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Pyrazolo[1, 5-a]pyridine compound and use thereof

A 5-a, pyridine-based technology, applied in the field of chemical medicine, can solve the problems of bedaquiline's toxic side effects and potential safety hazards

Active Publication Date: 2016-04-27
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 compound and use thereof
  • Pyrazolo[1, 5-a]pyridine compound and use thereof
  • Pyrazolo[1, 5-a]pyridine compound and use thereof

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 HNMR (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 HNMR (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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PUM

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Abstract

The invention discloses a pyrazolo[1, 5-a]pyridine compound with the structure characteristic shown in the formula (I) or its pharmaceutically acceptable salt, stereoisomer or prodrug molecule and a use thereof. The compound has good in-vitro anti-tubercle bacillus activity, has the minimal inhibitory concentration (MIC) less than 0.1 micrograms per milliliter and partial MIC of 0.01 micrograms per milliliter and has strong inhibition effects on a clinically sorted multi-drug-resistant tuberculosis (MDR-TB) strain. In an in-vivo experiment, at a dosage of 20mg / kg / d, the pyrazolo[1, 5-a]pyridine compound can effectively eliminate H37Ra infection in a mouse and is a novel anti-tuberculosis 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 (Tuberculosis, TB), caused by Mycobacterium tuberculosis (Mtb) infection, 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 44,0...

Claims

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Application Information

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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涂正超伍甜万军庭曹元元
Owner GUANGDONG GOOD MEDICINE & HEALTH TECH CO LTD
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