TH2482B - GRF analogues (GRF) - Google Patents

Abstract

A metabolite similar to human pancreatic GRF was synthesized to induce pituitary GH secretion in mammals. This synthetic has the following formula: H-R1-Ala-Asp-Ala-Ile-Phe-Thr-R8-Ser-R10-Arg-R12-R13-Le u-F15-Gln-Leu-R18-Ala-Arg-Lys. -Leu-Leu-R24-R25-Ile R27-R28-Arg-Gln-Gln-Gly-Glu-R34-Asn-Gln-Glu-R38- R39-R40-Arg-R42-R43-R44-Y where R1 or Tyr, Met, D-Tyr, Phe, D-Phe, Leu, D-Fis or His; R8 is Ser or Asn; R10 is Tyr, Phe or D-Tyr; R12 is Arg or Lys; R13 is Ile or Val. ; R15 is Gly or D-Ala; R18 is Tyr or Ser; R24 is His or Gln; R25 is Glu or Asp; R27 is selectively composed of D and L-isomers of Ala, Nle, Ile, Leu, Met and Val; R28 is Ser, Asn or D-Ala; R34 is Arg or Ser; R38 is Gln or Arg; R39 is Arg or Gly; R40 is Ser or Ala; R42 is Phe or Ala; R43 is Asn or Arg; R44 is a natural amino acid, or des-R44; and Y is the carboxy group of amino acids at the carbon end, which is -COOR, -CRO, -CONHNHR, -CON(R)(R'') or -CH2OR, where R and R'' are groups. small alkyl small fluoroalkyl or hydrogen and if R is Tyr, R27 is a non-Met radical, R8 is Ser, R12 is Arg, R13 is Ile, R18 is Tyr, R24 is His, R25 is Glu, R28 is Asn, R34 is Arg, R38 is Gln, R39 is Arg, R40 is Ser, R42 is Phe or R43 is Asn; It can also synthesize peptides with any oxidant. One or all of the radicals 28 to 44 were eliminated and bioactive fragments were obtained. or prepare a salt that is not The toxicity of this peptide generally peptides or fragments The length of these biologically active peptides from the nitrogen tip to the radical between the 27th and 32nd order includes the innocuous salts of these peptides. This peptide and its non-toxic salt can be used by animals. including people and aquatic animals

Claims (11)

1. The process for fabricating a substance with the formula (I) :H-R1-Ala-Asp-Ala-Ile-Phe-Thr-R8-Ser-R10-Arg-R12-R13- Leu-F15-Gln-Leu-R18-Ala-Arg-Lys-Leu-Leu-R24-R25-Ile R27-R28-Arg-Gln-Gln-Gly-Glu-R34-Asn-Gln-Glu-R38-R39- R40-Arg-R42-R43-R44-Y where R1 is Tyr, Met, D-Tyr, Phe, D-Phe, Leu, D-Fis or His; R8 is Ser or Asn; R10 is Tyr, Phe or D-Tyr; R12 is Arg or Lys; R13 is Ile or Val; R15 is Gly or D-Ala; R18 is Tyr or Ser; R24 is His or Gln; R25 is Glu or Asp; R27 is a selected group containing D and L-isomers of Ala, Nle, Ile, Leu, Met, and Val; R28 is Ser, Asn, or D-Ala; R34 is Arg or Ser; R38 is Gln or Arg; R39 is Arg or Gly; R40 is Ser or Ala; R42 is Phe or Ala; R43 is Asn or Arg; R44 is a naturally occurring amino acid or des-R44; Y represents the carboxylic group of the amino acid at the carbon end, which can be -COOR, -CRO, -CONHNHR, -CON(R)(R'), or -CH2OR, where R and R' are small alkyl groups, small fluoroalkyl groups, or hydrogen. If R is Tyr, R27 is another radical other than Met; R8 is Ser; R12 is Arg; R13 is Ile; R18 is Tyr; R24 is His; R25 is Glu; R28 is Asn; R34 is Arg; R38 is Gln; R39 is Arg; R40 is Ser; R42 is Phe; or R43 is Asn. This is also a process for preparing peptides in which one or all of radicals 28 through 44 are cleaved, resulting in a biologically active peptide fragment or its non-toxic salt. Consisting of (a) a teptide containing at least one protective group and having the formula (II) : X1-R1(X X2)-Ala-Asp(X3)-Ala-Ile-Phe-Thr(X4)-R8(X4 X5)-Ser(X4)-R10(X2)-Arg(X6)-R12(X6 X7)-R13-Leu-R15-Gln(X5)-Leu-R18(X2)-Ala-Arg(X6)-Lys(X7 )-Leu-Leu-R24(X or X5)-R25(X3)-Ile-R27-R28(X4 or X5)-Arg(X6)-Gln(X5)-Gln(X5)-Gly-Glu(X3)-R34(X4 or X6)-Asn(X5)-Gln(X5)-Glu(X3)-R38(X5 or X6)-R39 (X6)-R40(X4)-Arg(X6)-R42-R43(X5 or X6)-R44(X8)-X9 where X, X1, X2, X3, X4, X5, X6, X7 and X8 may be hydrogen or protective groups and X9 may be a protective group or a group that bonds to the supporting resin or des-X9 in the case where the carbon-terminal radical has a carboxylic group where Y ; (b) is separated from the protective group or bonding group of the peptide formula (II) and (c) if it is desired to convert the resulting peptide into a non-toxic salt form. 2. The procedure is the same as described in Reputation 1, where X1 is hydrogen or alpha-amino group defense; X is hydrogen or immicrol nitrogen group defense of His; X2 is hydrogen or phenolic hydroxyl group defense of Tyr; X3 is hydrogen or carboxy group defense of Asp or Glu; X4 is hydrogen or alcoholic hydroxyl group defense of Ser and Thr; X5 is hydrogen or amino group defense of Asn or Gln; X6 is hydrogen or guanitino group defense of Arg; X7 is hydrogen or side-amino chain defense of Lys. 3. The process is the same as described in Claim 2, where X is hydrogen or Tos, X1 is BOC, X2 is DCB, X3 is OBzl, X4 is Bzl, X5 is Xan, X6 is Tos, X7 is 2-chlorobenzyloxycarbonic and X8 is -NH- resin. 4. The procedure is the same as that described in any one of the claims 1-3, where R1 is His. 5. The procedure is the same as that described in any one of the claims 1-4, where Y is CONH2. 6. The procedure is the same as that described in any one of the claims 1-5, where R27 is Nle. 7. The procedure is the same as that described in any one of the claims from 1-6, where R10 is Tyr, R15 is Gly, and R28 is Ser. 8. The procedure is the same as that described in any one of the claims 1-6, where Tyr, R15 is D-Ala and R28 is D-Ala. 9. The procedure is the same as that described in any one of the claims 1-3, where R1 is D-Tyr and R27 is Nle, Val, or Ile. 10. The same procedure as described in claim 1 for the fabrication of a synthetic peptide with the following sequence: His-Ala-Asp-Ala-Ile-Phe-Thr-Ser-Ser-Tyr-Arg-Arg-Ile-Le u-Gly-Gln-Leu-Tyr-Ala-Arg-Lys-Leu-Leu-His-Glu-Ile-Met- Asn-Arg-Gln-Gln-Gly-Glu-Arg-Asn-Gln-Glu-Gln-Arg-Ser-Ar g-Phe-Asn 11. The procedure is the same as that described in any one of the claims 1-10, with radicals 33 through 44 omitted. (11 claims, 3 pages, Figure)