Details for Patent: 6,214,798

Title:	GnRH antagonists being modified in positions 5 and 6
Abstract:	Peptides are provided which have improved duration of GnRH antagonistic properties. These antagonists may be used to regulate fertility and to treat steroid-dependent tumors and for other short-term and long-term treatment indications. These antagonists have a derivative of aminoPhe or its equivalent in the 5- or the 5- and 6-positions. This derivative is modified so as to contain a carbamoyl group or heterocycle, including a urea moiety, in its side chain. Decapeptides having the formula: wherein Q.sub.2 is Cbm or MeCbm and Xaa.sub.10 is D-Ala-ol or Ala-ol are particularly effective and continue to exhibit very substantial suppression of LH secretion at 96 hours following injection.
Inventor(s):	Semple; Graeme (Gothenburg, SE), Jiang; Guangcheng (San Diego, CA)
Assignee:	Ferring BV (Hoofddorp, NL)
Filing Date:	Jan 03, 2000
Application Number:	09/402,698
Claims:	1. A GnRH antagonist peptide having the formula: or a pharmaceutically acceptable salt thereof wherein: X is an acyl group having not more than 7 carbon atoms or Q, with Q being ##STR11## and with R being H or lower alkyl; A is 4Cl, 4F, 4Br, 4NO.sub.2, 4CH.sub.3, 4OCH.sub.3, 3,4Cl.sub.2 or C.sup..alpha. Me4Cl; Xaa.sub.5 is 4Aph(Q.sub.1) or 4Amf(Q.sub.1) with Q.sub.1 being ##STR12## a D/L mixture of either, Xaa.sub.6 is D-4Aph(Q.sub.2), D-4Amf(Q.sub.2), D-Lys(Nic), D-Cit, D-Hci or D-3Pal, with Q.sub.2 being For, Ac, 3-amino-1,2,4-triazole(atz), Q or Q.sub.1 ; Xaa.sub.8 is Lys(ipr), Arg, Har, Arg(Et.sub.2) or Har(Et.sub.2); and Xaa.sub.10 is D-Ala-ol or Ala-ol; provided however that the .alpha.-amino group of Xaa.sub.5 may optionally be methylated; and provided further that when Xaa.sub.6 contains D- or L-Hor or D- or L-Imz or a D/L mixture of either, Xaa.sub.5 may have Ac, For or 3-amino-1,2,4-triazole as Q.sub.1. 2. A GnRH antagonist peptide according to claim 1 wherein Q is carbamoyl or methylcarbamoyl. 3. A GnRH antagonist according to claim 1 wherein Q.sub.1 is L-Hor or D-Hor. 4. A GnRH antagonist according to claim 1 wherein X is Ac and Xaa.sub.8 is Lys(ipr). 5. A GnRH antagonist according to claim 1 wherein Xaa.sub.5 is 4Aph(L- or D-Hor) and Xaa.sub.6 is D-4Aph(Ac), D-4Aph(atz), or D-3Pal. 6. A GnRH antagonist according to claim 1 wherein Xaa.sub.5 is 4Aph(L- or D-Hor), Q.sub.2 is Q and R is H or methyl. 7. A GnRH antagonist according to claim 1 wherein Xaa.sup.5 is 4Aph(L- or D-Hor) and Xaa.sub.6 is D-Cit or D-Hci. 8. A GnRH antagonist according to claim 1 wherein Xaa.sub.6 is D-4Aph(D-Hor). 9. A GnRH antagonist peptide according to claim 1 wherein: X is For, Ac, Acr, Pn, By, Vl, Vac, Bz or Q; A is 4Cl or 4F; Xaa.sub.5 is 4Aph(Q.sub.1) or 4Amf(Q.sub.1) with Q.sub.1 being a D-isomer, an L-isomer, or a D/L-isomer mixture of either Hor or Imz; Xaa.sub.6 is D-4Aph(Q.sub.2), D-4Amf(Q.sub.2), D-Cit, D-Lys(Nic) or D-3Pal, with Q.sub.2 being For, Ac, Q or Q.sub.1 ; and Xaa.sub.8 is Lys(ipr). 10. A GnRH antagonist according to claim 9 wherein Q.sub.1 is L- or D-Hor and Xaa.sub.6 is D-4Amf(Q), with R being H or methyl. 11. A GnRH antagonist according to claim 9 wherein X is Ac or Q; R is H or methyl; Xaa.sub.6 is D-4Aph(Q.sub.2), D-4Amf(Q.sub.2) or D-3Pal, with Q.sub.2 being Ac, Q or Q.sub.1. 