Novel steroid selective estrogen receptor modulator as well as preparation method and pharmaceutical application thereof

A pharmacy and carrier technology, applied in pharmaceutical formulations, sexually transmitted diseases, anti-tumor drugs, etc., can solve problems such as clinical treatment effects that are not as good as Tamoxifen, venous thrombosis, vasodilation, endometrial cancer and drug resistance.

Active Publication Date: 2016-07-13
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

SERMs currently on the market include more than ten kinds of SERMs drugs including Tamoxifen (capitalized later, consistent), Raloxifene, Lasofoxifene, Bazedoxifene, etc. Among them, Tamoxifen is the representative drug of the first generation of SERMs. Since it was approved for marketing in 1977, it has become a preventive and auxiliary drug The drug of choice for the treatment of female ER-(+) breast cancer, but studies have found that long-term use of Tamoxifen can easily...

Method used

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  • Novel steroid selective estrogen receptor modulator as well as preparation method and pharmaceutical application thereof
  • Novel steroid selective estrogen receptor modulator as well as preparation method and pharmaceutical application thereof
  • Novel steroid selective estrogen receptor modulator as well as preparation method and pharmaceutical application thereof

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specific Embodiment approach

[0032] The specific embodiment (described embodiment is only used to illustrate the present invention, is not used to limit the present invention)

[0033] The preparation of some compounds is carried out as follows:

[0034] 1 H-NMR nuclear magnetic resonance was measured by BrukerAV300 (300MHz) nuclear magnetic resonance instrument (TMS was the internal standard), and mass spectrometry was determined by Shimadzu GC / MS-QP2010 mass spectrometer (EI-MS), Agilent1100LC-MSD-Trap / SL Mass spectrometer (ESI-MS) determination.

[0035]The silica gel used for column chromatography is 100-200 mesh, 200-300 mesh or 300-400 mesh silica gel (Qingdao Ocean Chemical Factory), and the eluent is petroleum ether-ethyl acetate system or chloroform-methanol system. Thin-layer chromatography (TLC) uses a GF254 thin-layer chromatography plate (Yantai Jiangyou Silica Gel Development Co., Ltd.); the TLC development system is a petroleum ether-ethyl acetate system or a chloroform-methanol system, a...

Embodiment 1

[0037] Synthesis of 1,3,5(10),9(11)-Estratratene-3,17β-diol (IIIa)

[0038] Dissolve 20.0g (73.53mmol) of estradiol (IIa) in 300ml of dry methanol, add 25g (110.13mmol) of 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), and heat to reflux under nitrogen protection 3-5 hours, the end point is determined by TLC, the reaction solution is cooled, concentrated under reduced pressure to remove the solvent, the concentrate is dissolved in 300ml of ethyl acetate, and 300ml of saturated NaHCO is added 3 solution, stirred until no bubbles are generated, separated, saturated NaHCO 3 The solution was washed twice (300ml×2), the organic layer was dried over anhydrous sodium sulfate for 3 hours, concentrated under reduced pressure to remove the solvent, and 18.4g of a brownish yellow solid was obtained. Column chromatography (PE:EA=5:1) yielded 7.8 g of light yellow solid, yield 39.29%. MS (ESI, m / z): 269 [M-H] + .

Embodiment 2

[0040] Synthesis of 1,3,5(10),9(11)-estradiene-2,3,17β-triol-2-methyl ether (IIIb)

[0041] Dissolve 10g (33.1mmol) 2-methoxyestradiol (IIb) with 150ml of dry methanol, add 5.65g (49.7mmol) 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), Under the protection of nitrogen, heat and reflux for 3-5 hours, and determine the end point by TLC. After the reaction liquid is cooled, it is concentrated under reduced pressure to remove the solvent. The concentrate is dissolved in 150ml of ethyl acetate, and 150ml of saturated NaHCO is added. 3 solution, stirred until no bubbles are generated, separated, saturated NaHCO 3 The solution was washed twice (150ml×2), the organic layer was dried over anhydrous sodium sulfate for 3 hours, concentrated under reduced pressure to remove the solvent, and 18.3g of a brownish yellow solid was obtained. Column chromatography (PE:EA=4:1) gave 4.3 g of light yellow solid, yield 43.29%. MS (ESI, m / z): 299 [M-H] + .

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Abstract

The invention relates to the field of pharmaceutical chemistry, and discloses a novel steroid selective estrogen receptor modulator as well as a preparation method and a pharmaceutical application thereof, in particular to steroid derivatives of a general formula (I), a preparation method thereof, pharmaceutical compositions containing the compounds and a pharmaceutical application thereof. The steroid derivatives can be applicable to treat a plurality of medical indications related to postmenopausal symptoms, in particular to treat ER-(+) type breast cancer. Meanwhile, the compounds can be used to prepare medicaments as angiogenesis inhibitors. The general formula (I) is shown in the description.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a new class of steroid selective receptor modulators and their medical applications. These compounds can be used to treat various medical indications related to postmenopausal syndrome, and are especially suitable for treating ER-(+) breast cancer. At the same time, the compounds can also be used in the preparation of drugs as angiogenesis inhibitors. Background technique [0002] Tumors are diseases characterized by the uncontrolled proliferation and spread of abnormal cells. The 2014 "Global Cancer Facts and Figures" report by the American Cancer Society shows that in 2012, there were 14 million new cancer cases and 8.2 million deaths worldwide, of which 3.07 million new cancer patients were added in China and about 2.2 million people died. Accounting for 21.9% and 26.8% of the global total, respectively. The report predicts that global cancer cases will show a rapid growt...

Claims

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Application Information

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IPC IPC(8): C07J41/00C07J43/00A61K31/565A61K31/58A61P5/30A61P35/00A61P15/14A61P15/00
CPCC07J41/0072C07J43/003
Inventor 向华王叶俊唐智超吴成喆陈明琪尤启冬
Owner CHINA PHARM UNIV
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