Peptides having bradykinin antagonist action

CAFC
  • US 5,648,333 A
  • Filed: 06/07/1995
  • Issued: 07/15/1997
  • Est. Priority Date: 11/24/1988
  • Status: Expired due to Term
First Claim
Patent Images

1. A peptide of the formula I


  • space="preserve" listing-type="equation">A-B-C-E-F-K-P-G-M-F'"'"' I
in whichA is a1, a2, or a3, whereina1) ishydrogen,(C1 -C8)-alkyl,(C1 -C8)-alkanoyl,(C1 -C8)-alkoxycarbonyl or(C1 -C8 -alkylsulfonyl, in which in each case 1, 2 or 3 hydrogen atoms are optionally replaced by 1, 2 or 3 identical or different radicals selected fromcarboxyl,amino,(C1 -C4)-alkyl,(C1 -C4)-alkylamino,hydroxyl,(C1 -C4)-alkoxy,halogen,di-(C1 -C4)-alkylamino,carbamoyl,sulfamoyl,(C1 -C4)- alkoxycarbonyl,(C6 -C12)-aryl, and(C6 -C12)-aryl-(C1 -C5)-alkyl, or in which in each case 1 hydrogen atom is optionally replaced by a radical selected from(C3 -C8)-cycloalkyl,(C1 -C4)-alkylsulfonyl,(C1 -C4)-alkylsulfinyl,(C6 -C12)-aryl-(C1 -C4)-alkylsulfonyl(C6 -C12)-aryl-(C1 -C4)-alkylsulfinyl,(C6 -C12)-aryloxy,(C3 -C9)-heteroaryl and(C3 -C9)-heteroaryloxy and 1or 2 hydrogen atoms are replaced by 1 or 2 identical or different radicals selected fromcarboxyl,amino,(C1 -C4)-alkylamino,hydroxyl,(C1 -C4)-alkoxy,halogen,di-(C1 -C4)-alkylamino,carbamoyl,sulfamoyl,(C1 -C4)-alkoxycarbonyl,(C6 -C12)-aryl and(C6 -C12)-aryl-(C1 -C5)-alkyl, ora2) is(C3 -C8)-cycloalkyl,carbamoyl, which may be optionally substituted on the nitrogen by (C1 -C6)-alkyl or (C6 -C12)-aryl,(C6 -C12)-aryl,(C7 -C18)-aryloyl,(C6 -C12)-arylsulfonyl,(C3 -C9)-heteroaryl or(C3 -C9)-heteroaryloyl, wherein for the radicals defined under a1) and a2) in each case aryl, heteroaryl, aryloyl, arylsulfonyl, and heteroaryloyl is optionally substituted by 1, 2, 3 or 4 identical or different radicals selected fromcarboxyl,amino,nitro,(C1 -C4)-alkylamino,hydroxyl,(C1 -C4)-alkyl(C1 -C4)-alkoxy,halogen,cyano,di-(C1 -C4)-alkylamino,carbamoyl,sulfamoyl and(C1 -C4)-alkoxycarbonyl,a3) is a radical of the formula II ##STR8## R1 is defined as A under a1) or a2);

R2 is hydrogen or methyl,R3 is hydrogen or (C1 -C6)-alkyl which is optionally monosubstituted byamino,substituted amino,hydroxyl,carboxyl,carbamoyl,guanidino,substituted guanidino,ureido,mercapto,methylmercapto,phenyl,4-chlorophenyl,4-fluorophenyl,4-nitrophenyl,4-methoxyphenyl,4-hydroxyphenyl,phthalimido,4-imidazolyl,3-indolyl,2-thienyl,3-thienyl,2-pyridyl,3-pyridyl orcyclohexyl, wherein substituted amino is a compound of the formula --NH--A-- and substituted guanidino is a compound of the formula --NH--C(NH)--NH--A, in which A is defined under a1) or a2);

B is a basic amino acid in the L- or D-configuration, which may be substituted in the side chain;

C is a compound of the formula IIIa or IIIb ##STR9## in which G'"'"' independently of one another is a radical of the formula IV ##STR10## in which R4 and R5 together with the atoms carrying them form a heterocyclic monocyclic, bicyclic or tricyclic ring system having 2 to 15 carbon atoms, and n is 2 to 8;

E is a radical of an aromatic amino acid;

F is a radical of a neutral, acidic or basic, aliphatic or aromatic amino acid which may be substituted in the side chain, or is a direct bond;

P is a radical of the formula V ((D)-Tic);

##STR11## G is as defined above for G'"'"' or is a direct bond;

F'"'"' is a radical of a neutral, acidic or basic aliphatic or aromatic amino acid which may be substituted in the side chain, is a radical --NH--(CH2)n --, with n=2 to 8, or is a direct bond;

I is --OH, --NH2 or --NHC2 H5, wherein I is not directly bonded to P;

K is a radical --NH--(CH2)x --CO-- with x=1-4 or is a direct bond; and

M is as defined for F,or a physiologically tolerable salt of said peptide.

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