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
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
  • C07D487/14—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings

Definitions

• PYRROLO (3,4-C) CARBAZOLE AND PYRIDO (2, 3-B) PYRROLO (3, -E) INDOLE DERIVATIVES, THEIR PREPARATION METHOD AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
• the present invention relates to new derivatives of pyrrolo [3,4-c] carbazole and pyrido [2,3-b] pyrrolo [3,4-e] indole, 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.
• adenocarcinomas and carcinomas adenocarcinomas and carcinomas
• sarcomas adenocarcinomas and carcinomas
• gliomas adenocarcinomas and leukemias.
• the compounds of the invention can be advantageously combined with all of the cytotoxic treatments currently in use, but also with radiotherapy, the toxicity of which they do not increase, and with various hormone therapies for anticancer purposes (breast and prostate).
• Patent applications WO 95/07910 and WO 96/04906 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 WO 00/47583, WO 97/21677 and WO 96/11933 present cyclopenta [g] pyrrolo [3,4-e] indole derivatives fused by the indole part and the cyclopentene part of the derivatives, to a system aromatic or non-aromatic cyclic, and optionally comprising heteroatoms. These compounds have pharmacological activities making them particularly useful in the treatment of cancer.
• Patent application WO 01/85686 describes pyrrolo [3,4-c] carbazole derivatives useful in the treatment of neurodegenerative diseases, inflammations, ischemia and Cancer.
• A represents a cycle with 6 saturated peaks, partially or completely unsaturated which can possibly give an aromatic character to the cycle
• • / 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
• N represents a group chosen from hydrogen, halogen, cyano, nitro, azido, linear or branched (C ⁇ -C 6 ), aryl, aryl (C ⁇ -C 6 ) linear or branched, hydroxy, alkoxy ( C ⁇ -C 6 ) linear or branched, aryloxy, arylalkoxy (C ⁇ -C 6 ) linear or branched, for yl, carboxy, aminocarbonyl, . ⁇ R 3 R 4 , -C (O) -T ⁇ , -qO - ⁇ Rr-Tt, - ⁇ R 3 -C (O) -T ⁇ , -OC (O) -T ⁇ , -C (O) -OT
• ⁇ R 3 and R identical or different, each represent a group selected from hydrogen, alkyl (C ⁇ -C6) linear or branched, aryl, or aryl (C ⁇ -C6) linear or branched, or
• T_ represents a group chosen from linear or branched (C ⁇ -C 6 ) alkyl, optionally substituted by a group chosen from -OR 3 , -NR 3 R1, -CO 2 R 3 , -C (O) R 3 and -C (O) NR 3 R 4 in which R 3 and R * are as defined above, aryl, arylalkyl (C ⁇ -C 6 ) linear or branched, or Ti represents a linear alkenyl chain (C 2 -C 6 ) or branched optionally substituted by a group chosen from -OR 3 , -NR 3 R, -CO 2 R 3 , -C (O) R 3 and -C (O) NR 3 R 4 in which R 3 and R_j are as defined previously
• T represents a linear or branched alkylene chain (C ⁇ -C 6 ),
• t represents an integer between 0 and 2 inclusive, or a methylenedioxy or ethylenedioxy group
• W represents, with the carbon atoms to which it is bonded, a phenyl group or a pyridinyl group,
• R 6 represents a group selected from hydrogen, alkyl (C ⁇ -C6) linear or branched, aryl, aryl (C ⁇ -C6) linear or branched, cycloalkyl, cycloalkylalkyl (QC 6) linear or branched, -OR 3 , -NR 3 R4, -O-Tr-NR 3 R4, -NR ⁇ T -NRsR-i, linear or branched hydiOxyalkylamino (C ⁇ -C 6 ), linear or branched di (hydroxyalkyl) amino (C ⁇ -C 6 ), -C (O) -R 3 , -NH-C (O) -R 3 , and me alkylene chain (C ⁇ -C 6 ) linear or branched, substituted by one or more groups, identical or different, chosen from halogen atoms, cyano, nitro groups, -OR 3 , -NR 3 R 4 , -CO 2 R 3 , -OR
• Xx represents a group selected from a hydrogen atom, hydroxy group, alkoxy (C ⁇ -C6) linear or branched, mercapto, alkylthio (C ⁇ -C6) linear or branched
• Y represents a hydrogen atom
• X 2 represents a group selected from hydrogen atom, hydroxy group, alkoxy (C ⁇ -C6) linear or branched, mercapto, alkylthio (C ⁇ -C6) linear or branched
• Y 2 represents a hydrogen atom
