PEPTIDES WITH MODIFICATIONS AT THE N TERMINUS

摘要

HOE 92/F 098 Peptides with modifications at the N terminus Peptides of the formula I Z-P-A-B-C-E-F-R-(D)Q-G-M-F'-I (I) in which Z is optionally substituted (cyclo)alk(ano)yl(sul fonyl), (Cl-C8)-alkoxycarbonyl, (hetero)ar(o)yl (sulfonyl), carbamoyl, P is a direct linkage or a radical II -NR2-(U)-CO- (II) in which R2 is H, methyl or a urethane protective group, U is (cyclo)(aryl)(alkyl)idene,(hetero)arylidene or (CHR3)n, R3 is hydrogen, (cyclo)alkyl or (hetero)aryl, or in which R2 and R3 together with the atoms carrying them form 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 G'-H-(CH2)p-CO (IIIa) (IIIb) in which p is 2 to 8 and G' is, independently of one another, a radical of the formula IV -NR4-CHR5-CO- (IV) in which R4 and R5 together with the atoms carrying them form a heterocyclic ring system; E is the residue of a neutral, acidic or basic, aliphatic or alicyclic-aliphatic amino acid; F is, independently of one another, the residue of a neutral, acidic or basic, aliphatic or aromatic amino acid, or is a direct linkage; (D)Q is D-Tic, D-Phe, D-Dic, D-Thi or D-Nal, or is 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 can be a direct linkage if G is not 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 the physiologically tolerated salts thereof, are described. They have an excellent bradykininantagonistic action. They are obtained by reacting a fragment with a C-terminal free carboxyl group or its activated derivative with a corresponding fragment with an N-terminal free amino group or assembling the peptide stepwise, where appropriate eliminating in the compound obtained in this way one or more protective groups introduced temporarily to protect other functionalities, and where appropriate converting the compounds of the formula I obtained in this way into the physiologically tolerated salt thereof.