Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
  • C07H15/20—Carbocyclic rings
  • C07H15/24—Condensed ring systems having three or more rings
  • C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• the present invention relates to new derivatives of pyrido-pyrido- ⁇ yrrolo [3,2-g] pyrrolo [3,4-e] -indole and pyrido-pyrrolo [2,3 - «] py ⁇ : olo [3,4-c ] carbazole; their preparation process and the pharmaceutical compositions containing them.
• the needs of cancer therapy require the constant development of new antiproliferative agents, with the aim of obtaining both more active and better tolerated drugs.
• the compounds of the present invention have in particular anti-tumor properties, thus making them useful in the treatment of cancers.
• Patent applications WO95 / 07910 and WO96 / 04906 describe indole derivatives and claim them on the one hand for their antiviral activity and on the other hand for the treatment and prevention of restenosis.
• Patent applications WO00 / 47583, O97 / 21677 and WO96 / 11933 present cyclopenta [g] pyrrolo [3,4-e] indole derivatives fused by the indole part and the cyclopentene part of the derivatives, to an aromatic ring system or non-aromatic, and optionally comprising heteroatoms. These compounds have pharmacological activities making them particularly useful in the treatment of cancer cells.
• the compounds of the present application are widely distinguished from those described in the prior art and have particular pharmacological properties, and in particular a surprising activity in-vivo and in-vitro on various cell lines making them useful for the treatment of cancers.
• the present invention relates to the compounds of formula (I): in which :
• Wj, W 2 each represent, with the carbon atoms to which they are linked, a phenyl group or a pyridinyl group, it being understood that at least one of the Wi or W 2 groups represents a pyridinyl group,
• U represents a single bond or an alkylene chain (C ⁇ -C 6 ) linear or branched, optionally substituted by one or more groups, identical or different, chosen from halogen and hydroxy, and / or optionally containing one or more unsaturations
• V represents a group selected from hydrogen, halogen, cyano, nitro, azido, alkyl (-This) linear or branched, aryl, arylalkyl (-C ⁇ ) linear or branched, hydroxy, alkoxy (Ci-C O) linear or branched, aryloxy, arylalkoxy (C C ⁇ ) linear or branched, formyl, carboxy, aminocarbonyl, N ⁇ Z ,
• ⁇ R 6 and R 7 identical or different, each represent a group chosen from a hydrogen atom, linear or branched (Ci-C 6 ) alkyl, aryl, and linear or branched (CrC 6 ) arylalkyl, or
• R 6 + R 7 together form, with the nitrogen atom which carries them, a heterocycle of 5 to
• T ⁇ represents a group chosen from linear or branched (Ci-C 6 ) alkyl, aryl, linear or branched (Ci-C ⁇ ) alkyl, a chain linear or branched alkylene (CrC 6 ) substituted by a group chosen from -OR 6 , -NR 6 R 7 , -CO 2 R 6 , -C (O) R 6 and -C (
• R 3 represents a group chosen from hydrogen atom, linear or branched (C Î -C ⁇ ) alkyl group, linear or branched aryl, arylalkyl (C ⁇ -C 6 ), cycloalkyl, cycloalkylalkyl (dC 6 ), -OR 6 , -NReR 7 , -OT 2 -NR 6 R 7 , -NRe-T 2 - NR 6 R 7 , hydroxyalkylamino (dC ô ) linear or branched, di (hydroxyalkyl) amino (Ci- C 6 ) linear or branched, -C (O) -R 6 , -NH-C (O) -R 6 , and a linear or branched (Ci-C 6 ) alkylene chain, substituted by one or more groups, identical or different, chosen from atoms halogen, cyano, nitro, -OR 6 , -NR 6 R 7 groups ,
• X represents a group chosen from hydrogen atom, hydroxy group, linear or branched alkoxy (QC ⁇ ), mercapto, and linear or branched alkylthio (Q-Ce),
• Y represents a hydrogen atom
• Xj represents a group chosen from hydrogen atom, hydroxy group, linear or branched (Ci-C 6 ) alkoxy, mercapto, and linear or branched alkylthio (Ci-Ce),
• R 4 represents a group of formula (a)
• R 4 and, R 5 represent together, on the condition that in this case Qj and Q 2 together form an aromatic bond, a group of formula (b) or (c):
• R a , Rb, Rc and R are as defined above, • n takes the value 0 or 1,
• aryl a phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl or indanyl group, each of these groups being optionally substituted by one or more groups, identical or different, chosen from halogen, (Ci-C 6 ) alkyl linear or branched, trihaloalkyl (Ci-C 6 ) linear or branched, hydroxy, alkoxy (Ci-C 6 ) linear or branched, and amino optionally substituted by one or two alkyl groups (Ci-C 6 ) linear or branched.
