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Diaminopyrimidine compound and composition containing same

A technology of diaminopyrimidine and compounds, applied in the field of medicine, can solve problems such as visual impairment, elevated liver transaminase levels, and gastrointestinal side effects

Active Publication Date: 2016-12-07
SHENZHEN TARGETRX INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] However, crizotinib can cause the following side effects: visual disturbances, 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. Cool to room temperature, spin evaporate the acetone, add 20 mL of water to the residue, extract with ethyl acetate (30 mL x 3), combine the organic layers, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain 2.0 g of 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,2H), LC-MS(APCI):m / z=175.2(M+1) + ,95%.

[0101] (2) P...

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]

[0134] Include the following steps:

[0135] (1) Preparation of compound 16:

[0136] 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, extract the aqueous layer with ethyl acetate (30 mL x 2), concentrate , the residue was redissolved in ethyl acetate (50 mL), washed with saturated brine (20 m...

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Abstract

The invention provides a diaminopyrimidine compound and a composition containing the same and discloses the diaminopyrimidine compound shown as in a formula (I) and a drug combination containing the compound or salt thereof acceptable in crystal form and pharmacy, hydrate or solvent complex, stereoisomer, pro-drug or isotope variant. The diaminopyrimidine compound and the composition containing the same have excellent inhibition effect on protein kinase and have better pharmacokinetic parameter characteristics, and drug concentration of the compound in animal bodies can be increased to improve drug efficacy and safety.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to a diaminopyrimidine compound and a composition containing the compound. Background technique [0002] 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 lost. In this case, drug treatment is particularly important. Anaplastic lymphoma kinase (ALK) gene fusion has recently become an important biomarker, which can help patients in specific NSCLC subgroups to select and treat with corresponding inhibitors. The Internationa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6558A61K31/675A61P35/00A61P9/00A61P29/00A61P31/00A61P37/00A61P37/06A61P31/12A61P3/00
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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