Somatostatin analogs with dissociated biological activities

• US 4,133,782 A
• Filed: 04/07/1977
• Issued: 01/09/1979
• Est. Priority Date: 06/07/1976
• Status: Expired due to Term

• Current Assignee: Salk Institute for Biological Studies
• Original Assignee: Salk Institute for Biological Studies
• Inventors: Vale, Wylie W. Jr., Rivier, Jean E. F., Brown, Marvin R.
• Primary Examiner(s): Phillips, Delbert R.
• Application Number:
  US05/785,533
• Time in Patent Office: 642 Days
• Field of Search: 260/112.5 S, 260/8
• US Class Current: 525/54.11
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: C07K 14/6555 at least 1 amino acid in D-form
• CPC Class Codes: Y10S 930/12 Growth hormone, growth factor other than t-cell or b-cell growth factor, and growth hormone releasing factor; related peptides
• CPC Class Codes: Y10S 930/16 Somatostatin; related peptides

Abstract

The present invention relates to peptides having dissociated biological activity in respect to the inhibition of growth hormone, insulin, and glucagon secretion. The peptides are analogs of somatostatin.

Claims

1. A peptide selected from those of the formulae:

##STR4## and the non-toxic salts thereof, wherein X₁ is selected from Asn and des-Asn;

X₂ is selected from Trp and D-Trp;

X₃ is selected from Ser and D-Ser; and

X₄ is selected from Cys and D-Cys with the proviso that X₁ is des-Asn when X₂ is D-Trp, X₃ is Ser and X₄ is Cys;

X₃ is D-Ser when X₁ is Asn and X₄ is Cys; and

X₄ is D-Cys when X₁ is Asn and X₃ is Ser;

R is selected from the class consisting of H and an alpha-amino protecting group;

R¹ and R⁷ are selected from the group consisting of H and a protecting group for Cys selected from S-p-methoxybenzyl, S-p-methylbenzyl, S-acetamidomethyl, S-trityl and S-benzyl;

R² and R³ are selected from the group consisting of H and a side chain amino protecting group for Lys selected from the group consisting of benzyl, chlorobenzyloxycarbonyl, benzyloxycarbonyl, tosyl, t-amyloxycarbonyl, t-butyloxycarbonyl, R⁴, R⁵ and R⁶ are selected from the group consisting of H and a hydroxyl protecting group selected from the group consisting of acetyl, benzoyl, tert-butyl, trityl, benzyl and benzyloxycarbonyl;

with the proviso that at least one of R, R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ is other than hydrogen; and

X₅ is selected from the group consisting of hydroxy, methoxy, esters, amides, hydrozides, -O-CH₂ -polystyrene resin support and O-CH₂ -benzyl-polystyrene resin support.

2. A peptide in accordance with formula I of claim 1 wherein X¹ is des-Asn, X² is D-Trp, X³ is Ser and X⁴ is Cys.

3. A peptide in accordance with formula I of claim 1 wherein X¹ is Asn, X² is Trp, X³ is Ser and X⁴ is D-Cys.

4. A peptide in accordance with formula I of claim 1 wherein X¹ is Asn, X² is D-Trp, X³ is Ser and X⁴ is D-Cys.

5. A peptide in accordance with formula I of claim 1 wherein X¹ is Asn, X² is Trp, X³ is D-Ser, and X⁴ is Cys.

6. A peptide in accordance with formula I of claim 1 wherein X¹ is Asn, X² is D-Trp, X³ is D-Ser and X⁴ is Cys.

7. A peptide in accordance with formula II of claim 1 wherein X¹ is des-Asn, X² is D-Trp, X³ is Ser and X⁴ is Cys.

8. A peptide in accordance with formula II of claim 1 wherein X¹ is Asn, X² is Trp, X³ is Ser and X⁴ is D-Cys.

9. A peptide in accordance with formula II of claim 1 wherein X¹ is Asn, X² is D-Trp, X³ is Ser and X⁴ is D-Cys.

10. A peptide in accordance with formula II of claim 1 wherein X¹ is Asn, X² is Trp, X³ is D-Ser, and X⁴ is Cys.

11. A peptide in accordance with formula II of claim 1 wherein X¹ is Asn, X² is D-Trp, X³ is D-Ser and X⁴ is Cys.

12. A peptide in accordance with formula III of claim 1 wherein X¹ is des-Asn, X² is D-Trp, X³ is Ser and X⁴ is Cys.

13. A peptide in accordance with formula III of claim 1 wherein X¹ is Asn, X² is Trp, X³ is Ser and X⁴ is D-Cys.

14. A peptide in accordance with formula III of claim 1 wherein X¹ is Asn, X² is D-Trp, X³ is Ser and X⁴ is D-Cys.

15. A peptide in accordance with formula III of claim 1 wherein X¹ is Asn, X² is Trp, X³ is D-Ser, and X⁴ is Cys.

16. A peptide in accordance with formula III of claim 1 wherein X¹ is Asn, X² is D-Trp, X³ is D-Ser and X⁴ is Cys.

17. A peptide in accordance with formula III of claim 1 wherein X⁵ is -O-CH₂ -polystyrene resin support.

18. A peptide in accordance with formula III of claim 1 wherein X⁵ is -O-CH₂ -benzyl-polystyrene resin support.

19. A peptide in accordance with claim 17 wherein R is t-butyloxycarbonyl, R⁴, R⁵ and R⁶ are benzyl. R² and R³ are 2-chlorobenzyloxycarbonyl and R¹ and R⁷ are S-p-methoxybenzyl.

20. A peptide in accordance with claim 1 wherein Cys³ is D-Cys.