Antifungal compounds of (arylalkyl) azole derivatives in the structure of oxime ester

Abstract

This invention is related to the antifungal compounds having azole structure in Formula (1), and hydrates, solvates, pharmaceutically acceptable salts or geometric isomers thereof. Formula (1). ##STR00001##

Claims

1. A compound of the following formula ##STR00009## wherein, X is hydrogen, chlorine, fluorine, methyl, methoxy, nitro, or phenyl, X is hydrogen or chlorine, and Y is carbon and B has the following structure: ##STR00010## and wherein A is alkyl, cycloalkyl, arylalkyl, or aryl group; or a hydrate, solvate, pharmaceutically acceptable salt, or geometric isomer thereof.

2. A pharmaceutical formulation comprising a compound according to claim 1 as active ingredient and at least one pharmaceutically acceptable excipient.

3. A method for treating a fungal infection comprising administering a compound according to claim 1 to a subject in need thereof.

4. A method for treating a fungal infection comprising administering a composition according to claim 2 to a subject in need thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) This invention relates to antifungal compounds having azole structure. This invention provides compounds having a structure illustrated in Formula 1, geometric isomers or pharmaceutically acceptable salts thereof:

(2) ##STR00007##

(3) wherein

(4) X=hydrogen, chlorine, fluorine, methyl, methoxy, nitro, phenyl,

(5) X.sup.1=hydrogen or chlorine, and

(6) Y is either carbon or nitrogen. B has the following structure:

(7) ##STR00008##

(8) wherein A is selected from the group of alkyl, cycloalkyl, arylalkyl, or aryl compounds.

(9) Due to the potential pharmacophore “oximino” group, oxime and oxime esters have a wide range of pharmacological activity spectrum. Oximino group usually is an activity modifier or occasionally responsible for the direct activity. The compounds of the present invention are potential antifungal compounds with respect to their chemical structure for treatment of fungal infections.

(10) Compounds related to this invention are synthesized according to the following procedures.

(11) Bromination of Acetophenone/Substituted Acetophenone (Formation of Phenacyl/Substituted Phenacyl Bromides)

Synthesis of 2-bromo-1-phenyl/1-(substituted phenyl)ethanone derivatives

(12) The solution of 50 mmol acetophenone or substituted acetophenone in 50 ml acetic acid is stirred in ice bath and to this solution, three drops of hydrobromic acid is added. The solution of 50 mmol bromine diluted with 2.5 ml acetic acid was added drop wise to the reaction mixture while it is vigorously stirred. When the addition of bromine is completed, the reaction mixture is stirred for 2 hours at room temperature. The reaction mixture is poured in ice-water; the precipitate taken by filtration, is washed with sodium bicarbonate solution and dried in darkness. It is purified via crystallization from methanol/water mixture.

(13) N-Alkylation of Imidazole or Triazole

Synthesis of 2-(1H-imidazol-1-yl/1H-1,2,4-triazol-1-yl)-1-phenyl/1-(substituted phenyl) ethanone derivatives

(14) The solution of 10 mmol phenacyl bromide or substituted phenacyl bromide derivative in 2.5 ml dimethylformamide is slowly added to the solution of 30 mmol imidazole or triazole in 2.5 ml dimethylformamide (DMF) cooled in ice-bath. It is stirred for 2 hours in ice-bath then overnight at room temperature. Afterwards, it is poured in ice-water, the resulting precipitate is filtered, dried, and purified via crystallization.

Synthesis of 2-(1H-imidazol-1-yl/1H-1,2,4-triazol-1-yl)-1-phenyl/1-(substituted phenyl) ethanone oxime

(15) 0.015 mmol 2-(1H-imidazol-1-yl/1H-1,2,4-triazol-1-yl)-1-phenyl/1-(substituted phenyl) ethanone and 0.03 mol hydroxylamine hydrochloride are dissolved in 75 ml ethanol and alkalinized with the solution of 15 N sodium hydroxide to pH 11. The mixture is then heated under reflux for 3 hours. The resulting precipitate is filtered off and the filtrate is evaporated to dryness. The residual is dissolved in water and acidified with saturated hydrochloric acid to pH 5. The precipitate, which is taken by filtration, is purified via crystallization by methanol.

