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Last Updated: August 5, 2021

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Claims for Patent: 4,801,577


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Summary for Patent: 4,801,577
Title: Nonapeptide and decapeptide analogs of LHRH useful as LHRH antagonists
Abstract:Synthetic nona- and decapeptide LHRH antagonist analogs are disclosed, having a sterically hindered guanidino-substituted arginyl or homoarginyl residue at position 8, with no arginyl substituent at position 6.
Inventor(s): Nestor, Jr.; John J. (San Jose, CA), Vickery; Brian H. (Saratoga, CA)
Assignee: Syntex (U.S.A.) Inc. (Palo Alto, CA)
Application Number:07/010,923
Patent Claims: 1. A compound of the formula ##STR6## or a pharmaceutically acceptable salt thereof, wherein: A is an amino acyl residue selected from the group consisting of either the D- or the L-isomer of: N-Ac-D,L-.DELTA..sup.3,4 -prolyl, N-Ac-D,L-prolyl, N-Ac-D,L-phenylalanyl, N-Ac-D,L-p-chlorophenylalanyl, N-Ac-D,L,-p-fluorophenylalanyl, N-Ac-3-(1-naphthyl)-D,L-alanyl, N-Ac-3-(2-naphthyl)-D,L-alanyl, and N-Ac-3-(2,4,6-trimethylphenyl)-D,L-alanyl;

B is an amino acyl residue selected from the group consisting of D-phenylalanyl, D-p-chlorophenylalanyl, D-p-fluorophenylalanyl, D-p-nitrophenylalanyl, 2,2-diphenylglycyl, D-.alpha.-methyl-p-chlorophenylalanyl and 3-(2-naphthyl)-D-alanyl;

C is an amino acyl residue selected from the group consisting of D-tryptophanyl, D-phenylalanyl, 3-(3-pyridyl)-D-alanyl, and 3-(2-naphthyl)-D-alanyl;

D is an amino acyl residue selected from the group consisting of L-phenylalanyl, L-tyrosyl, and 3-(3-pyridyl)-alanyl, arginyl, or G;

E is 3-(2-naphthyl)-D-alanyl, 3-(3-pyridyl)-D-alanyl, D-tyrosyl, D-tryptophanyl, D-nicotinyl-lysyl, pyridylacetyl-lysyl, D-Glu(AA) or G;

F is an amino acyl residue selected from the group consisting of L-leucyl, L-norleucyl, L-phenylalanyl, L-tryptophanyl, and 3-(2-naphthyl)-L-alanyl;

G is an amino acyl residue selected from the group consisting of the radicals represented by the following structural formulas: ##STR7## wherein n is 1 to 5;

R.sup.1 is alkyl of 1 to 6 carbon atoms or fluoroalkyl;

R.sup.2 is hydrogen or R.sup.1 ; or R.sup.1 --HN--C.dbd.NR.sup.2 is a ring represented by the following structure formulas: ##STR8## wherein m is 1 to 4; A is hydrogen or alkyl of 1 to 6 carbon atoms; and X is halo or A; and ##STR9## wherein R.sup.3 is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl or phenylloweralkyl; and

J is D-alaninamide; D-leucinamide; glycinamide; or --NHR.sup.4 wherein R.sup.4 is lower alkyl or NHCONH.sub.2.

2. A compound of claim 2 wherein:

A is N-Ac-D-Nal(2) or N-Ac-D-pCl-Phe;

B is D-pCl-Phe or D-pF-Phe;

C is D-Trp, D-Nal(2) or D-Pal(3);

D is Pal(3), Tyr, Arg, Deh, Mbh, Bth or Pha;

E is D-Trp, D-Tyr, D-Nal(2), D-Pal(3), D-Deh, D-Bth, D-Mbh or D-Pha;

F is Leu or Phe;

G is Deh, Bth, Mbh, or Pha; and

J is D-AlaNH.sub.2 or GlyNH.sub.2 ;

or a pharmaceutically acceptable salt thereof.

3. A compound of claim 2 wherein:

A is N-Ac-D-Nal(2);

B is D-pCl-Phe;

C is D-Trp or D-Pal(3);

D is Tyr, Arg, Deh, Mbh, Bth or Pha;

F is Leu; and

J is D-AlaNH.sub.2 ;

or a pharmaceutically acceptable salt thereof.

