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Substituted n-((1',3'-heterazol-4'-yl)-methyl)-4-benzoyl hexahydropyridine compounds and uses thereof

A technology of compounds and uses, applied in the field of preparing anti-tuberculosis drugs, which can solve the problems of no new anti-tuberculosis drugs

Active Publication Date: 2017-01-25
MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, since the discovery of rifampicin in 1965, there has been no new anti-TB drug that can be used clinically

Method used

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  • Substituted n-((1',3'-heterazol-4'-yl)-methyl)-4-benzoyl hexahydropyridine compounds and uses thereof
  • Substituted n-((1',3'-heterazol-4'-yl)-methyl)-4-benzoyl hexahydropyridine compounds and uses thereof
  • Substituted n-((1',3'-heterazol-4'-yl)-methyl)-4-benzoyl hexahydropyridine compounds and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] Embodiment 1: Synthesis of N-acetylpiperidine-4-carboxylic acid

[0079]

[0080] Take 20.0g (154.8mmol) of piperidinecarboxylic acid, 30ml (317.4mmol) of acetic anhydride, and 12.5ml (155.3mmol) of pyridine in a 100ml round bottom flask, and reflux at 140°C for 2 hours to obtain a brown solution. Most of the solvent was evaporated under reduced pressure to obtain an emulsion, which was cooled. Add 40ml of ethyl acetate-ether (v / v=1:1) solution to the above emulsion, stir to precipitate a solid, filter with suction, and wash with ethyl acetate-ether (v / v=1:1) solution to obtain a white Solid, 20.9g, m.p.174~176℃, yield 78.9%: 1 H NMR (400MHz, CD 3 OD): δ=4.293(m,1H),3.805(m,1H),3.145(m,1H),2.789(m,1H),2.525(m,1H),2.036(s,3H),1.855(m ,2H),1.516(m,2H);MS(ESI):m / z[M+H] + 172.14.

Embodiment 2

[0081] Example 2: Synthesis of N-acetylpiperidin-4-ylbenzo-1',4'-dioxan-3-ylmethanone

[0082]

[0083] Take 5ml (0.076mol) of thionyl chloride and 30ml of dichloromethane in a 10ml round-bottomed flask, and add 5.0g (0.033mol) of synthetic N-acetylpiperidine-4-carboxylic acid under ice-bath and stirring conditions. Add 1 drop of DMF dropwise, and react at 40°C for 3 hours. The solvent was evaporated under reduced pressure to obtain a brown solid, which was eluted with 25ml of 1,2-dichloroethane in batches and placed in a constant pressure dropping funnel for later use.

[0084] Take 6.67g (0.05mol) of aluminum trichloride and 4.49g (0.033mol) of benzo-1,4-dioxane into a 100ml three-necked flask, add 12.5ml of 1,2-dichloroethane, drop at 0°C Add the above-mentioned acid chloride solution, and heat the reaction at 65°C for 16 hours after the addition. Allow to cool, pour into 100 ml of ice water, separate the organic phase, wash the water phase with 25 ml of dichloromethan...

Embodiment 3

[0085] Example 3: Synthesis of piperidin-4-ylbenzo-1',4'-dioxan-3-yl ketone hydrochloride

[0086]

[0087] Take 3.13g (0.01mol) of N-formylpiperidin-4-ylbenzo-1',4'-dioxan-3-ylmethanone in a 100ml round bottom flask, dissolve it in 25ml tetrahydrofuran, and then add 3mol / L hydrochloric acid solution 40ml, reflux at 100°C for 10 hours. The solvent was evaporated under reduced pressure to obtain a brown solid, which was recrystallized from methanol-ether to obtain 2.64 g of off-white solid, m.p.211~213°C, yield 93.3%: 1 H NMR (400MHz, DMSO-d 6):7.538~7.517(dd,J=8.4Hz,J=2.0Hz,1H),7.509(d,J=2.0Hz,1H),4.333~4.271(m,4H),3.660(m,1H),3.005 (t,2H),1.891(d,2H),1.700(m,2H); MS(ESI):m / z[M-HCl+H] + 248.52.

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Abstract

The invention discloses a substituted N-((1', 3'-azole-4'-yl)-methyl)-4-benzoyl-hexahydropyridine compound represented by formula I, a preparation method thereof, and applications of the substituted N-((1', 3'-oxazole-4'-yl)-methyl)-4-benzoyl-hexahydropyridine compound in preparation of antituberculous drugs. The substituted N-((1', 3'-azole-4'-yl)-methyl)-4-benzoyl-hexahydropyridine compound possesses activity on mycobacterium tuberculosis-susceptible strains, and also possesses activity on strains with tolerance on traditional first-line antituberculous drugs such as isoniazide and rifampicin, and is a novel mycobacterium tuberculosis resistant compound with a promising application prospect.

Description

technical field [0001] The present invention relates to a class of substituted N-((1',3'-heterazol-4'-yl)-methyl)-4-benzoyl hexahydropyridine compounds, and also relates to the preparation of said compounds The method and its use for the preparation of anti-tuberculosis drugs. Background technique [0002] Tuberculosis is a chronic infectious disease common to humans, livestock and poultry. In history, it was widely popular all over the world and claimed the lives of hundreds of millions of people. It was called the "white plague" by people. In 1882, Koch discovered that tuberculosis is an infectious disease caused by Mycobacterium tuberculosis (Mycobacterium tuberculosis, referred to as Mycobacterium tuberculosis). Since the 1950s, due to the continuous discovery and clinical application of various effective chemotherapy drugs, the prevalence of tuberculosis was once under control. However, in recent years, tuberculosis, which was once effectively controlled, has made a ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D413/14A61K31/454A61P31/06
CPCC07D413/14
Inventor 司书毅高娜娜姜威蒋建东李妍李东升李永臻张晶朱宁屿王智敏
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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