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Claims for Patent: 5,648,333

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Claims for Patent: 5,648,333

Title: Peptides having bradykinin antagonist action
Abstract:Peptides of the formula 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.
Inventor(s): Henke; Stephan (Hofheim am Taunus, DE), Anagnostopulos; Hiristo (Wiesbaden, DE), Breipohl; Gerhard (Frankfurt am Main, DE), Knolle; Jochen (Kriftel, DE), Stechl; Jens (Frankfurt am Main, DE), Scholkens; Bernward (Kelkeim/Taunus, DE), Fehlhaber; Hans-Wolfram (Idstein, DE), Gerhards; Hermann (Hofheim am Taunus, DE), Hock; Franz (Dieburg, DE)
Assignee: Hoechst Aktiengesellschaft (Frankfurt am Main, DE)
Application Number:08/487,442
Patent Claims: 1. A peptide of the formula I

in which

A is a.sub.1, a.sub.2, or a.sub.3, wherein

a.sub.1) is

hydrogen,

(C.sub.1 -C.sub.8)-alkyl,

(C.sub.1 -C.sub.8)-alkanoyl,

(C.sub.1 -C.sub.8)-alkoxycarbonyl or

(C.sub.1 -C.sub.8 -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,

(C.sub.1 -C.sub.4)-alkyl,

(C.sub.1 -C.sub.4)-alkylamino,

hydroxyl,

(C.sub.1 -C.sub.4)-alkoxy,

halogen,

di-(C.sub.1 -C.sub.4)-alkylamino,

carbamoyl,

sulfamoyl,

(C.sub.1 -C.sub.4)- alkoxycarbonyl,

(C.sub.6 -C.sub.12)-aryl, and

(C.sub.6 -C.sub.12)-aryl-(C.sub.1 -C.sub.5)-alkyl,

or in which in each case 1 hydrogen atom is optionally replaced by a radical selected from

(C.sub.3 -C.sub.8)-cycloalkyl,

(C.sub.1 -C.sub.4)-alkylsulfonyl,

(C.sub.1 -C.sub.4)-alkylsulfinyl,

(C.sub.6 -C.sub.12)-aryl-(C.sub.1 -C.sub.4)-alkylsulfonyl

(C.sub.6 -C.sub.12)-aryl-(C.sub.1 -C.sub.4)-alkylsulfinyl,

(C.sub.6 -C.sub.12)-aryloxy,

(C.sub.3 -C.sub.9)-heteroaryl and

(C.sub.3 -C.sub.9)-heteroaryloxy and

1or 2 hydrogen atoms are replaced by 1 or 2 identical or different radicals selected from

carboxyl,

amino,

(C.sub.1 -C.sub.4)-alkylamino,

hydroxyl,

(C.sub.1 -C.sub.4)-alkoxy,

halogen,

di-(C.sub.1 -C.sub.4)-alkylamino,

carbamoyl,

sulfamoyl,

(C.sub.1 -C.sub.4)-alkoxycarbonyl,

(C.sub.6 -C.sub.12)-aryl and

(C.sub.6 -C.sub.12)-aryl-(C.sub.1 -C.sub.5)-alkyl, or

a.sub.2) is

(C.sub.3 -C.sub.8)-cycloalkyl,

carbamoyl, which may be optionally substituted on the nitrogen by (C.sub.1 -C.sub.6)-alkyl or (C.sub.6 -C.sub.12)-aryl,

(C.sub.6 -C.sub.12)-aryl,

(C.sub.7 -C.sub.18)-aryloyl,

(C.sub.6 -C.sub.12)-arylsulfonyl,

(C.sub.3 -C.sub.9)-heteroaryl or

(C.sub.3 -C.sub.9)-heteroaryloyl,

wherein for the radicals defined under a.sub.1) and a.sub.2) 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,

