HK1063321B - New [3,4-a:3,4-c]carbazole compounds, a process for their preparation and pharmaceutical compositions containing them - Google Patents

Description

Novel [3, 4-a:3, 4-c ] carbazole compounds, process for their preparation and pharmaceutical compositions containing them

The present invention relates to novel [3, 4-a:3, 4-c ] carbazole compounds, processes for their preparation and pharmaceutical compositions containing them.

The need for anticancer therapy has provoked the continuous development of new antiproliferative drugs with the aim of obtaining more active and better tolerated drugs. The compounds of the invention have inter alia anti-tumour properties, thus making them useful for the treatment of cancer. Among the various cancers that can be treated with the compounds of the invention, adenocarcinoma and carcinomas, sarcomas, gliomas and leukemias may be mentioned without any restriction. In view of their properties, the compounds of the invention can advantageously be combined with all cytotoxic treatments currently used and with radiotherapy whose toxicity is not therefore increased, and with various hormonal therapies directed against cancers (blood and prostate).

The patent applications WO 95/07910 and WO 96/04906 describe indole compounds and claim their antiviral activity on the one hand and their treatment and prevention of restenosis on the other hand. Patent applications WO 00/47583, WO 97/21677 and WO 96/11933 disclose cyclopenta [ g ] pyrrolo [3, 4-e ] indole compounds which are fused to aromatic or non-aromatic ring systems on the indole and cyclopentene moieties of the compounds and optionally contain heteroatoms. These compounds have pharmacological properties that make them particularly useful for the treatment of cancer. Patent application WO 01/85686 describes pyrrolo [3, 4-c ] carbazole compounds which are useful in the treatment of neurodegenerative diseases, inflammation, ischemia and cancer. Patent application WO 02/24699 describes tetrahydrocarbazole compounds which are useful in antibacterial therapy on the one hand and as skin deodorants and disinfectants on the other hand.

The invention more particularly relates to compounds of formula (I), the enantiomers, diastereomers and addition salts thereof with a pharmaceutically acceptable acid or base:

wherein:

a represents a saturated or partially or fully unsaturated ring, wherein the unsaturation optionally imparts aromaticity to the ring,

·W₁together with the carbon atom to which it is bonded represents phenyl or pyridyl,

z represents one or more identical or different radicals of the formula U-V, in which:

v.u represents a single bond, linear or branched (C)₁-C₆) Alkylene chains or linear or branched (C)₂-C₆) Alkenyl chains, the latter being optionally substituted by one or more identical or different radicals from the group consisting of halogen and hydroxyl and/or optionally containing one or more unsaturated bonds,

v represents hydrogenAtoms, halogen atoms and radicals cyano, nitro, azido, linear or branched (C)₁-C₆) Alkyl, aryl in which the alkyl part may be linear or branched- (C)₁-C₆) Alkyl, hydroxy, linear or branched (C)₁-C₆) Alkoxy, aryloxy, aryl in which the alkoxy part may be linear or branched- (C)₁-C₆) Alkoxy, formyl, carboxyl, aminocarbonyl, NR₃R₄、-C(O)-T₁、-C(O)-NR₃-T₁、-NR₃-C(O)-T₁、-O-C(O)-T₁、-C(O)-O-T₁、-NR₃-T₂-NR₃R₄、-NR₃-T₂-OR₃、-NR₃-T₂-CO₂R₃、-O-T’₂-NR₃R₄、-O-T’₂-OR₃、-O-T’₂-CO₂R₃and-S (O) t-R₃，

Wherein:

→R₃and R₄May be the same or different and each represents a hydrogen atom and is linear or branched (C)₁-C₆) Alkyl, aryl and aryl in which the alkyl part may be linear or branched- (C)₁-C₆) Radical of alkyl, or R₃+R₄Together with the nitrogen atom which carries them, form a saturated monocyclic or bicyclic heterocycle having 5 to 10 ring atoms, optionally containing in the ring system a second heteroatom selected from oxygen and nitrogen and optionally being selected from linear or branched (C)₁-C₆) Alkyl, aryl in which the alkyl part may be linear or branched- (C)₁-C₆) Alkyl, hydroxy, linear or branched (C)₁-C₆) Alkoxy, amino, linear or branched mono- (C)₁-C₆) Alkylamino and di (C) s wherein the alkyl moiety may be linear or branched₁-C₆) The radical substitution of an alkylamino radical,

→T₁represents a group selected from: optionally selected from-OR₃、-NR₃R₄、-CO₂R₃、-C(O)R₃and-C (O) NR₃R₄Linear or branched (C) substituted by a group of₁-C₆) Alkyl radical, wherein R₃And R₄As previously defined; aryl, wherein the alkyl moiety may be a linear or branched aryl- (C)₁-C₆) An alkyl group; or T₁Represents optionally selected from-OR₃、-NR₃R₄、-CO₂R₃、-C(O)R₃and-C (O) NR₃R₄Linear or branched (C) substituted by a group of₂-C₆) Alkenyl chain, wherein R₃And R₄As previously defined;

→T₂represents linear or branched (C)₁-C₆) An alkylene chain, which is a linear chain of alkylene,

→T’₂represents linear or branched (C) optionally substituted by one or more hydroxyl groups₁-C₆) An alkylene chain, which is a linear chain of alkylene,

→ t represents an integer from 0 to 2, inclusive,

or Z represents a group selected from methylenedioxy or ethylenedioxy,

·Q₁represents a group selected from oxygen atoms and the group NR₂Wherein R is₂Represents a group selected from: hydrogen atom and linear or branched (C)₁-C₆) Alkyl, aryl in which the alkyl part may be linear or branched- (C)₁-C₆) Alkyl, cycloalkyl in which the alkyl part may be linear or branched- (C)₁-C₆) Alkyl, -OR₃、-NR₃R₄、-O-T₂-NR₃R₄、-NR₃-T₂-NR₃R₄Linear or branched (C)₁-C₆) Hydroxyalkylamino, di ((C) wherein the alkyl moiety may be linear or branched₁-C₆) Hydroxyalkyl) amino, -C (O) -R₃and-NH-C (O) -R₃(ii) a Or R₂Represents a linear or branched chain substituted by one or more identical or different groupsTransformation (C)₁-C₆) An alkylene chain, the radical being selected from halogen atoms and the radicals cyano, nitro, -OR₃、-NR₃R₄、-CO₂R₃、-C(O)R₃Linear or branched (C)₁-C₆) Hydroxyalkylamino, di ((C) wherein the alkyl moiety may be linear or branched₁-C₆) Hydroxyalkyl) amino and-C (O) -NHR₃Wherein the radical R₃、R₄And T₂As defined above, the above-mentioned materials,

·Q₂represents a group selected from oxygen atoms and a group NR'₂Wherein R'₂Represents a group selected from: hydrogen atom and linear or branched (C)₁-C₆) Alkyl, aryl in which the alkyl part may be linear or branched- (C)₁-C₆) Alkyl, cycloalkyl in which the alkyl part may be linear or branched- (C)₁-C₆) Alkyl, -OR₃、-NR₃R₄、-O-T₂-NR₃R₄、-NR₃-T₂-NR₃R₄Linear or branched (C)₁-C₆) Hydroxyalkylamino, di ((C) wherein the alkyl moiety may be linear or branched₁-C₆) Hydroxyalkyl) amino, -C (O) -R₃and-NH-C (O) -R₃(ii) a Or R'₂Represents linear or branched (C) substituted by one or more identical or different groups₁-C₆) An alkylene chain, the radical being selected from halogen atoms and the radicals cyano, nitro, -OR₃、-NR₃R₄、-CO₂R₃、-C(O)R₃Linear or branched (C)₁-C₆) Hydroxyalkylamino, di ((C) wherein the alkyl moiety may be linear or branched₁-C₆) Hydroxyalkyl) amino and-C (O) -NHR₃Wherein the radical R₃、R₄And T₂As defined above, the above-mentioned materials,

·X₁represents a radical chosen from hydrogen atoms and the hydroxyl radicals, linear or branched (C)₁-C₆) Alkoxy, mercapto and linear or branched (C)₁-C₆) The radical of an alkylthio group,

·Y₁represents a hydrogen atom, or

·X₁And Y₁Together with the carbon atom bearing them, form a carbonyl or thiocarbonyl group,

·X₂represents a radical chosen from hydrogen atoms and the hydroxyl radicals, linear or branched (C)₁-C₆) Alkoxy, mercapto and linear or branched (C)₁-C₆) The radical of an alkylthio group,

·Y₂represents a hydrogen atom, or

·X₂And Y₂Together with the carbon atom bearing them, form a carbonyl or thiocarbonyl group,

·X′₁represents a radical chosen from hydrogen atoms and the hydroxyl radicals, linear or branched (C)₁-C₆) Alkoxy, mercapto and linear or branched (C)₁-C₆) The radical of an alkylthio group,

·Y′₁represents a hydrogen atom, or

·X′₁And Y'₁Together with the carbon atom bearing them, form a carbonyl or thiocarbonyl group,

·X′₂represents a radical chosen from hydrogen atoms and the hydroxyl radicals, linear or branched (C)₁-C₆) Alkoxy, mercapto and linear or branched (C)₁-C₆) The radical of an alkylthio group,

