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Benzothiazine-4-one compound containing 2,7-diazaspiro[3.5]nonane fragments and preparation method thereof

A technology of diazaspiro and compound is applied in the field of anti-tuberculosis pharmaceutical composition, benzothiazinone compound and preparation thereof, and can solve the problems of poor water solubility, unpredictable in vivo activity of BTZ043 and the like

Active Publication Date: 2018-09-14
ZHEJIANG STARRY PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Its representative BTZ043 has broad-spectrum anti-tuberculosis activity in vitro (Antimicrob Agent Chemother, 2010, 54(4): 1616-1618; 2012, 56(7): 3984-3985), but due to poor water solubility, the in vivo activity of BTZ043 Much worse than expected (EMBO Mol Med, 2014, 6:372–383)

Method used

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  • Benzothiazine-4-one compound containing 2,7-diazaspiro[3.5]nonane fragments and preparation method thereof
  • Benzothiazine-4-one compound containing 2,7-diazaspiro[3.5]nonane fragments and preparation method thereof
  • Benzothiazine-4-one compound containing 2,7-diazaspiro[3.5]nonane fragments and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0086] Example 1.2-(2-Benzyl-2,7-diazaspiro[3.5]nonan-7-yl)-6-trifluoromethyl-8-nitro-4H-benzo[e][1 ,3] Thiazin-4-one

[0087] To a solution of tert-butyl 2,7-azaspiro[3,5]nonane-7-carboxylate (199 mg, 0.88 mmol) in acetonitrile (15 mL) was added benzyl bromide (171 mg, 1 mmol) and potassium carbonate at room temperature (276mg, 2mmol), stirred at room temperature for 2 hours. Distilled water (30 mL) was added to the reaction liquid, and extracted with ethyl acetate (20 mL×3). Several layers were combined, dried over anhydrous magnesium sulfate, concentrated, and subjected to silica gel column chromatography (DCM:MeOH:NH 3 h 2 O=200:10:0.2) to obtain pale yellow oil (260mg).

[0088] At room temperature, the above oil (260 mg) was dissolved in anhydrous dichloromethane (10 mL), trifluoroacetic acid (3 mL) was added dropwise with stirring, stirred at the same temperature for 1 hour, and concentrated to obtain a yellow oil.

[0089] Add 2-methylthio-6-trifluoromethyl-8-nitro-...

Embodiment 2

[0092] Example 2.2-[2-(4-fluorobenzyl)-2,7-diazaspiro[3.5]nonan-7-yl]-6-trifluoromethyl-8-nitro-4H-benzo [e][1,3]thiazin-4-one

[0093] The preparation method is the same as in Example 1, and 4-fluorobenzyl bromide is used to replace the benzyl bromide in Example 1 to obtain the target compound.

[0094] 1 H NMR (400MHz, CDCl 3 )δ9.09(s,1H),8.74(s,1H),7.38(d,J=7.5Hz,2H),7.07(d,J=7.5Hz,2H),4.20-3.70(m,4H), 3.79 (s, 2H), 3.14 (brs, 4H), 1.93 (brs, 4H).

[0095] MS-ESI(m / z):509.1[M+H] + .

Embodiment 3

[0096] Example 3.2-[2-(4-Chlorobenzyl)-2,7-diazaspiro[3.5]nonan-7-yl]-6-trifluoromethyl-8-nitro-4H-benzo [e][1,3]thiazin-4-one

[0097] The preparation method is the same as in Example 1, and 4-chlorobenzyl bromide is used instead of bromobenzyl in Example 1 to obtain the target compound.

[0098] 1 H NMR (400MHz, CDCl 3 )δ9.09(s,1H),8.74(s,1H),7.39(d,J=7.5Hz,2H),7.32(d,J=7.5Hz,2H),4.20-3.70(m,4H), 3.77 (s, 2H), 3.14 (brs, 4H), 1.93 (brs, 4H).

[0099] MS-ESI(m / z):525.1[M+H] + .

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Abstract

The invention relates to a benzothiazine-4-one compound containing 2,7-diazaspiro[3.5]nonane fragments and a preparation method thereof and in particular relates to 6-trifluoromethyl-8-nitro-4H-benzo[e][1,3]thiazine-4-one compounds. The 2-position substituent group is 2,7-diazaspiro[3.5]nonane-7-yl, wherein Ar represents phenyl, pyridyl, naphthyl, quinolyl, pyrazinyl, pyrimidyl, pyrazolyl, imidazolyl, furyl or thienyl, and optionally, the hydrogen atom at any position of the groups can be substituted by the group R; the group R is selected from alkyl having 1-4 carbon atoms, alkoxy having 1-3carbon atoms, halogen, -CF3, -OCF3, -NO2 or -CN.

Description

technical field [0001] The present invention belongs to the field of medicinal chemistry, and relates to benzothiazinone compounds containing basic azaspirocyclic fragments with anti-tuberculosis activity and a preparation method thereof, and an anti-tuberculosis pharmaceutical composition containing them; more specifically, the present invention The invention relates to 6-trifluoromethyl-8-nitro-4H-benzo[e][1,3]thiazin-4-one compounds, whose 2-position substituent is 2,7-diazaspiro [3.5] Nonane Fragment. Background technique [0002] According to the World Health Organization (WHO), there were 10.4 million new cases of tuberculosis (TB) in the world in 2015, and 1.4 million people died of TB. In addition, nearly 1 / 3 of the world's population carries latent Mycobacterium tuberculosis, which is a potential risk of disease. In recent years, the increasing incidence of drug-resistant TB, especially multidrug-resistant TB (MDR-TB) and the emergence of extensively drug-resistan...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/10A61K31/5415A61P31/06
Inventor 刘明亮郭慧元吕凯汪阿鹏黄国成陶泽宇王洪建李霄宁张俊陈仕洪
Owner ZHEJIANG STARRY PHARMA
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