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CDKs inhibitor of beta-carboline parent nucleus and preparation method and anti-tumor application of CDKs inhibitor

A carboline and reaction technology, which is applied in the field of organic compound synthesis and pharmaceutical applications, can solve the problems of neutropenia, anemia or diarrhea, etc., and achieve the goal of inhibiting tumor-bearing growth, simple synthesis method, and inhibiting tumor cell migration and invasion Effect

Active Publication Date: 2022-04-22
GENERAL HOSPITAL OF THE NORTHERN WAR ZONE OF THE CHINESE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Despite the good response to these three drugs, adverse effects such as neutropenia, fatigue, often anemia, or diarrhea often occur after a period of administration

Method used

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  • CDKs inhibitor of beta-carboline parent nucleus and preparation method and anti-tumor application of CDKs inhibitor
  • CDKs inhibitor of beta-carboline parent nucleus and preparation method and anti-tumor application of CDKs inhibitor
  • CDKs inhibitor of beta-carboline parent nucleus and preparation method and anti-tumor application of CDKs inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Methyl 9H-pyrido[3,4-b]indole-1-carboxylate (compound 2)

[0036] In a 500ml round bottom flask was added tryptamine (compound 1, 3g, 18.72mmol), methyl glycolate (2.53g, 28.09mmol), IBX (15.73g, 56.17mmol) and 200ml ethyl acetate. After reflux for 36h, filter. The filtrate was concentrated and purified by column chromatography, and the crude product was recrystallized from PE / EA to give 2 as a yellow solid (36% yield). 1H NMR (600MHz, DMSO-d6) δ11.65(s, 1H), 8.48(d, J=4.9Hz, 1H), 8.41(d, J=4.9Hz, 1H), 8.30(d, J=7.8Hz ,1H),7.79(d,J=8.2Hz,1H),7.63–7.59(m,1H),7.30(t,J=7.5Hz,1H),4.02(s,3H).ESI-MS:m / z 227.1[M+H] + .

Embodiment 2

[0038] 9H-pyrido[3,4-b]indole-1-carboxylic acid (compound 3)

[0039] Compound 2 (0.9g, 4mmol) was added in a 50ml round bottom flask, and 15ml of hydrolyzate was added (hydrolyzate composition: C 2 h 5 OH 175ml, H 2 O 75ml, NaOH 15g). Reflux at 80°C for 1 hour, cool, add 2 mmol / L hydrochloric acid aqueous solution with stirring in an ice bath, and adjust the pH value to 3. Suction filtration gave a yellow solid (compound 3) (yield 96.89%). 1 H NMR (600MHz, DMSO-d 6 )δ11.84(s,1H),8.48(d,J=5.2Hz,1H),8.44(d,J=5.2Hz,1H),8.34(d,J=7.9Hz,1H),7.83(d, J=8.3Hz,1H),7.65–7.60(m,1H),7.34–7.29(m,1H).ESI-MS:m / z 213.1[M+H] + .

Embodiment 3

[0041] 5-(4-Methylpiperazin-1-yl)pyridinecarbonitrile (Compound 6)

[0042] Compound 4 (1g, 7.25mmol), Compound 5 (7.25mmol), X-Phos (0.73mmol), Pd 2 (dba) 3 (0.15mmol), K 3 PO 4 (14.5mmol) and 30ml of ethylene glycol dimethyl ether were added to a 100ml round bottom flask. Under the protection of nitrogen, the reaction was refluxed for 24 h, the solvent was evaporated to dryness under reduced pressure, and the yellow oily compound 6 was obtained by column chromatography (yield 36.26%). 1 H NMR (600MHz, CDCl 3 )δ8.27(d,J=3.0Hz,1H),7.47(d,J=8.8Hz,1H),7.06(dd,J=8.8,3.0Hz,1H),3.40–3.32(m,4H), 2.59–2.50(m,4H),2.32(s,3H).ESI-MS: m / z 203.1[M+H] + .

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Abstract

The invention relates to a preparation method of a CDKs inhibitor of a beta-carboline parent nucleus and an anti-tumor application of the CDKs inhibitor, and particularly provides a novel beta-carboline derivative with CDKs inhibition activity, an application of the novel beta-carboline derivative in anti-tumor, and a preparation method of the compound. The synthesis method is simple and mild; the compound disclosed by the invention can effectively inhibit CDK4, and has the activities of resisting tumor cell proliferation activity, inhibiting tumor cell migration and invasion, inducing tumor cell apoptosis, inhibiting nude mouse subcutaneous tumor-bearing growth and the like. Therefore, the compound as a lead compound plays an important role in tumor treatment.

Description

technical field [0001] The invention belongs to the technical field of organic compound synthesis and medical application, and specifically relates to a CDKs inhibitor of β-carbomorph core, a preparation method thereof and an anti-tumor application. Background technique [0002] Cyclin-dependent kinases (CDKs) are a group of serine / threonine protein kinases belonging to the CMGC family. According to their function, CDKs in mammals can be divided into 3 subfamilies related to cell cycle (CDK1, CDK4 and CDK5) and 5 subfamilies related to transcription (CDK7, CDK8, CDK9, CDK11 and CDK20). Kinases play important roles in the cell cycle and transcription. Cyclic and transcriptional abnormalities are the basic characteristics of tumor cells, so inhibiting CDKs can interfere with the cycle and transcription of tumor cells, thereby leading to apoptosis or death of tumor cells. In recent years, CDKs have become a popular target in the development of tumor drugs, and three CDK4 inhi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/437A61K31/4709A61K31/444A61K31/496A61P35/00
CPCC07D471/04A61P35/00
Inventor 赵庆春李德平许子华刘文武
Owner GENERAL HOSPITAL OF THE NORTHERN WAR ZONE OF THE CHINESE PEOPLES LIBERATION ARMY
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