• pharmaceutically acceptable bases non-limiting mention may be made of sodium hydroxide, potassium hydroxide, triethylamine, tertbutylamine, etc.
• the preferred compounds of the invention are those for which X and Y together form, with the carbon atom which carries them, a carbonyl group, and Xi and Yi together form with the carbon atom which carries them, a carbonyl group .
• the preferred compounds of the invention are the compounds of formula (I) corresponding more particularly to the formula (LA:
• Ri, R 2 , R, R 5 , R a , R, R c , R d , Wi and W 2 are as defined in formula (I).
• the preferred compounds of the invention are the compounds of formula (I) corresponding more particularly to the formula (IB):
• the preferred compounds of the invention are the compounds of formula (I) corresponding more particularly to the formula (IC):
• Ri, R, R 3 , R 5 , R a , R b , R c and R d are as defined in formula (I).
• the preferred compounds of the invention are the compounds of formula (I) corresponding more particularly to the formula (ID):
• R 15 R 2 , R 3 , R 5 , R a , R b , R c and d are as defined in formula (I).
• the preferred compounds of the invention are the compounds of formula (IE): in which, Ri, R 2 , R 3 , R 5 , R b , R c , R d , n, Wi and W 2 are as defined in formula (I).
• the preferred compounds of the invention are the compounds of formula (IF):
• the preferred compounds of the invention are the compounds of formula (IG): in which Ri, R 2 , R 3 , R 5 , R a , R b , R c and R d are as defined in formula (I).
• the preferred compounds of the invention are the compounds of formula (IH):
• the preferred compounds of the invention are the compounds of formula (IJ): in which Ri, R 2 , R 3 , R 5 , R a , R, R c and R d are as defined in formula (I).
• the preferred pyridine ring according to the invention is the unsubstituted ring.
• R 4 group is the glucopyranosyl group of formula:
• the preferred R 2 group according to the invention is the hydrogen atom.
• the preferred Ri groups according to the invention are the hydrogen atom, the halogen atoms, and the nitro group.
• the preferred compounds according to the invention are:
• the present invention also relates to the process for the preparation of the compounds of formula
• R b , R c , R d and n are as defined above,
• the compounds of formula (II), (III), (VI), (ai), (VIII) and (X) are either commercial compounds or are obtained according to conventional methods of organic synthesis easily accessible to humans from job.
• the compound of formula (IX) is useful as a synthesis intermediary for obtaining the compounds of formula (I).
• the compounds of formula (I) exhibit particularly advantageous anti-tumor properties.
• the characteristic properties of these compounds allow their use in therapy as anti-tumor agents.
• the present invention also relates to pharmaceutical compositions containing as active ingredient at least one compound of formula (I), its optical isomers, or one of its addition salts with a pharmaceutically acceptable acid or base, alone or in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or vehicles.
• compositions according to the invention particular mention will be made of those which are suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), per or transcutaneous, nasal, rectal, perlingual, ocular or respiratory administration, and in particular simple or coated tablets, sublingual tablets, capsules, capsules, suppositories, creams, ointments, dermal gels, injectable or drinkable preparations, aerosols, eye or nasal drops, etc.
• the pharmaceutical compositions containing as active ingredient said compounds of formula (I), are therefore particularly useful for the treatment of cancers.
• the useful dosage varies according to the age and weight of the patient, the route of administration, the nature and severity of the condition, and the taking of any associated treatments and ranges from 1 mg to 500 mg in one or several doses per day.
