Patent EA-004571-B1 (EA)
Title: New indenoindolone compounds, a process for their preparation and pharmaceutical compositions containing them
Inventor: WIERZBICKI MICHEL
IPC: C07D209/80
Filed: 2002-06-13
Abstract: 1. Compounds of formula (I): wherein: R represents: a hydrogen atom, a linear or branched (C1-C6)alkyl group optionally substituted by a carboxy group, by a linear or branched (C1-C6)alkoxycarbonyl group or by a NR10R11-group (wherein R10 and R11 which may be identical or different, each represents a linear or branched (C1-C6)alkyl group or together, with the nitrogen carrying them, form a nitrogen-containing heterocycle), or a linear or branched (C1-C6)alkenyl group, R1 to R8, which may be identical or different, each represents: a hydrogen atom, a linear or branched (C1-C6)alkyl group optionally substituted by an aryl, carboxy or linear or branched (C1-C6) (C1-C6)alkoxycarbonyl group, a hydroxy group, a linear or branched (C1-C6)acyloxy group, a group of formula NR12R13, wherein R12 and R13, which may be identical or different, each represents a hydrogen atom or a linear or branched (C1-C6)alkyl group optionally substituted by a group of formula NR14R15, wherein R14 and R15, which may be identical or different, each represents a linear or branched (C1-C6)-alkyl group or together, with the nitrogen atom carrying them, form a nitrogen-containing heterocycle, a carboxy group, a linear or branched (C1-C6)alkoxy group optionally substituted by an aryl group or by a group of formula NR14R15, wherein R14 and R15, which may be identical or different, each represents a linear or branched (C1-C6)alkyl group or together, with the nitrogen atom carrying them, form a nitrogen-containing heterocycle, a linear or branched (C1-C6)alkenyloxy group, or one of the groups R1 to R8 forms, with another of the groups R1 to R8 that is adjacent, a (C1-C2)alkylenedioxy group, X represents an oxygen atom or an NR16 group, wherein R16 represents a hydrogen atom or a linear or branched (C1-C6)alkyl group, an aryl group or an aryl-(C1-C6)alkyl group in which the alkyl moiety may be linear or branched, R9 represents a hydrogen atom or an aryl, heteroaryl, or linear or branched (C1-C6)alkyl group, wherein the alkyl group optionally contains one or more unsaturations and is optionally substituted by one or more identical or different groups selected from aryl, heteroaryl, (C3-C8)cycloalkyl, cyano and NR17R18 (wherein R17 and R18, which may be identical or different, each represents a linear or branched (C1-C6)alkyl group or together, with the nitrogen atom carrying them, form a nitrogen-containing heterocycle), isomers thereof, and also addition salts thereof with a pharmaceutically acceptable acid or base, wherein isomers are to be understood as optical isomers and geometrical isomers of the C= NXR9 double bond, wherein an aryl group is to be understood as: phenyl, biphenylyl or naphthyl, each of those groups optionally being substituted by one or more identical or different groups selected from halogen, linear or branched (C1-C6)alkyl (optionally substituted by one or more halogen atoms), linear or branched (C1-C6)alkenyl (optionally substituted by a phenyl group), linear or branched (C1-C6)alkoxy (optionally substituted by a phenyl group), phenoxy, nitro, cyano, ammo (optionally substituted by one or two linear or branched (C1-C6)alkyl groups) and (C1-C2)alkylenedioxy, a heteroaryl group is to be understood as an aromatic mono- or bi-cyclic group having from 5 to 12 ring members containing one, two or three hetero atoms selected from oxygen, nitrogen and sulphur, wherein the heteroaryl may optionally be substituted by one or more identical or different groups selected from halogen, linear or branched (C1-C6)-alkyl, hydroxy, linear or branched (C1-C6) alkoxy, linear or branched (C1-C6)polyhaloalkyl, and amino (optionally substituted by one or more linear or branched (C1-C6)alkyl groups), and a nitrogen-containing heterocycle is to be understood as a saturated monocyclic group having from 5 to 7 ring members containing one, two or three hetero atoms, one of those hetero atoms being a nitrogen atom, and the additional hetero atom or atoms optionally present being selected from the atoms oxygen, nitrogen and sulphur. 