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Claims for Patent: 5,925,730

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Claims 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(isopr opyl)-Pro-D-Ala-NH.sub.2, and Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(hydroorotyl)-D-4Amf(Q.sub.2)-Leu-Lys(isop ropyl)-Pro-D-Ala-NH.sub.2, wherein Q.sub.2 is Cbm or MeCbm.
Inventor(s): Semple; Graeme (Hampshire, GB), Jiang; Guangcheng (San Diego, CA)
Assignee: Ferring BV (Hoofddorp, NL)
Application Number:08/837,042
Patent Claims: 1. A GnRH antagonist peptide having the formula:

X-D-2Nal-(A)D-Phe-D-3Pal-Ser-Xaa.sub.5 -Xaa.sub.6 -Leu-Xaa.sub.8 -Pro-Xaa.sub.10

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, 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 ##STR11## 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, 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, 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.

2. A GnRH antagonist according to claim 1 wherein Q.sub.1 is L-Hor or D-Hor.

3. A GnRH antagonist according to claim 2 wherein Q.sub.2 is Q and R is H or methyl.

4. A GnRH antagonist according to claim 2 wherein Xaa.sub.6 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 Xaa.sub.8 is Lys(ipr).

7. A GnRH antagonist according to claim 2 wherein Xaa.sub.10 is D-Ala-NH.sub.2.

8. A GnRH antagonist according to claim 2 wherein X is --CONHCH.sub.3.

9. 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.

10. A GnRH antagonist according to claim 1 wherein Xaa.sub.5 is 4Aph(L- or D-Hor) and Q.sub.2 is Q and R is H or methyl.

11. A GnRH antagonist according to claim 1 wherein Xaa.sub.5 is 4Aph(L- or D-Hor) and Xaa.sub.6 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-Xaa.sub.5 -Xaa.sub.6 -Leu-Lys(ipr)-Pro-Xaa.sub.10

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;

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 ##STR12## 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.10 is D-Ala-NH.sub.2, NHCH.sub.2 CH.sub.3 or Gly-NH.sub.2.

13. A GnRH antagonist according to claim 12 wherein Q.sub.1 is L- or D-Hor and Xaa.sub.6 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; 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 ; and Xaa.sub.10 is D-Ala-NH.sub.2.

15. A GnRH antagonist according to claim 1 having the formula: Ac-D-2Nal-D-4ClPhe-D-3Pal-Ser-4Aph(L-Hor)-Xaa.sub.6 -Leu-Lys(ipr)-Pro-D-Ala-NH.sub.2, wherein Xaa.sub.6 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 Xaa.sub.6 is D-4Aph(carbamoyl).

17. The GnRH antagonist according to claim 15 wherein Xaa.sub.6 is D-4Amf(carbamoyl).

18. A GnRH antagonist according to claim 1 wherein Xaa.sub.5 is 4Aph(L-Hor) and Xaa.sub.6 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: X.sup.1 -D-2Nal-(A)D-Phe-D-3Pal-Ser(X.sup.2)-Xaa.sub.5 -Xaa.sub.6 -Leu-Lys(ipr) (X.sup.4)-Pro-X.sup.5 wherein:

X.sup.1 is an .alpha.-amino-protecting group;

A is 4Cl or 4F;

X.sup.2 is an hydroxyl-protecting group;

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 ##STR13## Xaa.sub.6 is D-4Aph(Q.sub.2), D-4Amf(Q.sub.2) or D-3Pal, with Q.sub.2 being Ac, Q.sub.1, carbamoyl or methylcarbamoyl;

X.sup.4 is an acid-labile amino-protecting group; and

X.sup.5 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-NH.sub.2.
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