Nitrocatechol derivatives as COMT inhibitors
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.
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):
wherein R 1 and R 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 3 represents a pyridine N-oxide group according to the formula A, B or C, which is connected as indicated by the unmarked bond:
where R 4 , R 5 , R 6 and R 7 independently from each other represent hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -thioalkyl, C 1 -C 6 -alkoxy, C 6 -C 12 -aryloxy or a C 6 -C 12 -thioaryl group, C 1 -C 6 -alkanoyl or C 7 -C 13 -aroyl group, amino, C 1 -C 6 -alkylamino, C 1 -C 6 -dialkylamino, C 3 -C 12 -cycloalkylamino or C 3 -C 12 -heterocycloalkylamino, C 1 -C 6 -alkylsulphonyl or C 6 -C 12 -arylsulphonyl, halogen, C 1 -C 6 -haloalkyl, trifluoromethyl, cyano, nitro or a heteroaryl group; or where two or more of residues R 4 , R 5 , R 6 and R 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) n —(Y) m —R 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):
wherein R 1 and R 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 3 represents a pyridine N-oxide group according to the formula A, B or C, which is connected as indicated by the unmarked bond:
where R 4 , R 5 , R 6 and R 7 independently from each other represent hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -thioalkyl, C 1 -C 6 -alkoxy, C 6 -C 12 -aryloxy or a C 6 -C 12 -thioaryl group, C 1 -C 6 -alkanoyl or C 7 -C 13 -aroyl group, amino, C 1 -C 6 -alkylamino, C 1 -C 6 -dialkylamino, C 3 -C 12 -cycloalkylamino or C 3 -C 12 -heterocycloalkylamino, C 1 -C 6 -alkylsulphonyl or C 6 -C 12 -arylsulphonyl, halogen, C 1 -C 6 -haloalkyl, trifluoromethyl, cyano, nitro or a heteroaryl group; or where two or more of residues R 4 , R 5 , R 6 and R 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) n —(Y) m —R 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):
wherein R 1 and R 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 3 represents a pyridine N-oxide group according to the formula A, B or C, which is connected as indicated by the unmarked bond:
where R 4 , R 5 , R 6 and R 7 independently from each other represent hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -thioalkyl, C 1 -C 6 -alkoxy, C 6 -C 12 -aryloxy or a C 6 -C 12 -thioaryl group, C 1 -C 6 -alkanoyl or C 7 -C 13 -aroyl group, amino, C 1 -C 6 -alkylamino, C 1 -C 6 -dialkylamino, C 3 -C 12 -cycloalkylamino or C 3 -C 12 -heterocycloalkylamino, C 1 -C 6 -alkylsulphonyl or C 6 -C 12 -arylsulphonyl, halogen, C 1 -C 6 -haloalkyl, trifluoromethyl, cyano, nitro or a heteroaryl group; or where two or more of residues R 4 , R 5 , R 6 and R 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) n —(Y) m —R 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]oxadiazol-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):
wherein R 1 and R 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 3 represents a pyridine N-oxide group according to the formula A, B or C, which is connected as indicated by the unmarked bond:
where R 4 , R 5 , R 6 and R 7 independently from each other represent hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -thioalkyl, C 1 -C 6 -alkoxy, C 6 -C 12 -aryloxy or a C 6 -C 12 -thioaryl group, C 1 -C 6 -alkanoyl or C 7 -C 13 -aroyl group, amino, C 1 -C 6 -alkylamino, C 1 -C 6 -dialkylamino, C 3 -C 12 -cycloalkylamino or C 3 -C 12 -heterocycloalkylamino, C 1 -C 6 -alkylsulphonyl or C 6 -C 12 -arylsulphonyl, halogen, C 1 -C 6 -haloalkyl, trifluoromethyl, cyano, nitro or a heteroaryl group; or where two or more of residues R 4 , R 5 , R 6 and R 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) n —(Y) m —R 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]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol.