Patent EA-003280-B1 (EA)
Title: Novel octahydro-6,10-dioxo-6h-pyridazino/1,2-a/ /1,2/diazepin-1-carboxylic acid derivatives, preparation method and use for preparing therapeutically active compounds
Inventor: COLLADANT COLETTE
IPC: C07K5/078
Filed: 1999-04-26
Abstract: 1. Compounds of general formula (I): of SR configuration or in the form of a SR+SS mixture, wherein R is a hydrogen atom, an alkyl radical comprising 1 to 4 carbon atoms, and R1 and R2 are H or an amine function protecting group. 2. The compounds according to claim 1, characterized in that the amino group is protected by phthalimido, of formula (IA1): of SR configuration or a SR+SS mixture. 3. The compounds of formula (I) according to claims 1 or 2, in which R is methyl. 4. A racemic mixture of the compounds of formula (I) according to claim 1, comprising: (1S-cis) methyl-9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-octahydro-6,10-dioxo-6H-pyridazino [1,2-a] [1,2]-diazepine-1-carboxylate and (1R-trans) methyl-9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-octahydro-6,10-dioxo-6H-pyridazino [1,2-a] [1,2]-diazepine-1-carboxylate. 5. A process for the preparation of a compound of the formula (I) according to one of previous claims, characterized in that the compound of formula (II) in which alc is an alkyl radical comprising 1 to 4 carbon atoms, and Hal i3 a halogen atom is subjected to the action of the compound of formula (III): in which aryl is a phenyl radical in order to obtain the compound of formula (IV): which is subjected to the action of a basic agent, in order to obtain the compound of formula (V): which is optionally subjected to the action of an alkylation agent in order to obtain the compound of formula (VI): which is subjected to the action of a compound of formula (VII): in which Hal1 is a halogen atom and Ar represents a benzyl radical, and R1 and R2 taken together with the nitrogen atom form a phthalimido group, in order to obtain the compound of formula (VIII): of SR configuration or in the form of a SR+ SS mixture, which is subjected to the action of a hydrogenation agent in order to obtain the compound of formula (IX): 6. Use of the compounds of formula (IV) according to claim 5 as intermediate products. 7. Use of the compounds of formula (VIII) according to claim 5 as intermediate products. 8. Use of the compounds of formula (IX) according to claim 5 as intermediate products. 9. Use of the compounds of formula (I) according to one of claims 1 to 4 in the form of SS+SR mixtures or in SR form, characterized in that a compound of formula (I) is subjected to the action of a deracemization agent of the asymmetric carbon carried by the ring with 6 members, in order to obtain the compound of formula (IAopt): in SS form, in which the amine function is free or protected the R is as defined in claim 1. 10. Use of the compounds for formula (IA1) according to claims 20 to 4 for the preparation of the compounds of formula (IAopt): in SS form, in which R, R1 and R2 form together a phthalimido group. 11. Use according to claim 9 or claim 10, characterized in that R represents a methyl radical. 12. Use according to any one of claims 9 or claim 11, characterized in that the amine function is protected in the form of phthalimido. 13. Use according to any one of claims 9 to 12, characterized in that the deracemization agent is a base. 14. Use according to claim 13, characterized in mat the base is a strong base such as an alkaline or alkaline-earth alcoholate or a lithiated amine. 15. 9. Use according to any one of claims 10 to 14, characterized in that the starting product is a racemic mixture of the compounds of formula (I) according to claim 4 and the prepared product is: -(1S-cis) methyl-9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-3,4,7,8,9,10-hexahydro-6,10-dioxo-6H-pyridazino[1,2-a][1,2]diazepine-l-carboxylate.