Details for Patent: 6,465,504
✉ Email this page to a colleague
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 ##STR1## in which R.sub.1 -R.sub.5 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): | Lattmann; Rene (Binningen, SE), Acklin; Pierre (Basel, SE) |
Assignee: | Novartis AG (Basel, CH) |
Filing Date: | Oct 30, 2000 |
Application Number: | 09/699,765 |
Claims: | 1. A compound of formula II ##STR7## wherein each of R.sub.1 and R.sub.5, 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 R.sub.2 and R.sub.4, 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; R.sub.3 is R.sub.6 R.sub.7 N--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 R.sub.3 is not phenyl substituted by halogen, nitro, nitrile, hydroxyl, lower alkyl, trifluoromethyl, lower alkoxy or lower alkoxycarbonyl if R.sub.2 and R.sub.4 are hydrogen, and R.sub.1 and R.sub.5 are hydrogen, halogen, lower alkyl, halo-lower alkyl, lower alkoxy or nitrile; and each of R.sub.6 and R.sub.7, 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 R.sub.1 and R.sub.5, independently, is hydrogen; halogen; lower alkyl; halo-lower alkyl; lower alkoxy; or halo-lower alkoxy; each of R.sub.2 and R.sub.4 is hydrogen; R.sub.3 is R.sub.6 R.sub.7 N--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 R.sub.3 is not phenyl substituted by halogen, nitro, nitrile, hydroxyl, lower alkyl, trifluoromethyl, lower alkoxy or lower alkoxycarbonyl if R.sub.1 and R.sub.5 are hydrogen, halogen, lower alkyl, halo-lower alkyl or lower alkoxy; and each of R.sub.6 and R.sub.7, 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 R.sub.1 and R.sub.5, independently, is hydrogen; halogen; or lower alkyl; each of R.sub.2 and R.sub.4 is hydrogen; R.sub.3 is R.sub.6 R.sub.7 N--C(O)-lower alkyl; aryl substituted by carboxyl or R.sub.8 R.sub.9 N--C(O); or aryl-lower alkyl substituted by N-lower alkylamino or N,N-di-lower alkylamino; each of R.sub.6 and R.sub.7, 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 R.sub.8 and R.sub.9, 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)ace tamide; 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)ace tamide; 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-hydroxymeth ylethyl)acetamide; 2-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-N-(2-hydroxyethyl)acetamid e; 2-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-N-(2-hydroxyethyl)-N-methy lacetamide; 2-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-N-(2-methoxyethyl)acetamid e; 2-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-N-[2-(2-hydroxyethoxy)ethy l]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]triazo le; 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]tr iazol-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. |