Estrogen mimetics lacking reproductive tract effects

• US 6,323,190 B1
• Filed: 07/28/1999
• Issued: 11/27/2001
• Est. Priority Date: 07/31/1998
• Status: Expired due to Term

• Current Assignee: The University of Georgia Research Foundation, Inc.
• Original Assignee: The University of Georgia Research Foundation, Inc.
• Inventors: Ruenitz, Peter C.
• Primary Examiner(s): Geist, Gary
• Assistant Examiner(s): Maier, Leigh C.
• Application Number:
  US09/363,911
• Time in Patent Office: 853 Days
• Field of Search: 514/129, 514/130, 514/381, 514/568, 514/569, 548/252, 548/250, 562/21, 562/468, 562/491
• US Class Current: 514/129
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: C07C 43/23 containing hydroxy or O-metal groups
• CPC Class Codes: C07C 59/68 the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
• CPC Class Codes: C07D 257/04 Five-membered rings
• CPC Class Codes: C07F 9/386 containing hydroxy substituents in the hydrocarbon radicals

Abstract

A method for treating symptoms, diseases and conditions in extra-reproductive tract tissues that are responsive to treatment with estrogen, using triarylethanes of formula (I)

wherein R₁ is —O(CH₂)_mR₃ or —(CH₂)_nR₃; wherein R₃ is an anionic substituent; m is an integer from 1 to 4; and n is an integer from 0 to 4; and wherein R₂ is either H or —OH. Each of R₁ and R₂ can be either meta or para to its respective phenyl ethyl linkage. Compounds having the formula (I) wherein R₁ is —O(CH₂)_mR₃ or —(CH₂)_nR₃; R₃ is an anionic substituent; m is 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; R₂ is H or —OH; and wherein each of R₁ and R₂ is independently meta or para to its respective phenyl ethyl linkage are also provided, with the proviso that R₂ is not para —OH when m is 1 and R₃ is —COOH.

Claims

1. A method for treating extra-reproductive tract tissues that are responsive to treatment with estrogen comprising administering to a patient an effective amount of a compound having the structure

wherein R₁ is —

O(CH₂)_mR₃ or —

(CH₂)_nR₃;

R₃ is an anionic substituent;

m is 1, 2, 3 or 4;

n is 0, 1, 2, 3 or 4;

R₂ is H or meta-OH.

2. The method of claim 1 wherein R₁ is —

O(CH₂)_mR₃.

3. The method of claim 1 wherein R₁ is —

(CH₂)_nR₃.

4. The method of claim 1 wherein R₂ is meta-OH.

5. The method of claim 1 wherein R₂ is H.

6. The method of claim 5 wherein the compound is 4-(1-phenyl-2-phenylethyl)phenoxyacetic acid such that R₁ is —

OCH₂R₃;

R₃ is —

COO⁻

; and

each of R₁ and R₂ is para to its respective phenyl ethyl linkage.

7. The method of claim 1 wherein the anionic substituent comprises a functional group selected from the group consisting of a carboxylate group, a tetrazolate group and a bisphosphonate group.

8. The method of claim 1 wherein the patient is a female.

9. The method of claim 8 wherein the patient is a perimenopausal or postmenopausal female.

10. The method of claim 1 wherein the compound is administered in an estrogen replacement therapy.

11. The method of claim 1 wherein the compound is administered to treat osteopenia.

12. A compound having the structure

wherein R₁ is —

O(CH₂)_mR₃ or —

(CH₂)_nR₃;

R₃ is an anionic substituent;

m is 1, 2, 3 or 4;

n is 0, 1, 2, 3 or 4;

R₂ is H or meta-OH.

13. The compound of claim 12 wherein R₁ is —

O(CH₂)_mR₃.

14. The compound of claim 12 wherein R₁ is —

(CH₂)_nR₃.

15. The compound of claim 12 wherein R₂ is meta-OH.

16. The compound of claim 12 wherein R₂ is H.

17. The compound of claim 16 which is 4-(1-phenyl-2-phenylethyl)phenoxyacetic acid such that R₁ is —

OCH₂R₃;

R₃ is —

COO⁻

; and

each of R₁ and R₂ is para to its respective phenyl ethyl linkage.

18. The compound of claim 12 wherein the anionic substituent comprises at least one functional group selected from the group consisting of a carboxylate group, a tetrazolate group and a bisphosphonate group.

19. A pharmaceutical composition comprising a compound having the structure

wherein R₁ is —

O(CH₂)_mR₃ or —

(CH₂)_nR₃;

R₃ is an anionic substituent;

m is 1, 2, 3 or 4;

n is 0, 1, 2, 3 or 4;

R₂ is H or meta-OH;

or a pharmaceutically acceptable salt thereof; and

a pharmaceutically acceptable carrier.

20. The pharmaceutical composition of claim 19 wherein R₁ is —

O(CH₂)_mR₃.

21. The pharmaceutical composition of claim 19 wherein R₁ is —

(CH₂)_nR₃.

22. The pharmaceutical composition of claim 19 wherein R₂ is meta-OH.

23. The pharmaceutical composition of claim 19 wherein R₂ is H.

24. The pharmaceutical composition of claim 23 wherein the compound is 4-(1-phenyl-2-phenylethyl)phenoxyacetic acid such that R₁ is —

OCH₂R₃;

R₃ is —

COO⁻

; and

each of R₁ and R₂ is para to its respective phenyl ethyl linkage.