TH17064B - Antagonist to polypeptide bombesin - Google Patents

Abstract

The pseudopeptide consists of peptide formula 1: X-A1-A2-Trp-Ala-Val-Gly-His-Leu-pai-A9-Q, where X represents hydrogen, the single bond linking the alpha-amino group of A1 to the carboxyl core on the 3-propionyl of A2, where A2 is or the group of formula R1 CO-, here R1 is selected from the group consisting of a) hydrogen, C1-10 alkyl, phenyl, or phenyl-C1-10-alkyl, p-HI-phenyl, p-HI-phenyl-C1-10-ilkyl, neptyl, neptyl-C1-10-alkyl, indoyl, indoyl-C1-10-ilkyl, pyridyl, pyridyl-C1-10-alkyl, thienyl, thienyl-C1-10-alkyl, cyclohexyl or cyclohexyl-C1-10-alkyl, here HI - F, Cl, Br, OH, CH3 or OCH3, b) N(R2) (R3)-, here R2 is hydrogen. C1-10 alkyl, phenyl, or phenyl--C1-10-alkyl, R5 is hydrogen or C1-10 alkyl, C) R4O- where R4 is C1-10 alkyl, phenyl, or phenyl-C1-10-alkyl, A1 is D- or L-. The remaining amino acids are selected from groups consisting of pHe, P-Hl-Phe, pGlu, Nal, Pal, Tpi, Trp that are not substituted, or Trp substituted in the benzene ring by one or more members selected from groups consisting of F, Cl, Br, NH2 or C1-3 alkyl, or A1 is the acyl peptide bond linkage of R1CO- with the alpha-amino portion of A2;;A2 is Gln, Glu[-], Glu(Y) or His, where [-] is a single bond linkage. The madarboxyl group of A2, where A2 is Glu, and the alpha-amino group of A1, where X is a single bond, Y is -OR5 or -N(R5)(R6), where R5 is hydrogen, C1-3 alkyl or phenyl, R6 is hydrogen or C1-3 alkyl, and R7 is hydrogen, C1-3 alkyl or -NHCONH2; Leu-pai is the reducing form of, where the C=O part of Leu represents -CH2-, where the bond of this -CH2- part is with the alpha-amino part of the remaining nearby part, i.e., a pseudopeptide bond, R9 is Tac, Mtac, or DMTac; and Q is NH2 or OQ1, where Q1 is hydrogen, C1-10 alkyl, phenyl or phenyl-C1-10 alkyl, and an acid or salt of a medicinally acceptable acid.

Claims (20)

