4-{6-[5-(2-chlorinde-6- methylaniline formyl)-thiazole-2-amido]-2-methyl pyrimidine-4}-piperazine-1- diethyl methylphosphate

A technology of diethyl methyl phosphate and methyl aniloyl, which is applied to compounds of group 5/15 elements of the periodic table, organic active ingredients, organic chemistry, etc., to achieve high bioavailability and obvious anti-tumor activity Effect

Active Publication Date: 2008-12-17
CHIA TAI TIANQING PHARMA GRP CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Although people have found many small molecule tyrosine kinase inhibitors, such as WO9903854, WO2004005281, WO0062778, WO2005013983 have made great contributions to this field, but in order to improve anti-cancer and immune disorders drugs, this field is still researching

Method used

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  • 4-{6-[5-(2-chlorinde-6- methylaniline formyl)-thiazole-2-amido]-2-methyl pyrimidine-4}-piperazine-1- diethyl methylphosphate
  • 4-{6-[5-(2-chlorinde-6- methylaniline formyl)-thiazole-2-amido]-2-methyl pyrimidine-4}-piperazine-1- diethyl methylphosphate
  • 4-{6-[5-(2-chlorinde-6- methylaniline formyl)-thiazole-2-amido]-2-methyl pyrimidine-4}-piperazine-1- diethyl methylphosphate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Example 1. Benzyl 4-(diethoxyphosphorylmethyl)-piperazine-1-carboxylate

[0046]

[0047] 2.2 g (10 mmol) piperazine-1-carboxylate benzyl ester and 1.38 g (10 mmol) diethyl phosphite and 1 ml of 37% formaldehyde and 120 ml of benzene were placed in a 250 ml flask and heated to reflux to After the reaction is complete, cool down, spin off the solvent, add ethyl acetate to dissolve, wash with sodium bicarbonate solution, wash with water, wash with salt, dry over anhydrous sodium sulfate, spin off the solvent, and separate with a short column to obtain the product 4-(diethoxyphosphorylmethyl Benzyl)-piperazine-1-carboxylate. 1 HNMR (300MHz, D-acetone), δ (ppm): 7.36 (m, 5H, ArH), 5.10 (s, 2H, ArH), 4.08 (m, 4H, 2OCH 2 ), 3.45(t, 4H, 2NCH 2 ), 2.60(t, 4H, 2NCH 2 ), 2.78 (s, 1H, CH 2 ), 2.74 (s, 1H, CH 2 ), 1.26(t, 6H, 2CH 3 ).FABMS: (M+1) + =371.

Embodiment 2

[0048] Example 2. Diethyl piperazine-1-methylphosphate

[0049]

[0050] Dissolve 370 mg (1 mmol) of benzyl 4-(diethoxyphosphorylmethyl)-piperazine-1-carboxylate in 25 ml of tetrahydrofuran / ethanol (1:1) mixed solvent, add palladium carbon (10 %, 180 mg), 40-50 ℃ normal pressure hydrogenation overnight, after the hydrogenation is complete, filter, and spin off the solvent to obtain the product piperazine-1-methyl diethyl phosphate. 1 HNMR (300MHz, D-acetone), δ (ppm): 4.09 (m, 4H, 2OCH 2 ), 2.85(t, 4H, 2NCH 2 ), 2.64(t, 4H, 2NCH 2 ), 2.74 (s, 1H, CH 2 ), 2.70 (s, 1H, CH 2 ), 1.27(t, 6H, 2CH 3 ).FABMS: (M+1) + =237.

Embodiment 3

[0051] Example 3.4-(6-Chloro-2-methylpyrimidin-4-yl)-piperazine-1-methyl diethyl phosphate

[0052]

[0053] Dissolve 236 mg (1 mmol) of piperazine-1-methyldiethylphosphate and 243 mg (1.5 mmol) of 2-methyl-4,6-dichloropyrimidine in 20 mL of anhydrous 1,4-di Add 130 mg (1 mmol) of diisopropylethylamine to oxyhexane, heat and reflux and stir until the raw materials disappear, spin off the solvent, add ethyl acetate to dissolve, wash with sodium bicarbonate solution, wash with water, and dry over anhydrous sodium sulfate. The liquid product 4-(6-chloro-2-methylpyrimidin-4-yl)-piperazine-1-methylphosphoric acid diethyl ester was obtained by spin-off solvent short column separation. 1 H NMR (300MHz, CDCl 3 ), δ (ppm) 6.30 (s, 1H, ArH), 4.12 (m, 4H, 2OCH 2 ), 3.64(t, 4H, 2NCH 2 ), 2.83 (s, 1H, CH 2 ), 2.79 (s, 1H, CH 2 ), 2.70(t, 4H, 2NCH 2 ), 2.45(s, 3H, CH 3 ), 1.31(t, 6H, 2CH 3 ). FABMS: (M+1) + =363.

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Abstract

The invention relates to a chemical compound of 4-(6-(5-(2-chlorine-6-methylaniline formoxyl)-thiazole-2-amido)-2-methylpyrimidine-4)-piperazine-1-methyl triethyl phosphate shown in general formula I, salts thereof for medical purposes, hydrates and solvates thereof, polycrystals and eutectic crystals thereof, precursors or derivatives thereof with the same biological function, a preparation method thereof, a composition containing one or more chemical compounds and the application of the chemical compound in the treatment of diseases relating to protein tyrosine kinase, such as immune disorder and oncology diseases.

Description

technical field [0001] The present invention relates to 4-{6-[5-(2-chloro-6-methylanilinoyl)-thiazole-2-amino]-2-methylpyrimidine-4}-piperazine-1 shown in formula I - diethyl methyl phosphate, its pharmaceutically acceptable salts, its hydrates and solvates, its polycrystals and co-crystals, its biologically functional precursors or derivatives, and processes for their preparation, containing one or more of these Composition of compounds, and use of the compounds in treating diseases related to protein tyrosine kinases, such as immune disorders and tumor diseases. Background technique [0002] In recent years, due to the amazing progress in the study of the molecular mechanism of tumor development, the research of new drugs has turned to specific molecular biological targets that play a role in the etiology and pathology of cancer (Science, 1993, 260 (5110), 918-919). (Science, 1995, 267(5205), 1782-1787). Studies have shown that more than 80% of oncogenes and proto-oncog...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6558A61K31/675A61P35/00
CPCY02P20/55
Inventor 冯志强李永强陈晓光刘鹤苏富琴
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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