Claims for Patent: 9,550,759

Summary for Patent: 9,550,759

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 (Valonga, PT), Kiss; Laszlo Erno (S. Mamede Do Coronado, PT), Palma; Pedro Nuno Leal (Leca de Palmeira, PT), Ferreira; Humberto Dos Santos (Maia, PT), Soares Da Silva; Patricio Manuel Vieira Araujo (Porto, PT)
Assignee:	BIAL--PORTELA & CA, S.A. (S. Mamede Do Coronado, PT)
Application Number:	14/541,654
Patent Claims:	1. A method of increasing the amount of orally administered L-DOPA which reaches the brain of a patient afflicted by Parkinson's disease and thereby treating Parkinson's disease which comprises administering orally to said patient a COMT-inhibitory effective amount of a compound of the 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.1-C.sub.6-dialkylamino, 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 method as claimed in claim 1, wherein the compound of Formula (I) is 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl- ]-3-nitrobenzene-1,2-diol. 3. A method of inhibiting COMT in the periphery which comprises the administration to a patient in need thereof a COMT-inhibitory amount of a compound of the Formula (I): ##STR00058## 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: ##STR00059## 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.1-C.sub.6-dialkylamino, 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. 4. A method as claimed in claim 3, wherein the compound of Formula (I) is 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. A method of manufacture of a pharmaceutical composition suitable for the treatment of Parkinson's disease which comprises formulating a compound of the Formula (I): ##STR00060## 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: ##STR00061## 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.1-C.sub.6-dialkylamino, 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 and a pharmaceutically acceptable carrier therefore. 6. A method as claimed in claim 5, wherein the compound of the Formula (I) is 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiaz- ol-5-yl]-3-nitrobenzene-1,2-diol. 7. A method of reducing O-methylation of L-DOPA in a patient suffering from Parkinson's disease treated with L-DOPA which comprises the administration of a compound of the Formula (I): ##STR00062## 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: ##STR00063## 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.1-C.sub.6-dialkylamino, 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. 8. A method as claimed in claim 7, wherein the compound of the Formula (I) is 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiaz- ol-5-yl]-3-nitrobenzene-1,2-diol.