Pyridin-2-one compounds and their use as modulators of the dopamine D3 receptor
View Patent ↗The invention relates to pyridin-2-one compounds of general formula (I) in which A represents a 4- to 6-membered hydrocarbon chain that can have 1 or 2 methyl groups as substituents, wherein 1 or 2 carbon atoms can be replaced by oxygen, a carbonyl group or sulfur, and the hydrocarbon chain can have a double bond or a triple bond; R 1 , R 2 , R 3 and R 4 have the meanings as cited in the claims and in the description. The invention also relates to the tautomers of compounds I and the physiologically acceptable salts of the compounds I and their tautomers. The invention also relates to the use of these compounds for treating diseases that respond to the influence of dopamine D 3 receptor antagonists or agonists.
1. A pyridin-2-one compound of the formula I
in which
A is a 4- to 6-membered hydrocarbon chain which may have 1 or 2 methyl groups as substituents, in which 1 or 2 carbon atoms may be replaced by oxygen, a carbonyl group or sulfur, and in which the hydrocarbon chain may have a double bond or a triple bond;
R 1 , R 2 are independently of one another hydrogen, CN, NO 2 , halogen, OR 5 , NR 6 R 7 , C(O)NR 6 R 7 , O—C(O)NR 6 R 7 , SR 8 , SOR 8 , SO 2 R 8 , SO 2 NR 6 R 7 , COOR 9 , O—C(O)R 10 , COR 10 , C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 2 -C 6 -haloalkenyl, C 3 -C 6 -cycloalkyl, 4- to 6-membered heterocyclyl having 1, 2 or 3 heteroatoms selected from O, S and N, which may have 1, 2 or 3 substituents which are selected independently of one another from C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, NR 6 R 7 , CN, OH, C 1 -C 2 -fluoroalkyl or halogen, phenyl which may have 1, 2 or 3 substituents which are selected independently of one another from C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, NR 6 R 7 , OH, CN, C 1 -C 2 -fluoroalkyl or halogen, C 1 -C 6 -alkyl which has a substituent which is selected from OR 5 , NR 6 R 7 , C(O)NR 6 R 7 , O—C(O)NR 6 R 7 , SR 8 , SOR 8 , SO 2 R 8 , SO 2 NR 6 R 7 , COOR 9 , O—C(O)R 10 , COR 10 , C 3 -C 6 -cycloalkyl, 5- or 6-membered heterocyclyl having 1, 2 or 3 heteroatoms selected from O, S and N, and phenyl, where phenyl and heterocyclyl may have 1, 2 or 3 substituents which are selected independently of one another from C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, NR 6 R 7 , CN, OH, C 1 -C 2 -fluoroalkyl or halogen, C 2 -C 6 -alkenyl which has a substituent selected from OR 5 , NR 6 R 7 , C(O)NR 6 R 7 , O—C(O)NR 6 R 7 , SR 8 , SOR 8 , SO 2 R 8 , SO 2 NR 6 R 7 , COOR 9 , O—C(O)R 10 , COR 10 , C 3 -C 6 -cycloalkyl, 5- or 6-membered heterocyclyl having 1, 2 or 3 heteroatoms selected from O, S and N, and phenyl, where phenyl and heterocyclyl in turn may have 1, 2 or 3 substituents which are selected independently of one another from C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, NR 6 R 7 , OH, CN, C 1 -C 2 -fluoroalkyl or halogen;
R 3 , R 4 are independently of one another OR 5 , NR 6 R 7 , CN, C 1 -C 6 -alkyl which is optionally substituted one or more times by OH, C 1 -C 4 -alkoxy, halogen or phenyl which in turn may have 1, 2 or 3 substituents selected from C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, NR 6 R 7 , OH, CN, C 1 -C 2 -fluoroalkyl or halogen, or C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 6 -cycloalkyl, C 4 -C 10 -bicycloalkyl, C 6 -C 10 -tricycloalkyl, where the last 5 groups mentioned may optionally be substituted one or more times by halogen or C 1 -C 4 -alkyl, or halogen, CN, C 1 -C 4 -alkoxy, 5- or 6-membered heterocyclyl having 1, 2 or 3 heteroatoms selected from O, S and N, and phenyl, where phenyl and heterocyclyl may optionally have 1, 2 or 3 substituents which are selected independently of one another from C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, NR 6 R 7 , CN, C 1 -C 2 ,-fluoroalkyl and halogen;
R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are independently of one another H, C 1 -C 6 -alkyl which is optionally substituted by OH, C 1 -C 4 -alkoxy or phenyl which in turn may have 1, 2 or 3 substituents selected from C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, NR 6 R 7 , OH, CN, C 1 -C 2 -fluoroalkyl or halogen, or C 1 -C 6 -haloalkyl or phenyl which in turn may have 1, 2 or 3 substituents selected from C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, NR 6 R 7 , OH, CN, C 1 -C 2 -fluoroalkyl or halogen, where
R 7 may also be a COR 11 group, and where
R 6 with R 7 may also, together with the nitrogen to which they are bonded, form a 4-, 5- or 6-membered, saturated or unsaturated heterocycle which may have a further heteroatom selected from O, S and NR 12 as ring member, where R 12 is hydrogen or C 1 -C 4 -alkyl, and which may be substituted by 1, 2, 3 or 4 alkyl groups; and
R 11 is hydrogen, C 1 -C 4 -alkyl or phenyl which is optionally substituted by 1, 2 or 3 radicals which are selected independently of one another from C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, NR 6 R 7 , CN, C 1 -C 2 -fluoroalkyl or halogen;
and the tautomers of the compound I, the physiologically acceptable salts of the compound I and the physiologically acceptable salts of the tautomers of the compound I.
2. A pyridin-2-one compound according to claim 1 , in which R 3 is C 1 -C 6 -alkyl, and R 4 is selected from C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl which optionally has 1 or 2 substituents selected from chlorine and methyl, and C 1 -C 2 -fluoroalkyl.
3. A pyridin-2-one compound according to claim 2 , in which R 3 is branched alkyl having 3, 4 or 5 C atoms or is C 3 -C 6 -cycloalkyl.
4. A pyridin-2-one compound according to claim 2 , in which R 4 is trifluoromethyl or C 3 -C 4 -alkyl.
5. A pyridin-2-one compound according to claim 2 , in which R 4 is cyclopropyl, cyclobutyl, cyclopentyl or 1-methylcyclopropyl.
6. A pyridin-2-one compound according to claim 1 , in which at least one of the radicals R 1 or R 2 is different from hydrogen.
7. A pyridin-2-one compound according to claim 6 , in which R 1 is selected from halogen, OR 5 , NR 6 R 7 , C 1 -C 4 -alkyl which is optionally substituted by OH, C 1 -C 4 -alkoxy or halogen, or aromatic 5- or 6-membered heterocyclyl having 1, 2 or 3 heteroatoms selected from O, S and N, which may have 1, 2 or 3 substituents which are selected independently of one another from C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, NR 6 R 7 , CN, OH, C 1 -C 2 -fluoroalkyl or halogen, and phenyl which may have 1, 2 or 3 substituents which are selected independently of one another from C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, NR 6 R 7 , OH, CN, C 1 -C 2 -fluoroalkyl or halogen.
8. A pyridin-2-one compound according to claim 7 , in which R 1 is selected from phenyl, OH, chlorine, methyl, methoxy and trifluoromethyl.
9. A pyridin-2-one compound according to claim 1 , in which R 2 is hydrogen.
10. A pyridin-2-one compound according to claim 1 , in which A is butane-1,4-diyl.
11. A pharmaceutical composition comprising at least one compound according to claim 1 and/or salt thereof, optionally together with physiologically acceptable carriers and/or excipients.
12. A method for treating a D3 receptor related condition comprising administering an effective amount of at least one compound of claim 1 to a subject in need thereof, wherein the condition is selected from the group consisting of Parkinson's disease, anxiety, schizophrenia, and depression.