·Y′₂represents a hydrogen atom, or

·X′₂And Y'₂Together with the carbon atom bearing them, form a carbonyl or thiocarbonyl group,

·R₁represents a radical selected from hydrogen atoms and linear or branched (C)₁-C₆) A radical of an alkyl radical, optionally substituted by one or more (C) substituents chosen from hydroxyl, linear or branched₁-C₆) Alkoxy, linear or branched (C)₁-C₆) Hydroxyalkoxy or NR₃R₄Wherein the group R is₃And R₄As previously defined; or R₁Represents a group of formula (a):

wherein:

√R_a、R_b、R_cand R_dMay be the same or different and each independently represents a bond or a group selected from: hydrogen atom, halogen atom, hydroxyl group, linear or branched (C)₁-C₆) Alkoxy, aryloxy, aryl in which the alkoxy part may be linear or branched- (C)₁-C₆) Alkoxy, linear or branched (C)₁-C₆) Alkyl, aryl in which the alkyl part may be linear or branched- (C)₁-C₆) Alkyl, aryl, wherein R₃And R₄-NR as defined hereinbefore₃R₄Azido, -N ═ NR₃(wherein R is₃As previously defined) and-O-C (O) -R₅Wherein R is₅Represents linear or branched (C)₁-C₆) Alkyl (optionally substituted by one or more groups selected from halogen, hydroxy, amino, linear or branched (C)₁-C₆) Alkylamino and di (C) s wherein the alkyl moiety may be linear or branched₁-C₆) Radical substitution of alkylamino); or R₅Represents aryl, aryl in which the alkyl part may be linear or branched- (C)₁-C₆) An alkyl, cycloalkyl or heterocycloalkyl group,

√R_erepresents methylene (H)₂C ═ or formula-U)₁-R_aIn which U is₁Represents a single bond or methylene and R_aAs defined above, the above-mentioned materials,

v n is 0 or 1,

it is understood that the radical of formula (a) is represented by R_a、R_b、R_c、R_dOr R_eBonded to the nitrogen atom, with the proviso that the compound of formula (I) is not:

-3b, 6a, 6b, 7-tetrahydro-1H-dipyrrolo [3, 4-a:3, 4-c ] carbazole-1, 3, 4, 6- (2H, 3aH, 5H) -tetraone;

-5-ethyl-3 b, 6a, 6b, 7-tetrahydro-1H-dipyrrolo [3, 4-a:3, 4-c ] carbazole-1, 3, 4, 6- (2H, 3aH, 5H) -tetraone;

-3b, 6a, 7, 11 c-tetrahydro-1H-dipyrrolo [3, 4-a:3, 4-c ] carbazole-1, 3, 4, 6- (2H, 3aH, 5H) -tetraone;

-3b, 6a, 6b, 7-tetrahydrofuro [3, 4-a ] pyrrolo [3, 4-c ] carbazole-1, 3, 4, 6- (2H, 3aH, 5H) -tetraone;

where aryl is understood to mean phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl or indanyl, each of which is optionally substituted by one or more identical or different radicals selected from halogen, linear or branched (C)₁-C₆) Alkyl, linear or branched (C)₁-C₆) Trihaloalkyl, hydroxy, linear or branched (C)₁-C₆) Alkoxy and NR₃R₄Wherein R is₃And R₄As previously defined.

Among the pharmaceutically acceptable acids, there may be mentioned, without any limitation, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulfonic acid, camphoric acid and the like.

Among the pharmaceutically acceptable bases, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine and the like may be mentioned without any restriction.

Preferred compounds of the invention are those wherein X₁And Y₁Together with the carbon atom bearing them forming a carbonyl group, X₂And Y₂Together with the carbon atom bearing them forming a carbonyl group, X'₁And Y'₁With carbon atoms carrying themTogether form carbonyl and X'₂And Y'₂Those which form, together with the carbon atom bearing them, a carbonyl group.

Advantageously, the preferred groups Q of the invention₁is-NR₂Group, wherein R₂As defined for formula (I).

Advantageously, the preferred groups Q of the invention₂is-NR'₂Group, wherein R'₂As defined for formula (I).

According to an advantageous embodiment, preferred compounds of the invention are compounds of formula (I) which more specifically correspond to formula (IA):

wherein R is₁、R₂、R′₂、W₁And Z is as defined for formula (I).

According to a second advantageous embodiment, preferred compounds of the invention are compounds of formula (I) which more particularly correspond to formula (IB):

wherein R is₁、R₂、R′₂And Z is as defined for formula (I).

According to a third advantageous embodiment, preferred compounds of the invention are compounds of formula (I) which more specifically correspond to formula (IC):

wherein R is₁、R₂、R′₂And Z is as defined for formula (I).

According to a fourth advantageous embodiment, preferred compounds of the invention are compounds of formula (I) which more specifically correspond to formula (ID):

wherein R is₂、R′₂、W₁、Z、R_b、R_c、R_dAnd R_eAs defined for formula (I).

According to a fifth advantageous embodiment, preferred compounds of the invention are compounds of formula (I) which more specifically correspond to formula (IE):

wherein R is₂、R′₂、Z、R_b、R_c、R_dAnd R_eAs defined for formula (I).

According to a sixth advantageous embodiment, preferred compounds of the invention are compounds of formula (I) which more particularly correspond to formula (IF):

wherein R is₂、R′₂、Z、R_b、R_c、R_dAnd R_eAs defined for formula (I).

Preferably, the preferred substituents Z according to the invention are groups of the formula U-V, in which U represents a single bond and V represents a group chosen from a hydrogen atom, a halogen atom and the group nitro, linear or branched (C)₁-C₆) Alkyl, hydroxy, linear or branched (C)₁-C₆) Alkoxy, aryl in which the alkoxy moiety may be linear or branched- (C)₁-C₆) Alkoxy and NR₃R₄Wherein R is₃And R₄Each represents a hydrogen atom。

Even more preferably, the preferred substituents Z according to the invention are groups of the formula U-V, wherein U represents a single bond and V represents a group selected from a hydrogen atom, a halogen atom and a hydroxyl group and an aryl- (C) wherein the alkoxy moiety may be linear or branched₁-C₆) A radical of an alkoxy group.

In an interesting embodiment, the preferred radicals R according to the invention₁Is a hydrogen atom, linear or branched (C)₁-C₆) Alkyl or by R_aA group of formula (a) bonded to a nitrogen atom:

wherein:

·R_b、R_cand R_dRepresents hydroxy, aryl in which the alkoxy moiety may be linear or branched- (C)₁-C₆) Alkoxy or a group-O-C (O) -R₅Wherein R is₅Represents linear or branched (C)₁-C₆) An alkyl group, a carboxyl group,

·R_crepresentative type U₁-R_aIn which U is₁Represents a methylene group and R_aHaving a radical of formula (I) with R_b、R_cAnd R_dThe same definition, and n is 0.

In an even more interesting embodiment, the preferred radicals R according to the invention₁Is hydrogen.

In an interesting embodiment, the preferred radicals R according to the invention₂Is hydrogen, linear or branched (C)₁-C₆) Alkyl, OR₃、NR₃R₄OR by a group OR₃Or NR₃R₄Substituted linear or branched (C)₁-C₆) An alkylene chain, wherein R₃And R₄As defined for formula (I).

Are even more interestingIn embodiments, preferred radicals R according to the invention₂Is hydrogen, linear or branched (C)₁-C₆) Alkyl or by radicals NR₃R₄Substituted linear or branched (C)₁-C₆) An alkylene chain, wherein R₃And R₄As defined for formula (I).

In an interesting embodiment, the radicals R 'preferred according to the invention'₂Is hydrogen, linear or branched (C)₁-C₆) Alkyl or by radicals NR₃R₄Substituted linear or branched (C)₁-C₆) An alkylene chain, wherein R₃And R₄As defined for formula (I).

In an interesting embodiment, a preferred group of formula (a) according to the invention is a glucopyranosyl group of formula:

the following compounds are preferred according to the invention:

1H-dipyrrolo [3, 4-a:3, 4-c ] carbazole-1, 3, 4, 6- (2H, 5H, 7H) -tetraone,

2-methyl-1H-dipyrrolo [3, 4-a:3, 4-c ] carbazole-1, 3, 4, 6- (2H, 5H, 7H) -tetrone,

2, 5-dimethyl-1H-dipyrrolo [3, 4-a:3, 4-c ] carbazole-1, 3, 4, 6- (2H, 5H, 7H) -tetrone,

2- [2- (diethylamino) ethyl ] -5-methyl-1H-dipyrrolo [3, 4-a:3, 4-c ] carbazole-1, 3, 4, 6- (2H, 5H, 7H) -tetraone,

10-hydroxy-1H-dipyrrolo [3, 4-a:3, 4-c ] carbazole-1, 3, 4, 6- (2H, 5H, 7H) -tetrone.

The enantiomers, diastereomers and addition salts thereof with a pharmaceutically acceptable acid or base of preferred compounds form an integral part of the present invention.

