Combinations for the treatment of fungal infections
(19) AUSTRALIAN PATENT OFFICE (54) Title Combinations for the treatment of fungal infections (51)6 International Patent Classification(s) A61K 031/435 (21) Application No: 2003258983 (22) Applic (87) WIPO No: WO04/002430 (30) Priority Data (31) Number (32) Date 60/393,034 2002 .06 .28 60/393,155 2002.07.02 (33) Country US US 200511037 (43) (43) Publication Date : 2004 .01.19 Publication Journal Date : 2004 .03.04 (71) Applicant(s) COMBINATORX INCORPORATED (54) Title Combinations for the treatment of fungal infections (51)6 International Patent Classification(s) A61K 031/435 (21) Application No: 2003258983 (22) Applic (87) WIPO No: WO04/002430 (30) Priority Data (31) Number (32) Date 60/393,034 2002 .06 .28 60/393,155 2002.07.02 (33) Country US US 200511037 (43) (43) Publication Date : 2004 .01.19 Publication Journal Date : 2004 .03.04 (71) Applicant(s) COMBINATORX INCORPORATED 2003 .06.30 (72) Inventor(s) Serbedzija, George N.; Nichols, James M.: Keith, Curtis; Zimmermann, Grant R.; Auspitz, Benjamin A.; Gaw, Debra A.; Johansen, Lisa M.-1- The invention features a method for treating or preventing fungal growth by contacting fungal cells with (I) an aromatic diamidine or analog thereof or a compound formula (I); and (ii) an aminopyridine, a quaternary ammonium compound, or a compound of formula (II) or (III) simultaneously or within 14 days of each other in amounts sufficient to reduce or inhibit fungal growth. Claims 1. A method for treating a patient who has a fungal infection, or inhibiting the development of a fungal infection in a patient who is at risk for developing a fungal infection, said method comprising administering to said patient (i) an aromatic diamidine or an analog thereof or a compound of formula (I) ; and (ii) an aminopyridine, a quaternary ammonium compound, or a compound of formula (II) or (III), wherein the two compounds are administered simultaneously or within 10 days of each other, in amounts sufficient to treat or inhibit the development of a fungal infection in said patient.
2. The method of claim 1, wherein said aromatic diamidine is selected from the group consisting of pentamidine, propamidine, butamidine, heptamidine, nonamidine, stilbamidine, hydroxystilbamidine, diminazene, benzamidine, 4,4'- (pentamethylenedioxy) di-, dihydrochloride, phenamidine, dibrompropamidine, 1,3-bis (4-amidino-2-methoxyphenoxy) propane, netropsin, distamycin, and phenamidine.
3. The method of claim 1, wherein said aminopyridine is phenazopyridine, 4-aminopyridine, 3,4-diaminopyridine, 2,5-diamino-4- methylpyridine, 2,3, 6-triaminopyridine, 2,4, 6-triaminopyridine, or 2,6- diaminopyridine.
4. The method of claim 1, wherein said quaternary ammonium compound is pentolinium, hexamethonium, pentamethonium, tetramethylammonium, tetraethylammonium, trimethaphan, or chlorisondamine. <Desc/Clms Page number 57> 5. The method of claim 1, wherein said aromatic diamidine is pentamidine and said aminopyridine is phenazopyridine.
6. The method of claim 1, wherein said aromatic diamidine is pentamidine and said quaternary ammonium compound is pentolinium.
7. The method of any of claims 1-6, wherein the two compounds are administered within five days of each other.
8. The method of claim 7, wherein the two compounds are administered within 24 hours of each other.
9. The method of claim 8, wherein the two compounds are administered within one hour of each other.
10. The method of claim 9, wherein the two compounds are administered simultaneously.
11. The method of any one of claims 1-10, wherein said patient has or is at risk of developing tinea capitis, tinea corporis, tinea pedis, tinea barbae, tinea cruris, tinea versicolor, onychomycosis, perionychomycosis, pityriasis versicolor, tinea unguium, oral thrush, vaginal candidosis, respiratory tract candidosis, biliary candidosis, eosophageal candidosis, urinary tract candidosis, systemic candidosis, mucocutaneous candidosis, mycetoma, cryptococcosis, aspergillosis, mucormycosis, chromoblastomycosis, paracoccidioidomycosis, North American blastomycosis, histoplasmosis, coccidioidomycosis, or sporotrichosis. <Desc/Clms Page number 58> 12. The method of any one of claims 1-10, wherein said fungal infection is an infection of Candida albicans, Candida krusei, Candida glabrata, Cryptococcus neoformans or Aspergillus spp.
