HK1065039A

HK1065039A - Pyrido-pyrido-pyrrolo pyrrolo-indole and pyrido-pyrrolo pyrrolo carbazole derivatives, method for the production thereof and pharmaceutical compositions containing said derivatives

Info

Publication number: HK1065039A
Application number: HK04107933.1A
Authority: HK
Inventors: Prudhomme Michelle; Marminon Christelle; Routier Sylvain; Coudert Gerard; Merour Jean-Yves; Hickman John; Pierre Alain; Renard Pierre; Pfeiffer Bruno
Original assignee: Les Laboratoires Servier
Priority date: 2001-06-29
Filing date: 2002-06-28
Publication date: 2005-02-08

Description

Pyridopyridopyrrolo [3, 2-g ] pyrrolo [3, 4-e ] indole and pyridopyrrolo [2, 3-a ] pyrrolo [3, 4-c ] carbazole compounds, processes for preparing them and pharmaceutical compositions containing them

The present invention relates to novel pyridopyridopyrrolo [3, 2-g ] pyrrolo [3, 4-e ] indole and pyridopyrrolo [2, 3-a ] pyrrolo [3, 4-c ] carbazole compounds, processes for preparing them and pharmaceutical compositions containing them.

Cancer therapy often requires the development of new antiproliferative agents in order to obtain more active and better tolerated agents. The compounds of the invention have particular anti-tumor properties and are useful in cancer therapy.

The patent applications WO95/07910 and WO96/04906 disclose indole compounds which are claimed, on the one hand, for their antiviral activity and, on the other hand, for their activity in the treatment and prophylaxis of restenosis. Patent applications WO00/47583, WO97/21677 and WO96/11933 disclose cyclopenta [ g ] pyrrolo [3, 4-e ] indole compounds in which the indole and cyclopentene moieties are fused to aromatic or non-aromatic ring systems and optionally contain heteroatoms. The compounds have pharmacological activity and are particularly useful for treating cancer cells.

The compounds of the present application differ greatly from the compounds disclosed in the prior art, have specific pharmacological properties, in particular a surprising in vivo and in vitro activity on various cell lines, and can be used for the treatment of cancer.

More particularly, the present invention relates to compounds of formula (I), and their enantiomers and diastereomers, and addition salts formed with a pharmaceutically acceptable acid or base:

wherein:

W₁，W₂together with the carbon atom to which they are bound each represents phenyl or pyridyl, wherein at least one W₁Or W₂Represents a pyridyl group, wherein the pyridyl group,

R₁，R₂may be the same or different and each independently represents a group of formula U-V wherein:

u represents a single bond, or optionally substituted by one or more identical or different groups selected from halogen and hydroxyl, and/or a linear or branched chain (C) optionally containing one or more unsaturated bonds₁-C₆) An alkylene chain, which is a linear chain of alkylene,

v represents a group selected from: hydrogen, halogen atoms, cyano groups, nitro groups, azido groups, straight-chain or branched (C)₁-C₆) Alkyl, aryl- (C)₁-C₆) Alkyl (wherein the alkyl moiety may be linear or branched), hydroxy, linear or branched (C)₁-C₆) Alkoxy, aryloxy, aryl (C)₁-C₆) Alkoxy (wherein the alkoxy moiety may be straight or branched), formyl, carboxy, aminocarbonyl, NR₆R₇，-C(O)-T₁，-C(O)-NR₆-T₁，-NR₆-C(O)-T₁，-O-C(O)-T₁，-C(O)-O-T₁，-O-T₂-NR₆R₇，-O-T₂-OR₆，-O-T₂-CO₂R₆，-NR₆-T₂-NR₆R₇，-NR₆-T₂-OR₆，-NR₆-T₂-CO₂R₆and-S (O)_t-R₆，

Wherein:

R₆and R₇Which may be the same or different, each represents a group selected from: hydrogen atom and straight or branched chain (C)₁-C₆) Alkyl, aryl and aryl- (C)₁-C₆) Alkyl (wherein the alkyl moiety may be straight or branched), or R₆+R₇Together with the nitrogen atom to which they are attached form a saturated, monocyclic or bicyclic heterocyclic ring optionally containing 5 to 10 atoms, in which the second heteroatom is selected from oxygen and nitrogen and optionally from linear or branched (C)₁-C₆) Alkyl, aryl- (C)₁-C₆) Alkyl (wherein the alkyl moiety is straight or branched chain), hydroxy, straightChain or branched (C)₁-C₆) Alkoxy, amino, straight or branched mono (C)₁-C₆) Alkylamino, and di (C)₁-C₆) Alkylamino (wherein each alkyl group may be straight or branched) groups,

T₁represents a group selected from: straight or branched C₁-C₆Alkyl, aryl- (C)₁-C₆) Alkyl (wherein the alkyl moiety is linear OR branched) selected from-OR₆，-NR₆R₇，-CO₂R₆，-C(O)R₆and-C (O) NR₆R₇Group (wherein R)₆And R₇As defined above) substituted straight or branched chain (C)₁-C₆) An alkylene chain, and a substituted OR unsubstituted alkylene group selected from-OR₆，-NR₆R₇，-CO₂R₆，-C(O)R₆and-C (O) NR₆R₇Group (wherein R)₆And R₇As defined above) substituted straight or branched chain (C)₂-C₆) An alkenylene chain in which the alkylene group is bonded to,

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

t represents an integer of 0 to 2,

R₃represents a group selected from: hydrogen atom and straight or branched chain (C)₁-C₆) Alkyl, aryl- (C)₁-C₆) Alkyl (where the alkyl moiety may be linear or branched), cycloalkyl- (C)₁-C₆) -alkyl (where the alkyl moiety may be linear OR branched), -OR₆，-NR₆R₇，-O-T₂-NR₆R₇，-NR₆-T₂-NR₆R₇Straight or branched chain (C)₁-C₆) Hydroxyalkylamino, di ((C)₁-C₆) Hydroxyalkyl) amino (wherein each alkyl moiety may be straight or branched), -C (O) -R₆and-NH-C (O) -R₆And one or more same or different groups selected from halogen atoms and cyano, nitro，-OR₆，-NR₆R₇，-CO₂R₆，-C(O)R₆Straight or branched chain (C)₁-C₆) Hydroxyalkylamino, di ((C)₁-C₆) Hydroxyalkyl) amino (wherein each alkyl moiety may be straight or branched), and-C (O) -NHR₆Group (wherein R)₆，R₇And T₂As defined above) substituted straight or branched chain (C)₁-C₆) An alkylene chain, which is a linear chain of alkylene,

x represents a linear or branched (C) group selected from a hydrogen atom and a hydroxyl group₁-C₆) Alkoxy, mercapto and straight or branched chain (C)₁-C₆) The radical of an alkylthio group,

y represents a hydrogen atom, or

X and Y together with the carbon atom to which they are bound form a carbonyl or thiocarbonyl group,

X₁represents a linear or branched (C) group selected from a hydrogen atom and a hydroxyl group₁-C₆) Alkoxy, mercapto and straight or branched chain (C)₁-C₆) The radical of an alkylthio group,

Y₁represents a hydrogen atom, or

X₁And Y₁Together with the carbon atom to which they are bound form a carbonyl or thiocarbonyl group,

Q₁，Q₂represents a hydrogen atom, or

Q₁And Q₂Together with the carbon atoms to which they are bonded form an aromatic bond,

R₄represents a group of formula (a):

wherein:

R_a，R_band R_cThe same or different ground surfaces can be used and are independent of each otherRepresents a group selected from: hydrogen atom and halogen atom, and hydroxyl group, straight chain or branched chain (C)₁-C₆) Alkoxy, aryloxy, aryl (C)₁-C₆) Alkoxy (wherein the alkoxy moiety is linear or branched), linear or branched (C)₁-C₆) Alkyl, aryl- (C)₁-C₆) Alkyl (wherein the alkyl moiety is linear or branched), aryl, -NR₆R₇(wherein R is₆And R₇As defined above), azido, -N ═ NR₆(wherein R is₆As defined above), and-O-C (O) -R₈Wherein R is₈Represents a straight chain or branched chain (C)₁-C₆) Alkyl (optionally substituted by a group selected from halogen, hydroxy, amino, straight or branched chain (C)₁-C₆) Alkylamino, and di (C)₁-C₆) Alkylamino (wherein each alkyl moiety may be linear or branched) substituted with one or more substituents, aryl- (C)₁-C₆) Alkyl (where the alkyl moiety is straight or branched), cycloalkyl or heterocyclylalkyl,

R_drepresents methylene or formula-U₁-R_aGroup (I) wherein U₁Represents a single bond or a methylene group, R_aThe definition is as above-mentioned,

n is a number of 0 or 1,

R₅represents a hydrogen atom and a linear or branched chain (C)₁-C₆) Alkyl, aryl- (C)₁-C₆) Alkyl (wherein the alkyl moiety is linear or branched), arylsulfonyl, linear or branched (C)₁-C₆) Alkoxycarbonyl, -OR₆and-C (O) -R₆(wherein R is₆A radical as defined above), or

R₄And R₅Together represent a group of formula (b) or (c) (provided that Q₁And Q₂Together forming an aromatic linkage):

wherein:

carbon atom 1 is bonded to the ring (A) nitrogen atom, carbon atom 2 is bonded to the ring (B) nitrogen atom,

R_a，R_b，R_cand R_dThe definition is as above-mentioned,

n is a number of 0 or 1,

aryl is understood to mean phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl or 2, 3-indanyl, each of which is optionally substituted by one or more identical or different substituents selected from halogen, straight-chain or branched (C)₁-C₆) Alkyl, straight or branched (C)₁-C₆) Trihaloalkyl, hydroxy, straight or branched chain (C)₁-C₆) Alkoxy, and optionally one or two straight or branched chains (C)₁-C₆) Alkyl substituted amino groups.

