Gonadotropin releasing hormone analogues conjugates with steroid hormones

1. A compound comprising a gonadotrophin releasing hormone (GnRH) analogue conjugated to a steroid hormone or a progesterone derivative which is able to bind to a plasma hormone binding protein, wherein the steroid hormone is estradiol, progesterone, cortisol, corticosterone, estrone, testosterone or dihydroxytestosterone, and wherein the progesterone derivative is 11α-hydroxyprogesterone or 21-hydroxyprogesterone.

2. A compound according to claim 1 wherein the GnRH analogue is a peptide analogue.

3. A compound according to claim 2 wherein the GnRH analogue is a nonapeptide or a decapeptide.

4. A compound according to claim 1 wherein one of the amino acid residues of the GnRH analogue is a D-amino acid.

5. A compound according to claim 4 wherein the D-amino acid is D-Lys.

6. A compound according to claim 4 wherein the D-amino acid is at position 6.

7. A compound according to claim 1 wherein the GnRH analogue is a GnRH antagonist.

8. A compound according to claim 7 wherein the GnRH antagonist is [AcD-Nal 1 , D-Cpa 2 , D-Pal 3 , Arg 5 , D-Lys 6 , D-Ala 10 ]GnRH, or [Ac-ΔPro 1 , D-Fpa 2 , D-Trp 3 , D-Lys 6 ]GnRH.

9. A compound according to claim 7 wherein the GnRH antagonist is Cetrorelix, Ganirelix, Abarelix, Antide, Teverelix, FE200486, Nal-Glu, A-75 998, A-76154, A-84861, D-26344, D-63153, ramorelix, degarelix, NBI-42902, Org-30850, detirelix, iturelix, TAK-013, TAK810, AN 207, AcD-Nal-D-Cpa-D-Pal-Ser-Arg-D-Lys-Leu-Arg-Pro-D-Ala-NH 2 ; Ac-ΔPro-D-Fpa-D-Trp-Ser-Tyr-D-Lys-Leu-Arg-Pro-Gly-NH 2 ; AcD-Nal-D-Cpa-D-Pal-Ser-Arg-D-Lys-Lys-Leu-Arg-D-Ala-NH 2 ; D-Pal-Ser-Arg-D-Lys-Leu-Arg-Pro-D-Ala-NH 2 ; AcD-Nal-D-Cpa-D-Pal-Ser-Arg-D-Lys-Lys-Arg-Pro-D-Ala-NH 2 ; [D-Pyr 1 , D-Phe 2 , D-Trp 3-6 ]GnRH; D-Lys 6 Antide; Lys 5 Antide or Lys 8 Antide.

10. A compound according to claim 1 wherein the GnRH analogue is a GnRH agonist.

11. A compound according to claim 10 wherein the GnRH agonist is pGlu-His-Trp-Ser-Tyr-D-lys-Leu-Arg-Pro-GlyNH 2 , Lupron, Zoladex, Supprelin, Synarel, Buserelin, leuprolide, goserelin, deslorelin, ProMaxx-100, avorelin, histrelin, nafarelin, leuprorelin or triptorelin.

12. A compound according to claim 1 wherein the compound retains the in vivo hormonal activity of the steroid hormone or progesterone derivative.

13. A compound according to claim 1 wherein the compound has no in vivo hormonal activity of the steroid hormone or progesterone derivative.

14. A compound according to claim 1 wherein the steroid hormone or progesterone derivative binds to a plasma hormone binding protein in vivo.

15. A compound according to claim 1 wherein the hormone binding protein is a globulin.

16. A compound according to claim 15 wherein the plasma hormone binding protein is cortisol binding globulin (CBG), sex hormone binding globulin (SHBG), or progesterone binding globulin (PBG) or albumin.

17. A compound according to claim 1 wherein the conjugated GnRH analogue and the steroid hormone or progesterone derivative are cleavable.

18. A compound according to claim 1 wherein the GnRH analogue and the steroid hormone or progesterone derivative are directly conjugated.

19. A compound according to claim 1 wherein the GnRH analogue and the steroid hormone or progesterone derivative are conjugated via a linking group.

20. A compound according to claim 19 wherein the linking group comprises a succinate linker or a derivative thereof.

21. A compound according to claim 1 wherein the GnRH analogue has a D-lysine residue, and the GnRH analogue is conjugated to the steroid hormone or progesterone derivative via the D-lysine.

