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Ethylene derivative serving as selective estrogen receptor modulators (SERMs)

A solvate and selected technology, applied in the field of ethylene derivatives, can solve the problem of poor clinical effect of breast cancer

Inactive Publication Date: 2012-07-04
CENTAURUS BIOPHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Its clinical effect in the treatment of breast cancer is not superior to tamoxifen (Tamoxifen), and can cause adverse reactions such as hot flushes, leg cramps, headaches and weight gain (Davies GC, et al., ObstetGyneco 193:558- 565 (1999)

Method used

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  • Ethylene derivative serving as selective estrogen receptor modulators (SERMs)
  • Ethylene derivative serving as selective estrogen receptor modulators (SERMs)
  • Ethylene derivative serving as selective estrogen receptor modulators (SERMs)

Examples

Experimental program
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preparation example Construction

[0113] Preparation of compounds of the present invention

[0114] The following reaction schemes illustrate the preparation of the compounds of the invention.

[0115] It should be understood by those skilled in the art that in the following description, combinations of substituents are permissible only when such combination can result in a stable compound.

[0116] Those skilled in the art will also understand that in the methods described below, the functional groups of intermediate compounds may need to be protected by appropriate protecting groups. Such functional groups include hydroxyl, amino, mercapto and carboxylic acid. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl groups (eg tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , tetrahydropyranyl, benzyl, etc. Suitable protecting groups for amino, amidino and guanidino include tert-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable protecting groups for mercapt...

Embodiment 1

[0126] 4-[2-(2,3-Dihydro-5-benzofuryl)-1-{4-[2-(methylamino)ethoxy]phenyl}but-1-ene]phenol

[0127]

[0128] Step A: 1-(2,3-Dihydrobenzofuran-5-yl)propyl-1-one

[0129]

[0130] Dissolve 2,3-dihydrobenzofuran (10 g, 1.0 equivalent) in 200 mL of dichloromethane, and add propionyl chloride (14 g, 1.8 equivalent) and anhydrous aluminum chloride (11.1 g , 1.0 equivalent) in 200 mL of dichloromethane solution. Stir at room temperature for 1 hour after the dropwise addition, add ice water to quench the reaction, extract the aqueous phase with dichloromethane, combine the organic phases and dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product was added with n-hexane (100 mL), cooled to 0°C, stirred for 30 minutes, the suspension was filtered with suction and washed with cold n-hexane to obtain the title compound (11.8 g, 80%).

[0131] 1 H NMR (400MHz, CDCl 3 )δ7.86(s, 1H), 7.81(d, J=8.4Hz, 1H), 6.80(...

Embodiment 2

[0148] (Z)-4-(2-(1H-indazol-5-yl)-1-{4-[2-(methylamino)ethoxy]phenyl}but-1-enyl)phenol

[0149]

[0150] Step A: Methyl 4-amino-3-methylbenzoate

[0151]

[0152]At room temperature, add methyl 4-nitro-3-methylbenzoate (50g, 1.0 equivalent) into 1L of methanol solution, install a mechanical stirrer, add ammonium chloride (137g, 10 equivalent) and dissolve the solid in 60mL of water of aqueous solution. Iron powder (96 g, 7 equivalents) was added, and the reaction mixture was refluxed at 75° C. for 4 hours. After the reaction, it was cooled to room temperature, filtered, washed with water, extracted with ethyl acetate, dried and concentrated to directly obtain the title compound (26 g, 62%) as a white solid.

[0153] Step B: Methyl 4-diazotetrafluoroborate-3-methylbenzoate

[0154]

[0155] At room temperature, add 4-amino-3-methylbenzoic acid methyl ester (15g, 1.0 equivalent) into tetrafluoroboric acid solution (40% aqueous solution), cool to 0°C with an ice bath,...

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PUM

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Abstract

The invention provides an ethylene derivative represented by a formula I. Serving as selective estrogen receptor modulators (SERMs), the ethylene derivative can be used for preventing and / or treating diseases or disease symptoms influenced by selective estrogen receptor modulation. The formula I is shown in the specifications.

Description

technical field [0001] The present invention relates to a series of ethylene derivatives as selective estrogen receptor modulators, their pharmaceutical compositions, their use in pharmacy and their use in the treatment and / or prevention of estrogen-mediated method of disease or disease. Background technique [0002] Estrogen receptor (ER) is an important class of nuclear transcription factors, which play important physiological roles in reproductive system, bone tissue, cardiovascular and central nervous system. There are more than 400 sites containing estrogen receptors in the female body, mainly distributed in the uterus, vagina, breast, pelvis (ligaments and connective tissue), skin, bladder, urethra, bones and brain. When a woman enters menopause, with the massive reduction of estrogen, the tissues, organs, and systems where estrogen receptors are located are changed, and a series of menopausal symptoms will appear, such as hot flashes, sweating, insomnia, depression, ...

Claims

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Application Information

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IPC IPC(8): C07D307/79C07D263/56C07D285/14C07D231/56C07D235/06C07D307/82C07D405/06A61K31/343A61K31/423A61K31/433A61K31/416A61K31/4184A61K31/443A61K31/5377A61K31/4025A61K31/4525A61K31/496A61K31/55A61K31/4439A61P5/30A61P15/12A61P13/00A61P15/02A61P15/00A61P35/00A61P25/24A61P3/10A61P19/08A61P19/10
Inventor 校登明祝力胡远东余荣胡伟赵娜彭勇罗鸿韩永信
Owner CENTAURUS BIOPHARMA
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