Patent EA-004711-B1 (EA)
Title: New indenoindolone compounds, a process for their preparation and pharmaceutical compositions containing them
Inventor: WIERZBICKI MICHEL
IPC: C07D209/80
Filed: 2002-03-18
Abstract: 1. Compound of formula (I): wherein: R represents a hydrogen atom or a linear or branched (C1-C6)alkenyl or linear or branched (C1-C6))alkyl group optionally substituted by a carboxy group or by a group of formula -NRaRb wherein each of Ra and Rb, which may be identical or different, represents a hydrogen atom or a linear or branched (C1-C6)alkyl group, or form together with the nitrogen atom carrying them a nitrogen-containing heterocycle, each of R1, R2, R3, R4, R5, R6, R7 and R8, which may be identical or different, represents a hydrogen atom or a linear or branched (C1-C6)alkyl group, a linear or branched (C1-C6)alkenyl group, a hydroxy group, a linear or branched (C1-C6)alkoxy group, a linear or branched (C1-C6)alkenyloxy group, an aryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, an aryl-(C1-C6)alkoxy group in which the alkoxy moiety is linear or branched, a carboxy group, a linear or branched (C1-C6)acyloxy group, or an arylcarbonyloxy group, or one of the groups R1 to R8 forms with an adjacent one of the groups R1 to R8 a (C1-C2)alkylenedioxy group, its optical isomers when they exist, and addition salts thereof with a pharmaceutically acceptable acid or base, with the proviso that: - when R does not represent a hydrogen atom, then at least one of the groups R1 to R8 represents a hydroxy group or a linear or branched (C1-C6)acyloxy group, - and the compounds of formula (I) are other than indeno[1,2-b]indol-10(5H)-one, it being understood that the term "aryl group" is understood to mean "phenyl", "biphenylyl", "naphthyl" or "tetrahydronaphthyl", each of those groups being optionally substituted by one or more identical or different atoms or groups selected from halogen atoms and linear or branched (C1-C6)alkyl groups, hydroxy groups, linear or branched (C1-C6)alkoxy groups, linear or branched (C1-C6)polyhaloalkyl groups, amino groups (optionally substituted by one or more linear or branched (C1-C6)alkyl groups), nitro groups, linear or branched (C1-C6)acyl groups and (C1-C2)alkylenedioxy groups. 2. Compound of formula (I) according to claim 1 which is 2,3-dimethoxy-8-hydroxy-5-methyl-indeno[1,2-b]indol-10(5H)-one. 3. Compound of formula (I) according to claim 1 which is 2,4-dimethoxy-8-hydroxy-indeno[1,2-b]indol-10(5H)-one. 4. Compound of formula (I) according to claim 1 which is 2,3-dimethoxy-5-(2-dimethylaminoethyl)-8-hydroxy-indeno[1,2-b]indol-10(5H)-one. 5. Compound of formula (I) according to claim 1 which is 2,3-dimethoxy-8-hydroxy-5-[2-(4-morpholinyl)-ethyl]-indeno[1,2-b]indol-10(5H)-one. 6. Process for the preparation of compounds of formula (I) according to claim 1, characterised in that a compound of formula (II): wherein R1, R2, R3 and R4 are as defined for formula (I), is reacted with N-bromosuccinimide to yield a compound of formula (III): wherein R1, R2, R3 and R4 are as defined hereinbefore, which is reacted with triphenylphosphine to yield a compound of formula (IV): wherein R1, R2, R3 and R4 are as defined hereinbefore, which is reacted with a compound of formula (V): wherein R5, R6, R7 and R8 are as defined for formula (I), to yield a compound of formula (VI): wherein R1, R2, R3, R4, R5, R6, R7 and R8 are as defined hereinbefore, which is treated with a base to yield a compound of formula (VII): wherein R1, R2, R3, R4, R5, R6, R7 and R8 are as defined hereinbefore, which is subjected to the action of a reducing agent to yield, after separation of the isomers where necessary, a compound of formula (Ia), a particular case of the compounds of formula (I): wherein R1, R2, R3, R4, R5, R6, R7 and R8 are as defined hereinbefore, which is reacted, if desired, with a compound of formula (VIII): R'-Z			(VIII) Wherein R' represents a linear or branched (C1-C6)alkenyl or linear or branched (C1-C6)alkyl group optionally substituted by a carboxy group or by a group of formula -NRaRb wherein each of Ra and Rb, which may be identical or different, represents a hydrogen atom or a linear or branched (C1-C6)alkyl group, or form together with the nitrogen atom carrying them a nitrogen-containing heterocycle, and Z represents a leaving group, such as, for example, a halogen atom or a mesylate, tosylate or trifluoromethanesulphonate group, to yield a compound of formula (Ib), a particular case of the compounds of formula (I): wherein R1, R2, R3, R4, R5, R6, R7 and R8 and R' are as defined hereinbefore, which compounds of formulae (Ia) and (Ib) constitute the totality of the compounds of formula (I), which are purified, if necessary, in accordance with a conventional purification technique, are separated, where appropriate, into their isomers in accordance with a conventional separation technique, and converted, if desired, into addition salts thereof with a pharmaceutically acceptable acid or base. 7. Pharmaceutical composition comprising as active ingredient a compound of formula (I) according to any one of claims 1 to 5, in combination with one or more inert, non-toxic pharmaceutically acceptable carriers. 8. Pharmaceutical composition according to claim 7 for use in the manufacture of medicaments for treating disorders of the melatoninergic system.