(C.sub.1 -C.sub.4)-alkylamino,

hydroxyl,

(C.sub.1 -C.sub.4)-alkyl

(C.sub.1 -C.sub.4)-alkoxy,

halogen,

cyano,

di-(C.sub.1 -C.sub.4)-alkylamino,

carbamoyl,

sulfamoyl and

(C.sub.1 -C.sub.4)-alkoxycarbonyl,

a.sub.3) is a radical of the formula II ##STR8## R.sup.1 is defined as A under a.sub.1) or a.sub.2); R.sup.2 is hydrogen or methyl,

R.sup.3 is hydrogen or (C.sub.1 -C.sub.6)-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 a.sub.1) or a.sub.2);

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 R.sup.4 and R.sup.5 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--(CH.sub.2).sub.n --, with n=2 to 8, or is a direct bond;

I is --OH, --NH.sub.2 or --NHC.sub.2 H.sub.5, wherein I is not directly bonded to P;

K is a radical --NH--(CH.sub.2).sub.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.

2. A peptide of the formula I or salt as claimed in claim 1 in which

B is Arg, Lys, Orn, 2,4-diamino-butyroyl or an L-homoarginine radical, wherein in each case the amino or guanidino group of the side chain may be substituted by A as defined under a.sub.1) or a.sub.2);

C is a compound of the formula IIIa

in which

each G' independently is a radical of the formula IV ##STR12## in which R.sup.4 and R.sup.5 together with the atoms carrying them form a heterocyclic monocyclic, bicyclic or tricyclic ring system having 2 to 15 carbon atoms;

E is a radical of an aromatic amino acid in the L- or D-configuration, which contains 6 to 14 carbon atoms in the aryl moiety as ring members, which is optionally substituted by halogen in the 2-, 3- or 4-position, tyrosine, O-methyltyrosine, 2-thienylalanine, 2-pyridylalanine or naphthylalanine;

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

F' is a radical of a basic amino acid in the L- or D-configuration, wherein the guanidino group or amino group of the side chain may be replaced by A as defined under a.sub.1) or a.sub.2), or is a radical --NH--(CH.sub.2).sub.n -- with n=2 to 8;

K is a radical --NH--(CH.sub.2).sub.x --CO-- with x=1-4 or is a direct bond; and

M is Phe, Thia or a direct bond.

3. A peptide of the formula I or salt as claimed in claim 2 in which

F' is Arg or Lys, wherein the guanidino group or amino group of the side chain may be replaced by A as defined under a.sub.1) or a.sub.2), or is a radical --NH--(CH.sub.2).sub.n -- with n=2 to 8; and

G' is a heterocyclic monocyclic or bicyclic ring system having 3 or 4 carbon atoms if said ring system is monocyclic or having 7 to 9 carbon atoms if said ring system is bicyclic.

4. A peptide of the formula I or salt as claimed in claim 1 in which

B is Arg, Orn or Lys, wherein the guanidino group or the amino group of the side chain is unsubstituted or is substituted by (C.sub.1 -C.sub.8)-alkanoyl, (C.sub.7 -C.sub.13)-aryloyl, (C.sub.3 -C.sub.9)-heteroaryloyl, (C.sub.1 -C.sub.8)-alkylsulfonyl or (C.sub.6 -C.sub.12)-arylsulfonyl, wherein in each case the aryloyl, arylsulfonyl and heteroaryloyl radicals are optionally substituted by 1, 2, 3 or 4 identical or different radicals selected from

carboxyl,

amino,

nitro,

(C.sub.1 -C.sub.4)-alkylamino,

hydroxyl,

(C.sub.1 -C.sub.4)-alkyl,

(C.sub.1 -C.sub.4)-alkoxy,

halogen,

cyano,

di-(C.sub.1 -C.sub.4)-alkylamino,

carbamoyl,

sulfamoyl and

(C.sub.1 -C.sub.4)-alkoxycarbonyl;

E is phenylalanine, 2-chlorophenylalanine, 3-chlorophenylalanine, 4-chlorophenylalanine, 2-fluoro-phenylalanine, 3-fluorophenylalanine, 4-fluorophenylalanine, tyrosine, O-methyltyrosine or .beta.-(2-thienyl)alanine;