12. A GnRH antagonist according to claim 1 having the formula: Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(L-Hor)-Xaa.sub.6 -Leu-Lys(ipr)-Pro-Xaa.sub.10, wherein Xaa.sub.6 is D-4Aph(Ac), D-3Pal, D-4Aph(carbamoyl), D-4Amf(carbamoyl), D-4Amf(methylcarbamoyl) or D-4Aph(D-Hor). 13. A pharmaceutical composition for inhibiting the secretion of gonadotropins in mammals comprising, as an active ingredient, an effective amount of a GnRH antagonist according to claim 12 in association with a nontoxic diluent. 14. A method for inhibiting the secretion of gonadotropins in mammals comprising administering an amount of a pharmaceutical composition according to claim 13 which effects a substantial decrease in LH and FSH levels. 15. A method for in vivo or in vitro diagnosis of a condition where GnRH is causing excess hormonal secretion or tumor growth, which method comprises administering a GnRH antagonist peptide according to claim 12 and monitoring for hormonal secretion or for tumor cell proliferation. 16. A GnRH antagonist according to claim 1 having either the formula: Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(L-Hor)-D-4Aph(carbamoyl)-Leu-Lys(ipr)-Pro -D-Ala-ol; or the formula Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(L-Hor)-D-4Aph(carbamoyl)-Leu-Lys(ipr)-Pro -Ala-ol. 17. A GnRH antagonist according to claim 1 having either the formula: Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(L-Hor)-D-4Amf(carbamoyl)-Leu-Lys(ipr)-Pro -D-Ala-ol; or the formula: Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(L-Hor)-D-4Amf(carbamoyl)-Leu-Lys(ipr)-Pro -Ala-ol. 18. A GnRH antagonist peptide having the formula: or a pharmaceutically acceptable salt thereof wherein: X is an acyl group having not more than 7 carbon atoms or Q, with Q being ##STR13## and with R being H or lower alkyl; A is 4Cl, 4F, 4Br, 4NO.sub.2, 4CH.sub.3, 4OCH.sub.3, 3,4Cl.sub.2 or C.sup..alpha. Me4Cl; Xaa.sub.5 is 4Aph(Q.sub.1) or 4Amf(Q.sub.1) with Q.sub.1 being ##STR14## or a D/L mixture of either, Xaa.sub.6 is D-4Aph(Q.sub.2), D-4Amf(Q.sub.2), D-Lys(Nic), D-Cit, D-Hci or D-Pal, with Q.sub.2 being For, Ac, 3-amino-1,2,4-triazole, Q or Q.sub.1 ; Xaa.sub.8 is Lys(ipr), Arg, Har, Arg(Et.sub.2) or Har(Et.sub.2); and Xaa.sub.10 is D-Ala-NH.sub.2, D-Ala-ol, Ala-ol, NHCH.sub.2 CH.sub.3, Gly-NH.sub.2, Ala-NH.sub.2, AzaGly-NH.sub.2, Agl-NH.sub.2, D-Agl-NH.sub.2, Agl(Me)-NH.sub.2 or D-Agl(Me)-NH.sub.2, provided however that when Xaa.sub.6 contains D- or L-Hor or D- or L-Imz or a D/L mixture of either, Xaa.sub.5 may have Ac, For or 3-amino-1,2,4-triazole as Q.sub.1. 19. A GnRH antagonist peptide according to claim 18 wherein Q is carbamoyl or methylcarbamoyl; Q.sub.1 is L-Hor or D-Hor; and Xaa.sub.10 is D-Ala-NH.sub.2, D-Ala-ol or Ala-ol. 20. A GnRH antagonist peptide according to claim 18 wherein: X is For, Ac, Acr, Pn, By, Vl, Vac, Bz or Q; A is 4Cl or 4F; Xaa.sub.5 is Aph(Q.sub.1) or Amf(Q.sub.1) with Q.sub.1 being a D-isomer, an L-isomer, or a D/L-isomer mixture of either Hor or Imz; Xaa.sub.6 is D-Aph(Q.sub.2), D-Amf(Q.sub.2), D-Cit, D-Lys(Nic) or D-Pal, with Q.sub.2 being For, Ac, Q or Q.sub.1 ; and Xaa.sub.8 is Lys(ipr).