Synthetic peptides having pituitary growth hormone releasing activity

US 4,411,890 A
Filed: 12/28/1981
Issued: 10/25/1983
Est. Priority Date: 04/14/1981
Status: Expired due to Term

First Claim

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1. A peptide having a formula ##STR72## wherein X₁, X₂, and X₃ are selected from a group consisting of --R, --OR, RC(O)-- wherein R is selected from a group consisting of hydrogen and straight chain and branched chain alkyl groups containing 1-6 carbon atoms;

a and b are 0 or 1, provided that a and b are 0 when A₁ is a desamino residue;

A₁ and A₄ are selected from a group consisting of His, Arg, Lys, α

-Naphth, β

-Naphth, IQl, Tyr, Trp, Phe, homologues and analogues thereof, and, with respect to A₁, the desamino forms thereof;

A₂ and A₅ are selected from a group consisting of D-His, D-Arg, D-Lys, D-α

-Naphth, D-β

-Naphth, D-Iql, D-Tyr, D-Trp, D-Phe, and homologues and analogues thereof;

A₃ is selected from a group consisting of Gly, Ala, Val, Leu, Ile, Pro, Ser, Thr, Met, Asp, Glu, Asn, Gln, His, D-Ala, D-Val, D-Leu, D-Ile, D-Pro, D-Ser, D-Thr, D-Met, D-Asp, D-Glu, D-Asn, D-Gln, D-His, and homologues and analogues thereof;

A₆ is selected from a group consisting of amino acids of the L- and D-configuration, homologues and analogues thereof, and the descarboxy forms thereof; and

Y is selected from a group consisting of C-terminal and descarboxy alpha-carbon substitutions;

and the pharmaceutically acceptable salts thereof.

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Abstract

Novel peptides having the following amino acid sequence ##STR1## wherein X₁, X₂, and X₃ are selected from a group consisting of N-terminal and desamino alpha-carbon substitutions and a and b are 0 or 1, provided that a and b are always 0 when A₁ is a desamino residue; A₁ and A₄ are selected from a group consisting of histidyl, arginyl, lysyl, α-naphthylalanyl, β-naphthylalanyl, isoquinolyl, tyrosyl, tryptophyl, phenylalanyl, homologues and analogues thereof, and, with respect to A₁ only the desamino forms thereof; A₂ and A₅ are selected from a group consisting of D-histidyl, D-arginyl, D-lysyl, D-α-naphthylalanyl, D-β-naphthylalanyl, D-isoquinolyl, D-tyrosyl, D-tryptophyl, D-phenylalanyl, homologues and analogues thereof; A₃ is selected from a group consisting of glycyl, alanyl, valyl, leucyl, isoleucyl, prolyl, seryl, threonyl, methionyl, aspartyl, glutamyl, asparginyl, glutaminyl, histidyl, D-alanyl, D-valyl, D-leucyl, D-isoleucyl, D-prolyl, D-seryl, D-threonyl, D-methionyl, D-aspartyl, D-glutamyl, D-asparaginyl, D-glutaminyl, D-histidyl, and homologues and analogues thereof; A₆ is selected from a group consisting of amino acids of the L- and D- configuration, homologues and analogues thereof, and the descarboxy forms thereof; and Y is selected from a group consisting of C-terminal and descarboxy alpha-carbon substitutions; and the pharmaceutically acceptable salts thereof.

Citations

48 Claims

1. A peptide having a formula ##STR72## wherein X₁, X₂, and X₃ are selected from a group consisting of --R, --OR, RC(O)-- wherein R is selected from a group consisting of hydrogen and straight chain and branched chain alkyl groups containing 1-6 carbon atoms;
- a and b are 0 or 1, provided that a and b are 0 when A₁ is a desamino residue;
  
  A₁ and A₄ are selected from a group consisting of His, Arg, Lys, α
  
  -Naphth, β
  
  -Naphth, IQl, Tyr, Trp, Phe, homologues and analogues thereof, and, with respect to A₁, the desamino forms thereof;
  
  A₂ and A₅ are selected from a group consisting of D-His, D-Arg, D-Lys, D-α
  
  -Naphth, D-β
  
  -Naphth, D-Iql, D-Tyr, D-Trp, D-Phe, and homologues and analogues thereof;
  
  A₃ is selected from a group consisting of Gly, Ala, Val, Leu, Ile, Pro, Ser, Thr, Met, Asp, Glu, Asn, Gln, His, D-Ala, D-Val, D-Leu, D-Ile, D-Pro, D-Ser, D-Thr, D-Met, D-Asp, D-Glu, D-Asn, D-Gln, D-His, and homologues and analogues thereof;
  
