Estrogen Agonists/Antagonists For Preventing Breast Cancer

a technology of estrogen and breast cancer, applied in the field of estrogen agonists and antagonists, can solve the problems of increasing fragility, increasing the risk of osteoporosis, and not being clinically advisable to treat osteoporosis in intact women with fully active estrogen for prolonged periods, so as to reduce prostate weight, reduce bone strength, and reduce prostate weight

Inactive Publication Date: 2010-12-16
CAMERON KIMBERLY O +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Exemplifying this latter view, osteoporosis, a disease in which bone becomes increasingly more fragile, is greatly ameliorated by the use of fully active estrogens; however, due to the recognized increased risk of uterine cancer in patients chronically treated with active estrogens, it is not clinically advisable to treat osteoporosis in intact women with fully active estrogens for prolonged periods.
The elderly are at greatest risk of osteoporosis, and the problem is therefore predicted to increase significantly with the aging of the population.
However, estrogen stimulates the uterus and is associated with an increased risk of endometrial cancer.
Although the risk of endometrial cancer is thought to be reduced by a concurrent use of a progestogen, there is still concern about possible increased risk of breast cancer with the use of estrogen.
Long-term estrogen therapy, however, has been implicated in a variety of disorders, including an increase in the risk of uterine cancer and possibly breast cancer, causing many women to avoid this treatment.
Recently suggested therapeutic regimens, which seek to lessen the cancer risk, such as administering combinations of progestogen and estrogen, cause the patient to experience unacceptable bleeding.

Method used

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  • Estrogen Agonists/Antagonists For Preventing Breast Cancer
  • Estrogen Agonists/Antagonists For Preventing Breast Cancer
  • Estrogen Agonists/Antagonists For Preventing Breast Cancer

Examples

Experimental program
Comparison scheme
Effect test

example 1

Cis-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol

Step A

[0165]cis-1-{2-[4-(6-Methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine. A solution of 1-{2-[4-(6-methoxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine hydrochloride (nafoxidene hydrochloride) (1.0 g, 2.16 mmol) in 20 mL of absolute ethanol containing 1.0 g of palladium hydroxide on carbon was hydrogenated at 50 psi at 20° C. for 19 hr. Filtration and evaporation provided 863 mg (93%) of cis-1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine: 1H-NMR (CDCl3): δ 3.50-3.80 (m, 3H), 3.85 (s, 3H), 4.20-4.40 (m, 3H), 6.80-7.00 (m, 3H); MS 428 (P++1).

Step B

[0166]To a solution of 400 mg (0.94 mmol) of the product from Step A in 25 ml of methylene chloride at 0° C. was added, dropwise with stirring, 4.7 ml (4.7 mmol) of a 1.0 M solution of boron tribromide in methylene chloride. After 3 hours at room temperature, the reaction...

example 2

Trans-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol

Step A

[0173]To a solution of cis-1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine (500 mg, 1.17 mmol) in 10 ml of dimethyl sulfoxide at 10° C. was added slowly 4.7 ml (11.7 mmol) of 2.5 M n-butyl lithium in hexane. The reaction was allowed to warm to 20° C. and was stirred for 19 hrs. After addition of water and extraction with ether, the organic layers were combined, dried over magnesium sulfate, filtered and concentrated to dryness to yield 363 mg (73%) of the trans-6-methoxydihydronaphthalene. 1H-NMR (CDCl3): δ 3.45 (m, 2H), 3.82, (s, 3H), 4.06 (d, 1H), 4.45 (m, 2H), 6.80 (d, 2H).

Step B

[0174]Using the boron tribromide deprotection procedure described in Example 1 Step B, 363 mg (0.85 mmol) of the product of Step A was converted to 240 mg (68%) of the title compound. 1H-NMR (CDCl3): δ 4.02 (d, 1H), 4.45 (m, 2H), 7.00 (d, 2H). The corresponding hydrochloride...

example 3

1-(4′-Pyrrolidinoethoxyphenyl)-2-(4″-hydroxyphenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride

Step A

[0175]3-Methoxyphenylacet-4′-methoxyanilide. A solution of 20.0 g (0.120 mole) of 3-methoxyphenylacetic acid and 40 ml (65.3 g, 0.549 mole) of thionyl chloride in 100 ml of benzene was heated at reflux for 2 hours and evaporated to dryness to afford the corresponding acid chloride (assume 0.120 mole). The acid chloride was slurried in 50 ml of ether and added to a mixture of 4-methoxyaniline in 100 ml of ether at 0° C. After stirring at 20° C. overnight, the slurry was filtered to afford a solid which was washed with water, 5.5% aq HCl, water, and ether. Subsequent drying over P2O5 in vacuo for 4 hr. yielded 19.7 g (60%) of the title substance as a white solid.

[0176]1H-NMR (CDCl3): δ 3.70 (s, 2H), 3.77 (s, 3H), 3.81 (s, 3H).

Step B

[0177]N-(4-Methoxyphenyl)-2′-(3″-methoxy phenethylamine) hydrochloride: A slurry of 19.6 g (0.072 mol) of the product of Step A and 6.04 g (0.159...

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Abstract

Compounds of this formulaare useful for preventing breast cancer.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of Ser. No. 09 / 466,034, filed Dec. 17, 1999, which is a continuation of Ser. No. 08 / 849,726, filed Jun. 30, 1997, now U.S. Pat. No. 6,204,286, which is a §371 application of International Application no. PCT / IB95 / 00286, filed Apr. 24, 1995, which claims priority of 08 / 369,954, filed Jan. 9, 1995, now U.S. Pat. No. 5,552,412.FIELD OF THE INVENTION[0002]This invention relates to estrogen agonists and antagonists and their use to prevent breast cancer.BACKGROUND OF THE INVENTION[0003]The value of naturally occurring estrogens and synthetic compositions demonstrating “estrogenic” activity has been in their medical and therapeutic uses. A traditional listing of the therapeutic applications for estrogens alone or in combination with other active agents includes: oral contraception; relief for the symptoms of menopause; prevention of threatened or habitual abortion; relief of dysmenorrhea; relief of dysfunction...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/40C07D295/088A61P35/00A61KC07D295/06A61K31/00A61K31/395A61K31/425A61K31/426A61K31/428A61K31/44A61K31/4418A61K31/4427A61K31/445A61K31/47A61K31/4709A61K31/472A61K31/4725A61P3/06A61P5/30A61P5/32A61P9/00C07C35/36C07DC07D213/64C07D217/00C07D217/04C07D217/16C07D237/02C07D237/06C07D275/02C07D277/02C07D277/62C07D295/00C07D295/08C07D295/092C07D401/04C07D401/10C07D401/12C07D403/04
CPCA61K31/40C07D213/64C07D401/04C07D295/088C07D217/16A61P19/10A61P35/00A61P3/06A61P5/00A61P5/30A61P5/32A61P7/00A61P9/00C07D207/40C07D295/155
Inventor CAMERON, KIMBERLY O.DASILVA-JARDINE, PAUL A.KE, HUA ZHUROSATI, ROBERT L.
Owner CAMERON KIMBERLY O
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