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  • C07H19/23—Heterocyclic radicals containing two or more heterocyclic rings condensed among themselves or condensed with a common carbocyclic ring system, not provided for in groups C07H19/14 - C07H19/22
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus

Definitions

• the present invention relates to new derivatives of hydroxyalkyl indolocarbazole, their process of preparation and the pharmaceutical compositions which contain them.
• the compounds of the present invention constitute derivatives of rebeccamycin, this product having an inhibitory activity of topoisomerase I making it particularly useful in the treatment of tumors.
• Many chemical modifications of rebeccamycin have been made, both in terms of the functional groups present on the molecule (WO 98/07433) and their positions on the hexacyclic skeleton (WO 98/07433) and their positions on the hexacyclic skeleton (WO
• the compounds described by the Applicant surprisingly exhibit selective inhibitory activity on a kinase family and more specifically on the kinase GSK-3 (glycogen synthase kinase).
• Glycogen Synthase Kinase 3 is found in most human tissues
• GSK-3 (muscle, liver, pancreas, heart, intestine, ). This enzyme is involved in the insulin signaling pathway. Insulin via the PI 3-kinase pathway inhibits GSK-3, leading to an increase in the synthesis of glycogen stores. GSK-3 also phosphorylates the insulin substrate proteins resulting in desensitization of the insulin stimulation pathways. Experiments carried out in the Zucker rat (obese and diabetic) have shown that inhibition of GSK-3 leads to stimulation of glucose transport. It was also found that the activity of GSK-3 was increased in models or in pathological situations in animals as in humans (type II diabetes).
• GSK-3 activity makes it possible to prevent neuronal death in subjects suffering from neurodegenerative pathologies, as well as to prevent the death of healthy cells in a subject suffering from affection. tumor and treat with cytotoxic agents.
• the compounds capable of inhibiting the synthesis of GSK-3 are therefore particularly useful for the treatment of type II diabetes, obesity, pathologies of the central nervous system, Alzheimer's disease, Parkinson's disease , and to prevent normal cell apoptosis induced by anticancer drugs.
• the compounds described by the Applicant in addition to the fact that they are new, unexpectedly exhibit selective inhibitory activity with respect to the Glycogen Synthase Kinase 3, making them particularly useful for their use as a medicament, in the treatment of the pathologies mentioned above.
• Ri and R 2 identical or different, independently of each other, each represent a group chosen from hydrogen, alkyl (C ⁇ _-C 6 ) linear or branched, arylalkyl
• C ⁇ -C 6 linear or branched, hydroxy, hydroxyalkyl (C ⁇ -C 6 ) linear or branched, dihydroxyalkyl (C ⁇ -C 6 ) linear or branched, alkoxy (C ⁇ -C 6 ) linear or branched, alkoxy (C ⁇ -C 6) alkyl (C ⁇ -C6) linear or branched, amino, and aminoalkyl (C ⁇ -C6) linear or branched, the amino moiety in each of the groups being optionally substituted by one or two identical or different, selected from alkyl
• Ra and Rb identical or different, independently of each other, each represent a linear or branched alkylene chain (C ⁇ -C 6 ), • Xi, X 2 and X 3) identical or different, independently of each other, each represent a group chosen from hydroxy, alkoxy (C ⁇ -C 6 ) linear or branched, aryloxy, arylalkoxy (C ⁇ -C 6 ) linear or branched, alkyl (C ⁇ ⁇ C 6 ) linear or branched, amino (optionally substituted by one or two groups, identical or different, alkyl (C ⁇ -C 6 ) linear or branched), halogen, alkylcarbonyloxy (C ⁇ -C 6 ) linear or branched, and azido,
• aryl group is understood a phenyl or naphthyl group, and by isomers one understands the optical isomers (racemates, enantiomers and diastereoisomers).
• hydrochloric hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic, methane acids. sulfonic, camphoric, etc.
• Preferred Ri groups of the compounds of the invention are the hydrogen atom, the alkyl group (C ⁇ -C6) linear or branched alkyl or hydroxy (C ⁇ -C6) linear or branched.
• the preferred group R 2 of the compounds of the invention is the hydrogen atom.
• the preferred compounds are the compounds of formula (I) in which Ra and Rb, identical, represent a linear alkylene chain (C ⁇ -C).
• the groups X_. X and X 3 preferred, compounds of the invention are chosen from hydroxy, alkoxy (C ⁇ -C 6 ) linear or branched and alkylcarbonyloxy (C ⁇ -C 6 ) linear or branched.