The invention also relates to a process for preparing compounds of formula (I), characterized in that compounds of formula (II) are used as starting materials:

wherein R is_2aRepresents a hydrogen atom or a methyl group and R₁、X′₁、Y′₁、X′₂、Y′₂、W₁And Z is as defined for formula (I),

treating the compound of formula (II) with 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone to give a compound of formula (III):

wherein R is₁、R_2a、X′₁、Y′₁、X′₂、Y′₂、W₁And Z is as defined above, and Z is,

reacting a compound of formula (III):

^*treatment with aqueous sodium hydroxide, followed by the presence of hydrochloric acid, affords compounds of formula (IV):

wherein R is₁、X′_I、Y′₁、X′₂、Y′₂、W₁And Z is as defined above, and Z is,

treating a compound of formula (IV) with a compound of formula (V):

wherein R'₂、X₁、Y₁、X₂And Y₂As defined for formula (I), compounds of formulae (I/a) and (I/b), a special case of compounds of formula (I), are obtained:

wherein R is₁、R′₂、X₁、Y₁、X₂、Y₂、X′₁、Y′₁、X′₂、Y′₂、W₁And Z is as defined above, and Z is,

optionally treating the compound of formula (I/a) and/or (I/b) with trifluoroacetic acid to obtain a compound of formula (I/c) -a particular example of a compound of formula (I):

wherein R is₁、R′₂、X₁、Y₁、X₂、Y₂、X′₁、Y′₁、X′₂、Y′₂、W₁And Z is as defined above, and Z is,

all of the compounds of formulae (I/a), (I/b) and (I/c) constitute compounds of formula (I/d):

a, R therein₁、R′₂、X₁、Y₁、X₂、Y₂、X′₁、Y′₁、X′₂、Y′₂、W₁And Z is as defined above, and Z is,

optionally treating the compound of formula (I/d) with a compound of formula (VII):

R_2b-NH₂ (VII)

wherein R is_2bHaving the formula (I) as R₂Identical definitions, but not a hydrogen atom and a methyl group, give compounds of formula (I/e) -a special case of compounds of formula (I):

a, R therein₁、R′₂、R_2b、X₁、Y₁、X₂、Y₂、X′₁、Y′₁、X′₂、Y′₂、W₁And Z is as defined above, and Z is,

^*or sequentially subjected to the same reaction conditions as those of the compounds of the formulae (IV), (I/a) and (I/b) to give a compound of the formula (I/f) -a particular case of the compound of the formula (I):

a, R therein₁、R′₂、R_2a、X₁、Y₁、X₂、Y₂、X′₁、Y′₁、X′₂、Y′₂、W₁And Z is as defined above, and Z is,

all of the compounds of formulae (I/d), (I/e) and (I/f) constitute compounds of formula (I/g):

a, R therein₁、R′₂、Q₁、X₁、Y₁、X₂、Y₂、X′₁、Y′₁、X′₂、Y′₂、W₁And Z is as defined above, and Z is,

r'₂When representing a hydrogen atom or a methyl group, the compound of formula (I/g) is optionally subjected to the same reaction conditions as the compound of formula (III) in order to obtain a compound of formula (I/I) -a specific example of the compound of formula (I):

a, R therein₁、Q₁、X₁、Y₁、X₂、Y₂、X′₁、Y′₁、X′₂、Y ′₂、W₁And Z is as defined above, and Z is,

optionally treating the compound of formula (I/I) with a compound of formula (VIII):

R′_2b-NH₂ (VIII)

wherein R'_2bHas R 'in the formula (I)'₂Identical definitions, but not a hydrogen atom and a methyl group, give compounds of formula (I/I) -a special case of compounds of formula (I):

a, R therein₁、R′_2b、Q₁、X₁、Y₁、X₂、Y₂、X′₁、Y′₁、X′₂、Y′₂、W₁And Z is as defined above, and Z is,

the compounds of the formulae (I/a) to (I/j) constitute the entirety of the compound of the formula (I), which is purified, if appropriate, according to conventional purification techniques, and which can be separated, if desired, into its different isomers, the substituent R of which is_a、R_b、R_c、R_dAnd R_eThese compounds can be modified according to conventional methods for organic synthesis in the field of sugar chemistry and converted into addition salts with pharmaceutically acceptable acids or bases, if necessary.

The compounds of formula (II) can advantageously be obtained starting from compounds of formula (a):

wherein W₁And Z is as defined for formula (I),

reacting a compound of formula (a):

^*with a compound of formula (B):

wherein R is_2a、X′₁、Y′₁、X′₂And Y'₂As defined above, the above-mentioned materials,

to obtain a compound of formula (C):

wherein R is_2a、X′₁、Y′₁、X′₂、Y′₂、W₁And Z is as defined above, and Z is,

optionally treating the compound of formula (C) with a compound of formula (IX):

R_1a-G (IX)

wherein G represents hydroxy or a leaving group and R_1aAnd R in the formula (I)₁Have the same definition, but are not hydrogen atoms,

to obtain a compound of formula (D):

wherein R is_1a、R_2a、X′₁、Y′₁、X′₂、Y′₂、W₁And Z is as defined above, and Z is,

the compounds of formula (C) and (D) constitute the entirety of the compounds of formula (II),

^*or with a compound of formula (E) in the presence of an alkyl magnesium halide:

wherein R is_2a、X′₁、Y′₁、X′₂And Y'₂As defined above, the above-mentioned materials,

to give a compound of formula (F):

wherein R is_1a、R_2a、X′₁、Y′₁、X′₂、Y′₂、W₁And Z is as defined above, and Z is,

optionally subjecting the compound of formula (F) to the same reaction conditions as the compound of formula (C) to obtain a compound of formula (G):

wherein R is_1a、R_2a、X′₁、Y′₁、X′₂、Y′₂、W₁And Z is as defined above, and Z is,

the compound of formula (G) is hydrogenated according to conventional methods of organic synthesis to give the compound of formula (II).

The compounds of formulae (V), (VII), (VIII), (IX), (A), (B) and (E) are either commercially available products or products obtained according to conventional organic synthesis methods well known to the person skilled in the art.

The compounds of formula (I) have particularly interesting antitumor properties. The unique properties of these compounds make them therapeutically useful as antitumor agents.

The compounds of the invention may also be used in therapy in combination with another anticancer agent, such as paclitaxel, tamoxifen and its derivatives, cisplatin and its analogs, irinotecan and its metabolites, various alkylating agents, mainly cyclophosphamide, etoposide, vinca alkaloids, doxorubicin and other anthracyclines and nitrosoureas.

The present invention also relates to pharmaceutical compositions comprising, as active ingredient, at least one compound of formula (I), an optical isomer thereof or an addition salt thereof with a pharmaceutically acceptable acid or base, alone or in combination with one or more pharmaceutically acceptable inert, non-toxic excipients or carriers.

Among the pharmaceutical compositions of the invention, mention may be made more particularly of those suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), transdermal or transdermal, nasal, rectal, lingual, ocular or respiratory administration, in particular tablets or lozenges, sublingual tablets, gelatin capsules, suppositories, creams, ointments, dermal gels, injectable or drinkable preparations, aerosols, eye drops, nasal drops, etc.

Due to the specific pharmacological properties of the compounds of formula (I), pharmaceutical compositions comprising said compounds of formula (1) as active ingredient are particularly useful for the treatment of cancer.

Useful dosages vary depending on the age and weight of the patient, the route of administration, the nature and severity of the disease and the administration of any combination therapy and are from 1 to 500 mg/day, administered in one or several divided doses.

The following examples illustrate the invention without in any way limiting it. The starting materials used are known products or products prepared according to known procedures.

The structures of the compounds described in the examples were determined according to conventional spectroscopic techniques (infrared, nuclear magnetic resonance, mass spectrometry, etc.).

Preparation example a:

3b, 6a, 6b, 7-tetrahydro-1H-dipyrrolo [3, 4-a:3, 4-c ] carbazole-1, 3, 4, 6(2H, 3aH, 5H) -tetrone

Step A:3- (1H-indol-3-yl) -2, 5-pyrrolidinedione

The expected product is obtained according to the method described by J.bergman et al (Tetrahedron, 1999, 55, pp.2363-2370).

And B:3- (1H-indol-3-yl) -1H-pyrrole-2, 5-dione

The expected product was obtained according to the method described by J.bergman et al (Tetrahedron, 1999, 55, pp.2363-2370).

And C:3b, 6a, 6b, 7-tetrahydro-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 3aH, 5H) -tetrone

The expected product was obtained according to the method described by J.bergman et al (J.chem.Soc. (chem.Soc.), Perkin Trans.I, 2000, pp.2615-2621).

Preparation example B:

3- (1H-indol-3-yl) -1-methyl-1H-pyrrole-2, 5-dione

Step A:3- (1H-indol-3-yl) -1-methyl-2, 5-pyrrolidinedione

The expected product was obtained according to the method described by J.bergman et al (Tetrahedron, 1999, 55, pp.2363-2370).

And B:3- (1H-indol-3-yl) -1-methyl-1H-pyrrole-2, 5-dione

The expected product was obtained according to the method described by J.bergman et al (Tetrahedron, 1999, 55, pp.2363-2370).

Preparation example C:

3- [ 5-benzyloxy-1H-indol-3-yl ] -1-methyl-1H-pyrrole-2, 5-dione

Step A:3- [ 5-benzyloxy-1H-indol-3-yl]-1-methyl-2, 5-pyrrolidinedione

A mixture of 5-benzyloxyindole (8mmol) and N-methylmaleimide (8mmol) in 8ml acetic acid was refluxed for 48 hours. The acetic acid was distilled off. Purification by chromatography on silica gel (ethyl acetate/cyclohexane: 2/8-7/3) gave the expected product.

