TH11522A - Synthetic peptides that exhibit pituitary hormone-releasing activity. - Google Patents

Abstract

A novel peptide, having the following amino acid sequence (chemical formula), where X1, X2, and X3 are selected from groups containing substituents at the N-terminus and at the desamino-alpha-carbon, and a and b are either 0 or 1, with the requirement that a and b will always be 0, where A1 is the desamino portion, and A1 and A4 are selected from groups which... It comprises cystidyl, arginil, lysyl, (chemical formula) naphthyl alanil, (chemical formula) naphthyl alanil, isoquinolide, tyrosyl, tryptophyll, phenyl alanil, homologs and analogs of these groups, and only A1, the desamino form of these groups; A2 and A5 are selected from groups comprising D-histikyl, D-arginil, D-lysyl, D-naphthyl alanil, D-naphthyl alanil, D-isoquinolide, D-tyrosyl, D-tryptophyll, D-phenyl alanil, homologs and analogs of these groups; A3 is selected from groups comprising glycyl, alanil, valyl, leucine, isolucyl, prolyl, ceryl, threonil. Methionil, aspartyl, glutamyl, asparaginil, glutaminyl, histidyl, D-alanil, D-valyl, D-leucine, D-isoleucyl, D-prolyl, D-ceryl, D-threonil, D-methionil, D-aspartyl, D-glutamyl, D-asparaginil, D-glutaminyl, D-histidyl, and homologs and analogs of these groups; A6 selected from groups containing L- and D-configured amino acid segments, homologs and analogs of these groups, and descarboxylic forms of these groups; and Y selected from groups containing C-terminal and descarboxy alpha-carbon substituents, and pharmacologically recognized salts of these compounds.

Claims (46)

1. The peptides of the formula (chemical formula) are chosen from groups containing -R, -OR, RC(O)-, where R1 is chosen from groups containing hydrogen and other groups. Branched or unbranched alkyls with 1-6 carbon atoms, where a and b are 0 or 1, with the requirement that a and b are 0 when A1 is the desamino portion, A1 and A4 are selected from groups containing His, Arg, Lys, (chemical formulas), homologs and analogs of these groups, and, only A1, the desamino form of these groups, A2 and A5 are selected from groups containing D-His, D-Arg, D-Lys, (chemical formulas), homologs and analogs of these groups, and, only A1, the desamino form of these groups, A3 is selected from groups containing Gly, Ala, Val, Leu, Ile, Pro, Ser, Thr, Met, Asp, Glu, Asn, Hln, His, D-Ala, D-Val, D-Lue, D-Ile, D-Pro, D-Ser, D-Thr, D-Met, D-Asp. D-Glu, D-Asn, D-Gln, D-His, and homologs and analogs of these groups A6 is selected from groups containing amino acids with L- and D-continuation, homologs and analogs of these groups, and descarboxylic forms of these groups, and Y is selected from groups containing substituents at the C-terminus and at the descarboxy alpha-carbon, and pharmacologically recognized salts of these substances. 2. Peptides of claim 1, where a is 0 or 1 and b is 0. A1 and A4 are selected from groups containing His, Tyr, Trp, Phe, homologs and analogs of those groups, and only A1, the desamino form of those groups. a2 and A5 are selected from groups containing D-His, D-Tyr, D-Trp, D-Phe and homologs and analogs of those groups. A3 is selected from groups containing Gly, Ala, Ser, Asn, Pro, D-Ala, D-Ser, D-Asp, D-Pro and homologs and analogs of these groups. A6 is selected from groups containing... Arg, Lys, Orn, His, Asp, Glu, Asn, Gln, Asn, Gln, D-Arg, D-lys, D-Orn, D-His, D-Asp, D-Glu, D-Asn, D-Gln, D-Arg, and their homologs and analogs, and their dtaboxylic forms. Y is selected from groups containing -CH2OH, -OR, and -NR1R2, where R, R1, and R2 are selected from groups containing hydrogen and branched and unbranched alkyl groups with 1-6 carbon atoms, and their pharmacologically recognized salts. 