Among the pharmaceutically acceptable acids, mention may be made, without being limited thereto, of 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, there may be mentioned, without being limited thereto, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine and the like.

Preferred compounds of the invention are those in which X and Y together with the carbon atom to which they are bound form a carbonyl group, and X₁And Y₁Compounds which together with the carbon atom to which they are bound form a carbonyl group.

According to a preferred embodiment, preferred compounds of the invention are compounds of formula (I) which correspond in particular to formula (IA):

wherein R is₁，R₂，R₃，R₅，R_a，R_b，R_c，R_d，W₁And W₂As defined in formula (I).

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

wherein R is₁，R₂，R₃，R₅，R_a，R_b，R_cAnd R_dAs defined in formula (I).

According to a third preferred embodiment, preferred compounds of the invention are compounds of formula (I) corresponding in particular to formula (IC):

According to a fourth preferred embodiment, preferred compounds of the invention are compounds of formula (I) corresponding in particular to formula (ID):

According to a fifth preferred embodiment, preferred compounds of the invention are of formula (IE):

wherein R is₁，R₂，R₃，R₅，R_b，R_c，R_d，n，W₁And W₂As defined in formula (I).

According to a sixth preferred embodiment, preferred compounds of the invention are of formula (IF):

According to a seventh preferred embodiment, preferred compounds of the invention are of formula (IG):

According to an eighth preferred embodiment, preferred compounds of the invention are compounds of formula (IH):

According to a ninth preferred embodiment, preferred compounds of the invention are of formula (IJ):

Advantageously, the preferred pyridine rings according to the invention are unsubstituted rings.

Advantageously, R is preferred according to the invention₄The group is a glucopyranose group of the formula:

very advantageously, R is preferred according to the invention₂The radical is a hydrogen atom.

According to the invention, R is preferably₁The radicals are hydrogen atoms, halogen atoms and nitro groups.

Preferred compounds according to the invention are:

6-methyl-13- (β -D-glucopyranosyl) -12, 13-dihydro-5H-pyrido [3 ', 2': 4, 5] pyrrolo [2, 3-a ] -pyrrolo [3, 4-c ] carbazole-5, 7(6H) -dione,

6-methyl-12- (β -D-glucopyranosyl) -12, 13-dihydro-5H-pyrido [2, 3-b ] pyrido [3 ', 2': 4, 5] pyrrolo [3, 2-g ] pyrrolo [3, 4-e ] indole-5, 7(6H) -dione,

9-bromo-6-methyl-13- (β -D-glucopyranosyl) -12, 13-dihydro-5H-pyrido [3 ', 2': 4.5] pyrrolo [2, 3-a ] pyrrolo [3, 4-c ] carbazole-5, 7(6H) -dione,

13- (β -D-glucopyranosyl) -12, 13-dihydro-5H-pyrido [3 ', 2': 4, 5] pyrrolo [2, 3-a ] pyrrolo [3, 4-c ] carbazole-5, 7(6H) -dione,

9-nitro-13- (β -D-glucopyranosyl) -12, 13-dihydro-5H-pyrido [3 ', 2': 4, 5] pyrrolo [2, 3-a ] pyrrolo [3, 4-c ] carbazole-5, 7(6H) -dione,

12- (β -D-glucopyranosyl) -12, 13-dihydro-5H-pyrido [2, 3-b ] pyrido [3 ', 2': 4, 5] pyrrolo [3, 2-g ] pyrrolo [3, 4-e ] indole-5, 7(6H) -dione,

and 1-methyl-3- [1- (beta-D-glucopyranosyl) -1H-pyrrolo [2, 3-b ] pyridin-3-yl ] -4- (1H-pyrrolo [2, 3-b ] pyridin-3-yl) -1H-pyrrole-2, 5-dione.

The enantiomers and diastereomers of the preferred compounds, as well as the addition salts formed with pharmaceutically acceptable acids or bases, form integral parts of the invention.

The invention also relates to a process for the preparation of a compound of formula (I), which process is characterized in that a compound of formula (II) is used as starting material:

wherein BOM represents benzyloxymethyl and X, Y, X₁And Y₁As defined in formula (I),

treating a compound of formula (II) with an alkyl magnesium halide in the presence of a compound of formula (III):

wherein W₁As defined in formula (I),

to obtain a compound of formula (IV):

wherein the ratio of X, Y,X₁，Y₁BOM and W₁The definition is as above-mentioned,

reacting a compound of formula (IV) with benzenesulfonyl chloride in the presence of sodium hydride to give a compound of formula (V):

wherein BOM, X, Y, X₁，Y₁And W₁The definition is as above-mentioned,

reacting a compound of formula (V) with a compound of formula (VI) in the presence of lithium hexamethyldisilazane:

wherein W₂As defined in formula (I),

to give a compound of formula (VII):

wherein BOM, X, Y, X₁，Y₁，W₁And W₂The definition is as above-mentioned,

a compound of formula (VII) is reacted with a compound of formula (a) in the presence of triphenylphosphine and diethyl azodicarboxylate₁) Compound reaction:

wherein R is_a，R_b，R_c，R_dAnd n is as defined for formula (I),

a particular example of obtaining a compound of formula (I), a compound of formula (I/a):

wherein BOM, X, Y, X₁，Y₁，W₁，W₂，R_a，R_b，R_c，R_dAnd n is as defined above, and,

a particular example of a compound of formula (I) is obtained by optionally treating a compound of formula (I/a) with a solution of tetrabutylammonium fluoride in tetrahydrofuran, a compound of formula (I/b):

a particular example of a compound of formula (I) is obtained by irradiating a compound of formula (I/b), optionally with a UV lamp, in a nonpolar and aprotic solvent in the presence of iodine, a compound of formula (I/c):

the sum of the compounds of formulae (I/b) and (I/c) forms the compound of formula (I/d):

wherein BOM, X, Y, X₁，Y₁，W₁，W₂，R_a，R_b，R_c，R_dAnd n is as defined above, and,and Q₁And Q₂As defined in formula (I),

the compound of formula (I/d) is optionally substituted with:

treatment with a compound of formula (VIII) in a basic medium:

R′₅-Hal (VIII)，

wherein Hal represents a halogen atom, R'₅As defined for R in formula (I)₅(excluding the hydrogen atom),

specific examples of compounds of formula (I) are obtained, compounds of formula (I/e):

wherein BOM, X, Y, X₁，Y₁，W₁，W₂，R_a，R_b，R_c，R_d，n，Q₁，Q₂And R'₅The definition is as above-mentioned,

the sum of the compounds of formulae (I/d) and (I/e) forms the compound of formula (I/f):

wherein BOM, X, Y, X₁，Y₁，W₁，W₂，R_a，R_b，R_c，R_d，n，Q₁，Q₂And R'₅As defined above, R₅As defined in formula (I),

a particular example of a compound of formula (I) is obtained by subjecting a compound of formula (I/f), optionally in a hydrogen atmosphere, in the presence of palladium on carbon in a polar solvent, to a compound of formula (I/g):

wherein X, Y, X₁，Y₁，W₁，W₂，R_a，R_b，R_c，R_d，n，Q₁，Q₂And R₅The definition is as above-mentioned,

a particular case of compounds of formula (I) is obtained by optionally reacting a compound of formula (I/g) with an ammonium hydroxide solution in a protic medium, a compound of formula (I/h):

or, in which R_aRepresents a tosyl group and Q₁And Q₂In the particular case where they form an aromatic bond together with the carbon atom to which they are bound, treatment with sodium azide affords the particular case of compounds of formula (I), compounds of formula (I/I):

wherein BOM, X, Y, X₁，Y₁，W₁，W₂，R_b，R_c，R_dAnd n is as defined above, and,

(ii) optionally treating the compound of formula (I/I) in the same manner as the compound of formula (I/f) to give a special case of the compound of formula (I), the compound of formula (I/j):

wherein X, Y, X₁，Y₁，W₁，W₂，R_b，R_c，R_dAnd n is as defined above, and,

a particular example of a compound of formula (I) is obtained by optionally reacting formula (I/j) under the same reaction conditions as formula (I/g):

or, in which R_dRepresents a tosyl group and Q₁And Q₂In the particular case where they form an aromatic bond together with the carbon atom to which they are bound, treatment with sodium azide affords the particular case of compounds of formula (I), compounds of formula (I/l):

wherein X, Y, X₁，Y₁，W₁，W₂，R_a，R_b，R_cAnd n is as defined above, and,

a particular example of a compound of formula (I) is obtained by optionally treating a compound of formula (I/l) in the same manner as a compound of formula (I/f):

a particular example of a compound of formula (I) is obtained by optionally reacting formula (I/m) under the same reaction conditions as formula (I/g):

the sum of the compounds of formulae (I/h), (I/k) and (I/n) to form the compound of formula (I/o):

wherein X, Y, X₁，Y₁，W₁，W₂，R₄，R₅，Q₁And Q₂The compound is defined as (I),

optionally treating the compound of formula (I/o) with aqueous sodium hydroxide, followed by exposure to hydrochloric acid, to provide a compound of formula (IX):

wherein X, Y, X₁，Y₁，W₁，W₂，R₄，R₅，Q₁And Q₂The definition is as above-mentioned,

optionally reacting a compound of formula (IX) with a compound of formula (X):

R_3a-NH₂ (X)，

R_3aas defined for R in formula (I)₃(in which the hydrogen atoms are excluded),

a special case of obtaining compounds of formula (I), compounds of formula (I/p):

wherein X, Y, X₁，Y₁，W₁，W₂，R_3a，R₄，R₅，Q₁And Q₂The definition is as above-mentioned,

the sum of the compounds of formulae (I/o) and (I/p) forms the compound of formula (I/q):

wherein X, Y, X₁，Y₁，W₁，W₂，R₃，R₄，R₅，Q₁And Q₂As defined in formula (I),

a particular case of compounds of formula (I) is obtained by subjecting compounds of formula (I/q), optionally to aromatic electrophilic addition or aromatic nucleophilic addition reactions according to conditions common to organic syntheses well known to those skilled in the art, compounds of formula (I/r):

wherein X, Y, X₁，Y₁，W₁，W₂，R₃，R₄，R₅，Q₁And Q₂The definition is as above-mentioned,

and in addition to R_1aAnd R_2aR not both representing hydrogen atoms_1aAnd R_2aAre each as defined as R₁And R₂In the same way as above, the first and second,

the compounds of formulae (I/a) to (I/r), which constitute the sum of the compounds of formula (I), may, if desired, be purified according to conventional purification techniques, if desired be separated into their different isomers according to conventional separation techniques, if desired be used in the field of sugar chemistryOrganic Synthesis of Domain conventional methods modify its substituent R_a，R_b，R_cAnd R_dAnd if desired, converted into their addition salts with pharmaceutically acceptable acids or bases.

