A novel dual inhibitor of nampt and ido, its preparation method and medical application

A dual inhibitor and pharmaceutical technology, applied in the direction of antineoplastic drugs, drug combinations, organic chemistry, etc., can solve the problems of weak curative effect, large toxic and side effects, etc., and achieve the effect of inhibiting growth and proliferation and significant antitumor activity

Active Publication Date: 2021-08-24
YAOKANG ZHONGTUO (JIANGSU) PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Aiming at the deficiencies in the prior art, the present invention provides a dual-target inhibitor of furazan indoleamine 2,3-dioxygenase / nicotinamide phosphoribosyltransferase to solve the weak curative effect of existing anticancer drugs , toxic side effects and other issues

Method used

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  • A novel dual inhibitor of nampt and ido, its preparation method and medical application
  • A novel dual inhibitor of nampt and ido, its preparation method and medical application
  • A novel dual inhibitor of nampt and ido, its preparation method and medical application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0097] (Z)-N-(2-((4-(N-(3-bromo-4-fluorophenyl)-N'-hydroxymethylimidyl)-1,2,5-oxadiazol-3-yl )amino)ethyl)imidazol[1,2-a]pyridine-6-carboxamide preparation

[0098] (1) Preparation of (Z)-4-amino-N'-hydroxyl-N-(3-bromo-4-fluorophenyl)-1,2,5-oxadiazole-3-methylimidium

[0099]

[0100] At 0°C, acetic acid (5Ml), hydrochloric acid (4N) (5mL), NaNO 2(2.42g, 34.96mmol) in water (5mL) solution, warmed up to room temperature and reacted for 18h, added ethyl acetate (25ml), separated layers, extracted the aqueous phase with ethyl acetate (2*25ml), combined the organic phases, and used saturated Wash with brine (25 mL), dry over anhydrous sodium sulfate, and concentrate to give Intermediate 2 (4.5 g). To a solution of compound 2 (4.5 g) and 3-bromo-4-fluoroaniline (11.8 g, 62.0 mmol) in methanol (20 ml) was added NaHCO under nitrogen protection 3 (7.8g, 93.0mmol) in water (20ml), react at 50°C for 12 hours, TLC detects that the reaction is complete, concentrate, add ethyl acetat...

Embodiment 2

[0111] The difference with Example 1 is: the N-Boc-2-chloroethylamine in the step (2) of the synthetic method step is replaced by N-Boc-3-chloropropylamine, and the obtained (Z)-N-(2 -((4-(N-(3-bromo-4-fluorophenyl)-N'-hydroxymethylimidyl)-1,2,5-oxadiazol-3-yl)amino)propyl)imidazole[ 1,2-a] The structural formula of pyridine-6-carboxamide is as follows:

[0112]

[0113] Its H NMR spectrum is: 1 H NMR(400MHz,DMSO):δ11.06(s,1H),9.86(s,1H),8.83(s,1H),8.44(s,1H),7.71(d,J=3.6Hz,1H), 7.65(m,1H),7.46(s,2H),6.93(m,1H),6.76(m,1H),6.64(m,1H),6.05(s,1H),3.35(m,2H),3.05 (m,2H),1.93(m,2H)ppm.

[0114] Its carbon spectrum is: 13 C NMR (125MHz, DMSO): δ165.8, 1634.5, 155.3, 147.2, 145.2, 143.2, 138.4, 134.2, 129.3, 119.7, 117.2, 113.2, 110.6, 42.1, 41.2, 27.8.

[0115] Its mass spectrum is: MS (EI, m / z): 517 (M + +1).

Embodiment 3

[0117] The difference with Example 1 is: the N-Boc-2-chloroethylamine in the step (2) of the synthetic method step is replaced by N-Boc-4-chlorobutylamine, and the obtained (Z)-N-( 2-((4-(N-(3-bromo-4-fluorophenyl)-N'-hydroxymethylimidyl)-1,2,5-oxadiazol-3-yl)amino)butyl)imidazole The structural formula of [1,2-a]pyridine-6-carboxamide is as follows:

[0118]

[0119] Its H NMR spectrum is: 1 H NMR(400MHz,DMSO):δ11.06(s,1H),9.83(s,1H),8.79(s,1H),8.44(s,1H),7.91(d,J=3.5Hz,1H), 7.71(m,1H),7.37(s,2H),6.86(m,1H),6.78(m,1H),6.56(m,1H),6.06(s,1H),3.25(m,2H),3.05 (m,2H),1.50-1.48(m,4H)ppm.

[0120] Its carbon spectrum is: 13 C NMR (125MHz, DMSO): δ167.8, 163.5, 155.2, 153.3, 148.7, 147.2, 145.2, 143.2, 134.4, 133.2, 129.3, 119.2, 118.6, 117.2, 116.7, 114.2, 110.2, 42.1, 39.2, 2

[0121] Its mass spectrum is: MS (EI, m / z): 531 (M + +1).

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Abstract

The invention discloses a novel dual inhibitor of NAMPT and IDO and its preparation method and medical use, in particular to a furoxan compound or its pharmaceutically acceptable salt, solvate, prodrug, ester, and racemate And isomers and pharmaceutical compositions containing such compounds and applications of these compounds or pharmaceutical compositions in the preparation of antitumor drugs. In the present invention, the active fragments of IDO inhibitors and NAMPT inhibitors are rationally spliced ​​to obtain a furazan IDO / NAMPT dual-target inhibitor, which double inhibits NAD on the one hand + On the other hand, the inhibition of IDO activity can effectively promote the proliferation of T cells, thereby enhancing the body's ability to attack tumor cells. This type of furazan IDO / NAMPT dual-target inhibitor or its pharmaceutical composition has broad application prospects and is expected to become an antitumor drug.

Description

technical field [0001] The present invention belongs to the field of biotechnology medicine, and specifically relates to furoxan compounds shown in formula I or pharmaceutically acceptable salts, solvates, prodrugs, esters, racemates and isomers and compounds containing such compounds Pharmaceutical composition and the application of these compounds or pharmaceutical compositions in the preparation of antitumor drugs. [0002] Background technique [0003] Cancer is a major disease that plagues human health. Research and development of new anti-tumor drugs is a major topic and long-term task in the field of biomedicine. A large number of studies have shown that abnormal cell metabolism is one of the important signs of cancer. Nicotinamide adenine dinucleotide (NAD for short) + ) is an indispensable substance in the process of electron transfer and plays an important role in energy metabolism and signal transduction. In addition, NAD + The reduction of NADH is of great...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04C07D413/12C07D413/14A61P35/00A61P35/02A61P35/04
CPCA61P35/00A61P35/02A61P35/04C07D413/12C07D413/14C07D471/04
Inventor 蒋晟郝海平郭长缨吴筱星姚和权张阔军邱亚涛郑啸陈东
Owner YAOKANG ZHONGTUO (JIANGSU) PHARMA TECH CO LTD
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