Details for Patent: 7,459,561

Title:	N-substituted carbamoyloxyalkyl-azolium derivatives
Abstract:	N-substituted carbamoyloxyalkyl-azolium derivatives which have antifungal activity and are useful for the treatment of fungal diseases.
Inventor(s):	Fukuda; Hiroshi (Tokyo, JP), Hayase; Tadakatsu (Chigasaki, JP), Mizuguchi; Eisaku (Kamakura, JP), Shimma; Nobuo (Chigasaki, JP), Ohwada; Jun (Kamakura, JP), Oikawa; Nobuhiro (Kawasaki, JP), Sakaitani; Masahiro (Chigasaki, JP), Tsukazaki; Masao (Fujisawa, JP), Umeda; Isao (Yokohama, JP)
Assignee:	Basilea Pharmaceutica AG (Basel, CH)
Filing Date:	Aug 15, 2006
Application Number:	11/504,299
Claims:	1. A triazole compound consisting of an anion selected from pharmaceutically acceptable anions and a cation represented by the formula ##STR00037## wherein Q is a 1,2,4-triazole derivative selected from the group consisting of (2R, 3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-- triazol-1-yl)butan-2-ol, (2R, 3R)-3-[4-(4-cyanophenyl)thiazol-2-yl[-1-(1H-1,2,4-triazol-1-yl)-2-(2,4,5-- trifluorophenyl-butan-2-ol and (2R, 3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(3-fluorophenyl)-1-(1H-1,2,4-tria- zole-1-yl)-butan-2-ol, which triazole derivative is linked to the remainder of the said cation by a nitrogen in the triazole; R.sup.1 is hydrogen or alkyl; R.sup.2 is hydrogen, alkyl, alkylcarbonyloxyalkyl, alkoxycarbonyl, alkylcarbonyl, mono- or dialkylaminoalkylcarbonyloxyalkyl; R.sup.3 is pyridin-2-yl or substituted pyridin-2-yl, wherein R.sup.3 is substituted pyridin-2-yl, said cation is represented by the formula ##STR00038## wherein ##STR00039## is pyridin-2-yl; R.sup.4 and R.sup.5 are independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, carboxy, alkyloxycarbonyl, cyano, trifluoromethyl, trifluoromethoxy, nitro, aminosulfonyl and sulfo; and R.sup.6 is selected from the group consisting of hydroxy, alkoxycarbonylalkylamino, alkoxycarbonylamino, amino, alkylamino, alkylcarbonyloxy, alkoxycarbonylalkylaminoalkylcarbonyloxy alkoxycarbonylamino-alkylcarbonyloxy, alkylaminoalkylcarbonyloxy, aminoalkylcarbonyloxy, alkylcarbonylamino, alkylcarbonylalkylamino, acyloxy, acylamino, and acylalkylamino, wherein said acyl is a hydrolizable radical; or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 wherein R.sup.4 and R.sup.5 are independently selected from the group consisting of hydrogen, halogen and alkoxy. 3. The compound of claim 2 wherein R.sup.4 and R.sup.5 are hydrogen. 4. The compound of claim 3 wherein R.sup.6 is alkylaminoalkylcarbonyloxy. 5. The compound of claim 4 wherein R.sup.1 is hydrogen or alkyl. 6. The compound of claim 5 wherein R.sup.2 is alkyl. 7. The compound of claim 6, wherein Q is (2R, 3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-- triazol-1-yl)butan-2-ol. 8. The compound of claim 1, wherein Q is (2R, 3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-- triazol-1-yl)butan-2-ol, R.sup.1 is hydrogen or alkyl, R.sup.2 is alkyl, R.sup.4 and R.sup.5 are hydrogen, R.sup.6 is alkylaminoalkylcarbonyloxy and said pharmaceutically acceptable anion is an anion of a pharmaceutically acceptable acid. 9. The compound of claim 1, wherein said cation is (2R, 3R)-1-[[N-methyl-N-3-[(methylamino)acetoxymethyl]pyridin-2-yl]carbamoylox- y]ethyl-1-2-(2,4-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiazol-2-y- l]butyl]-1H-[1,2,4]triazol-4-ium. 10. The compound of claim 1, wherein said compound is 1-[[N-methyl-N-3-[(methylamino)acetoxymethyl]pyridin-2-yl]carbamoyloxy]et- hyl-1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiazo- l-2-yl ]butyl]-1H-[1,2,4]triazol-4-ium chloride or a pharmaceutically acceptable salt thereof. 