Melting point:49-53℃

IR(KBr)：v_C＝O＝1690，1700cm^-1；v_NH＝3300-3500cm^-1

mass spectrum (FAB):335.14[M+H⁺]

and B:3- [ 5-benzyloxy-1H-indol-3-yl]-1-methyl-1H-pyrrole-2, 5-dione

A solution of 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (2mmol) in 20ml dioxane was slowly added to a solution of the compound (2mmol) obtained in the previous step in 20ml dioxane. The reaction mixture was stirred at room temperature overnight. After filtration the dioxane was removed by evaporation and the reaction mixture was dissolved in isopropanol for recrystallization. The expected product is obtained by filtration and washing the precipitate formed with isopropane.

Melting point:176-182℃

IR(KBr)：v_C＝O＝1690，1700cm^-1；v_NH＝3300-3440cm^-1

mass spectrum (FAB):333.12[M+H⁺]

preparation example D:

3- (1H-indol-3-yl) -2, 5-furandione

A mixture of the compound from preparation B (0.884mmol) and sodium hydroxide particles (12.5mmol) in 100ml of distilled water was refluxed for 2 hours. The reaction mixture was cooled and concentrated hydrochloric acid was added dropwise until a precipitate formed. The expected product is obtained by filtering the precipitate.

Melting point:210-214℃

IR(KBr)：v_C＝O＝1740，1800cm^-1；v_NH＝3320cm^-1

preparation example F:

3- (1H-pyrrolo [2, 3-b ] pyridin-3-yl) -1H-pyrrole-2, 5-dione

Step A:3-bromo-4- (1H-pyrrolo [2, 3-b)]Pyridin-3-yl) -1H-pyrrole-2, 5-diones

A solution of ethylmagnesium bromide was prepared from magnesium (12.7mmol) suspended in bromoethane (12.7mmol) and anhydrous tetrahydrofuran (5 ml). The solution was stirred at room temperature for 1 hour, then 7-azaindole (12.7mmol) dissolved in 40ml of anhydrous toluene was added dropwise. After stirring at room temperature for 1 hour 30 minutes, a solution of 2, 3-dibromomaleimide (3.53mmol) in 40ml of anhydrous toluene was added dropwise. After 20 minutes 60ml of anhydrous dichloromethane were added and the reaction mixture was stirred at 40 ℃ for 75 hours and subsequently hydrolysed with saturated aqueous ammonium chloride. The organic product was extracted with ethyl acetate, and the combined organic phases were dried over magnesium sulfate and filtered. The expected product is isolated after removal of the solvent by evaporation and purification by chromatography on silica gel (cyclohexane/ethyl acetate: 3/2).

And B:3- (1H-pyrrolo [2, 3-b)]Pyridin-3-yl) -2, 5-pyrrolidinedione

A mixture of the compound obtained in the above step (0.327mmol) and a catalytic amount of 10% palladium on carbon in methanol (40ml) was hydrogenated at 1 atmosphere for 24 hours. The expected product is obtained after filtration of the mixture over celite and purification of the residue by chromatography on silica gel (using ethyl acetate as eluent).

And C:3- (1H-pyrrolo [2, 3-b)]Pyridin-3-yl) -1H-pyrrole-2, 5-diones

The expected product is obtained following the procedure described in preparation C, step B, starting from the compound of the preceding step.

Preparation example F:

1-methyl-3- [1- (2, 3, 4, 6-tetra-O-acetyl-beta-D-glucopyranosyl) -1H-pyrrolo [2, 3-b ] pyridin-3-yl ] -1H-pyrrole-2, 5-dione

Step A:3-bromo-1-methyl-4- (1H-pyrrolo [2, 3-b)]Pyridin-3-yl) -1H-pyrrole-2, 5-diones

The expected product was obtained following the procedure described in preparation E, step A, using N-methyl-2, 3-dibromomaleimide as starting material.

Melting point:158℃

and B:3-bromo-1-methyl-4- [1- (2, 3, 4, 6-tetra-O-acetyl-beta-D-glucopyranosyl) -1H-pyrrolo [2, 3-b [ ] -]Pyridin-3-yl]-1H-pyrrole-2, 5-dione

2, 3, 4, 6-tetra-O-acetylglucopyranose (1.95mmol) and triphenylphosphine (1.95mmol) are added dropwise to a solution of the compound of the above step (0.927mmol) in 40ml of anhydrous tetrahydrofuran. The temperature was allowed to slowly return to room temperature, and then the reaction mixture was stirred for another 15 hours. After hydrolysis the organic product was extracted with ethyl acetate. The organic phases are combined, dried over magnesium sulfate and filtered, and the solvent is evaporated off. The expected product is obtained after purification by chromatography on silica gel.

And C:1-methyl-3- [1- (2, 3, 4, 6-tetra-O-acetyl-beta-D-glucopyranosyl) -1H-pyrrolo [2, 3-b]Pyridin-3-yl]-2, 5-pyrrolidinedione

The expected product is obtained by following the procedure described in preparation E, step B, starting from the compound of the preceding step.

Step D:1-methyl-3- [1- (2, 3, 4, 6-tetra-O-acetyl-beta-D-glucopyranosyl) -1H-pyrrolo [2, 3-b]Pyridin-3-yl]-1H-pyrrole-2, 5-dione

The expected product is obtained following the procedure described in preparation C, step B, starting from the compound of the preceding step.

Preparation example G:

1-methyl-3- (1H-pyrrolo [2, 3-b ] pyridin-3-yl) -1H-pyrrole-2, 5-dione

Step A:1-methyl-3- (1H-pyrrolo [2, 3-b)]Pyridin-3-yl) -2, 5-pyrrolidinedione

A mixture of the compound from preparation F, step A (0.65mmol) and 10% palladium on carbon (20mg) in methanol (40ml) was hydrogenated at 1 atmosphere for 3.5 h. The mixture was filtered over celite. The filtrate was evaporated and the expected product was obtained after purification of the residue by flash chromatography on silica gel (AcOEt followed by AcOEt/MeOH 9: 1).

Melting point:199-202℃

IR(KBr)：v_C＝O＝1690，1770cm^-1；v_NH＝3250-3500cm^-1

and B:1-methyl-3- (1H-pyrrolo [2, 3-b)]Pyridin-3-yl) -1H-pyrrole-2, 5-diones

The expected product is obtained following the procedure described in preparation C, step B, starting from the compound of the preceding step.

Melting point:＞250℃

IR(KBr)：v_C＝O＝1700，1760cm^-1；v_NH＝3300-3600cm^-1

preparation example H:

3- (5-benzyloxy-1H-indol-3-yl) -1H-pyrrole-2, 5-dione

Step A:3- (5-benzyloxy-1H-indol-3-yl) -2, 5-pyrrolidinedione

The expected product was obtained following the procedure described in preparation C, step A, by replacing N-methylmaleimide with maleimide.

Melting point:175℃

IR(KBr)：v_C＝O＝1690，1780cm^-1；v_NH＝3210-3320cm^-1

and B:3- (5-benzyloxy-1H-indol-3-yl) -1H-pyrrole-2, 5-dione

The expected product is obtained following the procedure described in preparation C, step B, starting from the compound of the preceding step.

Melting point:211℃

IR(KBr)：v_C＝C＝1600cm^-1；v_C＝O＝1705，1755cm^-1；v_NH＝3150-3450cm^-1

preparation example I:

3- (5-bromo-1H-indol-3-yl) -1H-pyrrole-2, 5-dione

Step A:3- (5-bromo-1H-indol-3-yl) -2, 5-pyrrolidinedione

The expected product was obtained following the procedure described in preparation C, step A, by substituting maleimide for N-methylmaleimide and 5-benzylindole with 5-bromoindole.

Melting point:208-215℃

IR(KBr)：v_C＝O＝1700，1755cm^-1；v_NH＝3450cm^-1

and B:3- (5-bromo-1H-indol-3-yl) -1H-pyrrole-2, 5-dione

The expected product is obtained following the procedure described in preparation C, step B, starting from the compound of the preceding step.

Melting point:268℃

IR(KBr)：v_C＝C＝1595cm^-1；v_C＝O＝1705，1750cm^-1；v_NH＝3200，3340cm^-1

preparation example J:

3- (5-chloro-1H-indol-3-yl) -1H-pyrrole-2, 5-dione

Step A:3- (5-chloro-1H-indol-3-yl) -2, 5-pyrrolidinedione

The expected product was obtained following the procedure described in preparation I, step A, by substituting 5-chloroindole for 5-bromoindole.

IR(KBr)：v_C＝O＝1700，1780cm^-1；v_NH＝3200-3500cm^-1

And B:3- (5-chloro-1H-indol-3-yl) -1H-pyrrole-2, 5-dione

The expected product is obtained following the procedure described in preparation C, step B, starting from the compound of the preceding step.

Melting point:254-264℃

IR(KBr)：v_C＝C＝1605cm^-1；v_C＝O＝1710，1750cm^-1；v_NH＝3100-3350cm^-1

preparation example K:

3- (5-fluoro-1H-indol-3-yl) -1H-pyrrole-2, 5-dione

Step A:3- (5-fluoro-1H-indol-3-yl) -2, 5-pyrrolidinedione

The expected product was obtained following the procedure described in preparation I, step A, by substituting 5-fluoroindole for 5-bromoindole.

