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Tetrasubstituted alkene compounds and their use for the treatment of breast cancer

A compound, stereochemical technology, applied in organic chemistry, drug combination, medical preparations containing active ingredients, etc., can solve problems such as drug withdrawal

Inactive Publication Date: 2019-10-01
EISIA R&D MANAGEMENT CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Unanticipated, unrecognized or mismanaged drug-drug interactions (DDIs) are a significant cause of morbidity and mortality associated with prescription drug use and occasionally lead to the withdrawal of approved drugs from the market

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0313] Example 1: (E)-N,N-dimethyl-4-((2-(4-(4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl )-2-phenylbut-1-en-1-yl)phenoxy)ethyl)amino)butanamide (compound 1)

[0314]

[0315] Step-1: Synthesis of 5-bromo-3-fluoro-1H-indazole

[0316]

[0317] Into a 500-mL round bottom flask was placed 5-bromo-1H-indazole (20 g, 101.51 mmol, 1.00 equiv), fluorine reagent (selectfluor) (71.6 g, 2.00 equiv), AcOH (30 mL), and CH 3 CN (300 mL). The resulting solution was stirred at 80 °C in an oil bath until complete. The reaction was then quenched by adding 100 mL of water. The resulting solution was extracted with 3 x 100 mL of ethyl acetate, and the organic layers were combined. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (1:4). The collected fractions were combined and concentrated in vacuo to afford the title compound (11 g, 50%) as a white solid. LCMS: 215.1[M+H] + .

[0318] Step-2: Synthesis of 5-bromo-3-fluoro-1-((2-(trimethy...

Embodiment 2

[0350] Example 2: (Z)-N,N-dimethyl-4-((2-((5-(4,4,4-trifluoro-1-(3-fluoro-1H-indazole-5- Synthesis of -2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)ethyl)amino)butyramide (compound 2)

[0351]

[0352] Step-1: 5-((Z)-1-(6-(2-((tert-butoxycarbonyl)((E)-4-(dimethylamino)-4-oxobut-2-ene -1-yl)amino)ethoxy)pyridin-3-yl)-4,4,4-trifluoro-2-phenylbut-1-en-1-yl)-3-fluoro-1H-indazole -Synthesis of tert-butyl formate

[0353]

[0354] Put (E)-N,N-dimethyl-4-((2-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro -1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)ethyl)amino)but-2-enamide (80mg, 0.14mmol , 1.00 equivalents) (synthesized according to the method described in the patent application publication US 2016347717 A1), N,N-dimethylformamide (2 mL), potassium carbonate (58 mg, 0.42 mmol, 2.98 equivalents) and (Boc) 2 O (61 mg, 0.28 mmol, 1.98 equiv). The resulting solution was stirred at 20 °C until completion. The progress of the reaction was monitored by LCMS. The resulting solutio...

Embodiment 3

[0363] Example 3: (E)-N-methyl-4-(2-(5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl Synthesis of )-2-phenylbut-1-enyl)pyridin-2-yloxy)ethylamino)but-2-enamide (Compound 3)

[0364]

[0365] Step-1: Synthesis of 5-bromo-3-fluoro-1H-indazole

[0366]

[0367] Into a 5-L 3-necked round bottom flask purged with nitrogen and maintained under an inert nitrogen atmosphere was placed 5-bromo-1H-indazole (200 g, 1.0204 mol, 1.00 equiv), CH 3 CN (3.5 L), acetic acid (120 mL) and fluorine reagent (544 g, 1.5367 mol, 1.51 equiv). The resulting solution was stirred at 80 °C until completion. The progress of the reaction was monitored by LCMS. The resulting solution was diluted with 8 L ethyl acetate and washed with 3 × 4000 mL H 2 O washing. The organic layer was dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (0:100-15:85). The collected fractions were combined and...

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Abstract

Disclosed herein are compounds, or pharmaceutically acceptable salts thereof, and methods of using the compounds for treating breast cancer by administration to a subject in need thereof a therapeutically effective amount of the compounds or pharmaceutically acceptable salts thereof. The breast cancer may be an ER-positive breast cancer and / or the subject in need of treatment may express a mutantER-alpha protein.

Description

[0001] Cross References to Related Applications [0002] This application claims priority benefit from Indian Patent Application No. 201741018583 filed on May 26, 2017 and Indian Patent Application No. 201641040196 filed on November 24, 2016. Both applications are hereby incorporated by reference as if fully rewritten herein. Background technique [0003] Breast cancer is the most commonly diagnosed malignancy in women today, with nearly 200,000 / 1.7 million new cases diagnosed each year in the United States / worldwide, respectively. Since approximately 70% of breast tumors are positive for estrogen receptor alpha (ERα), a key oncogenic driver in this subtype of tumors, several types of therapeutic agents have been developed to antagonize ERα Functions, including: 1) Selective estrogen receptor down-regulators (SERDs), such as fulvestrant, 2) Selective estrogen receptor modulators (SERMs), such as tamoxifen , and 3) aromatase inhibitors that reduce systemic estrogen levels. T...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/12C07D401/14C07D231/56C07D401/06A61P35/00A61K31/416
CPCA61P35/00C07D231/56C07D401/06C07D401/10C07D401/14C07D403/12C07D413/12C07D413/14C07D401/12C07D403/10
Inventor 马克·巴克郝鸣鸿玛那芙·寇波维贾·库莫·涅维奈蒂濮阳晓玲苏珊塔·撒马杰达彼得·盖瑞德·史密斯王渊郑国茱朱平罗纳·海伦·米契尔尼可拉斯·拉森娜塔莉·里乌苏迪普·普莱加巴蒂多米尼克·雷诺兹摩根·奥谢西旺卡·莎玛拉库
Owner EISIA R&D MANAGEMENT CO LTD
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