13. The method of claim 1, wherein each of the compounds is, independently, administered to said patient by intravenous, rectal, oral, topical, intravaginal, ophthalmic, or inhalation administration.
14. The method of claim 1, wherein said aromatic diamidine or compound of formula (I) is administered in an amount between 0.001 and 2000 mg per day.
15. The method of claim 1, wherein said aminopyridine is administered in an amount between 0.001 mg per day per day and 2400 mg per day.
16. The method of claim 1, wherein said quaternary ammonium compound is administered in an amount between 0.5 and 500 mg per day.
17. The method of claim 1, wherein said aromatic diamidine is pentamidine, said aminopyridine is phenazopyridine, and said pentamidine and phenazopyridine are administered at a ratio of 2-1000 parts by molar ratio of phenazopyridine to one part by molar ratio of pentamidine.
18. The method of claim 1, wherein said aromatic diamidine is pentamidine, said quaternary ammonium compound is pentolinium, and said pentamidine and pentolinium are administered at a ratio of 2-1000 parts by molar ratio of pentolinium to one part by molar ratio of pentamidine. <Desc/Clms Page number 59> 19. A composition comprising (i) an aromatic diamidine or analog thereof or a compound of formula (I) ; and (ii) an aminopyridine, a quaternary ammonium compound, or a compound of formula (II) or (III), wherein the two compounds are present in amounts that together inhibit or reduce fungal growth.
20. The composition of claim 19, wherein said aromatic diamidine is pentamidine, propamidine, butamidine, heptamidine, nonamidine, stilbamidine, hydroxystilbamidine, diminazene, benzamidine, 4,4'- (pentamethylenedioxy) di-, dihydrochloride, phenamidine, dibrompropamidine, 1, 3-bis (4-amidino-2- methoxyphenoxy) propane, netropsin, distamycin, or phenamidine.
21. The composition of claim 19, wherein said aminopyridine is phenazopyridine, 4-amino-pyridine, 3,4-diaminopyridine, 2,5-diamino-4- methylpyridine, 2,3, 6-triaminopyridine, 2,4, 6-triaminopyridine, or 2,6- diaminopyridine.
22. The composition of claim 19, wherein said quaternary ammonium compound is pentolinium, hexamethonium, pentamethonium, tetramethylammonium, tetraethylammonium, trimethaphan, or chlorisondamine.
23. A pharmaceutical pack comprising (i) an aromatic diamidine or analog thereof or a compound of formula (I) ; and (ii) an aminopyridine, a quaternary ammonium compound, or a compound of formula (II) or (III). <Desc/Clms Page number 60> 24. The pharmaceutical pack of claim 23, wherein said aromatic diamidine is pentamidine, propamidine, butamidine, heptamidine, nonamidine, stilbamidine, hydroxystilbamidine, diminazene, benzamidine, 4,4'- (pentamethylenedioxy) di-, dihydrochloride, phenamidine, dibrompropamidine, 1, 3-bis (4-amidino-2-methoxyphenoxy) propane, netropsin, distamycin, or phenamidine.
25. The pharmaceutical pack of claim 23, wherein said aminopyridine is phenazopyridine, 4-amino-pyridine, 3,4-diaminopyridine, 2,5-diamino-4- methylpyridine, 2,3, 6-triaminopyridine, 2,4, 6-triaminopyridine, or 2,6- diaminopyridine.
26. The pharmaceutical pack of claim 23, wherein said quaternary ammonium compound is pentolinium, hexamethonium, pentamethonium, tetramethylammonium, tetraethylammonium, trimethaphan, or chlorisondamine.
27. The pharmaceutical pack of any one of claims 23-26, wherein the two compounds are formulated separately and in individual dosage amounts.
28. The pharmaceutical pack of any one of claims 23-26, wherein the two compounds are formulated together.
29. A method of preventing, stabilizing, or inhibiting the growth of fungal cells, said method comprising contacting said fungal cells with (i) an aromatic diamidine or analog thereof or a compound of formula (I) ; and (ii) an aminopyridine, a quaternary ammonium compound, or a compound of formula (II) or (III) in amounts that, in combination, are sufficient to prevent, stabilize, or inhibit the growth of the fungal cells. <Desc/Clms Page number 61> 30. A method for preventing, stabilizing, or inhibiting the growth of fungal cells on a surface, said method comprising contacting said surface with (i) an aromatic diamidine or analog thereof or a compound of formula (I) ; and (ii) an aminopyridine, a quaternary ammonium compound, or a compound of formula (II) or (III) in amounts sufficient to prevent stabilize, or inhibit growth of said fungal cells.