Melting point:190-195℃

IR(KBr)：v_C＝C＝1690，1775cm^-1；v_NH＝3360cm^-1

and B:3- (5-fluoro-1H-indol-3-yl) -1H-pyrrole-2, 5-dione

The expected product is obtained following the procedure described in preparation C, step B, starting from the compound of the preceding step.

Melting point:255-265℃

IR(KBr)：v_C＝C＝1605cm^-1；v_C＝O＝1720，1750cm^-1；v_NH＝3150-3350cm^-1

preparation example L:

3- (5-hydroxy-1H-indol-3-yl) -1H-pyrrole-2, 5-dione

Step A:3- (5-hydroxy-1H-indol-3-yl) -2, 5-pyrrolidinedione

10% Palladium on carbon (135mg) was added to a solution of the compound from preparation H, step A (450mg) in dry methanol (90 ml). After 20 minutes of vacuum purging, the reaction mixture was placed under a hydrogen atmosphere (1atm) for 3 hours. After filtration over celite and evaporation of the filtrate, the expected product is obtained.

IR (film):v_C＝C＝1700cm^-1；v_NH，OH＝3000-3700cm^-1

and B:3- (5-hydroxy-1H-indol-3-yl) -1H-pyrrole-2, 5-dione

The expected product is obtained following the procedure described in preparation C, step B, starting from the compound of the preceding step.

Melting point:292-298℃

IR(KBr)：v_C＝C＝1610cm^-1；v_C＝O＝1690，1760cm^-1；v_NH，OH＝3260，3370，3430cm^-1

preparation example M:

3- [1- (2, 3, 4, 6-tetra-O-benzyl-beta-D-glucopyranosyl) ] -1H-indol-3-yl ] -1H-pyrrole-2, 5-dione

Step A:3-bromo-4- (1H-indol-3-yl) -1-methyl-1H-pyrrole-2, 5-dione

A solution of 1.445g of indole in 29ml of anhydrous tetrahydrofuran was cooled to-20 to-10 ℃ under argon and 26ml of LiHMDS (1M in hexane) were added dropwise over 15 minutes. After 45 minutes at-10 ℃ the solution was diluted with an additional 15ml of tetrahydrofuran and a solution of 2g N-methyl-2, 3-dibromomaleimide in 17ml of tetrahydrofuran was added dropwise over 30 minutes. After 15 minutes at-10 ℃ and 15 minutes at 0 ℃ the reaction was stopped by adding 50ml of 0.3N hydrochloric acid solution at 0 ℃. The reaction mixture was extracted with ethyl acetate and the organic phase was washed with saturated NaCl solution and MgSO₄Dried and then evaporated under reduced pressure. The desired product was precipitated using methanol.

Melting Point＝167-168℃

And B:3-bromo-1-methyl-4- [1- (2, 3, 4, 6-tetra-O-benzyl-beta-D-glucopyranosyl) -1H-indol-3-yl]-1H-pyrrole-2, 5-dione

Mixing the compound of the step A and PPh₃A solution of (3 equivalents) and 2, 3, 4, 6-tetra-O-benzyl-D-glucopyranose (3 equivalents) in anhydrous THF was cooled to-78 ℃. DIAD (3 equivalents) was then added dropwise. The reaction mixture was stirred for 4 hours while warming to room temperature again. 0.2M HCl solution was poured and the mixture was extracted with ethyl acetate. The organic phase is successively treated with saturated NaHCO₃The aqueous solution and water were washed, then MgSO₄And (5) drying. The expected product is obtained after filtration and removal of the solvent by evaporation and chromatography on silica gel (toluene/ethyl acetate: 50/1).

Melting point:55℃

IR(KBr)：v_C＝C＝1640cm^-1；v_C＝O＝1710，1770cm^-1；v_NH＝3200-3600cm^-1

and C:1-methyl-3- [1- (2, 3, 4, 6-tetra-O-benzyl-beta-D-glucopyranosyl) -1H-indol-3-yl]-2, 5-pyrrolidinedione

A solution of the compound of step B above in methanol and anhydrous THF was hydrogenated (1 atmosphere) in the presence of 10% palladium on carbon and pyridine (0.5 eq.) for 3 hours. The expected product is obtained after filtration over celite and evaporation of the filtrate and chromatography on silica gel (cyclohexane/ethyl acetate).

Step D:1-methyl-3- [1- (2, 3, 4, 6-tetra-O-benzyl-beta-D-glucopyranosyl) -1H-indol-3-yl]-1H-pyrrole-2, 5-dione

The expected product is obtained following the procedure described in preparation C, step b.

Step E:3- [1- (2, 3, 4, 6-tetra-O-benzyl-beta-D-glucopyranosyl) -1H-indol-3-yl]-1H-pyrrole-2, 5-dione

A mixture of the compound of step D above and NaOH in distilled water was heated at reflux for 2 hours. After cooling, concentrated hydrochloric acid was poured in dropwise fashion until a yellow precipitate formed. The yellow solid was filtered on a frit and washed with water to give the desired anhydride, which was then treated with a solution of ammonium hydroxide in THF to give the desired compound.

Preparation example N:

3- { [1- (2, 3, 4, 6-tetra-O-benzyl- β -D-glucopyranosyl) ] -1H-pyrrolo [2, 3-b ] pyridin-3-yl ] -1H-pyrrole-2, 5-dione

Step A:3-bromo-1-methyl-4- [1- (2, 3, 4, 6-tetra-O-benzyl-beta-D-glucopyranosyl) -1H-pyrrolo [2, 3-b [ ] -]Pyridin-3-yl]-1H-pyrrole-2, 5-dione

2, 3, 4, 6-O-Benzylpyranoglucose (264mg) and triphenylphosphine (128mg) were added to a solution of the compound of preparation G, step A (50mg) in 4ml anhydrous THF. The reaction mixture was cooled to-78 ℃ and then DIAD (97. mu.l) was added dropwise. The temperature was slowly returned to room temperature and the reaction mixture was stirred for a further 15 hours. After hydrolysis (40ml of water), the organic product was extracted with ethyl acetate (3X 150 ml). The organic phases are combined, dried over magnesium sulfate and filtered, and the solvent is evaporated off. Purification by chromatography on silica gel (cyclohexane/ethyl acetate: 8/2-7/3) isolated the expected product.

IR(KBr)：v_C＝O＝1710，1740，1760cm^-1

And B:1-methyl-3- [1- (2, 3, 4, 6-tetra-O-benzyl-beta-D-glucopyranosyl) -1H-pyrrolo [2, 3-b]Pyridin-3-yl]-2, 5-pyrrolidinedione

NaHCO is added₃(66mg) and 10% Pd/C (65mg) were added to a suspension of the compound of step A (65mg) in 10ml of ethyl acetate. The mixture was left at room temperature under a hydrogen atmosphere (1 bar) for 24 hours. The catalyst was removed by filtration over celite and the filtrate was evaporated under reduced pressure. Purification by flash chromatography on silica gel (cyclohexane/ethyl acetate: 8/2-7/3) isolated the expected product.

IR(KBr)：v_C＝O＝1710-1750cm^-1

And C:1-methyl-3- { [1- (2, 3, 4, 6-tetra-O-benzyl- β -D-glucopyranosyl)]-1H-pyrrolo [2, 3-b]Pyridin-3-yl } -1H-pyrrole-2, 5-diones

The expected product is obtained following the procedure described in preparation C, step B, starting from the compound of the preceding step.

Step D:3- ([1- (2, 3, 4, 6-tetra-O-benzyl-beta-D-glucopyranosyl)]-1H-pyrrolo [2, 3-b]Pyridin-3-yl } -2, 5-furandiones

NaOH particles (14mmol) and THF were added to a suspension of the compound of step C (1mmol) in water. The mixture was stirred at room temperature for 2 hours and then acidified to pH 1 by the addition of concentrated hydrochloric acid. After stirring for 30 min, the organic product was extracted with ethyl acetate (3X 150 ml). The organic phases are combined, dried over magnesium sulfate and filtered, and the solvent is evaporated off. Purification by chromatography on silica gel isolated the expected product.

Step E:3- { [1- (2, 3, 4, 6-tetra-O-benzyl- β -D-glucopyranosyl)]-1H-pyrrolo [2, 3-b]Pyridin-3-yl } -1H-pyrrole-2, 5-diones

Adding a solution of the compound of step D in THF in a sealed tube with NH₃Saturated THF solution. The reaction mixture was stirred at 80 ℃ for 18 hours. After cooling, the mixture was poured into water and extracted repeatedly with ethyl acetate. The organic phases are combined, dried over magnesium sulfate and filtered, and the solvent is evaporated off. Purification is carried out by chromatography on silica gel, the expected product being isolated.

The compound of preparation O-AP is obtained according to the procedure of preparation C starting from the appropriate indole and substituting maleimide for N-methylmaleimide.