Synthesis of oxime ester derivatives

(16) The suspension or solution of the proper carboxylic acid (2.5 mmol) and 2-(1H-imidazol-1-yl/1H-1,2,4-triazol-1-yl)-1-phenyl/1-(substituted phenyl)ethanone oxime (2.5 mmol) in dry dichloromethane is stirred at 00° C. under gaseous nitrogen. To this mixture, the solution of N,N′-dicyclohexylcarbodiimide (2.5 mmol) and 4-dimethylaminopyridine (0.17 mmol) in dry dichloromethane is slowly added. The mixture is stirred at room temperature or at a proper temperature. The compounds are purified by appropriate methods.

(17) Isolation and purification steps of the compounds, separation of their E and Z isomers, and isolation of these isomers are the critical steps.

(18) As an embodiment of this invention, the synthesis of 2-(1H-imidazol-1-yl)-1-phenylethanone O-cinnamoyl oxime, one of the compounds of the invention, is given along with the synthesis of its starting materials:

Synthesis of 2-bromo-1-phenylethanone

(19) The solution of 50 mmol acetophenone in 50 ml acetic acid is stirred in ice bath and three drops of hydrobromic acid is added. To the reaction mixture, the solution of 50 mmol bromine diluted in 2.5 ml acetic acid was added drop wise while the reaction medium is vigorously stirred. When the addition of bromine solution is completed, the reaction mixture is stirred for 2 hours at room temperature. Then the reaction mixture is poured in ice-water. The precipitate, which is taken by filtration, is washed with sodium bicarbonate solution and dried in darkness. It is purified via crystallization from methanol/water mixture (melting point: 46° C., yield: 75%).

Synthesis of 2-(1H-imidazol-1-yl)-1-phenylethanone

(20) To the solution of 30 mmol imidazole in 2.5 ml DMF cooled in ice-bath, the solution of 10 mmol 2-bromo-1-phenylethanone in 2.5 ml DMF is added slowly. It is stirred for 2 hours in ice-bath then overnight at room temperature. Afterwards, it is poured in ice-water and the resulting precipitate is filtered, dried, and purified via crystallization from ethyl acetate/n-hexane (melting point: 109-10° C., yield: 70%).

Synthesis of 2-(1H-imidazol-1-yl)-1-phenylethanone oxime

(21) 2-(1H-imidazol-1-yl)-1-phenylethanone (15 mmol) and hydroxylamine hydrochloride (30 mmol) are dissolved in 75 ml ethanol and the pH of this solution is adjusted to 14 with 15 N aqueous sodium hydroxide. The mixture is heated under reflux for 3 hours, ethanol is evaporated under vacuum. The residue is dissolved in water and the derivative is acidified with the solution of hydrochloric acid. The compound precipitates at the point of pH 5. The precipitate is taken by filtration and purified via crystallization with methanol (melting point: 166° C., yield: 57%).

Synthesis of 2-(1H-imidazol-1-yl)-1-phenylethanone O-cinnamoyl oxime

(22) Suspension of 2-(1H-imidazol-1-yl)-1-phenylethanone oxime (1 mmol) in dry dichloromethane is stirred under room temperature. To this mixture, trans-cinnamic acid (2 mmol), the solution of dicyclohexylcarbodiimide (2 mmol) and dimethylaminopyridine (0.17 mmol) in dry dichloromethane are added. The reaction mixture is stirred at room temperature for 6-12 hours. Precipitating dicyclohexylurea is filtered off and following this, dichloromethane is removed by evaporation under vacuum. The residue is purified via column chromatography and crystallized from ethyl acetate/n-hexane (melting point: 136-138° C., yield: 30%).