11. The compound of claim 1, wherein said cation is 1-[[N-methyl-N-3-[(methylamino)acetoxymethyl]pyridin-2-yl]carbamoyloxy]et- hyl-1[(2R,3R)-2-(2,4,5-trifluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thia- zol-2-yl]butyl]-1H-[1,2,4]triazol-4-ium. 12. The compound of claim 1, wherein said compound is 1-[[N-methyl-N-3-[(methylamino)acetoxymethyl]pyridin-2]carbamoyloxy]ethyl- -1-[(2R,3R)-2-(2,4,5-trifluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiazo- l-2-yl]butyl]-1H-[1,2,4]triazol-4-ium chloride or a pharmaceutically acceptable salt thereof. 13. The compound of claim 1 wherein said cation is 1-[[N-methyl-N-3-[(methylamino)acetoxymethyl]pyridin-2-yl]carbamoyloxy]et- hyl-1-[(2R,3R)-2-(3-fluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiazol-2-- yl]butyl]-1H-[1,2,4]triazol-4-ium. 14. The compound of claim 1, wherein said compound is 1-[[N-methyl-N-3-[(methylamino)acetoxymethyl]pyridin-2-yl]carbamoyloxy]et- hyl-1-[(2R,3R)-2-(3-fluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiazol-2-- yl]butyl]-1H-[1,2,4]triazol-4-ium chloride or a pharmaceutically acceptable salt thereof. 15. A triazole compound consisting of an anion selected from pharmaceutically acceptable anions and a cation represented by the formula ##STR00040## wherein ##STR00041## is pyridin-2-yl; Q is a (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl)]-2-(2,5-difluorophenyl)-1-(1H-2- ,4-triazol-1-yl)-butan-2-ol moiety which is linked to the remainder of the cation by a nitrogen in the triazole; R.sup.1 is hydrogen or alkyl; R.sup.2 is hydrogen, alkyl, alkylcarbonyloxyalkyl, alkoxycarbonyl, alkylcarbonyl, mono- or dialkylaminoalkylcarbonyloxyalkyl; R.sup.4 and R.sup.5 are independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, carboxy, alkyloxycarbonyl, cyano, trifluoromethyl, trifluoromethoxy, nitro, aminosulfonyl, alkylaminocarboyloxyalkyl, sulfo, alkylcarbonyloxyalkyl and aminoalkylcarbonyloxyalkyl; R.sup.6 is alkylaminoalkylcarbonyloxy, or aminoalkylcarbonyloxy; or a pharmaceutically acceptable salt thereof. 16. The triazole compound of claim 15 wherein R.sup.4 and R.sup.5 are independently selected from the group consisting of hydrogen, halogen and alkoxy. 17. The triazole compound of claim 16 wherein R.sup.4 and R.sup.5 are hydrogen. 18. The triazole compound of claim 17 wherein R.sup.2 is alkyl. 19. The triazole compound of claim 15 wherein said cation is 1-[[N-methyl-N-3-[(methylamino)acetoxymethyl]pyridin-2-yl]carbamoyloxy]et- hyl-1-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiazo- l-2-yl]butyl]-1H-[1,2,4]triazol-4-ium. 20. The triazole compound of claim 15 wherein said cation is 1-[[N-methyl-N-3-[(methylamino)acetoxymethyl]pyridin-2-yl]carbamoyloxy]et- hyl-1-[(2R,3R)-2-(2,5-difluorophenyl-2-hydroxy-3-[4-(4-cyanophenyl)thiazol- -2-yl]butyl]-1H-[1,2,4]triazol-4-ium and said anion is an anion of a pharmaceutically acceptable inorganic acid. 21. The triazole compound of claims 20 wherein said anion is a chloride, bromide or sulfate.