Patent EA-001658-B1 (EA)
Title: Quinoxalinediones
Inventor: STOBIE ALAN
IPC: A61P25/16
Filed: 1998-02-24
Abstract: 1. A substantially pure compound of the formula:   or a pharmaceutically acceptable salt or solvate thereof. 2. A compound as claimed in Claim 1 that is at least of 90% w/w purity. 3. A compound as claimed in Claim 2 that is at least of 95% w/w purity. 4. A compound as claimed in Claim 3 that is at least of 98% w/w purity. 5. A compound as claimed in any one of Claims 1 to 4 wherein the pharmaceutically acceptable salt is a sodium salt. 6. A pharmaceutical composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of Claims 1 to 5, together with a pharmaceutically acceptable diluent or carrier. 7. A compound of the formula (I), or a pharmaceutically acceptable salt, solvate or composition thereof, as claimed in any one of Claims 1 to 5 and 6, respectively, for use as a medicament. 8. The use of a compound of the formula (I), or of a pharmaceutically acceptable salt, solvate or composition thereof, as claimed in any one of Claims 1 to 5 and 6, respectively, for the manufacture of a medicament for the treatment of a disease by producing an antagonist effect at a NMDA receptor. 9. Use as claimed in Claim 8 where the disease is an acute neurodegenerative or a chronic neurological disorder; 10. A method of treatment of a mammal to treat a disease by producing an antagonist effect at a NMDA receptor, which comprises treating said mammal with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt, solvate or composition thereof, as claimed in any one of Claims 1 to 5 and 6, respectively. 11. A method as claimed in Claim 10 where the disease is an acute neurodegenerative or a chronic neurological disorder. 12. A compound of the formula:   wherein R is group of the formula:   and R<1> and R<2>, either when taken alone or together, represent a group or groups that can be hydrolytically cleaved under acidic or basic conditions to provide the corresponding quinoxalinedione. 13. A compound of the formula (II) as claimed in Claim 12 wherein R<1> and R<2> are either each independently selected from C1-C4 alkyl (preferably methyl or ethyl) and benzyl, optionally ring-substituted by from 1 to 3 substituents each independently selected from C1-C4 alkyl, C1-C4 alkoxy, halo, nitro and trifluoromethyl, or, when taken together, represent C1-C6 alkylene, CH(phenyl), CH(4-methoxyphenyl) or CH(3,4-dimethoxyphenyl). 14. A compound of the formula:   wherein R<3> is a group of the formula:   and R<1> and R<2> are as defined in Claim 12 or 13. 15. A process for the preparation of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in Claim 1 comprising acidic or basic hydrolysis of a compound of the formula:   wherein R is group of the formula:    and R<1> and R<2> , either when taken alone or together, represent a group or groups that can be hydrolytically cleaved under acidic or basic conditions to provide the corresponding quinoxalinedione, said process being followed by: (i) when a compound of the formula (II) wherein R is a group of the formula (III) is used, separation of the atropisomer of the formula (I); and/or (ii) optionally, conversion of a compound of the formula (I) to a pharmaceutically acceptable salt or solvate thereof. 16. A process for the preparation of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in Claim 1 comprising N-oxidation of a compound of the formula:   where R<3> is a group of the formula:   followed by work-up of the reaction under silicon dioxide-free conditions, said process being followed by: (i) when a compound of the formula (XI) wherein R is a group of the formula (IX) is used, separation of the atropisomer of the formula (I); and/or (ii) optionally, conversion of a compound of the formula (I) to a pharmaceutically acceptable salt or solvate thereof. 17. A process as claimed in Claim 16 wherein the N-oxidation is carried out using OXONE (trade mark) in a reaction-inert solvent. 18. A process as claimed in Claim 17 wherein the reaction-inert solvent is water. 19. A process for the preparation of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in Claim 1 comprising acidic treatment of a silica complex of a compound of the formula (I), said process being optionally followed by conversion of a compound of the formula (I) to a pharmaceutically acceptable salt or solvate thereof.