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2-(2,4,5-substituted phenylamino)pyrimidine derivative as well as preparation method and application thereof to preparation of anti-tumor drug

A technology of pyrimidine derivatives and anti-tumor drugs, which is applied in the field of medicine, can solve the problems of lack of allylamine modification, and achieve the effects of high selectivity, inhibitory activity and low toxicity

Active Publication Date: 2018-05-18
HENAN GENUINE BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Existing research lacks partial modification of allylamine

Method used

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  • 2-(2,4,5-substituted phenylamino)pyrimidine derivative as well as preparation method and application thereof to preparation of anti-tumor drug
  • 2-(2,4,5-substituted phenylamino)pyrimidine derivative as well as preparation method and application thereof to preparation of anti-tumor drug
  • 2-(2,4,5-substituted phenylamino)pyrimidine derivative as well as preparation method and application thereof to preparation of anti-tumor drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Embodiment 1. Preparation of intermediate compound (1):

[0023]

[0024] Intermediate Compound (1) was prepared according to the method disclosed in International Patent WO 2013 / 01448. Its derivatives can also be prepared in a similar manner.

Embodiment 2

[0025] Example 2. Preparation of compound (III) and analogs:

[0026]

[0027] 187mg, (2mmol) CH 2 Cl 2 (5mL) solution was added to CH containing compound 1 (802mg, 1.8mmol) and N,N-diisopropylethylamine (DIPEA) (0.14mL, 4.2mmol) at 0°C 2 Cl 2 (5 mL) solution. The mixture was stirred at room temperature for 2 hours, washed with water, Na 2 SO 4 After drying, the solvent was evaporated and the residue was separated by silica gel column chromatography (0-10% 7N NH 3 MeOH / CH 2 Cl 2 ) to obtain compound III (754 mg, yield 83%). H-NMR (DMSO-d 6 ):2.22(6H,s),2.28(2H,t),2.73(3H,s),2.87(2H,t),3.85(3H,s),3.93(3H,s), 7.02(1H,s) ,7.16(1H,t),7.21-7.26(2H,m),7.52(1H,d),7.92(1H,s),8.23(1H,d),8.34(1H,d),8.67(1H,s ),9.12(1H,s),10.23(1H,s).m / z:503ES + [M+H] + ..

[0028] Using the same method as in Example 1, the following corresponding products were prepared with differently substituted acryloyl chlorides: compound (IV):

[0029]

[0030] Yield 81%. H-NMR (DMSO-d 6 ):2.2...

Embodiment 4

[0043] Embodiment 4. the mesylate salt (X) of preparation compound III

[0044]

[0045] Compound III (5.03g, 10mmol) was added to a 100mL flask containing EtOH (30mL) and EtOAc (20mL), and a solution of methanesulfonic acid (1.12g, 10mmol) in EtOAc (10mL) was added dropwise at room temperature within 30 minutes. After the addition was complete, the mixture was stirred at room temperature for 2 hours. After filtration, the filter cake was washed once with EtOAc / EtOH (2:1, v / v), and dried to obtain a yellow solid X (4.9 g, yield 80%).

[0046] The preparation of the mesylate (XI) of compound IV is the same as above: compound IV and methanesulfonic acid generate yellow solid XI with a yield of 85%.

[0047]

[0048] The X-ray powder diffraction of the crystalline form of the compound of formula XI has characteristic peaks and their relative intensities (%) at the following diffraction angles 2θ:

[0049]

[0050] X-ray powder diffraction (XRPD) of compound XI crystal:...

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Abstract

The invention discloses a novel 2-(2,4,5-substituted phenylamino)pyrimidine derivative as well as a preparation method and application thereof to preparation of an anti-tumor drug and belongs to the field of medicines. The novel 2-(2,4,5-substituted phenylamino)pyrimidine derivative has a structure shown as a general formula (I): (the formula (I) is shown in the description), wherein in the formula (I), R is independently selected from methyl and deuterated (D) methyl and can be the same or different at the same time; R1 is independently selected from H, D, methyl, C2 to C5 alkyl, Cl and F, Brand CF3; R2 is independently selected from H and D and can be the same or different at the same time. The compound or pharmaceutically acceptable salt thereof or a composition thereof is applied to preparation of a drug for treating cancers, and has advantageous physical properties (such as relatively high permeability and / or relatively low plasma protein binding) and relatively high selectivityand relatively low toxic characteristics; especially, the compound has a very good application prospect in the aspect of treating non-small-cell lung cancer.

Description

technical field [0001] The invention relates to a novel 2-(2,4,5-substituted anilino)pyrimidine compound and a pharmaceutically acceptable salt thereof, belonging to the field of medicine. Background technique [0002] Lung cancer is the number one killer of tumors, and about 85% of them are advanced non-small cell lung cancer. For a long time, chemotherapy with platinum-based agents was the only option for treating advanced non-small cell lung cancer (NSCLC). This treatment method increases overall survival (OS) of patients to some extent, but only has a response rate of 20% and a median survival time of 8-10 months. After a certain period of chemotherapy, cancer cells develop drug resistance due to new mutations. Among patients with lung adenocarcinoma, about 15% of Caucasians and 30-50% of East Asians have EGFR gene mutations. For those East Asians who have never smoked, the proportion is as high as 50-60%. EGFR, also called HER1 or ErbB1, is one of the four members o...

Claims

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Application Information

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IPC IPC(8): C07D403/04A61P35/00
Inventor 常俊标杜锦发
Owner HENAN GENUINE BIOTECH CO LTD
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