  A₆ is selected from a group consisting of amino acids of the L- and D-configuration, homologues and analogues thereof, and the descarboxy forms thereof; and
  
  Y is selected from a group consisting of C-terminal and descarboxy alpha-carbon substitutions;
  
  and the pharmaceutically acceptable salts thereof.
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25)
- - 2. The peptide of claim 1 wherein:
    - a is 0 or 1 and b is 0;
      
      A₁ and A₄ are selected from the group consisting of His, Tyr, Trp, Phe, homologues and analogues thereof, and with respect to A₁, the desamino forms thereof;
      
      A₂ and A₅ are selected from the group consisting of D-His, D-Tyr, D-Trp, D-Phe, and homologues and analogues thereof;
      
      A₃ is selected from the group consisting of Gly, Ala, Ser, Asn, Pro, D-Ala, D-Ser, D-Asn, D-Pro, and homologues and analogues thereof;
      
      A₆ is selected from the group consisting of Arg, Lys, Orn, His, Asp, Glu, Asn, Gln, D-Arg, D-Lys, D-Orn, D-His, D-Asp, D-Glu, D-Asn, D-Gln, D-Arg, homologues and analogues thereof, and descarboxy forms thereof;
      
      Y is selected from the group consisting of --CH₂ OH, --OR, and --NR₁ R₂, wherein R, R₁ and R₂ are selected from the group consisting of hydrogen and straight and branched chain alkyl groups containing 1-6 carbon atoms; and
      
      the pharmaceutically acceptable salts thereof.
  - 3. The peptide of claim 1 having the formula ##STR73## wherein a is 0 or 1;
    - X₂ is selected from the group consisting of RCO and R-- wherein R is selected from the group consisting of hydrogen and alkyl groups containing 1-2 carbon atoms;
      
      A₁ is selected from the group consisting of Tyr, O-Me-Tyr, His, 3-N-Me-His, p-Cl-Phe, and the desamino forms thereof;
      
      A₃ is selected from the group consisting of Ala, Ser, and D-Ala;
      
      A₄ is selected from the group consisting of Trp and Tyr;
      
      A₅ is selected from the group consisting of D-Phe, D-His, D-Tyr, and D-p-Cl-Phe;
      
      A₆ is selected from the group consisting of Arg, HomoArg, Lys, Orn, Asp, Glu, Asn, Gln, and D-Lys;
      
      Y is selected from the group consisting of --OR, and --NHR, wherein R is selected from the group consisting of hydrogen and alkyl groups containing 1-2 carbon atoms; and
      
      the pharmaceutically acceptable salts thereof.
  - 4. The peptide of claim 1 of the formulaH₂ -Tyr-D-Trp-Ala-Trp-D-Phe-Met-NH₂.
  - 5. The peptide of claim 1 of the formulaH₂ -Tyr-D-Trp-Ala-Trp-D-Phe-Thr-NH₂.
  - 6. The peptide of claim 1 of the formulaH₂ -Tyr-D-Trp-Ala-Trp-D-Phe-Gln-OH.
  - 7. The peptide of claim 1 of the formulaH₂ -Tyr-D-Trp-ALa-Trp-D-Phe-Gln-NH₂.
  - 8. The peptide of claim 1 of the formulaH₂ -Tyr-D-Trp-Ala-Trp-D-Phe-Asn-NH₂.
  - 9. The peptide of claim 1 of the formulaH₂ -His-D-Trp-Ala-Trp-D-Phe-Lys-NH₂.
  - 10. The peptide of claim 1 of the formulaH₂ -Tyr-Phe-D-Trp-Ala-Trp-D-Phe-Lys-NH₂.
  - 11. The peptide of claim 1 of the formulaH₂ -Tyr-D-Trp-Ala-Trp-D-Phe-Glu-NH₂.
  - 12. The peptide of claim 1 of the formulaH₂ -Tyr-D-Trp-Ala-Trp-D-Phe-Phe-NH₂.
  - 13. The peptide of claim 1 of the formulaH₂ -Tyr-D-Trp-Ala-Trp-D-Phe-Gln-NH₂.
  - 14. The peptide of claim 1 of the formulaH₂ -His-D-Trp-Ala-Trp-D-Phe-Lys-OH.
  - 15. The peptide of claim 1 of the formulaH₂ -His-D-Trp-Ala-Trp-D-Phe-Arg-NH₂.
  - 16. The peptide of claim 1 of the formulaH₂ -His-D-Trp-Ala-Trp-D-Phe-Gln-NH₂.
  - 17. The peptide of claim 1 of the formulaH₂ -His-D-Trp-Ala-Trp-D-Phe-Glu-NH₂.
  - 18. The peptide of claim 1 of the formulaH₂ -His-D-Trp-Ala-Trp-D-Phe-HomoArg-NH₂.
  - 19. The peptide of claim 1 of the formulaH₂ -3-N-Me-His-D-Trp-Ala-Trp-D-Phe-Lys-NH₂.
  - 20. The peptide of claim 1 of the formulaH₂ -His-D-Trp-ALa-Trp-D-Phe-Lys-NHCH₂ CH₃.
  - 21. The peptide of claim 1 of the formulaH₂ -His-D-Trp-Ala-Trp-D-Phe-Orn-NH₂.
  - 22. The peptide of claim 1 of the formulaH₂ -His-D-Trp-Val-Trp-D-Phe-Lys-NH₂.
  - 23. The peptide of claim 1 of the formulaH₂ -His-D-Trp-Ser-Trp-D-Phe-Lys-NH₂.
  - 24. A method of releasing growth hormone from a pituitary comprising contacting said pituitary with the peptide of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23.
  - 25. A method of releasing growth hormone in vivo from a pituitary comprising contacting said pituitary with the peptide of claim 9, 14, 15, 16, 17, 18, 19, or 20.

