A kind of ACC inhibitor and its medicinal use

A pharmacy and drug technology, applied in the fields of medicinal chemistry and pharmacotherapeutics, can solve the problems of weak tumor cell activity and inability to meet clinical needs, and achieve excellent application prospects, significant in vitro proliferation inhibitory activity, and good anti-tumor activity.

Active Publication Date: 2022-07-26
浙江永核药业科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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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  • A kind of ACC inhibitor and its medicinal use
  • A kind of ACC inhibitor and its medicinal use
  • A kind of ACC inhibitor and its medicinal use

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 (120 mL) of tert-butylhydrazine hydrochloride (3.74 g, 30 mmol) and glyoxal (4.5 g, 25 mmol) was reacted at room temperature for 2 h; the reaction solution was extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and then reduced Concentrated under pressure to obtain compound (E)-1-(2-(tert-butyl)hydrazino)propan-2-one. (E)-1-(2-(tert-butyl)hydrazino)propan-2-one (8.8g, 62mmol) and 40% glyoxal solution (25mL, 180mmol) were dissolved in 100mL distilled water, heated 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-...

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)-ketone. 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 (1 mmol, 265 mg) was reacted at room temperature for 12 h; the reaction solution was added to 50 mL of 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 Chromatographic purification to obtain the title compound I 2 .

[0110] Yellow solid, yield 80...

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)-ketone. 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 (1 mmol, 265 mg) was reacted at room temperature for 12 h; the reaction solution was added to 50 mL of 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 Chromatographic purification to obtain the title compound I 3 .

[0115] Yellow solid, yield 75...

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Abstract

The invention relates to an ACC inhibitor and its medicinal use, belonging to the fields of medicinal chemistry and medicinal therapy. The compounds, isomers or pharmaceutically acceptable salts thereof shown in formula I provided by the present invention not only have good enzymatic activity on ACC, but also have good anti-tumor activity, and can be used in the preparation of anti-tumor drugs, In particular, it 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 drug therapy, in particular 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 World Health Organization, in 2020, the number of cancer cases worldwide will reach 20 million, and the number of deaths 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 of abnormal and continuous proliferation of tumor cells. Among them, fatty acid is the main source of tumor cell energy and the basic component of cell membrane, and the increase of its synthesis rate is considered to be closely related to the occurrence and development of tumor. In many cancers,...

Claims

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Application Information

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Patent Type & Authority Patents(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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