Novel nicotinamide ribose phosphate transferase inhibitor as well as synthetic method and application thereof

A technology of phosphoribose and transferase, applied in the field of medicine, to achieve the effect of simple operation, excellent anti-tumor activity, and cheap synthetic raw materials

Inactive Publication Date: 2015-04-29
GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Nicotinamide phosphoribosyltransferase (Nampt) is a very good anti-tumor target, but so far only three Nampt inhibitors are in the clinical research stage, and clinical trials have shown that these three inhibitors have many shortcomings, and medicinal chemistry is urgently needed Design and synthesize more novel Nampt inhibitors to meet the needs of academic research and practical clinical applications

Method used

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  • Novel nicotinamide ribose phosphate transferase inhibitor as well as synthetic method and application thereof
  • Novel nicotinamide ribose phosphate transferase inhibitor as well as synthetic method and application thereof
  • Novel nicotinamide ribose phosphate transferase inhibitor as well as synthetic method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045]

[0046] Compound 9 (408mg, 1mmol) was dissolved in anhydrous DCM, triethylamine (0.4mL, 3mmol) was added at 0°C, then methanesulfonyl chloride (0.12mL, 1.5mmol) was slowly added dropwise, and the reaction was completed after the dropwise addition was completed. After 1 hour, add saturated sodium bicarbonate solution to quench the reaction, add DCM to dilute, then wash with saturated sodium bicarbonate and saturated brine, then dry over anhydrous magnesium sulfate, filter, and concentrate to obtain a crude product that is directly used in the next reaction.

[0047] Dissolve the crude product obtained in the previous step in DMF, add sodium azide (195mg, 3mmol), react at 80°C for 2 hours, cool to room temperature, spin off DMF under reduced pressure, add diethyl ether for extraction, and use saturated ammonium chloride for the organic phase , washed with saturated brine, then dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a crude product ...

Embodiment 2

[0051]

[0052]Compound 10 (18mg, 0.12mmol) was dissolved in DMF, then EDCI (38mg, 0.2mmol), HOBt (20mg, 0.15mmol), TEA (0.03mL, 0.2mmol) were added successively, and finally compound 3 (41mg, 0.1 mmol), the reaction was stirred at room temperature for 5 hours, and the solvent was removed by rotary evaporation, then extracted with ethyl acetate, the organic phase was washed with saturated sodium bicarbonate and saturated brine successively, then dried over anhydrous magnesium sulfate, filtered, and the column layer was concentrated Compound 11 (46 mg, 86%) was obtained as a yellow solid.

[0053] 1 H NMR (400MHz, CDCl 3 ):δ8.72(s,1H),8.55-8.53(m,1H),7.77-7.73(m,1H),7.58(d,J=16.0Hz,1H),7.33(d,J=8.0Hz, 2H),7.30-7.16(m,1H),7.15(d,J=8.0Hz,2H),6.45(d,J=16.0Hz,1H),5.98(s,1H),5.33(s,1H), 3,39-3.32(m,2H),3.31(s,6H),2.60(t,J=8.0Hz,2H),1.67-1.55(m,4H),1.41-1.35(m,2H)ppm.MS (ESI,m / z):369(M + +1).

Embodiment 3

[0055]

[0056] Dissolve compound 11 (40mg, 0.07mmol) in ethyl acetate, then slowly add 3mol / L HCl (0.1mL, 0.3mmol) dropwise, react at room temperature for 12 hours, add saturated sodium bicarbonate solution dropwise to adjust the pH of the reaction solution When the value reached 7, ethyl acetate was added to dilute, the organic phase was washed with saturated sodium bicarbonate and saturated brine successively, then dried over anhydrous magnesium sulfate, filtered, and concentrated by column chromatography to obtain compound 12 (28 mg, 90%). 1 H NMR (400MHz, CDCl 3 ):δ9.94(s,1H),8.71(d,J=0.8Hz,1H),8.54-8.53(m,1H),7.78-7.73(m,3H),7.58(d,J=15.6Hz, 1H), 7.31-7.27(m, 2H), 6.47(d, J=15.6Hz, 1H), 6.08(s, 1H), 3.40-3.35(m, 2H), 2.68(t, J=8.0Hz, 2H ),1.71-1.57(m,4H),1.43-1.37(m,2H)ppm. 13 C NMR (125MHz, CDCl 3 ): δ191.9, 165.1, 150.2, 149.9, 149.0, 137.1, 134.4, 134.3, 130.7, 129.9, 129.0, 123.7, 122.9, 39.6, 35.9, 30.5, 29.4, 26.4ppm.

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Abstract

The invention discloses a novel nicotinamide ribose phosphate transferase inhibitor as well as a synthetic method and application thereof. The novel nicotinamide ribose phosphate transferase inhibitor is a compound or pharmaceutically acceptable salts thereof shown in the structural formula I in the specification. The novel nicotinamide ribose phosphate transferase inhibitor is prepared from cheap synthetic raw materials, concise in route, simple in operation and suitable for industrial production; the obtained compound is excellent in antitumor activity and is expected to be developed as a new antitumor drug.

Description

Technical field: [0001] The invention relates to the technical field of medicine, in particular to a novel nicotinamide phosphoribosyltransferase inhibitor and its synthesis method and application. Background technique: [0002] Nicotinamide phosphoribosyltransferase (Nampt) is the rate-limiting enzyme of the mammalian nicotinamide adenine dinucleotide (NAD) synthesis pathway, which regulates the level of NAD in cells. NAD is the coenzyme of many enzymes in the living body and plays an important role in many cellular physiological processes. In order to maintain a high proliferation rate, tumor cells need more energy and more NAD-dependent enzymes. Therefore, tumor cells need to synthesize and replenish more NAD, and are more dependent on intracellular NAD levels than normal cells. In addition, studies have shown that Nampt also has pro-angiogenic activity, supporting the growth of some tumor cells. These studies make Nampt a very attractive target in anticancer drug rese...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07D471/04C07D213/56A61K31/4439A61K31/444A61K31/4406A61P35/00A61P35/02
CPCA61K31/4406A61K31/4439A61K31/444C07D213/56C07D401/12C07D471/04
Inventor 蒋晟涂正超郑多秦东光白进红覃筱楚姚毅武刘洋汉邱亚涛陈家轩
Owner GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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