A nitrogen-containing condensed heterocyclic compound, its preparation method, composition and application

A compound and fused heterocycle technology, applied in the field of nitrogen-containing fused heterocycle compounds, can solve the problems of large clinical side effects, poor selectivity, low specificity, etc.

Active Publication Date: 2019-05-17
上海医药集团(本溪)北方药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The purpose of the present invention is to overcome the defect that the existing cell cycle regulators in the prior art show relatively large clinical side effects due to reasons such as low specificity and poor selectivity, or the defect that although the selectivity is high but the activity is not good, and Provided are a nitrogen-containing fused heterocyclic compound, a pharmaceutically acceptable salt thereof, and their enantiomers, diastereoisomers, tautomers, solvates, metabolic precursors or prodrugs, Its preparation method, its pharmaceutical composition and application

Method used

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  • A nitrogen-containing condensed heterocyclic compound, its preparation method, composition and application
  • A nitrogen-containing condensed heterocyclic compound, its preparation method, composition and application
  • A nitrogen-containing condensed heterocyclic compound, its preparation method, composition and application

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0141] Embodiment 1' (preparation of intermediate):

[0142]

[0143] first step:

[0144] 2,6-dichloro-4-methylnicotine nitrile (5g, 26.7mmol) (compound shown in formula 1-a) was placed in a sealed tube, and tert-butylamine (3.12mL, 29.4mmol) and DIPEA were added thereto (5.3mL, 32.1mmol), heated to 120°C for 18h. After the reaction, the reaction solution was cooled to room temperature, the reaction solution was diluted with ethyl acetate, washed with water, the organic phase was dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA=80:20 elution) to obtain 1.77 g of white solid (compound as shown in formula 1-b). 1 H-NMR (400MHz, CDCl 3 ):δ=6.15(1H,s),5.00(1H,s),2.37(3H,s),1.44(9H,s).LC-MS m / z:(M+H) + = 224.10.

[0145] Step two:

[0146] 6-(tert-butylamino)-2-chloro-4-methylnicotine nitrile (1.77g, 7.94mmol) (compound shown in formula 1-b) was dissolved in 40mL of glacial acetic acid, and the solution was added dropwise Bromi...

Embodiment 2

[0153] Embodiment 2' (preparation of intermediate):

[0154]

[0155] first step:

[0156] Dissolve sodium hydride (1.092g, 27.3mmol) in 25ml of anhydrous tetrahydrofuran, add diethyl cyanomethyl phosphate (2.66ml, 16.38mmol) to it under the protection of argon at 0°C, react at room temperature for 0.5h, and then add Add 1-(4-amino-2-(methylthio)pyrimidin-5-yl)ethanone (1g, 5.46mmol) (compound shown in formula I-16-e) dissolved in 5ml THF, room temperature React overnight. After the reaction was completed, water was slowly added to the reaction liquid to quench, and then extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, filtered, evaporated to dryness, purified by silica gel column chromatography (DCM:MeOH=97:3 washing off), to obtain 635 mg of yellow solid (compound shown in formula 2-a). 1 H-NMR (400MHz, d-DMSO): δ = 8.93 (1H, s), 7.33 (2H, s), 6.54 (1H, d, J = 1.2Hz), 2.51 (3H, s), 2.48 (3H, d,J=0.8Hz).LC-MS m / z:(M+H) + =207.00...

Embodiment 3

[0161] Embodiment 3' (preparation of intermediate):

[0162]

[0163] first step:

[0164] 1-(4-amino-2-(methylthio)pyrimidin-5-yl)ethanone (1g, 5.46mmol) (compound as shown in formula I-16-e) was dissolved in ethyl acetoacetate (3ml , 27.85mmol), heated to 180°C for 3h, after the reaction, cooled to room temperature, added 10ml of ethyl acetate to the reaction solution, filtered the insoluble solid, and dried to obtain 1.069g of yellow solid (as shown in formula 3-a compound of). 1 H-NMR (400MHz, d-DMSO): δ=12.60(1H,s), 9.02(1H,s), 2.58(3H,s), 2.44(3H,s), 2.34(3H,s).LC- MS m / z: (M+H) + =250.05.

[0165] Step two:

[0166] 6-acetyl-5-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (0.353g, 1.42mmol) (as shown in formula 3-a The compound) was dissolved in phosphorus oxychloride (3ml, 32.77mmol), heated to 110°C to react overnight, after the reaction was completed, cooled to room temperature, evaporated to dryness, the residue was dissolved in saturated sodium bic...

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Abstract

The invention discloses a nitrogen-containing fused heterocycle compound shown by a formula I, a pharmaceutically acceptable salt thereof, or enantiomers, diastereoisomers, tautomers, solvates, metabolic precursors or prodrugs of the nitrogen-containing fused heterocycle compound and the pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the nitrogen-containing fused heterocycle compound and an application of the nitrogen-containing fused heterocycle compound. The nitrogen-containing fused heterocycle compound disclosed by the invention has relatively good antitumor activity.

Description

technical field [0001] The present invention specifically relates to a nitrogen-containing condensed heterocyclic compound, its preparation method, composition and application. Background technique [0002] Cyclin-dependent kinase (CDK) is a kind of serine (Ser) / threonine (Thr) kinase, as an important signal transduction molecule in cells, and CDK-cyclin formed by cyclin Complex, involved in cell growth, proliferation, dormancy or apoptosis. Cell cycle regulatory proteins play an important role in the regulation of cell proliferation. In tumor cells, the abnormality of cyclins and CDKs in G1 phase is the most frequent, and there may be multiple mechanisms involved in these changes. These changes often lead to tumorigenesis through the activation of oncogenes and the silencing of tumor suppressor genes. Malignant cells affect the expression of cell cycle regulatory proteins through genetic and epigenetic mechanisms, resulting in overexpression of cyclins and loss of express...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/14C07D519/00A61K31/5377A61K31/519A61K31/541A61K31/551A61P35/00
CPCY02P20/55
Inventor 万惠新许志勇石辰李春丽许振民夏广新马珂李玉峰
Owner 上海医药集团(本溪)北方药业有限公司
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