Preparation example O:3- (5-amino-1H-indol-3-yl) -1H-pyrrole-2, 5-dione

Preparation example P:3- (4-amino-1H-indol-3-yl)) -1H-pyrrole-2, 5-dione

Preparation Q:3- (5, 6-dimethoxy-1H-indol-3-yl) -1H-pyrrole-2, 5-dione

Preparation example R:3- (4-Nitro-1H-indol-3-yl) -1H-pyrrole-2, 5-dione

Preparation example S:3- (4-fluoro-1H-indol-3-yl) -1H-pyrrole-2, 5-dione

Preparation example T:3- (6-fluoro-1H-indol-3-yl) -1H-pyrrole-2, 5-dione

Preparation example U:3- (4-hydroxy-1H-indol-3-yl) -1H-pyrrole-2, 5-dione

Preparation example V:3- (5-hydroxy-1H-indol-3-yl) -1H-pyrrole-2, 5-dione

Preparation example W:3- (4-methoxy-1H-indol-3-yl) -1H-pyrrole-2, 5-dione

Preparation X:3- (5-methoxy-1H-indol-3-yl) -1H-pyrrole-2, 5-dione

Preparation example Y:3- (6-methoxy-1H-indol-3-yl) -1H-pyrrole-2, 5-dione

Preparation example Z:3- (7-methoxy-1H-indol-3-yl) -1H-pyrrole-2, 5-dione

Preparation example AA:3- (4-methyl-1H-indol-3-yl) -1H-pyrrole-2, 5-dione

Preparation example AB:3- (5-methyl-1H-indol-3-yl) -1H-pyrrole-2, 5-dione

Preparation example AC:3- (6-methyl-1H-indol-3-yl) -1H-pyrrole-2, 5-dione

Preparation example AD:3- (7-methyl-1H-indol-3-yl) -1H-pyrrole-2, 5-dione

Preparation example AE:3- (4-chloro-1H-indol-3-yl) -1H-pyrrole-2, 5-dione

Preparation example AF:3- (5-chloro-1H-indol-3-yl) -1H-pyrrole-2, 5-dione

Preparation example AG:3- (6-chloro-1H-indol-3-yl) -1H-pyrrole-2, 5-dione

Preparation example AH:3- (7-chloro-1H-indol-3-yl) -1H-pyrrole-2, 5-dione

Preparation example AI:3- (4-bromo-1H-indol-3-yl) -1H-pyrrole-2, 5-dione

Preparation AJ:3- (6-bromo-1H-indol-3-yl) -1H-pyrrole-2, 5-dione

Preparation example AK:3- (7-bromo-1H-indol-3-yl) -1H-pyrrole-2, 5-dione

Preparation example AL:3- (5-methoxy-4-methyl-1H-indol-3-yl) -1H-pyrrole-2, 5-dione

Preparation example AM:3- [ 7-benzyloxy-1H-indol-3-yl]-1H-pyrrole-2, 5-dione

Preparation example AN:3- [ 6-benzyloxy-1H-indol-3-yl]-1H-pyrrole-2, 5-dione

Preparation example AO:3- [ 5-benzyloxy-6-methoxy-1H-indol-3-yl]-1H-pyrrole-2, 5-dione

Preparation example AP:3- (1-methyl-1H-indol-3-yl) -1H-pyrrole-2, 5-dione

Example 1:1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

The compound of preparation A (0.388mmol) was heated at reflux in 24ml dioxane in the presence of trifluoroacetic acid (400 μ l) for 24 h. After removal of the solvent by evaporation, the crystals were dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The expected product is obtained by filtering the crystals on a frit.

Melting point:＞300℃

IR(KBr)：v_C＝O＝1690，1730，1745，1780cm^-1；v_NH＝3280-3380cm^-1

mass spectrum (FAB):306.05[M+H⁺]

example 2:2, 5-dimethyl-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

A mixture of the compound from preparation B (1mmol) and N-methylmaleimide (1.10mmol) in 17ml of p-xylene was refluxed for 24 hours. After cooling, the yellow precipitate is filtered off and washed with p-xylene. Chromatography on a silica column (ethyl acetate/cyclohexane: 1/1; ethyl acetate/methanol: 98/2) gave an isomer mixture which was heated at reflux in 25ml dioxane in the presence of trifluoroacetic acid for 84 hours. After removal of the solvent by evaporation, the crystals were dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The expected product is obtained by filtering the crystals on a frit.

Melting point:＞300℃

IR(KBr)：v_C＝O＝1695，1720cm^-1；v_NH＝3410cm^-1

mass spectrum (FAB):334.08[M+H⁺]

example 3:2-methyl-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

The expected product is obtained following the procedure described in example 2 starting from the compound of preparation B and maleimide.

Melting point:＞300℃

IR(KBr)：v_C＝O＝1710，1720，1760，1780cm^-1；v_NH＝3260-3395cm^-1

mass spectrum (FAB):320.06[M+H⁺]

example 4:10-benzyloxy-2, 5-dimethyl-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

The expected product is obtained following the procedure described in example 2 starting from the compound of preparation C and N-methylmaleimide.

Melting point:＞300℃

IR(KBr)：v_C＝O＝1700，1720，1775cm^-1；v_NH＝3480cm^-1

mass spectrum (FAB):440.12[M+H⁺]

example 5:5-methylfuro [3, 4-c ]]Pyrrolo [3, 4-a]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -one

The expected product is obtained following the procedure described in example 2, starting from the compound of preparation D and N-methylmaleimide.

Melting point:294 deg.C (decomposition)

IR(KBr)：v_C＝O＝1775，1840cm^-1；v_NH＝3370cm^-1

Mass spectrum (FAB):321.05[M+H⁺]

example 6:2- [2- (diethylamino) ethyl group]-5-methyl-1-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone hydrochloride

N, N-diethylethylenediamine (0.132mmol) was added dropwise to a solution of the compound of example 5 (0.088mmol) in 5.2ml of anhydrous tetrahydrofuran. The mixture was heated at 65 ℃ for 4 days in the dark, then cooled and dissolved in a mixture of 1N aqueous hydrochloric acid (40ml) and ethyl acetate. The organic product was extracted with ethyl acetate. The aqueous phase was dissolved in ethyl acetate and the pH was adjusted to 12 by addition of saturated aqueous sodium bicarbonate. The organic product was extracted with ethyl acetate. The organic phases are combined, dried over magnesium sulfate and filtered, and the solvent is then distilled off in the cold state. To a solution of the thus obtained amine dissolved in 400. mu.l of methanol cooled to 0 ℃ was added dropwise a 1N aqueous hydrochloric acid solution (190. mu.l). The mixture was stirred for 30 minutes. The solvent was distilled off and the expected product was isolated.

Melting point:184 deg.C (decomposition)

IR(KBr)：v_C＝O＝1710，1720，1765，1775cm^-1；v_NH＝3300-3600cm^-1

Mass spectrum (FAB):419.17[M+H⁺]

example 7:1H-pyrido [2, 3-b]Dipyrrolo [3, 4-e: 3, 4-g]Indole-1, 3, 4, 6(2H, 5H, 7H) -tetrones

The expected product is obtained following the procedure described in example 2 starting from the compound of preparation E and maleimide.

Example 8:2-methyl-7- (2, 3, 4, 6-tetra-O-acetyl-beta-D-glucopyranosyl) -1H-pyrido [2, 3-b]Dipyrrolo [3, 4-e: 3, 4-g]Indole-1, 3, 4, 6(2H, 5H, 7H) -tetrones

The expected product is obtained following the procedure described in example 2 starting from the compound of preparation F and maleimide.

Example 9:2-methyl-1H-pyrido [2, 3-b]Dipyrrolo [3, 4-e: 3, 4-g]Indole-1, 3, 4, 6(2H, 5H, 7H) -tetrones

A mixture of the compound of preparation G (55.0mg) and maleimide (25.9mg) in xylene (5ml) was heated at reflux for 20 hours. After cooling, the mixture was filtered and washed with xylene. The resulting solid (70.8mg) was heated at reflux in the presence of 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (115.5mg) in dioxane (5ml) for 3 days. After removal of the solvent by evaporation, the residue was dissolved in water, the resulting solid was filtered off and washed with water and ethyl acetate to give the expected product.

Melting point:＞300℃

IR(KBr)：v_C＝C＝1600cm^-1；v_C＝O＝1710，1730，1770，1780cm^-1；v_NH＝3200cm^-1

example 10:2-methylfuro [3, 4-a ]]Pyrrolo [3, 4-c]Carbazole-1, 3, 4, 6(2H, 7H) -tetrone

A mixture of the compound of preparation B (315mg) and maleic anhydride (164mg) in p-xylene (24ml) was heated at reflux for 40 hours. After returning to room temperature, the mixture was filtered and the crystals were washed with p-xylene and then dried. The resulting solid (357mg) was heated at reflux in dioxane (8ml) in the presence of 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (540mg) for 3 days. After returning to room temperature, water and ethyl acetate were added. The solid at the interface was filtered on a frit and washed with water and ethyl acetate to isolate the desired product.

