Compounds and methods for modulation of estrogen receptors
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A compound and composition technology, applied in the field of compounds that selectively modulate estrogen beta-receptor activity, can solve problems such as side effects
Inactive Publication Date: 2006-10-25
SIGNAL PHARMA LLC
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For example, although estrogen replacement therapy has been associated with many beneficial effects (e.g., bone protection, cardiovascular effects, prevention of hot flashes, dementia, bone metabolism, etc.), this therapy also has side effects (e.g., breast and endometrial cancer, thrombosis Wait)
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Embodiment 1
[0154] 2-(4-Hydroxybenzylacetone)-5-methoxyphenol
[0155]
[0156] To 3-methoxyphenol (50g, 0.40mol), 4-hydroxyphenylacetic acid (71g, 0.46mol) and ZnCl 2 (174g, 1.28mol) was added POCl 3 (100ml, 1.6mol). The mixture was stirred at 65°C for 2 hours, poured into ice water (2 L) and stirred until the ice melted. The clear supernatant was decanted and the residue was rinsed with water (1 L) and partitioned between EtOAC and water. The organic layer was washed with brine, dried (MgSO 4 ), filtered and concentrated. The resulting oil provided chromatography (SiO 2 , 20% EtOAc / n-Hexane) to give 2-(4-hydroxyphenylacetone)-5-methoxyphenol (34.1 g, 33% yield) as a slightly white solid; mp 137-140°C.
[0160] To 2-(4-hydroxyphenylacetyl)-5-methoxyphenol (10g, 0.038mole), NEt 3 (6ml, 0.042mole) in CH 2 Cl 2 To the mixture in (50ml) was added triisopropylsilyl chloride (9ml, 0.042mole). The mixture was stirred for 22 h, concentrated and the residue was dissolved in EtOAc and H 2 O distribution. The organic layer was washed with NaOH (1N), HCl (1N) and brine. Dry the organic layer (MgSO 4 ), filtered and concentrated. The residue was treated with n-hexane to give 2-(4-triisopropylsilylbenzylacetone)-5-methoxyphenol (6.2 g, 38% yield) as a slightly white solid; mp 66-68°C.
[0164] To 2-(4-triisopropylsilylbenzylacetone)-5-methoxyphenol (4g, 9.6mmole), K 2 CO3 (4g, 29mmoles) in CH 3 To the mixture in CN (50ml) was added phenylacetyl chloride (2.3ml, 14mmole). The mixture was stirred at reflux for 22 h, poured into H 2 O (0 °C) (500ml) and extracted with EtOAc (2x). Dry the organic layer (MgSO 4 ), filtered and concentrated. Residue and Et 2 O was stirred and the resulting solid was filtered and recrystallized (EtOH) to give 3-phenyl-4-(4-hydroxybenzyl)-7-methoxycoumarin (0.88 g, 15% yield) as White solid; mp235-236°C.
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Abstract
Compounds that modulate gene expression through the estrogen receptor (ER) are disclosed having formula (I), as well as pharmaceutical compositions containing the same wherein R1, R2, R3, n and p are as defined here. In a specific embodiment, the compounds are selective modulators for ER- beta over ER- alpha . Methods are also disclosed for modulating ER- beta in cells and / or tissues expressing the same, including cells and / or tissues that preferentially express ER- beta . More generally, methods for treating estrogen-related conditions are also disclosed, including conditions such as breast cancer, testicular cancer, osteoporosis, endometriosis, cardiovascular disease, hypercholesterolemia, prostatic hypertrophy, prostatic carcinomas, obesity, hot flashes, skin effects, mood swings, memory loss, urinary incontinence, hairloss, cataracts, natureal hormonal imbalances, and adverse reproductive effects associated with exposure to environmental chemicals.
Description
[0001] Cross-Referenced Related Applications [0002] This application claims priority to U.S. Provisional Application No. 60 / 114,472 (filed December 30, 1998), and is PCT / US99 / 31290 (filed December 30, 1999), U.S. Application No. 09 / 475,776 (filed December 30, 1999) , filed December 30, 2000) and US Application No. 09 / 492,939 (filed January 27, 2000) (each of which is hereby incorporated by reference in its entirety). technical field [0003] The present invention relates broadly to estrogen antagonists and agonists, and compounds that inhibit cytokines, and more specifically to compounds that selectively modulate the activity of estrogen β-receptors (ER-β), as well as their pharmaceutical compositions and about the method. Background of the invention [0004] Estrogens have a broad spectrum of effects on tissues in both females and males. Many of these biological effects are positive, including maintenance of bone density, cardiovascular protection, central nervous syste...
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