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Diaminopyrimidine compound and composition containing same

一种二氨基嘧啶、化合物的技术，应用在医药领域，能够解决视觉障碍、肝转氨酶水平升高、胃肠道副作用等问题

Inactive Publication Date: 2018-12-07
SHENZHEN TARGETRX INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, crizotinib has side effects such as visual disturbance, gastrointestinal side effects, and grade 3-4 elevated liver transaminase levels in 16% of cases

Method used

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  • Diaminopyrimidine compound and composition containing same
  • Diaminopyrimidine compound and composition containing same
  • Diaminopyrimidine compound and composition containing same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0095] Prepare 5-chloro-N according to the following synthetic route 4 -[2-(Dimethylphosphoryl)phenyl]-N 2 -{2-d3-methoxy-4-[4-(4-methylpiperazin-1-yl)-piperidin-1-yl]phenyl}pyrimidine-2,4-diamine (synthesized below Compound 9 in the scheme):

[0096]

[0097] Prepared using the following steps:

[0098] (1) Preparation of compound 2:

[0099] Add 30mL of acetone to a 100mL single-necked bottle, and add 5-fluoro-2-nitrophenol (2.0g, 12.7mmol), anhydrous potassium carbonate (3.5g, 25.4mmol), deuteroiodomethane (2.4g, 16.5mmol), heated to 60°C and kept stirring for 2h. After cooling to room temperature, the acetone was evaporated by rotary evaporation, the residue was added to 20 mL of water, extracted with ethyl acetate (30 mL x 3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 2.0 g of a white solid with a yield of 90%.

[0100] 1 H NMR (300MHz, CDCl 3 )(δ / ppm)8.00-7.95(m,1H),6.83-6.71(m,2...

Embodiment 2

[0113] Prepare 5-chloro-N according to the following synthetic route 4 -[2-(Dimethylphosphoryl)phenyl]-N 2 -{2-methoxy-4-[4-(4-d3-methylpiperazin-1-yl)-piperidin-1-yl]phenyl}pyrimidine-2,4-diamine (synthesized below Compound 15 in the scheme):

[0114]

[0115] Include the following steps:

[0116] (1) Preparation of Compound 10:

[0117] Add N,N-dimethylformamide (10mL) into a 100mL single-necked flask, and add 4-fluoro-2-methoxynitrobenzene (2g, 11.8mmol) and piperidin-4-one hydrochloride in sequence under stirring (2.23g, 16.5mmol), anhydrous potassium carbonate (4.88g, 35.4mmol), the reaction mixture was warming up to 80 ° C, N 2 react overnight under atmosphere. Cooled to room temperature, poured into ice water (80mL), precipitated a large amount of yellow solid, filtered, dissolved in DCM (100mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 2.2g of yellow solid, yield 74.6%.

[0118] LC-MS(APCI):m / z=251.2(M+1) + ; 1...

Embodiment 3

[0131] Prepare 5-chloro-N according to the following synthetic route 4 -[2-(Dimethylphosphoryl)phenyl]-N 2 -{2-methoxy-4-[4-(4-methylpiperazin-1-yl)-4-d-piperidin-1-yl]phenyl}pyrimidine-2,4-diamine (under Compound 20 in the above synthetic route):

[0132]

[0133] Include the following steps:

[0134] (1) Preparation of compound 16:

[0135] Add 10 mL of deuterated methanol into a 50 mL single-necked flask, add 1-(3-methoxy-4-nitrophenyl)piperidin-4-one (0.25 g, 1 mmol) under stirring in an ice-water bath, and slowly Add deuterated sodium borohydride (42mg, 1mmol), ice water bath N 2 Stir the reaction under atmosphere for 5 min, add heavy water (2 mL) to quench the reaction, and stir at room temperature for 30 min, add water (30 mL) and ethyl acetate (30 mL) successively, separate the organic layer, and extract the aqueous layer with ethyl acetate (30 mL x 2) , concentrated, the residue was redissolved in ethyl acetate (50 mL), washed with saturated brine (20 mL x 1),...

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Abstract

The invention provides a diaminopyrimidine compound and a composition containing the same. The invention discloses the diaminopyrimidine compound represented by a formula (I) and pharmaceutical composition containing the compound, or a crystal form, pharmaceutically acceptable salt, hydrate or solvate, a stereisomer, prodrug or an isotope variant of the compound. The diaminopyrimidine compound andthe composition containing the diaminopyrimidine compound have excellent inhibition capability to protein kinase and simultaneously have relatively good pharmacokinetic parameter properties, the drugconcentration in an animal body can be increased, and the treatment effect and safety of the drug are improved.

Description

[0001] This application is a divisional application of an invention patent application with an application date of July 22, 2016, an application number of 201610587472.0, and an invention title of "a diaminopyrimidine compound and a composition containing the compound". technical field [0002] The invention belongs to the technical field of medicine, in particular to a diaminopyrimidine compound and a composition containing the compound. Background technique [0003] In the past 30 years, the mortality rate of lung cancer has increased by 465%, and the incidence rate has increased by 26.9% every year. It has become the first cause of death from malignant tumors in my country. Among them, non-small cell lung cancer (NSCLC) accounts for more than 80% of all lung cancers, only one-third of NSCLC patients have the opportunity for surgical treatment, and about 70% of patients are locally advanced at the time of treatment Or distant metastasis occurs, and the chance of surgery is...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6558A61K31/675A61P35/00A61P9/10A61P29/00A61P37/02A61P31/12A61P3/00A61P37/06C07B59/00
CPCC07F9/65583A61P37/02A61P9/10A61P3/00A61P31/12A61P37/06A61P29/00A61P35/00C07B59/004C07B2200/05A61K31/505C07D239/28
Inventor 王义汉李焕银
Owner SHENZHEN TARGETRX INC
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