Formula (II), (III), (VI), (a)₁) Any of (VIII) and (X) are commercially available or obtainable according to conventional methods of organic synthesis readily available to those skilled in the art.

The compounds of formula (IX) are useful as synthetic intermediates for the preparation of compounds of formula (I).

The compounds of formula (I) have particularly valuable antitumor properties. The properties of these compounds make them useful in therapy as antitumor agents.

The 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 inert, non-toxic, pharmaceutically acceptable excipients or carriers.

Among the pharmaceutical compositions according to the invention, there may be mentioned more particularly those suitable for oral, parenteral (intravenous, intramuscular or subcutaneous injection), trans-or trans-dermal, nasal, rectal, lingual, ocular or respiratory administration, in particular tablets or dragees, sublingual tablets, soft capsules, hard capsules, suppositories, emulsions, ointments, dermal gels, injectable or drinkable preparations, aerosols, eye or nasal drops and the like.

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

The dosage used varies according to the age and weight of the patient, the route of administration, the nature and severity of the disease and the administration of the combination therapy, and ranges from 1 mg to 500 mg per day in one or more divided doses.

The examples which follow are intended to illustrate the invention without limiting it in any way. The starting materials are known substances or can be prepared according to known methods.

The structures of the compounds disclosed in the examples have been determined according to usual spectrophotometric techniques (infrared, nuclear magnetic resonance, mass spectrometry, etc.).

Preparation example a: 1- [ (benzyloxy) methyl ] -3- [1- (phenylsulfonyl) -1H-indol-3-yl ] -4- (1H-pyrrolo [2, 3-b ] pyridin-3-yl) -1H-pyrrole-2, 5-dione

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

An ethylmagnesium bromide solution was prepared, magnesium (6.75 mmol) was suspended in ethyl bromide (6.75 mmol) and anhydrous tetrahydrofuran (5 ml). The solution was stirred at room temperature for 15 minutes and then heated at 40 ℃ for 20 minutes. A solution of indole (6.75 mmol) in 40 ml of anhydrous tetrahydrofuran is then added dropwise. After stirring at 40 ℃ for 1 hour, the reaction mixture was cooled, and then a solution of N-benzyloxymethyl-2, 3-dibromomaleimide (3.38 mmol) in 40 ml of anhydrous tetrahydrofuran was added dropwise. The reaction mixture was stirred for 15 hours and then hydrolyzed with saturated aqueous ammonium chloride solution. The organic product was extracted with ethyl acetate, then the organic phases were combined, dried over magnesium sulfate and filtered. After evaporation of the solvent, the residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate: 4/1) and the expected product is isolated.

Melting point 115-.

And B: 1- [ (benzyloxy) methyl ] -3-bromo-4- [1- (phenylsulfonyl) -1H-indol-3-yl ] -1H-pyrrole-2, 5-dione

To a suspension of sodium hydride (5.45 mmol) in 10 ml of anhydrous tetrahydrofuran cooled to 0 ℃ is added dropwise a solution of the compound obtained in step A (2.53 mmol) in 20 ml of tetrahydrofuran. After stirring at 0 ℃ for 1 hour, benzenesulfonyl chloride (4.04 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 4 hours, and then hydrolyzed with saturated aqueous ammonium chloride solution. The organic product was extracted with ethyl acetate, then the organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and filtered. After evaporation of the solvent, the residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate: 85/15) and the expected product is isolated.

Melting point 49-51 ℃.

And C: 1- [ (benzyloxy) methyl ] -3- [1- (phenylsulfonyl) -1H-indol-3-yl ] -4- (1H-pyrrolo [2, 3-b ] pyridin-3-yl) -1H-pyrrole-2, 5-dione

To a solution of 7-azaindole (1.542 mmol) in 10 ml of anhydrous toluene maintained at-15 deg.C was added dropwise a 1M solution of LiHMDS in hexane (1.78 mmol). After stirring at-15 ℃ for 1 hour, a solution of the compound of step B (0.637 mmol) in 10 ml of dry toluene was added dropwise at-20 ℃. After 24 hours at room temperature, the reaction mixture was hydrolyzed with saturated aqueous ammonium chloride solution, and then the pH was adjusted to 7. The mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and filtered. After purification by chromatography on silica gel (cyclohexane/ethyl acetate: 3/2), the expected product is isolated.

Melting point 94-96 ℃.

Preparation example B: 1- [ (benzyloxy) methyl ] -3- [ 1H-indol-3-yl ] -4- [1- (phenylsulfonyl) -1H-pyrrolo [2, 3-b ] pyridin-3-yl ] -1H-pyrrole-2, 5-dione

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

An ethylmagnesium bromide solution was prepared, and magnesium (6.00 mmol) was suspended in ethyl bromide (6.00 mmol) and anhydrous tetrahydrofuran (2.5 ml). The solution was stirred at room temperature for 1 hour, and then a solution of 7-azaindole (6.00 mmol) in 20 ml of anhydrous toluene was added dropwise. After stirring at room temperature for 1 hour and 30 minutes, a solution of N-benzyloxymethyl-2, 3-dibromomaleimide (2.01 mmol) in 20 ml of anhydrous toluene was added dropwise. After 20 minutes, 30 ml of anhydrous dichloromethane were added; the reaction mixture was then stirred at 40 ℃ for 65 hours and hydrolyzed with saturated aqueous ammonium chloride solution. The organic product was extracted with ethyl acetate, then the organic phases were combined, dried over magnesium sulfate and filtered. After evaporation of the solvent, the residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate: 3/2, then toluene/ethyl acetate: 7/3) and the expected product is isolated.

Melting point 168-.

And B: 1- [ (benzyloxy) methyl ] -3-bromo-4- [1- (phenylsulfonyl) -1H-pyrrolo [2, 3-b ] pyridin-3-yl ] -1H-pyrrole-2, 5-dione

Using the product obtained in step A above as a substrate, the product was obtained according to the procedure of step B of preparation A.

Melting point 123-.

And C: 1- [ (benzyloxy) methyl ] -3- (1H-indol-3-yl) -4- [1- (phenylsulfonyl) -1H-pyrrolo [2, 3-b ] pyridin-3-yl ] -1H-pyrrole-2, 5-dione

An ethylmagnesium bromide solution was prepared, and magnesium (0.62 mmol) was suspended in ethyl bromide (0.62 mmol) and anhydrous tetrahydrofuran (0.4 ml). The solution was stirred at room temperature for 15 minutes and then heated at 40 ℃ for 20 minutes. A solution of indole (0.65 mmol) in 3ml of dry toluene is then added dropwise. After stirring at 40 ℃ for 1 hour, the reaction mixture was cooled and then a solution of the compound obtained in step B (0.254 mmol) in 5 ml of anhydrous toluene was added dropwise. The reaction mixture was stirred for 15 hours and then hydrolyzed with saturated aqueous ammonium chloride solution. The organic product was extracted with ethyl acetate, then the organic phases were combined, dried over magnesium sulfate and filtered. After evaporation of the solvent, the residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate: 3/2) and the expected product is isolated.

Melting point 86-88 ℃.

Preparation example C: 1- [ (benzyloxy) methyl ] -3- [1- (phenylsulfonyl) -1H-pyrrolo [2, 3-b ] pyridin-3-yl ] -4- (1H-pyrrolo [2, 3-b ] pyridin-3-yl) -1H-pyrrole-2, 5-dione

Using the compound obtained in step B of preparation B as a substrate, the product was obtained according to the procedure of step C of preparation A.

Melting point 115-.

Preparation example D: 1-methyl-3- [1- (phenylsulfonyl) -1H-pyrrolo [2, 3-b ] pyridin-3-yl ] -4- (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-dione

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

Melting point 158 ℃.

And B: 3-bromo-1-methyl-4- [1- (phenylsulfonyl) -1H-pyrrolo [2, 3-b ] pyridin-3-yl ] -1H-pyrrole-2, 5-dione

A solution of the compound from step A (1.89 mmol) in 40 ml of tetrahydrofuran and 5 ml of dimethylformamide is added dropwise to a suspension of sodium hydride (4.00 mmol) in 10 ml of anhydrous tetrahydrofuran, cooled to 0 ℃. After stirring at 0 ℃ for 1 hour, benzenesulfonyl chloride (3.02 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 4 hours, and then hydrolyzed with saturated aqueous ammonium chloride solution. The organic product was extracted with ethyl acetate, then the organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and filtered. After evaporation of the solvent, the residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate: 4/1) and the expected product is isolated.

Melting point 198 ℃.

