Novel NAMPT and IDO dual inhibitor, and preparation method and medical applications thereof

A dual inhibitor, a new type of technology, applied in the direction of antineoplastic drugs, drug combinations, organic chemistry, etc., can solve the problems of high toxicity and side effects, weak curative effect, etc.

Active Publication Date: 2018-09-14
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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  • Novel NAMPT and IDO dual inhibitor, and preparation method and medical applications thereof
  • Novel NAMPT and IDO dual inhibitor, and preparation method and medical applications thereof
  • Novel NAMPT and IDO dual inhibitor, and preparation method and medical applications thereof

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 NAMPT and IDO dual inhibitor, and a preparation method and medical applications thereof, and more specifically relates to a furazan compound, or pharmaceutically acceptable salts, solvates, prodrugs, esters, racemic compounds, and isomers of the furazan compound, and pharmaceutical compositions containing the furazan compound, and applications of the furazan compound or the pharmaceutical compositions in the field of anti-tumor drug preparation. According to the preparation method, reasonable combination of active segments of an IDO inhibitor and a NAMPT inhibitor is adopted so as to obtain the furazan kind IDO / NAMPT double target inhibitor. On one hand, the furazan kind IDO / NAMPT double target inhibitor is capable of realizing dual inhibition of NAD<+> biosynthesis, and possesses higher anti-tumor inhibition activity, and one the other hand, inhibition of IDO activity is capable of promoting T cell propagation effectively, so that the impurity of bodies on tumor cell attacks is improved. The furazan kind IDO / NAMPT double target inhibitor or the pharmaceutical compositions of the furazan kind IDO / NAMPT double target inhibitor are promising in application prospect, and are promising to be developed into anti-tumor drugs.

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 Applications(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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