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Benzothiazine-4-ketone compounds containing basic nitrogen heterocyclic fragments and preparing methods of benzothiazine-4-ketone compounds

A compound, the technology of thiazide, which is applied in the field of medicinal chemistry, can solve the problems of poor water solubility and the in vivo activity of BTZ043, which is not as expected

Active Publication Date: 2016-06-15
ZHEJIANG STARRY PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Its representative BTZ043 has broad-spectrum anti-tuberculosis activity in vitro (AntimicrobAgentChemother, 2010, 54(4): 1616-1618; 2012, 56(7): 3984-3985), but due to poor water solubility, the in vivo activity of BTZ043 is far inferior to that of Anticipation (EMBOMolMed, 2014, 6:372–383)

Method used

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  • Benzothiazine-4-ketone compounds containing basic nitrogen heterocyclic fragments and preparing methods of benzothiazine-4-ketone compounds
  • Benzothiazine-4-ketone compounds containing basic nitrogen heterocyclic fragments and preparing methods of benzothiazine-4-ketone compounds
  • Benzothiazine-4-ketone compounds containing basic nitrogen heterocyclic fragments and preparing methods of benzothiazine-4-ketone compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 12

[0068] Example 12-[3-(cyclohexylmethyl)(methyl)aminoazetidin-1-yl]-6-trifluoromethyl-8-nitro-4H-benzo[e][1, 3] Thiazin-4-one

[0069] 2-Methylthio-6-trifluoromethyl-8-nitro-4H-benzo[e][1,3]thiazin-4-one (0.16g, 0.5mmol) was dissolved in absolute ethanol ( 8mL), added triethylamine (0.10g, 1.0mmol), added dropwise a solution of 3-(cyclohexylmethyl)(methyl)aminoazetidine (0.18g, 1.0mmol) in absolute ethanol (10mL), The reaction was stirred at 60° C. for 3 h, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography to obtain a yellow solid (51% yield).

[0070] 1 HNMR (500MHz, CDCl 3 )δ9.12(s,1H),8.78(s,1H),3.73–3.36(m,5H),2.26(s,3H),2.18-2.09(m,2H),1.90–1.56(m,5H) ,1.35–1.13(m,6H).

[0071] MS-ESI(m / z):457(M+H) + .

Embodiment 22-

[0072] Example 22-[3-(p-methoxybenzyl)(ethyl)aminoazetidin-1-yl]-6-trifluoromethyl-8-nitro-4H-benzo[e] [1,3]thiazin-4-one

[0073] With the preparation method of the compound of Example 1, 3-(p-methoxybenzyl) (ethyl) amino azetidine and 2-methylthio-6-trifluoromethyl-8-nitro-4H- Benzo[e][1,3]thiazin-4-one was condensed to give a yellow solid (55% yield).

[0074] 1 HNMR (500MHz, CDCl 3 )δ9.12(s,1H),8.78(s,1H),7.25-7.02(m,4H),3.92(s,3H),3.75–3.41(m,7H),2.64(q,2H),1.02 (t,3H).

[0075] MS-ESI(m / z):495(M+H) + .

Embodiment 32

[0076] Example 32-[3-(cyclohexylmethyl)(methyl)aminopyrrolidin-1-yl]-6-trifluoromethyl-8-nitro-4H-benzo[e][1,3] Thiazin-4-one

[0077] With the preparation method of the compound of Example 1, 3-(cyclohexylmethyl)(methyl)aminopyrrolidine and 2-methylthio-6-trifluoromethyl-8-nitro-4H-benzo[e] [1,3] Thiazin-4-one was condensed to give a yellow solid (53% yield), mp: 126-129°C.

[0078] 1 HNMR (500MHz, CDCl 3 )δ9.17(s,1H),8.78(s,1H),4.36–4.18(m,4H),4.15–4.03(m,1H),3.91(s,3H),3.80–3.61(m,2H) ,1.89–1.45(m,7H),1.33–1.13(m,6H).

[0079] MS-ESI(m / z):471(M+H) + .

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Abstract

The invention relates to benzothiazine-4-ketone compounds (shown in the formula I and formula I' in the description) containing basic nitrogen heterocyclic fragments, preparing methods and medical application of the benzothiazine-4-ketone compounds and antituberculosis drug compositions with the benzothiazine-4-ketone compounds as effective constituents, in particular to a 6-trifluoromethyl-8-nitryl-4H-benzo[e][1,3] thiazine-4-ketone compound. A 2-substituent group is 1-nitrogen heterocyclic alkyl or dinitrogen heterocyclic alkyl. R represents H, an alkyl group of 1-4 C atoms, heterocyclic alkyl of 4-7 C atoms, a phenyl group and a substituted phenyl; R1 represents H, an alkyl group of 1-3 C atoms and heterocyclic alkyl of 3-6 C atoms; R2 represents H, an alkyl group of 1-4 C atoms, heterocyclic alkyl of 4-7 C atoms, a phenyl group and substituted phenyl; n1 represents 0-1; n2 represents 1-3; n3 represents 1 and 3.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to benzothiazin-4-one compounds containing basic nitrogen heterocyclic fragments with anti-tuberculosis activity, a preparation method thereof, and an anti-tuberculosis pharmaceutical composition containing them; more specifically , The present invention relates to 6-trifluoromethyl-8-nitro-4H-benzo[e][1,3]thiazin-4-one compounds, whose 2-position substituent is 1- Azacycloalkyl or diazacycloalkyl. Background technique [0002] Tuberculosis (TB) is one of the major infectious diseases caused by Mycobacterium tuberculosis (MTB), which seriously endangers human health. Since the 1980s, the incidence of drug-resistant TB, especially multi-drug-resistant TB (MDR-TB), has been increasing and the combination of TB and HIV / AIDS has caused the TB epidemic to rise again, becoming a major public health problem and a global concern. social problem. According to statistics, there are 8 milli...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/04A61K31/5415A61K31/551A61P31/06
CPCC07D417/04
Inventor 刘明亮郭慧元张芮李林虎王春兰李宵宁沈伟艺陈仕洪
Owner ZHEJIANG STARRY PHARMA
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