Claims
- 1. A method for increasing the antifungal activity of an antifungal agent, comprising administering said antifungal agent in combination with an effective amount of a substituted tetracycline compound, such that the antifungal activity of said antifungal agent is increased.
- 2. The method of claim 1, wherein said antifungal agent is a polyene.
- 3. The method of claim 2, wherein said antifungal agent is amphotericin B.
- 4. The method of any one of claims 1-3, wherein said antifungal activity is inhibiting the growth of a fungus.
- 5. The method of any one of claims 1-3, wherein the antifungal activity is killing the fungus.
- 6. The method of any one of claims 1-5, wherein the effective amount of said antifungal agent is reduced five fold or greater, from the effective amount when the antifungal agent is administered alone.
- 7. The method of claim 6, wherein the antifungal activity of said antifungal agent is reduced eight fold or greater.
- 8. The method of claim 7, wherein the antifungal activity of said antifungal agent is reduced ten fold or greater.
- 9. The method of any one of claims 1-8, wherein said substituted tetracycline compound is of formula I:
- 10. The method of claim 9, wherein R2′, R3, R10, R11, and R12 are each hydrogen or a prodrug moiety and R4 is dimethyl alkyl.
- 11. The method of any one of claims 9 or 10, wherein X is CR6R6′; and R2, R5, R6, R6′, R8 and R9 are each hydrogen.
- 12. The method of any one of claims 9-11, wherein R7 is substituted or unsubstituted aryl.
- 13. The method of claim 12, wherein R7 is substituted or unsubstituted phenyl.
- 14. The method of claim 13, wherein said substituted or unsubstituted phenyl is substituted with at least one alkyl, amino, heterocycle, alkoxy, halogen, nitro, alkoxycarbonyl, dialkylamino, or alkylamino.
- 15. The method of claim 12, wherein R7 is substituted or unsubstituted heteroaryl.
- 16. The method of claim 15, wherein R7 is thienyl.
- 17. The method of any one of claims 9-11, wherein R7 is substituted or unsubstituted alkyl.
- 18. The method of claim 12, wherein said alkyl is C1-C10.
- 19. The method of claim 17, wherein said alkyl is substituted with a substituted or unsubstituted heterocycle, a substituted or unsubstituted phenyl, a hydroxy, or combinations thereof.
- 20. The method of any one of claims 9-11, wherein R7 is substituted or unsubstituted alkenyl.
- 21. The method of claim 20, wherein said substituted alkenyl is substituted with substituted or unsubstituted cyclic moiety.
- 22. The method of claim 21, wherein said cyclic moiety is heterocyclic, cycloalkenyl, cycloalkyl, or aryl.
- 23. The method of claim 22, wherein said cyclic moiety is substituted or unsubstituted phenyl.
- 24. The method of any one of claims 9-11, wherein R7 is substituted or unsubstituted alkynyl.
- 25. The method of claim 24, wherein said substituted alkynyl is substituted with a cyclic moiety or a tetracycline dimer moiety.
- 26. The method of claim 25, wherein said cyclic moiety is heterocyclic, cycloalkenyl, cycloalkyl, or aryl.
- 27. The method of claim 26, wherein said cyclic moiety is substituted or unsubstituted phenyl or substituted or unsubstituted cycloalkyl.
- 28. The method of any one of claims 9-11, wherein R7 is substituted or unsubstituted alkyl carbonyl or substituted or unsubstituted amino.
- 29. The method of claim 9 or 10, wherein X is CR6R6′; and R2, R5, R6, R6′, and R8 are each hydrogen.
- 30. The method of claim 29, wherein R9 is alkyl and R7 is substituted or unsubstituted aminomethyl.
- 31. The method of claim 29, wherein R7 is alkyl and R9 is substituted or unsubstituted aminomethyl.
- 32. The method of claim 9 or 10, wherein X is CR6R6′; and R2, R5, R6, R6′, and R8 are each hydrogen, and R7 is dimethyl amino.
- 33. The method of claim 32, wherein R9 is substituted or unsubstituted aryl or aralkyl.
- 34. The method of claim 33, wherein said aryl is substituted or unsubstituted phenyl.
- 35. The method of claim 34, wherein said phenyl is substituted with one or more substituents selected from the group consisting of amido, alkyl, aminoalkyl, heterocycle, carboxylic acid, formyl, chlorine, fluorine, or acetyl.
- 36. The method of claim 32, wherein R9 is substituted or unsubstituted alkenyl or alkynyl.
- 37. The method of claim 36, wherein said alkynyl is substituted with one or more substituents selected from the group consisting of substituted and unsubstituted aryl, substituted and unsubstituted alkyl, carboxylic acid, cycloalkyl, cycloalkenyl, or alkoxycarbonyl.
- 38. The method of claim 32, wherein R9 is substituted or unsubstituted alkyl or alkylamino.
- 39. The method of claim 32, wherein R9c is hydrogen, Z is S or O, and Z′ is NH.
