Peptides having bradykinin antagonist action
DC CAFCFirst Claim
1. A peptide of the formula 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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Abstract
Peptides of the formula I
A-B-C-E-F-K-P-G-M-F'"'"'-I (I),
wherein the terms A, B, C, E, F, K, P, G, M, F'"'"', and I are defined in the specification, have bradykinin antagonist action. Their therapeutic utility includes all pathological states which are mediated, caused or supported by bradykinin and bradykinin-related peptides.
23 Citations
33 Claims
- 1. A peptide of the formula I
- space="preserve" listing-type="equation">A-B-C-E-F-K-P-G-M-F'"'"' I
in which A is a1, a2, or a3, wherein a1) is hydrogen, (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 from carboxyl, 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 from carboxyl, 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, or a2) 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 from carboxyl, 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 by amino, 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 or cyclohexyl, 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. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 25, 26, 27)
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12. A peptide of the formula
H-D-Arg-Arg-Hyp-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH, H-D-Arg-Arg-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH, H-D-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH, H-D-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH, H-D-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-D-Tic-Tic-Arg-OH, H-D-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH, H-D-Arg-Arg-Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH, H-D-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH, H-D-Arg-Arg(NO2)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH, or H-Arg(Tos)-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH, or a physiologically tolerable salt of said peptide.
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13. A peptide of the formula
H-D-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH, H-D-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH, or H-Arg (Tos)-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH, or a physiologically tolerable salt of said peptide.
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14. A peptide of the formula
H-D-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH or a physiologically tolerable salt of said peptide.
- 15. A peptide of the formula I
- space="preserve" listing-type="equation">A-B-C-E-F-K-P-G-M-F'"'"'-I (I)
in which A a1) is hydrogen, (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 identical or different radicals selected from carboxyl, 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 from carboxyl, amino, (C1 -C4)-alkylamino, hydroxyl, (C1 -C4)-alkoxy, halogen, di-(C1 -4)-alkylamino, carbamoyl, sulfamoyl, (C1 -C4)-alkoxycarbonyl, (C6 -C12)-aryl, and (C6 -C12)-aryl-(C1 -C5)-alkyl, a2) 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 from carboxyl, amino, nitro, (C1 -C4)-alkylamino, hydroxyl, (C1 -C4)-alkyl, (C1 -C4)-alkoxy, halogen, cyano, di-(C1 -C4)-alkylamino, carbamoyl, sulfamoyl and (C1 -C4)-alkoxycarbonyl, or a3) is a radical of the formula II ##STR16## 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 by amino, 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 or cyclohexyl, 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 ##STR17## in which each G'"'"' independently is a radical of the formula IV ##STR18## 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 D-phenylalanine ((D)-Phe) which may be optionally substituted in the phenyl moiety; G is a radical of the formula IV in which R4 and R5 together with the atoms carrying them form a heterocyclic bicyclic or tricyclic ring system having 7 to 15 carbon atoms; 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 radical --NH--(CH2)n --, with n=2 to 8, or is a direct bond; I is --OH, --NH2 or --NHC2 H5 ; 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 thereof. - View Dependent Claims (16, 17, 18, 19, 20, 28, 29, 30)
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21. A peptide of the formula
H-(D)-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-(D)-Phe-Oic-Arg-OH or a physiologically tolerable salt of said peptide.
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22. A peptide of the formula
H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-(D)-Phe-Oic-Arg-OH or a physiologically tolerable salt of said peptide.
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23. A peptide of the formula
H-(D)-Arg-Arg-Pro-Pro-Gly-Phe-Ser-(D)-(p-Cl)Phe-Oic-Arg-OH or a physiologically tolerable salt of said peptide.
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24. A peptide of the formula
H-(D)-Arg-Arg-Pro-Hyp-Gly-Tbg-Ser-(D)-Tic-Oic-Arg-OH or a physiologically tolerable salt of said peptide.
Specification