F is Ser, hSer, Leu, Val, Nle, Thr, Gin, Trp, (D)Asn, Opr, (D)Ser, (D)Gln or a direct bond;

F' is Arg, wherein the guanidino group of the side chain may be replaced by A as defined under a.sub.1) or a.sub.2), or is a radical --NH--(CH.sub.2).sub.n -- with n=2 to 8;

K is a radical--NH--(CH.sub.2).sub.x --CO-- with x=1 or is a direct bond;

M is a direct bond; and

I is OH or NH.sub.2.

5. A peptide of the formula I or salt as claimed in claim 1 in which

A is hydrogen, (D)- or (L)-H-Arg, (D)- or (L)-H-Lys or (D)- or (L)-H-Orn;

B is Arg, Orn or Lys, wherein the guanidino group or the amino group of the side chain is optionally substituted by (C.sub.1 -C.sub.8)-alkanoyl, (C.sub.7 -C.sub.13)-aryloyl, (C.sub.3 -C.sub.9)-heteroaryloyl, (C.sub.1 -C.sub.12)-alkylsulfonyl or (C.sub.6 -C.sub.12)-arylsulfonyl, wherein the aryloyl, arylsulfonyl and heteroaryloyl radicals are optionally substituted with 1, 2, 3 or 4 identical or different radicals selected from the group consisting of methyl, methoxy and halogen;

C is Pro-Pro-Gly, Hyp-Pro-Gly or Pro-Hyp-Gly;

E is Phe or Thia;

F is Ser, hSer, Leu, Val, Nle, Thr, Gln, Trp, (D)Asn, Opr, (D)Ser, (D)Gln or a direct bond;

K is a radical --NH--(CH.sub.2).sub.x --CO-- with x=1 or is a direct bond;

M is a direct bond;

G is a radical of the formula IV ##STR13## in which R.sup.4 and R.sup.5 together with the atoms carrying them form a heterocyclic monocyclic, bicyclic or tricyclic ring system having 2 to 15 carbon atoms;

F' is Arg; and

I is OH.

6. A peptide of the formula I or salt as claimed in claim 1 in which

A is hydrogen, (D)- or (L)-H-Arg, (D)- or (L)-H-Lys or (D)- or (L)-H-Orn;

B is Arg, Orn or Lys, wherein the guanidino group or the amino group of the side chain is optionally substituted by (C.sub.1 -C.sub.8)-alkanoyl, (C.sub.7 -C.sub.13)-aryloyl, (C.sub.3 -C.sub.9)-heteroaryloyl, (C.sub.1 -C.sub.8)-alkylsulfonyl or (C.sub.6 -C.sub.12)-arylsulfonyl, wherein the aryloyl, arylsulfonyl and heteroaryloyl radicals are optionally substituted with 1, 2, 3 or 4 identical or different radicals selected from the group consisting of methyl, methoxy and halogen;

C is Pro-Pro-Gly, Hyp-Pro-Gly or Pro-Hyp-Gly;

E is Phe or Thia;

F is Ser or a direct bond;

K is a direct bond or --NH--(CH.sub.2).sub.x --CO-- with x=1-4, wherein when F is serine, K is a direct bond, and when K is --NH--(CH.sub.2).sub.x --CO--, F is a direct bond;

M is a direct bond;

G is a radical of the formula IV ##STR14## in which R.sup.4 and R.sup.5 together with the atoms carrying them form a heterocyclic monocyclic, bicyclic or tricyclic ring system having 2 to 15 carbon atoms;

F' is Arg; and

I is OH.