Preparation example C: 1-methyl-3- [1- (phenylsulfonyl) -1H-pyrrolo [2, 3-b ] pyridin-3-yl ] -4- (1H-pyrrolo [2, 3-b ] pyridin-3-yl) -1H-pyrrole-2, 5-dione

Using the product obtained in step B above as a substrate, the product was obtained according to the procedure of step C of preparation A.

Melting point 180 ℃.

Preparation example E: 3- [ 1-methyl-2, 5-dioxo-4- (1H-pyrrolo [2, 3-b ] pyridin-3-yl) -2, 5-dihydro-1H-pyrrol-3-yl ] -1H-indole-1-carboxylic acid tert-butyl ester

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

A solution of 1.445 g of indole in 29 ml of anhydrous tetrahydrofuran was kept at-20 to-10 ℃ under argon and 26 ml of LiHMDS (1M in hexane) were added dropwise over 15 minutes. After leaving at-10 ℃ for 45 minutes, the solution was diluted with another 15 ml of tetrahydrofuran and a solution of 2 g of 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 50 ml of 0.3N hydrochloric acid solution at 0 ℃. The reaction mixture was extracted with ethyl acetate, the organic phase was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The desired product was precipitated using methanol.

Melting point 167-.

And B: 3- (4-bromo-1-methyl-2, 5-dioxo-2, 5-dihydro-1H-pyrrol-3-yl) -1H-indole-1-carboxylic acid tert-butyl ester

Under an inert gas atmosphere, 1 g of the product obtained in step AThe resulting product, 30 mg of 4-dimethylaminopyridine, 1.58 g of Boc₂The solution of O and 15 ml of anhydrous tetrahydrofuran was stirred at room temperature for 24 hours. After removal of the solvent under reduced pressure, the crude reaction product (petroleum ether/AcOEt/NEt) was purified by chromatography₃: 8/2/1%), the expected product is isolated.

Melting point 137-138 ℃.

And C: 3- [ 1-methyl-2, 5-dioxo-4- (1H-pyrrolo [2, 3-b ] pyridin-3-yl) -2, 5-dihydro-1H-pyrrol-3-yl ] -1H-indole-1-carboxylic acid tert-butyl ester

To a solution of 7-azaindole (1.78 mmol) in 10 ml of anhydrous toluene maintained at-10 ℃ was added dropwise a commercial LiHMDS solution (1M in hexane) (4.6 mmol). After stirring at-10 ℃ for 1 hour, a solution of the product obtained in step B (0.85 mmol) in 10 ml of anhydrous toluene is added dropwise at room temperature. After stirring at room temperature for 24 hours, the reaction mixture was hydrolyzed with saturated aqueous ammonium chloride solution, and then the pH was adjusted to 7. The mixture was extracted with ethyl acetate. The combined organic phases were washed with aqueous sodium chloride solution and dried over magnesium sulfate. After purification by chromatography on silica gel (cyclohexane/ethyl acetate/triethylamine: 7/3/1%), the expected product is isolated.

Melting point 180 ℃.

Preparation example F: 13- (β -D-glucopyranosyl) -12, 13-dihydrofuro [3, 4-c ] pyrido [3 ', 2': 4, 5] pyrrolo [2, 3-a ] carbazole-5, 7-diones

Step A: 3- (1H-indol-3-yl) -4- [1- (beta-D-glucopyranosyl) -1H-pyrrolo [2, 3-b ] pyridin-3-yl ] -1H-furan-2, 5-dione

To a suspension of the compound of example 16b (0.488 mmol) in 40 ml of water were added sodium hydroxide (7 mmol) and 30 ml of tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 hour 30 minutes, acidified to pH 1 using 2N hydrochloric acid solution, and further stirred for 30 minutes. The reaction mixture was transferred to a water/ethyl acetate mixture and the organic product was extracted with ethyl acetate. The organic phases are combined, dried over magnesium sulfate and filtered, and the solvent is distilled off. The product was purified by silica gel chromatography (ethyl acetate/methanol: 95/5) to isolate the expected product.

Melting point 182-.

Infrared Spectrum (KBr), upsilon_C＝O＝1755，1820cm^-1；υ_NH＝3000-3600cm^-1。

And B: 13- (β -D-glucopyranosyl) -12, 13-dihydrofuro [3, 4-c ] pyrido [3 ', 2': 4, 5] pyrrolo [2, 3-a ] carbazole-5, 7-diones

The product was obtained according to the procedure of example 1c, using the compound of step a above as substrate.

Melting point: is > 300 ℃.

Infrared Spectrum (KBr), v_C＝O＝1755，1825cm^-1；ν_NH＝3200-3600cm^-1。

Preparation example G: 1-methyl-3- (1H-indol-3-yl) -4- [1- (phenylsulfonyl) -1H-pyrrolo [2, 3-b ] pyridin-3-yl ] -1H-pyrrole-2, 5-dione

Using the product obtained in step B of preparation D as a substrate, the product was obtained according to the procedure in step C of preparation B.

Preparation example H: 3- [ 1-methyl-2, 5-dioxo-4- (1H-pyrrolo [3, 2-c ] pyridin-3-yl) -2, 5-dihydro-1H-pyrrol-3-yl ] -1H-indole-1-carboxylic acid tert-butyl ester

To a solution of 5-azaindole (7.89 mmol) in 15 ml of anhydrous toluene maintained at room temperature was added dropwise a solution of LiHMDS (1M in hexane) (6.25 mmol). After stirring at room temperature for 1 hour 15 minutes, a solution of the product of preparation E, step B (3.77 mmol) in 10 ml of toluene and 15 ml of dichloromethane was added at room temperature. After stirring at room temperature for 12 hours, the mixture was extracted with ethyl acetate. The organic phases were combined, dried over magnesium sulfate and filtered. After purification by chromatography on silica gel (petroleum ether/ethyl acetate/triethylamine: 1/1/1% and then ethyl acetate/triethylamine: 9/1), the expected product is isolated.

Melting point: decomposing at 218 ℃.

Infrared Spectrum (KBr), v_C＝O＝1703，1735cm^-1；ν_NH＝3200-3300cm^-1。

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

To a solution of the compound of preparation A (0.927 mmol) in 40 ml of anhydrous tetrahydrofuran were added 2, 3, 4, 6-tetra-O-acetylglucopyranose (1.95 mmol) and triphenylphosphine (1.95 mmol). The reaction mixture was cooled to-78 ℃ and then DEAD (1.95 mmol) was added dropwise. The temperature was slowly raised to room temperature, and then the reaction mixture was further stirred for 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 distilled off. Purification by silica gel chromatography (cyclohexane/ethyl acetate: 65/35 followed by toluene/ethyl acetate 3/2) gave the β -glycosylated compound as yellow crystals and the α -glycosylated compound admixed with triphenylphosphine oxide.

Melting point 105-.

Example 1 b: 1- [ (benzyloxy) methyl ] -3- (1H-indol-3-yl) -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

To a solution of the β -glycosylated compound of example 1a (0.565 mmol) in 20 ml of anhydrous tetrahydrofuran was added a solution of tetrabutylammonium fluoride (1.1M in tetrahydrofuran) (1.86 mmol). The reaction mixture was stirred at room temperature for 2.30 hours. After hydrolysis, the organic product was extracted with ethyl acetate. The organic phases were combined, dried over magnesium sulfate and filtered. After evaporation of the solvent, the residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate: 2/3) and the expected product is isolated.

Melting point 117-.

Example 1 c: 6- [ (benzyloxy) methyl ] -13- (2, 3, 4, 6-tetra-O-acetyl- β -D-glucopyranosyl) -12, 13-dihydro-5H-pyrido [3 ', 2': 4, 5] pyrrolo [2, 3-a ] pyrrolo [3, 4-c ] carbazole-5, 7(6H) -dione

To a solution of the compound of example 1b (0.409 mmol) in 500 ml of benzene was added iodine (4.90 mmol). The mixture was irradiated in a quartz reactor equipped with a 400W penetrating medium pressure mercury vapor u.v. lamp for 1 hour 30 minutes. Evaporating the solvent; the crude reaction product was transferred to ethyl acetate, washed with aqueous sodium thiosulfite solution and then with saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate and filtered, and the solvent is distilled off. After purification by chromatography on silica gel (cyclohexane/ethyl acetate: 3/2), the expected product is isolated.

Melting point 109-.

Infrared Spectrum (KBr), v_C＝O＝1710，1760cm^-1；ν_NH＝3300-3500cm^-1。

Example 2: 6- (hydroxymethyl) -13- (2, 3, 4, 6-tetra-O-acetyl- β -D-glucopyranosyl) -12, 13-dihydro-5H-pyrido [3 ', 2': 4, 5] pyrrolo [2, 3-a ] pyrrolo [3, 4-c ] carbazole-5, 7(6H) -dione

To a solution of the compound of example 1c (0-067 mmol) in 3ml of anhydrous methanol and 1 ml of anhydrous ethyl acetate was added 10% palladium on carbon (18.1 mg). The reaction mixture was degassed twice and then stirred at room temperature under a hydrogen atmosphere (1 bar). After 24 hours, an additional 10% palladium on carbon (21.0 mg) was added. The reaction mixture was degassed again and then placed under a hydrogen atmosphere for 48 hours. The mixture was filtered through celite, and the solid was washed with methanol and ethyl acetate. After evaporation of the solvent, the residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate: 65/35) and the expected product is isolated.

Melting point 154-.