• Stage A 1 - [(benzyloxy) methyl] -3-bromo-4- (1H-indol-3-yl) -lH-pyrrole-2,5-dione
• ethylmagnesium bromide is prepared from magnesium (6.75 mmol) suspended in bromoethane (6.75 mmol) and dry tetrahydrofuran (5 ml). The solution is stirred for 15 minutes at room temperature and then heated at 40 ° C for 20 minutes. A solution of indole (6.75 mmol) in 40 ml of dry tetrahydrofuran is then added dropwise.
• a solution of ethylmagnesium bromide is prepared from magnesium (6.00 mmol) suspended in bromoethane (6.00 mmol) and dry tetrahydrofuran (2.5 ml). The solution is stirred for 1 hour at room temperature then 7-azaindole (6.00 mmol), dissolved in 20 ml of anhydrous toluene, is added dropwise. After 1.5 hours of stirring at room temperature, a solution of N-benzyloxymethyl-2,3-dibromomaleimide (2.01 mmol), in 20 ml of anhydrous toluene, is added dropwise.
• the product is obtained according to the process of stage B of preparation A using the product obtained in preceding stage A as a substrate. Melting point ⁇ 123-125 ° C.
• a solution of ethylmagnesium bromide is prepared from magnesium (0.62 mmol) suspended in bromoethane (0.62 mmol) and dry tetrahydrofuran (0.4 ml). The solution is stirred for 15 minutes at room temperature and then heated at 40 ° C for 20 minutes. A solution of indole (0.65 mmol) in 3 ml of anhydrous toluene is then added dropwise. After 1 hour of stirring at 40 ° C, the reaction medium is cooled, then a solution of the compound obtained in stage B (0.254 mmol), in 5 ml of anhydrous toluene, is added dropwise.
• the reaction mixture is left under stirring for 15 hours, then hydrolyzed with a saturated aqueous solution of ammonium chloride.
• Stage B 3-bromo-1-methyl-4- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -1H-pyrrole-2,5,5-dione
• the organic product is extracted with ethyl acetate, then the combined organic phases, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and filtered. After evaporation of the solvent, and purification of the residue by chromatography on silica gel (cyclohexane / ethyl acetate: 4/1), the expected product is isolated.
• a solution containing 1.445 g of indole dissolved in 29 ml of dry tetrahydrofuran is brought to between -20 and -10 ° C under argon, then 26 ml of LiHMDS (1 M in hexane) are added dropwise over 15 minutes. After 45 minutes at -10 ° C, the solution is diluted with 15 ml of additional tetrahydrofuran and a solution containing 2 g of N-methyl-2,3-dibromomaleimide dissolved in 17 ml of tetrahydrofuran is added dropwise over 30 minutes.
• reaction is stopped by the addition at 0 ° C of 50 ml of a 0.3N hydrochloric acid solution.
• the reaction mixture is extracted with ethyl acetate, the organic phases washed with a saturated NaCl solution, dried over MgSO 4 and then evaporated under reduced pressure.
• the desired product is precipitated with methanol. Melting point - 167-168 ° C.
• Stage B 3- (4-bromo-1-methyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl) -lH-indole-1-tert-butyl carboxylate
• Stage B 13- ( ⁇ -D-glucopyranosyl) -12,13-dihydrofuro [3,4-c] pyrido [3 ', 2': 4,5] pyrrolo [2,3-a] carbazole-5, 7 -dione
• the product is obtained according to the method of example le using the compound of stage A above as substrate.
• the product is obtained according to the process of stage C of preparation B, using as product the product obtained in stage B of preparation D.