- 40. The method of claim 39, wherein R9a comprises substituted or unsubstituted phenyl.
- 41. The method of claim 9 or 10, wherein X is C═CR13Y; and R2, R5, R6, R6′, R7, R8, R9 and Y are each hydrogen.
- 42. The method of claim 41, wherein R13 is substituted or unsubstituted aryl.
- 43. The method of any one of claims 1-9, wherein said substituted tetracycline compound is selected from the group consisting of:
- 44. The method of any one of claims 1-43, wherein said tetracycline compound is non-antibacterial.
- 45. The method of any one of claims 1-43, wherein said tetracycline compound has anti-inflammatory activity.
- 46. The method of any one of claims 1-9, wherein said tetracycline compound is a compound shown in Table 2.
- 47. A method for treating a fungal associated disorder in a subject, comprising administering to said subject an effective amount of a substituted tetracycline compound in combination with an antifungal agent such that said subject is treated for said fungal associated disorder.
- 48. The method of claim 47, wherein said antifungal agent is a polyene.
- 49. The method of claim 47, wherein said antifungal agent is amphotericin B.
- 50. The method of any one of claims 47-49, where said effective amount has a lower cytotoxicity than an effective amount of the antifungal agent when administered alone.
- 51. The method of any one of claims 47-50, wherein said substituted tetracycline compound is of formula I:
- 52. The method of any one of claims 47-51, wherein said fungal disorder is associated with a fungus selected from the group consisting of A. nidulans, L. orientalis, C. neoformans, C. tropicalis, C. parapsilosis, C. lusitaniae, C. krusei, C. guilliermondii, C. glabrata, C. dubliniensis, or C. albicans.
- 53. The method of any one of claims 47-52, wherein said fungal associated disorder is histoplasmosis, systemic candidiasis, aspergillosis, blastomycosis, coccidioidomycosis, paracoccidioidomycosis, 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.
- 54. The method of any one of claims 47-52, wherein said subject is a plant.
- 55. The method of any one of claims 47-53, wherein said subject is a mammal.
- 56. The method of claim 55, wherein said mammal is a human.
- 57. The method of claim 55 or 56, wherein said mammal is immunocompetent.
- 58. The method of claim 52 or 53, wherein said mammal is immunocompromised.
- 59. The method of claim 58, wherein said human is immunodeficient.
- 60. The method of claim 59, wherein said human has AIDS.
- 61. The method of claim 59, wherein said human has undergone chemotherapy.
- 62. The method of any one of claims 47-61, further comprising the administration of a pharmaceutically acceptable carrier.
- 63. The method of any one of claims 47-62, wherein said tetracycline compound is non-antibacterial.
- 64. The method of any one of claims 47-62, wherein said tetracycline compound has anti-inflammatory activity.
- 65. The method of any one of claims 47-62, wherein said tetracycline compound is a compound shown in Table 2.
- 66. A method for treating a fungal associated disorder in a mammal, comprising administering to said mammal a synergistically effective amount of a substituted tetracycline compound in combination with an effective amount amphotericin B, such that said mammal is treated for said fungal associated disorder.
- 67. The method of claim 66, wherein the amount of said synergistically effective substituted tetracycline compounds and said effective amount of amphotericin B is not toxic to the subject.
- 68. A pharmaceutical composition comprising a synergistically effective amount of a substituted tetracycline compound, an effective amount of an antifungal agent, and a pharmaceutically acceptable carrier.
- 69. The pharmaceutical composition of claim 68, wherein said tetracycline compound and said antifungal agent are combined in the same pharmaceutically acceptable carrier.
- 70. The pharmaceutical composition of claim 68, wherein said pharmaceutical composition comprises two or more pharmaceutically acceptable carriers.
- 71. The pharmaceutical composition of any one of claims 68-70, wherein said effective amounts are effective to treat histoplasmosis, systemic candidiasis, aspergillosis, blastomycosis, coccidioidomycosis, paracoccidioidomycosis, 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.
- 72. The pharmaceutical composition of any one of claims 68-71, wherein said substituted tetracycline compound is of the formula:
- 73. The pharmaceutical composition of claim 68-72, wherein said pharmaceutical composition comprises a substituted tetracycline compound shown in Table 2.
- 74. A method of killing fungus, comprising contacting said fungus with a synergistically effective amount of a substituted tetracycline compound and a effective amount of an antifungal agent, such that said fungus is killed.
- 75. The method of claim 74, wherein said antifungal agent is amphotericin B.
- 76. The method of claim 74 or 75, wherein said substituted tetracycline compound is of the formula:
RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Patent Application Serial No. 60/275,899, entitled “Substituted Tetracycline Compounds as Synergistic Antifungal Agents,” filed Mar. 14, 2001, incorporated herein by reference in its entirety.
Provisional Applications (1)
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Number |
Date |
Country |
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60275899 |
Mar 2001 |
US |