Infrared Spectrum (KBr), v_C＝O＝1705，1760cm^-1；ν_NH＝3200-3600cm^-1。

Example 3: 13- (β -D-glucopyranosyl) -12, 13-dihydro-5H-pyrido [3 ', 2': 4, 5] pyrrolo [2, 3-a ] pyrrolo [3, 4-c ] carbazole-5, 7(6H) -dione

To a solution of the compound of example 2 (0.030 mmol) in 9.4 ml of methanol was added 28% aqueous ammonium hydroxide (8 ml). The mixture was stirred at room temperature for 19 hours. After evaporation of the solvent, the residue was transferred into a water/ethyl acetate mixture and then filtered through a fritted glass filter. The crystals were washed with ethyl acetate and methanol in this order. The expected compound is obtained in the form of yellow crystals.

The melting point is greater than 300 ℃.

Infrared Spectrum (KBr), v_C＝O＝1710，1740cm^-1；ν_NH，OH＝3100-3600cm^-1。

Example 4: 9-bromo-13- (β -D-glucopyranosyl) -12, 13-dihydro-5H-pyrido [3 ', 2': 4, 5] pyrrolo [2, 3-a ] pyrrolo [3, 4-c ] carbazole-5, 7(6H) -dione

To a solution of the compound of example 3 (0.043 mmol) in 2 ml of tetrahydrofuran cooled to 0 ℃ was added dropwise a solution of N-bromosuccinimide (0.866 mmol) in 1.5 ml of tetrahydrofuran. The mixture was stirred at room temperature for five days and stored in the dark. After 15 minutes of hydrolysis, a saturated aqueous solution of sodium thiosulfite was added. The residue was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and filtered, and the solvent was evaporated. The resulting residue was dissolved in 8 ml of methanol, followed by addition of 28% aqueous ammonium hydroxide solution (9 ml). The mixture was stirred at room temperature for 22 hours and stored in the dark. After evaporation of the solvent, the residue was transferred into a water/ethyl acetate mixture and then filtered through a fritted glass filter. The crystals were washed with ethyl acetate to give the expected product.

The melting point is greater than 300 ℃.

Infrared Spectrum (KBr), v_C＝O＝1710，1750cm^-1；ν_NH，OH＝3200-3600cm^-1。

Example 5: 9-nitro-13- (β -D-glucopyranosyl) -12, 13-dihydro-5H-pyrido [3 ', 2': 4, 5] pyrrolo [2, 3-a ] pyrrolo [3, 4-c ] carbazole-5, 7(6H) -dione

Mallinckrodt's ether solution (13ml tetrahydrofuran, 2.1 ml fuming nitric acid) (14 ml) was added dropwise to the compound of example 3 (0.061 mmol) at 0 ℃ and cooled to 0 ℃. After 10 minutes, the mixture was warmed to room temperature and stirred for 21 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 distilled off. The residue was dissolved in 10 ml of methanol, followed by dropwise addition of 28% aqueous ammonium hydroxide solution (17 ml). The mixture was stirred at room temperature for 16 hours. After evaporation of the solvent, the residue was transferred into a water/ethyl acetate mixture and then filtered through a fritted glass filter. The crystals were washed with ethyl acetate and the expected product was isolated.

The melting point is greater than 300 ℃.

Infrared Spectrum (KBr), v_C＝O＝1710，1760cm^-1；ν_NH，OH＝3300-3600cm^-1。

Example 6 a: 1- [ (benzyloxy) methyl ] -3- (1H-indol-3-yl) -4- [1- (2, 3, 4, 6-tetra-O-acetyl alpha-D-glucopyranosyl) -1H-pyrrolo [2, 3-b ] pyridin-3-yl ] -1H-pyrrole-2, 5-dione

To a solution of the α -glycosylated compound of example 1a (0.034 mmol) in 3ml of anhydrous tetrahydrofuran was added a solution of tetrabutylammonium fluoride (1.1M in tetrahydrofuran) (0.132 mmol). The reaction mixture was stirred at room temperature for 2.30 hours. After hydrolysis, the organic product was extracted with ethyl acetate. The organic phases were combined, dried over magnesium sulfate and filtered. After evaporation of the solvent, the residue was purified by silica gel chromatography (cyclohexane/ethyl acetate: 2/3) to give the expected product.

Example 6 b: 6- [ (benzyloxy) methyl ] -13- (2, 3, 4, 6-tetra-O-acetyl- α -D-glucopyranosyl) -12, 13-dihydro-5H-pyrido [3 ', 2': 4, 5] pyrrolo [2, 3-a ] pyrrolo [3, 4-c ] carbazole-5, 7(6H) -dione

The product was obtained according to the procedure of example 1 c.

Example 7 a: 1- [ (benzyloxy) methyl ] -3- (1- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyl) -1H-indol-3-yl) -4- [1- (phenylsulfonyl) -1H-pyrrolo [2, 3-b ] pyridin-3-yl ] -1H-pyrrole-2, 5-dione

The product was obtained after silica gel chromatography as in example 1a, using the compound of preparation B as substrate.

Melting point 80-82 ℃ (β -glycosylated compound).

Infrared Spectrum (KBr), v_C＝O＝1710，1760cm^-1。

Example 7 b: 1- [ (benzyloxy) methyl ] -3- [1- (2, 3, 4, 6-tetra-O-acetyl-beta-D-glucopyranosyl) -1H-indol-3-yl ] -4- [ 1H-pyrrolo [2, 3-b ] pyridin-3-yl ] -1H-pyrrole-2, 5-dione

The product was obtained according to the procedure of example 1b, using the compound of example 7a as substrate.

Melting point 115-.

Infrared Spectrum (KBr), v_C＝O＝1700，1760cm^-1；ν_NH＝3100-3600cm^-1。

Example 7 c: 6- [ (benzyloxy) methyl ] -12- (2, 3, 4, 6-tetra-O-acetyl- β -D-glucopyranosyl) -12, 13-dihydro-5H-pyrido [3 ', 2': 4, 5] pyrrolo [2, 3-a ] pyrrolo [3, 4-c ] carbazole-5, 7(6H) -dione

The product was obtained according to the procedure of example 1c, using the compound of example 7b as substrate.

Melting point 166-.

Infrared Spectrum (KBr), v_C＝O＝1710，1760cm^-1；ν_NH＝3360-3420cm^-1。

Example 8: 6- (hydroxymethyl) -12- (2, 3, 4, 6-tetra-O-acetyl- β -D-glucopyranosyl) -12, 13-dihydro-5H-pyrido [3 ', 2': 4, 5] pyrrolo [2, 3-a ] pyrrolo [3, 4-c ] carbazole-5, 7(6H) -dione

To a solution of the compound of example 7c (0.090 mmol) in 40 ml of anhydrous methanol and 20 ml of anhydrous ethyl acetate was added 10% palladium on carbon (60 mg). The reaction mixture was degassed twice and then stirred at room temperature under a hydrogen atmosphere (1 bar). After 17 hours, a further 10% palladium on carbon (31 mg) was added. The reaction mixture was degassed again and then placed under a hydrogen atmosphere for 21 hours. The mixture was filtered through celite, and the solid was washed with methanol and chloroform. After evaporation of the solvent, the residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate: 1/1) and the expected product is isolated.

Melting point 264 and 266 ℃.

Infrared Spectrum (KBr), v_C＝O＝1710，1760cm^-1；ν_NH＝3300-3600cm^-1。

Example 9: 12- (beta-D-glucopyranosyl-12, 13-dihydro-5H-pyrido [3 ', 2': 4, 5] pyrrolo [2, 3-a ] pyrrolo [3, 4-c ] carbazole-5, 7(6H) -2-dione

To a solution of the compound of example 8 (0.040 mmol) in 13ml of methanol was added 28% aqueous ammonium hydroxide (9 ml). The mixture was stirred at room temperature for 15 hours. After evaporation of the solvent, the residue was transferred into a water/ethyl acetate mixture and then filtered through a fritted glass filter. The crystals were washed successively with ethyl acetate and methanol to isolate the expected product.

Melting point is higher than 250 deg.C, and decomposing.

Infrared Spectrum (KBr), v_C＝O＝1720，1760cm^-1；ν_NH，OH＝3100-3600cm^-1。

Example 10 a: 1- [ (benzyloxy) methyl ] -3- [1- (2, 3, 4, 6-tetra-O-acetyl-beta-D-glucopyranosyl) -1H-pyrrolo [2, 3-b ] pyridin-3-yl ] -4- [1- (phenylsulfonyl) -1H-pyrrolo [2, 3-b ] pyridin-3-yl ] -1H-pyrrole-2, 5-dione

The product was obtained after silica gel separation according to the method of example 1a, using the compound of preparation C as substrate.

Melting point 108-.

Infrared Spectrum (KBr), v_C＝O＝1720，1760cm^-1。

Example 10 b: 1- [ (benzyloxy) methyl ] -3- [1- (2, 3, 4, 6-tetra-O-acetyl-beta-D-glucopyranosyl) -1H-pyrrolo [2, 3-b ] pyridin-3-yl ] -4- (1H-pyrrolo [2, 3-b ] pyridin-3-yl) -1H-pyrrole-2, 5-dione

The product was obtained according to the procedure of example 1b, using the compound of example 10a as substrate.

Melting point 127-.

Infrared Spectrum (KBr), v_C＝O＝1710，1750cm^-1；ν_NH＝3300-3500cm^-1。

Example 10 c: 6- [ (benzyloxy) methyl ] -12- (2, 3, 4, 6-tetra-O-acetyl- β -D-glucopyranosyl) -12, 13-dihydro-5H-pyrido [2, 3-b ] pyrido [3 ', 2': 4, 5] pyrrolo [3, 2-g ] pyrrolo [3, 4-e ] carbazole-5, 7(6H) -dione

The product was obtained according to the procedure of example 1c, using the compound of example 10b as substrate.

Melting point 194 ℃ and 196 ℃.

