Cyclopeptides and pharmaceutical preparations thereof and also processes for their manufacture

• US 4,328,214 A
• Filed: 06/25/1980
• Issued: 05/04/1982
• Est. Priority Date: 07/04/1979
• Status: Expired due to Term

• Current Assignee: Ciba-Geigy Corporation (Novartis Ag)
• Original Assignee: Ciba-Geigy Corporation (Novartis Ag)
• Inventors: Sieber, Peter, Rink, Hans, Kamber, Bruno
• Primary Examiner(s): Phillips, Delbert R.
• Application Number:
  US06/162,712
• Time in Patent Office: 678 Days
• Field of Search: 260/112.5 S, 424/177
• US Class Current: 514/7.1
• 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: C07K 14/6555 at least 1 amino acid in D-form
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
• CPC Class Codes: Y10S 930/16 Somatostatin; related peptides

Abstract

The somatostatin-analogous cyclic octapeptides according to the invention of the general formula ##STR1## in which trp represents L-Trp or D-Trp, in which the benzene ring may be substituted by a halogen atom, and

Gaba(Ar) represents the residue of a γ-aminobutyric acid substituted by a cyclic hydrocarbyl radical,

and their acid addition salts and complexes are distinguished by a strong inhibition of the insulin and glucagon secretion of the pancreas and are therefore therapeutically acceptable, preferably in the form of pharmaceutical preparations, in similar indications to those of somatostatin, especially as anti-diabetics. The compounds are manufactured by conventional processes of peptide synthesis, especially by liberation from corresponding protected intermediates after intramolecular cyclization of a corresponding linear octapeptide.

Claims

1. A cyclic octapeptide of the formula ##STR44## in which trp represents D-Trp, and

Gaba(Ar) represents the residue of a γ

-amino-butyric acid substituted in the β

-position by cyclohexyl, phenyl or naphthyl or by a phenyl or naphthyl which is substituted by halogen, nitro or phenoxy, a pharmaceutically acceptable acid addition salt and a complex thereof.

2. A compound according to claim 1, in which trp represents D-Trp and Gaba(Ar) represents the residue of 4-amino-3-cyclohexylbutyric acid, 4-amino-3-phenylbutyric acid, 4-amino-3-(1-naphthyl)-butyric acid or 4-amino-3-(2-naphthyl)-butyric acid, in the form of a diastereoisomeric mixture or of an individual diastereoisomer, a pharmaceutically acceptable acid addition salt and a complex thereof.

3. Isomer B of a compound defined in claim 2, which is defined as the diastereoisomer derived from the more hydrophilic component obtained by the countercurrent distribution of a diastereoisomer mixture of a corresponding derivative having the -Lys⁹ - and/or -Thr¹⁰ -residue in a protected form.

4. A compound according to claim 1, in which trp represents D-Trp and Gaba(Ar) represents the residue of 4-amino-3-(4-fluorophenyl)-butyric acid, 4-amino-3-(4-nitrophenyl)-butyric acid, 4-amino-3-(4-chloro-1-naphthyl)-butyric acid or 4-amino-3-(3-phenoxyphenyl)-butyric acid, in the form of a diastereoisomeric mixture or of an individual diastereoisomer, a pharmaceutically acceptable acid addition salt and a complex thereof.

5. Isomer B of a compound defined in claim 4, which is defined as the diastereoisomer derived from the more hydrophilic component obtained by the countercurrent distribution of a diastereoisomer mixture of a corresponding derivative having the -Lys⁹ - and/or -Thr¹⁰ -residue in a protected form.

12. A pharmaceutical preparation for treating, in mammals, diabetes or blood losses in gastro-intestinal tract containing an effective amount of at least one of the compounds according to any one of claims 1 to 11 in combination with at least one pharmaceutically acceptable excipient.

13. A method of treating, in mammals, diabetes or blood losses in the gastro-intestinal tract, which method comprises administering to said mammal a compound defined in any one of claims 1 to 11 in an amount sufficient to effect, in said mammal, an anti-diabetic response or, respectively, to prevent blood losses.

6. [D-Trp⁸ ;

β

-cyclohexyl-Gaba¹² ]-cyclosomatostatin(5-12)-octapeptide, in the form of a diastereoisomeric mixture or of an individual diastereoisomer, a pharmaceutically acceptable acid addition salt and a complex thereof.

7. Isomer B of a compound defined in claim 6, which is defined as the diastereoisomer derived from the more hydrophilic component obtained by the countercurrent distribution of a diastereoisomer mixture of a corresponding derivative having the -Lys⁹ - and/or -Thr¹⁰ -residue in a protected form.

8. [D-Trp⁸ ;

β

-(3-phenoxyphenyl)-Gaba¹² ]-cyclosomatostatin(5-12)-octapeptide, in the form of a diastereoisomeric mixture or of an individual diastereoisomer, a pharmaceutically acceptable acid addition salt and a complex thereof.

9. Isomer B of a compound defined in claim 8, which is defined as the diastereoisomer derived from the more hydrophilic component obtained by the countercurrent distribution of a diastereoisomer mixture of a corresponding derivative having the -Lys⁹ - and/or -Thr¹⁰ -residue in a protected form.

10. [D-Trp⁸ ;

β

-(1-naphthyl)-Gaba¹² ]-cyclosomatostatin(5-12)-octapeptide, in the form of a diastereoisomeric mixture or of an individual diastereoisomer, a pharmaceutically acceptable acid addition salt and a complex thereof.

11. Isomer B of a compound defined in claim 10, which is defined as the diastereoisomer derived from the more hydrophilic component obtained by the countercurrent distribution of a diastereoisomer mixture of a corresponding derivative having the -Lys⁹ - and/or -Thr¹⁰ -residue in a protected form.

14. A compound of the formula ##STR45## in which trp represents [L-Trp or] D-Trp, and

Gaba(Ar) represents the residue of a γ

-amino-butyric acid substituted in the β

-position by cyclohexyl, phenyl or naphthyl, or by a phenyl or naphthyl which is substituted by halogen, nitro or phenoxy,

A represents an γ

-amino-protecting group or hydrogen and

B represents a hydroxyl-protecting group or hydrogen,

it being possible for only one of the symbols A and B to represent hydrogen, and an acid addition salt thereof.

15. A linear peptide of the formula