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Arylphosphine oxide and arylphosphine sulfide compounds, and preparation method and application thereof

A technology of aryl phosphorus oxides and compounds, applied in the field of medicine, can solve the problem of less HIF-2a inhibitors, and achieve the effect of strong in vitro binding ability

Active Publication Date: 2019-05-21
QINGDAO MARINE BIOPHARMACEUTICAL RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] At present, there are few reports on HIF-2a inhibitors, and only one inhibitor, PT2385, is in Phase 1 clinical stage

Method used

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  • Arylphosphine oxide and arylphosphine sulfide compounds, and preparation method and application thereof
  • Arylphosphine oxide and arylphosphine sulfide compounds, and preparation method and application thereof
  • Arylphosphine oxide and arylphosphine sulfide compounds, and preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] 3-[7-(dimethylphosphoryl)-2,2-difluoro-1-hydroxyl-2,3-dihydro-1H-indan-4-yl]oxygen-5-fluorobenzonitrile ( Compound 1) synthesis, the structural formula of the compound 1 is as follows:

[0032]

[0033] The preparation method of the compound 1 comprises the following steps:

[0034] (1a): Preparation of 4-methoxy-1-indanone

[0035]

[0036] 4-Hydroxy-1-indanone (2.00g, 13.5mmol) and potassium carbonate (7.5g, 54.0mmol) were added to acetone (40mL), methyl iodide (3.8g, 27.0mmol) was added, the temperature was raised to 60°C, Stir for 5h. TLC showed that the reaction was complete, cooled to room temperature, poured the reaction mixture into water, added ethyl acetate to extract twice, washed the organic phase with brine, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 4-methoxy- 1-Indanone (2.18 g, 99% yield).

[0037] LCMS (ESI): m / z: 163.1 [M+1].

[0038] (1b): Preparation of 7-iodo-4-methoxy-indan-1-one

[0039]

[0040] To a...

Embodiment 2

[0074] 3-[(1S)-7-(dimethylphosphoryl)-2,2-difluoro-1-hydroxy-2,3-dihydro-1H-indan-4-yl]oxy-5-fluoro Benzonitrile (Compound 2)

[0075]

[0076] At 0°C, RuCl(p-isopropyltoluene)[(R,R)-Ts-DPEN] (16 mg, 0.025 mmol) was added to nitrogen-flushed 3-[(7-(dimethylphosphoryl)- 2,2-Difluoro-1-oxo-indan-4-yl)oxy]-5-fluoro-benzonitrile (150mg, 0.40mmol), formic acid (80mg, 1.58mmol) and triethylamine (0.15 mL, 1.0 mmol) in dichloromethane (20 mL). The vial was sealed and placed in a 4°C refrigerator overnight. TLC showed that the reaction was complete, the reaction mixture was spin-dried and the residue was purified by column chromatography (dichloromethane:methanol=40:1) to obtain 3-[(1S)-7-(dimethylphosphoryl)-2 , 2-Difluoro-1-hydroxy-2,3-dihydro-1H-indan-4-yl]oxy-5-fluorobenzonitrile (120 mg, 80%).

[0077] 1 H NMR (500MHz, DMSO-d 6 ): δ7.72(m, 2H), 7.68(d, J=4Hz, 1H), 7.45(dd, J=12Hz, 1H), 7.10(d, J=8Hz, 1H), 6.76(d, J= 8 Hz, 1H), 5.45 (m, 1H), 3.40 (m, 2H), 1.77 (t, 6H). L...

Embodiment 3

[0079] 3-[(1R)-7-(dimethylphosphoryl)-2,2-difluoro-1-hydroxy-2,3-dihydro-1H-indan-4-yl]oxy-5-fluoro Benzonitrile (compound 3)

[0080]

[0081] At 0°C, RuCl(p-isopropyltoluene)[(S,S)-Ts-DPEN] (16 mg, 0.025 mmol) was added to nitrogen-flushed 3-[(7-(dimethylphosphoryl)- 2,2-Difluoro-1-oxo-indan-4-yl)oxy]-5-fluoro-benzonitrile (150mg, 0.40mmol), formic acid (80mg, 1.58mmol) and triethylamine (0.15 mL, 1.0 mmol) in dichloromethane (20 mL). The vial was sealed and placed in a 4°C refrigerator overnight. TLC showed that the reaction was complete, the reaction mixture was spin-dried and the residue was purified by column chromatography (dichloromethane:methanol=40:1) to obtain 3-[(1R)-7-(dimethylphosphoryl)-2 , 2-Difluoro-1-hydroxy-2,3-dihydro-1H-indan-4-yl]oxy-5-fluorobenzonitrile (122 mg, 81%).

[0082] 1 H NMR (500MHz, DMSO-d 6 ): δ7.71(m, 2H), 7.68(d, J=4Hz, 1H), 7.45(dd, J=12Hz, 1H), 7.10(d, J=8Hz, 1H), 6.76(d, J= 8 Hz, 1H), 5.44 (m, 1H), 3.40 (m, 2H), 1.77 (t, 6H). L...

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Abstract

The invention discloses arylphosphine oxide and arylphosphine sulfide compounds, and a preparation method and an application thereof. The arylphosphine oxide and arylphosphine sulfide compounds can beused as an HIF-2alpha inhibitor to prepare drugs for treating and / or preventing diseases or symptoms related with an anoxic induction factor 2alpha in mammals. The structural formula of the arylphosphine oxide and arylphosphine sulfide compounds is shown in the description.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a new class of aryl phosphorus oxygen and aryl phosphorus sulfur compounds with anti-tumor activity, their preparation method and application. Background technique [0002] Renal cancer is a malignant tumor originating from the urinary tubular epithelial system of the renal parenchyma. Renal cancer accounts for about 2% to 3% of adult malignant tumors and 80% to 90% of adult renal malignant tumors. In recent years, the rate of increase in the incidence of renal cancer ranks first among malignant tumors. Clinical treatment shows that RCC is not sensitive to radiotherapy and chemotherapy. Targeted antineoplastic drugs represented by VEGFR inhibitors Sorafenib and Sunitinib are the first-line treatment drugs for advanced RCC. Although there are as many as ten drugs approved by the FDA for the treatment of renal cancer, all of these drugs have limited curative effect o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/53A61P3/00A61P3/04A61P3/06A61P29/00A61P35/00A61P11/00A61P1/00A61P13/12A61P19/02A61P31/00A61K31/662
Inventor 陈栋徐涛赵维峰秦玉婷张守会单甜甜
Owner QINGDAO MARINE BIOPHARMACEUTICAL RES INST