Infrared Spectrum (KBr), v_C＝O＝1690，1730cm^-1；ν_NH＝3300-3400cm^-1。

Example 11: 6- (hydroxymethyl) -12- (2, 3, 4, 6-tetra-O-acetyl- β -D-glucopyranosyl) -12, 13-dihydro-5H-pyrido [2, 3-b ] pyrido [3 ', 2': 4, 5] pyrrolo [3, 2-g ] pyrrolo [3, 4-e ] carbazole-5, 7(6H) -dione

To a solution of the compound from example 10c (0.090 mmol) in 4.5 ml dry methanol and 1.5 ml dry ethyl acetate was added 10% palladium on carbon (84.0 mg). The reaction mixture was degassed twice and then stirred at room temperature under a hydrogen atmosphere (1 bar) for 24 hours. After 24 hours, an additional 10% palladium on carbon (42.0 mg) was added. The reaction mixture was degassed again and then left under a hydrogen atmosphere for 24 hours. The mixture was filtered through celite, and the solid was washed with methanol and chloroform. After evaporation of the solvent, the residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate: 3/2) and the expected product is isolated.

The melting point is greater than 300 ℃.

Infrared Spectrum (KBr), v_C＝O1710，1760cm^-1；ν_NH＝3300-3600cm^-1。

Example 12: 12- (β -D-glucopyranosyl) -12, 13-dihydro-5H-pyrido [2, 3-b ] pyrido [3 ', 2': 4, 5] pyrrolo [3, 2-g ] pyrrolo [3, 4-c ] indole-5, 7(6H) -dione

To a solution of the compound of example 11 (0.053 mmol) in 15 ml of methanol was added 28% aqueous ammonium hydroxide (13 ml). The mixture was stirred at 40 ℃ for 21 hours. After evaporation of the solvent, the residue was transferred into a water/ethyl acetate mixture and then filtered through a fritted glass filter. The crystals were washed successively with ethyl acetate and methanol to isolate the expected product.

The melting point is greater than 300 ℃.

Infrared Spectrum (KBr), v_C＝O＝1710，1760cm^-1；ν_NH，OH＝3200-3600cm^-1。

Example 13: 6- [ (benzyloxy) methyl ] -12- (. beta. -D-glucopyranosyl) -12, 13-dihydro-5H-pyrido [2, 3-b ] pyrido [3 ', 2': 4, 5] pyrrolo [3, 2-g ] pyrrolo [3, 4-e ] indole-5, 7(6H) -dione

To a solution of the compound of example 10c (0.054 mmol) in 13ml of methanol was added 28% aqueous ammonium hydroxide (13 ml). The mixture was stirred at 40 ℃ for 19 hours. After evaporation of the solvent, the residue was transferred into a water/ethyl acetate mixture and then filtered through a fritted glass filter. The crystals were washed successively with ethyl acetate and methanol to isolate the expected product.

The melting point is greater than 300 ℃.

Infrared Spectrum (KBr), v_C＝O＝1700，1750cm^-1；ν_NH，OH＝3300-3600cm^-1。

Example 14 a: 3- [1- (2, 3, 4, 6-tetra-O-acetyl-beta-D-glucopyranosyl) -1H-pyrrolo [2, 3-b ] pyridin-3-yl ] -1-methyl-4- [1- (phenylsulfonyl) -1H-pyrrolo [2, 3-b ] pyridin-3-yl ] -1H-pyrrole-2, 5-dione

Using the compound of preparation D as a substrate, the product was obtained after silica gel chromatography according to the method of example 1 a.

Melting point 116-.

Example 14 b: 3- [1- (2, 3, 4, 6-tetra-O-acetyl-beta-D-glucopyranosyl) -1H-pyrrolo [2, 3-b ] pyridin-3-yl ] -1-methyl-4- (1H-pyrrolo [2, 3-b ] pyridin-3-yl) -1H-pyrrole-2, 5-dione

To a solution of the compound from example 14a (0.046 mmol) in 4 ml of dry tetrahydrofuran was added tetrabutylammonium fluoride solution (1.1M in tetrahydrofuran) (0.137 mmol). The reaction mixture was stirred at room temperature for 2.30 hours. After hydrolysis, the organic product was extracted with ethyl acetate. The organic phases were combined, dried over magnesium sulfate and filtered. After evaporation of the solvent, the residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate: 3/7) and the expected product is isolated.

Melting point 148-.

Infrared Spectrum (KBr), v_C＝O＝1700，1760cm^-1；ν_NH＝3300-3600cm^-1。

Example 14 c: 1-methyl-3- ([1- (beta-D-glucopyranosyl) -1H-pyrrolo [2, 3-b ] pyridin-3-yl ] -4- (1H-pyrrolo [2, 3-b ] pyridin-3-yl) -1H-pyrrole-2, 5-dione

To a solution of the compound of example 14b (0.054 mmol) in 14 ml of methanol was added 28% aqueous ammonium hydroxide (10 ml). The reaction mixture was stirred at room temperature for 26 hours. After evaporation of the solvent, the residue is purified by chromatography on silica gel (ethyl acetate/methanol: 9/1) and the expected product is isolated.

Melting point 195 ℃ and 197 ℃.

Infrared Spectrum (KBr), v_C＝O＝1700，1710cm^-1；ν_NH＝3200-3600cm^-1。

Example 14 d: 6-methyl-12- (2, 3, 4, 6-tetra-O-acetyl- β -D-glucopyranosyl) -12, 13-dihydro-5H-pyrido [2, 3-b ] pyrido [3 ', 2': 4, 5] pyrrolo [3, 2-g ] pyrrolo [3, 4-e ] carbazole-5, 7(6H) -dione

The product was obtained according to the procedure of example 1c, using the compound of example 14b as substrate.

The melting point is greater than 300 ℃.

Infrared Spectrum (KBr), upsilon_C＝O＝1703，1757cm^-1；υ_NH＝3373cm^-1。

Example 15: 6-methyl-12- (β -D-glucopyranosyl) -12, 13-dihydro-5H-pyrido [2, 3-b ] pyrido [3 ', 2': 4, 5] pyrrolo [3, 2-g ] pyrrolo [3, 4-e ] indole-5, 7(6H) -dione

To a solution of the compound of example 14c (0.066 mmol) in 40 ml of methanol was added 28% aqueous ammonium hydroxide (28 ml). The mixture was stirred at 55 ℃ for 26 hours. After evaporation of the solvent, the residue was transferred into a water/ethyl acetate mixture and then filtered through a fritted glass filter. The crystals were washed successively with ethyl acetate and methanol to isolate the expected product.

The melting point is greater than 300 ℃.

Infrared Spectrum (KBr), v_C＝O＝1650，1700cm^-1；ν_NH，OH＝3200-3600cm^-1。

Example 16 a: 3- {4- [1- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyl) -1H-pyrrolo [2, 3-b ] pyridin-3-yl ] -1-methyl-2, 5-dioxo-2, 5-dihydro-1H-pyrrol-3-yl } -1H-indole-1-carboxylic acid tert-butyl ester

To a solution of the compound of preparation E (0.491 mmol) in 15 ml of anhydrous tetrahydrofuran were added 2, 3, 4, 6-tetra-O-acetylglucopyranose (1.09 mmol) and triphenylphosphine (1.09 mmol). The reaction mixture was cooled to-78 ℃ and then DEAD (1.09 mmol) was added dropwise. The temperature was slowly raised to room temperature, and then the reaction mixture was further stirred for 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 distilled off. After purification by chromatography on silica gel (cyclohexane/ethyl acetate/triethylamine: 4/1/1%), the expected product is isolated.

Melting point 89-91 ℃.

Example 16 b: 3- (1H-indol-3-yl) -4- [1- (2, 3, 4, 6-tetra-O-acetyl-beta-D-glucopyranosyl) -1H-pyrrolo [2, 3-b ] pyridin-3-yl ] -1-methyl-1H-pyrrole-2, 5-dione

The compound from example 16a (0.114 mmol) was dissolved in 20 ml of formic acid. After stirring at room temperature for 24 hours, the solution was neutralized by dropwise addition of triethylamine and then a saturated aqueous solution of sodium hydrogencarbonate. The mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated aqueous sodium chloride solution, then dried over magnesium sulfate and filtered; the solvent was evaporated. After purification by chromatography on silica gel (cyclohexane/ethyl acetate: 1/1), the expected product is isolated.

Melting point 119-.

Infrared Spectrum (KBr), upsilon_C＝O＝1700，1752cm^-1；υ_NH＝3300-3500cm^-1。

Example 16 c: 13- (2, 3, 4, 6-tetra-O-acetyl- β -D-glucopyranosyl) -6-methyl-12, 13-dihydro-5H-pyrido [3 ', 2': 4, 5] pyrrolo [2, 3-a ] pyrrolo [3, 4-c ] carbazole-5, 7(6H) -dione

The product was obtained according to the procedure of example 1c, using the compound of example 16b as substrate.

Melting point 302-.

Infrared Spectrum (KBr), v_C＝O＝1700，1750cm^-1；ν_NH＝3200-3600cm^-1。

Example 17: 13- (β -D-glucopyranosyl) -6-methyl-12, 13-dihydro-5H-pyrido [3 ', 2': 4, 5] pyrrolo [2, 3-a ] pyrrolo [3, 4-c ] carbazole-5, 7(6H) -dione

To a solution of the compound of example 16c (0.067 mmol) in 20 ml of methanol was added 28% aqueous ammonium hydroxide (31 ml). The mixture was stirred at 65 ℃ for 22 hours. After evaporation of the solvent, the residue was transferred into a water/ethyl acetate mixture and then filtered through a fritted glass filter. The crystals were washed with ethyl acetate and the expected product was isolated.

The melting point is greater than 300 ℃.

