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):	Learmonth; David Alexander (Valongo, PT), Kiss; Laszlo Erno (Lavra, PT), Palma; Pedro Nuno Leal (Leca da Palmeira, PT), Ferreira; Humberto Dos Santos (Maia, PT), da Silva; Patricio Manuel Vieira Ara (Porto, PT)
Assignee:	Portela & CA., S.A. (S. Mamede do Coronado, PT)
Application Number:	11/989,447
Patent Claims:	1. A compound of formula (I): ##STR00056## wherein R.sub.1 and R.sub.2 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; R.sub.3 represents a pyridine N-oxide group according to the formula A, B or C, which is connected as indicated by the unmarked bond: ##STR00057## where R.sub.4, R.sub.5, R.sub.6 and R.sub.7 independently from each other represent hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-thioalkyl, C.sub.1-C.sub.6-alkoxy, C.sub.6-C.sub.12-aryloxy or a C.sub.6-C.sub.12-thioaryl group, C.sub.1-C.sub.6-alkanoyl or C.sub.7-C.sub.13-aroyl group, amino, C.sub.1-C.sub.6-alkylamino, C.sub.3-C.sub.12-cycloalkylamino or C.sub.3-C.sub.12-heterocycloalkylamino, C.sub.1-C.sub.6-alkylsulphonyl or C.sub.6-C.sub.12-arylsulphonyl, halogen, C.sub.1-C.sub.6-haloalkyl, trifluoromethyl, cyano, nitro or a heteroaryl group; or where two or more of residues R.sub.4, R.sub.5, R.sub.6 and R.sub.7 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).sub.n--(Y).sub.m--R.sub.3 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-ben- zene-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-y- l]-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-y- l]-3-nitro-benzene-1,2-diol, 5-[3-(6-methyl-1-oxy-4-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-y- l]-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]oxad- iazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(6-methyl-1-oxy-2-phenyl-4-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxad- iazol-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-n- itro-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 R.sup.1 is hydrogen, R.sup.2 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.