ACC inhibitor and medical application thereof

A C1-C3, C1-C6 technology, applied in the field of medicinal chemistry and pharmacotherapeutics, can solve the problems of weak tumor cell activity and failure to meet clinical needs

Active Publication Date: 2020-08-25
浙江永核药业科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Based on this, the applicant has carried out the anti-tumor activity determination of the preferred compound PF-1 disclosed in the patent, and the experimental data shows that its activity on tumor cells is relatively weak, which cannot meet the clinical needs

Method used

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  • ACC inhibitor and medical application thereof
  • ACC inhibitor and medical application thereof
  • ACC inhibitor and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0102]

[0103] 2'-(tert-butyl)-1-(2-phenylquinoline-4-carbonyl)-2'H-spiro[piperidine-4,5'-pyrano[3,2-c]pyrazole ]-7'(6'H)-one (I 1 )

[0104] The aqueous solution (120mL) of tert-butylhydrazine hydrochloride (3.74g, 30mmol) and methylglyoxal (4.5g, 25mmol) was reacted at room temperature for 2h; Concentrate under reduced pressure to obtain compound (E)-1-(2-(tert-butyl)hydrazino)propan-2-one. Dissolve (E)-1-(2-(tert-butyl)hydrazino)propan-2-one (8.8g, 62mmol) and 40% glyoxal solution (25mL, 180mmol) in 100mL distilled water, and heat to reflux for 5h After cooling to room temperature, the reaction solution was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the compound 1-tert-butyl-4-hydroxypyrazole-3-ethanone. Dissolve 1-tert-butyl-4-hydroxypyrazole-3-ethanone (4.4g, 24mmol), tetrahydropyrrole (568mg, 8mmol), N-BOC-piperidone (5.54g, 28mmol) in 45mL methanol The sol...

Embodiment 2

[0107]

[0108] 2'-(tert-butyl)-1-(2-(p-methylphenyl)quinoline-4-carbonyl)-2'H-spiro[piperidine-4,5'-pyrano[3,2 -c]pyrazole]-7'(6'H)-one (I 2 )

[0109] According to the method of Example 1, the compound 2'-(tert-butyl)-2'H-spiro[piperidine-4,5'-pyrano[3,2-c]pyrazole]-7'( 6'H)-keto. Under ice bath conditions, 2'-(tert-butyl)-2'H-spiro[piperidine-4,5'-pyrano[3,2-c]pyrazole]-7'(6'H )-ketone (400mg, 1.1mmol), HATU (458mg, 1.2mmol), triethylamine (0.2ml, 1.2mmol) were dissolved in 10mL DMF, stirred at 0°C for 0.5h, added 2-(p-methylphenyl) Quinoline-4-carboxylic acid (1mmol, 265mg) was reacted at room temperature for 12h; the reaction solution was added to 50mL ice water, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was passed through a silica gel column Purified by chromatography to obtain the title compound I 2 .

[0110] Yellow solid, yield 80%, m.p.164....

Embodiment 3

[0112]

[0113] 2'-(tert-butyl)-1-(2-(o-methylphenyl)quinoline-4-carbonyl)-2'H-spiro[piperidine-4,5'-pyrano[3,2 -c]pyrazole]-7'(6'H)-one (I 3 )

[0114] According to the method of Example 1, the compound 2'-(tert-butyl)-2'H-spiro[piperidine-4,5'-pyrano[3,2-c]pyrazole]-7'( 6'H)-keto. Under ice bath conditions, 2'-(tert-butyl)-2'H-spiro[piperidine-4,5'-pyrano[3,2-c]pyrazole]-7'(6'H )-ketone (400mg, 1.1mmol), HATU (458mg, 1.2mmol), triethylamine (0.2ml, 1.2mmol) were dissolved in 10mL DMF, stirred at 0°C for 0.5h, added 2-(o-methylphenyl) Quinoline-4-carboxylic acid (1mmol, 265mg) was reacted at room temperature for 12h; the reaction solution was added to 50mL ice water, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was passed through a silica gel column Purified by chromatography to obtain the title compound I 3 .

[0115] Yellow solid, yield 75%, m.p.159....

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Abstract

The invention relates to an ACC inhibitor and medical application thereof, and belongs to the field of medicinal chemistry and pharmacotherapeutics. The compound as shown in the formula I, the isomeror the pharmaceutically acceptable salt thereof not only has good enzyme activity on ACC, but also has good antitumor activity, can be applied to preparation of antitumor drugs, and particularly has excellent application prospects in anti-lung cancer, anti-liver cancer or anti-breast cancer drugs.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and pharmacotherapeutics, and in particular relates to an ACC inhibitor and its application in preparing medicines for tumor-related diseases. Background technique [0002] Malignant tumor is an important disease that endangers human life, health and safety, and the mortality rate is extremely high in both developed and developing countries. According to the report of the World Health Organization, the number of cancer cases worldwide will reach 20 million in 2020, and the death toll will reach 12 million. The change of cell metabolism is one of the signs that tumor cells are different from normal cells, and it is also a factor for the abnormal and continuous proliferation of tumor cells. Among them, fatty acids are the main source of energy for tumor cells and the basic components of cell membranes. The increase in the synthesis rate of fatty acids is considered to be closely related to the oc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/20A61P35/00A61K31/4709A61K31/5377A61K31/496
CPCC07D491/20A61P35/00
Inventor 黄统辉吴鑫安琳印晓星
Owner 浙江永核药业科技有限公司
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