4. A compound of claim 3 wherein G is Deh or Bth or a pharmaceutically acceptable salt thereof.

5. A compound of claim 4 wherein G is Bth or a pharmaceutically acceptable salt thereof.

6. A compound of claim 3 which is

N-Ac-D-Nal(2)-D-pCl-Phe-C-Ser-Tyr-E-Leu-G-Pro-D-AlaNH.sub.2 wherein E is D-Pal(3) or D-Trp;

or a pharmaceutically acceptable salt thereof.

7. A compound of claim 6 wherein C and E are the same or a pharmaceutically acceptable salt thereof.

8. A compound of claim 3 which is

N-Ac-D-Nal(2)-D-pCl-Phe-C-Ser-Tyr-E-Leu-G-Pro-D-AlaNH.sub.2, wherein E is D-Deh, D-Bth, D-Mbh or D-Pha;

or a pharmaceutically acceptable salt thereof.

9. A compound of claim 3 which is

N-Ac-D-Nal(2)-D-pCl-Phe-C-Ser-Arg-E-Leu-G-Pro-D-AlaNH.sub.2, wherein E is D-Trp, D-Pal(3), D-Nal(2), or D-Tyr;

or a pharmaceutically acceptable salt thereof.

10. A compound of claim 9 wherein E is D-Tyr;

or a pharmaceutically acceptable salt thereof.

11. A compound of claim 9 wherein E is D-Trp or D-Pal(3);

or a pharmaceutically acceptable salt thereof.

12. A compound of claim 11 wherein C and E are the same;

or a pharmaceutically acceptable salt thereof.

13. A compound of claim 3 which is

N-Ac-D-Nal(2)-D-pCl-Phe-C-Ser-D-E-Leu-G-Pro-D-AlaNH.sub.2, wherein D is Deh, Bth, Mbh or Pha, and E is D-Tyr, D-Nal(2), D-Trp or D-Pal(3);

or a pharmaceutically acceptable salt thereof.

14. A compound of claim 13 wherein E is D-Tyr or D-Pal(3) or a pharmaceutically acceptable salt thereof.

15. A compound of claim 3 which is N-Ac-D-Nal(2)-D-pCl-Phe-D-Trp-Ser-Tyr-E-Leu-G-Pro-D-AlaNH.sub.2, wherein E is D-Trp, D-Tyr, or D-Nal(2);

or a pharmaceutically acceptable salt thereof.

16. A compound of claim 3 which is

N-Ac-D-Nal(2)-D-pCl-Phe-C-Ser-D-E-Leu-G-Pro-D-AlaNH.sub.2, wherein D and G are independently Deh, Bth, Mbh or Pha, and C and E are independently D-Trp or D-Pal(3);

or a pharmaceutically acceptable salt thereof.

17. A compound of claim 3 which is

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Tyr-D-Pal(3)-Leu-G-Pro-D-AlaNH.sub.2 ;

or a pharmaceutically acceptable salt thereof.

18. A compound of claim 3 selected from the group consisting of:

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Tyr-D-Pal(3)-Leu-Deh-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Tyr-D-Pal(3)-Leu-Bth-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Tyr-D-Pal(3)-Leu-Mbh-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Tyr-D-Pal(3)-Leu-Pha-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Trp-Ser-Tyr-D-Trp-Leu-Deh-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCL-Phe-D-Trp-Ser-Tyr-D-Trp-Leu-Bth-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Trp-Ser-Tyr-D-Trp-Leu-Mbh-Pro-D-AlaNH.sub.2 ; and

N-Ac-D-Nal(2)-D-pCl-Phe-D-Trp-Ser-Tyr-D-Trp-Leu-Pha-Pro-D-AlaNH.sub.2 ;

or a pharmaceutically acceptable salt thereof.

19. A compound of claim 3 selected from the group consisting of:

N-Ac-D-Nal(2)-D-pCl-Phe-D-Trp-Ser-Tyr-D-Deh-Leu-Deh-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Trp-Ser-Tyr-D-Mbh-Leu-Mbh-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Trp-Ser-Tyr-D-Bth-Leu-Bth-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCL-Phe-D-Trp-Ser-Tyr-D-Pha-Leu-Pha-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Tyr-D-Deh-Leu-Deh-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Tyr-D-Mbh-Leu-Mbh-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Tyr-D-Bth-Leu-Bth-Pro-D-AlaNH.sub.2 ; and

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Tyr-D-Pha-Leu-Pha-Pro-D-AlaNH.sub.2 ;

or a pharmaceutically acceptable salt thereof.

