Azole compounds as anti-fungal agents

A compound of Formula II,

• 6
• and its pharmaceutically acceptable salts, enantiomers, diastereomers, N-oxides, prodrugs or metabolites
• wherein X is selected from the group consisting of CH2, CO, CS, and SO2;
• Ar is a substituted phenyl group having one to three substituents independently selected from a halogen (e.g., fluorine, chlorine, bromine, or iodine) C1-C4 alkyl, halogenated lower (C1-C4) alkyl group and halogenated lower (C1-C4) alkoxy group such as 2,4-difluorophenyl, 2,4-dichlorophenyl, 4-chlorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-fluorophenyl, 4-trifluoromethylphenyl, 2-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, 4-trifluoromethoxyphenyl, 2,4,6-trifluorophenyl, 4-bromophenyl;
• R1 and R2 are each independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, amino, hydroxy, nitro, cyano, carboxyl, protected carboxyl, and SO2 R′ wherein R′ is hydrogen, alkyl or aryl;
• and
• X1, X2, Y1, Y2 and Z are independently selected from the group consisting of hydrogen halogen, nitro, cyano, amino, sulphonyl, aryl, C1-C4, alkyl, C1-C4 alkoxy, halogenated lower (C1-C4) alkyl group, halogenated lower (C1 -C4 )alkoxy group and carboxyl, or protected carboxyl.

A method of treating or preventing fungal infection in mammals comprising administering to said mammal a compound of Formula I

• 7
• and its pharmaceutically acceptable salts, enantiomers, diastereomers, N-oxides prodrugs or metabolites,
• wherein X is selected from the group consisting of CH2, CO, CS, and SO2;
• Ar is a substituted phenyl group having one to three substituents independently selected from a halogen (e.g., fluorine, chlorine, bromine, or iodine), C1-C4 alkyl, halogenated lower (C1-C4) alkyl group and halogenated lower (C1-C4) alkoxy group such as 2,4-difluorophenyl, 2,4-dichlorophenyl, 4-chlorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-fluorophenyl, 4-trifluoromethylphenyl, 2-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, 4-trifluoromethoxyphenyl, 2,4,6-trifluorophenyl, 4-bromophenyl;
• R1 and R2 are each independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, amino, hydroxy, nitro, cyano, carboxyl, protected carboxyl, and SO2 R′ wherein R′ is hydrogen, alkyl or aryl;
• Y is a phenyl group which is unsubstituted or substituted by 1-3 substituents each independently selected from the group consisting of halogen, nitro, amino, cyano, carboxyl, protected carboxyl, hydroxy, C1-C4 alkyl, C1-C4 alkoxy and SO2R′ wherein R′ is hydrogen, alkyl or aryl;
• R3 is selected from the group consisting of hydrogen, C1-C4 alkyl group, C1-C4 alkoxy, nitro, amino, cyano, carboxyl, protected caboxyl and SO2R′ wherein R′ is hydrogen, alkyl or aryl;
• and
• X1, X2, Y1, Y2 and Z are independently selected from the group consisting of hydrogen halogen, nitro, cyano, amino, sulphonyl, aryl, C1-C4, alkyl, C1-C4 alkoxy, halogenated lower (C1-C4) alkyl group, halogenated lower (C1-C4 )alkoxy group and carboxyl, or protected carboxyl.

A method of treating or preventing fungal infection in mammals comprising administering to said mammal a compound of Formula II

• 8
• and its pharmaceutically acceptable salts, enantiomers, diastereomers, N-oxides, prodrugs or metabolites
• wherein X is selected from the group consisting of CH2, CO, CS, and SO2;
• Ar is a substituted phenyl group having one to three substituents independently selected from a halogen (e.g., fluorine chlorine bromine or iodine) C1-C4 alkyl, halogenated lower (C1-C4) alkyl group and halogenated lower (C1-C4) alkoxy group such as 2,4-difluorophenyl, 2,4-dichlorophenyl, 4-chlorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-fluorophenyl, 4-trifluoromethylphenyl, 2-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, 4-trifluoromethoxyphenyl, 2,4,6-trifluorophenyl, 4-bromophenyl;
• R1 and R2 are each independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, amino, hydroxy, nitro, cyano, carboxyl, protected carboxyl, and SO2 R′ wherein R′ is hydrogen, alkyl or aryl;
• and
• X1, X2, Y1, Y2 and Z are independently selected from the group consisting of hydrogen halogen, nitro, cyano, amino, sulphonyl, aryl, C1-C4, alkyl, C1-C4 alkoxy, halogenated lower (C1-C4) alkyl group, halogenated lower (C1-C4 )alkoxy group and carboxyl, or protected carboxyl.

