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Application of selective estrogen receptor modulator

A technology of selection and reaction, applied in the field of stilbene derivatives, can solve problems such as toxic and side effects, and achieve the effects of low cost, simple method operation and mild conditions

Inactive Publication Date: 2013-04-24
ZHEJIANG ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The SERMs closest to the market in recent years are bazedoxifene, arzoxifene, and lasofoxifene, but they still have the above-mentioned toxic and side effects and have not yet been approved for marketing

Method used

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  • Application of selective estrogen receptor modulator
  • Application of selective estrogen receptor modulator
  • Application of selective estrogen receptor modulator

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Step a) Synthesis of 3-(4-methoxyphenyl)coumarin IIa

[0025] Under nitrogen protection, 10 mmol of salicylaldehyde, 10 mmol of 4-methoxyphenylacetic acid, 10 mmol of potassium acetate, and 30 mL of acetic acid were sequentially added into the three-neck flask, and the reaction was refluxed for 3 hours. After the reaction, cool, neutralize, extract, collect the organic layer, and concentrate to obtain a light yellow solid powder, mp143-144°C.

[0026] Step b) synthesis of target product Ia

[0027] The product of step a above was dissolved in anhydrous dichloromethane, and a certain amount of DIBAL-H solution was slowly added dropwise at -30°C. After dropping, the system naturally rose to room temperature, and stirred for 3 hours. After the reaction was completed, it was quenched and filtered to obtain the target product. White solid, mp124-125℃. 1 H NMR (400MHz, DMSO-d 6 )δ:7.57-7.55(2H,d,J=8.8Hz),7.46-7.44(1H,d,J=8.0Hz),7.11(1H,t,J=7.6Hz),6.94-6.91(3H,m ),6.87-6...

Embodiment 2

[0029] Step a) Synthesis of 7-methoxy-3-(4-methoxyphenyl)coumarin IIb

[0030] According to the method shown in step a of Example 1, using 4-methoxysalicylaldehyde and 4-methoxyphenylacetic acid as raw materials, the target product was synthesized, a white solid, mp186-187°C

[0031] Step b) synthesis of target product Ib

[0032] According to the method shown in step b of Example 1, IIb was placed in dichloromethane, using DIBALH as a reducing agent, and reacted at -15°C for 5h to obtain a white solid with a melting point of 128-129°C. 1 H NMR (400MHz, DMSO-d 6 )δ:7.52(2H,d,J=8.8Hz),7.40(1H,d,J=8.0Hz),6.92(2H,d,J=9.2Hz),6.84(1H,s),6.43-6.41( 2H,m), 4.39(2H,s), 3.75(3H,s), 3.70(3H,s). 13 C NMR (100MHz, DMSO-d 6 )δ: 160.1(s), 158.7(s), 156.9(s), 137.4(s), 134.5(s), 1301.0(s), 127.7(d), 124.4(s), 117.5(s), 114.0( d),104.7(s),101.4(s),59.1(s),55.3(d).IR(KBr)cm -1 :3494,3268,1610,1432,1232,1019,839,811.MS(EI)m / z(%):286(M+ ), 267, 253, 161, 137. HRMS (EI) Calcd for C17H18O4: ...

Embodiment 3

[0034] Step a) Synthesis of 3-(3,4-dimethoxyphenyl)coumarin IIc

[0035] According to the method shown in step a of Example 1, using salicylaldehyde and 3,4-dimethoxyphenylacetic acid as raw materials, the target product was synthesized, a white solid, mp122-123°C

[0036] Step b) synthesis of target product Ic

[0037] According to the method shown in step b of Example 1, IIb was placed in dichloromethane, using aluminum hydride as a reducing agent, and reacted at -20°C for 5h to obtain a white solid, mp154-156°C. 1 H NMR (400MHz, DMSO-d 6 )δ:7.44(1H,d,J=7.6Hz),7.16-7.08(3H,m),6.93(1H,d,J=8.2Hz),6.88(1H,s),6.84-6.78(2H,m ), 4.39(2H,s), 3.78(3H,s), 3.75(3H,s). 13 C NMR (100MHz, DMSO-d 6 )δ: 155.8(s), 148.9(s), 148.6(s), 139.2(s), 134.8(s), 130.5(s), 128.9(s), 125.0(s), 124.6(s), 119.2( s),119.1(s),115.7(s),112.0(s),110.7(s),58.8(s),55.9(d).IR(KBr)cm-1:3467,3214,1598,1456,1243 ,1004,897,860,803,762.MS(EI)m / z(%):286(M + ), 267, 237, 165, 151, 73, 57. HRMS (EI) Calcd for C...

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Abstract

The invention discloses a stilbene compound, a preparation method and application of the stilbene compound. According to the invention, a substituted coumarin is adopted and used as a raw material, and the raw material is processed by reduction reaction in an organic solvent so as to the stilbene compound. The preparation method of the stilbene compound has the characteristics that the raw material is wide in source and low in cost, the method is simple in operation and mild in condition. The stilbene compound has combinability respect to ER Alpha higher than that respect to ER Beta and is relatively high in selectivity, some compounds show antagonistic effect to the ER Alpha and show partial agonistic action to ER Beta, therefore, the stilbene compound can be applied to preparation of a pharmaceutic preparation for preventing or treating diseases caused by estrogen deficiency or relative lack of estrogen, such as breast cancers, premature ovarian failure, climacteric syndrome, osteoporosis, polycystic ovarian syndrome and infertility.

Description

technical field [0001] The invention relates to a stilbene derivative, in particular to a stilbene compound, its synthesis method and its application as a selective estrogen receptor modulator. Background technique [0002] The pleiotropic effects of estrogens in mammalian tissues have been documented, and estrogens are now found to affect many organ systems. Estrogen acts on tissues in several ways, the best characterized of which is its interaction with estrogen receptors, resulting in changes in gene transcription. [0003] Two estrogen receptors have been discovered so far, and the estrogen receptor discovered earlier is called ERα [Green et al., Nature 320:134-9 (1986)]. A second receptor was discovered later and is called ER[beta] [Kuiper et al., Proceedings of the National Academy of Sciences of the United States of America 93:5925-5930 (1996)]. The two subtypes have different tissue distribution and different functions. ERα is mainly found in breast, ovary, adrenal...

Claims

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Application Information

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IPC IPC(8): C07C41/26C07C43/23C07C37/055C07C39/21C07C39/367A61K31/09A61K31/085A61K31/055A61K31/05A61P35/00A61P15/12A61P19/10A61P15/00A61P5/30
Inventor 张萍杨叶伟王尊元郑晓亮马臻沈正荣
Owner ZHEJIANG ACAD OF MEDICAL SCI
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