Infrared Spectrum (KBr), v_C＝O＝1690，1750cm^-1；ν_NH＝3300-3600cm^-1。

Example 18: 13- (2, 3, 4, 6-tetra-O-acetyl- β -D-glucopyranosyl) -9-bromo-6-methyl-12, 13-dihydro-5H-pyrido [3 ', 2': 4, 5] pyrrolo [2, 3-a ] pyrrolo [3, 4-c ] carbazole-5, 7(6H) -dione

The product was obtained according to the procedure of example 4 using the compound of example 16c as a substrate.

Melting point 280 ℃ and 282 ℃.

Infrared Spectrum (KBr), v_C＝O＝1700，1760cm^-1；ν_NH＝3360-3400cm^-1。

Example 19: 13- (β -D-glucopyranosyl) -9-bromo-6-methyl-12, 13-dihydro-5H-pyrido [3 ', 2': 4, 5] pyrrolo [2, 3-a ] pyrrolo [3, 4-c ] carbazole-5, 7(6H) -dione

The product was obtained by following the procedure of example 4 using the compound of example 17 as a substrate.

The melting point is greater than 300 ℃.

Infrared Spectrum (KBr), v_C＝O＝1680，1760cm^-1；ν_NH，OH＝3300-3600cm^-1。

Example 20: 12, 13- (. beta. -D-glucopyranosyl) -5H-pyrido [2, 3-b ] pyrido [3 ', 2': 4, 5] pyrrolo [3, 2-g ] pyrrolo [3, 4-e ] indole-5, 7(6H) -dione

Step 1: 12- (2-O-tosyl- β -D-glucopyranosyl) -12, 13-dihydro-5H-pyrido [2, 3-b ] pyrido [3 ', 2': 4, 5] pyrrolo [3, 2-g ] pyrrolo [3, 4-e ] indole-5, 7(6H) -dione

To a solution of the compound of example 12 (0.17 mmol) in 10 ml of tetrahydrofuran were added 23.5 mg of potassium carbonate and 1.7 mmol of p-toluenesulfonyl chloride. The mixture was heated at reflux for 48 hours. After evaporation of the solvent, the residue was transferred into a water/ethyl acetate mixture and then filtered through a fritted glass filter. The crystals were washed successively with ethyl acetate and methanol to isolate the expected product.

Step 2: 12, 13- (. beta. -D-mannopyranosyl) -5H-pyrido [2, 3-b ] pyrido [3 ', 2': 4, 5] pyrrolo [3, 2-g ] pyrrolo [3, 4-e ] indole-5, 7(6H) -dione

To a solution of the compound obtained in step 1 (0.062 mmol) in 1.6 ml of dimethylformamide was added 0.62 mmol of sodium azide. The mixture was stirred at 70 ℃ for 6 min, then cooled, poured into water and extracted with ethyl acetate. The organic phase was washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution and dried over magnesium sulfate. The solvent was evaporated and the residue recrystallized, the expected product was isolated.

Example 21: 13- (β -D-glucopyranosyl) -6- [2- (diethylamino) ethyl ] -12, 13-dihydro-5H-pyrido [3 ', 2': 4, 5] pyrrolo [2, 3-a ] pyrrolo [3, 4-c ] carbazole-5, 7(6H) -dione hydrochloride

To a solution of the compound of production example F (0.102 mmol) in 6 ml of tetrahydrofuran was added dropwise N, N-diethylethylenediamine (0.153 mmol). The mixture was heated under reflux for 5 days, stored in the dark, then cooled and transferred to 1N aqueous hydrochloric acid (40 ml). The organic product was extracted with ethyl acetate. The aqueous phase was collected and the pH adjusted to 12 by addition of saturated sodium bicarbonate solution. The organic product was extracted with ethyl acetate. The organic phases are combined, dried over magnesium sulfate and filtered, and the solvent is distilled off. To a solution of the resulting amine cooled to 0 ℃ in 500. mu.l of methanol was added dropwise a 1N aqueous hydrochloric acid solution (200. mu.l). The mixture was stirred for 30 minutes. The solvent was evaporated and the desired product isolated.

The melting point is greater than 300 ℃.

Example 22 a: 1-methyl-3- [1- (2, 3, 4, 6-tetra-O-acetyl-beta-D-glucopyranosyl) -1H-indol-3-yl ] -4- [1- (phenylsulfonyl) -1H-pyrrolo [2, 3-b ] pyridin-3-yl ] -1H-pyrrole-2, 5-dione

The product was obtained according to the procedure of example 1a, using the compound of preparation G as substrate.

Example 22 b: 1-methyl-3- [1- (2, 3, 4, 6-tetra-O-acetyl-beta-D-glucopyranosyl) -1H-indol-3-yl ] -4- (1H-pyrrolo [2, 3-b ] pyridin-3-yl) -1H-pyrrole-2, 5-dione

The product was obtained according to the procedure of example 1b, using the compound of example 22a as substrate.

Example 22 c: 6-methyl-12- (2, 3, 4, 6-tetra-O-acetyl- β -D-glucopyranosyl) -12, 13-dihydro-5H-pyrido [3 ', 2': 4, 5] pyrrolo [2, 3-a ] pyrrolo [3, 4-c ] carbazole-5, 7(6H) -dione

The product was obtained according to the procedure of example 1c, using the compound of example 22b as substrate.

Example 23: 6-methyl-12- (β -D-glucopyranosyl) -12, 13-dihydro-5H-pyrido [3 ', 2': 4, 5] pyrrolo [2, 3-a ] pyrrolo [3, 4-c ] carbazole-5, 7(6H) -dione

The product was obtained by following the procedure of example 15 using the compound of example 22c as a substrate.

Example 24 a: 3- {4- [1- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyl) -1H-pyrrolo [3, 2-c ] pyridin-3-yl ] -1-methyl-2, 5-dioxo-2, 5-dihydro-1H-pyrrol-3-yl } -1H-indole-1-carboxylic acid tert-butyl ester

The product was obtained according to the procedure of example 16a, using the compound of preparation H as substrate.

Example 24 b: 3- (1H-indol-3-yl) -4- [1- (2, 3, 4, 6-tetra-O-acetyl-beta-D-glucopyranosyl) -1H-pyrrolo [3, 2-c ] pyridin-3-yl ] -1-methyl-1H-furan-2, 5-dione

The product was obtained by following the procedure of example 16b, using the compound of example 24a as substrate.

Example 24 c: 13- (2, 3, 4, 6-tetra-O-acetyl- β -D-glucopyranosyl) -6-methyl-12, 13-dihydro-5H-pyrido [3 ', 4': 4, 5] pyrrolo [2, 3-a ] pyrrolo [3, 4-c ] carbazole-5, 7(6H) -dione

The product was obtained according to the procedure of example 16c, using the compound of example 24b as substrate.

Example 25: 13- (β -D-glucopyranosyl) -6-methyl-12, 13-dihydro-5H-pyrido [3 ', 4': 4, 5] pyrrolo [2, 3-a ] pyrrolo [3, 4-c ] carbazole-5, 7(6H) -dione

The product was obtained by following the procedure of example 17 using the compound of example 24c as a substrate.

Example 26: 6-amino-13- (β -D-glucopyranosyl) -12, 13-dihydro-5H-pyrido [3 ', 2': 4, 5] pyrrolo [2, 3-a ] pyrrolo [3, 4-c ] carbazole-5, 7(6H) -dione

A mixture of the compound of preparation F (0.04 mmol) and hydrazine hydrate (384. mu.l) was stirred for 24 hours. Water (15 ml) was added followed by 1N aqueous hydrochloric acid (20 ml). The precipitate is filtered and washed with water to isolate the desired product.

The melting point is greater than 300 ℃.

Infrared Spectrum (KBr), v_C＝O＝1700，1750cm^-1；ν_NH＝3320-3500cm^-1。

Example 27: 13- (6-chloro-6-deoxy- β -D-glucopyranosyl) -6-methyl-12, 13-dihydro-5H-pyrido [3 ', 2': 4, 5] pyrrolo [2, 3-a ] pyrrolo [3, 4-c ] carbazole-5, 7(6H) -dione

To a solution of the compound of example 17 (0.353 mmol) in 2.5 ml of pyridine were added a triphenylphosphine solution (1.415 mmol) and carbon tetrachloride (0.707 mmol). The mixture was stirred at room temperature for 2.30 hours, and then poured into water. The mixture was transferred to ethyl acetate, and the organic layer was washed successively with a 1N aqueous hydrochloric acid solution, water and a saturated sodium bicarbonate solution. After evaporation of the solvent, the residue is purified by chromatography on silica gel (ethyl acetate) and the expected product is isolated.

Melting point 275 ℃ and 280 ℃ and decomposing.

Infrared Spectrum (KBr), v_C＝O＝1695，1750cm^-1；ν_NH，OH＝3100-3600cm^-1。

Pharmacological study of the Compounds of the invention

Example 28: in vitro Activity

Murine leukemia L1210

Murine leukemia L1210 was used for in vitro testing. Cells were cultured in RPMI 1640 complete medium at pH 7.4 containing 10% fetal bovine serum, 2mM glutamine, 50 units/ml penicillin, 50. mu.g/ml streptomycin and 10mM Hepes. The cells were distributed on microplates and exposed to cytotoxic compounds for 4 double cycles, or 48 hours. The number of viable cells was determined by colorimetric quantification means of the Microculture Tetrazolium Assay (J.Carmichael et al.. cancer Res..47.936-942, (1987)). IC for result₅₀Expressed as the concentration of cytotoxic agent that inhibits proliferation of 50% of the treated cells. All compounds of the invention showed good cytotoxicity for this cell line. By way of illustration, the IC's of the compounds of examples 4, 5, 9 and 12₅₀All values are better than 10^-7M。

Human cell line

The compounds of the invention were tested on human cell lines following the same experimental protocol as described for murine leukemia L1210, except that the incubation time was 4 days instead of 2 days. For example, the compounds of examples 3, 4, 5, 15, 17 and 19 were used for the following cell lines IC₅₀Values are all less than 1 μ M: neuroblastoma SK-N-MC, squamous cell carcinoma a431 and small cell lung carcinoma H69. Each result clearly demonstrates the strong antitumor potential of the compounds of the present invention.

