Cyclic and bridged cyclic somatostatin analogs useful as local anti-inflammatory agents

• US 4,585,755 A
• Filed: 04/29/1985
• Issued: 04/29/1986
• Est. Priority Date: 04/29/1985
• Status: Expired due to Fees

• Current Assignee: Merck & Co., Inc.
• Original Assignee: Merck & Co., Inc.
• Inventors: Steelman, Sanford L., Morgan, Evan R.
• Primary Examiner(s): Phillips, Delbert R.
• Application Number:
  US06/728,019
• Time in Patent Office: 365 Days
• Field of Search: 514/11, 514/806, 260/112.55
• US Class Current: 514/11.1
• CPC Class Codes: A61K 38/31 Somatostatins
• 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: Y10S 930/16 Somatostatin; related peptides

Abstract

Cyclic and bridged cyclic somatostatin analogs have been found to be useful as local anti-inflammatory agents in the treatment of such conditions, as, for example, psoriasis, eczema, seborrhea, and other localized inflammatory and allergic conditions.

Claims

1. A method of locally treating inflammatory and allergic conditions comprising applying to the area to be treated an anti-inflammatory and anti-allergically effective amount of a compound having the Formulae:

##STR4## wherein in each of the compounds of Formulae I, II and III;

W is S or (CH₂)_n wherein n is 0, 1, or 2;

X and Z are S or CH₂ provided that at least one of X or Z is S;

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

R₁ and R₂ are independently loweralkyl, benzyl, substituted benzyl where 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 benzyl wherein the substituent may be loweralkyl, loweralkoxy, hydroxy, halogen, amino or nitro; and

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

2. The method of claim 1 wherein said Formula I compound is a member of the group:

Cyclo-(N-Me-Ala-Tyr-D-Trp-Lys-Thr-Phe);

Cyclo-(N-Me-Ala-Phe-D-Trp-Lys-Thr-Phe);

Cyclo-(N-Me-Ala-Phe-L-Trp-Lys-Thr-Phe);

Cyclo-(N-Me-Ala-Phe-D-Trp-Lys-Thr-p-Cl-Phe);

Cyclo-(N-Me-Ala-Phe-D-5-F-Trp-Lys-Thr-Phe);

Cyclo-(N-Me-Ala-Phe-L-5-F-Trp-Lys-Thr-Phe);

Cyclo-(N-Me-Ala-Phe-D-Trp-Lys-Ser-Phe);

Cyclo-(N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe);

Cyclo-(N-Me-Ala-Tyr-D-Trp-Lys-Val-Trp);

Cyclo-(N-Me-Ala-Tyr-L-Trp-Lys-Val-Phe); and

,

Cyclo-(Ser-Ala-N-Me-Phe-His-D-Trp-Lys).

3. The method of claim 1 wherein said Formula II compound is a member of the group:

Cyclo-(Pro-Tyr-D-Trp-Lys-Thr-Phe);

Cyclo-(Pro-Phe-D-Trp-Lys-Thr-Phe);

Cyclo-(Pro-Phe-L-Trp-Lys-Thr-Phe);

Cyclo-(Pro-Phe-D-Trp-Lys-Thr-p-Cl-Phe);

Cyclo-(Pro-Phe-D-5-F-Trp-Lys-Thr-Phe);

Cyclo-(Pro-Phe-L-5-F-Trp-Lys-Thr-Phe); and

,

Cyclo-(Pro-Phe-D-Trp-Lys-Ser-Phe).

4. The method of claim 1 wherein said Formula III compound is a member of the group:

##STR5##

5. A method of locally treating atopic eye diseases comprising applying to the area to be treated an anti-atopically effective amount of a compound having the Formulae:

##STR6## wherein in each of the compounds of Formulae I, II and III;

W is S or (CH₂)_n wherein n is 0, 1, or 2;

X and Z are S or CH₂ provided that at least one of X or Z is S;

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

R₁ and R₂ are independently loweralkyl, benzyl, substituted benzyl where 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 benzyl wherein the substituent may be loweralkyl, loweralkoxy, hydroxy, halogen, amino or nitro; and

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

6. The method of claim 5 wherein said Formula I compound is a member of the group:

Cyclo-(N-Me-Ala-Tyr-D-Trp-Lys-Thr-Phe);

Cyclo-(N-Me-Ala-Phe-D-Trp-Lys-Thr-Phe);

Cyclo-(N-Me-Ala-Phe-L-Trp-Lys-Thr-Phe);

Cyclo-(N-Me-Ala-Phe-D-Trp-Lys-Thr-p-Cl-Phe);

Cyclo-(N-Me-Ala-Phe-D-5-F-Trp-Lys-Thr-Phe);

Cyclo-(N-Me-Ala-Phe-L-5-F-Trp-Lys-Thr-Phe);

Cyclo-(N-Me-Ala-Phe-D-Trp-Lys-Ser-Phe);

Cyclo-(N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe);

Cyclo-(N-Me-Ala-Tyr-D-Trp-Lys-Val-Trp);

Cyclo-(N-Me-Ala-Tyr-L-Trp-Lys-Val-Phe); and

,

Cyclo-(Ser-Ala-N-Me-Phe-His-D-Trp-Lys).

7. The method of claim 5 wherein said Formula II compound is a member of the group:

Cyclo-(Pro-Tyr-D-Trp-Lys-Thr-Phe);

Cyclo-(Pro-Phe-D-Trp-Lys-Thr-Phe);

Cyclo-(Pro-Phe-L-Trp-Lys-Thr-Phe);

Cyclo-(Pro-Phe-D-Trp-Lys-Thr-p-Cl-Phe);

Cyclo-(Pro-Phe-D-5-F-Trp-Lys-Thr-Phe);

Cyclo-(Pro-Phe-L-5-F-Trp-Lys-Thr-Phe); and

,

Cyclo-(Pro-Phe-D-Trp-Lys-Ser-Phe).

8. The method of claim 5 wherein said Formula III compound is a member of the group:

##STR7##