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Estrogen receptor ligands and methods of use thereof

A technology for use and serum testosterone, applied in the field of estrogen receptor ligands and its use, can solve problems such as limiting clinical use

Inactive Publication Date: 2015-01-07
GTX INCORPORATED
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Unfortunately, very potent pure estrogens such as DES and estradiol are often associated with a high risk of serious cardiovascular and thromboembolic complications, which limits their clinical use

Method used

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  • Estrogen receptor ligands and methods of use thereof
  • Estrogen receptor ligands and methods of use thereof
  • Estrogen receptor ligands and methods of use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0248] General Synthetic Methods for Compounds of Formula II-XII and Synthetic Intermediates

[0249] Organic solvents, surfactants, antioxidants, etc. useful in the compositions described herein are generally readily available from commercial sources. For example, PEG-300, polysorbate 80, Captex TM 200、Capmul TM MCM C8 can be purchased from, for example, Dow Chemical Company (Midland, MI), ICI Americas, Inc (Wilmington, DE), or Abitec Corporation (Janesville, WI).

[0250] The estrogen receptor ligands described herein can be prepared in a variety of ways known to those skilled in the art. For example, the estrogen receptor ligands described herein can be prepared by the synthetic methods described in US Patent Application Publication 2009 / 0062341 (the disclosure of each of which is incorporated herein by reference in its entirety).

[0251] General Synthesis of N,N-Diarylbenzamide Derivatives

[0252] General Synthesis of Diarylanilines ( Figure 5 ). Arylamine (1.5 ...

Embodiment 2

[0276] The synthesis of the compound of formula IV ( Figure 6 ).

[0277]

[0278] Step 1: Synthesis of 4-fluoro-N-(4-methoxyphenyl)aniline (1c).

[0279] In a dry 1L three-neck round bottom flask equipped with a stir bar, reflux condenser, and argon gas inlet, 4-fluoroaniline (78.63 g, 0.708 mol), 4-iodoanisole (138.00 g, 0.590 mol ), anhydrous K 2 CO 3 (122.23g, 0.884mol), CuI (11.23g, 58.96mmol) and a mixture of L-proline (13.58g, 0.118mol) were stirred together. Anhydrous DMSO (300 mL) was added at room temperature. The reaction mixture was stirred under argon and heated to 90 °C for 20 hours. Then, the mixture was cooled to room temperature and hydrolyzed with water (300 mL). EtOAc (200 mL) was added to partition the solution. The EtOAc layer was separated. The aqueous layer was extracted with 100 mL EtOAc. Combine the EtOAc layers, wash with brine (2x100 mL), wash over anhydrous MgSO 4 (50 g) dried. The solvent was removed under reduced pressure. The brow...

Embodiment 3

[0287] The synthesis of the compound of formula VI ( Figure 7 ).

[0288]Synthesis of 4-(benzyloxy)-N-(4-methoxyphenyl)aniline (1d).

[0289] At room temperature, 4-benzyloxyaniline (16.6g, 83.31mmol), 4-iodoanisole (15.0g, 64.09mmol), K 2 CO 3 (17.72g, 128.18mmol), CuI (1.22g, 6.41mmol) and a mixture of L-proline (1.48g, 12.82mmol) were stirred together and dissolved in anhydrous DMSO (120mL). Then, the reaction mixture was stirred and heated to 90 °C for 48 hours. The mixture was cooled to room temperature and hydrolyzed with water. EtOAc was added to partition the solution. The EtOAc layer was separated, washed with brine, and washed with anhydrous MgSO 4 dry. The solvent was removed under reduced pressure. The solid residue was purified by flash column chromatography (silica gel) using EtOAc / hexanes (1 / 9 v / v) to afford the corresponding diarylaniline as a yellow solid, 9.8 g, 50% yield. M.p.108.0-108.4°C. 1 H NMR (CDCl 3 , 300MHz) δ7.34-7.25 (m, 5H), 6.90-6.81 ...

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Abstract

The present invention relates to methods for reducing testosterone levels by reduction of luteinizing hormone (LH) or independent of LH levels in a male subject and methods of treating, suppressing, reducing the incidence, reducing the severity, or inhibiting advanced prostate cancer and palliative treatment of advanced prostate cancer.

Description

field of invention [0001] The present invention relates to methods for reducing testosterone levels in male individuals, either by reducing luteinizing hormone (LH) or independently of LH levels, and to treating advanced prostate cancer, suppressing advanced prostate cancer, reducing the incidence of advanced prostate cancer The incidence, severity, or suppression of advanced prostate cancer and palliative care for advanced prostate cancer. Background of the invention [0002] Estrogens refer to a group of endogenous and synthetic hormones that are important and useful for tissue and bone maintenance. Estrogens are endocrine regulators of cellular processes involved in the development and maintenance of the reproductive system. The role of estrogen in reproductive biology is well established - prevention of postmenopausal hot flashes and prevention of postmenopausal osteoporosis. Estradiol is the major endogenous human estrogen and is present in both women and men. [000...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C235/56C07C233/65A61K31/165A61P5/30A61P19/10
CPCA61K31/445A61K31/55A61P13/08A61P17/06A61P19/10A61P35/00A61P5/12A61P5/28A61P5/30A61P5/42
Inventor J·T·多尔顿M·S·斯坦纳
Owner GTX INCORPORATED
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