Peptides with N-terminal modifications having bradykinin antagonistic activity

• Main Authors: HENKE, STEPHAN, GERHARDS, HERMANN, ALPERMANN, HANS-GEORG, WIRTH, KLAUS, BREIPOHL, GERHARD, SCHOELKENS, BERNWARD, DR, KNOLLE, JOCHEN
• Format: Patent
• Language: English; French; German
• Published: 11.08.1999
• Edition: 6
• Subjects: CHEMISTRY; HUMAN NECESSITIES; HYGIENE; MEDICAL OR VETERINARY SCIENCE; METALLURGY; ORGANIC CHEMISTRY; PEPTIDES; PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES; SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS ORMEDICINAL PREPARATIONS

Peptides of the formula I Z - P - A - B - C - E - F - K - (D)Q - G- M- F' - I (I), in which Z is optionally substituted (cyclo)alk(ano)yl(sulphonyl), (C1-C8)-alkoxycarbonyl, (hetero)ar(o)yl(sulphonyl), carbamoyl, P is a direct linkage or a radical II -NR -(U)-CO- (II> in which R is H, methyl or a urethane protective group, U is (cyclo)(aryl)alkylidene, (hetero)arylidene or (CHR )n, R is hydrogen, (cyclo)alkyl, (hetero)aryl, or in which R and R form, together with the atoms carrying them, a ring system; A is defined as P; B is a basic amino acid in the L or D configuration, C is a compound of the formula IIIa or IIIb G'-G'-Gly (IIIa> G'-NH-(CH2)p-CO (IIIb> in which p is 2 to 8 and G' are, independently of one another, a radical of the formula IV -NR -CHR -CO- (IV> in which R and R form, together with the atoms carrying them, a heterocyclic ring system; E is the residue of a neutral, acid or basic, aliphatic or alicyclic-aliphatic amino acid; F are, independently of one another, the radical of a neutral, acid or basic, aliphatic or aromatic amino acid, or a direct linkage; (D)Q is D-Tic, D-Phe, D-Dic, D-Thi or D-Nal, or a radical of the formula (V) in which X is O, S or a direct linkage, and R is H, (cyclo)alkyl or aryl(alkyl), G is defined as G' above or is a direct linkage; F' is defined as F, is a radical -NH-(CH2)q- with q = 2 to 8 or, if G is not a direct linkage, can be a direct linkage, and I is -OH, -NH2 or NHC2H5; K is the radical -NH-(CH2)x-CO- with x = 1-4 or is a direct linkage, and M is defined as F and their physiologically tolerated salts are described. They have excellent bradykinin-antagonistic action. They are obtained by reacting a fragment with a C-terminal free carboxyl group or its activated derivative with an appropriate fragment with an N-terminal free amino group, or by assembling the peptide stepwise, eliminating one or more protective groups temporarily introduced where appropriate to protect other functionalities in the compound obtained in this way, and converting the compounds of the formula I obtained in this way where appropriate into their physiologically tolerated salt.