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Benzoisoxazole spiropyrimidinetrione compound, preparation method and uses thereof

A compound and mixture technology, applied in organic chemistry methods, organic chemistry, pharmaceutical formulations, etc., can solve the problems of unsatisfactory metabolic properties, limitations, and weak antibacterial activity of spiropyrimidine triketone compounds, etc., and achieve excellent in vivo metabolic properties, good medicinal effect

Active Publication Date: 2019-01-01
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, these spiropyrimidine triketone compounds such as AZD0914 still have the problems of weak antibacterial activity and unsatisfactory metabolic properties, which lead to large clinical overdose, which limits their possibility as a drug for treating systemic infections to a certain extent.

Method used

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  • Benzoisoxazole spiropyrimidinetrione compound, preparation method and uses thereof
  • Benzoisoxazole spiropyrimidinetrione compound, preparation method and uses thereof
  • Benzoisoxazole spiropyrimidinetrione compound, preparation method and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0110] Example 1: (2R,4S,4aS)-11-fluoro-2,4-dimethyl-8-(5-oxo-4-oxo-6-azaspiro[2.4]heptane-6-yl )-1,2,4,4a-tetrahydro-2'H,6H-spiro[isoxazol[4,5-g][1,4]oxazine[4,3-a]quinoline-5, 5'-pyrimidine]-2',4',6'(1'H,3'H)-trione (compound 1)

[0111] (a) 1-(((5-(1,3-dioxolan-2-yl)-6,7-difluorobenzo[d]isoxazol-3-yl)amino)methyl)- 1-Cyclopropanol (I-3-1)

[0112]

[0113] Intermediate A (1g, 4.048mmol) was added to 20ml of N,N-dimethylformamide, stirred to dissolve it, N-chlorosuccinimide (650mg, 4.868mmol) was added at room temperature, raised to React at 40°C for 30min, TLC (thin layer chromatography) monitors the completion of the reaction, cool the reaction solution to 0°C, slowly add 1-aminomethyl-1-cyclopropanol (1.06g, 12.144mmol), return to room temperature and react for 1h , TLC monitors that the reaction is complete, adds cesium carbonate (4.567g, 12.144mmol), rises to 60°C for 2h, TLC monitors that the reaction is complete, cools down to room temperature, adds water and et...

Embodiment 2

[0126] Example 2: (2R,4S,4aS)-11-fluoro-2,4-dimethyl-8-(6-oxo-2,5-dioxo-7-azaspiro[3.4]octane- 7-yl)-1,2,4,4a-tetrahydro-2'H,6H-spiro[isoxazol[4,5-g][1,4]oxazin[4,3-a]quinoline -5,5'-pyrimidine]-2',4',6'(1'H,3'H)-trione (compound 2)

[0127] (a) 3-(((5-(1,3-dioxolan-2-yl)-6,7-difluorobenzo[d]isoxazol-3-yl)amino)methyl)oxy Heterobutanol (I-3-2)

[0128]

[0129] According to the synthetic method of intermediate I-3-1, intermediate A (1.2g, 4.857mmol), N-chlorosuccinimide (778mg, 5.828mmol), 3-(aminomethyl)oxetane Butanol (1.25g, 12.142mmol) and cesium carbonate (4.748g, 14.571mmol) were used as raw materials to synthesize 1-(((5-(1,3-dioxolan-2-yl)-6,7-di Fluorobenzo[d]isoxazol-3-yl)amino)methyl)oxetanol 949mg, white solid, yield 59.5%, 1 H NMR (400MHz, DMSO) δ8.08(d, J=5.7Hz, 1H), 7.41(t, J=5.7Hz, 1H), 6.09(s, 1H), 6.01(s, 1H), 4.48(dd , J=15.1, 6.6Hz, 4H), 4.12–3.99(m, 4H), 3.55(d, J=5.8Hz, 2H).

[0130] (b) 7-(5-((1,3-dioxolan-2-yl)-6,7-difluorobenzo[d]isoxazol-3-yl...

Embodiment 3

[0142] Example 3: (2R,4S,4aS)-11-fluoro-2,4-dimethyl-8-(6-oxo-5-oxo-7-azaspiro[3.4]octane-7-yl )-1,2,4,4a-tetrahydro-2'H,6H-spiro[isoxazol[4,5-g][1,4]oxazine[4,3-a]quinoline-5, 5'-pyrimidine]-2',4',6'(1'H,3'H)-trione (compound 3)

[0143] (a) 1-(((5-(1,3-dioxolan-2-yl)-6,7-difluorobenzo[d]isoxazol-3-yl)amino)methyl)cyclo Butanol (I-3-3)

[0144]

[0145] According to the synthetic method of intermediate I-3-1, intermediate A (750mg, 3.036mmol), N-chlorosuccinimide (527mg, 3.947mmol), 1-(aminomethyl)cyclobutanol ( 675mg, 6.679mmol) and cesium carbonate (3.957g, 12.144mmol) as raw materials, synthesis of 1-(((5-(1,3-dioxolan-2-yl)-6,7-difluorobenzo[ d] isoxazol-3-yl)amino)methyl)cyclobutanol 710mg, white solid, yield 72%, 1 H NMR (400MHz, DMSO) δ8.15 (d, J = 5.9Hz, 1H), 7.23 (t, J = 5.4Hz, 1H), 6.08 (s, 1H), 5.27 (s, 1H), 4.11–3.99 (m, 4H), 3.34 (d, J=5.6Hz, 2H), 2.12–1.92 (m, 4H), 1.72–1.45 (m, 2H).

[0146] (b) 7-(5-((1,3-dioxolan-2-yl)-6,7-difluorobenzo[d]isoxazol-3-...

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Abstract

The invention discloses a benzoisoxazole spiropyrimidinetrione compound, a preparation method and uses thereof, wherein the structure is represented by a formula I, and each substituent is defined inthe specification and claims. According to the present invention, the benzoisoxazole spiropyrimidinetrione compound has high antibacterial activity in vivo and in vitro and excellent metabolic property. The formula I is defined in the specification.

Description

technical field [0001] The invention relates to a spiropyrimidine triketone compound containing benzisoxazole group, its pharmaceutical composition, its preparation method and its application in anti-infection medicine. Background technique [0002] With the widespread use and even abuse of antibacterial drugs, the multidrug resistance of pathogenic bacteria has become a serious problem threatening human health. A series of drug-resistant pathogens represented by multidrug-resistant Staphylococcus aureus MRSA, It poses a great challenge to clinical treatment. Although some new antibacterial drugs such as linezolid and daptomycin have been launched in recent years, which can effectively control the infection of Gram-positive bacteria such as MRSA, but with more than 10 years of clinical application, bacteria have also begun to slowly respond to these drugs. slow emergence of drug-resistant strains. Therefore, it is an urgent scientific research task and a major unmet clinic...

Claims

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Application Information

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IPC IPC(8): C07D498/22C07D519/00C07D413/04C07D413/14C07D498/10C07D317/30C07D261/20A61K31/5386A61P31/04
CPCC07D261/20C07D317/30C07D413/04C07D413/14C07D498/10C07D498/22C07D519/00C07B2200/07
Inventor 杨玉社张银勇石程辉陈乾
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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