20. A compound of claim 3 selected from the group consisting of:

N-Ac-D-Nal(2)-D-pCl-Phe-D-Trp-Ser-Arg-D-Trp-Leu-Deh-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Trp-Ser-Arg-D-Trp-Leu-Bth-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Trp-Ser-Arg-D-Trp-Leu-Mbh-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Trp-Ser-Arg-D-Trp-Leu-Pha-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Arg-D-Pal(3)-Leu-Bth-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Arg-D-Pal(3)-Leu-Mbh-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Arg-D-Pal(3)-Leu-Deh-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Arg-D-Pal(3)-Leu-Pha-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Trp-Ser-Arg-D-Tyr-Leu-Deh-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Trp-Ser-Arg-D-Tyr-Leu-Bth-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Trp-Ser-Arg-D-Tyr-Leu-Mbh-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Trp-Ser-Arg-D-Tyr-Leu-Pha-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Arg-D-Tyr-Leu-Bth-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Arg-D-Tyr-Leu-Mbh-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Arg-D-Tyr-Leu-Deh-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Arg-D-Tyr-Leu-Pha-Pro-D-AlaNH.sub.2 ; and

or a pharmaceutically acceptable salt thereof.

21. A compound of claim 3 selected from the group consisting of:

N-Ac-D-Nal(2)-D-pCl-Phe-D-Trp-Ser-Deh-D-Tyr-Leu-Deh-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Trp-Ser-Mbh-D-Tyr-Leu-Mbh-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Trp-Ser-Bth-D-Tyr-Leu-Bth-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Trp-Ser-Pha-D-Tyr-Leu-Pha-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Trp-Ser-Deh-D-Trp-Leu-Deh-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Trp-Ser-Mbh-D-Trp-Leu-Mbh-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Trp-Ser-Bth-D-Trp-Leu-Bth-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Trp-Ser-Pha-D-Trp-Leu-Pha-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Deh-D-Pal(3)-Leu-Deh-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Mbh-D-Pal(3)-Leu-Mbh-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Bth-D-Pal(3)-Leu-Bth-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Pha-D-Pal(3)-Leu-Pha-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Trp-Ser-Deh-D-Nal(2)-Leu-Deh-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Trp-Ser-Mbh-D-Nal(2)-Leu-Mbh-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Trp-Ser-Bth-D-Nal(2)-Leu-Bth-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Trp-Ser-Pha-D-Nal(2)-Leu-Pha-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Pal(3)-D-Pal(3)-Leu-Deh-Pro-D-AlaNH.su b.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Pal(3)-D-Pal(3)-Leu-Bth-Pro-D-AlaNH.su b.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Pal(3)-D-Pal(3)-Leu-Pha-Pro-D-AlaNH.su b.2 ; and

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Pal(3)-D-Pal(3)-Leu-Mbh-Pro-D-AlaNH.su b.2 ;

or a pharmaceutically acceptable salt thereof.

22. A compound of claim 3 selected from the group consisting of:

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Tyr-D-Pal(3)-Leu-Deh-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Mbh-D-Pal(3)-Leu-Mbh-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Pal(3)-D-Pal(3)-Leu-Bth-Pro-D-AlaNH.su b.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Arg-D-Pal(3)-Leu-Deh-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Tyr-D-Pal(3)-Leu-Bth-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Tyr-D-Pal(3)-Leu-Mbh-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Tyr-D-Pal(3)-Leu-Pha-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Trp-Ser-Tyr-D-Trp-Leu-Bth-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Trp-Ser-Arg-D-Trp-Leu-Deh-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Trp-Ser-Arg-D-Trp-Leu-Bth-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Trp-Ser-Arg-D-Trp-Leu-Pha-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Arg-D-Pal(3)-Leu-Pha-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Trp-Ser-Tyr-D-Bth-Leu-Bth-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Trp-Ser-Tyr-D-Phe-Leu-Pha-Pro-D-AlaNH.sub.2 ;

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Tyr-D-Deh-Leu-Deh-Pro-D-AlaNH.sub.2 ; and

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Tyr-D-Bth-Leu-Bth-Pro-D-AlaNH.sub.2 ;

or a pharmaceutically acceptable salt thereof.

23. A compound of claim 3 which is:

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Tyr-D-Pal(3)-Leu-Deh-Pro-D-AlaNH.sub.2 ;

or a pharmaceutically acceptable salt thereof.

