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Coumarin compounds as well as preparation method and application thereof

A technology of coumarins and compounds, applied in the field of medicine

Active Publication Date: 2021-06-11
南京易腾药物研究院有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Except for MLN4924, no other NEDD8 activating enzyme inhibitors have entered clinical trials, and no NEDD8 activating enzyme inhibitors have been marketed. Therefore, finding and developing new NEDD8 activating enzyme inhibitors will be of great significance for cancer treatment

Method used

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  • Coumarin compounds as well as preparation method and application thereof
  • Coumarin compounds as well as preparation method and application thereof
  • Coumarin compounds as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Example 1: 8-cyclopentyl-2-(4-(phenethylamino)piperidin-1-yl)-6-(3,4-dimethylphenyl)pyrido[2,3-d ] Synthesis of pyrimidin-7-one (compound 1).

[0053]

[0054] synthetic route:

[0055]

[0056] Step 1 Synthesis of compound 1-1: Add the raw material 4-chloro-2-methylthiopyrimidine-5-carboxylate ethyl ester (36.5g, 156.9mmol) into a 500mL round bottom flask, dissolve it in 300mLTHF, and then add cyclopentyl Amine (20.0 g, 235.3 mmol) and triethylamine (31.8 g, 313.8 mmol) were stirred at room temperature for 1 h, and the reaction was complete. Filtrate, remove THF by distilling off the filtrate under reduced pressure, add 300mL ethyl acetate to dissolve, and use saturated NH 4 Cl solution was washed (200mL*3), then washed with saturated brine (200mL*3), and the organic phase was washed with anhydrous Na 2 SO 4 After drying and filtering, the filtrate was evaporated under reduced pressure to remove the solvent, and then 20 mL of toluene was added and concentrate...

Embodiment 2

[0075] Example 2: 8-cyclopentyl-2-(4-(phenethylamino)piperidin-1-yl)-6-phenylpyrido[2,3-d]pyrimidin-7-one (compound 2 ) Synthesis.

[0076]

[0077] synthetic route:

[0078]

[0079] Referring to the preparation method of Example 1, the difference is that compound 1-11 is reacted with phenylboronic acid to obtain compound 2-1, and then compound 2-1 is reacted with trifluoroacetic acid to obtain compound 2.

[0080] 1 H NMR (500MHz, CDCl 3 )δ: 9.73(s, 1H), 8.42(s, 1H), 7.60(d, J=7.5Hz, 2H), 7.49(s, 1H), 7.39(t, J=7.5Hz, 2H), 7.22- 7.34(m, 4H), 7.17(d, J=7Hz, 2H), 5.89(t, J=8.8Hz, 1H), 4.98(d, J=13.5Hz, 2H), 3.30(s, 1H), 3.20 (s,2H),2.94-3.05(m,4H),2.37(s,2H),2.20(d,J=5Hz,2H),2.01(s,2H),1.78(q,J=13.7Hz,4H ), 1.64(d,J=4Hz,2H).

[0081] HRMS(ESI)(m / z):494.2911[M+H] + , calculated for C 31 h 35 N 5 O,493.28382.

Embodiment 3

[0082] Example 3: 8-cyclopentyl-6-(4-fluoro-3-methylphenyl)-2-(4-(phenethylamino)piperidin-1-yl)pyrido[2,3- d] Synthesis of pyrimidin-7-one (compound 3).

[0083]

[0084] synthetic route:

[0085]

[0086] Referring to the preparation method of Example 1, the difference is that compound 3-1 is obtained by reacting compound 1-11 with 4-fluoro-3-methylphenylboronic acid. Compound 3-1 is then reacted with trifluoroacetic acid to obtain compound 3.

[0087] 1 H NMR (500MHz, CDCl 3 )δ:9.73(s,1H),8.42(s,1H),7.44(t,J=6.5Hz,2H),7.37(d,J=5Hz,1H), 7.22-7.31(m,3H),7.17 (d, J=7Hz, 2H), 7.02(t, J=9Hz, 1H), 5.88(t, J=9Hz, 1H), 4.98(d, J=13.5Hz, 2H), 3.30(s, 1H) ,3.20(s,2H),3.02(q,J=8.7Hz,2H),2.96(d,J=12.5Hz,2H),2.36(q,J=6.2Hz,2H), 2.31(d,J= 10Hz, 3H), 2.21(d, J=11.5Hz, 2H), 2.01(s, 2H), 1.76-1.84(m, 4H), 1.64(d, J=5Hz, 2H).

[0088] HRMS(ESI)(m / z):526.2981[M+H] + , calculated for C 32 h 36 FN 5 O,525.29083.

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Abstract

The invention discloses coumarin compounds with different general formula structures and pharmaceutically acceptable salts, solvates, polymorphic substances, tautomers, metabolites or prodrugs thereof. The invention also discloses an effect of the compound as an NEDD8 activating enzyme inhibitor and an application of the compound in preparation of drugs for treating diseases related to NEDD8 activating enzyme abnormality. The invention also discloses an intermediate for preparing the coumarin compound and a preparation method thereof. Pharmacological results show that the compound has high NEDD8 inhibitory activity, tumor cell proliferation resistance and tumor cell apoptosis promotion effects.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a coumarin compound and its preparation method and application. Background technique [0002] Malignant tumors are a large class of common multiple diseases that seriously endanger human health, with a high fatality rate, second only to cardiovascular and cerebrovascular diseases. According to the statistics of the World Health Organization, about 8.2 million people died of cancer in the world in 2012, and it is estimated that the number of people who died of cancer will exceed 11 million in 2030. China is a country with a high incidence and mortality rate of cancer, which causes economic losses of hundreds of billions of yuan every year, and with the aging of the population, the deterioration of the ecological and living environment, this trend is more likely to intensify. Therefore, finding effective drugs for the treatment of tumors has attracted much attention. [0003] ...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/519A61P35/00
CPCC07D471/04A61P35/00
Inventor 陆鹏王亮张英王玉斌
Owner 南京易腾药物研究院有限公司
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