Substituted olefin compound, and preparation method and application thereof

A compound and solvate technology, applied in the field of medicine, can solve the problems of poor drug characteristics and low efficacy

Active Publication Date: 2018-05-01
SICHUAN KELUN BIOTECH BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Fulvestrant is currently the only SERDs drug approved for clinical use, but its drug-forming properties are poor, it must be injected intramuscularly, and its efficacy is low. The dose of 500mg / month can only reach less than 50% of patients Degradation of estrogen receptors (Wardell, et al., Biochem.Pharm., 2011, 82:122-130)

Method used

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  • Substituted olefin compound, and preparation method and application thereof
  • Substituted olefin compound, and preparation method and application thereof
  • Substituted olefin compound, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0179] Example 1: (E)-3-(4-((E)-2-(3-chloropyridin-4-yl)-1-(1H-indol-4-yl)-1-butenyl) Phenyl)acrylic acid (Compound 1)

[0180] Reaction route:

[0181]

[0182] The first step: N-acetyl-4-bromo-indole (compound 1-2)

[0183] Under nitrogen atmosphere, DMAP (122 mg, 1 mmol) was added to a suspension of 4-bromoindole (1.96 g, 10 mmol) in acetic anhydride (50 mL), and the reaction mixture was heated to about 140°C for about 3-4 hours. The reaction mixture was cooled to room temperature, poured into ice water, extracted with ethyl acetate, the organic phases were combined, washed with saturated aqueous sodium bicarbonate solution, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain an oil Purified by column chromatography (PE:EA=10:1) to obtain N-acetyl-4-bromo-indole (2.2 g, yield 92%).

[0184] MS m / z(ESI):238[M+H] + .

[0185] The second step: N-acetyl-4-butynyl-indole (compound 1-4...

Embodiment 2

[0204] Example 2: (E)-3-(4-((Z)-2-(2-chlorophenyl)-1-(1H-indazol-5-yl)-1-butenyl)-3- Fluorophenyl)acrylic acid (Compound 2)

[0205] Reaction route:

[0206]

[0207]The first step: 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0208] To a solution of 5-bromoindazole (1.97 g, 10 mmol) in dichloromethane (50 mL) under nitrogen atmosphere, were added 3,4-dihydro-2H-pyran (1.26 g, 15 mmol) and p-toluenesulfonic acid ( 194mg, 1mmol), the reaction mixture was reacted at room temperature for about 11-12h. Workup gave 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (2.52 g, yield: 90%).

[0209] MS m / z(ESI):281[M+H] + .

[0210] The second step: 5-(1-butynyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0211] Under nitrogen atmosphere, to 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (2.5g, 8.9mmol) in N,N-dimethylacetamide (45mL) solution In, add cesium carbonate (5.8g, 17.8mmol), dppf (500mg, 0.9mmol), cuprous iodide (171mg, 0.9mmol), palladium acetate (200mg, 0.9...

Embodiment 3

[0232] Example 3: (E)-3-(4-((3E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indol-4-yl)-1-butenyl ) phenyl) acrylic acid (Compound 3)

[0233]

[0234] The first step: tert-butyl 4-bromo-1H-indolyl-1-carbonate

[0235] To a solution of 4-bromoindole (1.96g, 10mmol) in dichloromethane (50mL), DMAP (122mg, 1mmol) and di-tert-butyl dicarbonate (2.4g, 11mmol) were added, and the reaction system was stirred at room temperature for 8h, then Work-up gave tert-butyl 4-bromo-1H-indolyl-1-carbonate (2.96 g, 99% yield).

[0236] MS m / z(ESI):241[M-56+1] + .

[0237] The second step: tert-butyl 4-(1-butynyl)-1H-indole-1-carbonate

[0238] The operation is the same as the second step in Example 2, replacing 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole with 4-bromo-1H-indolyl-1 - tert-butyl carbonate to give tert-butyl 4-(1-butynyl)-1H-indole-1-carbonate (2.15 g, yield 80%).

[0239] MS m / z(ESI):214[M-56+1] + .

[0240] The third step: (Z)-4-(1,2-diboronic acid pinacol ester-1-butenyl)...

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Abstract

The invention provides a substituted olefin compound, and a preparation method and application thereof. Specifically, the application provides a substituted olefin compound, a stereoisomer, prodrug, solvate, and pharmaceutically acceptable salt or ester of the substituted olefin compound, a preparation method of the substituted olefin compound, and an application in preparing medicines for treating diseases relative to an excessive activity of estrogen receptors (such as ERalpha).

Description

technical field [0001] The present application relates to the field of medicine, specifically, the present application relates to a substituted olefinic compound and its preparation method and use; more specifically, the present application relates to compounds shown in formulas I-III in inhibiting estrogen receptor activity, Use in down-regulating the expression level of estrogen receptors or inducing the degradation of estrogen receptors; the application also relates to the use of compounds represented by formulas I-III in the preparation of drugs for preventing or treating diseases related to estrogen receptor overactivity Uses, especially estrogen receptor-positive (ER+) drug-resistant diseases (such as breast cancer that is resistant to anti-estrogen therapy, etc.). Background technique [0002] Estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) are steroid hormone receptors and members of a large family of nuclear receptors. Both receptors are involved in ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/06C07D231/56C07D209/08A61K31/4439A61K31/416A61K31/404A61P35/00A61P25/00A61P25/32A61P25/06A61P25/28A61P25/16A61P9/00A61P9/10A61P9/12A61P37/02A61P29/00A61P19/02A61P1/16A61P13/02A61P3/04A61P25/14A61P25/24A61P25/18A61P15/00A61P15/08A61P5/32
CPCC07D209/08C07D231/56C07D401/06
Inventor 刘钢于华董振文杜静王润江张园园曾宏宋宏梅葛勇王利春王晶翼
Owner SICHUAN KELUN BIOTECH BIOPHARMACEUTICAL CO LTD
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