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Novel 2,3-indane derivative compound, preparation method and application

A compound, C1-C4 technology, applied in the field of new compounds, can solve the problems of poor kidney cancer, less than 10% survival rate, and missing

Active Publication Date: 2022-04-12
WUHAN OPTICS VALLEY YATAI PHARM RES INST CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the relatively hidden location of the kidney and the lack of obvious clinical symptoms in the early stages of renal cancer, most renal cancer patients already have metastasis at the time of diagnosis. Once renal cancer metastasizes (advanced stage), the prognosis is often very poor, and the 5-year survival rate is less than 10%.
The most obvious of these is RCC, 90% of which lack the E3 ligase of VHL (Von Hippel-Lindau, a tumor suppressor gene), leading to uncontrolled degradation of HIF

Method used

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  • Novel 2,3-indane derivative compound, preparation method and application
  • Novel 2,3-indane derivative compound, preparation method and application
  • Novel 2,3-indane derivative compound, preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] 3-((((1S,2S,3R)-7-(cyclopropyl(methyl)phosphoryl)-2,3-difluoro-1-hydroxy-2,3-dihydro-1H-indene-4 Preparation of -yl)oxyl]-5-fluorobenzonitrile (compound 1)

[0067] (or )

[0068] Step a: Ethyl (7-(3-cyano-5-fluorophenoxy)-3-oxo-2,3-dihydro-1H-inden-4-yl)(methyl)phosphinate ( 1-1)

[0069]

[0070] Under nitrogen protection, the complex of 30mg (0.04mmol) [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride and dichloromethane (1:1,Pd( dppf)Cl 2 ) and 165mg (1.5mmol) triethylamine were added to (350mg, 1.0mmol) 3-((7-bromo-1-oxo-2,3-dihydro-1H-4-yl)oxy)-5-fluoro Benzonitrile, (130mg, 1.2mmol) ethyl methylphosphinate in 5mL pure dimethylformamide suspension. The reaction mixture was stirred at 110° C. for 16 hours, monitored by TLC plate spotting, the reaction was stopped after the reaction of the raw materials was complete, cooled to room temperature, the reaction mixture was poured into water, and extracted with ethyl acetate (20 mL×3). The combi...

Embodiment 2

[0111] 3-((((5R,6S,7S)-1-((dimethyl(oxo)-6-sulfinimino)amino)-5,6-difluoro-7-hydroxyl-6,7 Preparation of -dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)-5-fluorobenzonitrile (compound 2)

[0112]

[0113] Step a:

[0114] 3-((1-bromo-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2'-[1,3]dioxolan]-4-yl)oxy)-5-fluoro Benzonitrile (2-1)

[0115]

[0116] method 1:

[0117] 17.9g (0.288mol) of ethylene glycol, 1.49g (0.0086mol) of p-toluenesulfonic acid and 10g (0.0288mol) of 3-((1-bromo-7-oxo-6,7-dihydro-5H -Cyclopenta[c]pyridin-4-yl)oxy)-5-fluorobenzonitrile (0.0288mol) was added to 30mL toluene, the temperature was raised to reflux and the water was separated for 12 hours, cooled to room temperature, diluted with ethyl acetate, and the organic layer was separated Washed with 5% sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the crude product was purified by column chromatography (dichloromethane:methanol=20:1~40:...

Embodiment 3

[0160] 3-((1S,2S,3R)-2,3-difluoro-1-hydroxy-7-(1-phosphine-1-yl)-2,3-dihydro-1H-inden-4-yl) Preparation of oxy)-5-fluorobenzonitrile (compound 3)

[0161]

[0162] Except replacing 3-((7-bromo-1-oxo-2,3-dihydro-1H-4-yl)oxy)-5-fluorobenzonitrile in step a with 3-fluoro-5-(( 7-(1-phosphinyl-1-yl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile, the substrate in step c and methyl Except for the omission of the Grignard reagent reaction, the same operation was performed as in Example 1 to obtain compound 3.

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Abstract

The invention discloses a novel 2,3-indane derivative compound, a preparation method and application thereof. The novel 2,3-indane derivative compound described in the present invention can be used as a HIF-2α (Hypoxia-Inducible Factors-2α) inhibitor for the preparation of medicines for treating and / or preventing diseases related to HIF-2α in mammals .

Description

technical field [0001] The present invention relates to a novel compound, in particular to a novel 2,3-indane derivative compound, a preparation method and an application. Background technique [0002] Renal cell carcinoma (RCC) is one of the deadliest tumors of the urinary system and can be divided into three main histological subtypes: clear cell renal cell carcinoma (ccRCC) accounts for 70% of cases; Symptomatic and chromophobe renal cell carcinoma, accounting for 25% of cases; medullary and collecting system tumors, accounting for 5% of cases. These subtypes are caused by distinct genetic factors and, therefore, are treated very differently. [0003] ccRCC is the most common renal malignancy. It is estimated that in 2018, there were 65,000 new cases of kidney cancer in the United States, and 14,000 deaths; in China, the incidence rate of kidney cancer is 3.8 / 100,000, and there are about 67,000 new patients every year, which is already the highest morbidity and mortalit...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/53C07D221/04C07C381/10C07D333/36C07F9/6568C07F9/576C07F9/58C07F9/32A61K31/662A61K31/435A61K31/675A61K31/277A61K31/381A61P35/00A61P35/02A61P29/00A61P11/00A61P1/00A61P13/12A61P19/02A61P31/00A61P3/04A61P3/06
CPCC07F9/5325C07D221/04C07C381/10C07D333/36C07F9/65685C07F9/5765C07F9/58C07F9/3264A61P35/00A61P35/02A61P29/00A61P11/00A61P1/00A61P13/12A61P19/02A61P31/00A61P3/04A61P3/06A61K31/277A61K31/381A61K31/435A61K31/662A61K31/675C07F9/32C07F9/53C07F9/576C07F9/6568C07C43/225A61K31/085C07D471/04
Inventor 戚祖德袁胜峰
Owner WUHAN OPTICS VALLEY YATAI PHARM RES INST CO LTD
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