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A class of thieno[3,2-d]pyrimidine derivatives, its preparation method, pharmaceutical composition and use

A compound and a pharmaceutical technology are applied in the fields of a class of thieno[3,2-d]pyrimidine derivatives, their preparation, pharmaceutical compositions and uses, which can solve the problems of limited development and low cell activity, and achieve good cell proliferation. Inhibitory effect

Inactive Publication Date: 2021-08-17
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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  • A class of thieno[3,2-d]pyrimidine derivatives, its preparation method, pharmaceutical composition and use
  • A class of thieno[3,2-d]pyrimidine derivatives, its preparation method, pharmaceutical composition and use
  • A class of thieno[3,2-d]pyrimidine derivatives, its preparation method, pharmaceutical composition and use

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0065] Preparation Example 1 Compound 4a

[0066]

[0067] 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%.

[0068] 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

[0069] Example 1 Compound 2-1a

[0070]

[0071] 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., Bioorg Med Chem Lett 2016, 26(18), 4472-4476) in Add N,N-diisopropylethylamine (3.9μl, 22.26μmol), EDC (5.1mg, 26.58μmol), HOBT (3.6mg, 26.44μmol) to DMF (1mL), react overnight at room temperature, spot plate to confirm the raw material The reaction is complete, 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%.

[0072] 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

[0073] Preparation Example 2 Compound 7a

[0074]

[0075] 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%.

[0076] 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 a compound represented by formula 1 or a pharmaceutically acceptable salt thereof, as well as its preparation method and application. The present invention combines an immunosuppressant, such as bomalidomide or lenalidomide, with Menin-MLL1 protein The -protein interaction inhibitor is combined with an appropriate linker arm, and the obtained compound shows certain Menin-MLL1 protein-protein interaction inhibitory activity and better cell proliferation inhibitory 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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Patent Type & Authority Patents(China)
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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