Substituted tetracycline compounds as synergistic antifungal agents
View Patent ↗Methods and compositions for treating for the synergistic treatment of fungal associated disorders are discussed.
1. A pharmaceutical composition comprising an effective amount of a substituted tetracycline compound and an effective amount of an antifungal agent, and a pharmaceutically acceptable carrier, wherein the substituted tetracycline compound is of formula (I):
wherein
X is CR 6 ′R 6 ;
R 2 and R 2 ′ are each hydrogen;
R 4 ′ and R 4 ″ are each alkyl;
R 4 is NR 4 ′R 4 ″;
R 3 , R 10 , R 11 and R 12 are each hydrogen;
R 5 is hydroxyl or hydrogen;
R 6 and R 6 ′ are each independently hydrogen or alkyl;
R 7 is unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted aryl, alkoxy, unsubstituted or substituted alkylcarbonyl, or —(CH 2 ) 0-3 NR 7c C(═W′)WR 7a ;
R 9 is hydrogen;
W is CR 7d R 7e , S, NR 7b or O;
W′ is O, NR 7e or S;
R 7a , R 7b , R 7c , R 7d and R 7e are each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic or heteroaromatic;
R 8 is hydrogen;
further wherein said antifungal agent is selected from the group consisting of: fluconazole, itraconazole, ketoconazole, miconazole, clotrimazole, voriconazole, posaconazole, ravuconazole, natamycin, lucensomycin, nystatin, amphotericin B and caspofungin acetate, and
further wherein said pharmaceutical composition is effective against one or more fungi selected from the group consisting of: Aspergillus flavus, Aspergillus fumigatus, Aspergillus terreus, Candida albicans, Candida glabrata, Candida guilliermondii, Candida krusei, Candida lusitaniae, Candida parapsilosis, Candida tropicalis, Cryptococcus neoformans, Issatchenkia orientalis , and Saccharomyces cerevisiae.
2. The pharmaceutical composition of claim 1 , wherein said substituted tetracycline compound and said antifungal agent are combined in the same pharmaceutically acceptable carrier.
3. The pharmaceutical composition of claim 1 , wherein said pharmaceutical composition comprises two or more pharmaceutically acceptable carriers.
4. The pharmaceutical composition of claim 1 , wherein said effective amounts are effective to treat histoplasmosis, systemic candidiasis, aspergillosis, blastomycosis, cryptococcosis, dermatophyte infections, tinea pedis, tinea cruris, candidiasis, actinomycosis, mycoses, aspergillosis, candidosis, chromomycosis , entomophthoromycosis, epizootic lymphangitis, geotrichosis, histoplasmosis, mucormycosis, mycetoma, north american blastomycosis, oomycosis, paecilimycosis, penicilliosis, rhinosporidiosis, or sprotrichiosis.
5. The pharmaceutical composition of claim 1 , wherein said pharmaceutical composition comprises a substituted tetracycline compound selected from the group consisting of:
pharmaceutically acceptable salts and enantiomers thereof.
6. A pharmaceutical composition comprising an effective amount of a substituted tetracycline compound and an effective amount of an antifungal agent, and a pharmaceutically acceptable carrier, wherein the substituted tetracycline compound is of formula (I):
wherein
X is CR 6 ′R 6 ;
R 2 and R 2 ′ are each hydrogen;
R 4 ′ and R 4 ″ are each alkyl;
R 4 is NR 4 ′R 4 ″;
R 3 , R 10 , R 11 and R 12 are each hydrogen;
R 5 is hydroxyl or hydrogen;
R 6 and R 6 ′ are each independently hydrogen or alkyl;
R 7 is halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted aryl, alkoxy, unsubstituted or substituted alkylcarbonyl, or —(CH 2 ) 0-3 NR 7c C(═W′)WR 7a ;
R 9 is halogen, nitro, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted aryl, alkoxy, unsubstituted or substituted alkylcarbonyl, or —(CH 2 ) 0-3 NR 9c C(═Z′)ZR 9a ;
Z is CR 9d R 9e , S, NR 9b or O;
Z′ is O, S, or NR 9e ;
W is CR 7d R 7e , S, NR 7b or O;
W′ is O, NR 7e or S;
R 7a , R 7b , R 7c , R 7d , R 7e , R 9a , R 9b , R 9c , R 9d and R 9e are each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic or heteroaromatic;
R 8 is hydrogen;
further wherein said antifungal agent is selected from the group consisting of: fluconazole, itraconazole, ketoconazole, miconazole, clotrimazole, voriconazole, posaconazole, ravuconazole, natamycin, lucensomycin, nystatin, amphotericin B and caspofungin acetate, and
further wherein said pharmaceutical composition is effective against one or more fungi selected from the group consisting of: Aspergillus flavus, Aspergillus fumigatus, Aspergillus terreus, Candida albicans, Candida glabrata, Candida guilliermondii, Candida krusei, Candida lusitaniae, Candida parapsilosis, Candida tropicalis, Cryptococcus neoformans, Issatchenkia orientalis , and Saccharomyces cerevisiae.
7. The pharmaceutical composition of claim 6 , wherein said substituted tetracycline compound and said antifungal agent are combined in the same pharmaceutically acceptable carrier.
8. The pharmaceutical composition of claim 6 , wherein said pharmaceutical composition comprises two or more pharmaceutically acceptable carriers.
9. The pharmaceutical composition of claim 6 , wherein said effective amounts are effective to treat histoplasmosis, systemic candidiasis, aspergillosis, blastomycosis, cryptococcosis, dermatophyte infections, tinea pedis, tinea cruris, candidiasis, actinomycosis, mycoses, aspergillosis, candidosis, chromomycosis , entomophthoromycosis, epizootic lymphangitis, geotrichosis, histoplasmosis, mucormycosis, mycetoma, north american blastomycosis, oomycosis, paecilimycosis, penicilliosis, rhinosporidiosis, or sprotrichiosis.
10. A pharmaceutical composition comprising an effective amount of a substituted tetracycline compound and an effective amount of an antifungal agent, and a pharmaceutically acceptable carrier, wherein the substituted tetracycline compound is selected from the group consisting of:
and pharmaceutically acceptable salts and enantiomers thereof;
further wherein said antifungal agent is selected from the group consisting of: fluconazole, itraconazole, ketoconazole, miconazole, clotrimazole, voriconazole, posaconazole, ravuconazole, natamycin, lucensomycin, nystatin, amphotericin B and caspofungin acetate; and
further wherein said pharmaceutical composition is effective against one or more fungi selected from the group consisting of: Aspergillus flavus, Aspergillus fumigatus, Aspergillus terreus, Candida albicans, Candida glabrata, Candida guilliermondii, Candida krusei, Candida lusitaniae, Candida parapsilosis, Candida tropicalis, Cryptococcus neoformans, Issatchenkia orientalis , and Saccharomyces cerevisiae.
11. The pharmaceutical composition of claim 1 , wherein the antifungal agent is selected from the group consisting of: natamycin, lucensomycin, nystatin and amphotericin B; and further wherein said pharmaceutical composition is effective against one or more fungi selected from the group consisting of: Aspergillus flavus, Aspergillus fumigatus, Aspergillus terreus, Issatchenkia orientalis , and Saccharomyces cerevisiae.
12. The pharmaceutical composition of claim 6 , wherein the antifungal agent is selected from the group consisting of: natamycin, lucensomycin, nystatin and amphotericin B; and further wherein said pharmaceutical composition is effective against one or more fungi selected from the group consisting of: Aspergillus flavus, Aspergillus fumigatus, Aspergillus terreus, Issatchenkia orientalis , and Saccharomyces cerevisiae.