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Estrogen receptor modulator compounds and uses thereof

A compound and selected technology, applied in the fields of organic chemistry, drug combination, organic chemistry methods, etc., can solve the problems of limiting the efficacy of the highest dose and failing to fully realize the degradation of ER.

Active Publication Date: 2022-03-01
SIMCERE ZAIMING PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

A number of research data have shown that patients treated with fulvestrant have not fully achieved ER degradation, but it may also be due to the dose of fulvestrant (up to 500mg, mainly due to its pharmacodynamic characteristics and muscle The internal route of administration limits the maximum dose it can give to patients) limits its efficacy

Method used

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  • Estrogen receptor modulator compounds and uses thereof
  • Estrogen receptor modulator compounds and uses thereof
  • Estrogen receptor modulator compounds and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0131] Example 1: 3-(((1R,3R)-1-(2,6-difluoro-4-((1-((((1R,2R)-2-fluorocyclopropyl)methyl)nitrogen Heterobutan-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)- 2,2-Difluoropropan-1-ol

[0132]

[0133] Step 1: Synthesis of 5-bromo-2-(diethoxymethyl)-1,3-difluorobenzene

[0134]

[0135] Add 4-bromo-2,6-difluorobenzaldehyde (2.19g, 10.0mmol) into 50mL ethanol, add triethyl orthoformate (1.48g, 10.0mmol), add 1 drop of concentrated sulfuric acid and heat to 60 After stirring at ℃, the reaction was completed after 4 hours, and the title compound was obtained after the reaction solution was spin-dried.

[0136] Step 2: Synthesis of tert-butyl 3-(((4-(diethoxymethyl)-3,5-difluorophenyl)amino)azetidine-1-carboxylate

[0137]

[0138] 5-Bromo-2-(diethoxymethyl)-1,3-difluorobenzene (2.94g, 10.0mmol), 1-tert-butoxycarbonyl-3-aminocyclobutylamine (2.06g, 12.0 mmol), tris(dibenzylideneacetone)dipalladium (458mg, 0.5mmol) 4,5-bisdiphenylphosphine-9,...

Embodiment 2

[0156] Example 2: 3-(((1R,3R)-1-(2,6-difluoro-4-((1-((((1S,2S)-2-fluorocyclopropyl)methyl)nitrogen Heterobutan-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)- 2,2-Difluoropropan-1-ol

[0157]

[0158] The preparation method is similar to Example 1, except that (1R, 2R)-2-fluorocyclopropane-1-carboxylic acid in step 6 in Example 1 is replaced by (1S, 2S)-2-fluorocyclopropane- 1-Carboxylic acid, the last two-step reaction of Example 1 was carried out in the same way to obtain the title compound.

[0159] DMSO-d6δ H 10.50(s,1H),7.38-7.36(m,1H),7.19-7.17(m,1H),7.00-6.91(m,2H),6.70-6.68(m,1H),6.11-6.08(m,2H ),5.25-5.20(m,1H),5.05(s,1H),4.82-4.78(m,0.5H),4.65-4.62(m,0.5H),3.95-3.92(m,1H),3.69-3.60 (m,3H),3.47-3.37(m,2H),3.14-3.03(m,1H),2.85-2.80(m,3H),2.64-2.50(m,3H),2.47-2.42(m,1H) ,1.07-1.05(m,3H),0.91-0.85(m,1H),0.79-0.71(m,1H),0.59-0.49(m,1H).

[0160] LC / MS (m / z, MH + ):535.2

Embodiment 3

[0161] Example 3: 3-(((1R,3R)-1-(2,6-difluoro-4-((1-((((1S,2R)-2-fluorocyclopropyl)methyl)nitrogen Heterobutan-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)- 2,2-Difluoropropan-1-ol

[0162]

[0163] The preparation method is similar to Example 1, except that (1R, 2R)-2-fluorocyclopropane-1-carboxylic acid in step 6 in Example 1 is replaced by (1S, 2R)-2-fluorocyclopropane- 1-Carboxylic acid, the last two-step reaction of Example 1 was carried out in the same way to obtain the title compound.

[0164] DMSO-d6δ H 10.51(s,1H),7.38-7.35(m,1H),7.19-7.17(m,1H),7.00-6.91(m,2H),6.70-6.68(m,1H),6.11-6.08(m,2H ),5.25-5.20(m,1H),5.05(s,1H),4.82-4.78(m,0.5H),4.65-4.62(m,0.5H),3.95-3.92(m,1H),3.69-3.60 (m,3H),3.47-3.37(m,2H),3.14-3.03(m,1H),2.85-2.80(m,3H),2.64-2.49(m,3H),2.47-2.42(m,1H) ,1.07-1.05(m,3H),0.91-0.85(m,1H),0.79-0.71(m,1H),0.59-0.49(m,1H).

[0165] LC / MS (m / z, MH+):535.2

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Abstract

Described herein are compounds having estrogen receptor modulating activity or function and pharmaceutically acceptable salts thereof, the compounds having the structure of Formula (I) and having the substituents and structural characteristics described herein. The invention also describes a pharmaceutical composition containing the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof, and application of the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof in preparation of medicines for preventing or treating estrogen receptor related diseases.

Description

[0001] This application claims the priority of the previous application submitted to the State Intellectual Property Office on August 28, 2020, with the patent application number 202010886642.1 and the invention title "Estrogen Receptor Modulator Compounds and Uses thereof". The entirety of said prior application is incorporated by reference into this application. technical field [0002] The present invention relates to an estrogen receptor modulator compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound, and its use in preventing or treating estrogen receptor-related diseases. Background technique [0003] Estrogen (E2) and estrogen alpha receptor (ERα) are important drivers of breast cancer development. More than 2 / 3 of breast cancer patients express ER transcription factors, and in most ER-positive patients, ER is still a key driver even in tumors that progress after early endocrine therapy, so ER is A major target f...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61P35/00A61P5/30A61K31/444A61K31/437
CPCC07D471/04A61P35/00A61P5/30C07B2200/07
Inventor 张雁杨圣伟庞司林唐锋王峰彭少平任晋生
Owner SIMCERE ZAIMING PHARM CO LTD
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