3. A peptide of claim 1, whose chemical formula a is 0 or 1, is selected from groups containing RCO and R-, where R is selected from groups containing hydrogen and alkyl groups with 1-2 carbon atoms. A1 is selected from groups containing Tyr, O-Me-Tyr, His, 3-N-Me-His-P-Cl-Phe. And the amino acid forms of those groups A3 selected from groups containing Ala, Ser, and D-Ala; A4 selected from groups containing Trp and Tyr; A5 selected from groups containing D-Phe, D-His, D-Tyr, and D-p-Cl-Phe; A6 selected from groups containing Arg, Hymo Arg, Lys, Orn, Asp, Glu, Asp, Gln, and D-Lys; Y selected from groups containing -OR and -NHR; R selected from groups containing hydrogen and alkyl groups with 1-2 carbon atoms and their pharmacologically acceptable salts. 4. The peptide of claim 1, with the formula H2-Tyr-D-Trp-Ala-Trp-D-Phe-Met-NH2. 5. The peptide of claim 1, with the formula H2-Tyr-D-Trp-Ala-Trp-D-Phe-Thr-NH2. 6. The peptide of claim 1, with the formula H2-Tyr-D-Trp-Ala-Trp-D-Phe-Gln-OH. 7. The peptide of claim 1, with the formula H2-Tyr-D-Trp-Ala-Trp-D-Phe-Gln-NH2. 8. The peptide of claim 1, with the formula H2-Tyr-D-Trp-Ala-Trp-D-Phe-Asn-NH2. 9. The peptide of claim 1, with the formula H2-Tyr-D-Trp-Ala-Trp-D-Phe-Lys-NH2. 10. The peptide of claim 1, with the formula H2-Tyr-Phe-D-Trp-Ala-Trp-D-Phe-Lys-NH2. 11. The peptide of claim 1, with the formula H2-Tyr-D-Trp-Ala-Trp-D-Phe-Glu-NH2. 12. The peptide of claim 1, with the formula H2-Tyr-D-Trp-Ala-Trp-D-Phe-Phe-NH2. 13. The peptide of claim 1, with the formula H2-Tyr-D-Trp-Ala-Trp-D-Phe-Gln-NH2. 14. The peptide of claim 1, with the formula H2-His-D-Trp-Ala-Trp-D-Phe-Lys-OH. 15. The peptide of claim 1, with the formula H2-His-D-Trp-Ala-Trp-D-Phe-Arg-NH2. 16. The peptide of claim 1, with the formula H2-His-D-Trp-Ala-Trp-D-Phe-Gln-NH2. 17. The peptide of claim 1, with the formula H2-His-D-Trp-Ala-Trp-D-Phe-Gln-NH2. 18. The peptide of claim 1, with the formula H2-His-D-Trp-Ala-Trp-D-Phe-HomoArg-NH2. 19. The peptide of claim 1, with the formula H2-3-N-Me-His-D-Trp-Ala-Trp-D-Phe-Lys-NH2. 20. The peptide of claim 1, with the formula H2-His-D-Trp-Ala-Trp-D-Phe-Lys-NHCH2CH3. 21. The peptide of claim 1, with the formula H2-His-D-Trp-Ala-Trp-D-Phe-Orn-NH2. 22. The peptide of claim 1, with the formula H2-His-D-Trp-Val-Trp-D-Phe-Lys-NH2. 23. The peptide of claim 1, with the formula H2-His-D-Trp-Ser-Trp-D-Phe-Lys-NH2. 