Cyclic hexapeptide somatostatin analogs

• US 4,235,886 A
• Filed: 10/31/1979
• Issued: 11/25/1980
• Est. Priority Date: 10/31/1979
• Status: Expired due to Term

• Current Assignee: Merck & Co., Inc.
• Original Assignee: Merck & Co., Inc.
• Inventors: Veber, Daniel F., Freidinger, Roger M.
• Primary Examiner(s): Phillips, Delbert R.
• Application Number:
  US06/089,827
• Time in Patent Office: 391 Days
• Field of Search: 260/112.5 S, 424/177
• 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 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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: Y10S 930/16 Somatostatin; related peptides

Abstract

Somatostatin analogs are prepared wherein a cyclic hexapeptide contains a secondary amino acid which replaces seven of the ring amino acids of somatostatin. The cyclic hexapeptides are easier to synethesize, have a longer duration of activity, and many have a greater level of activity than somatostatin. The compounds have the properties of inhibiting the release of glucagon, growth hormone and insulin. Certain of the compounds also are capable of inhibiting the release of gastric acid secretions. The compounds are particularly useful in the treatment of acromegaly, diabetes, diabetic retinopathy and peptic ulcers. These cyclic hexapeptides are prepared by the solid phase method.

Claims

1. A compound having the formula:

##STR15## wherein X is (CH₂)_n wherein n is 0, 1 or 2 or sulfur;

Y is (CH₂)_m wherein m is 0, 1 or 2 or sulfur such that the sulfur may be in any position along the chain;

R₁ and R₂ are independently lower alkyl, benzyl, substituted benzyl wherein the substituent may be one or two of loweralkyl, halogen, hydroxy, amino, nitro or loweralkoxy; and

loweralkyl substituted with a 5- or 6-membered heterocyclic ring;

R₃ is 3-indolylmethyl or substituted 3-indolylmethyl wherein the substituent may be loweralkyl, loweralkoxy or halogen; and

R₄ is loweralkyl, hydroxyloweralkyl, benzyl, carboxyloweralkyl, aminoloweralkyl or substituted hydroxy benzyl wherein the substituent may be loweralkyl, loweralkoxy, hydroxy, halogen, amino or nitro.

2. A compound of claim 1 wherein X and Y are (CH₂)_n and n is 1;

R₁ and R₂ are as defined in claim 1;

R₃ is 3-indolylmethyl or substituted indolylmethyl wherein the substituent is methoxy or fluoro; and

R₄ is methyl, ethyl, hydroxymethyl or hydroxyethyl.

3. A compound of claim 2 wherein:

X and Y are methylene;

R₁ and R₂ are as defined in claim 1;

R₃ is 3-indolylmethyl; and

R₄ is hydroxyethyl.

4. The compound of claim 2 which is cyclo (Pro-Tyr-D-Trp-Lys-Thr-Phe).

5. The compound of claim 2 which is cyclo (Pro-Phe-D-Trp-Lys-Thr-Phe).

6. The compound of claim 2 which is cyclo (Pro-Phe-L-Trp-Lys-Thr-Phe).

7. The compound of claim 2 which is cyclo (Pro-Phe-D-5F-Trp-Lys-Thr-Phe).

8. The compound of claim 2 which is cyclo (Pro-Phe-L-5F-Trp-Lys-Thr-Phe).

9. The compound of claim 2 which is cyclo (Pro-Phe-D-Trp-Lys-Ser-Phe).

10. The compound of claim 2 which is cyclo (Pro-Phe-D-Trp-Lys-Thr-p-Cl-Phe).

11. A method for inhibiting the release of growth hormone which comprises administering to an animal an effective amount of a cyclic hexapeptide of claim 1.

12. A pharmaceutical composition for inhibiting the release of growth hormone comprising a therapeutically effective amount of the cyclic hexapeptide of claim 1 or the non-toxic acid addition salts thereof in a pharmaceutically acceptable liquid or solid carrier.