Claims for Patent: 4,801,577

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.