Hybrid molecules containing pharmacophores of fluconazole as antifungal agents and their preparation

Patent metadata

Field	Value
Publication number	US-9512087-B2
Application number	US-201213994323-A
Country	US
Kind code	B2
Filing date	Apr 4, 2012
Priority date	Jun 15, 2011
Publication date	Dec 6, 2016
Grant date	Dec 6, 2016

Abstract

Disclosed herein are novel antifungal compounds of Formula 1, containing fluconazole pharmacophore moieties coupled with other moieties including aryl enones and chalcones and pharmaceutically acceptable salts thereof, methods for preparing these compounds and pharmaceutical preparations containing these novel compounds for prevention and treatment of fungal infections.

First claim

We claim:

1. An antifungal compound of Formula (1), an (R) enantiomer thereof, an (S) enantiomer thereof, a racemate thereof, or a pharmaceutically acceptable salt thereof:

wherein:
X and Y are independently selected from the group consisting of hydrogen, fluorine, chlorine and bromine;
Z is selected from the group consisting of hydrogen, alkyl, alkenyl, and acyl;
R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of:
hydrogen;
a linear or branched alkyl group having 1 to 20 carbon atoms;
an alkoxy group having 1 to 4 carbon atoms;
a hydroxyl group,
a halogen selected from the group consisting of fluorine, chlorine, bromine and iodine; and
a nitro group;

A 1 and B 1 are independently selected from the group consisting of:
—C═O;
—CH═CH—;
alkyl;
brominated alkyl;
cycloalkyl;
aziridinyl;
an epoxy ring;
—CH(OR 5 ), wherein R 5 is H, alkyl or acyl;
—C═N—OR 6 wherein R 6 is H or alkyl;
—C═N—R 7 wherein R 7 is alkyl or aryl; and
—C═N—R 7 wherein R 7 is alkyl; and
—C(X′R 8 )Y′R 9 wherein X′ and Y′ are independently selected from the group consisting of O and S, and R 8 and R 9 are (a) independently selected from alkyl, or (b) linked with each other to form a heterocyclic five to eight-membered ring; or

A 1 -B 1 is a heterocyclic ring selected from the group consisting of 3,5-disubstituted (1H)-pyrazole or 3,5-disubstituted 4,5-dihydro(1H)-pyrazole;
C 1 is selected from the group consisting of hydrogen; phenyl, optionally substituted with at least one group selected from the group consisting of an alkyl group, an alkoxy group, fluorine, and bromine; heteroaryl; thienyl; naphthyl; anthracenyl; indolyl; cycloalkyl; and an alkyl group; and
‘*’ represents a chiral carbon atom.

2. An antifungal compound of Formula (1), an (R) enantiomer thereof, an (S) enantiomer thereof, a racemate thereof, or a pharmaceutically acceptable salt thereof:

wherein:
X and Y are independently selected from the group consisting of hydrogen, fluorine, chlorine and bromine;
Z is selected from the group consisting of hydrogen, alkyl, alkenyl, and acyl;
R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of hydrogen and an alkoxy group having 1 to 4 carbon atoms;
C 1 is selected from the group consisting of hydrogen; phenyl, optionally substituted with at least one group selected from the group consisting of an alkyl group, an alkoxy group, fluorine, and bromine; thienyl; naphthyl; anthracenyl; indolyl; N-methylindolyl; cycloalkyl; and an alkyl group; and
‘*’ represents a chiral carbon atom,
wherein said antifungal compound of Formula (1) is:

(i) Compound 1A, wherein Compound 1A is a compound of Formula (1) wherein either:
A 1 is —C═O and B 1 is —CH═CH—, or
A 1 is —CH═CH— and B 1 is —C═O;

(ii) Compound 1B, wherein Compound 1B is a compound of Formula (1), wherein either:
A 1 is —C═O, and B 1 is alkyl or an epoxy ring; or
A 1 is alkyl or an epoxy ring, and B 1 is —C═O;

(iii) Compound 1C, wherein Compound 1C is a compound of Formula (1), wherein either:
A 1 is —CH═CH—, and B 1 is —CH(OR 5 ); or
A 1 is —CH(OR 5 ), and B 1 is —CH═CH—;

(iv) Compound 1D, wherein Compound 1D is a compound of Formula (1), wherein A 1 -B 1 is a 3,5-disubstituted (1H)-pyrazole; or
(v) Compound 1E, wherein Compound 1E is a compound of Formula (1), wherein A 1 -B 1 is a 3,5-disubstituted 4,5-dihydro(1H)-pyrazole.

3. The antifungal compound of Formula (1) as claimed in claim 2 , wherein said antifungal compound of Formula (1) is Compound 1A, wherein Compound 1A is a compound of Formula (1) wherein either A 1 is —C═O and B 1 is —CH═CH—, or A 1 is —CH═CH— and B 1 is —C═O.

