Hormone-based nitrogen monoxide donor compounds and use thereof in obstetrics and gynecology

• US 20050222105A1
• Filed: 07/09/2003
• Published: 10/06/2005
• Est. Priority Date: 07/09/2002
• Status: Active Grant

• Current Assignee: Effik SA
• Original Assignee: Effik SA
• Inventors: Mendez, Felix, Grasset, Etienne Robert Alfred, Pavan, Carlo, Terracol, Didier
• Granted Patent: US 7,763,600 B2
• Time in Patent Office: Days
• US Class Current: 514/177
• CPC Class Codes: A61K 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61P 15/04 for inducing labour or abortion; Uterotonics
• CPC Class Codes: A61P 15/06 Antiabortive agents; Labour repressants
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 15/12 for climacteric disorders
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07J 41/0033 not covered by C07J41/0005

Abstract

The invention concerns compounds capable of being fixed on hormone receptors and having a nitrogen monoxide donor group, their use for preventing premature births, increasing cervical-dilatation, for use in hormone substitution therapy as anti-hypertensive drug and their therapeutic use for preparing a medicine for use in obstetrics and gynecology.

Claims

1. A compound selected from compounds capable of binding to hormone receptors and in that it comprises a nitrogen monoxide-donor nitric ester group, with the exception of estradiol substituted in the 11- and/or 17-position with a nitric ester group.

2. A compound of claim 1, wherein the hormone receptors are selected from the group consisting of steroid receptors, retinoid receptors and vitamin D derivative receptors.

3. A compound of claim 1 wherein the compound capable of binding to hormone receptors is a natural hormone.

4. A compound of claim 1 wherein the compound capable of binding to hormone receptors is a synthetic hormone.

5. A compound of claim 1 wherein the compound capable of binding to hormone receptors is selected from the group consisting of a progestogen hormone, an estrogen, an anti-mineralocorticoid, an androgen and an anti-androgen and a combination of these hormones.

6. A compound of claim 1 wherein the hormone capable of binding to hormone receptors is selected from the group consisting of protesterone, 17OH-progesterone, estradiol, ethynyl estradiol, aldosterone, sprironolactone, drospirenone, testosterone and cyproterone.

7. A compound of claim 1 comprising at least one NO₂ group bonded to the hormone directly via the oxygen atom of the enolic form or by benzyloxy.

8. A compound of claim 1 wherein the NO₂ group(s) is (are) bonded directly to the hormone via the oxygen atom of the enolic form of the hormone.

9. A compound of claim 1 wherein the NO₂ group(s) is (are) bonded to the hormone by benzyloxy.

10. A compound of claim 9, wherein the benzyloxy is bonded to the hormone by a group that establishes a bridge.

11. A compound of claim 10, wherein the bridge is C═

O or COO.

12. A compound of claim 1 wherein the hormone capable of binding to hormone receptors is progesterone.

13. A compound of claim 1 wherein the hormone capable of binding to hormone receptors is 17OH-progesterone.

14. A compound of claim 7, wherein it has a formula selected from the group consisting of

15. A compound of claim 1 wherein the hormone capable of binding to hormone receptors is estradiol.

16. A compound of claim 15, wherein it is substituted in the 17- and 3-position of the estradiol with an NO₂ group bonded to the oxygen atom of the OH function of the estradiol.

17. A compound of claim 15, wherein it is substituted in the 3-position of the estradiol with an NO₂ group bonded to the oxygen atom of the OH function of estradiol.

18. A compound of claim 16 wherein it corresponds to the formula

19. A compound of claim 1 wherein the hormone capable of binding to hormone receptors is spironolactone.

20. A compound of claim 19, wherein it comprises an NO₂ group bonded by benzyloxy.

21. A compound of claim 20, wherein it corresponds to the formula

34. A composition to prevent premature births comprising an amount of a compound of claim 1 sufficient to prevent premature births and an inert pharmaceutical carrier.

35. A method of preventing premature births in women comprising administering to women comprising administering to women in need thereof an amount of a compound of claim 1 sufficient to prevent premature births.

36. A method of controlling uterine mobility in women in need thereof an amount of a compound of claim 1 sufficient to control uterine mobility.

37. A method of increasing cervical dilation during labor in women comprising administering to women in need thereof of an amount of a compound of claim 1 sufficient to increase cervical dilation.

38. A method of treating uterine contraction anomalies in women comprising administering to women in need thereof an amount of a compound of claim 1 sufficient to treat uterine contraction anomalies.

39. A method of treating dysmenorrhea in women comprising administering to women in need thereof an amount of a compound of claim 1 sufficient to treat dysmenorrhea.

40. A method of hormone replacement in menopausal comprising administering to menopausal women in need thereof an amount of a compound of claim 1 sufficient for hormone replacement.

41. A method of treating arterial hypertension in women comprising administering to women in need thereof an amount of a compound of claim 1 sufficient to treat arterial hypertension.

42. A method of inducing an endometrial cycle in assisted reproduction in women comprising administering to women in need thereof an amount of a compound of claim 1 sufficient to induce an endometrial cycle.

22-33. -33. (canceled)