Novel cyclopeptides

• US 4,238,481 A
• Filed: 09/15/1978
• Issued: 12/09/1980
• Est. Priority Date: 09/28/1977
• 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:
  US05/942,565
• Time in Patent Office: 816 Days
• Field of Search: 424/177, 260/112.55
• US Class Current: 514/6.7
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/02 of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
• CPC Class Codes: C07K 14/6555 at least 1 amino acid in D-form
• CPC Class Codes: C07K 5/0821 with the first amino acid being heterocyclic, e.g. His, Pro, Trp
• 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

Sulphur-free cyclopeptides with somatostatin-analogous aminoacid partial sequences, of the formula ##STR1## in which R is Asn, Ala or de-R, trp is D-Trp or L-Trp, which can be substituted in the benzene ring by halogen atoms or nitro groups, W is a free or etherified hydroxyl group or halogen atom present as a substituent on the benzene ring of the L-phenylalanine radical, or is hydrogen, X is the radical of an ω-amino-lower alkane-(mono or di)-carboxylic acid or de-X and Y is the radical of an ω-amino-lower alkane-(mono or di)-carboxylic acid or de-Y, and also acid addition salts and complexes thereof have biological properties similar to those of somatostatin and can be used, especially in the form of pharmaceutical preparations, for the treatment of excessive secretion of somatotropin, insulin and/or glucagon. The compounds according to the invention are obtained by cyclising a corresponding linear peptide compound in which the ε-amino group of the lysine radical and, if desired, also the hydroxyl group of the threonine radical are protected and detaching the protective groups which are present.

Claims

1. A cyclopeptide of the formula ##STR56## in which R is Asn, trp is D-Trp or L-Trp, which can be substituted in the benzene ring by halogen atoms or nitro groups, W is a free or etherified hydroxyl group or halogen atom present as a substituent on the benzene ring of the L-phenylalanine radical, or is hydrogen, X is the radical of an ω

-amino-lower alkane-(mono or di)-carboxylic acid of the formula ##STR57## respectively in which n is an integer from 1 to 7 or de-X and Y is the radical of an ω

-amino-lower alkane-(mono or di)-carboxylic acid as defined above or de-Y, or an acid addition salt or complex thereof.

2. The compound according to claim 1 of the formula I, in which R is Asn, trp is D-Trp or L-Trp, W is hydrogen, X is the radical of an ω

-amino-lower alkane-mono-carboxylic acid of the formula

space="preserve" listing-type="equation">--NH--(CH.sub.2).sub.n --CO--

in which n is an integer from 2 to 4, or de-X and Y is the radical of an ω

-amino-lower alkane-monocarboxylic acid as defined above or de-Y, or an acid addition salt or a complex thereof.

3. A compound according to claim 2, in which R is Asn, the tryptophan⁸ radical has the D-configuration and --X--Y-- together are --[Gaba]_p --, in which p is 0, 1 or 2.

9. A pharmaceutical preparation for the treatment of excessive secretion of somatotrophin insulin and/or glucagon which contains an effective amount of at least one of the compounds characterised in any one of claims 3-9, 2 or 1 in combination or admixture with at least one inert, physiologically tolerable carrier and/or adjunct.

10. A method for the therapeutic treatment of excessive secretion of somatotropin, insulin and/or glucagon by administering a therapeutically effective dose of a compound characterised in any one of claims 3-7, 2 or 1.

4. A compound selected from the group consisting of a cyclic peptide of the formula ##STR58## in which R is Asn, trp is D-Trp or L-Trp, which can be substituted in the benzene ring by halogen atoms or nitro groups, W is a free or etherified hydroxyl group or halogen atom present as a substituent on the benzene ring of the L-phenylalanine radical, or is hydrogen, X is the radical of an ω

-amino-lower alkane-(mono or di)-carboxylic acid of the formula ##STR59## respectively in which n is an integer from 1 to 7 or de-X and Y is the radical of an ω

-amino-lower alkane-(mono or di)-carboxylic acid or as defined above de-Y, A is an ε

-amino protective group or hydrogen and B is a hydroxyl protective group or hydrogen, it being possible for only one of the symbols A and B to be hydrogen, and a corresponding linear piptide of the formula

space="preserve" listing-type="equation">H--[II'"'"']--C (III)

in which II'"'"' is a radical corresponding to the formula II characterised above, in which the amide bond between any two adjacent aminoacid radicals of the peptide ring is interrupted, and C is a free hydroxyl group, a hydroxyl group modified by an activating group or the hydrazine group --NH--NH₂, and acid addition salts thereof.

5. A linear peptide according to claim 4, of the formula

6. A compound characterised by the formula ##STR60##

7. A compound characterised by the formula ##STR61##

8. A compound characterised by the formula ##STR62## in which A is the tert.-butoxycarbonyl group and B is the tert.-butyl group and p is 1 or 2.