Melting point:＞300℃

IR(KBr)：v_C＝O＝1705，1760，1835cm^-1；v_NH＝3770cm^-1

example 11:5- [2- (diethylamino) ethyl group]-2-methyl-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone hydrochloride

N, N-diethylethylenediamine (20. mu.1) was added dropwise to a solution of the compound of example 10 in anhydrous tetrahydrofuran (5.5 ml). The mixture was heated at 65 ℃ for 4 hours in the dark. After returning to room temperature, the mixture was evaporated to dryness, dissolved with 1ml of acetic anhydride in the presence of AcONa (75mg) and then heated at 90 ℃ for 4 hours. The crude reaction mixture was cooled and then dissolved in a mixture of 1N aqueous hydrochloric acid (40ml) and ethyl acetate. The aqueous phase was then dissolved in ethyl acetate and treated with saturated aqueous sodium bicarbonate. The organic product was then extracted with ethyl acetate (3X 50 ml). The organic phases are combined and dried over magnesium sulfate, and the solvent is then distilled off at room temperature. The free amine thus obtained (32.8mg) was dissolved in methanol (1ml) and then cooled to 0 ℃. Then, 1N aqueous hydrochloric acid (172. mu.l) was added dropwise. The mixture was stirred for 30 minutes. The solvent was distilled off to give the expected product.

Melting point:＝278-280℃

IR(KBr)：v_C＝O＝1710，1770cm^-1；v_NH＝3200，3600cm^-1

example 12:5-methyl-1H-dipyrrolo [3, 4-a:3, 4-c [ carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetraone

The expected product is obtained following the procedure described in example 9 starting from the compound of preparation A and replacing the maleimide by N-methylmaleimide.

Melting point:＞300℃

IR(KBr)：v_C＝O＝1695，1725，1765，1775cm^-1；v_NH＝3220，3330cm^-1

example 13:furo [3, 4-a ]]Pyrrolo [3, 4-c]Carbazole-1, 3, 4, 6(2H, 7H) -tetrone

The expected product is obtained by following the procedure described in example 10 starting from the compound of preparation A.

Melting point:＞300℃

IR(KBr)：v_C＝C＝1610cm^-1；v_C＝O＝1700-1850cm^-1；v_NH＝3240，3380cm^-1

example 14:10-benzyloxy-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

The expected product is obtained by following the procedure described in example 9 starting from the compound of preparation H.

Melting point:＞300℃

IR(KBr)：v_C＝O＝1725，1755，1780cm^-1；v_NH＝3150-3500cm^-1

example 15:10-bromo-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

The expected product is obtained by following the procedure described in example 9 starting from the compound of preparation I.

Melting point:＞300℃

IR(KBr)：v_C＝C＝1600cm^-1；v_C＝O＝1710，1720，1760cm^-1；v_NH＝3150-3350cm^-1

example 16:10-chloro-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

The expected product is obtained by following the procedure described in example 9 starting from the compound of preparation J.

Melting point:＞300℃

IR(KBr)：v_C＝C＝1600cm^-1；v_C＝O＝1710，1720，1760cm^-1；v_NH＝3120-3380cm^-1

example 17:10-fluoro-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

The expected product is obtained by following the procedure described in example 9 starting from the compound of preparation K.

Melting point:＞300℃

IR(KBr)：v_C＝O＝1710，1780cm^-1；v_NH＝3100-3350cm^-1

example 18:10-hydroxy-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

The expected product is obtained by following the procedure described in example 9 starting from the compound of preparation L.

Melting point:＞300℃

IR(KBr)：v_C＝O＝1725，1770cm^-1；v_NH＝3100-3650cm^-1

example 19:7- [1- (2, 3, 4, 6-tetra-O-benzyl-beta-D-glucopyranosyl)]-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

The expected product is obtained following the procedure described in example 2 starting from the compound of preparation M and maleimide.

Example 20:7- (β -D-glucopyranosyl) -1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

By BBr₃The compound of example 19 was debenzylated in dichloromethane to give the expected compound.

Example 21:7- [1- (2, 3, 4, 6-tetra-O-benzyl-beta-D-glucopyranosyl)]-1H-pyrido [2, 3-b]Dipyrrolo [3, 4-e: 3, 4-g]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

The expected product is obtained by following the procedure described in example 9, starting from preparation N.

Example 22:7- (beta-D-glucopyranosyl) -1H-pyrido [2, 3-b]Dipyrrolo [3, 4-e: 3, 4-g]Indole-1, 3, 4, 6(2H, 5H, 7H) -tetrones

BBr is heated at-78 deg.C₃1M CH₂Cl₂Solution (8 equivalents) was added to a solution of the compound of example 21 in dichloromethane. After stirring at-78 ℃ for 10 minutes, the reaction mixture was hydrolyzed and returned to room temperature, and then extracted repeatedly with ethyl acetate. The organic phase was dried over magnesium sulfate and then concentrated under reduced pressure. The expected product is isolated by chromatography on silica gel.

The products of examples 23-50 were obtained according to the procedure described in example 9 from the compounds of preparation O-AP, respectively.

Example 23:10-amino-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

Example 24:11-amino-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

Example 25:9, 10-dimethoxy-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

Example 26:11-nitro-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

Example 27:11-fluoro-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

Example 28:9-fluoro-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

Example 29:11-hydroxy-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

Example 30:10-hydroxy-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

Example 31:11-methoxy-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

Example 32:10-methoxy-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

Example 33:9-methoxy-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

Example 34:8-methoxy-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

Example 35:11-methyl-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

Example 36:10-methyl-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

Example 37:9-methyl-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

Example 38:8-methyl-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

Example 39:11-chloro-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

Example 40:10-chloro-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

Example 41:9-chloro-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

Example 42:8-chloro-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

Example 43:11-bromo-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

Example 44:9-bromo-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

Example 45:8-bromo-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

Example 46:10-methoxy-11-methyl-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

Example 47:8-benzyloxy-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

Example 48:9-benzyloxy-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

Example 49:10-benzyloxy-9-methoxy-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

Example 50:7-methyl-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

Example 51:2-hydroxy-5-methyl-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

The expected product was obtained by following the procedure described in example 6, substituting hydroxylamine for N, N-diethylethylenediamine.

Example 52:2-amino-5-methyl-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

The expected product was obtained by following the procedure described in example 6, substituting hydrazine for N, N-diethylethylenediamine.

Example 53: 2- (dimethylamino) -5-methyl-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

The expected product was obtained by following the procedure described in example 6, replacing N, N-diethylethylenediamine with 1, 1-dimethylhydrazine.

Example 54: 2- (3-hydroxypropyl) -5-methyl-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

The expected product was obtained following the procedure described in example 6, substituting 3-amino-1-propanol for N, N-diethylethylenediamine.

Example 55: 2- (3-methoxypropyl) -5-methyl-1H-dipyrrolo [3, 4-a:3, 4-c]Carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone

The expected product was obtained following the procedure described in example 6 substituting 3-methoxypropylamine for N, N-diethylethylenediamine.

Pharmacological study of the Compounds of the invention

Example 56In vitro Activity

Three cell lines were used:

l1210 murine leukemia cells

A549 non-small cell human Lung cancer cell

DU145 prostate cancer cells

L1210 murine leukemia cells were used in vitro. Cells were cultured in RPMI 1640 complete medium containing 10% fetal bovine serum, 2mM glutamine, 50 units/ml penicillin, 50. mu.g/ml streptomycin and 10mM Hepes at pH 7.4. Distributing cells on microtiter platesAnd exposed to cytotoxic compounds for 4 doubling periods, i.e., 48 hours. The samples were then analyzed by colorimetric analysis-the Microculture Tetrazolium Assay (j. carmichael et al,Cancer Res.(cancer study); 47, 936-942(1987)) -quantification of viable cell number. The results are expressed as IC₅₀The concentration of cytotoxic agent that inhibits proliferation of treated cells by 50%. By way of example, the IC shown by the compound of example 2₅₀The values were 6.8. mu.M (L1210), 4.7. mu.M (A549) and 5.4. mu.M (DU 145).

Example 57: the pharmaceutical composition comprises: injectable solution

The compound of example 1

The

Claims (14)

1. A compound of formula (I), enantiomers, diastereomers and addition salts thereof with a pharmaceutically acceptable acid or base:

wherein:

a represents a partially or fully unsaturated ring, wherein the unsaturation optionally imparts aromaticity to the ring,

·W₁together with the carbon atom to which it is bonded represents phenyl or pyridyl,

z represents one or more identical or different radicals of the formula U-V, in which:

v.u represents a single bond or linear or branched (C)₁-C₆) An alkylene chain, which is a linear chain of alkylene,

v represents a radical chosen from a hydrogen atom, a halogen atom, a nitro group, a linear or branched (C)₁-C₆) Alkyl, hydroxy, linear or branched (C)₁-C₆) Alkoxy, aryl in which the alkoxy moiety may be linear or branched- (C)₁-C₆) Alkoxy and NR₃R₄Wherein the group R₃And R₄May be the same or different and each represents a radical selected from hydrogen atoms and linear and branched (C)₁-C₆) The radical of an alkyl group,

·Q₁represents a group selected from oxygen atoms and the group NR₂Wherein R is₂Represents a hydrogen atom, linear or branched (C)₁-C₆) Alkyl, -OR₃and-NR₃R₄A group of (a); or R₂Represents linear or branched (C) substituted by one or more identical or different groups₁-C₆) An alkylene chain, said group being selected from-OR₃and-NR₃R₄Wherein the radical R₃And R₄As defined above, the above-mentioned materials,

·Q₂represents a group selected from oxygen atoms and a group NR'₂Wherein R'₂Represents a radical selected from hydrogen atoms and linear or branched (C)₁-C₆) A group of alkyl groups; or R'₂Represents linear or branched (C) substituted by one or more identical or different groups₁-C₆) An alkylene chain, said group being selected from-NR₃R₄Wherein the radical R₃And R₄As defined above, the above-mentioned materials,

