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Pyrazolo[1,5‑a]pyridine compounds and their applications

A technology of pyridines and pyrazolo, applied in the field of chemical medicine, can solve the problems of potential safety hazards, toxic and side effects of bedaquiline, etc.

Active Publication Date: 2018-03-27
GUANGDONG GOOD MEDICINE & HEALTH TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, follow-up clinical trials have shown that bedaquiline also exhibits certain toxic and side effects, and potential safety hazards still exist

Method used

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  • Pyrazolo[1,5‑a]pyridine compounds and their applications
  • Pyrazolo[1,5‑a]pyridine compounds and their applications
  • Pyrazolo[1,5‑a]pyridine compounds and their applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] Example 1: 5-Chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidine-1-substituted)benzyl)pyrazol[1,5 -a]pyridine-3-carboxamide (TJ170298)

[0084]

[0085]

[0086] Step 1: tert-butyl 4-(4-(trifluoromethoxy)phenyl)-5,6-dihydropyridine-1(2H)-carbonate (A 1 )

[0087]

[0088] Add redistilled THF (100mL) and diisopropylamine (5mL, 36mmol) into a dry 500mL round-bottomed flask, and add 2.4M n-butyllithium cyclohexane dropwise under Ar protection and -78°C solution (36 mmol, 15 mL). After stirring for 1 h, 1-Boc-4-piperidone (36 mmol, 7.2 g) dissolved in 25 mL of anhydrous THF was added dropwise to the reaction system. After reacting for 1.5 h, N-phenylbis(trifluoromethanesulfonyl)imide (39.6 mmol, 14.15 g) dissolved in 5 mL of anhydrous THF was added dropwise to the flask, and the reaction was raised to room temperature and stirred overnight. The solvent was evaporated under reduced pressure to obtain a crude product, which was directly used in the next...

Embodiment 2

[0127] Example 2: 5-Chloro-2-ethyl-N-(4-(trifluoromethoxy)phenyl)pyrazol[1,5-a]pyridine-3-carboxamide (TJ170322)

[0128]

[0129] The synthesis method is as in steps 5-9 in Example 1.

[0130] 1 H NMR (400MHz, DMSO-d 6 ): δ8.74(d, J=7.2Hz, 1H), 8.32(t, J=6.0Hz, 1H), 7.96(s, 1H), 7.71(d, J=8.4Hz, 2H), 7.57(d ,J=8.0Hz,2H), 7.04(d,J=7.2Hz,1H), 4.57(d,J=5.6Hz,2H), 3.02(q,J=7.4Hz,2H), 1.25(t,J =7.4Hz, 2H).

[0131] MS(ESI),m / z:382(M + +H + ).

Embodiment 3

[0132] Example 3: 5-Chloro-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidine-1-substituted)benzyl)pyrazol[1,5-a]pyridine- 3-Formamide (TJ170371)

[0133]

[0134] The synthesis method is as in Example 1.

[0135] 1 H NMR (400MHz, DMSO-d 6 ): δ8.82(d, J=7.2Hz, 1H), 8.72(s1H), 8.63(s, 1H), 8.24(s, 1H), 7.40(d, J=8.4Hz, 2H), 7.28(d ,J=8.0Hz,2H), 7.20(d,J=8.0Hz,2H),7.13(d,J=7.2Hz,2H),6.94(d,J=8.0Hz,2H),4.38(d,J =5.2Hz, 2H), 3.77(m, 2H), 2.72(m, 3H), 1.86(m, 2H), 1.74(m, 2H).

[0136] MS(ESI),m / z:529(M + +H + ).

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Abstract

Disclosed in the invention are a pyrazolo[1,5-a]pyridine compound with the structural features as shown in formula (I) or a pharmaceutically acceptable salt, stereoisomer or prodrug molecule thereof and a use thereof. Such compounds have a good in vitro antituberculosis activity, and the minimal inhibitory concentration (MIC) of the compounds is lower than 0.1 μg / mL and partially achieves 0.01 μg / mL, and have a very strong inhibiting effect on clinically selected multi-drug resistant tuberculosis (MDR-TB) strains. In an in vivo experiment, the pyrazolo[1,5-a]pyridine compounds of the present invention can effectively scavenge the infectious dose of H37Ra in a mouse body at 20mg / kg / d doses, thereby being a new type of antituberculosis compound.

Description

technical field [0001] The invention belongs to the field of chemistry and medicine, in particular to pyrazolo[1,5-a]pyridine compounds and applications thereof. Background technique [0002] Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb) infection and is one of the most prevalent diseases in the world. Among human tuberculosis, pulmonary tuberculosis is the most common, accounting for 80-90% of the total number of tuberculosis in various organs. Due to the emergence of drug-resistant tuberculosis and the concurrent infection of AIDS, the therapeutic effect of existing clinical drugs has been greatly reduced. [0003] According to the 18th WHO Global Tuberculosis Report, there were about 8.6 million new tuberculosis patients worldwide in 2012, and the death toll reached 1.3 million. In China, the incidence rate of tuberculosis accounts for 12% of the world's incidence rate (1 million people), ranking second in the world, and the death toll is 44,000, ranki...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04A61K31/4545A61K31/437A61K31/444A61K31/506A61K31/496A61P31/06
CPCC07D471/04A61P31/06
Inventor 陆小云汤健丁克张天宇张现涛涂正超伍甜万军庭曹元元何盛江
Owner GUANGDONG GOOD MEDICINE & HEALTH TECH CO LTD
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