4. The antifungal compound of Formula (1) as claimed in claim 1 , wherein said antifungal compound of Formula (1) is Compound 1B, wherein Compound 1B is a compound of Formula (1), wherein either:
A 1 is —C═O, and B 1 is alkyl, brominated alkyl or an epoxy ring; or A 1 is alkyl, brominated alkyl or an epoxy ring, and B 1 is —C═O.

5. The antifungal compound of Formula (1) as claimed in claim 1 , wherein said antifungal compound of Formula (1) is Compound 1C, wherein Compound 1C is a compound of Formula (1), wherein either A 1 is —CH═CH—, and B 1 is —CH(OR 5 ), —C═N—OR 6 , —C═N—R 7 or —C(X′R 8 )Y′R 9 ; or A 1 is —CH(OR 5 ), —C═N—OR 6 , —C═N—R 7 or —C(X′R 8 )Y′R 9 , and B 1 is —CH═CH—.

6. The antifungal compound of Formula (1) as claimed in claim 2 , wherein said antifungal compound of Formula (1) is Compound 1D, wherein Compound 1D is a compound of Formula (1), wherein A 1 -B 1 is a 3,5-disubstituted (1H)-pyrazole.

7. The antifungal compound of Formula (1) as claimed in claim 2 , wherein said antifungal compound of Formula (1) is Compound 1E, wherein Compound 1E is a compound of Formula (1), wherein A 1 -B 1 is a 3,5-disubstituted 4,5-dihydro(1H)-pyrazole.

8. An antifungal compound selected from the group consisting of:
(E)-1-(4-(2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propoxy) phenyl)-3-phenylprop-2-en-1-one;
(E)-1-(4-(2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-l)propoxy)phenyl)-3-(4-methoxyphenyl)prop-2-en-1-one;
(E)-1-(4-(2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-l)propoxy)phenyl)-3-(2-methoxyphenyl)prop-2-en-1-one;
(E)-1-(4-(2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-l)propoxy)phenyl)-3-(3,5-dimethoxyphenyl)prop-2-en-1-one;
(E)-1-(4-(2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-l)propoxy)phenyl)-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one;
(E)-3-(4-Chlorophenyl)-1-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propoxy)phenyl)prop-2-en-1-one;
(E)-3-(2,4-dichlorophenyl)-1-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propoxy)phenyl)prop-2-en-1-one;
(E)-1-(4-(2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propoxy) phenyl)-3-(2-fluorophenyl)prop-2-en-1-one;
(E)-1-(4-(2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propoxy) phenyl)-3-(4-(octyloxy)phenyl)prop-2-en-1-one;
(E)-1-(4-(2-(4-Fluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propoxy)phenyl)-3-(4-methoxyphenyl)prop-2-en-1-one;
(E)-1-(4-(2-(4-Bromophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propoxy)phenyl)-3-(4-methoxyphenyl)prop-2-en-1-one;
(E)-3-(4-Chlorophenyl)-1-(4-(2-(4-fluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propoxy)phenyl)prop-2-en-1-one;
(E)-1-(4-(2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propoxy) phenyl)-3-(thiophen-2-yl)prop-2-en-1-one;
(E)-1-(4-(2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propoxy) phenyl)-3-(naphthalen-2-yl)prop-2-en-1-one;
(E)-3-(Anthracen-9-yl)-1-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propoxy)phenyl)prop-2-en-1-one;
(E)-1-(4-(2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propoxy) phenyl)-3-(1-methyl-1H-indol-3-yl)prop-2-en-1-one;
(E)-1-(4-(2-(4-Fluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propoxy)phenyl)-3-(thiophen-2-yl)prop-2-en-1-one;
(E)-3-(4-(2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propoxy) phenyl)-1-(4-methoxyphenyl)prop-2-en-1-one;
(E)-3-(4-(2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propoxy) phenyl)-1-(p-tolyl)prop-2-en-1-one;
(E)-1-(2,4-Dichlorophenyl)-3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propoxy)phenyl)prop-2-en-1-one;
(E)-3-(4-(2-(2,4-Difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propoxy)-3-methoxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one;
(E)-3-(4-(2-(2,

Assignees

• Borate Hanumant Bapurao
• Sawargave Sangmeshwer Prabhakar
• Chavan Subhash Prataprao
• Chandavarkar Mohan Anand
• Iyer Ramkrishnan Ramachaandran
• Tawte Amit Chandrakant
• Rao Deepali Damodar
• Council Scient Ind Res

Inventors

• Borate Hanumant Bapurao
• Sawargave Sangmeshwer Prabhakar
• Chavan Subhash Prataprao
• Chandavarkar Mohan Anand
• Iyer Ramkrishnan Ramachaandran
• Tawte Amit Chandrakant
• Rao Deepali Damodar

Classifications

• C07D249/10

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms · CPC title

• C07D249/08 Primary

  1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61P31/10

  Antimycotics · CPC title