7. A peptide of the formula I or salt as claimed in claim 1 in which

A is hydrogen, (D)- or (L)-H-Arg, (D)- or (L)-H-Lys or (D)- or (L)-H-Orn;

B is Arg, Orn or Lys, wherein the guanidino group or the amino group of the side chain is optionally substituted by (C.sub.1 -C.sub.8)-alkanoyl, (C.sub.7 -C.sub.13)-aryloyl, (C.sub.3 -C.sub.9)-heteroaryloyl, (C.sub.1 -C.sub.8)-alkylsulfonyl or (C.sub.6 -C.sub.12)-arylsulfonyl, wherein the aryloyl, arylsulfonyl and heteroaryloyl radicals are optionally substituted with 1, 2, 3 or 4 identical or different radicals selected from the group consisting of methyl, methoxy and halogen;

C is Pro-Pro-Gly, Hyp-Pro-Gly or Pro-Hyp-Gly;

E is Phe or Thia;

F is Cys

K is a radical --NH--(CH.sub.2).sub.x --CO-- with x=1 or is a direct bond;

M is a direct bond;

G is a radical of the formula IV ##STR15## in which R.sup.4 and R.sup.5 together with the atoms carrying them form a heterocyclic monocyclic, bicyclic or tricyclic ring system having 2 to 15 carbon atoms,

F' is Arg; and

I is OH.

8. A peptide of the formula I or salt as claimed in claim 5, in which

G is a radical selected from the group consisting of pyrrolidine (A), piperidine (B), tetra-hydroisoquinoline (C), cis- and trans-decahydroisoquinoline (D), cis-endo-, cis-exo, and trans-octahydroindole (E), cis-endo-, cis-exo-, and trans-octa-hydrocyclopentano[b]pyrrole (F), and hydroxyproline (V).

9. A peptide of the formula I or salt as claimed in claim 6, in which

G is a radical selected from the group consisting of pyrrolidine (A), piperidine (B), tetra-hydroisoquinoline (C), cis- and trans-decahydroisoquinoline (D), cis-endo-, cis-exo, and trans-octahydroindole (E), cis-endo-, cis-exo-, and trans-octa-hydrocyclopentano[b]pyrrole (F), and hydroxyproline (V).

10. A peptide of the formula I or salt as claimed in claim 1, in which

A is hydrogen or D-Arg,

B is Arg, Arg(NO.sub.2) or Arg(Tos),

C is Hyp-Pro-Gly, Pro-Hyp-Gly, or Pro-Pro-Gly

E is Thia or Phe,

F is Ser,

K is a direct bond,

G is Aoc, Tic or Oic,

M is a direct bond,

F' is Arg, and

I is OH.

11. A peptide of the formula I or salt as claimed in claim 1, in which

A is hydrogen or D-Arg,

B is Arg or Arg(Tos),

C is Pro-Hyp-Gly,

E is Thia,

F is Ser,

K is a direct bond,

G is Aoc or Oic,

M is a direct bond,

F' is Arg, and

I is OH.

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(NO.sub.2)-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.

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.

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

in which

A a.sub.1) is hydrogen,

(C.sub.1 -C.sub.8)-alkyl,

(C.sub.1 -C.sub.8)-alkanoyl,

(C.sub.1 -C.sub.8)-alkoxycarbonyl or

(C.sub.1 -C.sub.8)-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,

(C.sub.1 -C.sub.4)-alkyl,

(C.sub.1 -C.sub.4)-alkylamino,

hydroxyl,

(C.sub.1 -C.sub.4)-alkoxy,

halogen,

di-(C.sub.1 -C.sub.4)-alkylamino,

carbamoyl,

sulfamoyl,

(C.sub.1 -C.sub.4)-alkoxycarbonyl,

(C.sub.6 -C.sub.12)-aryl, and

(C.sub.6 -C.sub.12)-aryl-(C.sub.1 -C.sub.5)-alkyl,

or in which in each case 1 hydrogen atom is optionally replaced by a radical selected from

