Claims for Patent: 5,925,730

Summary for Patent: 5,925,730

Title:	GnRH antagonists
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- and/or 6-positions. This derivative contains a carbamoyl group or a heterocycle including a urea in its side chain. Particularly effective decapeptides, which continue to exhibit very substantial suppression of LH secretion at 96 hours following injection, have the formulae: Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(hydroorotyl)-D-4Aph(acetyl)-Leu-Lys(isopropyl)-Pro-D-Ala-NH2, and Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(hydroorotyl)-D-4Amf(Q2)-Leu-Lys(isopropyl)-Pro-D-Ala-NH2, wherein Q2 is Cbm or MeCbm.
Inventor(s):	Graeme Semple, Guangcheng Jiang
Assignee:	Ferring BV
Application Number:	US08/837,042
Patent Claims:	1. A GnRH antagonist peptide having the formula:X-D-2Nal-(A)D-Phe-D-3Pal-Ser-Xaa5 -Xaa6 -Leu-Xaa8 -Pro-Xaa10 or pharmaceutically acceptable salt thereof wherein: X is an acyl group having not more than 7 carbon atoms or Q,with Q being ##STR10## and with R being H or lower alkyl; A is 4Cl, 4F, 4Br, 4NO2, 4CH3, 4OCH3, 3,4Cl2 or C.sup.α Me4Cl; Xaa5 is 4Aph(Q1) or 4Amf(Q1) with Q1 being ##STR11## Xaa6 is D-4Aph(Q2), D-4Amf(Q2), D-Lys(Nic), D-Cit, D-Hci or D-3Pal, with Q2 being For, Ac, 3-amino-1,2,4-triazole, Q or Q1 ; Xaa8 is Lys(ipr), Arg, Har, Arg(Et2) or Har(Et2); and Xaa10 is D-Ala-NH2, NHCH2 CH3, Gly-NH2, Ala-NH2, AzaGly-NH2, Agl-NH2, D-Agl-NH2, Agl(Me)-NH2 or D-Agl(Me)-NH2. 2. A GnRH antagonist according to claim 1 wherein Q1 is L-Hor or D-Hor. 3. A GnRH antagonist according to claim 2 wherein Q2 is Q and R is H or methyl. 4. A GnRH antagonist according to claim 2 wherein Xaa6 is D-4Aph(D-Hor). 5. A GnRH antagonist according to claim 2 wherein X is Ac. 6. A GnRH antagonist according to claim 2 wherein Xaa8 is Lys(ipr). 7. A GnRH antagonist according to claim 2 wherein Xaa10 is D-Ala-NH2. 8. A GnRH antagonist according to claim 2 wherein X is --CONHCH3. 9. A GnRH antagonist according to claim 1 wherein Xaa5 is 4Aph(L- or D-Hor) and Xaa6 is D-4Aph(Ac), D-4Aph(atz), or D-3Pal. 10. A GnRH antagonist according to claim 1 wherein Xaa5 is 4Aph(L- or D-Hor) and Q2 is Q and R is H or methyl. 11. A GnRH antagonist according to claim 1 wherein Xaa5 is 4Aph(L- or D-Hor) and Xaa6 is D-Cit or D-Hci. 12. A GnRH antagonist peptide according to claim 1 having the formula:X-D-2Nal-(A)D-Phe-D-3Pal-Ser-Xaa5 -Xaa6 -Leu-Lys(ipr)-Pro-Xaa10 wherein: X is For, Ac, Acr, Pn, Bt, Vl, Vac, Bz or Q, with Q being defined as in claim 1; A is 4Cl or 4F; Xaa5 is 4Aph(Q1) or 4Amf(Q1) with Q1 being a D-isomer, an L-isomer, or a D/L-isomer mixture of either ##STR12## Xaa6 is D-4Aph(Q2), D-4Amf(Q2), D-Cit, D-Lys(Nic) or D-3Pal, with Q2 being For, Ac, Q or Q1 ; and Xaa10 is D-Ala-NH2, NHCH2 CH3 or Gly-NH2. 13. A GnRH antagonist according to claim 12 wherein Q1 is L- or D-Hor and Xaa6 is D-4Amf(Q), with R being H or methyl. 14. A GnRH antagonist peptide according to claim 12 wherein X is Ac or Q; R is H or methyl; Xaa6 is D-4Aph(Q2), D-4Amf(Q2) or D-3Pal, with Q2 being Ac, Q or Q1 ; and Xaa10 is D-Ala-NH2. 15. A GnRH antagonist according to claim 1 having the formula: Ac-D-2Nal-D-4ClPhe-D-3Pal-Ser-4Aph(L-Hor)-Xaa6 -Leu-Lys(ipr)-Pro-D-Ala-NH2, wherein Xaa6 is D-4Aph(Ac), D-3Pal, D-4Aph(carbamoyl), D-4Amf(carbamoyl), D-4Amf(methylcarbamoyl) or D-4Aph(D-Hor). 16. The GnRH antagonist according to claim 15 wherein Xaa6 is D-4Aph(carbamoyl). 17. The GnRH antagonist according to claim 15 wherein Xaa6 is D-4Amf(carbamoyl). 18. A GnRH antagonist according to claim 1 wherein Xaa5 is 4Aph(L-Hor) and Xaa6 is D-Aph(Q) or D-Amf(Q) with R being H or methyl. 19. 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 1 in association with a nontoxic diluent. 20. A method for inhibiting the secretion of gonadotropins in mammals comprising administering an amount of a pharmaceutical composition according to claim 19 which effects a substantial decrease in LH and FSH levels. 21. An intermediate for making a GnRH antagonist peptide having the formula: X1 -D-2Nal-(A)D-Phe-D-3Pal-Ser(X2)-Xaa5 -Xaa6 -Leu-Lys(ipr) (X4)-Pro-X5 wherein:X1 is an α-amino-protecting group; A is 4Cl or 4F; X2 is an hydroxyl-protecting group; Xaa5 is 4Aph(Q1) or 4Amf(Q1) with Q1 being a D-isomer, an L-isomer or a D/L-isomer mixture of either ##STR13## Xaa6 is D-4Aph(Q2), D-4Amf(Q2) or D-3Pal, with Q2 being Ac, Q1, carbamoyl or methylcarbamoyl; X4 is an acid-labile amino-protecting group; and X5 is D-Ala-, Gly-, Ala-, Agl-, D-Agl-, Agl(Me)-, or D-Agl(Me)-resin support; or N(Et)-resin support; an amide of D-Ala, Gly or Ala; ethylamide; or AzaGly-NH2.