Acylpeptides

• US 4,369,179 A
• Filed: 12/05/1980
• Issued: 01/18/1983
• Est. Priority Date: 12/14/1979
• 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:
  US06/213,299
• Time in Patent Office: 774 Days
• Field of Search: 260/112.5 S, 424/177
• US Class Current: 514/6.9
• 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: C07K 14/6555 at least 1 amino acid in D-form
• CPC Class Codes: Y10S 930/16 Somatostatin; related peptides

Abstract

Acylpeptides derived from somatostatin or from a derivative thereof having analogous action, in which the amino acids sequence is modified by omitting individual amino acids and/or by exchanging them for other amino acids, and in which the ε-amino group of the lysine residue in the 9-position, and optionally also the ε-amino group of the lysine residue in the 4-position and/or the N-terminal α-amino group carries the acyl radical of an optionally substituted alkanecarboxylic acid, and salts and complexes thereof can be used as antidiabetics and/or for combating gastrointestinal bleeding. They are manufactured by conventional methods of peptide chemistry.

Claims

1. An acylpeptide of the formula ##STR33## in which A'"'"' represents H--Ala--Gly--, Ac--Ala--Gly, H-- or Ac--,

B represents Lys, Lys(Ac) or Lys(X) (wherein X is an ε

-amino-protecting group),

trp represents L-Trp, D-Trp or an analogous radical, which carries in the indole nucleus a halogen atom,

cys represents L-Cys or D-Cys and

Ac represents an acyl radical of an optionally substituted alkanecarboxylic acid, present at the free amino group,

and non-toxic salts and pharmacologically acceptable complexes thereof.

17. A pharmaceutical preparation for the treatment of diabetes and/or gastrointestinal bleeding in humans and mammals, containing an effective amount of at least one acylpeptide defined an any one of claims 9 or 1-5.

18. A therapeutic method for the treatment of diabetes and/or gastrointestinal bleeding in humans and mammals by administration of an effective amount of a acylpeptide defined in any one of claim 9 or 1-5, or in the form of a pharmaceutical preparation containing said acylpeptide.

2. An acylpeptide of the formula ##STR34## in which Bmp represents the desaminocysteine residue,

B represents Lys, Lys(Ac) or Lys(X) (wherein X is an ε

-amino-protecting group),

C'"'"' represents Asn or His,

trp represents L-Trp, D-Trp or an analogous radical, which carries in the indole nucleus a halogen atom,

G represents L-Ser, D-Ser or the residue of a secondary α

-amino acid having a maximum of 8 carbon atoms, and

Ac represents an acyl radical of an optionally substituted alkanecarboxylic acid, present at the free amino group,

and non-toxic salts and pharmacologically acceptable complexes thereof.

3. An acylpeptide of the formula ##STR35## in which cys represents L-Cys or D-Cys,

B represents Lys, Lys(Ac) or Lys(X) (wherein X is an ε

-amino-protecting group),

Ac represents an acyl radical of an optionally substituted alkanecarboxylic acid, present at the free amino group, and

a,b,c,f and g each represents, independently of one another, 0 or 1, and non-toxic salts and pharmacologically acceptable complexes thereof.

4. An acylpeptide of the formula ##STR36## in which trp represents L-Trp, D-Trp or an analogous radical, which carries in the indole nucleus a halogen atom, and

Ac represents an acyl radical of an optionally substituted alkanecarboxylic acid, present at the free amino group, and non-toxic salts and

pharmacologically acceptable complexes thereof.

5. An acylpeptide of the formula ##STR37## in which A" denotes the residue of an ω

-amino-lower alkanecarboxylic acid of the partial formula --NH--CH(R)--(CH₂)_n --CO-- (wherein n represents 0 or an integer from 1 to 6 and R represents hydrogen or carboxyl) which, if n=2 and R is hydrogen, can also be substituted by a cyclic hydrocarbyl radical and, in that case, is designated by the symbol Gaba(Ar),

B represents Lys, Lys(Ac) or Lys(X) (wherein X is an ε

-amino-protecting group),

C" represents Asn or Ala,

trp represents L-Trp, D-Trp or an analogous radical, which carries in the indole nucleus a halogen atom,

Ac represents an acyl radical of an optionally substituted alkanecarboxylic acid, present at the free amino group, and

a,b,c,f and g each represents, independently of one another, 0 or 1, and non-toxic salts and pharmacologically acceptable complexes thereof.

6. An acylpeptide according to claim 5, in which Ac represents an acyl radical of an optionally substituted alkanecarboxylic acid, present at the free amino group, trp represents D-Trp, A" denotes an ω

-amino-lower alkanecarboxylic acid residue, in which R represents hydrogen and n represents 0 or an integer from 1 to 3, B represents Lys, Lys(Ac) or Lys(INOC) and C" represents Asn or Ala, and f and at least one of the symbols a, b, c and g are equal to 1, whilst the others each represent independently of one another, 0 or 1.

7. An acylpeptide according to claim 5, in which Ac represents an acyl radical of an optionally substituted alkanecarboxylic acid, present at the free amino group, trp represents D-Trp, A" represents a radical Gaba(Ar) having the hydrocarbyl Ar in the β

-position, or the ω

-amino-lower alkylcarboxylic acid residue, C" represents Ala or Asn, a equals 1, c equals 0 or 1 and b, f and g equal 0.

8. An acylpeptide according to claim 7, in which A" represents the radical --NH--CH(R)--(CH₂)_n --CO, in which n=5 and R is hydrogen or carboxyl, a equals 1, and b, c, f and g all equal 0, and the other radicals have the meanings given in claim 7.

9. An acylpeptide of the formula ##STR38## in which trp₀ represents D-Trp or D-(5F)Trp, Ac represents an acyl radical of an optionally substituted alkanecarboxylic acid, present at the free amino group, and U represents hydrogen or an optionally substituted cyclic hydrocarbyl radical Ar.

10. An acylpeptide according to claim 9, in which U represents hydrogen and the other symbols have the meanings given in claim 9.

11. An acylpeptide according to claim 9, in which U represents the phenyl, cyclohexyl, 2-naphthyl, 1-naphthyl or 3-phenoxyphenyl radical and the other symbols have the meanings given in claim 9.

12. An acylpeptide according to claim 9 in which Ac represents the radical of an alkanemonocarboxylic acid having a maximum of 18 carbon atoms or an alkanedicarboxylic acid having a maximum of 9 carbon atoms.

13. An acylpeptide according to claim 9, in which Ac represents the residue of a naturally occurring α

-amino acid or a closely related analogue thereof.

14. An acylpeptide according to claim 9 of the formula IF, in which trp₀ represents D-Trp, U represents hydrogen and Ac represents glycyl, leucyl or phenylalanyl.

15. An acylpeptide according to claim 9 of the formula IF, in which trp₀ represents D-Trp, U represents hydrogen and Ac represents prolyl.

16. An acylpeptide according to claim 9 of the formula IF, in which trp₀ represents D-Trp, U represents hydrogen and Ac represents N.sup.α

-tert.-butoxycarbonyllysyl or lysyl.