2. Compound of formula (I) according to claim 1, wherein X represents an oxygen atom. 3. Compound of formula (I) according to either claim 1 or claim 2, wherein R1 to R6 and R8, which may be identical or different, each represents a hydrogen atom, a hydroxy group or a linear or branched (C1-C6)alkoxy group. 4. Compound of formula (I) according to any one of claims 1 to 3 wherein R7 represents a 2-dimethylaminoethoxy group or a 2-(1-pyrrolidinyl)-ethoxy group. 5. Compound of formula (I) according to claim 1, which is (10Z)-8-(2-dimethylaminoethoxy)-2,3-dimethoxyindeno[1,2-b]indole-10(5H)-one O-(1-phenyl-2-propynyl)oxime, isomers thereof, and also addition salts thereof with a pharmaceutically acceptable acid. 6. Compound of formula (I) according to claim 1, which is (10Z)-8-(2-dimethylaminoethoxy)-2,3-dimethoxyindeno[ 1,2-bjindole-10(5H)-one O-(2-propynyl)-oxime, isomers thereof, and also addition salts thereof with a pharmaceutically acceptable acid. 7. Compound of formula (I) according to claim 1, which is (10Z)-8-(2-dimethyl-aminoethoxy)-2,3-dimethoxyindeno[1,2-bjindole-10(5H)-one O-(1-methyl-2propynyl)-oxime, isomers thereof, and also addition salts thereof with a pharmaceutically acceptable acid. 8. Compound of formula (I) according to claim 1, which is (10Z)-8-(2-dimethylaminoethoxy)-2,3-dimethoxyindeno[1,2-b]indole-10(5H)-one O-[1-(3-furyl)-2-propynyl]oxime, isomers thereof, and also addition salts thereof with a pharmaceutically acceptable acid. 9. Compound of formula (I) according to claim 1, which is (10Z)-8-[2-(1-pyrrolidinyl)ethoxy]-2,3-dimethoxyindeno[1,2-biindole-10(5H)-one O-[1-(3-furyl)-2-propynyl]oxime, isomers thereof, and also addition salts thereof with a pharmaceutically acceptable acid. 10. Compound of formula (I) according to claim 1, which is (10Z)-8-(2-dimethylamino-ethoxy)-2,3-dimethoxyindeno[1,2-b]indole-10(5H)-one O-((1S)-1-methyl-2-propynyl)-oxime, isomers thereof, and also addition salts thereof with a pharmaceutically acceptable acid. 11. 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 placed in the presence of 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 isomers where necessary, a compound of formula (VIII) : wherein R1, R2, R3, R4, R5, R6, R7 and R8 are as defined hereinbefore, which is reacted, if desired, with a compound of formula (IX): R'-Z			(IX) wherein R' represents a linear or branched (C1-C6)alkyl group (optionally substituted by an aryl group or by an NR9R10 group, wherein R9 and R10, which may be identical or different, each represents a linear or branched (C1-C6)alkyl group or together, with the nitrogen atom carrying them, form a nitrogen-containing heterocycle) or a linear or branched (C1-C6)alkenyl group, 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 (X) : wherein R1, R2, R3, R4, R5, R6, R7, R8 and R' are as defined hereinbefore, which compounds of formula (VIII) or (X) are reacted with a compound of formula (XI) : H2NXR9			(XI) wherein X and R9 are as defined for formula (I), to yield a compound of formula (I) which is purified, if necessary, according to a conventional purification technique, is separated, if desired, into isomers according to a conventional separation technique and is converted, if desired, into addition salts with a pharmaceutically acceptable acid or base. 12. Pharmaceutical composition comprising as active ingredient a compound according to any one of claims 1 to 10, alone or in combination with one or more pharmaceutically acceptable, inert, non-toxic carriers. 13. Pharmaceutical composition according to claim 12 for use as an anti-cancer agent.