A process for preparing a compound of Formula I

• 9
• and its pharmaceutically acceptable salts, enantiomers, diastereomers, N-oxides prodrugs or metabolites,
• wherein X is selected from the group consisting of CH2, CO, CS, and SO2;
• Ar is a substituted phenyl group having one to three substituents independently selected from a halogen (e.g., fluorine, chlorine, bromine, or iodine), C1-C4 alkyl, halogenated lower (C1-C4) alkyl group and halogenated lower (C1-C4) alkoxy group such as 2,4-difluorophenyl, 2,4-dichlorophenyl, 4-chlorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-fluorophenyl, 4-trifluoromethylphenyl, 2-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, 4-trifluoromethoxyphenyl, 2,4,6-trifluorophenyl, 4-bromophenyl;
• R1 and R2 are each independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, amino, hydroxy, nitro, cyano, carboxyl, protected carboxyl, and SO2 R′ wherein R′ is hydrogen, alkyl or aryl;
• Y is a phenyl group which is unsubstituted or substituted by 1-3 substituents each independently selected from the group consisting of halogen, nitro, amino, cyano, carboxyl, protected carboxyl, hydroxy, C1-C4 alkyl, C1-C4 alkoxy and SO2R′ wherein R′ is hydrogen, alkyl or aryl;
• R3 is selected from the group consisting of hydrogen, C1-C4 alkyl group, C1-C4 alkoxy, nitro, amino, cyano, carboxyl, protected caboxyl and SO2R′ wherein R′ is hydrogen, alkyl or aryl;
• and
• X1, X2, Y1, Y2 and Z are independently selected from the group consisting of hydrogen halogen, nitro, cyano, amino, sulphonyl, aryl, C1-C4, alkyl, C1-C4 alkoxy, halogenated lower (C1-C4) alkyl group, halogenated lower (C1-C4 )alkoxy group and carboxyl, or protected carboxyl;
• which comprises reacting the oxo compound of Formula III (Scheme I), wherein X, Ar, R1, R2, Y, R3, Xi, X2, Y1, Y2 and Z have the same meanings, as defined above, with modified Lawesson's reagent of Formula V (Scheme I) to afford the desired compound of Formula I.

A process for preparing a compound of Formula II

• 10
• and its pharmaceutically acceptable salts, enantiomers, diastereomers, N-oxides, prodrugs or metabolites
• wherein X is selected from the group consisting of CH2, CO, CS, and SO2;
• Ar is a substituted phenyl group having one to three substituents independently selected from a halogen (e.g., fluorine, chlorine, bromine, or iodine) C1-C4 alkyl, halogenated lower (C1-C4) alkyl group and halogenated lower (C1-C4) alkoxy group such as 2,4-difluorophenyl, 2,4-dichlorophenyl, 4-chlorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-fluorophenyl, 4-trifluoromethylphenyl, 2-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, 4-trifluoromethoxyphenyl, 2,4,6-trifluorophenyl, 4-bromophenyl;
• R1 and R2 are each independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, amino, hydroxy, nitrocyano, carboxyl, protected carboxyl, and SO2 R′ wherein R′ is hydrogen, alkyl or aryl;
• and
• X1, X2, Y1, Y2 and Z are independently selected from the group consisting of hydrogen halogen, nitro, cyano, amino, sulphonyl, aryl, C1-C4, alkyl, C1-C4 alkoxy, halogenated lower (C1-C4) alkyl group, halogenated lower (C1-C4 )alkoxy group and carboxyl, or protected carboxyl;
• which comprises reacting the oxo compound of Formula IV (Scheme II) wherein X, Ar, R1, R2, X1l X2, Y1, Y2 and Z are the same as defined above, with modified Lawesson's reagent of Formula V (Scheme II) to afford the desired compound of Formula II.