• Example la l - [(benzyloxy) methyl] -3- [l- (2,3,4,6-tetra-O-acetyl- 3-D- gIucopyranosyl) -l / f-pyrrolo [2,3- £ ] pyridin-3-yI] -4- [l- (phenylsulfonyl) -l-fiT-indol-3-yl] -lH-pyrrole-2,5-dione
• Example 1b l - [(benzyloxy) methyl] -3- (1H-indol-3-yl) -4- [l- (2,3,4,6-tetra-O-acetyl-
• Example la To a solution of the ⁇ -glycosylated compound of Example la (0.565 mmol) dissolved in 20 ml of dry tetrahydrofuran, is added a solution of tetrabutylammom ' um fluoride (1.1M in tetrahydrofuran) (1.86 mmol). The reaction mixture is stirred for 2.30 hours at room temperature. After hydrolysis, the organic product is extracted with ethyl acetate. The organic phases are 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) allowing the expected product to be isolated.
• silica gel cyclohexane / ethyl acetate: 2/3
• Example 6a l - [(benzyloxy) methyl] -3- (1H-indol-3-yl) -4- [l- (2,3,4,6-tetra-O-acetyl- ûr-D-glucopyranosyl) -lH-pyrrolo [2,3-6] pyridin-3-yl] -lH-pyrrole- 2,5-dione
• Example 6b 6 - [(benzyloxy) methyl] -13- (2,3,4,6-tetra-0-acetyl- ⁇ -D- glucopyranosyl) -12,13-dihydro-5H-pyrido [3 ', 2 , : 4.5] pyrrolo [2,3- ⁇ ] pyrrolo [3,4-c] carbazole-5,7 (6H) -dione
• the product is obtained according to the method of example le
• Example 7a l - [(benzyloxy) methyl] -3- [l- (2,3,4,6-tetra-O-acetyl - ⁇ - D- glucopyranosyl) -lH-indol-3-yl] -4- [1- (phenylsulfonyl) -1H- pyrrolo [2,3-6] pyridin-3-yl] -li-pyrrole-2,5-dione
• Example 7b l - [(benzyloxy) methyl] -3- [l- (2,3,4,6-tetra-O-acetyl-> SD-glucopyranosyl) -lH-indol-3-yl] -4- ( l J H-pyrrolo [2,3-b] pyridin-3-yl) - l / f-pyrrole ⁇ S-dione
• Example 7c 6 - [(benzyloxy) methyl] -12- (2,3,4,6-tetra-O-acetyl-yf? -D- glucopyranosyI) -12,13-dib.ydro-5H-pyrido [3 ', 2': 4.5] pyrrolo [2,3- ⁇ ] pyrrolo [3,4-c] carbazole-5,7 (6H) -dione
• the product is obtained according to the method of example le using the compound of example 7b as a substrate.
• Example 8 6- (hydroxymethyl) -12- (2,3,4,6-tetra-O-acetyl ⁇ D-glucopyranosyl) - 12,13-dihydro-5H-pyrido [3 ', 2: 4, 5] pyrrolo [2,3- ⁇ ] 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 dry methanol and
• Example 10a l - [(benzyloxy) methyl] -3- [l- (2,3,4,6-tetra-0-acetyl-> SD-glucopyranosyl) -li-pyrrolo [2,3-6] pyridin- 3-yl] -4- [1- (phenylsulfonyl) -lH-pyrrolo [2,3-6] pyridin-3-yl] -lfl-pyrrole-2,5- dione
• Example 10b l - [(benzyloxy) methyl] -3- [l- (2,3,4,6-tetra-O-acetyl - ⁇ - D- glucopyranosyl) -lH r -pyrrolo [2,3-6] pyridin-3-yl] -4- (l J H r -pyrrolo [2,3-ô] pyridin-3-yl) -lH-pyrrole-2,5-dione
• the product is obtained according to the method of Example 1b using the compound of Example 10a as a substrate.
• Example 10c 6 - [(benzyloxy) methyl] -12- (2,3,4,6-tetra-O-acetyl- ⁇ D- gmcopyranosyl) -12,13-dihydro-5i ⁇ -pyrido [2,3- £ ] pyrido [3 ', 2': 4.5] pyrrolo [3,2 - ⁇ ] pyrrolo [3,4-e] indole-5,7 (6H) -dione
• the product is obtained according to the method of example le using the compound of example 10b as a substrate.
