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Details for Patent: 7,189,858

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Details for Patent: 7,189,858

Title:N-phenyl 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 (CH)
Filing Date:Sep 03, 2004
Application Number:10/933,577
Claims:1. A compound of the formula (I), ##STR00037## wherein Q is a 1,2,4-triazole derivative selected from the group consisting of 3-[4-(4-cyanophenyl)thiazol-2-yl)]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-tri- azol-1-yl)-butan-2-ol; 3-[4-(4-cyanophenyl)thiazol-2-yl)]-1-(1H-1,2,4-triazol-1-yl)-2-(2,4,5-tri- fluorophenyl)-butan-2-ol; 3-[4-(4-cyanophenyl)thiazol-2-yl)]-2-(2,5-difluorophenyl)-1-(1H-1,2,4-tri- azol-1-yl)butan-2-ol; and 3-[4-(4-cyanophenyl)thiazol-2-yl)]-2-(3-fluorophenyl)-1-(1H-1,2,4-triazol- e-1-yl)-butan-2-ol, which derivative is linked to the remainder of the compound of formula (I) 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 phenyl and substituted phenyl; and X.sup.- is a pharmaceutically acceptable anion, and when R.sup.3 is substituted phenyl either the substituents are selected from the group consisting of aminoalkylcarbonyl, nitro, alkylaminoalkyl, trifluoromethoxy, alkyl, halogen, alkoxy, cyano, and alkylaminoalkylcarbonyloxyalkyl; or the substituted phenyl is substituted with all of the substituents R.sup.4, R.sup.5 and --CH.sub.2--R.sup.6 where 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, trifluormethoxy, nitro, aminosulfonyl, alkylaminocarboyloxyalkyl, sulfo, aminoalkylcarbonyl or alkylaminoalkyl; R.sup.6 is hydroxy, alkoxycarbonylalkylamino, alkoxycarbonylamino, amino, alkylamino, alkylcarbonyloxy, alkoxycarbonylalkylaminoalkylcarbonyloxy, alkoxycarbonylamino-alkylcarbonyloxy, alkylaminoalkylcarbonyloxy, aminoalkylcarbonyloxy, alkylcarbonylamino, alkylcarbonylalkylamino, acyloxy, acylamino, or acylalkylamino; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 where R.sup.3 is a substituted phenyl which is substituted with R.sup.4, R.sup.5 and --CH.sub.2--R.sup.6 and R.sup.4, R.sup.5 and R.sup.6 are as above.

3. The compound of claim 1 having formula (III), ##STR00038## wherein R.sup.1, R.sup.2, Q, and X are as above; 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 or sulfo; R.sup.6 is hydroxy, alkoxycarbonylalkylamino, alkoxycarbonylamino, amino, alkylamino, alkylcarbonyloxy, alkoxycarbonylalkylaminoalkylcarbonyloxy, alkoxycarbonylaminoalkylcarbonyloxy, alkylaminoalkylcarbonyloxy, aminoalkylcarbonyloxy, alkylcarbonylamino, alkylcarbonylalkylamino, acyloxy, acylamino, acylalkylamino; and group ##STR00039## is phenyl.

4. The compound of claim 3 wherein R.sup.4 and R.sup.5 are independently selected from the group consisting of hydrogen, halogen, alkoxy, cyano, trifluoromethyl, trifluoromethoxy and nitro.

5. The compound of claim 4 wherein R.sup.4 and R.sup.5 are independently selected from the group consisting of hydrogen, halogen and alkoxy.

6. The compound of claim 3 wherein R.sup.4 and R.sup.5 are hydrogen.

7. The compounds of claim 3 wherein R.sup.6 is alkylamino, alkylcarbonyloxy, alkylaminoalkylcarbonyloxy or aminoalkylcarbonyloxy.

8. The compounds of claim 7 wherein R.sup.6 is alkylaminoalkylcarbonyloxy.

9. The compounds of claim 1 wherein group R.sup.3 is phenyl substituted with aminoalkylcarbonyl, nitro, alkylaminoalkyl, trifluoromethoxy, alkyl, halogen, alkoxy, cyano, or alkylaminoalkylcarbonyloxyalkyl.