24. An intermediate mixture whose formula is chosen from a group containing (chemical formula) where Pr1 is the acid-protecting group, (chemical formula) amino a, b, m, q, r, and s, each with 0 or 1; X1, X2, and X3 are chosen from a group containing -R, -OR, RC(O)-, where R is chosen from a group containing hydrogen and branched or unbranched alkyl groups with 1-6 carbon atoms; B1 and B4 are chosen from a group containing His, Arg, Lys, (chemical formula)-Naphyh, B-Naphth, Igl, Tyr, Trp, Phe, Hymoloc, and Ana. The homologs of those groups, the form in which the sidesens of those groups are protected, only B1, the desamino forms of those groups, B2 and B5 selected from groups containing D-His, D-Arg, D-Lys, D-(chemical formula)-Naphyh, D-B-Naphth, D-Igl, D-Tyr, D-Trp, D-Phe, homologs and analogs of those groups, the form in which the sidesens of those groups are protected, only B1, the desamino forms of those groups, B3 selected from groups containing amino acids with L- and D-configuration, homologs and analogs of those groups, the form in which the sidesens of those groups are protected, and only B6, the descarboxylic forms of those groups. R is the resin, Y is selected from groups containing substituents at the C-terminus and descarboxylic asphacarbons, and Pr2 is the protective carboxylic group. 25. An intermediate mixture of claim 24, which B1 and B4 select from groups containing His, Tyr, Trp, Phe, homologs and analogs of those groups, for B1 the desamino forms of those groups, and the shielded sidesen forms of those groups; B2 and B5 select from groups containing D-His, D-Tyr, D-Trp, D-Phe, homologs and analogs of those groups, and the shielded sidesen forms of those groups; B3 select from groups containing Gly, Ala, Ser, Asn, Pro, D-Ala, D-Ser, D-Asn, D-Pro, homologs and analogs of those groups. The homologs and analogs of those groups, and the descarboxylic forms of those groups, and B6 and B6 select from the groups comprising Arg, Lys, Orn, His, Asp, Glu, Asn, D-Arg, D-Orn, D-Lys, D-His, D-Asp, D-Glu, D-Asn, D-Gln, homologs and analogs of those groups, and only the descarboxylic forms of those groups, and the descarboxylic forms of those groups. 26. An intermediate mixture of claim 24, whose formula is chosen from groups containing (chemical formulas) which B1 is chosen from groups containing Tyr, O-Me-Tyr, His, 3-N-Me-His, P-Cl-Phe, the desamino forms of these groups, and the shielded forms of these groups; B3 is chosen from groups containing Ala, Ser, D-Ala, and the shielded forms of these groups; B4 is chosen from groups containing Trp, Tyr, and the shielded forms of these groups; B5 is chosen from groups containing D-Phe, D-His, D-Tyr, D-P-Cl-Phe, and the shielded forms of these groups; and B6 and B6 are chosen from groups containing Arg, homo Arg, Lys, Orn, Asp, Glu, Asn, Gln, D-Lys, the descarboxylic forms of these groups, and the shielded forms of these groups. 27. An intermediary mixture of claim 24, which has the formula (chemical formula) where Brz is 0-bromobenzyloxycarbonyl, Boc is t-butyloxycarbonyl, and R is p-methylbenzhydrylamine resin. 28. An intermediary mixture of claim 24, which has the formula (chemical formula) where Bzl is benzyl, Brz is 0-bromobenzyloxycarbonyl, Boc is t-butyloxycarbonyl, and R is p-methylbenzhydrylamine resin. 29. An intermediary mixture of claim 24, which has the formula (chemical formula) where Pr3 is 0-bromobenzyloxycarbonyl, Boc is t-butyloxycarbonyl, and R is p-methylbenzhydrylamine resin. 30. An intermediary mixture of claim 24, which has the formula (chemical formula) in which Brz is 0-bromobenzyloxycarbonyl, Boc is t-butyloxycarbonyl, and R is p-methylbenzhydrylamine resin. 