• Example 11 6- (hydroxymethyl) -12- (2,3,4,6-tetra-O-acetyl - & - D-glucopyranosyl) - 12,13-dihydro-5H-pyrido [2,3-ô] pyrido [3 ', 2 ! : 4.5] pyrrolo [3,2- ⁇ ] pyrrolo [3,4-e] indole-5,7 (6H) -dione
• Example 12 12- ( ⁇ D-glucopyranosyl) -12,13-dihydro-5 J H-pyrido [2,3-ô] pyrido [3 ', 2': 4,5] pyrrolo [3,2-g] pyrrolo [3,4-e] indole-5,7 (6H) -dione
• Example 13 6 - [(benzyloxy) methyl] -12- ( ⁇ D-glucopyranosyl) -12,13-dihydro-5iî- pyrido [2,3-ô] pyrido [3 ', 2': 4,5] pyrrolo [3,2-gJpyrrolo [3,4-e] indole- 5,7 (6H) -dione
• Example 10c To a solution of the compound of Example 10c (0.054 mmol) dissolved in 13 ml of methanol is added a 28% aqueous solution of ammonium hydroxide (13 ml). The mixture is stirred for 19 hours at 40 ° C. After evaporation of the solvents, the residue is taken up in a water / ethyl acetate mixture, then filtered through a frit. The crystals are washed successively with ethyl acetate and then methanol, allowing the expected product to be isolated. Melting point> 300 ° C.
• Example 14a 3- [1- (2,3,4,6-tetra-O-acetyl-JD-glucopyranosyl) -1H-pyrrolo [2,3-ô] pyridin-3-yl] -1-methyl-4 - [1- (phenylsulfonyl) -1H-pyrroIo [2,3- £] pyridin-3-yl] -1H-pyrrole-2,5-dione
• Example 14b 3- [1- (2,3,4,6-tetra-O-acetyl- i ff-D-glucopyranosyl) -lH r -pyrrolo [2,3-ô] pyridin-3-yl] -l -methyl-4- (1H-pyrrolo [2,3-6] pyridin-3-yl) -lH r - pyrrole-2,5-dione
• Example 14c 1-methyl-3- [1 - (yS-D-glucopyr nosyl) -lH-pyrrolo [2,3-b] pyridin-3-yl] - 4- (1H-pyrrolo [2,3- ⁇ ] pyridin-3-yl) -lh-pyrrole-2,5-dione
• Example 14d 6-methyl-12- (2,3,4,6-tetra-O-acetyl-? -D-glucopyranosyl) -12,13- dihyd o-SH-pyridop ⁇ -AJ ridoP ' ⁇ ' ⁇ jSJ yrroloP ⁇ - ⁇ l yrrolop ⁇ -e] indole-5,7 (6fi) -dione
• the product is obtained according to the method of example le, using the compound of example 14b as a substrate.
• Example 15 6-methyl-12 - ( ⁇ - D-glucopyranosyl) -12,13-dil ⁇ ydro-5H r -pyrido [2,3-ô] pyrido [3 ', 2': 4,5] pyrrolo [3, 2 - #] pyrrolo [3,4-e] indole-5,7 (6H) -dione
• Example 14c To a solution of the compound of Example 14c (0.066 mmol) dissolved in 40 ml of methanol is added a 28% aqueous solution of ammonium hydroxide (28 ml). The mixture is stirred for 26 hours at 55 ° C. After evaporation of the solvents, the residue is taken up in a water / ethyl acetate mixture, then filtered through a frit. The crystals are washed successively with ethyl acetate and then methanol, allowing the expected product to be isolated.
