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Pteridinone derivatives and applications as flt3 inhibitors

A technology of medicine and use, applied in pteridone derivatives, the application field of medicine, can solve problems such as unsatisfactory clinical effect and the like

Active Publication Date: 2020-08-14
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

So far, no FLT3 inhibitor has been approved for clinical use, and the clinical effects of many FLT3 inhibitors in clinical trials are still not ideal

Method used

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  • Pteridinone derivatives and applications as flt3 inhibitors
  • Pteridinone derivatives and applications as flt3 inhibitors
  • Pteridinone derivatives and applications as flt3 inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0143] 1) Synthesis of 8-(4-aminophenyl)-2-(4-methoxy-2-methylphenyl)-7(8H)-pteridinone (F-1)

[0144] ① Synthesis of (4-aminophenyl) tert-butyl carbamate

[0145]

[0146] Weigh p-phenylenediamine (890mg, 8.23mmol) and put it in a 100mL round bottom flask, add 40mL of dichloromethane, stir under ice bath, and take di-tert-butyl dicarbonate (449mg, 2.06mmol) and dissolve it in dichloromethane In the middle, it was added dropwise to the above reaction solution, and then continued to stir overnight at room temperature. After the reaction was completed, the solvent was removed by rotary evaporation, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate=3:1, v / v) to obtain 398 mg of tert-butyl (4-aminophenyl)carbamate, with a yield of 93 %.

[0147] 1 H NMR (400MHz, CDCl 3 ): δ7.14(d, J=8.0Hz, 2H), 6.65(d, J=8.4Hz, 2H), 6.26(s, 1H), 1.52(s, 9H). Melting point 112-113℃, literature value [97] 112-114°C.

[0148] ②Synthesis of...

Embodiment 2

[0227] The synthesis steps of compound 1 are as follows, and the synthesis of compound 2-31 is carried out with reference to the synthesis of compound 1:

[0228] Synthesis of (S)-3-((2-chloro-5-nitropyrimidine)4-amino)pyrrolidine-1-carboxylic acid tert-butyl ester

[0229]

[0230] Weigh 2,4-dichloro-5-nitropyrimidine (3.23g, 16.28mmol) into a 250mL low-temperature reaction flask, add 80mL of dichloromethane to dissolve, stir and cool at -70°C, and take another (S)-1 - tert-butoxycarbonyl-3-aminopyrrolidine (3.03g, 16.28mmol), N,N-diisopropylethylamine (2.52g, 19.53mmol) were dissolved in 20mL of dichloromethane, and added dropwise to the above reaction solution After the dropwise addition was completed, the mixture was stirred at -70°C for 0.5 hour, followed by TLC until the raw material was completely converted. The solvent was removed by rotary evaporation, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate=12:1, v / v)...

Embodiment 3

[0250] Biological Activity Test Section

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Abstract

The present invention relates to a pteridinone derivative serving as an FLT3 inhibitor, and uses thereof. Specifically, the present invention relates to a compound represented by formula (I), a pharmaceutical composition containing the compound represented by formula (I), and uses of the compound in the preparation of drugs for treating diseases mediated by FLT3 or for inhibiting the FLT3: (I).

Description

technical field [0001] The invention relates to the field of medicinal chemistry; specifically, the invention relates to a novel pteridinone derivative, its synthesis method and its application as an FLT3 inhibitor in the preparation of drugs for tumors and immune diseases. Background technique [0002] Protein tyrosine kinase (protein tyrosine kinase) is a class of proteins that catalyze the transfer of γ-phosphate on ATP to specific amino acid residues in proteins. It plays a very important role in intracellular signal transduction pathways and regulates cell growth, A series of physiological processes such as differentiation and death. It has been shown that more than 50% of proto-oncogenes and their products have protein tyrosine kinase activity, and their abnormal expression will lead to the disorder of cell life cycle, and then lead to the occurrence of tumors. In addition, abnormal expression of tyrosine kinases is also closely related to tumor metastasis and chemoth...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D475/00A61K31/519A61P35/00A61P37/02A61P17/00A61P17/06A61P35/02A61P19/02A61P29/00A61P1/00A61P19/08A61P3/10A61P21/04A61P5/14A61P7/06A61P1/16A61P27/02A61P37/06A61P37/08A61P11/02
CPCC07D475/00A61K31/519
Inventor 李洪林徐玉芳陈卓孙德恒吕剑昆赵振江宋文琳周伟杨宇
Owner EAST CHINA UNIV OF SCI & TECH
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