·X₁and Y₁Together with the carbon atom bearing them form a carbonyl group,

·X₂and Y₂Together with the carbon atom bearing them form a carbonyl group,

·X′₁and Y'₁Together with the carbon atom bearing them form a carbonyl group,

·X′₂and Y'₂Together with the carbon atom bearing them form a carbonyl group,

·R₁represents a radical selected from hydrogen atoms and linear or branched (C)₁-C₆) A group of alkyl groups; or R₁Represents a group of formula (a):

wherein:

√R_a、R_b、R_cand R_dMay be the same or different and each represents a bond or is selected from the group consisting of hydroxy, aryloxy and-O-C (O) -R₅Wherein R is₅Represents linear or branched (C)₁-C₆) An alkyl group, a carboxyl group,

√R_eis represented by formula-U₁A radical of the formula-Ra, in which U₁Represents a methylene group and R_aAs defined above, the above-mentioned materials,

the value of v is 1, n is,

it is understood that the radical of formula (a) is represented by R_aBonded to a nitrogen atom, and is,

with the proviso that the compound of formula (I) is not:

-3b, 6a, 6b, 7-tetrahydro-1H-dipyrrolo [3, 4-a:3, 4-c ] carbazole-1, 3, 4, 6- (2H, 3aH, 5H) -tetraone;

-5-ethyl-3 b, 6a, 6b, 7-tetrahydro-1H-dipyrrolo [3, 4-a:3, 4-c ] carbazole-1, 3, 4, 6- (2H, 3aH, 5H) -tetraone;

-3b, 6a, 7, 11 c-tetrahydro-1H-dipyrrolo [3, 4-a:3, 4-c ] carbazole-1, 3, 4, 6- (2H, 3aH, 5H) -tetraone;

-3b, 6a, 6b, 7-tetrahydrofuro [3, 4-a ] pyrrolo [3, 4-c ] carbazole-1, 3, 4, 6- (2H, 3aH, 5H) -tetraone;

where aryl is understood to mean phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl or indanyl, each of which is optionally substituted by one or more identical or different radicals selected from halogen, linear or branched (C)₁-C₆) Alkyl, linear or branched (C)₁-C₆) Trihaloalkyl, hydroxyLinear or branched (C)₁-C₆) Alkoxy and NR₃R₄Wherein R is₃And R₄As previously defined.

2. A compound of formula (I), its enantiomers, diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base according to claim 1, characterized in that Q is₁represents-NR₂Group, wherein R₂As defined for formula (I).

3. A compound of formula (I), its enantiomers, diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base according to claim 1 or 2, characterized in that Q is₂represents-NR'₂Group, wherein R'₂As defined for formula (I).

4. Compounds of formula (I), their enantiomers, diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base according to claim 1 or 2, characterized in that they represent compounds of formula (IA):

wherein R is₁、R₂、R′₂、W₁And Z is as defined for formula (I).

5. Compounds of formula (I), their enantiomers, diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base, according to claim 1 or 2, characterized in that they represent compounds of formula (IB):

wherein R is₁、R₂、R′₂And Z is as defined for formula (I).

6. Compounds of formula (I), their enantiomers, diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base according to claim 1 or 2, characterized in that they represent compounds of formula (IC):

wherein R is₁、R₂、R′₂And Z is as defined for formula (I).

7. Compounds of formula (I), their enantiomers, diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base according to claim 1 or 2, characterized in that they represent compounds of formula (ID):

wherein R is₂、R′₂、W₁、Z、R_b、R_c、R_dAnd R_eAs defined for formula (I).

8. Compounds of formula (I), their enantiomers, diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base, according to claim 1 or 2, characterized in that they represent compounds of formula (IE):

wherein R is₂、R′₂、Z、R_b、R_c、R_dAnd R₃As defined for formula (I).

9. Compounds of formula (I), their enantiomers, diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base, according to claim 1 or 2, characterized in that they represent compounds of formula (IF):

wherein R is₂、R′₂、Z、R_b、R_c、R_dAnd R_eAs defined for formula (I).

10. A compound of formula (I), its enantiomers, diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base according to claim 1 or 2, characterized in that R₁Represents a hydrogen atom.

11. A compound of formula (I) according to claim 1, which is

1H-dipyrrolo [3, 4-a:3, 4-c ] carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetraone,

2-methyl-1H-dipyrrolo [3, 4-a:3, 4-c ] carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetraone,

2, 5-dimethyl-1H-dipyrrolo [3, 4-a:3, 4-c ] carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetraone,

2- [2- (diethylamino) ethyl ] -5-methyl-1H-dipyrrolo [3, 4-a:3, 4-c ] carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetraone,

10-hydroxy-1H-dipyrrolo [3, 4-a:3, 4-c ] carbazole-1, 3, 4, 6(2H, 5H, 7H) -tetrone.

12. Process for the preparation of compounds of formula (I) according to claim 1, characterized in that compounds of formula (II) are used as starting materials:

wherein R is_2aRepresents a hydrogen atom or a methyl group and R₁、X′₁、Y′₁、X′₂、Y′₂、W₁And Z is as defined for formula (I),

treating the compound of formula (II) with 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone to give a compound of formula (III):

wherein R is₁、R_2a、X′₁、Y′₁、X′₂、Y′₂、W₁And Z is as defined above, and Z is,

reacting a compound of formula (III):

^*treatment with aqueous sodium hydroxide, followed by the presence of hydrochloric acid, affords compounds of formula (IV):

wherein R is₁、X′₁、Y′₁、X′₂、Y′₂、W₁And Z is as defined above, and Z is,

treating a compound of formula (IV) with a compound of formula (V):

wherein R'₂、X₁、Y₁、X₂And Y₂As defined for formula (I), compounds of formulae (I/a) and (I/b), a special case of compounds of formula (I), are obtained:

wherein R is₁、R′₂、X₁、Y₁、X₂、Y₂、X′₁、Y′₁、X′₂、Y′₂、W₁And Z is as defined above, and Z is,

optionally treating the compound of formula (I/a) and/or (I/b) with trifluoroacetic acid to obtain a compound of formula (I/c) -a particular example of a compound of formula (I):

wherein R is₁、R′₂、X₁、Y₁、X₂、Y₂、X′₁、Y′₁、X′₂、Y′₂、W₁And Z is as defined above, and Z is,

all of the compounds of formulae (I/a), (I/b) and (I/c) constitute compounds of formula (I/d):

a, R therein₁、R′₂、X₁、Y₁、X₂、Y₂、X′₁、Y′₁、X′₂、Y′₂、W₁And Z is as defined above, and Z is,

optionally treating the compound of formula (I/d) with a compound of formula (VII):

R_2b-NH₂ (VII)

wherein R is_2bHaving the same definition as R2 in formula (I), but not being a hydrogen atom and a methyl group, to give a compound of formula (I/e) -a special case of compounds of formula (I):

a, R therein₁、R′₂、R_2b、X₁、Y₁、X₂、Y₂、X′₁、Y′₁、X′₂、Y′₂、W₁And Z is as defined above, and Z is,

^*or sequentially subjected to the same reaction conditions as those of the compounds of the formulae (IV), (I/a) and (I/b) to give a compound of the formula (I/f) -a particular case of the compound of the formula (I):

a, R therein₁、R′₂、R_2a、X₁、Y₁、X₂、Y₂、X′₁、Y′₁、X′₂、Y′₂、W₁And Z is as defined above, and Z is,

all of the compounds of formulae (I/d), (I/e) and (I/f) constitute compounds of formula (I/g):

a, R therein₁、R′₂、Q₁、X₁、Y₁、X₂、Y₂、X′₁、Y′₁、X′₂、Y′₂、W₁And Z is as defined above, and Z is,

r'₂When representing a hydrogen atom or a methyl group, the compound of formula (I/g) is optionally subjected to the same reaction conditions as the compound of formula (III) in order to obtain a compound of formula (I/I) -a specific example of the compound of formula (I):

a, R therein₁、Q₁、X₁、Y₁、X₂、Y₂、X′₁、Y′₁、X′₂、Y′₂、W₁And Z is as defined above, and Z is,

optionally treating the compound of formula (I/I) with a compound of formula (VIII):

R′_2b-NH₂ (VIII)

wherein R'_2bHas R 'in the formula (I)'₂The same definition, but not a hydrogen atom and a methyl group, gives compounds of formula (I/j) -a special case of compounds of formula (I):

a, R therein₁、R′_2b、Q₁、X₁、Y₁、X₂、Y₂、X′₁、Y′₁、X′₂、Y′₂、W₁And Z is as defined above, and Z is,

compounds of formulae (I/a) - (I/j) comprise compounds of formula (I)If appropriate purified according to conventional purification techniques, and if desired separated into its different isomers, their substituents R_a、R_b、R_c、R_dAnd R_eThese compounds can be modified according to conventional methods for organic synthesis in the field of sugar chemistry and converted into addition salts with pharmaceutically acceptable acids or bases, if necessary.

13. A pharmaceutical composition comprising, as active ingredient, at least one compound of formula (I) according to claim 1, alone or in association with one or more pharmaceutically acceptable inert, non-toxic excipients or carriers.

14. Use of at least one compound according to claim 1 in the manufacture of a medicament for the treatment of cancer.