(C.sub.3 -C.sub.8)-cycloalkyl,

(C.sub.1 -C.sub.4)-alkylsulfonyl,

(C.sub.1 -C.sub.4)-alkylsulfinyl,

(C.sub.6 -C.sub.12)-aryl-(C.sub.1 -C.sub.4)-alkylsulfonyl

(C.sub.6 -C.sub.12)-aryl-(C.sub.1 -C.sub.4)-alkylsulfinyl,

(C.sub.6 -C.sub.12)-aryloxy,

(C.sub.3 -C.sub.9)-heteroaryl and

(C.sub.3 -C.sub.9)-heteroaryloxy and

1or 2 hydrogen atoms are replaced by 1 or 2 identical or different radicals selected from

carboxyl,

amino,

(C.sub.1 -C.sub.4)-alkylamino,

hydroxyl,

(C.sub.1 -C.sub.4)-alkoxy,

halogen,

di-(C.sub.1 -.sub.4)-alkylamino,

carbamoyl,

sulfamoyl,

(C.sub.1 -C.sub.4)-alkoxycarbonyl,

(C.sub.6 -C.sub.12)-aryl, and

(C.sub.6 -C.sub.12)-aryl-(C.sub.1 -C.sub.5)-alkyl,

a.sub.2) is (C.sub.3 -C.sub.8)-cycloalkyl,

carbamoyl, which may be optionally substituted on the nitrogen by (C.sub.1 -C.sub.6)-alkyl or (C.sub.6 -C.sub.12)-aryl,

(C.sub.6 -C.sub.12)-aryl,

(C.sub.7 -C.sub.18)-aryloyl,

(C.sub.6 -C.sub.12)-arylsulfonyl,

(C.sub.3 -C.sub.9)-heteroaryl or

(C.sub.3 -C.sub.9)-heteroaryloyl,

wherein for the radicals defined under a.sub.1) and a.sub.2) 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,

(C.sub.1 -C.sub.4)-alkylamino,

hydroxyl,

(C.sub.1 -C.sub.4)-alkyl,

(C.sub.1 -C.sub.4)-alkoxy,

halogen,

cyano,

di-(C.sub.1 -C.sub.4)-alkylamino,

carbamoyl,

sulfamoyl and

(C.sub.1 -C.sub.4)-alkoxycarbonyl, or

a.sub.3) is a radical of the formula II ##STR16## R.sup.1 is defined as A under a.sub.1) or a.sub.2), R.sup.2 is hydrogen or methyl,

R.sup.3 is hydrogen or (C.sub.1 -C.sub.6)-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 a.sub.1) or a.sub.2);

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 R.sup.4 and R.sup.5 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 R.sub.4 and R.sub.5 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--(CH.sub.2).sub.n --, with n=2 to 8, or is a direct bond;

I is --OH, --NH.sub.2 or --NHC.sub.2 H.sub.5 ;

K is a radical --NH--(CH.sub.2).sub.x --CO-- with x=1-4 or is a direct bond, and

M is as defined for F,

or a physiologically tolerable salt thereof.

16. A peptide of the formula I or salt as claimed in claim 15 in which

B is Arg, Lys, Orn, 2,4-diaminobutyroyl or an L-homoarginine radical, wherein in each case the amino or guanidino group of the side chain may be substituted by A as defined under a.sub.1) or a.sub.2);

C is a compound of the formula IIIa ##STR19## in which each G' independently is a radical of the formula IV ##STR20## in which R.sup.4 and R.sup.s together with the atoms carrying them form a heterocyclic monocyclic, bicyclic or tricyclic ring system having 2 to 15 carbon atoms;

E is a radical of an aromatic amino acid in the L- or D-configuration, which contains 6 to 14 carbon atoms in the aryl moiety as ring members, which is optionally substituted by halogen in the 2-, 3- or 4-position, tyrosine, O-methyltyrosine, 2-thienylalanine, 2-pyridylalanine or naphthylalanine;

P is D-Phe which is optionally substituted in the phenyl moiety by halogen or (C.sub.1 -C.sub.4)-alkoxy;

F' is a radical of a basic amino acid in the L- or D-configuration, wherein the guanidino group or amino group of the side chain may be replaced by A as defined under a.sub.1) or a.sub.2), or is a radical --NH--(CH.sub.2).sub.n -- with n=2 to 8;

G is a radical of the formula IV in which R.sup.4 and R.sup.5 together with the atoms carrying them form a heterocyclic bicyclic ring system having from 7 to 9 carbon atoms;

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

K is a direct bond.