• Preferred groups X 4 are selected from -R c-Xi groups in which Rc represents a methylene and X group. represents a group chosen from hydroxy, halogen, alkoxy (C ⁇ -C 6 ) linear or branched and alkylcarbonyloxy (C _ -C 6 ).
• the preferred compounds are the compounds of formula (LA):
• R_, R 2 , Ra, Rb, Xi, X, X 3 and X 4 are as defined in formula (I).
• the preferred compound of the invention is 3,9-bis (hydroxymethyl) -12- (4-O-methyl- ⁇ -D- glucopyranosyl) -12,13-dihydro-5H-indolo [2,3- ⁇ ] pyrrolo [3,4-c] carbazole-5,7 (6H) -dione
• the isomers as well as the addition salts with a pharmaceutically acceptable acid or base of the preferred compounds form an integral part of the invention.
• the present invention also relates to the process for preparing the compounds of formula (I), characterized in that a compound of formula (II) is used as starting material:
• the compounds of formula (II), (IV), and (VIII) are either commercial compounds, or obtained according to conventional methods of organic synthesis easily accessible to those skilled in the art.
• the compounds of formula (I) have a completely surprising selective inhibitory activity GSK-3 (glycogen Synthase Kinase-3). This characteristic property allows their use in the treatment of type II diabetes, obesity, pathologies of the central nervous system, Alzheimer's disease, Parkinson's disease, and for apoptosis.
• the present invention also relates to pharmaceutical compositions containing as active principle at least one compound of formula (I), one of its 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, intravaginal, rectal, nasal, perlingual, buccal administration. , ocular or respiratory.
• compositions according to the invention for parenteral injections include in particular aqueous and non-aqueous sterile solutions, dispersions, suspensions or emulsions as well as sterile powders for the reconstitution of injectable solutions or dispersions.
• compositions according to the invention for solid oral administrations, include in particular simple or coated tablets, sublingual tablets, sachets, capsules, granules, and for oral, nasal, buccal or ocular administrations, include in particular emulsions, solutions, suspensions, drops, syrups and aerosols.
• compositions for rectal or vaginal administration are preferably suppositories, and those for per or trans-cutaneous administration include in particular powders, aerosols, creams, ointments, gels and patches.
• compositions cited above illustrate the invention but do not limit it in any way.
• inert, non-toxic, pharmaceutically acceptable excipients or vehicles mention may be made, by way of indication and without limitation, of diluents, solvents, preservatives, wetting agents, emulsifiers, dispersing agents, binders, swelling agents, disintegrants, retardants, lubricants, absorbents, suspending agents, colorants, flavorings, etc ...
• the useful dosage varies according to the age and weight of the patient, the route of administration, the pharmaceutical composition used, the nature and severity of the condition, and the taking of any associated treatments. The dosage ranges from 0.5 mg to 500 mg in one or more doses per day.
• the starting materials used are known products or prepared according to known procedures. The different stages of preparation lead to synthesis intermediates useful for the preparation of the compounds of the invention.
• Example 1 3,9-bis (hy roxymethyl) -l 2- (4-0-methyl- ⁇ -D-glucopyranosy ⁇ ) -l 2,13- dihydro-5i ⁇ -in (Iolo [2,3-] pyrro ⁇ o [3,4-cJcarbazole-5,7 (6H) -diione,
• Stage A 12- (2 5 3,6-tri-0-acetyl-4-f9-methyl- ⁇ -D-glucopyranosyl) -12,13-dihydro-5H- indolo [2,3-fllpyrrolo [3,4 c] carbazole-5,7 (6ii) -dione,
• Stage C 3,9-DîformyI-12- (4-t -methyl- ⁇ -D-glucopyranosyl) -12,13-dihydro-5Er- indolo [2,3- ⁇ ] pyrrolo [3,4-clcarbazole-5 , 7 (6jfif) -dione.
• stage B The compound obtained in stage B is dissolved in 13 ml of methanol, then 6 ml of a 30% aqueous solution of NH 4 OH are added. After 24 hours of stirring at room temperature, the reaction medium is evaporated to dryness. The residue is dissolved in an ethyl acetate / tetrahydrofuran mixture, acidified with an IN solution of hydrochloric acid and then extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated under reduced pressure. Chromatography on silica gel of the residue (cyclohexane / acetone: 20/80) allows the expected product to be isolated. Melting point:> 300 ° C
• Stage D 3,9-bis (hydroxymethyl) -12- (4-0-methyl- ⁇ -D-glycopranosyl) -12,13- dihydro-5i-indolo [2,3- ⁇ ] pyrrolo [3,4- c] carbazoIe-5-7 (6E -dione.