31. An intermediary mixture of claim 24, which has the formula (chemical formula) where Brz is 0-bromobenzyloxycarbonyl, Boc is t-butyloxycarbonyl, and R is p-methylbenzhydrylamine resin. 32. An intermediary mixture of claim 24, which has the formula (chemical formula) where Clz is 0-chlorbromobenzyloxycarbonyl, Tos is p-toluene sulfonyl, Boc is t-butyloxycarbonyl, and R is p-methylbenzhydrylamine resin. 33. An intermediary mixture of claim 24, which has the formula (chemical formula) where Clz is 0-chlorbromobenzyloxycarbonyl, Tos is p-toluene sulfonyl, Brz is p-bromobenzyloxycarbonyl, Boc is t-butyloxycarbonyl, and R is p-methylbenzhydrylamine resin. 34. An intermediary mixture of claim 24, which has the formula (chemical formula) in which -Byl is -benzyl ester, Brz is p-bromobenzyloxycarbonyl, Boc is t-butyloxycarbonyl, and R is p-methylbenzhydrylamine resin. 35. An intermediary mixture of claim 24, which has the formula (chemical formula) where Brz is p-bromobenzyloxycarbonyl, Boc is t-butyloxycarbonyl, and R is p-methylbenzhydrylamine resin. 36. An intermediary mixture of claim 24, which has the formula (chemical formula) where ONP is p-nitropenol ester, Br is p-bromobenzyloxycarbonyl, Boc is t-butyloxycarbonyl, and R is p-methylbenzhydrylamine resin. 37. An intermediary mixture of claim 24, which has the formula (chemical formula) where Clz is 0-chlorbromobenzyloxycarbonyl, Tos is p-toluene sulfonyl, Boc is t-butyloxycarbonyl, and R is p-methylbenzhydrylamine resin. 38. An intermediary mixture of claim 24, which has the formula (chemical formula) where Tos is p-toluene sulfonyl, Boc is t-butyloxycarbonyl, and R is p-methylbenzhydrylamine resin. 39. An intermediary mixture of claim 24, which has the formula (chemical formula) where ONP is p-nitrophenyl ester, Tos is p-toluene sulfonyl, Boc is t-butyloxycarbonyl, and R is p-methylbenzhydrilamine resin. 40. An intermediary mixture of claim 24, whose formula (chemical formula) is: BZl represents -benzyl ester, Tos is p-toluene sulfonyl, Boc is t-butyloxycarbonyl, and R is p-methylbenzhydrylamine resin. 41. An intermediary mixture of claim 24, which has the formula (chemical formula) where Tos is p-toluene sulfonyl, Boc is t-butyloxycarbonyl, and R is p-methylbenzhydrylamine resin. 42. An intermediary mixture of claim 24, which has the formula (chemical formula) where Clz is 0-chlorbromobenzyloxycarbonyl, Boc is t-butyloxycarbonyl, and R is p-methylbenzhydrylamine resin. 43. An intermediary mixture of claim 24, which has the formula (chemical formula) where Clz is 0-chlorbromobenzyloxycarbonyl, Tos is p-toluene sulfonyl, Boc is t-butyloxycarbonyl, and R is p-methylbenzhydrylamine resin. 44. An intermediary mixture of claim 24, which has the formula (chemical formula) where Z is benzyloxycarbonyl, Tos is p-toluene sulfonyl, Boc is t-butyloxycarbonyl, and R is p-methylbenzhydrylamine resin. 45. An intermediary mixture of claim 24, which has the formula (chemical formula) where Clz is 0-chlorbromobenzyloxycarbonyl, Tos is p-toluene sulfonyl, Boc is t-butyloxycarbonyl, and R is p-methylbenzhydrylamine resin. 46. An intermediary mixture of claim 24, which has the formula (chemical formula) where Clz is 0-chlorbromobenzyloxycarbonyl, Bzl is -benzyl, Tos is p-toluene sulfonyl, Boc is t-butyloxycarbonyl, and R is p-methylbenzhydrylamine resin. (46 claims, 16 pages, 0 images)