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Sulfone imine compound, and preparation method and application thereof

A compound, a technology, applied in organic chemistry, drug combinations, pharmaceutical formulations, etc., can solve problems such as poor prognosis, and achieve the effects of improving PK properties, reducing glucuronidation levels, and improving inhibitory effects.

Pending Publication Date: 2021-11-02
JIANGXI JEMINCARE GRP CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Clinically found that patients with high expression of HIF2α in malignant glioma have worse prognosis

Method used

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  • Sulfone imine compound, and preparation method and application thereof
  • Sulfone imine compound, and preparation method and application thereof
  • Sulfone imine compound, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] Example 1: Compound 1

[0077]

[0078] synthetic route:

[0079]

[0080] Step 1: Preparation of Compound 1-2

[0081] Compound 1-1 (50.0g, 211.0mmol) was dissolved in 800mL DMF, and Na 2 CO 3 (45.0 g, 424.0 mmol). Under nitrogen protection, CH was added dropwise at room temperature 3 I (33.0 g, 232.0 mmol). The reaction solution was stirred at room temperature for 16 h. TLC showed the reaction was complete. Add 1500 mL of water, extract three times with 3000 mL of ethyl acetate, combine the organic phases, wash with water and saturated brine, and dry over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to obtain compound 1-2. 1 H NMR (400MHz, Chloroform-d) δ = 7.63 (ddd, J = 9.0, 7.5, 5.6Hz, 1H), 6.90 (td, J = 8.9, 1.7Hz, 1H), 3.96 (s, 3H).

[0082] Step 2: Preparation of Compound 1-3

[0083] Compound 1-2 (55.0 g, 210.0 mmol) and sodium methyl mercaptide (18.5 g, 264.0 mmol) were added to 600 mL DMA, and stirred for 16 h at 7...

Embodiment 2

[0102] Example 2: Compound 2

[0103]

[0104] synthetic route:

[0105]

[0106] synthetic route:

[0107] Step 1: Preparation of Compound 2

[0108] Compound 1 (6.0 mg, 0.013 mmol) was dissolved in 0.2 mL DMF, and cuprous cyanide (3.6 mg, 0.040 mmol) was added. It was sealed under nitrogen atmosphere, and the reaction solution was heated to 170° C. with microwave and stirred for 1 h. LCMS showed the reaction was complete. 2 mL of water was added, extracted four times with 8 mL of dichloromethane, the combined organic phases were washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and purified by preparative HPLC to obtain compound 2. 1 H NMR (400MHz, Chloroform-d) δ=7.94(dd,J=8.8,1.6Hz,1H),7.20-7.11(m,2H),6.98-6.96(m,1H),6.84-6.78(m,1H ), 6.12 (dd, J=50.8, 9.6Hz, 1H), 4.18 (brs, 1H), LCMS m / z=390.8[M+1] + .

Embodiment 3

[0109] Embodiment 3: compound 3, compound 4

[0110]

[0111] synthetic route:

[0112] Step 1: Preparation of Compound 3 and Compound 4

[0113] Compound 1 (20.0 mg, 0.045 mmol) was dissolved in 1 mL of 1,4-dioxane, and dimethylphosphine oxide (3.5 mg, 0.045 mmol), triethylamine (9.1 mg, 0.090 mmol) and Pd( dppf)Cl 2 (3.3 mg, 0.004 mmol). Under the protection of nitrogen, the reaction solution was stirred at 90° C. for 16 h. LCMS showed the reaction was complete. Add 3 mL of water, extract three times with 9 mL of dichloromethane, wash the combined organic phase with water and saturated brine, and dry over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and purified by preparative HPLC to obtain compound 3 and compound 4.

[0114] Compound 3: 1 H NMR (400MHz, Chloroform-d)δ=8.17-7.98(m,1H),7.20-7.13(m,1H),7.09-7.06(m,1H),6.97-6.94(m,1H),6.80(dt ,J=8.8,2.4Hz,1H),6.27-5.98(m,1H),4.87-4.58(m,1H),2.10-1.89(m,6H),LCMS m / z=442.0[M+1] + .

[01...

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PUM

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Abstract

The invention discloses a sulfoximine compound, a preparation method and application thereof, and application of the compound as an HIF2alpha inhibitor.

Description

technical field [0001] The present invention relates to the compound represented by formula (I), its optical isomer and its pharmaceutically acceptable salt, and the application of the compound as HIF2α inhibitor. Background technique [0002] Renal cancer accounts for about 2% to 3% of adult malignant tumors and 80% to 90% of adult renal malignant tumors. According to statistics, in 2018, there were 403,000 newly diagnosed patients with kidney cancer worldwide, and 175,000 people died of it. The current incidence of kidney cancer in my country is about 4.0 / 100,000, while the incidence in cities is about 6.0 / 100,000. Based on this calculation, it is calculated that there are about 52,000 to 78,000 new patients with kidney cancer every year in my country, and the total number of kidney cancer patients is estimated to be more than 460,000. Glioma accounts for 40-50% of brain tumors and is the most common intracranial malignant tumor. Malignant gliomas are derived from glia,...

Claims

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Application Information

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IPC IPC(8): C07D333/62A61K31/381A61P35/00
CPCC07D333/62A61P35/00
Inventor 牟剑锋张健民彭建彪俞清方陈喆李宏业叶艳郭海兵
Owner JIANGXI JEMINCARE GRP CO LTD
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