• Example 16a 3- ⁇ 4- [1- (2,3,4,6-tetra-O-acetyl- ⁇ D-glucopyranosyl) -1H-pyrroIo
• Example 16c 13- (2,3,4,6-tetra-O-acetyl - ⁇ - D-glucopyranosyl) -6-methyl-12,13- dihydro-5J ⁇ T-pyrido [3 ', 2': 4,5 ] pyrrolo [2,3- ⁇ ] pyrrolo [3,4-c] carbazole- 5,7 (6iî) -dione
• Example 17 13- S-D-glucopyranosyl) -6-methyl-12,13-dihydro-5H- yridoP ' ⁇ ' ⁇ jSlpyrrolop ⁇ - ⁇ j yrrolop ⁇ -cJcarbazole-S ⁇ ⁇ yj-dione
• Example 16c To a solution of the compound of Example 16c (0.067 mmol) dissolved in 20 ml of methanol is added a 28% aqueous solution of ammonium hydroxide (31 ml). The mixture is stirred for 22 hours at 65 ° C. After evaporation of the solvents, the residue is taken up in a water / ethyl acetate mixture, then filtered through a frit. The crystals are washed with ethyl acetate, making it possible to isolate the expected product. Melting point> 300 ° C.
• Example 18 13- (2,3,4,6-tetra-O-acetyl-) SD-glucopyranosyl) -9-bromo-6-methyl- 12,13-dihydro-5fl-pyrido [3 ', 2 f : 4,5Ipyrrolo [2,3- ⁇ ] pyrrolo [3,4-c] carbazole-5,7 (6i ⁇ ) -dione
• the product is obtained according to the method of Example 4 using the compound of Example 16c as the substrate.
• Stage 1 12- (2-0-tosyl- ⁇ -D-glucopyranosyl) -12,13-dihydro-5H-pyrido [2,3-b] pyrido [3 '2': 4, 5] yrrolo [3, 2-g] pyrrolo [3, 4-e] indole-5, 7 (6H) -dione
• Example 12 To a solution of the compound of Example 12 (0.17 mmol) in 10 ml of tetrahydrofuran are added 23.5 mg of potassium carbonate and 1.7 mmol of para-toluene sulfonic acid chloride. The mixture is brought to reflux for 48 hours. After evaporation of the solvent, the residue is taken up in a water / ethyl acetate mixture, then filtered through a frit. The crystals are washed successively with ethyl acetate and then methanol allowing the expected product to be isolated.
• stage 1 To a solution of the compound obtained in stage 1 (0.062 mmol) in 1.6 ml of dimethylformamide is added 0.62 mmol of sodium azide. The mixture is stirred at 70 ° C for 6 days, then cooled, poured into water and extracted with ethyl acetate. The organic phase is washed with a saturated NaHCO solution, then a saturated NaCl solution and dried over magnesium sulfate. The solvent is evaporated and the residue recrystallized allowing the expected product to be isolated.
• Example 21 13 ⁇ hydrochloride ( ⁇ D-glucopyranosyl-6- [2- (diethylamino) ethyl] - ⁇ ⁇ lS-dihydro-SH-pyridoP ' ⁇ ' ⁇ jSJpyrroloP-S- ⁇ Jpyrrolop ⁇ -c] carbazole-5, 7 (6H) -dione
• Example 22a 1-methyl-3- [1- (2,3,4,6-tetra-O-acetyl-y3-D-glucopyranosyl) -1J3-indol-3-yl] -4- [1- (phenylsulfonyl ) -lH-pyrrolo [2,3-A] pyridin-3-yl] -lH-pyrrole- 2,5-dione
• the product is obtained according to the method of Example la, using the compound of preparation G as a substrate.
• Example 22b 1-methyl-3- [1- (2,3,4,6-tetra-O-acetyl- ⁇ D-glucopyranosyl) -1 J H-indol-3-yl] -4- (1H r - pyrrolo [2.3-6] pyridin-3-yl) -lh-pyrrole-2,5-dione
• the product is obtained according to the method of Example 1b using the compound of Example 22a as a substrate.
• Example 22c 6-methyl-12- (2,3,4,6-tetra-O-acetyl - ⁇ - D-glucopyranosyl) -12,13- dihydro-5/7-pyrido [3 ⁇ 2 ': 4, 5] pyrrolo [2,3- ⁇ ] pyrrolo [3,4-c] carbazole- 5.7 (6H) -dione
• the product is obtained according to the method of example le using the compound of example 22b as a substrate.