26. An intermediate composition having a formula selected from a group consisting of ##STR74##

space="preserve" listing-type="equation">B.sub.1 -B.sub.2 -B.sub.3 -B.sub.4 -B.sub.5 -B'"'"'.sub.6 -Y (VI)
whereinPr₁ is an α

-amino acid protecting group;

a, b, m, q, r, and s are each 0 or 1;

X'"'"'₁, X'"'"'₂, and X'"'"'₃ are selected from a group consisting of --R, --OR, RC(O)-- wherein R is selected from the group consisting of hydrogen and straight chain and branched chain alkyl groups containing 1-6 carbon atoms;

B₁ and B₄ are selected from a group consisting of His, Arg, Lys, α

-Naphth, β

-Naphth, Igl, Tyr, Trp, Phe, homologues and analogues thereof, the side-chain protected forms thereof, and, with respect to B₁, the desamino forms thereof;

B₂ and B₅ are selected from a group consisting of D-His, D-Arg, D-Lys, D-α

-Naphth, D-β

-Naphth, D-Igl, D-Tyr, D-Trp, D-Phe, homologues and analogues thereof, and the side-chain protected forms thereof;

B₃ is selected from a group consisting of amino acids of the L- and D-configurations, homologues and analogues thereof, the side-chain protected forms thereof, and, with respect to B'"'"'₆, the descarboxy forms thereof;

®

is a resin;

Y is selected from a group consisting of C-terminal and descarboxy alpha-carbon substitutions; and

Pr₂ is a carboxyl protecting group.
View Dependent Claims (27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48)

27. The intermediate composition of claim 26 wherein:
B₁ and B₄ are selected from the group consisting of His, Tyr, Trp, Phe, homologues and analogues thereof, and, with respect to B₁, the desamino forms thereof, and the side-chain protected forms thereof;

B₂ and B₅ are selected from the group consisting of D-His, D-Tyr, D-Trp, D-Phe, homologues and analogues thereof, and the side-chain protected forms thereof;

B₃ is selected from the group consisting of Gly, Ala, Ser, Asn, Pro, D-Ala, D-Ser, D-Asn, D-Pro, homologues and analogues thereof, and the side-chain protected forms thereof; and

B₆ and B'"'"'₆ are selected from the group consisting of Arg, Lys, Orn, His, Asp, Glu, Asn, Gln, D-Arg, D-Lys, D-Orn, D-His, D-Asp, D-Glu, D-Asn, D-Gln, homologues and analogues thereof, and, with respect to B'"'"'₆, the descarboxy forms thereof, and the side-chain protected forms thereof.