10. The compound of claim 1 wherein Q is ##STR00040##

11. The compound of claim 1 wherein R.sup.1 is methyl.

12. The compound of claim 1 wherein R.sup.2 is hydrogen or alkyl.

13. The compound of claim 12 wherein R.sup.2 is alkyl.

14. The compound of claim 1 wherein X is a halogen.

15. The compound of claim 14 wherein X is chloro.

16. The compound of claim 1 wherein Q is ##STR00041## Y is nitrogen; R.sup.1 is alkyl; R.sup.2 is alkyl; X-- is halogen; R.sup.4 and R.sup.5 are hydrogen; R.sup.6 is alkylaminoalkylcarbonyloxy; or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1 selected from the group consisting of: 1-[[N-methyl-N-2-(methylamino)acetoxymethyl-3-chloro-phenyl]carbamoyloxy]- ethyl-1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thia- zol-2-yl]butyl]-1H-[1,2,4]triazol-4-ium chloride hydrochloride; 1-[[N-methyl-N-2-(methylamino)acetoxymethyl-5-chloro-phenyl]carbamoyloxy]- ethyl-1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thia- zol-2-yl]butyl]-1H-[1,2,4]triazol-4-ium chloride hydrochloride; 1-([N-methyl-N-2-(methylamino)acetoxymethyl-3-chloro-phenyl)carbamoyloxy]- ethyl-1-[(2R,3R)-2-(2,4,5-trifluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)t- hiazol-2-yl]butyl]-1H-[1,2,4]triazol-4-ium chloride hydrochloride; 1-[(N-methyl-N-2-(methylamino)acetoxymethyl-5-chloro-phenyl]carbamoyloxy]- ethyl-1-[(2R,3R)-2-(2,4,5-trifluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)t- hiazol-2-yl]butyl]-1H-(1,2,4]triazol-4-ium chloride hydrochloride; 1-[[N-methyl-N-2-(methylamino)acetoxymethyl-3-chloro-phenyl]carbamoyloxy]- ethyl-1-[(2R,3R)-2-(3-fluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiazol-- 2-yl]butyl]-1H-(1,2,4]triazol-4-ium chloride hydrochloride; and 1-[[N-methyl-N-2-(methylamino)acetoxymethyl-5-chloro-phenyl]carbamoyloxy]- ethyl-1-[(2R,3R)-2-(3-fluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiazol-- 2-yl]butyl]-1H-(1,2,4]triazol-4-ium chloride hydrochloride.

