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cdk4/6 inhibitor, its pharmaceutical composition, preparation method and application

A technology of inhibitors and compositions, applied in drug combinations, pharmaceutical formulations, anti-tumor drugs, etc., can solve the problems of low anti-cancer activity and high toxicity, and achieve the effect of excellent activity

Active Publication Date: 2021-05-14
SHANGHAI SCIENPHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] However, the currently reported CDK4 / 6 kinase inhibitors still have the disadvantages of low anticancer activity and high toxicity.

Method used

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  • cdk4/6 inhibitor, its pharmaceutical composition, preparation method and application
  • cdk4/6 inhibitor, its pharmaceutical composition, preparation method and application
  • cdk4/6 inhibitor, its pharmaceutical composition, preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Example 1. 3-acetyl-1-cyclopentyl 7-((2-hydroxyethyl)(5-(piperazin-1-yl)pyridin-2-yl)amino)-4-methylquinoline -2(1H)-Kone (CDK4 / 6-01)

[0058]

[0059] Add 4-(6-((6-(1-butoxyvinyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido) to a 250ml three-necked flask [2,3-d]pyrimidin-2-yl)amino)tert-butyl)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester 10.0g (16.6mmol), N,N-dimethylformamide 80mL, potassium carbonate 9.2g (66.6mmol), potassium iodide 1.0g, stir, heat up to 50-60°C, add 4.0g (23.9mmol) of 2-bromoethyl acetate, keep the reaction at 90°C, and follow the reaction by LCMS, if The reaction is not complete, you can add an appropriate amount of cesium carbonate and 2-bromoethyl acetate until 4-(6-((6-(1-butoxyvinyl)-8-cyclopentyl-5-methyl -7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)tert-butyl)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester reaction complete , filtered, the filter cake was washed with an appropriate amount of DMF, adde...

Embodiment 2

[0062] Example 2. N-(3-acetyl-1-cyclopentyl-4-methyl-2-oxo-1,2-dihydroquinolin-7-yl)-N-(5-(piperazine -1-yl)pyridin-2-yl)sodium glycinate (CDK4 / 6-02)

[0063]

[0064] Add 4-(6-((6-(1-butoxyvinyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido [2,3-d]pyrimidin-2-yl)amino)tert-butyl)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester 6g (9.94mmol), potassium carbonate 4.14g (29.9mmol), N , N-dimethylformamide 40mL, ethyl bromoacetate 3.48g (20.8mmol), the temperature was raised to 60~90°C, and the reaction was tracked by LCMS until 4-(6-((6-(1-butoxyvinyl )-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)tert-butyl)pyridin-3-yl ) tert-butyl piperazine-1-carboxylate reacts completely, cools down to room temperature, adds water and ethyl acetate, stirs and separates liquids, extracts the aqueous phase with ethyl acetate once, combines the organic phases, washes the organic phases with water three times, and saturates Washed with brine three ...

Embodiment 3

[0067] Example 3. 3-acetyl-1-cyclopentyl-7-(ethyl(5-(piperazin-1-yl)pyridin-2-yl)amino)-4-methylquinoline-2(1H )-ketone (CDK4 / 6-03)

[0068]

[0069]Add 4-(6-((6-(1-butoxyvinyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido [2,3-d]pyrimidin-2-yl)amino)tert-butyl)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester 10.0g (16.6mmol), potassium carbonate 8.0g (57.9mmol), N,N-Dimethylformamide 100ml, stir, heat up to 40-50°C, add 1.5ml iodoethane, keep warm for reaction, LCMS to track the reaction, if the reaction is not complete, add iodoethane until 4-(6 -((6-(1-butoxyvinyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2- base) amino) tert-butyl) pyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester reacted completely, filtered, added water and ethyl acetate to the filtrate, stirred and separated, and the aqueous phase was extracted once with ethyl acetate, Combine the organic phases, wash the organic phase twice with water, wash once with s...

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Abstract

The invention discloses a CDK4 / 6 inhibitor, its pharmaceutical composition, preparation method and application, and belongs to the field of medicine. The CDK4 / 6 inhibitor, its pharmaceutically acceptable salt, hydrate, and solvent are in an inert solvent, and the compound of formula (a) is condensed with the corresponding active reagent to obtain the intermediate of formula (b), and then in acid Or under the action of base, deprotect to obtain the compound of formula (I). In addition, the application of a CDK4 / 6 inhibitor represented by formula (I), its pharmaceutically acceptable salt, hydrate, solvate, metabolic precursor or prodrug in the preparation of drugs for preventing or treating tumors is also disclosed . The CDK4 / 6 inhibitor provided by the invention has excellent anti-CDK4 / 6 activity and can be used to prepare various antitumor drug preparations.

Description

technical field [0001] The invention relates to the field of pharmacy, in particular to a CDK4 / 6 inhibitor, its pharmaceutical composition, preparation method and application. Background technique [0002] The occurrence of cancer and other diseases is related to the imbalance of various oncogenes and tumor suppressor genes. The functions and effects of almost all oncogenes and tumor suppressor genes are in the process of cell growth cycle. Therefore, it can be said that cancer is a cell cycle disease (CCD), and regulating or blocking abnormal cell cycle is one of the ways to treat cancer. [0003] Among the molecules that have been found related to cell cycle regulation, cyclin-dependent protein kinases (cyclin-dependent protein kinases, Cdks) are protein kinases that play a key role in cell cycle regulation. name. There are three main types of cyclin-dependent protein kinases in eukaryotic cells. [0004] CDKs are a group of serine (Ser) / threonine (Thr) protein kinases ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12C07D471/04A61P35/00A61K31/496A61K31/519
CPCA61P35/00C07D401/12C07D471/04Y02P20/55
Inventor 谢军姜春阳李惠张艳李红昌许全胜
Owner SHANGHAI SCIENPHARM CO LTD