17. A peptide of the formula I or salt as claimed in claim 16 in which

F' is Arg or Lys, wherein the guanidino group or amino group of the side chain may be replaced by A as defined under a.sub.1) or a.sub.2), or is a radical --NH--(CH.sub.2).sub.n -- with n=2 to 8;

G is a heterocyclic radical selected from octahydroindole (E), octahydrocyclopenta[b]pyrrole (F), deca-hydrocyclohepta[b]pyrrole (N), octahydroisoindole (O), and decahydroisoquinoline (D); and

G' is a heterocyclic monocyclic or bicyclic ring system having 4 or 5 carbon atoms if said ring system is monocyclic or having 7 to 9 carbon atoms if said ring system is bicyclic.

18. A peptide of the formula I or salt as claimed in claim 15 in which

B is Arg, Orn or Lys, wherein the guanidino group or the amino group of the side chain is unsubstituted or is substituted by (C.sub.1 -C.sub.8)-alkanoyl, (C.sub.7 C.sub.18)-aryloyl, (C.sub.3 -C.sub.9)-heteroaryloyl, (C.sub.1 -C.sub.8)-alkylsulfonyl or (C.sub.6 -C.sub.12)-arylsulfonyl, wherein in each case the aryloyl, arylsulfonyl and heteroaryloyl radicals are optionally substituted by 1, 2, 3 or 4 identical or different radicals selected from

carboxyl,

amino,

nitro,

(C.sub.1 -C.sub.4)-alkylamino,

hydroxyl,

(C.sub.1 -C.sub.4)-alkyl,

(C.sub.1 -C.sub.4)-alkoxy,

halogen,

cyano,

di-(C.sub.1 -C.sub.4)-alkylamino,

carbamoyl,

sulfamoyl and

(C.sub.1 -C.sub.4)-alkoxy-carbonyl;

C is a compound of the formula IIIa ##STR21## in which each G' independently is a radical of the formula IV ##STR22## in which R.sup.4 and R.sup.5 together with the atoms carrying them form a heterocyclic monocyclic, bicyclic or tricyclic ring system having 2 to 15 carbon atoms;

E is phenylalanine, 2-chlorophenylalanine, 3-chlorophenylalanine, 4-chlorophenylalanine, 2-fluorophenylalanine, 3-fluorophenylalanine, 4-fluorophenylalanine, tyrosine, O-methyltyrosine or .beta.-(2-thienyl)-alanine;

F is Ser, hSer, Lys, Leu, Val, Nle, Ile, D-Ser, D-Gln, or Thr;

F' is Arg;

P is D-Phe which is optionally substituted by fluorine, chlorine, bromine or methoxy;

K is a direct bond;

M is a direct bond; and

I is --OH, --NH.sub.2 or --NHC.sub.2 H.sub.5.

19. A peptide of the formula I or salt as claimed in claim 15 in which

A is hydrogen, (D)- or (L)-H-Arg, (D)- or (L)-H-Lys or (D)- or (L)-H-Orn;

B is Arg, Orn or Lys, wherein the guanidino group or the amino group of the side chain is optionally substituted by (C.sub.1 -C.sub.8)-alkanoyl, (C.sub.7 -C.sub.13)-aryloyl, (C.sub.3 -C.sub.9)-heteroaryloyl, (C.sub.1 -C.sub.8)-alkylsulfonyl or (C.sub.6 -C.sub.12)-arylsulfonyl, wherein the aryloyl, arylsulfonyl and heteroaryloyl radicals are optionally substituted with 1, 2, 3 or 4 identical or different radicals selected from the group consisting of methyl, methoxy and halogen;

C is Pro-Pro-Gly, Hyp-Pro-Gly or Pro-Hyp-Gly;

E is Phe or Thia;

F is Ser;

K is a direct bond;

M is a direct bond;

G is Oic;

F' is Arg; and

I is OH.

