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Dual-target parp/ezh2 inhibitor, preparation method and use

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

Active Publication Date: 2022-05-17
CHINA PHARM UNIV
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  • 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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  • Dual-target parp/ezh2 inhibitor, preparation method and use
  • Dual-target parp/ezh2 inhibitor, preparation method and use
  • Dual-target parp/ezh2 inhibitor, preparation method and use

Examples

Experimental program
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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 present invention discloses a dual-target PARP / EZH2 inhibitor of the structure shown in general formula (I) and (II) or a pharmaceutically acceptable salt thereof. The inhibitor of the present invention is effective against human breast cancer cells MDA-MB-231 and MDA‑MB‑468 and MCF‑7 have better inhibitory effect, less toxicity to human normal breast cell MCF‑10A and human normal liver cell L02, and maintain good inhibitory activity on PARP‑1 and EZH2 in vitro Great potential of anticancer drugs.

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 Patents(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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