24. A compound of claim 3 which is:

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Tyr-D-Pal(3)-Leu-Bth-Pro-D-AlaNH.sub.2 ;

or a pharmaceutically acceptable salt thereof.

25. A compound of claim 3 which is:

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Tyr-D-Pal(3)-Leu-Mbh-Pro-D-AlaNH.sub.2 ;

or a pharmaceutically acceptable salt thereof.

26. A compound of claim 3 which is:

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(2)-Ser-Tyr-D-Pal(3)-Leu-Pha-Pro-D-AlaNH.sub.2 ;

or a pharmaceutically acceptable salt thereof.

27. A compound of claim 3 which is:

N-Ac-D-Nal(2)-D-pCl-Phe-D-Trp-Ser-Tyr-D-Trp-Leu-Bth-Pro-D-AlaNH.sub.2 ;

or a pharmaceutically acceptable salt thereof.

28. A compound of claim 3 which is:

N-Ac-D-Nal(2)-D-pCl-Phe-D-Trp-Ser-Arg-D-Trp-Leu-Bth-Pro-D-AlaNH.sub.2 ;

or a pharmaceutically acceptable salt thereof.

29. A compound of claim 3 which is:

N-Ac-D-Nal(2)-D-pCl-Phe-D-Trp-Ser-Arg-D-Trp-Leu-Pha-Pro-D-AlaNH.sub.2 ;

or a pharmaceutically acceptable salt thereof.

30. A compound of claim 3 which is:

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Arg-D-Pal(3)-Leu-Bth-Pro-D-AlaNH.sub.2 ;

or a pharmaceutically acceptable salt thereof.

31. A compound of claim 3 which is:

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Arg-D-Pal(3)-Leu-Pha-Pro-D-AlaNH.sub.2 ;

or a pharmaceutically acceptable salt thereof.

32. A compound of claim 3 which is:

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Mbh-D-Pal(3)-Leu-Mbh-Pro-D-AlaNH.sub.2 ;

or a pharmaceutically acceptable salt thereof.

33. A compound of claim 3 which is:

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Pal(3)-D-Pal(3)-Leu-Bth-Pro-D-AlaNH.su b.2 ;

or a pharmaceutically acceptable salt thereof.

34. A compound of claim 3 which is:

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Arg-D-Pal(3)-Leu-Deh-Pro-D-AlaNH.sub.2 ;

or a pharmaceutically acceptable salt thereof.

35. A pharmaceutical composition for inhibiting ovulation in a mammalian female subject; preventing ovarian hyperstimulation in response to exogenous gonadotropins, treating premenstrual syndrome, or treating endometriosis in a female human subject; for treating prostatic hypertrophy or inhibiting spermatogenesis in a male mammalian subject; or for treating precocious puberty in a human subject; or interrupting heat in a female animal; or terminating pregnancy in a female mammalian subject; comprising an effective amount of the compound of claim 1 in admixture with at least one pharmaceutically acceptable excipient.

36. A compound of claim 3 which is

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Bth-D-Tyr-Leu-Bth-Pro-D-Ala-NH.sub.2 ;

or an optical isomer thereof; or a pharmaceutically acceptable salt thereof.

37. The compound of claim 3 which is

N-Ac-D-Nal(2)-D-pCl-Phe-D-Trp-Ser-Tyr-D-Bth-Leu-Bth-Pro-D-AlaNH.sub.2 ;

or an optical isomer thereof; or a pharmaceutically acceptable salt thereof.

38. The compound of claim 3 which is

N-Ac-D-Nal(2)-D-pCl-Phe-D-Trp-Ser-Tyr-D-Pha-Leu-Pha-Pro-D-AlaNH.sub.2

or an optical isomer thereof; or a pharmaceutically acceptable salt thereof.

39. The compound of claim 3 which is

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Tyr-D-Deh-Leu-Deh-Pro-D-AlaNH.sub.2 ;

or an optical isomer thereof; or a pharmaceutically acceptable salt thereof.

40. The compound of claim 3 which is

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Tyr-D-Bth-Leu-Bth-Pro-D-AlaNH.sub.2 ;

or an optical isomer thereof; or a pharmaceutically acceptable salt thereof.

41. The compound of claim 3 which is

N-Ac-D-Nal(2)-D-pCl-Phe-D-Pal(3)-Ser-Mbh-D-Pal(3)-Leu-Mbh-Pro-D-AlaNH.sub.2 ;

or an optical isomer thereof; or a pharmaceutically acceptable salt thereof.

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