• Ri represents a group chosen from a hydrogen atom, a linear or branched (C 1 -C 6 ) alkyl group optionally substituted by one or more hydroxy, linear or branched (C ⁇ -C 6 ) hydroxy, linear (C ⁇ -C 6 ) hydroxyalkoxy groups or branched, NR 3 R- ⁇ ., the groups R and t having the same definitions as above, or Ri represents a group of formula C (O) -OT 3 in which: T 3 represents an alkyl group (C ⁇ -C 6 ) linear or branched, aryl, arylalkyl (C ⁇ -C 6 ) linear or branched, or a group of formula (a):
• Q represents a group selected from oxygen atom or NR group in which R 2 represents a group selected from hydrogen, alkyl (C ⁇ -C6) linear or branched, aryl, aryl (C ⁇ -C 6) linear or branched, cycloalkyl, cycloalkylalkyl (C r C 6 ) linear or branched, -OR 3 , -NR 3 R4, -O-T2-NR3R4, - R3-T2-NR3R4, hydroxyalkylamino (C ⁇ -C 6 ) linear or branched , di (hydroxyalkyl) amino (C ⁇ ⁇ C 6 ) linear or branched, -C (O) -R3, -NH-C (O) -R 3 , and an alkylene chain (C ⁇ -C 6 ) linear or branched, substituted by one or more groups, identical or different, chosen from halogen atoms, cyano, nitro, -OR 3 , - R 3 R 4 R
• Wi represents, with the carbon atonies to which it is linked, a unsubstituted phenyl group or a phenyl group substituted by a bromine atom
• Ri represents a group chosen from a hydrogen atom or a glucopyranosyl group or (2,3,4,6-tetra-O-benzyl-glucopyranosyl) and R 2 represents a hydrogen atom
• W 2 represents a group chosen from:
• W 2 represents a group chosen from:
• aryl a phenyl, naphthyl, dihydiOiiaphtyle, tetraliydronaphthyl, indenyl or indanyl group, each of these groups being optionally substituted by one or more groups, identical or different, chosen from halogen, alkyl (C ⁇ -C 6 ) linear or branched, trihaloalkyl (C ⁇ -C 6 ) linear or branched, hydroxy, alkoxy (C ⁇ -C 6 ) linear or branched, NR 3 R-1, R 3 and R_ ⁇ having the same meanings as before.
• hydrochloric hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, flimaric, tartaric, maleic, citric, ascorbic, oxalic, methane acids. sulfonic, camphoric, etc.
• the preferred compounds of the invention are those for which Xi and Yi together form, with the carbon atom which carries them, a carbonyl group, and X 2 and Y 2 together form with the carbon atom which carries them, a carbonyl group.
• the preferred group Q according to the invention is the group NR, in which R 2 is as defined in formula (1).
• the preferred compounds of the invention are the compounds of formula (I) corresponding more particularly to the formula (LA):
• the preferred compounds of the invention are the compounds of formula (I) corresponding more particularly to the formula (D3): in which Ri, R 2 and Z are as defined in formula (I).
• the preferred compounds of the invention are the compounds of formula (I) corresponding more particularly to the formula (IC):
• the preferred compounds of the invention are the compounds of formula (I) corresponding more particularly to the formula (ID):
• the preferred compounds of the invention are the compounds of formula (I) corresponding more particularly to the formula (IE): in which Ri, R 2 , R 6 and Z are as defined in formula (I).
• the preferred compounds of the invention are the compounds of formula (I) corresponding more particularly to the formula (IF):
• the preferred compounds of the invention are the compounds of formula (I) corresponding more particularly to the formula (IG):
• the preferred compounds of the invention are the compounds of formula (I) corresponding more particularly to the formula (EH): in which Ri, R 2 and Z are as defined in formula (I).
• the preferred compounds of the invention are the compounds of formula (I) corresponding more particularly to formula (II):
• the preferred compounds of the invention are the compounds of formula (I) corresponding more particularly to the formula (IJ):
• the preferred compounds of the invention are the compounds of formula (I) corresponding more particularly to the formula (III): in which Ri, R 2 and Z are as defined in formula (I).
