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2, 4-diaminopyrimidine compound containing phenol fragment, preparation method, pharmaceutical compositions and use thereof

A technology of diaminopyrimidine and compound, which is applied to a class of 2,4-diaminopyrimidine compounds containing phenol fragments, their preparation, pharmaceutical compositions and application fields, can solve problems such as low activity, and achieve enhanced binding effect , Change the acidity and alkalinity, increase the effect of the site of action

Inactive Publication Date: 2018-01-16
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] At present, although there are many inhibitors against ALK kinase in clinical practice, few of them can effectively inhibit the G1202R mutation.
Judging from the results of in vitro activity, PF-06463922, which is in the second phase of clinical trials developed by Pfizer, has certain activity against the G1202R mutation, but the activity is not high

Method used

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  • 2, 4-diaminopyrimidine compound containing phenol fragment, preparation method, pharmaceutical compositions and use thereof
  • 2, 4-diaminopyrimidine compound containing phenol fragment, preparation method, pharmaceutical compositions and use thereof
  • 2, 4-diaminopyrimidine compound containing phenol fragment, preparation method, pharmaceutical compositions and use thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0056] Synthesis of Preparation Example 1 Compound S1

[0057]

[0058] Synthesis of intermediates 1-3:

[0059] Dissolve 1.2eq Boc-glycine (1-1) in 50ml of dry dichloromethane, add 2eq 2-(7-azobenzotriazole)-N,N,N',N' successively under ice-cooling -tetramethyluronium hexafluorophosphate (HATU), 2eq N-hydroxy-7-azabenzotriazole (HOAT), 1eq intermediate 1-2 and 5eq N,N-diisopropylethylamine ( DIPEA), raised to room temperature and stirred overnight, spin-dried dichloromethane, added ethyl acetate, extracted with 1N HCl, combined organic layers, washed with saturated sodium bicarbonate and sodium chloride successively, and dried over anhydrous sodium sulfate. Filtrate, spin dry and put on the column, petroleum ether: ethyl acetate = 2:1, the product 1-3 was obtained.

[0060] Synthesis of Intermediates 1-4:

[0061] Dissolve intermediate 1-3 in methanol, add 0.2eq palladium carbon (10% palladium content), and react overnight at room temperature after hydrogen replacement....

preparation Embodiment 2

[0076] Synthesis of Preparation Example 2 Compound S2

[0077]

[0078] The synthesis of compound S2 was the same as that of S1 except that intermediate 2-1 was used instead of intermediate 1-7.

[0079] 1 H NMR (300MHz, Methanol-d4) δ8.56(d, J=8.3Hz, 1H), 8.17(s, 1H), 8.06(s, 1H), 7.79(d, 1H), 7.65(d, J= 12.4Hz, 1H), 7.56(t, J=7.6Hz, 1H), 7.28–7.16(m, 3H), 7.06(t, J=7.5Hz, 1H), 6.46(s, 1H), 4.58(s, 2H), 3.36–3.33(m, 1H), 1.26(d, J=7.1Hz, 6H).

[0080] Synthesis of Intermediate 2-1:

[0081]

[0082] Synthesis of Intermediate 2-1-2:

[0083] Dissolve 1eq of raw material 2-1-1 in boron trifluoride ether solution, add 4eq of acetic acid, and reflux at 95°C for 3 hours under nitrogen protection. After the reaction is complete, add saturated sodium carbonate solution to quench, extract with ethyl acetate, and combine The organic layer was washed successively with saturated sodium bicarbonate and sodium chloride, and dried over anhydrous sodium sulfate. Filtrate, spin d...

preparation Embodiment 3

[0088] Synthesis of Preparation Example 3 Compound S3

[0089]

[0090] The synthesis of compound S3 was the same as that of S1 except that intermediate 3-1 was used instead of m-nitroaniline.

[0091] 1 H NMR (300MHz, Methanol-d4) δ8.56 (d, J = 8.5Hz, 1H), 8.14 (d, J = 2.5Hz, 1H), 7.81 (d, 1H), 7.61 (s, 1H), 7.55 (t, J=7.8Hz, 1H), 7.25(t, J=7.7Hz, 1H), 7.04(d, J=8.5Hz, 1H), 6.78(d, J=8.6Hz, 1H), 6.31(s ,1H), 4.59(s,3H), 4.17(s,2H), 3.27–3.12(m,2H), 1.22(d,J=6.9Hz,12H).

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Abstract

The invention discloses a 2, 4-diaminopyrimidine compound containing phenol fragment with a general formula I shown in the specification, pharmaceutically acceptable salts or pharmaceutically acceptable solvates, a preparation method thereof, pharmaceutical compositions containing the compounds, and use of the compounds in preparation of drugs for preventing or treating anaplastic lymphoma kinaserelated abnormal cell proliferation, morphological changes, hyperkinesia and other associated diseases in organisms, and angiogenesis or cancerometastasis associated diseases, especially use in drugsfor treating or preventing tumor growth and metastasis.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular, the invention relates to a class of 2,4-diaminopyrimidine compounds containing phenol fragments and pharmaceutically acceptable salts thereof, which have selective inhibitory activity on the mutation of anaplastic lymphoma enzyme G1202R Or a pharmaceutically acceptable solvate, a preparation method thereof, a pharmaceutical composition comprising the compound, and a pharmaceutical use of the compound. Background technique [0002] Anaplastic lymphoma enzyme (ALK) is a receptor tyrosine kinase that belongs to the insulin receptor superfamily. In 2011, the FDA approved the first multi-target inhibitor, crizotinib, for the treatment of advanced patients with ALK-rearranged non-small cell lung cancer (NSCLC). Although crizotinib has a response rate of 60%, resistance develops after one year, with secondary mutations accounting for one-third. In order to solve the problem of crizoti...

Claims

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Application Information

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IPC IPC(8): C07D239/48A61K31/505A61P35/00A61P35/04
Inventor 张翱耿美玉耿开俊艾菁彭霞
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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