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4,6-dibenzyl pyrimidine compounds, preparing method thereof and medical uses of the compounds

A compound and pharmaceutical technology, applied in the field of medicinal chemistry, can solve the problems that the clinical treatment effect is not as good as Tamoxifen, endometrial cancer and drug resistance, venous thrombosis, vasodilation, etc.

Active Publication Date: 2017-05-10
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are more than ten kinds of SERMs drugs currently on the market, including Tamoxifen, Raloxifene, Lasofoxifene, Bazedoxifene, etc. Tamoxifen is the representative drug of the first generation of SERMs. However, studies have found that long-term use of Tamoxifen can easily induce endometrial cancer and drug resistance, as well as side effects such as venous thrombosis and vasodilation; the second-generation SERMs represented by Raloxifene can induce uterine The probability of endometrial cancer is lower, but its clinical treatment effect is not as good as that of Tamoxifen. Since its approval in 2007, it has been mainly used for the prevention and treatment of breast cancer and osteoporosis in postmenopausal women

Method used

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  • 4,6-dibenzyl pyrimidine compounds, preparing method thereof and medical uses of the compounds
  • 4,6-dibenzyl pyrimidine compounds, preparing method thereof and medical uses of the compounds
  • 4,6-dibenzyl pyrimidine compounds, preparing method thereof and medical uses of the compounds

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specific Embodiment approach

[0054] The specific embodiment (described embodiment is only used to illustrate the present invention, is not used to limit the present invention)

[0055] The preparation of some compounds is carried out as follows:

[0056] 1 H-NMR nuclear magnetic resonance was determined by Bruker AV300 (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 type mass spectrometer (ESI-MS) measurement.

[0057] 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 sy...

Embodiment 1

[0059] Synthesis of 4,6-bis(4-methoxyphenyl)-3,4-dihydropyrimidin-2(1H)one (4)

[0060] Dissolve 4-methoxybenzaldehyde (0.4mL, 3.33mmol) in 12.5mL of acetonitrile, add hexahydrate, ferric chloride (90mg, 0.333mmol), 4-methoxyacetophenone (0.5 g, 3.33mmol), urea (0.3g, 5mmol) and trimethylchlorosilane (0.417mL, 3.33mmol), heated to 80°C under nitrogen protection and refluxed for 10h. After cooling to room temperature, the reaction solution was stirred with 50 mL of water, filtered, and the filter cake was washed with diethyl ether to obtain a light yellow solid 4 (0.6 g, 58%). MS (ESI, m / z): 311 [M+H] + .

Embodiment 2

[0062] Synthesis of 2-chloro-4,6-bis(4-methoxyphenyl)pyrimidine (5)

[0063] Compound 4 (1 g, 3.2 mmol) and 4 mL of phosphorus oxychloride were added to a 25 mL flask, and the temperature was raised to 110° C. for 5 h under reflux. Stop heating, cool to room temperature, and slowly add 50 mL of crushed ice. Extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, column chromatography gave light yellow solid 5 (0.6 g, 58%). MS (ESI, m / z): 327 [M+H] + .

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Abstract

The invention relates to the field of pharmaceutical chemistry, and specifically relates to 4,6-dibenzyl pyrimidine compounds shown as a general formula I or a general formula II. The compounds can be adopted as selective estrogen receptor modulators, can be used for treating or preventing a plurality of medical indications related to postmenopausal symptoms, and is particularly suitable for treatment of ER-(+) type breast carcinoma. In addition, the compounds can be used for preparing angiogenesis inhibitor medicines.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a class of 4,6-diphenylpyrimidine compounds. The compounds can be used as selective estrogen receptor modulators to treat or prevent 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 ...

Claims

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Application Information

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IPC IPC(8): C07D239/42A61K31/506A61K31/5377A61P35/00A61P5/30
CPCC07D239/42
Inventor 向华吴成喆唐智超劳可静陈明琪陈德英赵儒恒胥骞尤启冬
Owner CHINA PHARM UNIV
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