NOVEL ESTROGENIC COMPOUNDS

• US 20070142307A1
• Filed: 02/06/2007
• Published: 06/21/2007
• Est. Priority Date: 03/10/2000
• Status: Active Grant

• Current Assignee: Duramed Pharmaceuticals Incorporated
• Original Assignee: Barr Laboratories Incorporated (Teva Pharmaceutical Industries Limited)
• Inventors: Hill, Edward, Whittle, Robert, Sancilio, Frederick
• Granted Patent: US 7,459,445 B2
• Time in Patent Office: Days
• US Class Current: 514/26
• CPC Class Codes: C07J 1/00 Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
• CPC Class Codes: C07J 17/00 Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton cardanolide, bufanolide C07J19/00

Abstract

Novel estrogenic compounds of Formula I are provided.
wherein the bond represented by the wavy line may be a single or double bond such that when the wavy line is a single bond, R₁ is selected from the group consisting of hydrogen, sulfate and glucoronate or other esters, and when the wavy line is a double bond, R₁ does not exist; R₂ is lower alkyl; R₃ may be selected from the group consisting of hydrogen, sulfate, or glucuronide or other esters; and R₄ through R₁₃ may independently be selected from the group consisting of hydrogen, hydroxy, ketone, lower alkyl, lower alkoxy, halogen, and carbonyl groups and R₁₄ is selected from the group consisting of hydrogen, sulfate and glucoronide and other esters. When R₁ is hydroxy, the hydroxy or ester substituent may have either an α or a β orientation. Compositions of matter including compounds of the present invention are also provided as are methods of treating mammals in need of treatment using compounds of the present invention.

Claims

1. A compound having the following structure:

2. The compound of claim 1, wherein the compound is a calcium salt thereof.

3. The compound of claim 2, wherein the calcium salt is selected from the group consisting of calcium citrate, calcium lactate, calcium fumurate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium phosphate, calcium sulphate and calcium nitrate.

4. The compound of claim 1, wherein the compound is greater than about 95% pure.

5. A method of treating a subject in need of estrogen therapy, said method comprising administering an effective amount of a compound having the following structure:

6. The method of claim 5, wherein the compound or pharmaceutically acceptable salt is administered as a vaginal cream, gel, suppository or transdermal patch.

7. The method of claim 5, wherein the compound or pharmaceutically acceptable salt thereof is administered as part of a pharmaceutical composition, said composition further comprising at least one additional pharmaceutically active ingredient.

8. The method of claim 7, wherein the at least one additional pharmaceutically active ingredient is selected from the group consisting of estrogenic compounds, androgenic compounds, progestin compounds, vasodilation agents, calcium salts, and vitamin D, and mixtures and combinations thereof.

9. The method of claim 5, wherein the condition treatable by estrogen therapy is selected from the group consisting of vasomotor symptoms, atrophic vaginitis, osteoporosis, hypoestrogenism due to hypogonadism, hypoestrogenism due to castration, hypoestrogenism due to primary ovarian failure, breast cancer in selected persons with metastatic disease, advanced androgen-dependent carcinoma of the prostate, abnormal uterine bleeding, and kraurosis vulvae.

10. A compound having the following structure:

11. The compound of claim 10, wherein the compound is a calcium salt thereof.

12. The compound of claim 11, wherein the calcium salt is selected from the group consisting of calcium citrate, calcium lactate, calcium fumurate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium phosphate, calcium sulphate and calcium nitrate.

13. The compound of claim 10, wherein the compound is greater than about 95% pure.

14. A method of treating a subject in need of estrogen therapy, said method comprising administering an effective amount of a compound having the following structure:

15. The method of claim 14, wherein the compound or pharmaceutically acceptable salt is administered as a vaginal cream, gel, suppository or transdermal patch.

16. The method of claim 14, wherein the compound or pharmaceutically acceptable salt thereof is administered as part of a pharmaceutical composition, said composition further comprising at least one additional pharmaceutically active ingredient.

17. The method of claim 16, wherein the at least one additional pharmaceutically active ingredient is selected from the group consisting of estrogenic compounds, androgenic compounds, progestin compounds, vasodilation agents, calcium salts, and vitamin D, and mixtures and combinations thereof.

18. The method of claim 14, wherein the condition treatable by estrogen therapy is selected from the group consisting of vasomotor symptoms, atrophic vaginitis, osteoporosis, hypoestrogenism due to hypogonadism, hypoestrogenism due to castration, hypoestrogenism due to primary ovarian failure, breast cancer in selected persons with metastatic disease, advanced androgen-dependent carcinoma of the prostate, abnormal uterine bleeding, and kraurosis vulvae.

19. A topical pharmaceutical formulation comprising:

(a) a compound represented by Formula I;

or pharmaceutically acceptable salts thereof,

wherein;

the bond represented by the wavy line may be a single or double bond such that when the wavy line is a single bond, R₁ is selected from the group consisting of hydrogen, sulfate and glucuronide or other esters, and when the wavy line is a double bond, R₁ does not exist;

R₂ is lower alkyl;

R₃ is selected from the group consisting of hydrogen, sulfate and glucuronide;

R₄ through R₇ and R₁₀ through R₁₃ may be the same or different and each represents hydrogen, hydroxy, ketone, lower alkyl, lower alkoxy, halogen, or carbonyl group;

R₈ and R₉ are independently selected from the group consisting of hydrogen, hydroxy, lower alkyl, lower alkoxy, halogen, and carbonyl groups; and

R₁₄ is selected from the group consisting of hydrogen, sulfate and glucuronide;

said compound being present in chemically pure form; and

(b) a pharmaceutically active ingredient selected from the group consisting of estrogenic compounds, androgenic compounds, progestin compounds, vasodilation agents, calcium salts, and vitamin D, and mixtures and combinations thereof.

20. The topical pharmaceutical formulation of claim 19, wherein the formulation is a vaginal cream.

21. The topical pharmaceutical formulation of claim 19, wherein the formulation is a gel.

22. The topical pharmaceutical formulation of claim 19, wherein the formulation is a suppository.

23. The topical pharmaceutical formulation of claim 19, wherein the formulation is a transdermal patch.