28. The intermediate composition of claim 26 having the formula selected from the group consisting of ##STR75##

space="preserve" listing-type="equation">B.sub.1 -D-Trp-B.sub.3 -B.sub.4 -B.sub.5 -B'"'"'.sub.6 -Y (VI)
whereinB₁ is selected from the group consisting of Tyr, O-Me-Tyr, His, 3-N-Me-His, p-Cl-Phe, the desamino forms thereof, and the side-chain protected forms thereof;

B₃ is selected from the group consisting of Ala, Ser, D-Ala, and the side-chain protected forms thereof;

B₄ is selected from the group consisting of Trp, Tyr, and the side-chain protected forms thereof;

B₅ is selected from the group consisting of D-Phe, D-His, D-Tyr, D-p-Cl-Phe, and the side-chain protected forms thereof; and

B₆ and B'"'"'₆ are selected from the group consisting of Arg, HomoArg, Lys, Orn, Asp, Glu, Asn, Gln, D-Lys, the descarboxy forms thereof, and the side-chain protected forms thereof.

29. The intermediate composition of claim 26 of the formula

space="preserve" listing-type="equation">Boc-Tyr(Brz)-D-Trp-Ala-Trp-D-Phe-Met-®

whereinBrz is o-bromobenzyloxycarbonyl;

Boc is t-butyloxycarbonyl; and

®

is p-methylbenzhydrylamine resin.

30. The intermediate composition of claim 26 of the formula

space="preserve" listing-type="equation">Boc-Tyr(BrZ)-D-Trp-Ala-Trp-D-Phe-Thr(Bzl)-®

whereinBzl is benzylBrZ is p-bromobenzyloxycarbonyl;

Boc is t-Butyloxycarbonyl; and

®

is p-methylbenzhydrylamine resin.

31. The intermediate composition of claim 26 of the formula

space="preserve" listing-type="equation">Boc-Tyr(BrZ)-D-Trp-Ala-Trp-D-Phe-Glu-α

-benzyl ester-®

whereinBrZ is p-bromobenzyloxycarbonyl;

Boc is t-butyloxycarbonyl; and

®

is p-methylbenzhydrylamine resin.

32. The intermediate composition of claim 26 of the formula

space="preserve" listing-type="equation">Boc-Tyr(BrZ)-D-Trp-Ala-Trp-D-Phe-Gln-®

whereinBrZ is p-bromobenzyloxycarbonyl;

Boc is t-butyloxycarbonyl; and

®

is p-methylbenzhydrylamine resin.

33. The intermediate composition of claim 26 of the formula

space="preserve" listing-type="equation">Boc-Tyr(BrZ)-D-Trp-Ala-Trp-D-Phe-Asn-®

whereinBrZ is p-bromobenzyloxycarbonyl;

Boc is t-butyloxycarbonyl; and

®

is p-methylbenzhydrylamine resin.

34. The intermediate composition of claim 26 of the formula

space="preserve" listing-type="equation">Boc-His(Tos)-D-Trp-Ala-Trp-D-Phe-Lys(ClZ)-®

whereinClZ is o-chloro-benzyloxycarbonyl;

Tos is p-toluenesulfonyl;

Boc is t-butyloxycarbonyl; and

®

is p-methylbenzhydrylamine resin.

35. The intermediate composition of claim 26 of the formula

space="preserve" listing-type="equation">Boc-Tyr(BrZ)-D-Trp-Ala-Trp-D-His(Tos)-Lys(ClZ)-®

whereinClZ is o-chloro-benzyloxycarbonyl;

Tos is p-toluenesulfonyl;

BrZ is p-bromobenzyloxycarbonyl;

Boc is t-butyloxycarbonyl; and

®

is p-methylbenzhydryalmine resin.

36. The intermediate composition of claim 26 of the formula

space="preserve" listing-type="equation">Boc-Tyr(BrZ)-D-Trp-Ala-Trp-D-Phe-Glu-γ

-Bzl-®

whereinγ

-Bzl denotes γ

-benzyl ester;

BrZ is p-bromobenzyloxycarbonyl;

Boc is t-butyloxycarbonyl; and

®

is p-methylbenzhydrylamine resin.

37. The intermediate composition of claim 26 of the formula

space="preserve" listing-type="equation">Boc-Tyr(BrZ)-D-Trp-Ala-Trp-D-Phe-Phe-®

whereinBrZ is p-bromobenzyloxycarbonyl;

Boc is t-butyloxycarbonyl; and

®

is p-methylbenzhydrylamine resin.

38. The intermediate composition of claim 26 of the formula

space="preserve" listing-type="equation">Boc-Tyr(BrZ)-D-Trp-Gly-Trp-D-Phe-Gln-ONP-®

whereinONP is p-nitrophenyl ester;

BrZ is p-bromobenzyloxycarbonyl;

Boc is t-butyloxycarbonyl; and

®

is p-methylbenzhydryalmine resin.