Example 29: effect on cell cycle

L1210 cells were cultured at 37 ℃ for 21 hours in the presence of various concentrations of test compounds. The cells were then fixed with 70% (v/v) ethanol, washed twice in PBS, and incubated for 30 min at 20 ℃ in PBS containing 100. mu.g/ml RNAse and 50. mu.g/ml propidium iodide. The results are expressed as the percentage of cells accumulated in G2+ M after 21 hours compared to the control group (control: 20%). The compounds of the invention are particularly attractive. For example, the compounds of examples 3, 4 and 5, after 21 hours, at concentrations less than 0.5 μ M, resulted in at least 80% of the cells accumulating during the G2+ M phase.

Example 30: the pharmaceutical composition comprises: injectable solution

Compound example 310 mg

25 ml of distilled water for injectable preparation

Claims

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

wherein:

Wherein:

R₆and R₇Which may be the same or different, each represents a group selected from: hydrogen atom and straight or branched chain (C)₁-C₆) Alkyl, aryl and aryl- (C)₁-C₆) Alkyl (wherein the alkyl moiety may be straight or branched), or R₆+R₇Together with the nitrogen atom to which they are attached form a saturated, monocyclic or bicyclic heterocyclic ring optionally containing 5 to 10 atoms, in which the second heteroatom is selected from oxygen and nitrogen and optionally from linear or branched (C)₁-C₆) Alkyl, aryl- (C)₁-C₆) Alkyl (wherein the alkyl moiety is linear)Or branched), hydroxy, straight or branched (C)₁-C₆) Alkoxy, amino, straight or branched mono (C)₁-C₆) Alkylamino, and di (C)₁-C₆) Alkylamino (wherein each alkyl group may be straight or branched) groups,

t represents an integer of 0 to 2,

R₃represents a group selected from: hydrogen atom and straight or branched chain (C)₁-C₆) Alkyl, aryl- (C)₁-C₆) Alkyl (where the alkyl moiety may be linear or branched), cycloalkyl- (C)₁-C₆) -alkyl (where the alkyl moiety may be linear OR branched), -OR₆，-NR₆R₇，-O-T₂-NR₆R₇，-NR₆-T₂-NR₆R₇Straight or branched chain (C)₁-C₆) Hydroxyalkylamino, di ((C)₁-C₆) Hydroxyalkyl) amino (wherein each alkyl moiety may be straight or branched), -C (O) -R₆and-NH-C (O) -R₆And one OR more same OR different groups selected from halogen atoms and cyano, nitro, -OR₆，-NR₆R₇，-CO₂R₆，-C(O)R₆Straight or branched chain (C)₁-C₆) Hydroxyalkylamino, di ((C)₁-C₆) Hydroxyalkyl) amino (wherein each alkyl moiety may be straight or branched), and-C (O) -NHR₆Group (wherein R)₆，R₇And T₂As defined above) substituted straight or branched chain (C)₁-C₆) An alkylene chain, which is a linear chain of alkylene,

y represents a hydrogen atom, or

Y₁represents a hydrogen atom, or

Q₁，Q₂represents a hydrogen atom, or

R₄represents a group of formula (a):

wherein:

R_a，R_band R_cAnd may be the same or different, each independently represents a group selected from: hydrogen atom and halogen atom, and hydroxyl group, straight chain or branched chain (C)₁-C₆) Alkoxy, aryloxy, aryl (C)₁-C₆) Alkoxy (wherein the alkoxy moiety is linear or branched), linear or branched (C)₁-C₆) Alkyl, aryl- (C)₁-C₆) Alkyl (wherein the alkyl moiety isLinear or branched), aryl, -NR₆R₇(wherein R is₆And R₇As defined above), azido, -N ═ NR₆(wherein R is₆As defined above), and-O-C (O) -R₈Wherein R is₈Represents a straight chain or branched chain (C)₁-C₆) Alkyl (optionally substituted by a group selected from halogen, hydroxy, amino, straight or branched chain (C)₁-C₆) Alkylamino, and di (C)₁-C₆) Alkylamino (wherein each alkyl moiety may be linear or branched) substituted with one or more substituents, aryl- (C)₁-C₆) Alkyl (where the alkyl moiety is straight or branched), cycloalkyl or heterocyclylalkyl,

n is a number of 0 or 1,

wherein:

R_a，R_b，R_cand R_dThe definition is as above-mentioned,

n is a number of 0 or 1,

aryl is understood to mean phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl or 2, 3-indanyl, each radical optionally being composed of one or more identical or different radicalsSelected from halogen, straight or branched (C)₁-C₆) Alkyl, straight or branched (C)₁-C₆) Trihaloalkyl, hydroxy, straight or branched chain (C)₁-C₆) Alkoxy, and optionally one or two straight or branched chains (C)₁-C₆) Alkyl substituted amino groups.

2. A compound according to claim 1, characterized in that X and Y together with the carbon atom to which they are bound form a carbonyl group, and X₁And Y₁Together with the carbon atoms to which they are bound, form carbonyl groups, their enantiomers and diastereomers, and addition salts with pharmaceutically acceptable acids or bases.

3. A compound according to claim 1, characterized in that it is a compound represented by formula (IA):

wherein R is₁，R₂，R₃，R₅，R_a，R_b，R_c，R_d，W₁And W₂As defined for formula (I), their enantiomers and diastereomers, and addition salts with pharmaceutically acceptable acids or bases.

4. A compound according to claim 1 or 3, characterized in that it is a compound represented by formula (IB):

wherein R is₁，R₂，R₃，R₅，R_a，R_b，R_cAnd R_dAs defined for formula (I), their enantiomers and diastereomers, and addition salts with pharmaceutically acceptable acids or bases.

5. A compound according to claim 1 or 3, characterized in that it is a compound represented by formula (IC):

6. A compound according to claim 1 or 3, characterized in that it is a compound represented by formula (ID):

7. A compound according to claim 1, characterized in that it is a compound represented by formula (IE):

wherein R is₁，R₂，R₃，R₅，R_b，R_c，R_d，n，W₁And W₂As defined for formula (I), their enantiomers and diastereomers, and addition salts with pharmaceutically acceptable acids or bases.

8. A compound according to claim 1, characterized in that it is a compound represented by formula (IF):

9. A compound according to claim 1 or 8, characterized in that it is a compound represented by formula (IG):

10. A compound according to claim 1 or 8, characterized in that it is a compound represented by formula (IH):

11. A compound according to claim 1 or 8, characterized in that it is a compound represented by formula (IJ):

12. A compound of formula (I) according to claim 4, 5, 9 or 10, characterized in that the pyridine ring is unsubstituted.

13. A compound of formula (I) according to claim 1, characterized in that R₄The group is a group of the formula:

their enantiomers and diastereomers, and addition salts with a pharmaceutically acceptable acid or base.

14. A compound of formula (I) according to claim 1, characterized in that R₂The radicals are hydrogen atoms, their enantiomers and diastereomers, and addition salts with pharmaceutically acceptable acids or bases.

15. A compound of formula (I) according to claim 1, characterized in that R₁The group is hydrogen atom, halogen atom or nitro, their enantiomers and diastereoisomers, and addition salts with pharmaceutically acceptable acid or base.

16. Compounds of formula (I) according to claim 1, which are:

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

17. A process for the preparation of a compound of formula (I) according to claim 1, characterized in that a compound of formula (II) is used

The compound is used as a raw material:

wherein W₁As defined in formula (I),

to obtain a compound of formula (IV):

wherein X, Y, X₁，Y₁BOM and W₁The definition is as above-mentioned,

wherein BOM, X, Y, X₁，Y₁And W₁The definition is as above-mentioned,

wherein W₂As defined in formula (I),

to give a compound of formula (VII):

a compound of formula (VII) with a compound of formula (a) in the presence of triphenylphosphine and diethyl azodicarboxylate₁) Compound reaction:

wherein R is_a，R_b，R_c，R_dAnd n is as defined for formula (I),

wherein BOM, X, Y, X₁，Y₁，W₁，W₂，R_a，R_b，R_c，R_dAnd n is as defined above, and Q₁And Q₂As defined in formula (I),

the compound of formula (I/d) is optionally substituted with:

treatment with a compound of formula (VIII) in a basic medium:

R′₅-Hal (VIII)，

wherein Hal represents a halogen atom, R'₅As defined for R in formula (I)₅Except for the hydrogen atom, the oxygen atom,

the sum of the compounds of formulae (I/h), (I/k) and (I/n) forms the compound of formula (I/o):

optionally reacting a compound of formula (IX) with a compound of formula (X):

R_3a-NH₂ (X)，

wherein R is_3aAs defined for R in formula (I)₃With the exception of the hydrogen atom(s),

the compounds of formulae (I/a) to (I/R), which constitute the sum of the compounds of formula (I), may, if desired, be purified according to conventional purification techniques, if desired be separated into their different isomers according to conventional separation techniques, and if desired be modified in accordance with customary methods for organic synthesis in the field of carbohydrate chemistry for its substituent R_a，R_b，R_cAnd R_dAnd if desired, converted into their addition salts with pharmaceutically acceptable acids or bases.

18. Pharmaceutical compositions containing as active principle at least one compound of formula (I) according to any one of claims 1 to 16, alone or in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers.

19. A pharmaceutical composition according to claim 18 for use as a medicament in the treatment of cancer.

20. A compound of formula (IX):

useful as synthetic intermediates for the preparation of compounds of formula (I).