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A kind of o-quinone compound and its preparation method and medical application

A compound, o-quinone technology, applied in the application field of preparation of medicines, can solve the problems of weak curative effect, large toxic and side effects, etc.

Active Publication Date: 2022-05-24
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Purpose of the invention: Aiming at the deficiencies in the prior art, the present invention provides an active small molecule compound targeting NQO1 and NAMPT at the same time to solve the problems of weak curative effect and relatively large side effects of existing anticancer drugs

Method used

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  • A kind of o-quinone compound and its preparation method and medical application
  • A kind of o-quinone compound and its preparation method and medical application
  • A kind of o-quinone compound and its preparation method and medical application

Examples

Experimental program
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Effect test

Embodiment 1

[0093] Example 1: (E)-3-(pyridin-3-yl)-N-(4-(((1,6,6-trimethyl-10,11-dione-6,7,8,9 Synthesis of ,10,11-hexahydrophenanthrene[1,2-b]furan-2-yl)methyl)amino)phenyl)acrylamide

[0094]

[0095] Step 1: Synthesis of (E)-N-(4aminophenyl)-3-(pyridin-3-yl)acrylamide hydrochloride (6a)

[0096]Weigh (E)-3-(3-pyridine)acrylic acid 3 (500 mg, 3.35 mmol), dissolve it in anhydrous DMF (10 mL), add HATU (1.9 g, 5.03 mmol), DIPEA (10.05 mmol, 1.3 g in turn) ) and N-BOC-p-phenylenediamine 4a (697.7 mg, 3.35 mmol), the reaction was stirred at room temperature for 2 h, the reaction was stopped, and DMF was spin-dried under reduced pressure. To the reaction residue was added 5 ml of saturated NaHCO 3 solution, DCM (20ml×3), combined organic phases, saturated NH 4 Washed once with Cl (10ml), washed once with saturated brine (10ml), dried over anhydrous sodium sulfate, filtered, evaporated to dryness, made sand, separated and purified by column chromatography (DCM:MeOH=60:1~20:1 ) to give ...

Embodiment 2

[0103] Example 2: (E)-3-(pyridin-3-yl)-N-(4-(1-((1,6,6-trimethyl-10,11-dione-6,7,8 Synthesis of ,9,10,11-hexahydrophenanthrene[1,2-b]furan-2-yl)methyl)piperidin-4-yl)phenyl)acrylamide (S2)

[0104]

[0105] 1 H NMR (300MHz, DMSO-d 6 )δ10.22(s, 1H), 8.81(s, 1H), 8.58(d, J=4.7Hz, 1H), 8.03(d, J=8.0Hz, 1H), 7.79(d, J=8.2Hz, 1H), 7.75–7.53 (m, 4H), 7.48 (dd, J=8.0, 4.8Hz, 1H), 7.20 (d, J=8.2Hz, 2H), 6.91 (d, J=15.8Hz, 1H), 3.60(s, 2H), 3.10–3.02(m, 2H), 2.98(d, J=10.5Hz, 2H), 2.41(d, J=11.9Hz, 1H), 2.19(s, 3H), 2.14(d , J=10.9Hz, 2H), 1.84–1.67 (m, 4H), 1.67–1.55 (m, 4H), 1.28 (s, 6H). 13 C NMR (126MHz, Chloroform-d) δ: 183.8, 176.0, 163.4, 161.0, 150.6, 150.3, 149.3, 144.6, 142.5, 138.5, 136.3, 134.7, 133.9, 130.8, 127.5, 127.5, 126.6, 120.73.9, ,120.5,120.4,119.3,54.0,52.6,41.9,38.0,34.8,33.4,32.0,30.1,19.3,9.2.ESI-HRMS m / z calculated for C 39 H 40 N 3 O 4 [M+H] + 614.30133, found 614.30093.

Embodiment 3

[0106] Example 3: (E)-3-(pyridin-3-yl)-N-(4-((2-(((1,6,6-trimethyl-10,11-dione-6,7 ,8,9,10,11-Hexahydrophenanthrene[1,2-b]furan-2-yl)methyl)amino)ethyl)amino)phenyl)acrylamide (S3)

[0107]

[0108] 1 H NMR (300MHz, DMSO-d 6 )δ: 8.75(d, J=2.1Hz, 1H), 8.62–8.45(m, 1H), 8.22(t, J=5.7Hz, 1H), 8.00(d, J=8.0Hz, 1H), 7.76( d, J=8.2Hz, 1H), 7.52–7.39 (m, 3H), 6.99 (d, J=8.0Hz, 2H), 6.73 (d, J=15.9Hz, 1H), 6.64 (d, J=8.1 Hz, 2H), 4.27(s, 2H), 3.38–3.25(m, 2H), 3.02(d, J=6.5Hz, 2H), 2.62(t, J=7.5Hz, 2H), 2.20(s, 3H) ), 1.75–1.64(m, 2H), 1.63–1.53(m, 2H), 1.26(s, 6H). 13 C NMR (126MHz, DMSO-d 6 )δ: 182.4, 175.0, 164.3, 159.0, 151.7, 149.5, 149.2, 148.6, 148.5, 146.4, 142.8, 134.9, 134.5, 134.4, 133.4, 131.0, 129.1, 127.2, 126.6, 124.5, 124.4, 124. ,120.0,119.8,116.2,112.6,40.7,38.0,37.4,34.3,34.2,31.5,29.5,18.7,8.5.ESI-HRMS m / z calculated for C 36 H 36 N 3 O 4 [M+H] + 574.27003, found 574.26959.

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Abstract

The invention discloses an active small molecular compound targeting NQO1 and NAMPT, its preparation method and medical application, in particular to an o-quinone compound or its pharmaceutically acceptable salt, solvate, prodrug, ester, Racemates and isomers, pharmaceutical compositions containing such compounds, and applications of these compounds or pharmaceutical compositions in the preparation of antitumor drugs. In the present invention, the NQO1 substrate / NAMPT inhibitor is obtained by splicing rationally the pharmacophore of the activatable substrate Tanshinone IIA of NQO1 and the NAMPT inhibitor. These compounds can be reductively activated by NQO1, and at the same time can inhibit the activity of NAMPT, thereby consuming NAD+ Simultaneous inhibition of NAD + biosynthesis, showing stronger tumor suppressor activity. This kind of o-quinone derivatives or pharmaceutical compositions thereof targeting both NQO1 and NAMPT has broad application prospects and is expected to become an antitumor drug.

Description

technical field [0001] The invention belongs to the field of chemical medicine, in particular to a kind of o-quinone compound and its pharmaceutically acceptable salt and its prodrug molecule, the pharmaceutical composition containing this compound and the application of these compounds or compositions in preparing medicine . Background technique [0002] Nicotinamide adenine dinucleotide (NAD for short) + ) is an important cofactor for many redox reactions in energy metabolism, including oxidative phosphorylation, glycolysis, and pentose phosphate pathway, and is also a substrate for key enzymes in many signal transduction processes, such as acetylases (sirtuins, SIRT for short) deacetylation and ADP ribosylation, poly-ADP-ribose polymerase (poly-ADP-ribose polymerase, PARP) for poly-ADP ribosylation, etc. In addition, NAD + Its reduced form NADH is of great significance for maintaining the reducing environment in cells to protect cells from oxidative stress. Therefore,...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J73/00A61K31/58A61P35/00A61P35/02
CPCC07J73/003A61P35/00A61P35/02
Inventor 郝海平蒋晟卢之瑀王德祥张阔军张文波钱振龙韩佳玲张婉衡郑啸
Owner CHINA PHARM UNIV