18. The compound of claim 1 selected from the group consisting of: [[N-methyl-N-2-(acetoxymethyl)phenyl]carbamoyloxy]methyl-1-[(2R,3R)-2-(2,- 5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiazol-2-yl]butyl]-1H-[1,- 2,4]triazol-4-ium chloride; 1-[[N-methyl-N-2-(isopropylaminomethyl)phenyl]carbamoyloxy]ethyl-1-((2R,3- R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiazol-2-yl]butyl- ]-1H-[1,2,4]triazol-4-ium chloride hydrochloride; [[N-methyl-N-phenyl]carbamoyloxy]methyl-1-[(2R,3R)-2-(2,5-difluorophenyl)- -2-hydroxy-3-[4-(4-cyanophenyl)thiazol-2-yl]butyl]-1H-[1,2,4]triazol-4-ium chloride; [[N-2-(methyl)phenyl-N-2-(acetoxy)ethyl]carbamoyloxy]methyl-1-(- (2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiazol-2-yl]- butyl]-1H-[1,2,4]triazol-4-ium iodide; 1-[[N-2-[(isopropylamino)methyl]phenyl]carbamoyloxy]ethyl-1-[(2R,3R)-2-(2- ,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiazol-2-yl]butyl]-1H-[1- ,2,4]triazol-4-ium chloride hydrochloride; 1-[[N-2-[(pentan-3-ylamino)methyllphenyl]carbamoyloxy]ethyl-1-[(2R,3R)-2-- (2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiazol-2-yl]butyl]-1H-- [1,2,4]triazol-4-ium chloride hydrochloride; 1-[[N-methyl-N-2-[(methylamino)methyllphenyllcarbamoyloxy]ethyl-1-[(2R,3R- )-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiazol-2-yl]butyl]- -1H-[1,2,4]triazol-4-ium chloride hydrochloride; [[N-methyl-N-2-[(methylamino)acetoxymethyllphenyllcarbamoyloxy]methyl-1-[- (2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiazol-2-yl]- butyl]-1H-[1,2,4]triazol-4-ium chloride hydrochloride; 1-[[N-methyl-N-2-[(methylamino)acetoxymethyllphenyllcarbamoyloxy]ethyl-1-- [(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiazol-2-yl- ]butyl]-1H-[1,2,4]triazol-4-ium chloride hydrochloride; 1-[[N-methyl-N-2-(methylamino)acetoxymethyl-4,5-difluorophenyl]carbamoylo- xy]ethyl-1-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)t- hiazol-2-yl]butyl]-1H-[1,2,4]triazol-4-ium chloride hydrochloride; 1-[[N-methyl-N-2-(methylamino)acetoxylnethyl-4-fluoro-phenyl]carbamoyloxy- ]ethyl-1-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thi- azol-2-yl]butyl]-1H-[1,2,4]triazol-4-ium iodide hydrochloride; [[N-methyl-N-2-(methylamino)acetoxymethyl-4,5-dimethoxyphenyl]carbamoylox- y]methyl1-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)th- iazol-2-yl]butyl]-1H-[1,2,4]triazol-4-ium iodide hydrochloride; 1-[[N-methyl-N-2-(methylamino)acetoxymethyl-5-fluoro-phenyl]carbamoyloxy]- ethyl-1-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thia- zol-2-yl]butyl]-1H-[1,2,4]triazol-4-ium chloride hydrochloride; 1-[[N-methyl-N-2-(methylamino)acetoxymethyl-6-methyl-phenyl]carbamoyloxy]- ethyl-1-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thia- zol-2-yl]butyl]-1H-[1,2,4]triazol-4-ium iodide hydrochloride; 1-[[N-methyl-N-2-(methylamino)acetoxymethyl-4-chloro-phenyl]carbamoyloxy]- ethyl-1-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thia- zol-2-yl]butyl)-1H-[1,2,4]triazol-4-ium iodide hydrochloride; 1-[[N-(methylamino)acetoxyethyl-N-2,4-difluorophenyl]carbamoyloxy]ethyl-1- -[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiazol-2-y- l]butyl]-1H-[1,2,4]triazol-4-ium chloride hydrochloride; 1-[[N-methyl-N-2-(methylamino)acetoxymethyl-5-chloro-phenyl]carbamoyloxy]- ethyl-1-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thia- zol-2-yl]butyl]-1H-[1,2,4]triazol-4-ium iodide hydrochloride; 1-[[N-methyl-N-2-(methylamino)acetoxymethyl-5-nitro-phenyl]carbamoyloxy]e- thyl-1-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiaz- ol-2-yl]butyl]-1H-[1,2,4]triazol-4-ium chloride hydrochloride; 1-[[N-methyl-N-2-(methylamino)acetoxymethyl-3-fluoro-phenyl]carbamoyloxy]- ethyl-1-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thia- zol-2-yl]butyl]-1H-[1,2,4)triazol-4-ium chloride hydrochloride; 1-[[N-methyl-N-2-(methylamino)acetoxymethyl-5-cyano-phenyl]carbamoyloxy]e- thyl-1-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiaz- ol-2-yl]butyl]-1H-[1,2,4]triazol-4-ium chloride hydrochloride; 1-[[N-methyl-N-2-(methylamino)acetoxymethyl-3-chloro-phenyl]carbamoyloxy]- ethyl-1-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thia- zol-2-yl]butyl]-1H-[1,2,4]triazol-4-ium chloride hydrochloride; 1-[[N-methyl-N-2-(methylamino)acetoxymethyl-4-cyano-phenyl)carbamoyloxy]e- thyl-1-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiaz- ol-2-yl]butyl]-1H-[1,2,4]triazol-4-ium chloride hydrochloride; 1-[[N-methyl-N-2-(methylamino)acetoxymethyl-5-trifluoromethyl-phenyl]carb- amoyloxy)ethyl-1-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanoph- enyl)thiazol-2-yl]butyl]-1H-[1,2,4]triazol-4-ium iodide hydrochloride; 1-[[N-methyl-N-2-(amino)acetoxymethyl-3-chloro-phenyl]carbamoyloxy]ethyl-- 1-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiazol-2-- yl]butyl]-1H-[1,2,4]triazol-4-ium chloride hydrochloride; 1-[[N-ethyl-N-2-(methylamino)acetoxymethyl-3-chloro-phenyl]carbamoyloxy)e- thyl-1-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiaz- ol-2-yl]butyl]-1H-[1,2,4]triazol-4-ium chloride hydrochloride; 1-[[N-methyl-N-2-(methylamino)acetoxymethyl-3-methyl-phenyl]carbamoyloxy]- ethyl-1-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thia- zol-2-yl]butyl]-1H-[1,2,4]triazol-4-ium iodide hydrochloride; 1-[[N-ethoxycarbonyl-N-2-(methylamino)acetoxymethyl-phenyl]carbamoyloay]e- thyl-1-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiaz- ol-2-yl]butyl]-1H-[1,2,4]triazol-4-ium chloride hydrochloride; and 1-[[N-pivaloyl-N-2-(methylamino)acetoxymethyl-phenyl]carbamoyloxy]ethyl-1- -[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiazol-2-y- l]butyl]-1H-[1,2,4]triazol-4-ium chloride hydrochloride.

19. The compound of claim 1 wherein said compound of formula (I) is 1-[[N-methyl-N-2[(methylamino)acetyoxymethyl]phenyl]carbamoyloxy]ethyl-1-- [(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiazol-2-yl- ]butyl]-1H-[1,2,4]triazol-4-ium with X being as above.

20. The compound of claim 19 wherein the compound is a hydrochloride acid salt thereof.
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