1. The bombesin antagonist peptide has the formula ; X-A1-A2-Trp-Ala-Val-Gly-His-Leu-pai-A9-Q, where X is hydrogen, the single bond linking the alpha-amino group of A1 to the carboxyl core on the 3-propionyl portion of A2, where A2 is Glu[-], or the group with the formula R1 CO-, in this case R1 was selected from groups consisting of a) hydrogen C1-10 alkyl,phenyl,phenyl-C1-10-alkyl,p-HI-phenyl,p-HI-phenylC1-10-ilkyl, Naphthalenephthal-C1-10-alkyl, indoyl, indoyl-C1-10-ilkyl, pyridyl, pyridyl-C1-10-alkyl, thienyl, thienyl-C1-10-alkyl, cyclohexyl or cyclohexyl-C1-10-alkyl, here HI - F, Cl, Br, OH, CH3 or OCH3, b) (chemical formula) here R2 is hydrogen, C1-10 alkyl, phenyl or phenyl-C1-10-alkyl, R3 is hydrogen or C1-10 ilkyl, c) R4-O here R4 is C1-10 alkyl, phenyl or phenyl-C1-10-alkyl, A1 is residue D- or L-grosamino selected from the group consisting of Phe,p-HI-Phe, pGlu,Nal,Pal.Pal,Tpi,Trp are either unsubstituted or substituted in the benzene ring by one or more members selected from a group consisting of F,Cl,Br,NH2, or C1-3 alkyl, or peptide bonds linking the acyl portion of R1-CO to the alpha-amino portion of A2, where X-R1CO; A2 is Gln,Glu[-],Glu(Y), or His, where [-] is a single bond where X is a single bond and A2 is Glu[-]. This [-] links the carboxyl axis on the 3-propionyl portion of A2 to the group. The alpha-amino group of A1, Y is a) -OR5, where R3 is hydrogen, C1-10 alkyl, or phenyl, or b) (chemical formula), where R6 is hydrogen or C1-3 alkyl, and R7 is hydrogen, C1-3 alkyl, or -NHCONH2; Leu-pal- is the reducing form of Leu, where C=O represents -CH2-, in that the bond of this -CH2- portion to the adjacent alpha-amino group of A9 is a pseudopeptide bond, A9 is Tac, MTac, or DMTac; and Q is NH2 or OQ1, where Q1 is hydrogen, C1-10 alkyl, phenyl, or phenyl-C1-10 alkyl, and its pharmacologically acceptable acid or salt. 2. The peptide according to claim 1, where X is hydrogen, or R1CO; R is H or C1-10-alkyl; A1 is D-Cpa,D-Nal,L or D-Phe,D-Phe,L- or -D-Tpi or D-Tip; A2 is Gln or His; and Q is NH2. 3. The peptide under claim 2, where A9 is Tac. 4. The peptide under claim 2, here A9, is DMTac. 5. The peptides under claim 3, where X is H or Ac, A1 is D-Phe,L or D-Tpi, and A2 is Glm. 6. The peptide under claim 4, where X is H or Ac, A1 is D-Phe,L- or D-Tpi, and A2 is Gln. 7. Peptide according to claim 3 of formula Seq ID No.2 D-Phe-Gln-Trp-Ala-Val-Gly-His-Lue-psi-Tac-NH2- 8. Peptide according to claim 3 of formula Seq ID No.13 D-Trp-Gln-Trp-Ala-Val-Gly-His-Lue-psi-Tac-NH2- 9. Peptide according to claim 4 of formula Seq ID No.18 D-Phe-Gln-Trp-Ala-Val-Gly-His-Lue-psi-DMTac-NH2 10. The peptide antagonist Bombazin has the formula... X-A1-A2-Tep-Ala-Val-Giy-His-Leu-psi-A9-Q, where X is the hydrogen single bond linking the alpha-amino group of A1 to the carboxyl core on the 3-propionyl portion of A2, where A2 is Glu[-], or a group with the formula R1CO-, where R1 is selected from groups consisting of a) hydrogen C1-10 alkyl, phenyl, phenyl-C1-10-alkyl, b) (chemical formula), where R2 is hydrogen, C1-10 alkyl, phenyl, or phenyl-C1-10-alkyl, R3 is hydrogen or C1-10 alkyl, c) R4-O, where R4 is C1-10 alkyl, phenyl, or phenyl-C1-10-alkyl, A1 is a non-naturally occurring amino acid. Selected from groups containing L- or D-Pal, or L- or D-Tpi; A2 is Gln,Glu[-],Glu(Y) or His, where [-] is a single bond where X is a single bond and A2 is Glu[-], where [-] connects the gamma-carboxyl portion on the 3-propionyl portion of A2 to the alpha-amino group of A1, Y is a) -OR5, where R3 is hydrogen, C1-3 alkyl or phenyl, b) (chemical formula), where R6 is hydrogen, C1-3 alkyl and R7 is hydrogen, C1-3 alkyl or -NHCONH2; Leupsi- is the reducing form of Leu., where C-O represents -CH2-, in that the bond of this -CH2 portion to the adjacent alpha-amino group of the residue A9 is a pseudopeptide bond, A9 is Cys or Pen; And Q is NH2 or OQ, where Q1 is hydrogen, C1-10 alkyl, phenyl, or phenyl C1-10 alkyl, and its pharmaceutically acceptable acid or salt. 11. The antagonistic peptide Bombazim according to claim 1, where X is R1CO-, A1 is the peptide bond linking the acyl group of R1CO- to the alpha-amino portion of A2; A2 is Gln or His; and Q is Hil2. Q is NH2. 12. The peptides under claim 11 here are X, Hca, Hca, Paa, Mpp, or Naa, A2 is Gin, and A9 is Tac. 13. Peptide according to claim 12 of formula Seq ID No.14 Hca-GIn-Trp-Ala-Val-Gly-His-Leu-psi-Tac-NH2 14. Pharmaceutical mixtures containing the therapeuticly acceptable polypeptides as per claim 1, or their therapeuticly acceptable salt forms, or complexes of polypeptides and liquid or solid carriers of the pharmaceutically acceptable polypeptides. 15. The use of the polypeptides under claim 1, or their acids or salts, that are therapeutically acceptable in the manufacture of drugs for the treatment of pancreatic cancer in mammals. 16. Peptide according to claim 1, where A2 is Gln, A9 is Tac, and Q is NH2. 17. Peptide according to claim 16, where A1 is a residue D or L selected from groups containing Phe, p-HI-Phe, and Trp. 18. Selected peptide from the group containing (chemical formula). 19. The peptide under claim 18 with the formula D-Tpi-Gln-Trp-Ala-Val-Gly-His-Leu-psi-Tac-NH2. 20. Peptide under claim 18 with the formula D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-psi-DMTac-NH2