• the preferred compounds of the invention are the compounds of formula (I) corresponding more particularly to the formula (IL):
• the preferred Ri group according to the invention is the hydrogen atom, the group of formula C (O) -OT 3 in which T 3 represents a linear or branched alkyl group (C ⁇ -C 6 ) and the glucopyranosyl group of formula:
• the preferred R 2 group according to the invention is the hydrogen atom and the linear or branched alkyl group (C ⁇ -C 6 ).
• the preferred group R 6 according to the invention is the hydrogen atom.
• the preferred compounds of the invention are:
• the present invention also relates to the process for the preparation of the compounds of formula (I), characterized in that a compound of formula (II) is used as starting material:
• R a represents a hydrogen atom or a methyl group and, Xi, Yi, X 2 and Y 2 are as defined in formula (I), compound of formula (II) which is treated with a halide of alkylmagnesium in the presence of a compound of formula (III):
• Boc represents a tert-butylcarbonyloxy group and R 2a , Xi, Yi, X2. 2, Wi and Z are as defined above, composed of formula (N) which is:
• R 6 is as defined in formula (I) and Boc, R2 a , Xi, Yi, X2, Y2.
• Wi and Z are as defined above, composed of formula (VI) which is: * either irradiated with a halogen lamp to lead to the compound of formula (I / a), special case of the compounds of formula (I):
• R 7 represents a protective group of secondary amines well known to those skilled in the art, to lead to the compound of formula (XII):
• R la , R2 a , X_, Y ⁇ , X2, Y2, i and Z are as defined above,
• R 2a. R 7 , Xi, Yi, X 2 , Y2, Wi and Z are as defined above,
• R2 has , Xi, Yi, X2, Y2 . i and Z are as defined above,
• 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 compounds of the invention can also be used in therapeutic association with another anticancer agent such as, for example, paclitaxel, tamoxifen and its derivatives, cisplatin and its analogues, irinotecan and its metabolites, the various alkylating agents the leader of which is cyclophosphamide, etoposide, vincaalcalo ⁇ des , doxorubicin and other anthracyclines, nitrosoureas.
• another anticancer agent such as, for example, paclitaxel, tamoxifen and its derivatives, cisplatin and its analogues, irinotecan and its metabolites, the various alkylating agents the leader of which is cyclophosphamide, etoposide, vincaalcalo ⁇ des , doxorubicin and other anthracyclines, nitrosoureas.
• 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 principle 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 taken per day.
• the expected product is obtained according to the method described by V. Bocchi et al. (Tetrahedron, 1984, 40, pp. 3251-3256).
• the expected product is obtained according to the process described in preparation B from 5-bromo-indole.
• the expected product is obtained according to the process described in preparation B from 5-chloro-indole.
• PREPARATION E 3-f4-bro o-l-metl ⁇ yl-2 -dioxo-2,5-d ⁇ hvdro-1H-pyrrQl-3-yl) -lH- indole-l-carboxy.ate ferf-butyl
• a solution containing 1.445 g of indole dissolved in 29 ml of dry tetrahydrofuran is brought to -20 to -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 adding at 0 ° C 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.
• Stad B 3- (4-bronto-1-methyl-2,5-dioxo-2, S-dihydro-1H yrrol-3-yl) -lH-indole-1- tert-butyl teboxyl
• PREPARATION F 3- (4-bromo-l-methyl-2,5-dioxo-2., 5-d ⁇ hvdro-1H-pyrroI-3-vI) -lH r - pyrrolo [2,3-è1Pyridme-l-earboxyIate de tert- butyl
• the expected product is obtained according to the process described in stage B of preparation E from the compound described in the preceding stage.
• reaction mixture is then heated at 45 ° C for 5 hours. After returning to room temperature, water and then a saturated aqueous solution of sodium chloride are added. The mixture is extracted with ethyl acetate and the organic phase is dried over magnesium sulfate, filtered and then concentrated. After purification by chromatography column on silica gel (acetate ethyl / cyclohexane: 6/4), the expected product is obtained.
• a mixture of the compound of preparation A (0.274 mmol) of maleimide (0.548 mmol) and a catalytic amount of SnCl 2 in 15 ml of anhydrous toluene is brought to reflux for 24 hours. After evaporation of the toluene, the residue obtained is purified by chromatography on silica gel (ethyl acetate / cyclohexane: 3/7) to yield the expected product.
