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N-benzylbenzamide compounds and preparation method thereof

A technology of benzamide and compound, applied in the field of medicinal chemistry, can solve the problems of weak effect, ineffectiveness and long treatment period of latent MTB, and achieve the effects of low side effects, good curative effect and high activity

Active Publication Date: 2017-03-29
ZHEJIANG STARRY PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Traditional anti-TB drugs, such as streptomycin, isoniazid, rifampicin, ethambutol, and pyrazinamide, can cure more than 85% of newly diagnosed pulmonary tuberculosis patients, but there is a long treatment cycle (more than 6 months). months) and ineffective against MDR-TB, and the effect on latent MTB is not strong at the same time, so it is imminent to develop new anti-TB drugs to achieve effective treatment and control of TB (Foreign Medicine-Antibiotics Volume 2009, 30(1): 19 -twenty four)

Method used

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  • N-benzylbenzamide compounds and preparation method thereof
  • N-benzylbenzamide compounds and preparation method thereof
  • N-benzylbenzamide compounds and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Example 1 3-nitro-5-trifluoromethyl-N-[4-(4-trifluoromethylpiperidin-1-yl)benzyl]benzamide

[0061] Under nitrogen protection, 3-nitro-5-(trifluoromethyl)benzoic acid (0.23g, 0.1mmol), 4-(4-(trifluoromethyl)piperidin-1-yl)aniline, bis( A mixture of 2-oxo-3-oxazolidinyl)phosphoryl chloride (BOP-Cl, 0.28g, 0.11mmol), triethylamine (0.15g, 0.15mmol) and dichloromethane (25ml) was stirred at room temperature Reaction 2h. After the reaction was completed, it was washed with water (25 ml), and then the organic layer was washed with saturated sodium chloride solution. After concentration, the residue was separated by column chromatography to obtain 0.33 g of off-white solid (70.0% yield), mp: 143-144°C.

[0062] 1 H NMR (500MHz, CDCl 3 )δ9.54(t, J=5.5Hz, 1H), 8.97(s, 1H), 8.66(d, J=9.0Hz, 2H), 7.21(d, J=8.5Hz, 2H), 6.93(d, J=8.5Hz, 2H), 4.44(d, J=5.5Hz, 2H), 3.75(d, J=12.5Hz, 2H), 2.66-2.71(m, 2H), 2.45-2.49(m, 1H), 1.85 (d, J=12.5Hz, 2H), 1.49-1.57 (m, 2H).

[0063] MS...

Embodiment 2

[0065] Example 2 3,5-Dinitro-N-[(4-thiomorpholinyl)benzyl]benzamide

[0066] Same as the preparation method of the compound in Example 1, 3,5-nitrodibenzoic acid reacted with 4-(thiomorpholin-4-yl)aniline to obtain an off-white solid (yield 62.0%), mp: 184-186°C .

[0067] 1 H NMR (500MHz, CDCl 3 )δ9.65(t, J=5.5Hz, 1H), 9.08(d, J=2.0Hz, 2H), 8.95(s, J=2.0Hz, 1H), 7.21(d, J=9.0Hz, 2H) , 6.89 (d, J=9.0Hz, 2H), 4.44 (d, J=5.5Hz, 2H), 3.47-3.50 (m, 4H), 2.63-2.65 (m, 4H).

[0068] MS-ESI(m / z):403.2(M+H) + .

[0069] HRMS-ESI:m / z Calcd.for C 18 h 19 o 5 N 4 S(M+H) + : 403.19172; Found 403.19065.

Embodiment 3

[0070] Example 3 3,5-Dinitro-N-[4-(octahydro-2H-isoindol-2-yl)benzyl]benzamide

[0071] With the preparation method of the compound of Example 1, 3,5-nitrodiylbenzoic acid was reacted with 4-(octahydro-2H-isoindol-2-yl)aniline to obtain an off-white solid (yield 67.1%), mp: 188-189°C.

[0072] 1 H NMR (500MHz, CDCl 3 )δ9.65(t, J=5.5Hz, 1H), 9.08(d, J=2.0Hz, 2H), 8.95(s, J=2.0Hz, 1H), 7.21(d, J=9.0Hz, 2H) ,6.89(d,J=9.0Hz,2H),4.44(d,J=5.5Hz,2H),2.97-2.99(m,4H),1.58-1.53(m,6H),1.38-1.36(m,4H ).

[0073] MS-ESI(m / z):425.4(M+H) + .

[0074] HRMS-ESI:m / z Calcd.for C 22 h 25 o 5 N 4 (M+H) + :424.39263; Found 425.39195.

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Abstract

The invention relates to N-benzylbenzamide compounds represented by formula (I), a preparation method and a medicinal use thereof, and an anti-tuberculosis medicinal composition adopting the compounds as an effective component. The N-benzylbenzamide compounds are concretely characterized in that a substituent group in the para-position of a benzyl group of the N-benzylbenzamide compounds is a nitrogen-containing heterocyclic segment; and in the formula (I), R represents a trifluoromethyl group or a nitro group, and X represents a 4-thiomorpholinyl group, an octahydro-2H-isoindole-2-yl group, an isoindoline-2-yl group, a 4-substituted piperidine-1-yl group, a (4-substituted phenyl)piperidine-1-yl group or a (4-substituted phenyl)piperazine-1-yl group.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to N-benzyl benzamide compounds with anti-tuberculosis activity and a preparation method thereof, and an anti-tuberculosis pharmaceutical composition containing them; more specifically, a class of N- Benzyl-3-nitro-5-trifluoromethylbenzamide and N-benzyl-3,5-dinitrobenzamide compounds, the substituent on the benzyl para position is 4-thio Morpholinyl, octahydro-2H-isoindol-2-yl, isoindolin-2-yl, 4-substituted piperidin-1-yl, (4-substituted phenyl)piperidin-1-yl, (4-substituted phenyl)piperazin-1-yl. 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 ...

Claims

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Application Information

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IPC IPC(8): C07D295/135C07D209/44C07D211/18C07D211/38C07D211/46C07D211/22A61K31/54A61K31/4035A61K31/495A61K31/451A61P31/06
CPCC07D209/44C07D211/18C07D211/22C07D211/38C07D211/46C07D295/135
Inventor 刘明亮郭慧元李林虎柴芸吕凯汪阿鹏王洪建黄国成王强陈仕洪
Owner ZHEJIANG STARRY PHARMA
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