31. The method of claim 30, wherein said surface is selected from the group of process equipment, water sanitation systems, cooking utensils, food preparation areas, and medical devices.
32. The method of claim 31, wherein said medical devices are selected from the group consisting of surgical tools, dental tools, dental appliances, orthodontic braces, dentures, stents, endoscopy equipment, surgical implants, prosthetic devices, artificial joints, heart valves, pacemakers, vascular grafts, vascular catheters, cerebrospinal fluid shunts, urinary catheters, and continuous ambulatory peritoneal dialysis catheters.
33. The method of claim 29 or 30, wherein said aromatic diamidine is pentamidine, propamidine, butamidine, heptamidine, nonamidine, stilbamidine, hydroxystilbamidine, diminazene, benzamidine, 4,4'- (pentamethylenedioxy) di-, dihydrochloride, phenamidine, dibrompropamidine, 1, 3-bis (4-amidino-2- methoxyphenoxy) propane, netropsin, distamycin, or phenamidine.
34. The method of claim 29 or 30, wherein said aminopyridine is phenazopyridine, 4-amino-pyridine, 3,4-diaminopyridine, 2,5-diamino-4- methylpyridine, 2,3, 6-triaminopyridine, 2,4, 6-triaminopyridine, or 2,6- diaminopyridine. <Desc/Clms Page number 62> 35. The method of claim 29 or 30, wherein said quaternary ammonium compound is pentolinium, hexamethonium, pentamethonium, tetramethylammonium, tetraethylammonium, trimethaphan, or chlorisondamine.
36. A method for identifying combinations of compounds useful for treating a patient having a fungal infection, said method comprising the steps of : (a) contacting fungal cells in vitro with (i) an aromatic diamidine, a quaternary ammonium compound and/or an aminopyridine, and (ii); a candidate compound;STDC0718 and (b) determining whether the combination of said aromatic diamidine, a quaternary ammonium compound and/or an aminopyridine and said candidate compound reduces growth of said fungal cells relative to fungal cells contacted with said aromatic diamidine, a quaternary ammonium compound and/or an aminopyridine in the absence of said candidate compound, or fungal cells contacted with said candidate compound but not with said aromatic diamidine, a quaternary ammonium compound and/or an aminopyridine, wherein a decrease in fungal growth identifies said combination as a combination that is useful for treating a patient having a fungal infection.
37. A method for treating a patient who has a fungal infection, or inhibiting the development of a fungal infection in a patient who is at risk for developing a fungal infection, said method comprising administering to said patient (i) an antifungal agent and (ii) an aromatic diamidine, aminopyridine, or quaternary ammonium compound, or a compound of formula (1), (II), or (III), wherein the two compounds are administered simultaneously or within 10 days of each other, in amounts sufficient to treat or inhibit the development of a fungal infection in said patient. <Desc/Clms Page number 63> 38. The method of claim 37, wherein said antifungal agent is selected from the group consisting of : amphotericin B, fluconazole, nystatin, pimaricin, ketoconazole, miconazole, thiabendazole, emlkonazole, itraconazole, ravuconazole, posaconazole, voriconazole, dapsone, griseofulvin, carbol- fuchsin, clotrimzole, econazole, haloprogin, mafenide, naftifine, oxiconazole, silver sulfadiazine, sulconazole, terbinafine, amorolfine, tioconazole, tolnaftate, undecylenic acid, butoconazle, gentian violet, terconazole, flucytosine, ciclopirox, caspofungin acetate, micafungin, and V-echinocandin (LY303366).
39. The method of claim 37 or 38, wherein said aromatic diamidine is selected from the group consisting of pentamidine, propamidine, butamidine, heptamidine, nonamidine, stilbamidine, hydroxystilbamidine, diminazene, benzamidine, 4,4'- (pentamethylenedioxy) di-, dihydrochloride, phenamidine, dibrompropamidine, 1,3-bis (4-amidino-2-methoxyphenoxy) propane, netropsin, distamycin, and phenamidine.
40. The method of claim 37 or 38, wherein said aminopyridine is phenazopyridine, 4-amino-pyridine, 3,4-diaminopyridine, 2,5-diamino-4- methylpyridine, 2,3, 6-triaminopyridine, 2,4, 6-triaminopyridine, or 2,6- diaminopyridine.
41. The method of claim 37 or 38, wherein said quaternary ammonium compound is pentolinium, hexamethonium, pentamethonium, tetramethylammonium, tetraethylammonium, trimethaphan, or chlorisondamine.