Non-steroidal progesting

• US 7,388,006 B2
• Filed: 03/11/2003
• Issued: 06/17/2008
• Est. Priority Date: 03/11/2002
• Status: Expired due to Fees

• Current Assignee: Bayer Schering Pharma AG (Bayer AG)
• Original Assignee: Bayer Schering Pharma AG (Bayer AG)
• Inventors: Fuhrmann, Ulrike, Muhn, Peter, Klotzbuecher, Michael, Hegele-Hartung, Christa, Schmees, Norbert, Lehmann, Manfred
• Primary Examiner(s): Wilson; James O.
• Assistant Examiner(s): Ward; Paul V.
• Application Number:
  US10/384,775
• Publication Number:
  US 20030232824A1
• Time in Patent Office: 1,925 Days
• Field of Search: 514/230.5, 514/248, 514/259, 514/361, 514/362, 544/63, 544/237, 548/126, 548/260, 548/261
• US Class Current: 514/230.5
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/365 Lactones
• CPC Class Codes: A61K 31/535 having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
• CPC Class Codes: A61K 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• 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 15/18 Feminine contraceptives
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/30 Oestrogens
• CPC Class Codes: C07D 265/02 1,2-Oxazines; Hydrogenated 1,2-oxazines
• CPC Class Codes: C07D 307/88 with one oxygen atom directly attached in position 1 or 3

Abstract

The present invention relates to non-steroidal progestins of the general formula (I)

wherein

• R₁ and R₂ are independently of each other —H or —F,
• R₃ is —CH₃ or —CF₃, and
• Ar is

or a pharmaceutically acceptable derivative or analogue thereof. These progestins are suitable for selectively modulating progesterone receptor mediated effects in different target tissues, particularly in uterine tissue versus breast tissue. Therefore, the progestins of the present invention, optionally in combination with estrogens, may be used for contraception (in particular in estrogen-free oral contraceptives), hormone replacement therapy and the treatment of gynecological disorders. The present invention furthermore relates to methods for selectively modulating progesterone receptor mediated effects in different target tissues or organs.

Claims

1. A compound (I) which is:

(+)-5-{2-hydroxy-3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-trifluoromethyl-propionylamino}-phthalide,

(+)-6-{2-hydroxy-3-[1-(2-fluoro-3-trifluoromethylphenyl)-cyclopropyl]-2-trifluoromethyl-propionylamino}-4-methyl-2,3-benzoxazin-1-one,

(+)-5-{2-hydroxy-3-[1-(2-fluoro-3-trifluoromethylphenyl)-cyclopropyl]-2-trifluoromethyl-propionylamino}-phthalide, or

(+)-6-{2-hydroxy-3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-trifluoromethyl-propionylamino}-4-methyl-2,3-benzoxazin-1-one.

2. A compound of claim 1, which is:

(+)-5-{2-Hydroxy-3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-trifluoromethyl-propionylamino}-phthalide, or

(+)-6-{2-hydroxy-3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-trifluoromethyl-propionylamino}-4-methyl-2,3-benzoxazin-1-one.

3. A pharmaceutical composition comprising a compound (I) as defined in claim 1.

4. The pharmaceutical composition according to claim 3, comprising the compound:

(+)-5-{2-hydroxy-3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-trifluoromethyl-propionylamino}-phthalide or

(+)-6-{2-hydroxy-3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-trifluoromethyl-propionylamino}-4-methyl-2,3-benzoxazin-1-one.

5. A pharmaceutical composition comprising a compound (I) of claim 1 in an amount such that the daily dose is 0.01 to 2 mg.

6. The pharmaceutical composition of claim 4, comprising the compound (I) in an amount such that the daily dose is 0.01 to 2 mg.

7. The pharmaceutical composition of claim 3, further comprising 17α

-ethinyl estradiol.

8. The pharmaceutical composition of claim 4, further comprising 17α

-ethinyl estradiol.

9. The pharmaceutical composition of claim 5, further comprising 17α

-ethinyl estradiol.

10. The pharmaceutical composition of claim 6, further comprising 17α

-ethinyl estradiol.

11. The pharmaceutical composition according to claim 7, wherein the 17α

-ethinyl estradiol is present in an amount such that the daily dose is 0.01 to 0.05 mg.

12. The pharmaceutical composition according to claim 8, wherein the 17α

-ethinyl estradiol is present in an amount such that the daily dose is 0.01 to 0.05 mg.

13. The pharmaceutical composition according to claim 9, wherein the 17α

-ethinyl estradiol is present in an amount such that the daily dose is 0.01 to 0.05 mg.

14. The pharmaceutical composition according to claim 10, wherein the 17α

-ethinyl estradiol is present in an amount such that the daily dose is 0.01 to 0.05 mg.

15. A method for contraception, comprising administering to a female patient in need thereof an effective amount of a compound (I) of claim 1.

16. The method according to claim 15, wherein the compound (I) is administered orally.

17. The method according to claim 15, wherein the compound (I) is:

(+)-5-{2-hydroxy-3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-trifluoromethyl-propionylamino}-phthalide, or

(+)-6-{2-hydroxy-3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-trifluoromethyl-propionylamino}-4-methyl-2,3-benzoxazin-1-one.

18. The method according to claim 15, wherein compound (I) is administered in an amount such that the daily dose is 0.01 to 2 mg.

19. The method according to claim 17, wherein compound (I) is administered in the form of an estrogen-free oral contraceptive.

20. The method according to claim 17, wherein compound (I) is administered in an amount such that the daily dose is 0.01 to 2 mg.

21. The method according to claim 15, further comprising administering to the female patient in need thereof 17α

-ethinyl estradiol.

22. The method according to claim 17, further comprising administering to the female patient in need thereof 17α

-ethinyl estradiol.

23. The method according to claim 21, wherein the 17α

-ethinyl estradiol is administered in an amount such that the daily dose is 0.01 to 0.05 mg.

24. The method according to claim 22, wherein the 17α

-ethinyl estradiol is administered in an amount such that the daily dose is 0.01 to 0.05 mg.

25. The method according to claim 21, wherein the daily doses of the compound (I) and the 17α

-ethinyl estradiol to be administered vary independently of each other over the course of the female menstrual cycle.

26. The method according to claim 22, wherein the daily doses of the compound (I) and the 17α

-ethinyl estradiol to be administered vary independently of each other over the course of the female menstrual cycle.