20. A peptide of the formula I or salt as claimed in claim 19, in which

G is a heterocyclic radical selected from octahydroindole (E), octahydrocyclopenta[b]pyrrole (F), decahydrocyclohepta[b]pyrrole (N), octahydroisoindole (O), and decahydroisoquinoline (D).

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.

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.

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.

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.

25. A method for the treatment of a pathological state which is mediated, caused or supported by bradykinin and bradykinin-related peptides in a patient, wherein said pathological state is selected from the group consisting of wounds, burns, rashes, erythemas, edemas, angina, arthritis, asthma, allergies, rhinitis, shock, inflammations, low blood pressure, pain, itching, and changed sperm motility, wherein said method comprises administering to said patient an effective amount of the peptide as claimed in claim 1 or a physiologically tolerated salt of said peptide.

26. A method of treating asthma in a human comprising administering to said human an effective amount of the peptide as claimed in claim 1, or a physiologically tolerated salt of said peptide.

27. A pharmaceutical composition for the treatment of a pathological state which is mediated, caused or supported by bradykinin and bradykin-related peptides, wherein said pathological state is selected from the group consisting of wounds, burns, rashes, erythemas, edemas, angina, arthritis, asthma, allergies, rhinitis, shock, inflammations, low blood pressure, pain, itching, and changed sperm motility, wherein said pharmaceutical composition comprises an effective amount of the peptide as claimed in claim 1 or a physiologically tolerated salt of said peptide, and a pharmaceutically acceptable vehicle.

28. A method for the treatment of a pathological state which is mediated, caused or supported by bradykinin and bradykinin-related peptides in a patient, wherein said pathological state is selected from the group consisting of wounds, burns, rashes, erythemas, edemas, angina, arthritis, asthma, allergies, rhinitis, shock, inflammations, low brood pressure, pain, itching, and changed sperm motility, wherein said method comprises administering to said patient an effective amount of the peptide as claimed in claim 15, or a physiologically tolerated salt of said peptide.

29. A method of treating asthma in a human comprising administering to said human an effective amount of the peptide as claimed in claim 15, or a physiologically tolerated salt of said peptide.

30. A pharmaceutical composition for the treatment of a pathological state which mediated, caused or supported by bradykinin and bradykinin-related peptides, wherein said pathological state is selected from the group consisting of wounds, burns, rashes, erythemas, edemas, angina, arthritis, asthma, allergies, rhinitis, shock, inflammations, low blood pressure, pain, itching, and changed sperm motility, wherein said pharmaceutical composition comprises an effective amount of the peptide as claimed in claim 15 or a physiologically tolerated salt of said peptide, and a pharmaceutically acceptable vehicle.

31. A method for the treatment of a pathological state which is mediated, caused or supported by bradykinin and bradykinin-related peptides in a patient, wherein said pathological state is selected from the group consisting of wounds, burns, rashes, erythemas, edemas, tonsillitis, arthritis, asthma, allergies, rhinitis, shock, inflammations, low blood pressure, pain, pruritis, and changed sperm motility, wherein said method comprises administering to said patient an effective amount of the peptide as claimed in claim 24, or a physiologically tolerated salt of said peptide.

32. A method of treating asthma in a human comprising administering to said human an effective amount of the peptide as claimed in claim 24, or a physiologically tolerated salt of said peptide.

33. A pharmaceutical composition for the treatment of a pathological state which is mediated, caused or supported by bradykinin and bradykinin-related peptides, wherein said pathological state is selected from the group consisting of wounds, burns, rashes, erythemas, edemas, tonsillitis, arthritis, asthma, allergies, rhinitis, shock, inflammations, low blood pressure, pain, pruritis, and changed sperm motility, wherein said pharmaceutical composition comprises an effective amount of the peptide as claimed in claim 24 or a physiologically tolerated salt of said peptide, and a pharmaceutically acceptable vehicle.
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