Novel triazole antifungal compound, pharmaceutical composition and preparation method and application thereof

A compound, triazole technology, applied in the fields of drug synthesis, pharmacology, and pharmacology, can solve the problems of low oral bioavailability, low bioavailability, and the effect of which is greatly affected by food.

Inactive Publication Date: 2014-08-06
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, fluconazole has a narrow antibacterial spectrum and drug resistance is becoming more and more serious, while itraconazole has poor water solubility and low bioavailability. Another serious problem brought about by poor water solubility is that these drugs must be made into special preparations. It is effective orally, which greatly increases the cost of treatment for patients
Itraconazole injections used to rescue critically ill patients must add cyclodextrin to increase water solubility, and cyclodextrin will produce additional side effe...

Method used

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  • Novel triazole antifungal compound, pharmaceutical composition and preparation method and application thereof
  • Novel triazole antifungal compound, pharmaceutical composition and preparation method and application thereof
  • Novel triazole antifungal compound, pharmaceutical composition and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0137] Example 1 (2R,3R)-2-(2,4-difluorophenyl)-3-(5,6-dihydroimidazo[1,2-a]piperazin-7(8H)-yl)- Preparation of 1-(1H-1,2,4-triazol-1-yl)butan-2-ol (compound 1)

[0138]

[0139] Compound 2A (126.0 mg, 0.48 mmol) was dissolved in 10.0 ml of acetonitrile under Ar gas protection. Compound 3a-1 (118.0mg, 0.96mmol) and lithium perchlorate (102.0mg, 0.96mmol) were added, and the reaction mixture was heated to 80°C for 20 hours, then cooled to room temperature. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was washed with CH 2 Cl 2 dissolved, and the organic phase was washed 3 times with saturated NaCl solution, anhydrous NaCl 2 SO 4 After drying, filtering, and evaporating to dryness, the residue was separated by column chromatography (dichloromethane:methanol=100:1-50:1) to obtain 80.8 mg of white solid compound 1, melting point: 86-88°C, yield 45.0%.

[0140] 1 H NMR (300MHz, CDCl 3 )δ7.86(s,1H),7.79(s,1H),7.48-7.36(m,1H),7.15(...

Embodiment 2

[0141] Example 2 (2R,3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-(2-(trifluoromethyl base)-5,6-dihydroimidazo[1,2-a]piperazin-7(8H)-yl)butan-2-ol (compound 2)

[0142]

[0143] Compound 2A (100.0mg, 0.40mmol) was added to compound 3a-2 (152.0mg, 0.80mmol) and lithium perchlorate (85.1mg, 0.80mmol), and prepared in a similar manner to Example 1 to obtain 89.8mg of a white solid Compound 2, melting point: 141-143°C, yield 50.6%.

[0144] 1 H NMR (300MHz, CDCl 3 )δ7.83(s,1H),7.77(s,1H),7.48-7.36(m,1H),7.20(s,1H),6.81-6.66(m,2H),5.01(s,1H),4.96 -4.79(m,2H),4.18-4.00(m,3H),3.95-3.87(m,1H),3.75-3.79(m,1H),3.27(q,J=6.8Hz,1H),2.92-2.71 (m,1H),0.96(d,J=6.8Hz,3H).ESI-MS: 443.1(M+1).

Embodiment 3

[0145] Example 3 (2R,3R)-3-(2-tert-butyl-5,6-dihydroimidazo[1,2-a]piperazin-7(8H)-yl)-2-(2,4- Preparation of difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (compound 3)

[0146]

[0147] Compound 2A (126.0mg, 0.48mmol) was added to compound 3a-3 (172.0.0mg, 0.96mmol) and lithium perchlorate (102.0mg, 0.96mmol), and prepared in a similar manner to Example 1 to obtain 94.4mg of white Solid compound 3, melting point: 129-131°C, yield 45.6%.

[0148] 1H NMR (300MHz, CDCl 3 )δ7.84(s,1H),7.75(s,1H),7.39(m,1H),6.79-6.67(m,2H),6.62(s,1H),5.02(s,1H),4.97-4.80 (m,2H),4.28-4.21(m,2H),4.12-3.94(m,3H),3.29(q,J=6.8Hz,1H),2.89-2.74(m,1H),1.35(s,9H ),0.94(d,J=6.8Hz,3H).ESI-MS: 431.2(M+1).

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Abstract

The invention provides a triazole compound shown as a general formula (I), optical isomers or the pharmaceutically acceptable salts thereof, and application of the compound, optical isomers or pharmaceutically acceptable salts thereof to preparation of medicaments for resisting fungi, especially Candida albicans, Candida parapsilosis, Candida glabrata, Cryptococcus neoformans, Microsporum flavescens, Trichophyton rubrum and / or Aspergillus fumigatus. The invention provides a pharmaceutical composition, comprising a therapeutically effective amount of one or more selected from the compound shown in the formula (I), optical isomers and pharmaceutically acceptable salts thereof and pharmaceutic adjuvants.

Description

technical field [0001] The invention belongs to the field of pharmacy and relates to the fields of drug synthesis and pharmacology. More specifically, it relates to a triazole antifungal compound containing a nitrogen heterocycle, its pharmaceutical composition, its preparation method and its use in the preparation of antifungal drugs. Background technique [0002] In the past ten years, due to the continuous increase in the incidence of tumors, the widespread development of bone marrow and organ transplantation operations, and the substantial increase in the use of immunosuppressants and broad-spectrum antibiotics, deep fungal infections caused by Candida, Aspergillus, and Cryptococcus neoformans It is an increasingly common problem in clinical practice. Systemic deep fungal infection seriously endangers the lives of patients, and the mortality rate is as high as 50%. However, the existing antifungal drugs have shortcomings such as narrow antibacterial spectrum, high toxic...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D513/04A61K31/4985A61K31/506A61K31/437A61K31/444A61K31/4439A61P31/10
CPCC07D487/04C07D513/04A61P31/10
Inventor 杨玉社曹旭峰李战李炜
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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