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Substituted diaminopyrimidine compound, composition comprising compound and application of compound

A kind of technology of diaminopyrimidine and compound, applied in the field of medicine

Inactive Publication Date: 2016-11-23
SHENZHEN TARGETRX INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In addition, although EGFR inhibitors (EGFR-TKI) such as gefitinib and erlotinib have achieved remarkable curative effects against advanced NSCLC with EGFR mutations, primary drug resistance of EGFR-TKI in the treatment of NSCLC was subsequently discovered. Or secondary drug resistance, we are facing new challenges in the treatment of advanced NSCLC, and then carry out new explorations to find countermeasures

Method used

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  • Substituted diaminopyrimidine compound, composition comprising compound and application of compound
  • Substituted diaminopyrimidine compound, composition comprising compound and application of compound
  • Substituted diaminopyrimidine compound, composition comprising compound and application of compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] N-(3-(2-(4-acetylpiperazin-1-yl)2-d3-methoxyanilino)-5-trifluoromethylpyrimidinyl-4amino)phenyl was prepared according to the following synthetic route Acrylamide, i.e. compound 11 in the following synthetic route, i.e. the compound of synthetic formula (2);

[0043]

[0044] Take the following steps:

[0045] Step 1: Preparation of 3-(2-chloro-5-trifluoromethyl)pyrimidine-4-aminophenyl tert-butyl ester (compound 3);

[0046] equipped with a magnetic stirrer, N 2 Add n-butanol (9mL) into a 50mL three-necked flask with a bulb and a thermometer, cool in an ice-water bath, keep the internal temperature not exceeding 5°C, add 3-N-Boc-aniline (0.96g, 4.6mmol), slowly add 2,4 -Dichloro-5-trifluoromethylpyrimidine (1.0g, 4.6mmol), then N,N-diisopropylethylamine (0.67g, 5.5mmol) was slowly added dropwise into the reaction solution, and the mixture was iced Stir in a water bath for 1 h, then stir at room temperature for 4 h. A large amount of white solid formed was filtere...

Embodiment 2

[0063] The following synthetic route was used to prepare N-(3-(2-(4-d3-acetylpiperazin-1-yl)2-methoxyanilino)-5-trifluoromethylpyrimidinyl-4 amino)benzene Acrylamide (compound 15), the compound of synthetic formula (3);

[0064]

[0065] Take the following steps:

[0066] Step 1: The synthesis of compounds 12, 13, and 14 was synthesized with reference to compounds 9, 10, and 11 of Example 1, wherein the spectrum of compound 14 is: 1 HNMR(300MHz,DMSO-d6)δ(ppm):10.16(s,1H),8.65(br s,1H),8.29(s,1H),8.08(s,1H),7.76(br s,1H), 7.55-7.48(m,2H),7.27(t,J=8.1Hz,1H),7.17-7.14(m,1H),6.60(d,J=2.7Hz,1H),6.49-6.40(m,1H) ,6.28-6.21(m,2H),5.78-5.74(m,1H),3.77(s,3H),3.44(t,J=4.8Hz,4H),3.00(t,J=4.8Hz,4H), 1.43(s,9H).LC-MS(APCI):m / z=614.2(M+1) + ,purity: 96.1%.

[0067] Step 2: Preparation of N-(3-(2-(4-d3-acetylpiperazin-1-yl)2-methoxyanilino)-5-trifluoromethylpyrimidinyl-4amino)phenyl Acrylamide (compound 15)

[0068] Add tert-butyl-4-(4-(4-(3-acrylamidophenylamino)-5-trifluoromethylp...

Embodiment 3

[0071] The following synthetic route was used to prepare N-(3-(2-(4-acetyl-d8-piperazin-1-yl)2-methoxyanilino)-5-trifluoromethylpyrimidinyl-4-amino) Phenylacrylamide (compound 19), the compound of synthetic formula (4);

[0072]

[0073] According to the method described in Example 1, the difference is that this example uses N-acetyl-d8-piperazine instead of N-acetylpiperazine, thereby obtaining the target compound 19, 1 HNMR(300MHz,DMSO-D6)δ(ppm):10.52(s,1H),9.79(br s,1H),9.33(br s,1H),8.51(br s,1H),7.85(s,1H) ,7.62(d,J=8.1Hz,1H),7.45-7.42(m,1H),7.36(t,J=8.1Hz,1H),7.13-7.10(m,1H),6.77(s,1H), 6.58-6.49(m,1H),6.47-6.22(m,2H),5.78-5.74(m,1H),3.80(s,3H),2.06(s,3H).LC-MS(APCI):m / z=564.2(M+1) + ,purity: 97.2%.

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Abstract

The invention provides substituted diaminopyrimidine compound, a composition comprising the compound and application of the compound. The substituted diaminopyrimidine compound is diaminopyrimidine compound shown as in formula (I) or its crystal-form pharmaceutically acceptable salts and prodrugs, and stereoisomer, hydrate or solvent compound. The substituted diaminopyrimidine compound disclosed herein and the composition comprising the compound have excellent inhibitory action on EGFR (epidermal growth factor receptor) kinase, have better pharmacokinetics parameter characteristics, and can increase the drug concentration of the compound in an animal body to provide improved drug therapeutic effect and safety.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a substituted diaminopyrimidine compound, a composition containing the compound and an application thereof. Background technique [0002] Epidermal growth factor receptors, EGFR, ErbB-1, and HER1 are members of the ErbB receptor family, which are four closely related receptor tyrosine kinases EGFR (ErbB-1), HER2 / c-neu ( ErbB-2), a subfamily of Her3 (ErbB-3) and Her4 (ErbB-4). EGFR is a cell surface receptor for a member of the epidermal growth factor family (EGF family) of extracellular protein ligands. Mutations that affect EGFR expression or activity can lead to cancer. EGFR has been reported to be unregulated in most solid tumors such as lung, breast and brain tumors. An estimated 30% of epithelial cancers are associated with mutations, amplifications or dysregulation of EGFR or family members. [0003] Treatments based on inhibition of EGFR by antibody drugs ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/48A61K31/506A61P35/00A61P29/00A61P37/02A61P31/12A61P9/00A61P3/00A61P37/06
CPCA61K31/506C07D239/48C07B2200/05
Inventor 王义汉李焕银
Owner SHENZHEN TARGETRX INC
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