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Pyrazole carboxamide derivative and preparation method and application thereof

A technology of pyrazole carboxamide and derivatives, applied in the field of chemical medicine, can solve the problems of high toxicity, poor effect, non-single target point and the like

Pending Publication Date: 2022-07-01
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, so far, no mitochondrial electron transport chain complex I inhibitor has been approved for clinical tumor treatment at home and abroad.
At present, the existing mitochondrial complex I inhibitors include rotenone, fenopterine A, etc., but these inhibitors have problems such as high toxicity, multiple targets, and poor preclinical effects

Method used

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  • Pyrazole carboxamide derivative and preparation method and application thereof
  • Pyrazole carboxamide derivative and preparation method and application thereof
  • Pyrazole carboxamide derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Example 1. Preparation of 1-(3-bromobenzyl)-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (intermediate 1a)

[0045]

[0046] 300 mg (2.0 mmol) of raw material ethyl 3-methylpyrazole-5-carboxylate and 220 mg (4.0 mmol) of potassium hydroxide were placed in 5 ml of anhydrous tetrahydrofuran (THF), and 750 mg of m-bromobenzyl bromide (3.0 mg) was added dropwise under reflux. mmol) in THF, after monitoring the reaction by TLC, the reaction solution was cooled to room temperature, poured into a separatory funnel, extracted with ethyl acetate and saturated brine for 2-3 times, the organic phase was collected and washed with anhydrous Na 2 SO 4 It was dried, filtered, concentrated and purified by column chromatography, eluted with petroleum ether / ethyl acetate (10:1), to obtain 478 mg of a pale yellow oil with a yield of 74%. 1 H NMR (400MHz, DMSO-d 6 )δ7.48-7.46(m,1H),7.31-7.29(m,2H),7.11-7.09(m,1H),6.59(s,1H),5.42(m,2H),4.24(q,J= 7.1Hz, 2H), 2.24(s, 3H), 1.26(t, J=...

Embodiment 2

[0047] Example 2. Preparation of ethyl 1-(3-bromobenzyl)-1H-pyrazole-3-carboxylate (intermediate 1b)

[0048]

[0049] 280 mg (2.0 mmol) of raw material 3-ethoxycarbonylpyrazole and 220 mg (4.0 mmol) of potassium hydroxide were placed in 5 ml of anhydrous tetrahydrofuran (THF), and a solution of 750 mg (3.0 mmol) of m-bromobenzyl bromide in THF was added dropwise under reflux. , after monitoring the reaction by TLC, the reaction solution was cooled to room temperature, poured into a separatory funnel, extracted with ethyl acetate and saturated brine for 2-3 times, the organic phase was collected and washed with anhydrous Na 2 SO 4 It was dried, filtered, concentrated and purified by column chromatography, eluting with petroleum ether / ethyl acetate (10:1), to obtain 462 mg of a pale white solid with a yield of 75%. 1 H NMR (400MHz, DMSO-d 6 )δ7.43-7.41(m,2H),7.36(d,J=7.5Hz,1H),7.22-7.19(m,2H),6.82(d,J=7.5Hz,1H),5.38(m,2H) ), 4.39(q, J=7.1Hz, 2H), 1.39-1.32(m, 3H).

Embodiment 3

[0050] Example 3. Preparation of 1-(3-bromobenzyl)-5-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester (intermediate 1c)

[0051]

[0052] The raw material 5-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester 432 mg (2.0 mmol) and potassium hydroxide 220 mg (4.0 mmol) were placed in 5 ml of anhydrous tetrahydrofuran (THF), and m-benzyl bromide was added dropwise under reflux. A solution of bromine 750 mg (3.0 mmol) in THF, after monitoring the completion of the reaction by TLC, the reaction solution was cooled to room temperature, poured into a separatory funnel, extracted with ethyl acetate and saturated brine for 2-3 times, the organic phase was collected and washed with anhydrous Na 2 SO 4 It was dried, filtered, concentrated and purified by column chromatography, eluted with petroleum ether / ethyl acetate (10:1), to obtain 500 mg of pale yellow oil with a yield of 65%. 1 H NMR (400MHz, DMSO-d 6 )δ7.50(s, 1H), 7.42-7.23(m, 8H), 7.11(s, 1H), 5.40(m, 2H), 4.39(q, J=7.1Hz, 2H...

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Abstract

The invention belongs to the field of chemical medicines, and discloses a pyrazolecarboxamide derivative, which has a structure of a general formula I or pharmaceutically acceptable salt or solvate thereof, in the formula, X, Y and Z are C or N; the definition of each group is shown in the specification. Wherein most of the compounds have a remarkable inhibition effect on the mitochondrial complex I, and show a strong in-vivo and in-vitro anti-tumor effect on tumor cell strains such as human colorectal cancer cell strains (HCT116 and HCT15). The technical problem to be solved by the invention is that no inhibitor for targeting the mitochondrial complex I is used clinically at present. According to the scheme for solving the technical problem, the pyrazolecarboxamide derivative is provided, has a brand-new structure, remarkably inhibits the activity of a mitochondrial complex I, is high in malignant tumor resisting activity and has great value in development of malignant tumor treating drugs.

Description

technical field [0001] The invention belongs to the field of chemical medicine, and in particular relates to a pyrazolecarboxamide derivative and a preparation method and application thereof. Background technique [0002] Small molecule targeted anti-tumor drugs have become a hot spot and trend in tumor drug research and development in recent years due to their clear efficacy and high safety, which can achieve precise treatment for tumor patients. [0003] Tumor cells have significant features of energy metabolism reprogramming, especially mitochondria play an important role in both energy metabolism and material metabolism of tumor cells. Mitochondrial Electron Transport Chain (ETC) is an important basis for mitochondria to regulate energy metabolism. Mitochondrial complex I (Complex I), also known as NADH:ubiquinone oxidoreductase, is an important part of mitochondrial ETC. It facilitates cellular energy production by transferring electrons from NADH to ubiquinone and tra...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D231/14C07D401/12C07D401/10C07D403/10C07D405/12A61P35/00A61K31/4439A61K31/496A61K31/454A61K31/415A61K31/5377A61K31/4155A61K31/541
CPCC07D231/14C07D401/12C07D401/10C07D403/10C07D405/12A61P35/00
Inventor 赵瀛兰周扬罗有福
Owner SICHUAN UNIV
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