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Thieno[3,2-d]pyrimidine derivatives, and preparation method, medicinal composition and use thereof

A compound and pharmaceutical technology, applied in the fields of a class of thieno[3,2-d]pyrimidine derivatives, their preparation, pharmaceutical compositions and uses, can solve the problems of low cell activity and restricted development and the like

Inactive Publication Date: 2019-09-06
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

[0003] Menin-MLL1 protein-protein interaction inhibitors are potential tumor therapeutic compounds. Although their molecular activity has reached hundreds of nM levels reported in the literature, their cellular activity is low, which limits their further development.

Method used

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  • Thieno[3,2-d]pyrimidine derivatives, and preparation method, medicinal composition and use thereof
  • Thieno[3,2-d]pyrimidine derivatives, and preparation method, medicinal composition and use thereof
  • Thieno[3,2-d]pyrimidine derivatives, and preparation method, medicinal composition and use thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0066] Preparation Example 1 Compound 4a

[0067]

[0068] Dissolve compound 6a (200.0mg, 0.73mmol) and compound 7 (226.0mg, 2.19mmol) in DMF (5mL), add dropwise N,N-diisopropylethylamine (250.0mL, 1.44mmol), and react Stir the solution at 90°C overnight, spot the plate to confirm the complete reaction of the raw materials, wash the reaction solution with tertiary methyl ether and saturated brine, collect the organic phase and dry it with anhydrous sodium sulfate, concentrate the organic phase to dryness, and separate and purify the reaction product with silica gel column 4a (63.0 mg, 0.18 mmol), yield: 24%.

[0069] 1 H NMR (400MHz, deuterated chloroform) δ8.32(s,1H,),7.53–7.46(m,1H),7.10(d,J=7.0Hz,1H),6.93(d,J=8.5Hz,1H ),6.33(s,1H),4.91(dd,J=12.1,5.4Hz,1H),3.76(t,J=6.8Hz,1H),3.70(s,2H),3.37(q,J=6.6Hz ,2H),2.48(t,J=7.0Hz,2H),2.42(t,J=7.4Hz,1H),2.23–2.08(m,2H).

Embodiment 1

[0070] Example 1 Compound 2-1a

[0071]

[0072] Compound 4a (10.0 mg, 27.83 μmol) and compound 3a (13.1 mg, 33.70 μmol) were prepared according to literature methods: Ren, J.; Xu, W.; Tang, L.; Su, M.; Chen, D.; Chen, Y.-L.; Zang, Y.; Li, J.; Shen, J.; Zhou, Y.; Xiong, B., BioorgMed Chem Lett 2016, 26(18), 4472-4476) in DMF (1mL), add N,N-diisopropylethylamine (3.9μl, 22.26μmol), EDC (5.1mg, 26.58μmol), HOBT (3.6mg, 26.44μmol), react overnight at room temperature, spot the plate to confirm the reaction of raw materials Completely, with DCM, H 2 O washed the reaction solution, collected the organic phase and dried it with anhydrous sodium sulfate, concentrated the organic phase to dryness, and separated and purified by silica gel preparative thin-layer chromatography to obtain compound 2-1a (1.5 mg, 2.30 μmol), yield: 8%.

[0073] 1 H NMR (400MHz, deuterated chloroform) δ8.47(s, 1H), 7.52–7.47(m, 1H), 7.08(d, J=9.8Hz, 2H), 6.97(dt, J=8.5, 4.7Hz, 1H), 6.34(t, J=5.5Hz, 1H...

preparation Embodiment 2

[0074] Preparation Example 2 Compound 7a

[0075]

[0076] Take compound 8 (10.0g, 39.58mmol, prepared according to the literature method: Nat.Chem.Biol.2012,8,277) and compound 6a (13.1g, 79.16mmol) in a reaction flask, add a mixture of isopropanol and water solution (80mL, 1:1, V / V), and N,N-diisopropylethylamine (40.0mL, 237.00mmol) was added dropwise to the reaction solution, and the above system was stirred overnight at 60°C. Spot the plate to confirm that the raw materials have reacted completely, add DCM (50mL) to the reaction solution, wash the reaction solution with saturated sodium bicarbonate solution (30mL) and saturated saline solution (30mL) successively, collect the organic phase and dry it with anhydrous sodium sulfate. The phase was concentrated to dryness, separated and purified by silica gel column to obtain white amorphous solid 7a (9.9 g, 28.67 mmol), yield: 72.4%.

[0077] 1 H NMR (400MHz, deuterated chloroform) δ8.47(s, 1H), 7.10(s, 1H), 5.23(d, J=8...

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Abstract

The present invention provides compounds represented by formula 1, or pharmaceutically acceptable salts thereof, and also provides a preparation method and a use thereof. Immunosuppressive agents suchas pomalidomide or lenalidomide, and a Menin-MLL1 protein-protein interaction inhibitor are combined by a suitable linker, so the obtained compounds have a certain Menin-MLL1 protein-protein interaction inhibition activity and a good cell proliferation inhibition activity.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a class of thieno[3,2-d]pyrimidine derivatives or pharmaceutically acceptable salts thereof, their preparation methods, pharmaceutical compositions and applications. The thieno[3,2-d]pyrimidine derivatives d] Pyrimidine derivatives show certain Menin-MLL1 protein-protein interaction inhibitory activity and better cell proliferation inhibitory activity, exceeding the cell proliferation inhibitory activity of Menin-MLL1 protein-protein interaction inhibitors reported in the literature. [0002] technical background [0003] Menin-MLL1 protein-protein interaction inhibitors are potential tumor therapeutic compounds. Although their molecular activity has reached hundreds of nM levels reported in the literature, their cellular activity is low, which limits their further development. Contents of the invention [0004] Since Menin-MLL1 protein-protein interaction inhibitor...

Claims

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Application Information

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IPC IPC(8): C07D495/04A61K31/519A61P35/00
CPCC07D495/04
Inventor 沈竞康李佳熊兵周宇波陈越磊陈丹琦陈亚宾王晓文李聪宋宁
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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