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 process for the preparation of compounds according to formula I,
wherein
R 1 and R 2 independently from each other represent hydrogen, optionally substituted lower alkanoyl or optionally substituted lower aroyl;
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:
comprising steps wherein a compound of formula IIA, IIB or IIC,
wherein 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, a C 6 -C 12 -thioaryl group, C 1 -C 6 -alkanoyl, a C 7 -C 13 -aroyl group, amino, C 1 -C 6 -alkylamino, C 1 -C 6 -dialkylamino, C 3 -C 12 -cycloalkylamino, C 3 -C 12 -heterocycloalkylamino, C 1 -C 6 -alkylsulphonyl, 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,
is subjected to cyclisation with a compound of formula III,
wherein R 8 and R 9 independently from each other represent hydrogen or suitable protective groups for aromatic hydroxyl groups, under conditions suitable to produce oxadiazole derivatives of formula IVA, IVB or IVC,
optionally followed by removal of the protecting groups R 8 and or R 9 .
2. A process for the preparation of compounds according to formula I,
wherein
R 1 and R 2 independently from each other represent hydrogen, optionally substituted lower alkanoyl or optionally substituted lower aroyl;
R 3 represents a pyridine group according to the formula A, B or C, which is connected as indicated by the unmarked bond:
comprising steps wherein a compound of formula VA, VB, or VC,
wherein 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, a C 6 -C 12 -thioaryl group, C 1 -C 6 -alkanoyl, a C 7 -C 13 -aroyl group, amino, C 1 -C 6 -alkylamino, C 1 -C 6 -dialkylamino, C 3 -C 12 -cycloalkylamino, C 3 -C 12 -heterocycloalkylamino, C 1 -C 6 -alkylsulphonyl, 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,
is subjected to cyclisation with a compound of formula III
under conditions suitable to produce oxadiazole derivatives of formula VIA, VIB or VIC,
followed by oxidation of the pyridyl nitrogen atom to give a compound according to formula IVA, IVB or IVC,
optionally followed by removal of the protecting groups R 8 and/or R 9 , wherein R 8 and R 9 independently from each other represent hydrogen or suitable protective groups for aromatic hydroxyl groups.
3. The process according to claim 1 , wherein the compound of formula III is activated by reaction with thionyl chloride or 1,1-carbonyldiimidazole.
4. The process according to claim 1 , wherein the cyclisation step consisting of condensation and dehydration is conducted sequentially in a one-pot reaction.
5. The process according to claim 1 , wherein the cyclisation step is carried out in the presence of a suitable organic base.
6. The process according to claim 5 , wherein the cyclisation step is carried out in the presence of pyridine.
7. The process according to claim 1 , wherein the groups R 8 and R 9 are independently from each other or jointly removed and replaced with hydrogen.
8. The process according to claim 1 , wherein R 8 and R 9 of the compound of formula III independently from each other represent methyl or hydrogen.
9. The process according to claim 8 , wherein the methyl group is removed by reaction with aluminium chloride and pyridine in N-methylpyrrolidinone.
10. The process according to claim 1 , wherein the condensation and dehydration is performed in a dipolar aprotic solvent.
11. The process according to claim 10 , wherein the condensation and dehydration is performed in dimethylacetamide, N-methylpyrrolidinone, or dimethylsulfoxide.
12. The process according to claim 2 , wherein the pyridyl nitrogen atom of the oxadiazolyl compound of formula VIA, VIB or VIC is oxidised by hydrogen peroxide, peracetic acid, trifluoroperacetic acid, or urea-hydrogen peroxide complex and trifluoroacetic anhydride.
13. The process according to claim 1 , wherein the compound of formula IIA, IIB or IIC is obtained by the reaction of compound VIIA, VIIB, or VIIC, respectively,
wherein R 4 , R 5 , R 6 , and R 7 are defined as in the general formula I in claim 1 , with hydroxylamine in the presence of a chelating agent under conditions suitable to produce amidoxime derivatives.
14. The process according to claim 2 , wherein the compound of formula VA, VB or VC is obtained by the reaction of compound VIIIA, VIIIB or VIIIC, respectively,
wherein R 4 , R 5 , R 6 and R 7 are defined as in the general formula I in claim 2 , with hydroxylamine in the presence of a chelating agent under conditions suitable to produce amidoxime derivatives.
15. The process according to claim 13 , wherein the chelating agent is selected from the group consisting of 8-hydroxyquinoline, ortho-phenanthroline and hydrates or derivatives thereof.
16. Process for the preparation of compounds according to formula I in claim 1 , comprising the oxidation of the respective pyridine compound to the pyridine N-oxide compound.