• a suspension of the compound of the preceding stage (0.358 mmol) and of palladium black (0.358 mmol) in 5 ml of nitrobenzene is heated under reflux for 8 hours.
• the reaction crude is cooled to room temperature, diluted with cyclohexane (5 ml) and placed on a frit containing a plug (5 to 6 cm) of silica gel.
• the nitrobenzene is eluted using cyclohexane, then a cyclohexane-dichloromethane mixture (95/5).
• the reaction product is eluted with a dichloromethane / methanol / triffuoroacetic acid mixture (10/1 / 0.05).
• the expected product is obtained according to the process described in stage A of Example 1 using N-methylmaleimide.
• Step B 2-mêthvl ⁇ vrwlof3 ', 4, 5-t âIindolizittof8,7 blindote ⁇ l, 3 (2H, 8H) -dione
• the expected product is obtained according to the method described in stage B of Example 1 from the compound described in the preceding stage.
• the expected product is obtained according to the process described in stage A of Example 1 from the compound described in Preparation B. Melting point: 103-107 ° C
• Stage B ll- (benzyloxy) pyrrolo ⁇ 4 '; S % 6] mdoUzino [8 f 7-bJindale-l f 3 (2H, 8H) dione
• the expected product is obtained according to the method described in stage B of Example 1 from the compound described in the preceding stage.
• the expected product is obtained according to the process described in stage A of Example 1 from the compound described in Preparation B and N-methylmaleimide.
• the expected product is obtained according to the method described in stage B of Example 1 from the compound described in the preceding stage.
• Example 6 ll-hydroxy-2-méthylpyrroIor3'.4,: 5.61 doIizinof8.7- & 1indoIe-1 (2H.8H-dion
• the expected product is obtained according to the process described in stage A of Example 4 from of the compound described in stage A of Example 5.
• Stage B 114tydroxy ⁇ 2 ' methylpyrrolo ⁇ 4 t : 5 f 6 ⁇ ndolizino ⁇ r 7-bJmdole-1,3, (2H, 8H ' dione)
• the expected product is obtained according to the method described in stage B of Example 1 from the compound described in the preceding stage.
• the expected product is obtained according to the process described in stage A of Example 1 from the compound described in Preparation C.
• Stage B 11-bromopyrtoto ⁇ 4 ': 5.6] ittdolizin ⁇ , 74>] mdole-l, 3 (2H, 8H) -dîone
• the expected product is obtained according to the method described in stage B of Example 1 from the compound described in the preceding stage. Melting point:> 300 ° C
• EXAMPLE 8 ll-bromo-2-methylpyrror3 4 t : 5.61ipdoIiz; ipof8.7- r1mdoIe-1.3 (2H, 8H) - dione
• the expected product is obtained according to the process described in stage A of Example 1 from the compound described in Preparation C and N-methylmaleimide.
• the expected product is obtained according to the method described in stage B of Example 1 from the compound described in the preceding stage.
• EXAMPLE 9 ll-chloropyrrQlor3 ', 4 t : 5,61mdoI ⁇ zmof8,7-MindoIe-L3f2H, 8H) -dione
• the expected product is obtained according to the process described in stage A of Example 1 from the compound described in preparation D. Melting point: 138-144 ° C
• Stage B U-chtoropyrrolo ⁇ 4 'iSMndattzino ⁇ , 7-b ⁇ indote-l, 3 (2H, 8H) -dione
• the expected product is obtained according to the method described in stage B of Example 1 from the compound described in the preceding stage.
• the expected product is obtained according to the process described in stage A of Example 1 from the compound described in Preparation D and N-methyhnaleimide.
• the expected product is obtained according to the method described in stage B of Example 1 from the compound described in the preceding stage.
• Stage A 3- [1-thyt-2 f 5-dioo-4- (2-pyrrolyl) -2 f 5-dîhydro-1H yrrol-3-yl] - lH4ndole-l- carboxylate of tert4 ⁇ utyle
• Stage B 2-methyi ⁇ l : t 3 - dioxo ⁇ l, 2 ⁇ 3,44étrahydro-'7Sf-d ⁇ pyrroh ⁇ f 2-a: 3 f 4 ⁇ cJcarbazole ⁇ 7 ⁇ tert-butyie carboxylate
• Example 11 The compound described in Example 11 (0.164 mmol) is dissolved in 40 ml of formic acid. After 16 hours of stirring at room temperature, the solution is neutralized by adding dropwise triethylamine and then an aqueous solution of sodium hydrogencarbonate. The mixture is extracted several times with ethyl acetate. The organic phases are combined and then washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and then concentrated.
• the expected product is obtained according to the process described in stage A of example li from the compound described in preparation F and imidazole.
• the expected product is obtained according to the process described in stage B of preparation E from the compound described in the preceding stage.
• the expected product is obtained according to the process described in stage B of example li from the compound described in the preceding stage.
• EXAMPLE 14 e-methyl-S -dio o-e -dihvdroimidazon ⁇ -gl yr orS ' ⁇ ' ⁇ JI yrroIo 2 -c
• the expected product is obtained according to the process described in Example 12 from the compound described in Example 14.
• EXAMPLE 16 2-methvI-1,3, dioxo-2,3,3a, 12c-tetrahvdroimidazori.5- 1pyrido B '' ⁇ Sl pyrroIof2,3-c1Pyrrolo [3,4-g1p ⁇ ridine-8 (1H) -carboxyIate of tert- bntyle
• the expected product is obtained according to the process described in stage B of example li from the compound of preparation F.
• EXAMPLE 17 2-methvI-1,3, diox-2,3-dihvdroimidazori., S-g1Pyridor3 ! , 2 t : 4, SlPyrrQlo f2,3-c1PyrrQlo [3 ⁇ 4-e1pyridine-8flJE ⁇ -tert-bntyle earboxyIate
• the expected product is obtained according to the process described in Example 14 from the compound described in Example 16.
• EXAMPLE 18 2-methyli ⁇ nidazori., 5-glpyridof3 t , 2 t : 4,51pyrrolof2 3- PyrroIor3,4-e1 pyridipe-1,3, (2H, 8H) -dione
• the expected product is obtained according to the process described in Example 12 from the compound described in Example 17.
• EXAMPLE 20 2-methyl-8- (2,3,4,6-tetra-Q-acetyl- ⁇ -i? -GlttCQPyranQSyl) -8,12c- dihvdro ⁇ roidazo.l, 5-1pyrido t , 2 t : 4, 51pyrrolof2,3-clpyrrQlQf3,4-eTpyridine- l., 3 (2-fir, 3aH) -diope
• Stage A 3- (1H4midazol-1 ⁇ yl) -l-methyl-4- ⁇ - (2, 4.64 etm ⁇ 0-acetyl ⁇ ⁇ -D ⁇ glucopyra-nosyl) -lH-pyrrolo ⁇ f 34> Jpyridin-3 -yl ⁇ -lH-pyrrole ⁇ 2, 5-dione
• the expected product is obtained according to the process described in Example 14 from the compound described in Example 20.
• Example 21 To a solution of the compound described in Example 21 (0.032 mmol) in 6 ml of anhydrous methanol is added dropwise a solution of IN sodium methylate (20 ⁇ l). The mixture is left stirring at room temperature for 12 hours. The solvent is evaporated to dryness and the solid is washed on a frit with methanol, making it possible to isolate the expected product.
• the expected product is obtained according to the process described in stage B of Example 20.
• EXAMPLE 24 6-ethyl-12-f2., 3,4., 6-tetra-0-acetyl- ⁇ -D-glueopyranosvI) -im ⁇ dazofl, 2- 1Pyrido [3 2 t : 451pyrrQlof2 -clPyrroIof3,4-g] pyr ⁇ dipe-5,7f6if., 12H) -diope
• the expected product is obtained according to the process described in Example 14 from the compound described in Example 23.
• EXAMPLE 25 6-méthvI-12- ( ⁇ -D-glPcopyranosvI) -in ⁇ idazoFl, 2- lpyridor3,, 2; pyrrolof2,3-c 4,51
• the expected product is obtained according to the process described in Example 22 from the compound described in Example 24.
• Stage B pyrido ⁇ ', 2 t : 4 f 5] pyrrolo ⁇ , 2-gJpyrrolo ⁇ i 4-e] indolizitte-l i 3 ⁇ 2H f 8H) -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 mM glutamine, 50 U / ml of penicillin, 50 ⁇ g / ml of streptomycin and 10 mM 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. Cannichael 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%.
• the compound of Example 1 has IC50s of 3.1 ⁇ M on L1210, 1.99 ⁇ M on A549, 3.3 ⁇ M on HT29 and 1.4 ⁇ M on DU145.

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