 6 carbon atoms, a benzyl group, a C1-6 alkoxy, C1-6 carbonylalkyl, C1-6 carboxyalkyl or C1-6 hydroxyalkyl group ; R3 and R4 , which may be identical or different, each represent an alkyl, hydroxyalkyl, alkenyl or alkynyl group each having up to 6 carbon atoms, or form together with the nitrogen to which they are attached a saturated heterocyclic group selected from among morpholino, thiomorpholino, pyrrolidino, either unsubstituted or substituted by a C1-6 alkoxy, carbonyl or carboxy group, piperazino, 4-(C1-6 alkyl)-piperazino, 4-(C1-6 hydroxyalkyl)-piperazino, or piperidino with either unsubstituted or substituted by a C1-6 alkyl group, benzyl, hydroxy, C1-6 hydroxyalkyl, amino, C1-6 aminoalkyl, hydroxyamin, C1-6 alkoxy, carbonyl or carboxy ; Ar represents a phenyl, alpha-naphthyl, beta-naphthyl, methoxycarbonylphenyl group or a heteroaryl group selected from among the pyridyl, quinolinyl, isoquinolinyl or methyl-quinolinyl groups ; and the addition salts thereof with pharmaceutically acceptable organic or inorganic acids and the stereoisomers or mixtures thereof, characterized in that the N alpha-alkylated 4-cyano-phenylalaninamide of formula (II)   see diagramm : EP0236163,P48,F2   wherein R2 , R3 and R4 have the same meanings as in formula (I), is reacted with an acid of formula (III)   see diagramm : EP0236163,P48,F3   in its activated form (IV)   see diagramm : EP0236163,P48,F4   wherein Ar and R1 have the same meanings as in formula (I) and R represents a good nucleophobic group such as alkoxycarbonyloxy or heteroaryl chlorine, to obtain the compound of formula (V)   see diagramm : EP0236163,P49,F1   wherein Ar, R1 , R2 , R3 and R4 have the same meanings as in formula (I), which is treated with an excess of a saturated solution of hydrochloric gas in an alcohol of formula X-OH wherein X represents a lower alkyl radical, in order to obtain the imidoester of formula (VI) in the form of the hydrochloride (VI)   see diagramm : EP0236163,P49,F2   wherein Ar, R1 , R2 , R3 , R4 and X have the meanings given hereinbefore, which is then treated with an excess of a solution of ammonia gas in a lower alcohol at the boiling temperature of the reaction mixture in order to obtain the desired compound of formula (I).