Cyclic hexapeptide somatostatin analogs

• US 4,486,415 A
• Filed: 08/15/1983
• Issued: 12/04/1984
• Est. Priority Date: 08/15/1983
• Status: Expired due to Fees

• Current Assignee: Merck & Co., Inc.
• Original Assignee: Merck & Co., Inc.
• Inventors: Freidinger, Roger
• Primary Examiner(s): Phillips, Delbert R.
• Application Number:
  US06/523,224
• Time in Patent Office: 477 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: 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 synthesize, 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 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:

##STR24## 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 hydroxy, carboxy, amino, guanidino, or a 5- or 6-membered heterocyclic ring;

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

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

R₅ is loweralkyl, benzyl, or substituted benzyl wherein the substituent is loweralkyl, loweralkoxy, hydroxy, halogen, amino or nitro; and

R₆ and R₇ are independently hydrogen or straight chain loweralkyl provided at least one of R₆ and R₇ is loweralkyl.

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

Y, R₁, and R₂ are as defined in claim 1;

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

R₄ is methyl, ethyl, isopropyl, hydroxymethyl or hydroxyethyl;

R₅ is methyl or benzyl; and

one or both of R₆ and R₇ are methyl.

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;

R₄ is hydroxyethyl;

R₅ is methyl or benzyl; and

one or both of R₆ and R₇ are methyl.

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

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

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

7. The compound of claim 2 which is cyclo (Pro-Phe-L-Trp-D-N-Me-Lys-Thr-Phe).

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

9. 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.

10. A pharmaceutical composition for the treatment of diabetes 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.