Modified D-retro cyclic hexapeptide somatostatin analogs

• US 4,360,516 A
• Filed: 04/13/1981
• Issued: 11/23/1982
• Est. Priority Date: 04/13/1981
• Status: Expired due to Fees

• 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:
  US06/254,010
• Time in Patent Office: 589 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 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 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: 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

Highly active and long lasting cyclic hexapeptide analogs of somatostatin are prepared. A single amino acid of D-configuration, functioning as a spacer for the remaining amino acids, replaces seven of the ring amino acids of somatostatin. The amino acid adjacent to this spacer amino acid is methylated on the nitrogen and is of the D-configuration. The two amino acids on either side of this dipeptide are also of D-configuration. The remaining two amino acids, Trp and Lys are either D- or L-. The order of the amino acids is reversed relative to the sequence found in somatostatin. The structures therefore represent a modified form of D-retro peptide analogs. 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 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 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;

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

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

the two asymmetric centers marked with an asterisk (*) may be either D or L provided the two centers of asymmetry are not the same, while the other asymmetric centers are D.

2. A compound of claim 1 wherein Y is (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;

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

R₅ is as defined in claim 1.

3. A compound of claim 2 wherein R₅ is methyl or ethyl.

4. A compound of claim 3 wherein:

Y is methylene;

R₁ and R₂ are as defined in claim 1.

R₃ is 3-indolylmethyl;

R₄ is hydroxyethyl; and

R₅ is methyl.

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

6. The compound of claim 2 which is cyclo (D-Ala-N-Me-D-Phe-D-Val-L-Lys-D-Trp-D-Phe).

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

8. The compound of claim 2 which is cyclo-(D-Abu-N-Me-D-Phe-D-Val-L-Lys-D-Trp-D-Tyr).

9. A method for the treatment of acromegaly, diabetes, diabetic retinopathy and gastric ulcers which comprises administering to an animal requiring such treatment an effective amount of a D-retro cyclic hexapeptide of claim 1.

10. A pharmaceutical composition useful for the treatment of acromegaly, diabetes, diabetic retinopathy and gastric ulcers comprising a therapeutically effective amount of the D-retro cyclic hexapeptide of claim 1 or the non-toxic acid addition salts thereof in a pharmaceutically acceptable liquid or solid carrier.