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Carbazole sulfamide derivative or pharmaceutical slat thereof as well as preparation method and application thereof

A technology of carbazole sulfonamide and derivatives, which is applied in the field of medicine and can solve the problems of neurotoxic side effects, poor bioavailability, limitations, etc.

Active Publication Date: 2017-11-24
MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the application and preparation of these tubulin inhibitor drugs have the following problems: as a natural product of macromolecules, it is very difficult to synthesize; the bioavailability is poor, and it has neurotoxic side effects, especially, The emergence of multidrug-resistant glycoprotein (P-gp) has seriously challenged the effectiveness of its treatment, which to some extent limits the development and application of paclitaxel and vinblastine-based tubulin inhibitors

Method used

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  • Carbazole sulfamide derivative or pharmaceutical slat thereof as well as preparation method and application thereof
  • Carbazole sulfamide derivative or pharmaceutical slat thereof as well as preparation method and application thereof
  • Carbazole sulfamide derivative or pharmaceutical slat thereof as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0104] Example 1: N-(2,6-dimethoxypyridin-3-yl)-N-(acetamido-2-yl)-9-methyl-3-carbazolesulfonamide (1)

[0105] N-(2,6-dimethoxypyridin-3-yl)-9-methyl-3-carbazolesulfonamide (IMB105) was prepared according to Mitsumori, Susumu; Tsuri, Tatsuo; Honma, Tsunetoshi et al., Journal of Synthesized by the method in Medicinal Chemistry (2003), 46 (12), 2436-2445. Dissolve N-(2,6-dimethoxypyridin-3-yl)-9-methyl-3-carbazolesulfonamide (IMB105) (0.30 g, 0.78 mmol) in 5 mL of anhydrous DMF, add iodine Acetamide (0.20 g, 1.1 mmol) and sodium hydride (40 mg, 60% in oil, 1.0 mmol) were reacted at 70° C. for 8 h, and the reaction was complete as detected by TLC. DMF was removed under reduced pressure, the residue was extracted with dichloromethane, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was separated and purified by column chromatography (CDM / MeOH / concentrated ammonia water=40 / 1 / 0.1) to obtain a solid 0.35 g (98% yi...

Embodiment 2

[0106] Example 2: N-(N,N-dimethylethyl)-N-(2,6-dimethoxypyridin-3-yl)-9-methyl-3-carbazolesulfonamide (4)

[0107] (1) Preparation of N-(2-bromoethyl)-N-(2,6-dimethoxypyridin-3-yl)-9-methyl-3-carbazolesulfonamide(2)

[0108] Dissolve IMB105 (1.0g, 2.5mmol) in 20mL of anhydrous tetrahydrofuran, add bromoethanol (0.22mL, 3.0mmol), triphenylphosphine (1.3g, 5.0mmol), and add DEAD (azo Diethyl diformate 40% intoluene, 2.0 mL, 4.25 mmol), stirred for about 10 min, and stirred at room temperature until the reaction was detected by TLC (about 5 h). Ethyl acetate (50 mL) was added to the reaction solution, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and separated and purified by column chromatography (PE / AcOEt=4 / 1-2 / 1) to obtain 1.2 g of solid (product rate 95%). 1 HNMR (CDCl 3 ,400MHz)δppm 3.39(3H,s),3.51(2H,t,J=7.2Hz),3.90(3H,s),3.96(5H,br s),6.36(1H,d,J=8.4Hz), 7.37(1H,t,J=8.4Hz),7.45(2H,d,J=8.8Hz),7.51(1H,d,J=8.4Hz),7.61(1H,dd,J=8.8,1....

Embodiment 3

[0111] Example 3: N-(2,6-dimethoxypyridin-3-yl)-N-[2-(pyrrol-1-yl)-ethyl]-9-methyl-3-carbazolesulfonamide (5)

[0112] The synthesis method is the same as that of the above-mentioned compound (4). N-(2-bromoethyl)-N-(2,6-dimethoxypyridin-3-yl)-9-methyl-3-carbazolesulfonamide (2) (0.5g, 1.0mmol) and Tetrahydropyrrole (0.42mL, 5.0mmoL) was reacted, separated and purified by column chromatography (DCM / MeOH / concentrated ammonia water=20 / 1 / 0.1) to obtain an oily substance. 1 HNMR (CDCl 3,400MHz)δppm 1.60(4H,brs),2.48(4H,brs),2.58(2H,brs),3.40(3H,s),3.82(2H,brs),3.88(3H,s),3.91 (3H,s),6.32(1H,d,J=8.4Hz),7.35(1H,t,J=8.0Hz),7.44(2H,d,J=8.8Hz),7.50(1H,d,J=8.0Hz),7.50(1H,d,J=8.0Hz) 8.4Hz), 7.54(1H,d,J=8.0Hz), 7.59(1H,t,J=8.4Hz), 7.83(1H,dd,J=8.0,1.6Hz), 8.13(1H,d,J= 8.0Hz), 8.47(1H,d,J=1.6Hz); HRMS(ESI+) 495.2070, Calcd for C 26 h 31 N 4 o 4 S495.2061[M+H]+.

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Abstract

The invention provides a carbazole sulfamide derivative or pharmaceutical slat thereof as well as a preparation method and an application thereof. The carbazole sulfamide derivative or the pharmaceutical slat thereof has the general formula (I). As a small-molecular tubulin inhibitor, the carbazole sulfamide derivative or the pharmaceutical slat thereof has an anti-tubulin function and significant anti-tumor activity, and meanwhile, the carbazole sulfamide derivative or pharmaceutical slat thereof is small in molecular weight, is simple to synthesize and has small toxic and side effects.

Description

technical field [0001] The invention relates to a carbazole sulfonamide derivative or a pharmaceutically acceptable salt thereof, a preparation method and application thereof, and belongs to the technical field of medicine. Background technique [0002] Tumor cells have the ability to proliferate rapidly, and maintain the shape, function and proliferation of cells through mitosis. If the process of mitosis is blocked, the proliferation of tumor cells will be blocked. Based on the important role of microtubules in the process of mitosis, anti-tumor drugs targeting tubulin have become a research hotspot. Traditional anti-mitotic agents, mainly tubulin inhibitors, such as paclitaxel and vinblastine antineoplastic drugs, can inhibit the polymerization or depolymerization of microtubules by binding to special sites of tubulin, so that tumor cells can During mitosis, the spindle body is difficult to form, thereby blocking the growth of tumor cells. [0003] Paclitaxel and vinbla...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07D401/14C07D471/10C07F9/58A61K31/4439A61K31/4545A61K31/496A61K31/5377A61K31/541A61K31/675A61P35/00
CPCC07D401/12C07D401/14C07D471/10C07F9/58
Inventor 胡来兴刘永华武燕彬
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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