• Example 23 6-methyl-12- (y? -D-glucopyranosyl) -12,13-dil ⁇ ydro-5H-pyrido [3 ', 2': 4,5] pyrrolo [2,3- ⁇ ] pyrrolo [3, 4-c] carbazole-5,7 (6H) -dione
• the product is obtained according to the method of Example 15 using the compound of Example 22c as a substrate.
• Example 24a 3- (4-ri- (2,3,4,6-tetra-O-acetyl-? -D-glucoPvranosvI) -lH-pvrrolor3,2-c1 pyridin-3-yl) -l-methyl- 2.5-dioxo-2,5-dihydro-l ⁇ -pyrrol-3-yl] -lH- tert-butyl indole-1-carboxylate
• the product is obtained according to the method of Example 16a, using the compound of Preparation H as a substrate.
• Example 24b 3- (1H r -indol-3-vl) -4-r - (2,3,4,6-tetra-O-acetyl- ⁇ D-gIucopvranosvn-1H- pyrrolo [3,2-c] pyridin-3-yl] -l-methyl-lH-pyrrole-2,5-dione
• the product is obtained according to the method of Example 16b, using the compound of Example 24a as a substrate.
• Example 24c 13- (2,3,4,6-tetra-O-acetyl - ⁇ - D-glucopyranosyl) -6-methyl-12,13- dihy dro-5iî-py rido [3 ', 4': 4 , 5] pyrrolo [2,3- ⁇ ] pyrrolo [3,4-c] carb azole- 5.7 (6H) -dione
• the product is obtained according to the method of Example 16c, using the compound of Example 24b as the substrate.
• Example 25 13-ff-D-glucopyranosyl) -6-methyl-12,13-dihydro-5 J H-pyrido [3 ', 4': 4.5] pyrrolo [2,3-] pyrrolo [3,4 c] carbazole-5,7 (6J3) -dione
• the product is obtained according to the method of Example 17, using the compound of Example 24c as the substrate.
• Example 27 13- (6-chloro-6-deoxy-yff-D-glucopyranosyl) -6-methyl-12,13-dihydro-5 £ - r - pyrido [3 ', 2': 4.5] pyrrolo [ 2,3-fl] pyrrolo [3,4-c] carbazole-5,7 (6 J H) -dione
• Murine leukemia L1210 has been used in vitro.
• the cells are cultured in complete RPMI 1640 culture medium containing 10% fetal calf serum, 2 M of glutamine, 50 U / ml of penicillin, 50 ⁇ g / ml of streptomycin and 10 mM of Hepes, pH: 7, 4.
• the cells are distributed in microplates and exposed to cytotoxic compounds for 4 doubling times, ie 48 hours. The number of viable cells is then quantified by a colorimetric test, the Microculture Tetrazolium Assay (J. Carmichael et al., Cancer Res .; 47, 936-942, (1987)).
• IC 50 a concentration of cytotoxic agent which inhibits the proliferation of the treated cells by 50%. All the products of the invention show good cytotoxicity on this cell line. By way of illustration, the compounds of Examples 4, 5, 9 and 12 all have IC 50 values better than 10 "7 M.
• the compounds of the invention were also tested on human cell lines according to the same experimental protocol as that described on murine leukemia L1210 but with incubation times of 4 days instead of 2 days. As an indication, the compounds of Examples 3, 4, 5, 15, 17 and 19 all have IC 50 values of less than 1 ⁇ M on the following cell lines: SK-N-MC neuroblastoma, A431 epidermoid carcinoma and carcinoma small cell lung H 69.
• the L1210 cells are incubated for 21 hours at 37 ° C. in the presence of different concentrations of the product tested.
• the cells are then fixed with 70% (v / v) ethanol, washed twice in PBS and incubated for 30 minutes at 20 ° C. in PBS containing 100 ⁇ g / ml of RNAse and 50 ⁇ g / ml of propidium iodide.
• the results are expressed as a percentage of cells accumulated in the G2 + M phase after 21 hours compared to the control (control: 20%).
• the compounds of the invention are particularly interesting.
• the compounds of Examples 3, 4 and 5 induce an accumulation of at least 80% of the cells in the G2 + M phase after 21 hours at a concentration of less than 0.5 ⁇ M.

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