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Sulfamide derivative, preparation method and application thereof in resisting tumor

A technology of derivatives and sulfonamides, which is applied in the field of sulfonamide derivatives, preparation and anti-tumor applications, can solve problems such as interference and achieve good activity

Inactive Publication Date: 2018-04-13
田立志
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Prior art has demonstrated that FK866 interferes with nicotinamide adenine dinucleotide biosynthesis and induces apoptotic cell death without any DNA damaging effects

Method used

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  • Sulfamide derivative, preparation method and application thereof in resisting tumor
  • Sulfamide derivative, preparation method and application thereof in resisting tumor
  • Sulfamide derivative, preparation method and application thereof in resisting tumor

Examples

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Embodiment 1

[0020] Example 1: Synthesis of 1-((4,5-dihydro-1H-imidazol-1-yl)sulfonyl)pyrrolidine-3-carbonyl chloride

[0021]

[0022] A solution of pyrrolidine-3-carbonyl chloride (16.8ml, 0.2mol) in anhydrous toluene (40ml) was added dropwise to 4,5-dihydro-1H-imidazole-1-sulfonyl chloride (33.72g, 0.2mol) In a cold (-10°C) solution in toluene (30ml) such that the internal temperature does not exceed -5°C. Once the addition was complete, the mixture was stirred at -5°C for thirty minutes before water (50ml) was added. The layers were separated, the organic layer was washed with HCl (2mol / l, 50ml), washed with anhydrous MgSO 4 Drying and evaporation in vacuo gave a clear oil (9.6g). The oil is a 2:1 mixture of the desired sulfamoyl chloride and 1-((4,5-dihydro-1H-imidazol-1-yl)sulfonyl)pyrrolidine-3-carbonyl chloride. 42.4 g of 1-((4,5-dihydro-1H-imidazol-1-yl)sulfonyl)pyrrolidine-3-carbonyl chloride was obtained by column chromatography with a yield of 80%. 1 H-NMR (400 MHz, CDCl...

Embodiment 2

[0023] Example 2: N-(2,6-dichloropyridin-4-yl)-1-((4,5-dihydro-1H-imidazol-1-yl)sulfonyl)pyrrolidine-3-carboxamide synthesis

[0024]

[0025] 1-((4,5-Dihydro-1H-imidazol-1-yl)sulfonyl)pyrrolidine-3-carbonyl chloride (53.14 g, 0.2 mol) was dissolved in anhydrous CH 2 Cl 2 (36 mL) was carefully added to 2,6-dichloro-4-aminopyridine (32.60 g, 0.2 mol) and triethylamine (27 mL) in anhydrous CH at 0 °C 2 Cl 2 (90mL) solution). The reaction mixture was stirred in an ice bath for 1 hour, then allowed to warm to room temperature and stirred overnight. Add cold water (100 mL), and separate the CH from the aqueous solution 2 Cl 2 layer. Organic phase with saturated NaHCO 3 solution (2 x 40 mL) and washed with water, with anhydrous MgSO 4 Drying, filtration and concentration gave the crude product, which was recrystallized from ethyl acetate / n-hexane (1:5) to give N-(2,6-dichloropyridin-4-yl)-1- ((4,5-Dihydro-1H-imidazol-1-yl)sulfonyl)pyrrolidine-3-carboxamide 66.68g, yield...

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Abstract

The invention discloses a sulfamide derivative which is as shown in a formula (I), wherein the formula (I) is a new structure. The invention also discloses a preparation method of the formula (I) andapplication of the formula (I), which is used as an NAMPT (Nicotinamide Phosphoribosyl Transferase) inhibitor, in anti-tumor drugs. Very good activity is expressed in an activity experiment of inhibiting NAMPT and an experiment of determining inhibition functions of the formula (I) on different tumor cells through an MTT (Methyl Thiazolyl Tetrazolium) method. The structure of the formula (I) is asshown in the description.

Description

technical field [0001] The invention relates to a sulfonamide derivative, a preparation method and an antitumor application thereof. Background technique [0002] Nicotinamide phosphoribosyl transferase (nicotinamide phosphoribosyl transferase, NAMPT), also known as visfatin or pre-B cell clone enhancer factor PBEF, regulates the level of NAD, an essential energy substance in mammalian cells. Cancer cells have a high NAD consumption and metabolic rate, so NAMPT, the rate-limiting enzyme in the NAD synthesis pathway, has become a new target for cancer therapy. The enzyme inhibitors FK866 and CHS-828 are typical NAMPT inhibitors, and have been carried out in the field of cancer therapy. Extensive clinical studies. [0003] FK866 ((E)-N-[4-(1-benzoylpiperidin-4-yl)butyl]-3-(pyridin-3-yl)acrylamide) induced apoptosis in HepG2 cells, but Has no initial effect on cellular energy metabolism. FK866 can be used to treat diseases involving dysregulation of apoptosis such as cancer....

Claims

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Application Information

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IPC IPC(8): C07D401/14A61P35/00A61P35/02
CPCC07D401/14
Inventor 田立志
Owner 田立志