22. A compound according to claim 1 which has a longer half-life in vivo than native GnRH.

23. A compound according to claim 1 which has a longer duration of activity in vivo than native GnRH.

24. A compound according to claim 1 having the formula

25. A compound according to claim 1 which is: AcD-Nal-D-Cpa-D-Pal-Ser-Arg-D-Lys-Leu-Arg-Pro-D-Ala-NH 2 conjugated to 21-hydroxyprogesterone 21-succinate at the ε amine of D-Lys at position 6; Ac-ΔPro-D-Fpa-D-Trp-Ser-Tyr-D-Lys-Leu-Arg-Pro-Gly-NH 2 conjugated to 21-hydroxyprogesterone 21-succinate at the ε amine of D-Lys at position 6; AcD-Nal-D-Cpa-D-Pal-Ser-Arg-D-Lys-Lys-Leu-Arg-D-Ala-NH 2 conjugated to 21-hydroxyprogesterone 21-succinate at the ε amine of Lys at position 7; D-Pal-Ser-Arg-D-Lys-Leu-Arg-Pro-D-Ala-NH 2 conjugated to 21-hydroxyprogesterone 21-succinate at the N-terminal amine of D-Pal; AcD-Nal-D-Cpa-D-Pal-Ser-Arg-D-Lys-Lys-Arg-Pro-D-Ala-NH 2 conjugated to 21-hydroxyprogesterone 21-succinate at the ε amine of Lys at position 7; or [DLys 6 ]GnRH conjugated to 11α-hydroxyprogesterone 11-succinate at the ε amine group of the D-Lys at position 6.

26. A compound according to claim 1 which is bound to a plasma hormone binding protein.

27. A compound according to claim 26 wherein the plasma hormone binding protein is CBG, SHBG, or albumin.

28. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient, carrier or diluent.

29. A pharmaceutical composition according to claim 28 which is suitable for oral administration.

30. A pharmaceutical composition according to claim 28 which is a slow-release formulation.

31. A method of reducing the fertility of an individual comprising administering a compound according to claim 1 to the individual.

32. A method of treating a hormone-dependent disease or condition comprising administering a compound according to claim 1 to an individual in need thereof.

33. A method according to claim 32 wherein the hormone-dependent disease or condition is selected from a hormone-dependent cancer, benign prostatic hypertrophy, endometriosis, uterine fibroids, premenstrual syndrome, polycystic ovarian syndrome, hirsutism, acne vulgaris, precocious puberty, acute intermittent porphyria, cryptoorchidism and delayed puberty.

34. A method according to claim 33 wherein the hormone-dependent cancer is breast cancer, prostate cancer, uterine cancer or endometrial cancer.

35. A method of treating infertility comprising administering a compound according to claim 1 to an individual in need thereof.

36. A method of modulating the production of gonadotrophins or sex hormones in vivo comprising administering a compound according to claim 1 to an individual.

37. A method of modifying a GnRH analogue so that it has an increased in vivo half-life compared to GnRH, the method comprising conjugating the GnRH analogue to a steroid hormone or progesterone derivative which is able to bind to a plasma hormone binding protein, wherein the steroid hormone is estradiol, progesterone, cortisol, corticosterone, estrone, testosterone or dihydroxytestosterone, and wherein the progesterone derivative is 11α-hydroxyprogesterone or 21-hydroxyprogesterone.

38. A method of modifying a GnRH analogue so that it has an increased duration of activity in vivo compared to GnRH, the method comprising conjugating the GnRH analogue to a steroid hormone or progesterone derivative which is able to bind to a plasma hormone binding protein, wherein the steroid hormone is estradiol, progesterone, cortisol, corticosterone, estrone, testosterone or dihydroxytestosterone, and wherein the progesterone derivative is 11α-hydroxyprogesterone or 21-hydroxyprogesterone.

39. A method according to claim 37 wherein the conjugating step comprises conjugating the GnRH analogue and the steroid hormone or progesterone derivative via a linking group.

40. A method according to claim 37 further comprising binding the steroid hormone or progesterone derivative to a plasma hormone binding protein.

41. A method according to claim 40 wherein the plasma hormone binding protein is CBG, SHBG, or albumin.

42. A method according to claim 37 further comprising determining the in vivo half-life of the conjugated GnRH analogue.

43. A method according to claim 42 further comprising comparing the in vivo half-life of the conjugated GnRH analogue with the in vivo half-life of GnRH to identify a GnRH analogue having an increased in viva half-life compared to GnRH.

44. A method according to claim 31 wherein the compound is present in a pharmaceutical composition that comprises a pharmaceutically acceptable excipient, carrier or diluent.

45. A method according to claim 32 wherein the compound is present in a pharmaceutical composition that comprises a pharmaceutically acceptable excipient, carrier or diluent.

46. A method according to claim 35 wherein the compound is present in a pharmaceutical composition that comprises a pharmaceutically acceptable excipient, carrier or diluent.

47. A method according to claim 36 wherein the compound is present in a pharmaceutical composition that comprises a pharmaceutically acceptable excipient, carrier or diluent.

48. A method according to claim 38 wherein the conjugating step comprises conjugating the GnRH analogue and the steroid hormone or progesterone derivative via a linking group.

49. A method according to claim 48 further comprising binding the steroid hormone or progesterone derivative to a plasma hormone binding protein.

50. A method according to claim 49 wherein the plasma hormone binding protein is CBG, SHBG, or albumin.

51. A method according to claim 38 further comprising determining the in vivo duration of activity of the conjugated GnRH analogue.

52. A method according to claim 51 further comprising comparing the in vivo duration of activity of the conjugated GnRH analogue with the in vivo duration of activity of GnRH to identify a GnRH analogue having an increased in vivo duration of activity compared to GnRH.