TH2218A - GRF analogues - Google Patents

Abstract

Characteristics and synthesis of GRF from human pancreas (phGRF), GRF from rat hypothalamus (rGRF), and GRF from pork hypothalamus (pGRF) have been conducted. Represents synthetic peptides. This is very strong in stimulating the secretion of pituitary GH in animals including humans. And has the ability to resist degradation by the enzyme in the body. This peptide has the following sequence. R1-R2-R3-Ala-Ile-Phe-Thr-R8-Ser-R10-Arg-R12- R13 -Leu-R15-Gln-R17-R18-Ala-Arg-Lys-Leu-R23- R24-R25 Ile -R27-R28-Arg-Gln-Gly-Glu-R34- Asn-Gln-Glu-R38-R39-R40-Arg-R42-R43-R44 where R1 is Tyr-D-Tyr, Met, Phe, D- Phe, pCl-Phe-Leu, His or D-His, where C (alpha) Me or N (alpha) Me is replaced or without R2 is Ala or D-Ala; R3 is Asp or D-Asp, R8 is Ser, Asn, D-Ser or D-Asn; R10 is Tyr or D-Tyr; R12 is Arg or Lys;; R13 is Ile or Val; R15 is Gly or D-Ala; R17 is Leu or D-Leu; R18 is Tyr or Ser; R23 is Leu or D-Leu; R24 is His or Gln; R25 is Glu, Asp, D-Glu or D-Asp; R327 is Met, D-Met, Ala, Nle, Ile, Leu, Nva. Or Val; R28 is Ser; R34 is Arg or Ser; R38 is Gln or Arg; R39 is Arg or Gly; R40 is Ser or Ala; R42 is Phe, Ala, or Aal; R43 is Asn or Arg; R44 is amine. Natural And the peptide at (a) R1 replaced C (alpha) Me or N (alpha) Me or (b) R17 and / or R23 is D-Leu or (c) R25, possibly D-Glu or D-Asp and also provides one or all of the radical peptides from R29 to R44 missing or giving their salts non-toxic. The carbon tip of this peptide is popular as amide. This peptide and its non-toxic salts can be given to animals, including cold-blooded humans and animals, to induce CH secretion or be used in the diagnosis of:

Claims (2)

1. Process for producing peptides with this sequence R1-R2-R3-Ala-Ile-Phe-Thr-R8-Ser-R10-Arg-R12-R13-Ler-R15-Gln-R17 - R18-Ala-Arg-Lys-Leu-R23-R24-R25 Ile-R27-R28-Arg-Gln-Gly-Glu-R34 -Asn-Gln-Glu-R38-R39-R40-Arg-R42-R43-R44 where R1 is Tyr-D-Tyr, Met, Phe, D. -Phe, pCl-Phe-Leu, His or D-His, with C (alpha) Me or N (alpha) Me replacement or without R2 is Ala or D-Ala; R3 is Asp or D-Asp, R8 is Ser, Asn, D-Ser or D-Asn; R10 is Tyr or D-Tyr; R12 is Arg or Lys;; R13 is Ile or Val; R15 is Gly or D-Ala; R17 is Leu or D-Leu; R18 is Tyr or Ser; R23 is Leu or D-Leu: R24 is His or Gln; R25 is Glu, Asp, D-Glu or D-Asp; R327 is Met, D-Met, Ala, Nle, Ile, Leu, Nva or Val; R28 is Ser; R34 is Arg or Ser; R38 is Gln or Arg; R39 is Arg or Gly; R40 is Ser or Ala; R42 is Phe, Ala or Aal; R43 is Asn or Arg; R44 is amino acid. Natural Mino And the peptide at (a) R1 replaced C (alpha) Me or N (alpha) Me or (b) R17 and / or R23 is D-Leu or (c) R25, possibly D-Glu or D-Asp and peptides with one or all radicals between R29 and R44 are missing, consisting of (i) forming a compound with at least one protection group and the formula (II) X1-R1 ( X or X2) -R2-R3 (X3) -Ala-Ile-Phe-Thr (X4) -R8 (X4 or X5) -Ser (X4) -R10 (X2) -Arg (X6) -R12 (X6 or X7 ) -R13-Leu-R15- (Gln (X5) -R17-R18 (X2) -Ala-Arg (X6) -Lys (X7) -Leu-R23R24 (X5 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) - where (X), (X1), (X2), (X3), (X4), (X5), (X6), (X7) and (X8. ) Are either hydrogen or a protection group, and where (X9) may be an amide group or a hydroxy group. And (ii) cut off the protection group from the compound having formula II and gave the peptide with formula (I) or its parts that are biologically active. And if desired (iii) convert the resulting peptide into its non-toxic salt form 2. The process in claim 1 where R25 is D-Glu 3. The process mentioned in claim 1 Where R25 is D-Asp 4. the aforementioned process in Claim 1, 2 or 3 where R23 is D-Leu 5. The aforementioned process in any of the Clause 1-4 where R23 is D. -Leu 6. The aforementioned process in any of Clause 1-5 where R27 is Nle 7. The process in any of Clause 1-6 where R1 replaces C (alpha ) Me or N (alpha) Me 8. As mentioned in any of Claims 1-7 where X1 is hydrogen or alpha-amino defense group, X2 is hydrogen or feed group. Tyr's nalic hydroxy; X3 is the hydrogen or the Asp or Glu carboxy block; X4 is the hydrogen or defense group. Alcohol hydroxy T hr; X5 is hydrogen or Ser hydroxy alcohol protection group; X6 is hydrogen or Arg nidino protection group; R7 is the hydrogen or Lys lateral chain amino defense group; X8 is the hydrogen or the appropriate lateral chain amino defense group, X is the hydrogen or His nitrogen immidazol nitrogen defense group; And X9 was selected from the OH, OCH3, Ester, Amide, Hydrazide, -OCH2-supported resin, and -NH-Support resin 9. The aforementioned process in claim 8 where X1 is BOC, X2 is 2,6 dichlorobenzyl, X3 is Bzl, X4 is Bzl, X5 is Bzl, X6 is Tos, X7 is 2-chlorobenzyl oxccarbonyl and X9 is -O. -CH2- Resin supports 1.0. As mentioned in claim 8, X1 is BOC, X2 is 2,6-Dichlorobenzyl, X3 is Bzl, X4 is Bzl, X5 is Bzl, X6 is Tos. , X7 is 2-chlorobenzyl oxccarbonyl and X9 is -NH-resin backing 1. 1.How to improve agriculture Where GH release in non-human warm-blooded animals Stimulated to increase muscle tone And / or milk production By using peptides or salt Which is defined in claim number 1 in effective quantity 1 2. Methods for improving agriculture. Where GH release in cold-blooded animals Was stimulated to accelerate the growth of those animals. By using peptides or salt Which is defined in claim number 1 in effective quantities