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Substituted benzothiazole compound as well as preparation method and application thereof

A technology of benzothiazole and compound, applied in the application field as antifungal drug, can solve problems such as narrow antibacterial spectrum

Inactive Publication Date: 2013-07-10
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, FTR1335 has a narrow antibacterial spectrum and only has in vitro inhibitory effect on Candida albicans (K.Yamazaki, Y.Kaneko, K.Suwa, S.Ebara, K.Nakazawa, K.Yasuno, Synthesis of potent and selective inhibitors of Candida albicans N-myristoyltransferase based on the benzothiazole structure, Bioorg Med Chem, 13(2005) 2509-2522.), and there is no literature report to expand the antibacterial spectrum of FTR1335 and improve its antifungal activity through structural modification

Method used

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  • Substituted benzothiazole compound as well as preparation method and application thereof
  • Substituted benzothiazole compound as well as preparation method and application thereof
  • Substituted benzothiazole compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Embodiment 1: Preparation of N-(6-nitrobenzothiazol-2-yl) cyclopentanamide (II)

[0051] Dissolve 2-amino-6-nitrobenzothiazole (4.00g, 0.02mol, 1equiv) and cyclopentanecarboxylic acid (2.28g, 0.02mol, 1equiv) in 50mL of dichloromethane, add 1-ethyl-( 3-Dimethylaminopropyl) carbodiimide hydrochloride (5.75g, 0.03mol, 1.5equiv) and 4-dimethylaminopyridine (0.40g, 2mmol, 0.1equiv), stirred at room temperature for 16h. After the reaction, the reaction solution was washed with 5% hydrochloric acid (3×30mL), 5% sodium bicarbonate (3×30mL), saturated sodium chloride solution (3×30mL), and washed with anhydrous Na 2 SO 4 Drying. Filtration, evaporation of the solvent under reduced pressure, and purification of the residue by silica gel column chromatography (developing solvent: hexane:EtOAc=10:1, v / v) to obtain 5.66 g of a light yellow solid with a yield of 97.3%. 1 H-NMR (300MHz, CDCl 3 ):9.15(brs,1H),8.76(d,1H,J=2.4Hz),8.34(dd,1H,J=9.0,2.4Hz),7.82(d,1H,J=9.0Hz),2.80-2.96 ...

Embodiment 2

[0052] Example 2: Preparation of N-(6-aminobenzothiazol-2-yl)cyclopentamide (Ⅲ)

[0053] Compound Ⅱ (1.00g, 3.4mmol, 1equiv) and stannous chloride (2.30g, 10.2mmol, 3equiv) were dissolved in 50mL of ethanol, heated to reflux for 2h. After the reaction was completed, the reaction liquid was evaporated to dryness, 50 mL of 5% sodium hydroxide solution and 100 mL of ethyl acetate were added, mixed and oscillated thoroughly, and the aqueous layer was extracted with ethyl acetate (2×100 mL). The organic phases were combined, washed with saturated sodium chloride solution (3 × 30mL), anhydrous Na 2 SO 4 dry. After filtration, the solvent was evaporated to dryness under reduced pressure, and the residue was recrystallized from 20 mL of ethyl acetate to obtain 0.45 g of a white solid, with a yield of 50.6%. 1 H-NMR (300MHz, DMSO-d 6 ):11.97(s,1H),7.37(d,1H,J=8.5Hz),6.97(d,1H,J=1.5),6.68(dd,1H,J=8.5,1.5Hz),5.14(s, 2H),2.83-2.97(m,1H),1.78-1.95(m,2H),1.45-1.95(m,6H).ESI-MS(m / z):262...

Embodiment 3

[0054] Example 3: Preparation of tert-butyl-N-cis-3-[(2-[(cyclopentylcarbonyl)amino]benzothiazole-6-amino)carbonyl]cyclohexylcarbamate (IV)

[0055] Take III (1.00g, 3.83mmol, 1equiv) and cis-3-(tert-butoxycarboxyamino)cyclohexylcarboxylic acid (0.93g, 3.83mmol, 1equiv) and dissolve in 25mL of dichloromethane, add 1-ethyl-(3 -Dimethylaminopropyl) carbodiimide hydrochloride (1.10g, 5.75mmol, 1.5equiv) and 1-hydroxybenzotriazole (0.78g, 5.75mmol, 0.1equiv), stirred at room temperature for 18h. After the reaction, the white precipitate was filtered out and washed with 20 mL of dichloromethane to obtain 0.91 g of a light yellow solid with a yield of 54.2%. 1H-NMR(300MHz,DMSO-d6):12.45(s,1H),10.21(s,1H),8.50(d,1H,J=1.8Hz),7.83(d,1H,J=8.7Hz),7.68 (dd,1H,J=8.7,1.8Hz),7.04(s,1H),3.07-3.22(m,1H),2.72-2.81(m,1H),2.55-2.66(m,1H),1.67-2.17 (m,12H),1.57(s,9H),1.20-1.53(m,4H).ESI-MS(m / z):485[M-1].

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Abstract

The invention belongs to the technical field of medicaments and provides a substituted benzothiazole compound and a pharmaceutically acceptable salt thereof. The structural formula of the substituted benzothiazole compound is as shown in formula I, wherein in formula I, R is a substituted naphthalene ring or a substituted aromatic heterocycle. The invention also provides the applications of the substituted benzothiazole compound and the pharmaceutically acceptable salt thereof to the preparation of medicaments for resisting fungi, tumors, viruses, high blood pressure and thrombus and topoisomerase inhibitors.

Description

technical field [0001] The present invention relates to the field of medical technology, in particular to a new substituted benzothiazole compound—cis-N-{2-[(cyclopentylcarbonyl)amino]benzothiazol-6-yl}-3-[ (Substituted) amino]cyclohexylcarboxamide compounds and salts thereof, preparation methods, and application as antifungal drugs. Background technique [0002] In recent years, with the widespread application of antibiotics, tumor radiotherapy and chemotherapy, and organ transplantation, as well as the sharp increase in the prevalence of AIDS, a large number of patients with deep fungal infections such as Candida albicans, Aspergillus fumigatus, and Cryptococcus neoformans increase in magnitude. Therefore, deep fungal infection has become the main cause of death from major diseases such as AIDS and tumors. However, clinically ideal anti-deep fungal drugs are still very lacking, and the existing drugs generally have the following various problems. Azole drugs (such as fl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/12C07D277/82A61K31/4709A61K31/428A61P31/10A61P35/00A61P31/12A61P9/12A61P7/02
Inventor 盛春泉张万年刘杨张玲缪震元姚建忠董国强
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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