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Anti-pulmonary tuberculosis nitroimidazole derivative

An alkyl and cyano technology, applied in the field of diseases caused by drug resistance combined with mycobacteria, can solve problems such as low activity and high side effects

Inactive Publication Date: 2017-07-14
MEDSHINE DISCOVERY INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Combination drugs of this type used in patients with MDR-TB (often treated for more than 2 years) generally have lower activity and higher side effects than the first-line drugs currently on the market

Method used

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  • Anti-pulmonary tuberculosis nitroimidazole derivative
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  • Anti-pulmonary tuberculosis nitroimidazole derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0214] 2-methyl-6-nitro-2-((2-phenyl-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methyl)-2,3-dihydro Imidazo[2,1-B]oxazole

[0215]

[0216] step 1:

[0217] 6-Benzyl-2-phenyl-5,6,7,8-tetrahydro-1,6-naphthalene

[0218]

[0219] To the key intermediate A (1.10 g, 4.25 mmol) in dioxane / water (11 ml, 10 / 1) mixed solution was added potassium phosphate (2.23 g, 10.51 mmol), phenylboronic acid (1.03 g) , 8.45 mmol) and Pd (PPh 3 ) 4 (734.00 mg, 635.19 micromolar), the mixture was stirred at 130 degrees Celsius for 3 hours. The mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=10 / 0, 10 / 1) to obtain 6-benzyl-2-phenyl-7,8-dihydro-5H -1,6-Naphthalene (750.00 mg, 58.75%), a white solid. H NMR(400MHz, CDCl 3 ): δ7.96(d, J=7.2Hz, 2H), 7.53-7.36(m, 10H), 3.76(s, 2H), 3.69(s, 2H), 3.16(t, J=5.9Hz, 2H) , 2.93 (t, J = 5.9 Hz, 2H). LCMS (ESI) m / z: 301 (M+1). LCMS (ESI) m / z: 301 (M+1).

[0220] Step 2:

[0221] 2-...

Embodiment 2

[0233] 2-methyl-6-nitro-2-((2-(4-(trifluoromethoxy)phenyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl )Methyl)-2,3-dihydro[2,1-B]oxazole

[0234]

[0235] step 1:

[0236] 6-Benzyl-2-(4-(trifluoromethoxy)phenyl)-5,6,7,8-tetrahydro-1,6-naphthalene

[0237]

[0238] To a mixed solution of key intermediate A (1.20 g, 4.64 mmol, 1.00 equivalent) in dioxane (5 mL) and water (0.5 mL) was added potassium phosphate (2.46 g, 11.60 mmol, 2.50 equivalent), Add Pd(PPh 3 ) 4 (536.18 mg, 464.00 micromole, 0.10 equivalent), (4-(trifluoromethoxy)phenyl)boronic acid (1.43 g, 6.96 mmol, 1.50 equivalent). The mixture was stirred at 120 degrees Celsius for 3 hours. The mixture was cooled and concentrated under reduced pressure at 50 degrees Celsius. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=50 / 1, 15 / 1) to obtain 6-benzyl-2-(4-(tri (Fluoromethoxy)phenyl)-5,6,7,8-tetrahydro-1,6-naphthalene (1.30 g, 3.38 mmol, 72.89% yield) as a yellow solid. LCMS(ESI) m / z: 385(M+...

Embodiment 3

[0252] (S)-2-Methyl-6-nitro-2-((2-(3-(trifluoromethoxy)phenyl)-7,8-dihydro-1,6-naphthyridine-6( 5H)-yl)methyl)-2-,3-dihydroimidazo[2,1-B]oxazole

[0253]

[0254] The key intermediate B (120.00 mg, 343.08 micromole, 1.00 equivalent) and [3-(trifluoromethoxy)phenyl]boronic acid (70.65 mg, 343.08 micromole, 1.00 equivalent) were dissolved in dioxane (5.00 Ml) and water (500.00 microliters), the solution was added Pd(dppf)Cl at 30 degrees Celsius under nitrogen protection 2 (25.10 mg, 34.31 micromole, 0.10 equivalent), sodium carbonate (90, 91 mg, 857.70 micromole, 2.5 equivalent). The mixture was stirred at 110 degrees Celsius for 12 hours. After the reaction, the mixture was cooled to 30 degrees Celsius and concentrated under reduced pressure at 45 degrees Celsius. The residue was poured into water (10 mL) and stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with saturated brine (10 mL×2), dried over anh...

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Abstract

The invention discloses a substituted nitroimidazole derivative, which is mainly used for treating related diseases caused by mycobacterium infection, such as Mycobacterium tuberculosis, especially for diseases caused by drug-resistant Mycobacterium tuberculosis.

Description

[0001] references: [0002] The contents of the following documents are incorporated into this article by reference [0003] U.S.patent NO.5,668,127 [0004] U.S.patent NO.6,087,358 [0005] JP 2005330266 [0006] WO 2004 / 033463 [0007] WO 2007 / 075872 [0008] WO 2008 / 140090 [0009] WO 2008 / 008480 [0010] WO 2009 / 120789 [0011] WO 2011 / 151320 [0012] WO 2011 / 093529 [0013] WO 2011 / 087995 [0014] WO 2011 / 014774 [0015] WO 2011 / 014776 [0016] WO 2013072903 Technical field [0017] The present invention relates to a substituted nitroimidazole derivative, which is mainly used to treat related diseases caused by mycobacterial infection, such as Mycobacterium tuberculosis, and is especially suitable for diseases caused by drug-resistant combined mycobacteria. Background technique [0018] Mycobacterium tuberculosis is the causative agent of tuberculosis. As a worldwide and fatal infectious disease, according to statistics from the World Health Organization, more than 8 million people are infec...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D519/00A61K31/4375A61K31/4545A61K31/5377A61K31/437A61K31/4985A61K31/519A61K31/4355A61K31/429A61K31/424A61K31/55A61K31/439A61P31/06A61P31/04
CPCC07D519/00
Inventor 罗微丁照中黄志刚
Owner MEDSHINE DISCOVERY INC
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