Acrylic acid derivative, preparation method therefore and medical application of acrylic acid derivative

A technology of compounds and mixtures, applied in the field of medicine, can solve problems such as hot flashes, venous thrombosis, and endometrial hyperplasia

Active Publication Date: 2017-03-22
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

SERMs currently on the market include Tamoxifen, Raloxifene, Bazedoxifene, Toremifene, etc., but studies have found that SERMs currently on the market still have severe For example, long-term use of tamoxifen and toremifene can cause endometrial hyperplasia, polyps, and endometrial cancer, while common side effects of raloxifene include hot flashes, leg pain, breast tenderness, and venous Embolism, etc.

Method used

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  • Acrylic acid derivative, preparation method therefore and medical application of acrylic acid derivative
  • Acrylic acid derivative, preparation method therefore and medical application of acrylic acid derivative
  • Acrylic acid derivative, preparation method therefore and medical application of acrylic acid derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0144] (E)-3-(4-(cyclohexylene(1H-indazol-5-yl)methyl)phenyl)acrylic acid

[0145]

[0146] first step

[0147] (4-bromophenyl)(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)methanol

[0148] 5-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole 1a (500mg, 1.8mmol, using the known method "Journal of Organic Chemistry, 2009, 74(16), 6331 -6334" prepared) was dissolved in 20mL tetrahydrofuran, cooled to -78°C, n-butyllithium (0.8mL, 1.98mmol) was added dropwise, stirred for 5 minutes, and pre-made 3mL p-bromobenzaldehyde (300mg, 1.62 mmol) in tetrahydrofuran, stirred and reacted at -78°C for 2 hours. After the reaction, add 10mL saturated ammonium chloride solution to quench the reaction, extract with ethyl acetate (50mL×2), dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and use silica gel column chromatography to elute Purification of the resulting residue with Reagent System B afforded the title product (4-bromophe...

Embodiment 2

[0172] (E)-3-(4-((1H-indazol-5-yl)(3,3,5,5-tetramethylcyclohexylene)methyl)-2,6-difluorophenyl)acrylic acid

[0173]

[0174]

[0175] first step

[0176] (4-(Benzyloxy)-3,5-difluorophenyl)(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)methanol

[0177] 5-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole 1a (1.87g, 6.65mmol) was dissolved in 30mL tetrahydrofuran, and 2.5M n-butyl was added dropwise at -78°C Lithium base (3.0mL, 7.32mmol), stirring for 10 minutes after the dropwise addition, added dropwise 5mL of pre-made 4-(benzyloxy)-3,5-difluorobenzaldehyde 2a (1.65g, 6.65mmol, using the patent application " WO2014069963" prepared by the method disclosed) tetrahydrofuran solution, naturally raised to 25 ° C, stirred and reacted for 12 hours. After the reaction was completed, 20 mL of saturated ammonium chloride solution was added to quench the reaction, extracted with ethyl acetate (20 mL×3), the organic phase was concentrated under reduced pressure, and the resulting re...

Embodiment 3

[0202] (E)-3-(4-((1H-indazol-5-yl)(3,3,5,5-tetramethylcyclohexylene)methyl)-3,5-difluorophenyl)acrylic acid

[0203]

[0204] first step

[0205] (4-bromo-2,6-difluorophenyl)(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)methanol

[0206] Dissolve 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole 1a (560mg, 2mmol) in 10mL ether, add 2.5M n-butyllithium dropwise at -78°C (1.7mL, 2.2mmol), stirred for 10 minutes after the addition was completed, added dropwise 2mL of a pre-made ether solution of 4-bromo-2,6-difluorobenzaldehyde (442mg, 2mmol), naturally rose to 25°C, and stirred for 60 Hour. After the reaction was completed, 10 mL of saturated ammonium chloride solution was added to quench the reaction, extracted with ethyl acetate (10 mL×3), the organic phase was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title product (4-Bromo-2,6-difluorophenyl)(1-(tetrahydro-2H-pyran-2...

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PUM

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Abstract

The invention relates to an acrylic acid derivative, a preparation method thereof and medical application of the acrylic acid derivative. Particularly, the invention relates to the acrylic acid derivative as shown in a general formula (I) defined in the description, the preparation method thereof, a pharmaceutical composition containing the derivative and application of the derivative serving an estrogen receptor modulator for treating estrogen receptor mediated or dependent diseases or symptoms, and the disease of a breast cancer is particularly preferable. All substituents of the formula (I) are the same as the definition in the description.

Description

technical field [0001] The invention belongs to the field of medicine, and relates to an acrylic acid derivative, its preparation method and its application in medicine. In particular, the present invention relates to acrylic acid derivatives represented by general formula (I), their preparation methods and pharmaceutical compositions containing the derivatives, and as estrogen receptor modulators for the treatment of estrogen receptor-mediated or Use in a disease or condition of dependence, particularly preferably breast cancer. Background technique [0002] After long-term basic research and clinical monitoring, it has been found that diseases such as breast cancer, ovarian cancer, osteoporosis, schizophrenia, and Alzheimer's are closely related to abnormalities in estrogen signaling pathways. Estrogen is a steroid hormone secreted by the endocrine system, which plays an important role in the reproductive system, bone tissue, cardiovascular, immune system and central nerv...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D231/56C07D405/06A61K31/416A61P35/00A61P25/00A61P9/00A61P7/00A61P15/00A61P29/00A61P37/02A61P35/02A61P25/06A61P25/32A61P9/10A61P9/12A61P1/16A61P3/04A61P19/02A61P19/10A61P25/16
CPCC07D231/56C07D405/06
Inventor 杨方龙王春飞王阳何明勋胡齐悦贺峰
Owner JIANGSU HENGRUI MEDICINE CO LTD
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