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Posaconazole derivative, synthesis and application in prolonged action preparation thereof

A posaconazole and drug technology, applied in the field of prodrugs and pharmaceutical preparations, can solve the problems of high workload of clinical staff, poor patient compliance, resistant fungus strains, etc.

Inactive Publication Date: 2017-02-22
HC SYNTHETIC PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This dosing schedule results in a high workload for clinical staff and, more importantly, poor patient compliance, thus increasing the likelihood of sub-dose administration, ultimately leading to the emergence of resistant fungal strains

Method used

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  • Posaconazole derivative, synthesis and application in prolonged action preparation thereof
  • Posaconazole derivative, synthesis and application in prolonged action preparation thereof
  • Posaconazole derivative, synthesis and application in prolonged action preparation thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0171]Embodiment 1: 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1,2,4-triazole-1- Methyl)oxolan-3-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one-2-[(2S, 3S) Pent-3-yl-2-yl]-2-(trimethylammonium)-ethyl phosphate

[0172] Process 1

[0173]

[0174] As shown in Scheme 1 above, choline chloride was reacted with the phosphorylating reagent cyanoethyl N,N-diisopropylamine in anhydrous dichloromethane at room temperature in the presence of N,N-diisopropylethylamine. Propyl chlorophosphoramidite reaction, followed by coupling with posaconazole, followed by oxidation with 30% aqueous hydrogen peroxide gave the crude posaconazole derivative in a one-step process. The cyanoethyl protecting group was cleaved with ammonium hydroxide in methanol at room temperature. The resulting phosphodiester was further converted to the corresponding ammonium phosphate zwitterion salt by reaction with aqueous sodium hydroxide (0.1M) in methanol.

Embodiment 2

[0175] Embodiment 2: Preparation of 2-(decanoyloxy)ethyl-4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)-5- (1,2,4-Triazol-1-ylmethyl)oxolan-3-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-tri Sodium oxazol-3-one-2-[(2S,3S)pent-3-yl-2-yl]phosphate

[0176] Process 2

[0177]

[0178] As shown in Scheme 2 above, the reaction between 1-decanoyl chloride and ethylene glycol in anhydrous dichloromethane at room temperature in the presence of triethylamine affords the hydroxy ester. At room temperature, in anhydrous dichloromethane, in the presence of N, N-diisopropylethylamine, react with the phosphorylating reagent cyanoethyl N, N-diisopropylphosphoramidite chloride, followed by reaction with Coupling of posaconazole followed by oxidation with 30% aqueous hydrogen peroxide afforded posaconazole derivatives in a one-step process. The cyanoethyl protecting group was cleaved with ammonium hydroxide in methanol at room temperature. The resulting phosphodiester was further saponif...

Embodiment 3

[0179] Example 3: Preparation of 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1,2,4-triazole-1 -ylmethyl)oxolan-3-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one-2-[(2S ,3S)Sodium pent-3-yl-2-yl]-2-(nonyloxy)ethyl phosphate

[0180] Process 3

[0181]

[0182] As shown in Scheme 3 above, the reaction between 1-nonanol and ethylene glycol in refluxing toluene in the presence of p-toluenesulfonic acid gives the hydroxy ether. The resulting hydroxyl ether was reacted with the phosphorylating reagent cyanoethyl N,N-diisopropylphosphoramidite chloride in the presence of N,N-diisopropylethylamine in anhydrous dichloromethane at room temperature The reaction, followed by coupling with posaconazole followed by oxidation with 30% aqueous hydrogen peroxide affords the posaconazole derivative in a one-step process. The cyanoethyl protecting group was cleaved with ammonium hydroxide in methanol at room temperature and the resulting phosphodiester was converted to the ...

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PUM

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Abstract

The invention relates to a posaconazole derivative, synthesis and an application in a prolonged action thereof. The invention relates to a formula of a compound and salt, N-oxide, quaternary ammonium and stereoisomer of the compound, wherein R1-R8 are defined according to what is claimed. The invention also relates to a preparation formula of an intermediate body and a method of the compound. The invention further relates to a formula of an application of the compound as a drug, especially the application in preventing or treating fungal infection. The detailed formulas are in the specification.

Description

technical field [0001] The present invention relates to organic chemistry, particularly prodrugs and drug formulations. Background technique [0002] Posaconazole (Posaconazolc), molecular formula: C 37 h 42 f 2 N 8 o 4 . Posaconazole is a derivative of itraconazole, a second-generation triazole antifungal drug launched in 2006. Broad antibacterial spectrum, for Candida, histoplasma capsulata, Sedosporum, bipolar zygomycetes, Fusarium, yeast. Including fluconazole-resistant non-albicans strains, Cryptococcus neoformans and Aspergillus have strong inhibitory activity; especially against relatively rare but life-threatening fungal diseases (zygomycosis, fusarium and coccidioidomycosis, etc. ) also works. This product is suitable for the treatment of a variety of adult invasive fungal infections that are intolerant or refractory to amphotericin; it is used as a prophylactic drug for high-risk patients, and it is used for patients over 13 years old and immunocompromised,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6558A61K31/685A61P31/10
Inventor 陆华龙
Owner HC SYNTHETIC PHARMA CO LTD
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