Hydroxy-peptide bestatin derivs. - with aminopeptidase B, leucine-aminopeptidase and bleomycin hydrolase inhibiting and bleomycin antitumour potentiating activity

摘要

New bestatin derivs. are cpds. of formula R1CH(NH2).CH(OH).CO.NH.CH(R2).COOH (I), where R1 is hydroxybenzyl; and R2 is 1-6C alkyl, hydroxyalkyl, mercaptoalkyl, carboxamidoalkyl, alkoxyalkyl, alkylmercaptoalkyl, carboxyalkyl, aryl, aralkyl or substd. aralkyl. Specific cpds. (I) include (2RS, 3RS)-3-amino-2-hydroxy-4-(p-hydroxyphenyl)-butyryl-(5)-leucine. In an example, this is prepd. by (a) refluxing Z-(2RS, 3RS)-3-amino-2-hydroxy-4-(p-methoxyphenyl)butyronitrile with conc. HCl and dioxan in the presence of anisole; (b) reacting the resulting (2RS, 3RS)-3-amino-2-hydroxy-4-(p-hydroxyphenyl)butyric acid with Z-Cl in the presence of NaOH; (c) reacting the resulting Z-(2RS, 3RS)-3-amino-2-hydroxy-4-(p-OZ-phenyl)butyric acid with Leu-OB3I in the presence of N-hydroxybenzotriazole; and (d) hydrogenating the resulting Z-(2RS, 3RS)-3-amino-2-hydroxy-4-(p-OZ-phenyl)-butyryl-(5)-leucine benzyl ester over palladium black.