Claims for Patent: 8,168,793

Summary for Patent: 8,168,793

Title:	Nitrocatechol derivatives as COMT inhibitors
Abstract:	New compounds of formula I are described. The compounds have potentially valuable pharmaceutical properties in the treatment of some central and peripheral nervous system disorders.
Inventor(s):	David Alexander Learmonth, Laszlo Erno Kiss, Pedro Nuno Leal Palma, Humberto Dos Santos Ferreira, Patricio Manuel Vieira Araújo Soares da Silva
Assignee:	Bial Portela and Cia SA
Application Number:	US11/989,447
Patent Claims:	1. A compound of formula (I): wherein R1 and R2 are independently from each other hydrogen, optionally substituted lower alkanoyl or aroyl; X represents a methylene group; Y represents an atom of oxygen, NH or sulphur; n represents the number 0, 1, 2 or 3 and m represents the number 0 or 1; R3 represents a pyridine N-oxide group according to the formula A, B or C, which is connected as indicated by the unmarked bond: where R4, R5, R6 and R7 independently from each other represent hydrogen, C1-C6-alkyl, C1-C6-thioalkyl, C1-C6-alkoxy, C6-C12-aryloxy or a C6-C12-thioaryl group, C1-C6-alkanoyl or C7-C13-aroyl group, amino, C1-C6-alkylamino, C3-C12-cycloalkylamino or C3-C12-heterocycloalkylamino, C1-C6-alkylsulphonyl or C6-C12-arylsulphonyl, halogen, C1-C6-haloalkyl, trifluoromethyl, cyano, nitro or a heteroaryl group; or where two or more of residues R4, R5, R6 and R7 taken together represent aliphatic or heteroaliphatic rings or aromatic or heteroaromatic rings; and wherein P represents a central unit selected from the regioisomers of 1,3,4-oxadiazol-2,5-diyl and 1,2,4-oxadiazol-3,5-diyl, wherein the regioisomers of the central unit include both regioisomers realizable by exchange of the nitrocatechol moiety and the —(X)n—(Y)m—R3 moiety. 2. A compound according to claim 1, selected from the group consisting of 5-[3-(3,5-dichloro-1-oxy-pyridin-4-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(2-chloro-1-oxy-pyridin-4-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(2-morpholin-4-yl-1-oxy-pyridine-4-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 3-nitro-5-[3-(1-oxy-4-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol, 5-[3-(4-bromo-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(2-chloro-6-methyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(2-morpholin-4-yl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 3-nitro-5-[3-(1-oxy-6-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol, 5-[3-(2-methyl-1-oxy-6-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(6-methyl-1-oxy-4-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(2,6-dimethyl-1-oxy-4-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(2-methyl-1-oxy-6-phenyl-4-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(6-methyl-1-oxy-2-phenyl-4-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(2-bromo-6-methyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(2-chloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(2-bromo-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(2-bromo-4,5,6-trimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol, 5-[3-(2-chloro-4,5,6-trimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol, 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol, 5-[3-(2-bromo-5-chloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol and 3-nitro-5-[3-(1-oxy-2-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol. 3. A compound according to claim 1, wherein P is 1,2,4-oxadiazol-3,5-diyl. 4. A compound according to claim 1, wherein R1 is hydrogen, R2 is hydrogen, n is 0 and m is 0. 5. The compound, 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol. 6. A method of treating a subject afflicted by a disorder selected from: a mood disorder, Parkinson's disease, a parkinsonian disorder, restless legs syndrome, a gastrointestinal disturbance and an edema formation state, comprising administering to the subject an amount of a compound according to claim 1 effective to treat said disorder of the subject. 7. A method of treating a subject afflicted by a disorder selected from: a mood disorder, Parkinson's disease, a parkinsonian disorder, restless legs syndrome, a gastrointestinal disturbance and an edema formation state, comprising administering to the subject an amount of a compound according to claim 2 effective to treat said disorder of the subject. 8. A method of treating a subject afflicted by a disorder selected from: a mood disorder, Parkinson's disease, a parkinsonian disorder, restless legs syndrome, a gastrointestinal disturbance and an edema formation state, comprising administering to the subject an amount of a compound according to claim 3 effective to treat said disorder of the subject. 9. A method of treating a subject afflicted by a disorder selected from: a mood disorder, Parkinson's disease, a parkinsonian disorder, restless legs syndrome, a gastrointestinal disturbance and an edema formation state, comprising administering to the subject an amount of a compound according to claim 4 effective to treat said disorder of the subject. 10. A method of treating a subject afflicted by a disorder selected from: a mood disorder, Parkinson's disease, a parkinsonian disorder, restless legs syndrome, a gastrointestinal disturbance and an edema formation state, comprising administering to the subject an amount of a compound according to claim 5 effective to treat said disorder of the subject. 11. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 in combination with a pharmaceutically acceptable carrier. 12. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 2 in combination with a pharmaceutically acceptable carrier. 13. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 3 in combination with a pharmaceutically acceptable carrier. 14. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 4 in combination with a pharmaceutically acceptable carrier. 15. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 5 in combination with a pharmaceutically acceptable carrier. 16. A method of treating a subject afflicted by a disorder selected from: Parkinson's disease, a parkinsonian disorder, comprising administering to the subject an amount of a compound according to claim 5 effective to treat said disorder of the subject.