Substituted [1,2,4]triazolo[1,5-a]pyrimidines and their use as potassium channel modulators
This invention relates to novel substituted [1,2,4]triazolo[1,5-a]pyrimidines and their use as modulators of potassium channels. In other aspects the invention relates to the use of these compounds, in a method for therapy and to pharmaceutical compositions comprising the compounds of the invention.
1. A compound of the formula (I)
a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, wherein
R 1 , R 2 , R 3 and R 4 , independently of each other, are hydrogen, halogen, C 1-6 -alkyl, C 3-7 -cycloalkyl or C 1-6 -alkoxy;
X is halogen;
R′ and R″, independently of each other, are hydrogen or C 1-6 -alkyl, and
R is hydrogen or C 1-6 -alkyl;
with the proviso that the compound is not
N-{7-[1-(4-Chloro-2-methylphenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine; or
N-{7-[1-(4-Fluorophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine.
2. A compound of the formula (I),
a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, wherein
R 1 , R 2 , R 3 and R 4 , independently of each other, are hydrogen, halogen, C 1-6 -alkyl, C 3-7 -cycloalkyl or C 1-6 -alkoxy;
X is halogen;
R′ and R″, independently of each other, are hydrogen or C 1-6 -alkyl, and
R is hydrogen or C 2-6 -alkyl.
3. A compound of the formula (I)
a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, wherein
R 1 , R 2 , R 3 and R 4 , independently of each other, are hydrogen, halogen, C 1-6 -alkyl, C 3-7 -cycloalkyl or C 1-6 -alkoxy;
X is halogen;
R′ and R″, independently of each other, are hydrogen or C 2-6 -alkyl, or R′ and R″ both are hydrogen; or R′ and R″ both are methyl; and
R is hydrogen or C 1-6 -alkyl.
4. A compound of the formula (I)
a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, wherein
R 1 , R 2 , and R 3 , independently of each other, are hydrogen, halogen, C 1-6 -alkyl, C 3-7 -cycloalkyl or C 1-6 -alkoxy;
R 4 is hydrogen, halogen, C 2-6 -alkyl, C 3-7 -cycloalkyl or C 1-6 -alkoxy;
X is chlorine, bromine or iodine;
R′ and R″, independently of each other, are hydrogen or C 1-6 -alkyl, and
R is hydrogen or C 1-6 -alkyl.
5. The compound according to claim 1 , which is:
N-{7-[1-(4-Bromophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;
N-{7-[1-(2,4-Dichlorophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;
N-{7-[1-(4-Chlorophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;
N-{7-[1-(4-Chloro-2-methylphenoxy)-ethyl]-6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-hydroxy-formamidine;
N-{7-[1-(4-Chloro-2-methylphenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-propyloxy-formamidine;
N-{7-[1-(4-Chloro-2-methylphenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-isopropyloxy-formamidine; or
N-{7-[1-(4-Chloro-2-methylphenoxy)-1-methyl-ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;
or a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof.
6. A pharmaceutical composition comprising a therapeutically effective amount of the compound of the formula (I)
a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, wherein
R 1 , R 2 , R 3 and R 4 , independently of each other, are hydrogen, halogen, C 1-6 -alkyl, C 3-7 -cycloalkyl or C 1-6 -alkoxy;
X is halogen;
R′ and R″, independently of each other, are hydrogen or C 1-6 -alkyl, and
R is hydrogen or C 1-6 -alkyl.
7. The pharmaceutical composition according to claim 6 , wherein the compound is:
N-{7-[1-(4-Chloro-2-methylphenoxy)ethyl]-[1,2,4]-triazolo[1,5-c]pyrimidin-2-yl}-N′-methoxy-formamidine;
N-{7-[1-(4-Fluorophenoxy)ethyl]-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl}-N′-methoxy-formamidine;
N-{7-[1-(4-Bromophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;
N-{7-[1-(2,4-Dichlorophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;
N-{7-[1-(4-Chlorophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;
N-{7-[1-(4-Chloro-2-methylphenoxy)-ethyl]-6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-hydroxy-formamidine;
N-{7-[1-(4-Chloro-2-methylphenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-propyloxy-formamidine;
N-{7-[1-(4-Chloro-2-methylphenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-isopropyloxy-formamidine; or
N-{7-[1-(4-Chloro-2-methylphenoxy)-1-methyl-ethyl]-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl}-N′-methoxy-formamidine;
or a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof.
8. A method of modulating SK channels in a living animal body, which method comprises the step of administering to such a living animal body in need thereof, a therapeutically effective amount of the compound of the formula (I)
a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, wherein
R 1 , R 2 , R 3 and R 4 , independently of each other, are hydrogen, halogen, C 1-6 -alkyl, C 3-7 -cycloalkyl or C 1-6 -alkoxy;
X is halogen;
R′ and R″, independently of each other, are hydrogen or C 1-6 -alkyl, and
R is hydrogen or C 1-6 -alkyl.
9. The method according to claim 8 , wherein the compound is:
N-{7-[1-(4-Chloro-2-methylphenoxy)ethyl]-[1,2,4]thiazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;
N-{7-[1-(4-Fluorophenoxy)ethyl]-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl}-N′-methoxy-formamidine;
N-{7-[1-(4-Bromophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;
N-{7-[1-(2,4-Dichlorophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;
N-{7-[1-(4-Chlorophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;
N-{7-[1-(4-Chloro-2-methylphenoxy)-ethyl]-6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-hydroxy-formamidine;
N-{7-[1-(4-Chloro-2-methylphenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-propyloxy-formamidine;
N-{7-[1-(4-Chloro-2-methylphenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-isopropyloxy-formamidine; or
N-{7-[1-(4-Chloro-2-methylphenoxy)-1-methyl-ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;
or a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof.