Carbamate/urea derivatives
The invention relates to compound of the formula I or a salt thereof, wherein the substituents are as defined in the specification; to its preparation, to its use as medicament and to medicaments comprising it.
1. A compound of the formula I
or a salt thereof, wherein
R 1 is isopropyl or cyclobutyl; m is 1; n is 0, 1 or 2; each R 2 independently is halogen, C 1-4 alkyl, C 1-4 halogenalkyl, C 1-4 alkoxy, C 1-4 halogenalkoxy or C 3-4 cycloalkyl; or two R 2 at the same carbon atom form together with said carbon atom a C 3-4 cycloalkyl;
X 1 is oxygen;
p is 1 and q is 1; r is 0, 1 or 2; wherein each R 3 independently is halogen, C 1-4 alkyl, C 1-4 halogenalkyl, C 1-4 alkoxy, C 1-4 halogenalkoxy or C 3-4 cycloalkyl; or two R 3 at the same carbon atom form together with said carbon atom a C 3-4 cycloalkyl; A is selected from A3 and A4
wherein the bond marked with the asterisk is attached to the nitrogen atom;
R 5 is hydrogen or methyl;
s is 0, 1 or 2; and
each R 6 independently is halogen, C 1-4 alkyl, C 1-4 halogenalkyl, C 1-4 alkoxy, C 1-4 halogenalkoxy or C 3-4 cycloalkyl.
2. A compound of formula I according to claim 1 , wherein said compound is selected from the group consisting of
1-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)piperidin-4-yl 4-isopropylpiperazine-1-carboxylate;
1-(2-oxo-1,2-dihydropyridin-4-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate; and
1-(2-oxo-1,2-dihydropyridin-4-yl)piperidin-4-yl 4-isopropylpiperazine-1-carboxylate or salts of these compounds.
3. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 and one or more pharmaceutically acceptable carriers.
4. A compound of formula II-1
or a salt thereof, in which p is 1 and q is 1; r is 0, 1 or 2; wherein each R 3 independently is halogen, C 1-4 alkyl, C 1-4 halogenalkyl, C 1-4 alkoxy, C 1-4 halogenalkoxy or C 3-4 cycloalkyl; or two R 3 at the same carbon atom form together with said carbon atom a C 3-4 cycloalkyl; A is selected from A3 and A4
wherein the bond marked with the asterisk is attached to the nitrogen atom;
R 5 is hydrogen or methyl;
s is 0, 1 or 2;
each R 6 independently is halogen, C 1-4 alkyl, C 1-4 halogenalkyl, C 1-4 alkoxy, C 1-4 halogenalkoxy or C 3-4 cycloalkyl; and R a is halogen or 4-nitrophenyloxy.
5. A free form of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in crystalline form; or a salt of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate in crystalline form, wherein said salt is the citrate, hydrochloride, fumarate, adipate, maleate or sebacate of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate.
6. A pharmaceutical composition, which comprises a free form or a salt as defined in claim 5 as active ingredient and at least one pharmaceutically acceptable carrier.
7. A compound 1-(6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate having the following formula
or a salt thereof.
8. A compound 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-isopropylpiperazine-1-carboxylate having the following formula
or a salt thereof.
9. A compound 1-(6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-isopropylpiperazine-1-carboxylate having the following formula
or a salt thereof.
10. A compound 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate
or a salt thereof.
11. A compound selected from the group consisting of: 1-(6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclopropylpiperazine-1-carboxylate; 1-(1-ethyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-isopropylpiperazine-1-carboxylate; and 1-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-4-yl 4-isopropylpiperazine-1-carboxylate; or a pharmaceutically acceptable salt thereof.
12. A method of ameliorating obesity comprising administration of an effective amount of a compound according to claim 1 to a subject in need of treatment thereof.
13. A method of ameliorating epilepsy comprising administration of an effective amount of a compound according to claim 1 to a subject in need of treatment thereof.
14. A method of treating ameliorating narcolepsy comprising administration of an effective amount of a compound according to claim 1 to a subject in need of treatment thereof.
15. A method for ameliorating narcolepsy in a subject in need of treatment thereof comprising administration of an effective amount of a compound according to claim 1 in combination with another active agent selected from the group consisting of: a noradrenaline-dopamine reuptake inhibitor, a tri- or tetracyclic antidepressant, a serotonin-noradrenaline reuptake inhibitor, a selective serotonin reuptake inhibitor, a noradrenaline reuptake inhibitor, a MAO-B inhibitor, a gamma-hydroxy-butyrate and a psychostimulant.
16. The method according to claim 15 wherein the other active agent is selected from the group consisting of: modafinil, armodafinil, clomipramine, venlafaxine, duloxetine, paroxetine, reboxetine, atomoxetine, selegiline and methylphenidate.
17. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 7 and one or more pharmaceutically acceptable carriers.
18. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 8 and one or more pharmaceutically acceptable carriers.
19. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 9 and one or more pharmaceutically acceptable carriers.
20. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 10 and one or more pharmaceutically acceptable carriers.