Water-soluble triazole antifungal compound

A compound, triazole technology, applied in the field of water-soluble triazole antifungal compounds and its preparation, can solve problems such as safety risks

Active Publication Date: 2009-11-11
NANJING HUAWE MEDICINE TECH DEV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But it also brings security risks

Method used

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  • Water-soluble triazole antifungal compound
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  • Water-soluble triazole antifungal compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] (a) 4-[2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)-2-propoxy]-4- Oxobutanoic acid.

[0066]

[0067] Add 30.6g (0.1mol) of 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)-2-propanol into the three-necked flask (fluconazole), 13g (1.3mol) of succinic anhydride, 5mL triethylamine, 100mL acetone. The temperature was raised to reflux for 5 hours under stirring, and the temperature was lowered. 100 mL of water was added to the reaction mixture, crystallization was carried out under stirring, and the solid was collected by filtration. Recrystallized in 75% ethanol to obtain 31.6g of product, yield: 77.8%, [M+1] + : 407.12, H-NMR (CDCI 3 )δppm: 8.15(m, 2H), 8.11(m, 2H), 7.16(d, 1H), 6.67(d, 1H), 6.56(m, 1H), 4.26(s, 4H), 2.63(t, 2H ), 2.55(t, 2H).

[0068] (b) 4-[2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)-2-propoxy]-4- Sodium oxobutyrate.

[0069]

[0070] Take 20.3 g (0.05 mol) of the product from the previous step, dissolve it in 200 m...

Embodiment 2

[0072] (a) L-2-amino-4-[2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)-2-propane Oxy]-4-oxobutanoic acid.

[0073]

[0074] Add 15g (0.11mol) of L-2-aminosuccinic acid, 150mL PCl 3 Raise the temperature to 60°C for 3 hours. Recover excess PCl under reduced pressure 3 , 250 mL of acetone was added to the residue, and 30.6 g (0.1 mol) of 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazole-1- base)-2-propanol (fluconazole), heated to reflux reaction for 5hr under stirring, cooled down, added 100mL water to the reaction mixture, crystallized under stirring, and collected the solid by filtration. Recrystallized in 75% ethanol to obtain 28.9g of product, yield: 68.6%, [M+1] + : 422.1, H-NMR (CDCI 3 )δppm: 8.17(m, 2H), 8.03(m, 2H), 7.44(d, 1H), 6.96(d, 1H), 6.35(m, 1H), 4.22(s, 4H), 4.13(t, 1H ), 2.87(d, 1H), 2.61(d, 1H).

[0075] (b) L-2-amino-4-[2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)-2-propane Sodium oxy]-4-oxobutanoate.

[0076]

[0077]Take 21.1 ...

Embodiment 3

[0079] (a) (2Z)-4-[2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)-2-propoxy ]-4-oxo-2-butenoic acid.

[0080]

[0081] Add 30.6g (0.1mol) of 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)-2-propanol into the three-necked flask (fluconazole), 13g (1.3mol) of maleic anhydride, 5mL triethylamine, 100mL acetone. The temperature was raised to reflux for 5 hours under stirring, and the temperature was lowered. 100 mL of water was added to the reaction mixture, crystallization was carried out under stirring, and the solid was collected by filtration. Recrystallized in 75% ethanol to obtain 29.6g of product, yield: 73.3%, [M+1] + : 405.1, H-NMR (CDCl 3 )δppm: 8.21(m, 2H), 8.14(m, 2H), 7.25(d, 1H), 6.88(d, 1H), 6.79(m, 1H), 6.51(s, 1H), 6.35(s, 1H ), 4.31(s, 4H).

[0082] (b) (2Z)-4-[2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)-2-propoxy ]-Sodium 4-oxo-2-butenoate.

[0083]

[0084] Take 21.3 g (0.05 mol) of the product from the previous step, dissol...

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Abstract

The invention belongs to the field of pharmaceutical preparations, in particular discloses a water-soluble triazole antifungal compound and a preparation method thereof. The water-soluble triazole antifungal compound has a structural formula like a formula Ia, a formula Ib or a formula Ic, wherein R1 is a group of a formular II. The compound is formed by inducing a new group on a structural basis of a broad-spectrum and high-efficiency antifungal compound in the processes of clinical application and new drug development so as to improve the water solubility of the compound and lower the toxicity, is used as a prodrug of triazole antifungal medicaments and has the advantages of wide antifungal spectrum, strong antifungal activity resistance, good safety, and the like.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations, and relates to a water-soluble triazole antifungal compound and a preparation method thereof. Background technique [0002] Triazole is a five-membered heterocyclic ring in which one carbon atom in the imidazole ring is replaced by nitrogen. As a pharmacophore, triazole has lower toxicity than imidazole, and it is widely used in many types of medicines and pesticides. So far, there have been many The triazole drugs are used in clinical and agricultural; as an important functional group, triazole has a strong ability to complex metal ions and form hydrogen bonds, so it is favored in the chemical field. [0003] Triazole antifungal drugs are currently the most widely used drugs for the treatment of mycoses, especially deep mycoses. Its mechanism of action is that N-4 on the triazole ring coordinates with the iron atom of the iron porphyrin center in the fungal cytochrome P-450 to inhibit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D249/08C07D417/06C07D403/06A61K31/4196A61K31/506A61K31/427A61P31/10
Inventor 张孝清肖涛朱宏彬
Owner NANJING HUAWE MEDICINE TECH DEV
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