Cyclic octapeptides and pharmaceutical preparations thereof, as well as processes for their manufacture, and their use

• US 4,603,120 A
• Filed: 12/20/1982
• Issued: 07/29/1986
• Est. Priority Date: 12/24/1981
• Status: Expired due to Fees

• Current Assignee: Ciba-Geigy Corporation (Novartis Ag)
• Original Assignee: Ciba-Geigy Corporation (Novartis Ag)
• Inventors: Kamber, Bruno
• Primary Examiner(s): Phillips, Delbert R.
• Assistant Examiner(s): Moezie, F. T.
• Application Number:
  US06/451,630
• Time in Patent Office: 1,317 Days
• Field of Search: 260/112.5 R, 514/15, 514/16, 514/11
• US Class Current: 514/11.1
• 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: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: C07K 14/6555 at least 1 amino acid in D-form
• CPC Class Codes: Y10S 930/16 Somatostatin; related peptides

Abstract

Cyclic octapeptides of the formula ##STR1## in which Aaa represents a radical of a straight-chained α,ω-diaminoalkanoic acid having from 4 to 7 carbon atoms,

trp represents a radical L-Trp or, especially, D-Trp, or a radical derived therefrom, which carries a halogen atom in the indole nucleus,

Ac_A represents an acyl radical Ac of an optionally substituted carboxylic acid which is positioned at the ω-amino group, or represents an amidino group or hydrogen, and

Ac_B represents an acyl radical Ac¹ of an amino acid or of an oligopeptide which is positioned at the ε-amino group, or, preferably, represents hydrogen,

as well as physiologically tolerable salts and therapeutically acceptable complexes thereof can be used as antidiabetics and for the treatment of gastro-intestinal bleeding in an analogous manner to somatostatin. They can be obtained by conventional processes of peptide chemistry, especially by the cyclization of corresponding linear peptides.

Claims

1. A compound selected from the group consisting of

(a) a cyclic octapeptide of the formula:

##STR62## in which Aaa is the radical of a straight-chained α

,ω

-diaminoalkanoic acid having from 4 to 7 carbon atoms;

trp is the radical of L-Trp or D-Trp which is unsubstituted or substituted with halogen in the indole nucleus; and

Ac_A is bound to the nitrogen of the terminal amino group of Aaa and is

(i) hydrogen

(ii) amidino,

(iii) the acyl residue of Lys, Pro or Phe,

(iv) the acyl residue of a di- or tripeptide of lysine.

(b) a therapeutically acceptable salt thereof in which said octapeptide carries a charge and is comprised in the anionic or cationic moiety of the salt, and

(c) a therapeutically acceptable complexes of said octapeptide with a metal compound or a polymeric organic peptide comlex-forming compound.

2. A compound according to claim 1 wherein trp is D-Trp, Aaa is Lys, Orn or Arg, and Ac_A is hydrogen.

3. A compount according to claim 1 wherein trp is D-Trp, Aaa is Lys, Orn or Arg, and Ac_A is a di- or tripeptide of lysine.

4. A cyclic peptide according to claim 1, which is [Lys⁵,D-Trp⁸,Gaba¹² ]-cyclo-somatostatin(5-12) octapeptide or a physiologically tolerable salt or a thereapeutically acceptable complex thereof.

5. A cyclic peptide according to claim 1, which is [Orn⁵,D-Trp⁸,Gaba¹² ]-cyclo-somatostatin(5-12) octapeptide or a physiologically tolerable salt or a therapeutically acceptable complex thereof.

6. A cyclic peptide according to claim 1, which is [Nε

-(Pro)-Lys⁵,D-Trp⁸,Gaba¹² ]-cyclo-somatostatin-(5-12)-octapeptide or a physiologically tolerable salt or a therapeutically acceptable complex thereof.

7. A cyclic peptide according to claim 1, which is [Nε

-(Phe)-Lys⁵,D-Trp⁸,Gaba¹² ]-cyclo-somatostatin-(5-12)octapeptide or a physiologically tolerable salt or a therapeutically acceptable complex thereof.

8. A cyclic peptide according to claim 1, which is [Nε

-(Lys-Lys-Lys)-Lys⁵,D-Trp⁸,Gaba¹² ]-cyclo-somatostatin(5-12)-octapeptide or a physiologically tolerable salt or a therapeutically acceptable complex thereof.

9. A therapeutic method for treating conditions responsive to somatostatin in warm-blooded animals comprising administering a somatostatinanalogous cyclooctapeptide according to claim 1 in a preventatively or curatively effective amount to a warm-blooded animal for which such a treatment is indicated.

10. A method according to claim 9 wherein the warm-blooded animal treated is a human.

11. A pharmaceutical composition for the treatment of conditions responsive to somatostatin comprising an effective amount of the cyclic octapeptide according to claim 1, or a physiologically acceptable salt or therapeutically acceptable complex thereof, and a therapeutically acceptable carrier.