39. The intermediate composition of claim 26 of the formula

space="preserve" listing-type="equation">Boc-His(Tos)-D-Trp-Ala-Trp-D-Phe-Lys(ClZ)-®

whereinClZ is o-chloro-benzyloxycarbonylTos is p-toluenesulfonyl;

Boc is t-butyloxycarbonyl; and

®

is hydroxymethyl resin.

40. The intermediate composition of claim 26 of the formula

space="preserve" listing-type="equation">Boc-His(Tos)-D-Trp-Ala-Trp-D-Phe-Arg(Tos)-®

whereinTos is p-toluenesulfonyl;

Boc is t-butyloxycarbonyl; and

®

is p-methylbenzhydryalmine resin.

41. The intermediate composition of claim 26 of the formula

space="preserve" listing-type="equation">Boc-His(Tos)-D-Trp-Ala-Trp-D-Phe-Gln-ONP-®

whereinONP is p-nitrophenyl ester;

Tos is p-toluenesulfonyl;

Boc is t-butyloxycarbonyl; and

®

is p-methylbenzhydryalmine resin.

42. The intermediate composition of claim 26 of the formula

space="preserve" listing-type="equation">Boc-His(Tos)-D-Trp-Ala-Trp-D-Phe-Glu-γ

-Bzl-®

whereinγ

-Bzl denotes γ

-benzyl ester;

Tos is p-toluenesulfonyl;

Boc is t-butyloxycarbonyl; and

®

is p-methylbenzhydryalmine resin.

43. The intermediate composition of claim 26 of the formula

space="preserve" listing-type="equation">Boc-His(Tos)-D-Trp-Ala-Trp-D-Phe-HomoArg(Tos)-®

whereinTos is p-toluenesulfonyl;

Boc is t-butyloxycarbonyl; and

®

is p-methylbenzhydryalmine resin.

44. The intermediate composition of claim 26 of the formula

space="preserve" listing-type="equation">Boc-3-N-Me-His-D-Trp-Ala-Trp-D-Phe-Lys(ClZ)-®

whereinClZ is o-chloro-benzyloxycarbonyl;

Boc is t-butyloxycarbonyl; and

®

is p-methylbenzhydryalmine resin.

45. The intermediate composition of claim 26 of the formula

space="preserve" listing-type="equation">Boc-His(Tos)-D-Trp-Ala-Trp-D-Phe-Lys(ClZ)-®

whereinClZ is o-chloro-benzyloxycarbonyl;

Tos is p-toluenesulfonyl;

Boc is t-butyloxycarbonyl; and

®

is p-methylbenzhydryalmine resin.

46. The intermediate composition of claim 26 of the formula

space="preserve" listing-type="equation">Boc-His(Tos)-D-Trp-Ala-Trp-D-Phe-Orn(Z)-®

whereinZ is benzyloxycarbonyl;

Tos is p-toluenesulfonyl;

Boc is t-butyloxycarbonyl; and

®

is p-methylbenzhydryalmine resin.

47. The intermediate composition of claim 26 of the formula

space="preserve" listing-type="equation">Boc-His(Tos)-D-Trp-Val-Trp-D-Phe-Lys(ClZ)-®

whereinClZ is o-chlorobenzyloxycarbonyl;

Tos is p-toluenesulfonyl;

Boc is t-butyloxycarbonyl; and

®

is p-methylbenzhydryalmine resin.

48. The intermediate composition of claim 26 of the formula

space="preserve" listing-type="equation">Boc-His(Tos)-D-Trp-Ser(Bzl)-Trp-D-Phe-Lys(ClZ)-®

whereinClZ is o-chloro-benzyloxycarbonyl;

Bzl is benzyl;

Tos is p-toluenesulfonyl;

Boc is t-butyloxycarbonyl; and

®

is p-methylbenzhydryalmine resin.

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Current Assignee
Smithkline Beecham Corporation (GSK plc)
Original Assignee
Beckman Instruments, Inc. (Danaher Corporation)
Inventors
Momany, Frank A.
Primary Examiner(s)
Phillips, Delbert R.

Application Number

US06/335,011
Time in Patent Office

666 Days
Field of Search

260/112.5 R, 424/177
US Class Current

514/11.3
CPC Class Codes

A61K 38/00   Medicinal preparations cont...

C07K 7/06   having 5 to 11 amino acids

Y10S 930/12   Growth hormone, growth fact...

Synthetic peptides having pituitary growth hormone releasing activity

First Claim

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Abstract

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48 Claims

Specification

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Synthetic peptides having pituitary growth hormone releasing activity

First Claim

3 Assignments

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Abstract

Citations

48 Claims

Specification

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