1,2,4,-triazin-3,5-dione compounds suitable for treating disorders that respond to modulation of the dopamine D
View Patent ↗The invention relates to compounds of the formula I: wherein A is a saturated or unsaturated hydrocarbon chain having a chain length of 4 to 6 carbon atoms, the hydrocarbon chain being unsubstituted or substituted by 1, 2 or 3 methyl groups; R 1 is selected from the group consisting of hydrogen, C 1 -C 3 alkyl and fluorinated C 1 -C 3 alkyl; R 2 is hydrogen, halogen, cyano, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, fluorinated C 1 -C 3 alkyl or fluorinated C 1 -C 3 alkoxy; R 3 is selected from the group consisting of branched C 4 -C 6 alkyl and C 3 -C 6 cycloalkyl, and R 4 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, fluorinated C 1 -C 3 -alkyl and fluorinated C 3 -C 6 cycloalkyl. and the physiologically tolerated salts of these compounds and the N-oxides thereof. The invention also relates to a pharmaceutical composition that comprises at least one compound of the formula I and/or at least one physiologically tolerated acid addition salt thereof, and further to a method for treating disorders that respond beneficially to dopamine D 3 receptor antagonists or dopamine D 3 agonists, said method comprising administering an effective amount of at least one compound or physiologically tolerated acid addition salt of the formula I to a subject in need thereof.
1. A 1,2,4-triazin-3,5-dione compound of the formula I
wherein
A is a saturated or unsaturated hydrocarbon chain having a chain length of 4 to 6 carbon atoms, the hydrocarbon chain being unsubstituted or substituted by 1, 2 or 3 methyl groups;
R 1 is selected from the group consisting of hydrogen, C 1 -C 3 alkyl and fluorinated C 1 -C 3 alkyl;
R 2 is hydrogen, halogen, cyano, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, fluorinated C 1 -C 3 alkyl or fluorinated C 1 -C 3 alkoxy;
R 3 is selected from the group consisting of branched C 4 -C 6 alkyl and C 3 -C 6 cycloalkyl; and
R 4 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, fluorinated C 1 -C 3 -alkyl or fluorinated C 3 -C 6 cycloalkyl;
or a physiologically tolerated salt, tautomer, or N-oxide thereof.
2. The compound as claimed in claim 1 , wherein R 1 is hydrogen.
3. The compound as claimed in claim 1 , wherein R 2 is selected from the group consisting hydrogen, methyl, ethyl, fluorinated C 1 -alkyl, fluorine or chlorine.
4. The compound as claimed in claim 1 , wherein R 2 is hydrogen.
5. The compound as claimed in claim 1 , wherein R 2 is methyl.
6. The compound as claimed in claim 1 , wherein A is selected from the group consisting of (CH 2 ) 4 , CH 2 —CH 2 —CH(CH 3 )—CH 2 , CH 2 —CH(CH 3 )—CH 2 —CH 2 , cis CH 2 —CH═CH—CH 2 , trans CH 2 —CH═CH—CH 2 , cis CH 2 —CH═C(CH 3 )—CH 2 , trans CH 2 —CH═C(CH 3 )—CH 2 , cis CH 2 —C(CH 3 )═CH—CH 2 and trans CH 2 —C(CH 3 )═CH—CH 2 .
7. The compound as claimed in claim 6 , wherein A is (CH 2 ) 4 .
8. The compound as claimed in claim 1 , wherein R 3 is branched C 4 -C 6 -alkyl.
9. The compound as claimed in claim 8 , wherein R 3 is tert-butyl.
10. The compound as claimed in claim 1 , wherein R 4 is fluorinated C 1 -C 2 -alkyl, n-propyl, n-butyl, tert-butyl or cyclobutyl.
11. The compound as claimed in claim 10 , wherein R 4 is trifluoromethyl.
12. The compound as claimed in claim 1 , wherein A is (CH 2 ) 4 , R 1 is hydrogen; R 2 is hydrogen or methyl; R 3 is branched C 4 -C 6 -alkyl; and R 4 is fluorinated C 1 -C 2 -alkyl, n-propyl, n-butyl, tert-butyl or cyclobutyl.
13. The compound as claimed in claim 12 , wherein R 2 is hydrogen.
14. The compound as claimed in claim 12 , wherein R 3 is tert-butyl.
15. The compound as claimed in claim 12 , wherein R 4 is trifluoromethyl.
16. The compound according to claim 1 , selected from the group consisting of:
2-{4-[4-(2-tert-Butyl-6-trifluoromethyl-pyrimidin-4-yl)-piperazin-1-yl]butyl}-2H-[1,2,4] triazine-3,5-dione;
2-{4-[4-(2-tert-Butyl-6-propyl-pyrimidin-4-yl)-piperazin-1-yl]butyl}-2H-[1,2,4] triazine-3,5-dione;
2-{4-[4-(2,6-Di-tert-butyl-pyrimidin-4-yl)-piperazin-1-yl]butyl}-2H-[1,2,4] triazine-3,5-dione;
2-{4-[4-(2-tert-Butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]butyl}-2H-[1,2,4] triazine-3,5-dione;
2-{4-[4-(2-tert-Butyl-6-trifluoromethyl-pyrimidin-4-yl)-piperazin-1-yl]butyl}-6-methyl-2H-[1,2,4] triazine-3,5-dione;
2-{4-[4-(2-tert-Butyl-6-propyl-pyrimidin-4-yl)-piperazin-1-yl]butyl}-6-methyl-2H-[1,2,4]triazine-3,5-dione; and
2-{4-[4-(2-tert-Butyl-6-trifluoromethyl-pyrimidin-4-yl)-piperazin-1-yl]butyl}-4-methyl-2H-[1,2,4] triazine-3,5-dione;
or a pharmacologically tolerated salt or tautomer thereof.
17. A pharmaceutical composition comprising at least one compound as claimed in claim 1 , together with at least one physiologically acceptable carrier or auxiliary substance.
18. A method for treating schizophrenia comprising administering an effective amount of at least one compound as claimed in claim 1 to a subject in need thereof.
19. A method for treating a bipolar disorder comprising administering an effective amount of at least one compound as claimed in claim 1 to a subject in need thereof.
20. A method for treating drug addiction comprising administering an effective amount of at least one compound as claimed in claim 1 to a subject in need thereof.