2-aminopyrimidine compounds as well as pharmaceutical compositions and applications thereof

一种化合物、氨基的技术，应用在化学医药领域，能够解决药代性质差、选择性差、不能解决药物耐药性临床压力等问题

Active Publication Date: 2016-05-25
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the current EGFR-TKI still cannot solve the clinical pressure caused by drug resistance, and most of the existing drugs are EGFR reversible or irreversible inhibitors based on quinazoline or quinoline amines. Toxic side effects caused by poor selectivity of wild-type cells are also inevitable
[0007] Therefore, there is an urgent need for new types of compounds in this field, especially compounds with novel frameworks to solve the problems of drug resistance, poor selectivity, and poor pharmacokinetic properties.

Method used

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  • 2-aminopyrimidine compounds as well as pharmaceutical compositions and applications thereof
  • 2-aminopyrimidine compounds as well as pharmaceutical compositions and applications thereof
  • 2-aminopyrimidine compounds as well as pharmaceutical compositions and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0192] (E)-N-((3-((5-chloro-4-((naphthalen-2-yl)amino))pyrimidin-2-yl)amino)-4-methoxyphenyl)-4-( Dimethylamino)-2-butenamide (CCB118563)

[0193]

[0194] Step 1.2, 5-Dichloro-N-(naphthalen-2-yl)pyrimidin-4-amine (2)

[0195] 2,4,5-Trichloropyrimidine (6g, 32.7mmol), 2-naphthylamine (4.92g, 34.4mmol), sodium carbonate (6.94g, 65.4mmol) were dissolved in absolute ethanol (100mL) and stirred overnight at room temperature . Ice water (300 mL) was added with stirring, and a large amount of solid precipitated out. Filter under reduced pressure and dry under vacuum to obtain a brown solid (8.38 g, yield 88%).

[0196] 1 HNMR (400MHz, DMSO-d6): δ9.74(s,1H), 8.42(s,1H), 8.09(d, J=1.6Hz, 1H), 7.95-7.86(m,3H), 7.73(d, J=8.8Hz, 1H), 7.54-7.47 (m, 2H).

[0197] MS(ESI): m / z291[M+H] + .

[0198] Step 2.5-Chloro-N 2 -(2-Methoxy-5-nitrophenyl)-N 4 -(Naphthyl-2-yl)pyrimidine-2,4-diamine (3)

[0199] Add 2,5-dichloro-N-(naphthalene-2-yl)pyrimidin-4-amine (2) (3g, 10.3mmol), 2-methoxy-5-nitroaniline...

Embodiment 2

[0211] (E)-N-((3-((5-chloro-4-((quinolin-6-yl)amino))pyrimidin-2-yl)amino)-4-methoxyphenyl)-4- (Dimethylamino)-2-butenamide (CCB145213)

[0212]

[0213] The synthesis method is as in Example 1.

[0214] 1 HNMR (400MHz, DMSO-d6): δ 9.85 (s, 1H), 9.00 (s, 1H), 8.73 (s, 1H), 8.39 (s, 1H), 8.27 (s, 1H), 8.18 (s, 1H), 8.07-8.01 (m, 2H), 7.98 (s, 1H), 7.87 (d, J = 8.8 Hz, 2H), 7.39 (m, 1H), 7.02 (d, J = 8.8 Hz, 1H), 6.64-6.58(m,1H), 6.12(d,J=15.6Hz,1H), 3.76(s,3H), 3.00(d,J=4.8Hz,2H), 2.14(s,6H).

[0215] MS(ESI); m / z504[M+H] + .

Embodiment 3

[0217] (E)-N-((3-((5-chloro-4-((quinolin-3-yl)amino))pyrimidin-2-yl)amino)-4-methoxyphenyl)-4- (Dimethylamino)-2-butenamide (CCB145221)

[0218]

[0219] The synthesis method is as in Example 1.

[0220] 1 HNMR(400MHz,DMSO-d6): δ9.81(s,1H),9.17(s,1H),9.15(d,J=2.4Hz,1H), 8.71(d,J=2.0Hz,1H), 8.28 (s, 1H), 8.19 (s, 1H), 7.97 (d, J = 2.0 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.60 (t,J=8.0Hz,1H), 7.56(dd,J=8.8Hz,2.4Hz,1H), 7.49(t,J=8.0Hz,1H), 7.01(d,J=8.8Hz,1H), 6.64-6.57(m,1H), 6.13(d,J=15.6Hz,1H), 3.76(s,3H), 3.01(d,J=5.6Hz,2H), 2.15(s,6H).

[0221] MS(ESI): m / z504[M+H] + .

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Abstract

The invention discloses 2-aminopyrimidine compounds as well as pharmaceutical compositions and applications thereof. The structure of the 2-aminopyrimidine compounds is shown in the formula I, definitions of R1, R2, R3, R4, R5, X, Y, Z and W in the formula are shown in the specification and the claim. The compounds can effectively inhibit growths of a plurality of tumor cells, generate inhibition effects for EGFR and IGF1R protease, and is used for preparing antitumor drugs; the compounds can overcome drug resistance which is induced by prior medicaments Gefitinib and Erlotinib and the like, has selectivity for tumor, especially wild type non-small cell lung cancers, and has good pharmacokinetics property.

Description

Technical field [0001] The invention belongs to the field of chemical medicine, and particularly relates to 2-aminopyrimidine compounds and their pharmaceutical compositions and applications. Background technique [0002] Tumor molecular targeted therapy is a treatment method that selectively kills tumor cells through chemical or biological means based on key molecules closely related to tumor growth. The characteristics of targeted therapy are: high specificity, strong selectivity, and mild side effects; when combined, it can enhance the efficacy of traditional chemotherapy and radiotherapy and reduce postoperative recurrence. Targeted tumor therapy is a hot spot and development trend of tumor therapy. [0003] Protein tyrosine kinases (PTKs) are a class of protein enzymes that can catalyze the phosphorylation of phenolic hydroxyl groups on tyrosine residues of a variety of important proteins, thereby activating the functions of functional proteins. Studies have shown that more ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/48C07D401/12C07D403/12C07D239/47A61K31/505A61K31/506A61K31/5377A61P35/00A61P35/02
CPCA61K31/505A61K31/506A61K31/5377C07D401/02C07D239/47C07D239/48C07D403/12A61K31/4523A61K31/53A61K31/551C07D401/12A61P35/00A61P35/02A61P43/00
Inventor 丁克丁健陈成斌耿美玉任小梅谢华涂正超陈奕
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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