Claims for Patent: 6,465,504

Summary for Patent: 6,465,504

Title:	Substituted 3,5-diphenyl-1,2,4-triazoles and their use as pharmaceutical metal chelators
Abstract:	The use is described of 3,5-diphenyl-1,2,4-triazoles of the formula I in which R1-R5 are as defined in the description. The compounds have useful pharmaceutical properties and are particularly active as iron chelators. They can be used for the treatment of iron overload in warm-blooded animals.
Inventor(s):	René Lattmann, Pierre Acklin
Assignee:	Novartis AG, Norvartis AG
Application Number:	US09/699,765
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 6,465,504
Patent Claims:	1. A compound of formula II wherein each of R1 and R5, independently, is hydrogen; halogen; lower alkyl; halo-lower alkyl; lower alkoxy; halo-lower alkoxy; carboxyl; carbamoyl; N-lower alkylcarbamoyl; N,N-di-lower alkylcarbamoyl; or nitrile; each of R2 and R4, independently, is hydrogen; unsubstituted lower alkanoyl; lower alkanoyl substituted by halogen, hydroxyl, lower alkoxy, trifluoromethyl, cyclo-lower alkyl or phenyl; unsubstituted aroyl; or aroyl substituted by one or two substituents selected from lower alkyl, lower alkoxy, hydroxyl, nitro, halogen, trifluoromethyl, carboxyl, lower alkoxycarbonyl, amino, N-lower alkylamino, N,N-di-lower alkylamino, aminocarbonyl, lower alkylaminocarbonyl, di-lower alkylaminocarbonyl and nitrile; R3 is R6R7N—C(O)-lower alkyl; aryl substituted by one or two substituents selected from lower alkyl, lower alkoxy, hydroxyl, nitro, halogen, trifluoromethyl, carboxyl, lower alkoxycarbonyl, amino, N-lower alkylamino, N,N-di-lower alkylamino, aminocarbonyl, lower alkylaminocarbonyl, di-lower alkylaminocarbonyl and nitrile; or aryl-lower alkyl substituted by N-lower alkylamino or N,N-di-lower alkylamino; with the proviso that R3 is not phenyl substituted by halogen, nitro, nitrile, hydroxyl, lower alkyl, trifluoromethyl, lower alkoxy or lower alkoxycarbonyl if R2 and R4 are hydrogen, and R1 and R5 are hydrogen, halogen, lower alkyl, halo-lower alkyl, lower alkoxy or nitrile; and each of R6 and R7, independently, is hydrogen; lower alkyl; hydroxy-lower alkyl; alkoxy-lower alkyl; hydroxyalkoxy-lower alkyl; amino-lower alkyl; N-lower alkylamino-lower alkyl; N,N-di-lower alkylamino-lower alkyl; N-(hydroxy-lower alkyl)amino-lower alkyl; or N,N-di(hydroxy-lower alkyl)amino-lower alkyl; or a salt thereof. 2. A compound according to claim 1 wherein each of R1 and R5, independently, is hydrogen; halogen; lower alkyl; halo-lower alkyl; lower alkoxy; or halo-lower alkoxy; each of R2 and R4 is hydrogen; R3 is R6R7N—C(O)-lower alkyl; aryl substituted by one or two substituents selected from lower alkyl, lower alkoxy, hydroxyl, nitro, halogen, trifluoromethyl, carboxyl, lower alkoxycarbonyl, amino, N-lower alkylamino, N,N-di-lower alkylamino, aminocarbonyl, lower alkylaminocarbonyl, di-lower alkylaminocarbonyl and nitrile; or aryl-lower alkyl substituted by N-lower alkylamino or N,N-di-lower alkylamino; with the proviso that R3 is not phenyl substituted by halogen, nitro, nitrile, hydroxyl, lower alkyl, trifluoromethyl, lower alkoxy or lower alkoxycarbonyl if R1 and R5 are hydrogen, halogen, lower alkyl, halo-lower alkyl or lower alkoxy; and each of R6 and R7, independently, is hydrogen; lower alkyl; hydroxy-lower alkyl; alkoxy-lower alkyl; hydroxyalkoxy-lower alkyl; amino-lower alkyl; N-lower alkylamino-lower alkyl; N,N-di-lower alkylamino-lower alkyl; N-(hydroxy-lower alkyl)amino-lower alkyl; or N,N-di(hydroxy-lower alkyl)amino-lower alkyl; or a salt thereof. 3. A compound according to claim 1 wherein each of R1 and R5, independently, is hydrogen; halogen; or lower alkyl; each of R2 and R4 is hydrogen; R3 is R6R7N—C(O)-lower alkyl; aryl substituted by carboxyl or R8R9N—C(O); or aryl-lower alkyl substituted by N-lower alkylamino or N,N-di-lower alkylamino; each of R6 and R7, independently, is hydrogen; lower alkyl; hydroxy-lower alkyl; alkoxy-lower alkyl; hydroxyalkoxy-lower alkyl; amino-lower alkyl; N-lower alkylamino-lower alkyl; N,N-di-lower alkylamino-lower alkyl; N-(hydroxy-lower alkyl)amino-lower alkyl; or N,N-di(hydroxy-lower alkyl)amino-lower alkyl; and each of R8 and R9, independently, is hydrogen or lower alkyl; or a pharmaceutically acceptable salt thereof. 4. A compound selected from the group consisting of 2-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-N,N-bis(2-hydroxyethyl)acetamide; 2-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-N,N-dimethylacetamide; 2-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-N-(2,3-dihydroxypropyl)acetamide; 2-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-N-(2-dimethylaminoethyl)-N-methylacetamide; 2-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-N-(2-hydroxy-1-hydroxymethylethyl)acetamide; 2-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-N-(2-hydroxyethyl)acetamide; 2-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-N-(2-hydroxyethyl)-N-methylacetamide; 2-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-N-(2-methoxyethyl)acetamide; 2-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-N-[2-(2-hydroxyethoxy)ethyl]acetamide; 2-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-N-methylacetamide; 3,5-bis(2-hydroxyphenyl)-1-(4-diethylaminobenzyl)-1H-[1,2,4]triazole; 3,5-bis(5-chloro-2-hydroxyphenyl)-1-(4-dimethylaminobenzy)-1H-[1,2,4]triazole; 4-[3,5-bis(2-hydroxy-5-methylphenyl)-[1,2,4]triazol-1-yl]benzoic acid; 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid; 4-[3,5-bis(5-chloro-2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid; 4-[3,5-bis(5-fluoro-2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid; N-{2-(bis(2-hydroxyethyl)amino]ethyl}-2-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetamide; N-benzyl-2-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-N-methylacetamide; or a pharmaceutically acceptable salt thereof. 5. A compound according to claim 4 which is 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid, or a pharmaceutically acceptable salt thereof. 6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof. 7. A compound according to claim 1 which is 2-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid, or a pharmaceutically acceptable salt thereof. 8. A pharmaceutical composition according to claim 6 comprising a therapeutically effective amount of 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid, or a pharmaceutically acceptable salt thereof. 9. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a therapeutically effective amount of a compound of claim 4 or a pharmaceutically acceptable salt thereof.