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Double-target PARP/EZH2 inhibitor as well as preparation method and application thereof

A dual-target, inhibitor technology, applied in pharmaceutical formulations, medical preparations containing active ingredients, bulk chemical production, etc.

Active Publication Date: 2021-06-25
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But 80% of TNBC patients do not have BRCA mutations, these patients can only choose chemotherapy

Method used

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  • Double-target PARP/EZH2 inhibitor as well as preparation method and application thereof
  • Double-target PARP/EZH2 inhibitor as well as preparation method and application thereof
  • Double-target PARP/EZH2 inhibitor as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0031] Compound (I-1): nitrogen-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3)methyl)-3-(6-(4-(2-fluoro- 5-((4-oxo-3,4-phthalazinyl-1)methyl)benzoyl)piperazine-1-)pyridine-3)-3-amino-2-methylbenzamide. Yield 52%.mp: 192-194°C; 1 H NMR (500MHz, DMSO-d 6 )δ(ppm): 12.61(s, 1H), 11.48(s, 1H), 8.33(d, J=2.5Hz, 1H), 8.27(d, J=7.5Hz, 1H), 8.02(t, J= 2.5Hz, 1H), 7.99(m, 1H), 7.90(t, J=7.5Hz, 1H), 7.85(t, J=7.5Hz, 1H), 7.74(m, 1H), 7.46-7.39(m, 2H), 7.26(t, J=9.0Hz, 1H), 6.90(d, J=9.0Hz, 1H), 6.87(d, J=2.5Hz, 1H), 6.67(d, J=2.5Hz, 1H, 5.86(s, 1H), 5.04(s, 2H), 4.35(s, 2H), 4.26(d, J=7.5Hz, 2H), 3.75-3.73(m, 2H), 3.67-3.65(m, 2H) , 3.52-3.49(m, 2H), 3.31-3.28(m, 2H), 2.20(s, 3H), 2.11(s, 3H), 2.02(s, 3H); 13 C NMR (125MHz, DMSO-d 6 )δ (ppm): 164.46, 163.98, 163.05, 159.40, 157.75, 156.42 (C, d, J C-F =202.5Hz), 149.39, 147.53, 145.00, 144.90, 138.80, 135.59, 134.86 (C, d, J C-C-C-C-F =2.5Hz), 133.53, 131.73 (C, d, J C-C-C-F =7.5Hz), 131.60, 129.10, 129.00 (C, d, J C-C-C-F =2.5Hz)...

example 2

[0033] Compound (I-2): nitrogen-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3)methyl)-3-(6-(4-(2-fluoro- 5-((4-oxo-3,4-phthalazinyl-1)methyl)benzoyl)piperazine-1-)pyridine-3)-3-ethylamino-2-methylbenzamide. Rate: 53%.mp: 192-194°C; 1 H NMR (500MHz, DMSO-d 6 )δ(ppm): 12.61(s, 1H), 11.47(s, 1H), 8.42(d, J=2.5Hz, 1H), 8.27(t, J=5.0Hz, 1H), 8.04(t, J= 5.0Hz, 1H), 7.98(d, J=5.0Hz, 1H), 7.91(t, J=7.5Hz, 1H), 7.86(t, J=7.5Hz, 1H), 7.61(s, 1H), 7.46 -7.40(m, 2H), 7.26(t, J=9.0Hz, 1H), 6.90(d, J=9.0Hz, 1H), 6.68(d, J=9.0Hz, 2H), 5.86(s, 1H) , 4.35(s, 2H), 4.27(d, J=2.5Hz, 2H), 3.75-3.73(m, 2H), 3.67-3.65(m, 2H), 3.52-3.49(m, 2H), 3.31-3.28 (m, 2H), 2.80(d, J=5.0Hz, 3H), 2.69(s, 1H), 2.20(s, 3H), 2.10(s, 3H), 2.03(s, 3H); 13 CNMR (125MHz, DMSO-d 6 )δ (ppm): 169.51, 163.98, 163.03, 159.40, 157.74, 156.42 (C, d, J C-F =202.5Hz), 149.39, 147.24, 145.23, 144.91, 142.67, 138.63, 135.90, 135.13, 134.86 (C, d, J C-C-C-C-F =2.5Hz), 133.54, 131.73 (C, d, J C-C-C-F =7.5Hz), 131.62, 129.10, ...

example 3

[0035] Compound (I-3): nitrogen-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3)methyl)-3-(6-(4-(2-fluoro- 5-((4-Oxo-3,4-phthalazinyl-1)methyl)benzoyl)piperazine-1-)pyridine-3)-3-acetamido-2-methylbenzamide. Yield: 50%.mp: 220-222°C; 1 H NMR (500MHz, DMSO-d 6 )δ(ppm): 12.61(s, 1H), 11.49(s, 1H), 9.44(s, 1H), 8.41(d, J=2.5Hz, 1H), 8.28(t, J=5.0Hz, 1H) , 7.98(d, J=5.0Hz, 1H), 7.91(t, J=7.5Hz, 1H), 7.85(t, J=7.5Hz, 2H), 7.61(s, 1H), 7.46-7.40(m, 2H), 7.29(s, 1H), 7.25(t, J=9.0Hz, 1H), 6.92(d, J=9.0Hz, 1H), 5.87(s, 1H), 4.35(s, 2H), 4.31( d, J=2.5Hz, 2H), 3.75-3.73(m, 2H), 3.67-3.65(m, 2H), 3.52-3.49(m, 2H), 3.31-3.28(m, 2H), 2.20(s, 3H), 2.16(s, 3H), 2.11(s, 3H), 2.08(s, 3H); 13 C NMR (125MHz, DMSO-d 6 )δ (ppm): 168.59, 168.44, 163.99, 163.02, 159.42, 157.92, 156.42 (C, d, J C-F =202.5Hz), 149.58, 145.30, 144.92, 142.78, 138.94, 137.51, 135.78, 134.86 (C, d, J C-C-C-C-F =2.5Hz), 134.43, 133.55, 131.73 (C, d, J C-C-C-F =7.5Hz), 131.62, 129.11, 129.00 (C, d, J C-C-C-F =2.5Hz),...

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Abstract

The invention discloses a double-target PARP / EZH2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the double-target PARP / EZH2 inhibitor has a structure represented by general formulas (I) and (II). The inhibitor has a relatively good inhibition effect on human breast cancer cells MDA-MB-231, MDA-MB-468 and MCF-7, has relatively small toxicity on human normal mammary gland cells MCF-10A and human normal hepatocytes L02, keeps good in-vitro inhibition activity on PARP-1 and EZH2, and has huge potential as an anti-tumor drug.

Description

technical field [0001] The present invention relates to chemical industry and medicine, in particular to dual-target PARP / EZH2 inhibitor, preparation method and application. Background technique [0002] Breast cancer is one of the most common cancers in the world and the most common disease. Triple-negative breast cancer (TNBC), which tests negative for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 protein (HER-2), accounts for 12-20 of all breast cancers %. Current treatment options for TNBC are limited to highly toxic and incurable chemotherapy regimens. Developing potential targeted drugs for the treatment of TNBC remains a great challenge for medicinal chemists. The biggest clinical breakthrough came in the discovery of PARP inhibitors (PARPi). This class of inhibitors has been approved for the treatment of BRCA1 / 2 mutated tumors, with significant clinical benefits. But 80% of TNBC patients do not have BRCA mutatio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14A61K31/502A61P35/00
CPCC07D401/14A61P35/00Y02P20/55
Inventor 孔令义王小兵王成
Owner CHINA PHARM UNIV
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