• Example 2 3,9-bis (hydroxymethyl) -6-methyl-I2- (4-0-methyl- ⁇ -D- glucopyranosyl) -12,13-dihydro-5i ⁇ -mdolo [2,3-] pyrrolo [3 , 4-c] carbazole-5,7-dione.
• Stage A 12- (4-0-methyl- ⁇ -D-glucopyranosyl) -12,13-dihydrofuro [3,4-cl indolo [2,3-fl] carbazole-5,7 »dione.
• Stage B 6-methyl U2- (4-0-hy hyI- ⁇ -D-glueopyra ⁇ osyI) -12,13-dihydro-5H- mdolo [2,3 - «] pyrrolo [3,4-c] carbazole-5, 7-dione.
• Stage C 3-9-bis (hydroxymethyl) -6-methyl-12- (4-? -Methyl- ⁇ -D-glucopyranosyl) - 12-13-dihydro-5i ⁇ -indolo [2-3- ⁇ ] pyrroIo [ 3,4-c] carbazole-5,7-dio ⁇ e.
• Example 3 6- (2-hydroxyethyl) -3,9-bis (hydroxymethyl) -12- (4- "9-methyl- ⁇ -D- glucopyranosyl) -1,213-dihy dro-5H-indolo [2 , 3 - "] pyrrolo [3,4-c] carbazole-5,7-dione.
• Stage A 6- (2-hydroxyethyl) -12- (4- * -methyl- ⁇ -D-glucopyranosyl) -12,13-dihydro- 5iî-mdoIo [2,3- ⁇ ] pyrroIo [3,4-c ] earbazole-5,7-diQne.
• Stage B 6- (2-hydroxyethyl) -3,9-bis (hydroxymethyl) -12- (4- ⁇ 9-methyl- ⁇ -D- glucopyranosyl) -12,13-dihydro-5 J ff-mdoloP, 3- ⁇ ] pyrroIo [3,4-c] carbazole-5,7-dione.
• the product is obtained according to the method of Example 1, from stages A to D, using the compound obtained in preceding stage A as a substrate.
• Example 4 6-diethylaminoethyl-3,9-bis (hydroxymethyl) -12- (4- "-methyl- ⁇ -D- glucopyranosyl) -12,13-dihydro-5H-mdolol2,3- ⁇ ] pyrrolo [3, 4-c] earbazole-5,7-dione.
• Stage A 6-diethylammoethyl-12- (4-0-methyl- ⁇ -D-glucopyranosyl) -12,13-dîhydro- 5i ⁇ -indolo [2,3- ⁇ ] pyrroIo [3,4-c] carbazole-5 , 7-dione.
• Stage B 6-diethylaminoethyl-3,9-bis (hydroxymethyl) -12- (4-0-methyl- ⁇ -D- glucopyranosyl) -12, I3-dihydro-5H-indolo [2,3- ⁇ ] pyrrolo [ 3,4-c] carbazol
• the product is obtained according to the method of Example 1, from stages A to D, using the compound obtained in preceding stage A as a substrate.
• the product is obtained according to the method of stage D of example 1, using as compound the compound obtained in stage B of example 1.
• Example 6 3,9-bîs (hydroxymethyl) -12- (6-chloro-6-deoxy-4-0-methyl-I- ⁇ -D ⁇ glucopyranosyl) -12,13-dib.ydro-5H- whatsoeverolo [2, 3- ⁇ t] pyrrolo [3,4-c] carbazole-5,7 (6H) -diotte.
• Stage A 12- (6-chloro-6-deoxy-4-0-methyl- ⁇ -D-glucopyranosyl) -12,13-dihydro-5jH r - itt QloP î S- ⁇ lpyrrolop ⁇ - lcarbazole-S CôE -d ⁇ Otte.
• the product is obtained according to the method of Example 1, from stages A to D, using the compound obtained in preceding stage A as a substrate.
• Glycogen synthase kinase 3 was purified from Sf9 cells transfected as described in Eur. J. Biochem., 1992, 305-311.
• Example 1 has an IC 50 of 0.03 ⁇ M. It is therefore active vis-à-vis GSK-3 and this activity is selective as evidenced by the results set out in Examples 8 and 9 described below.
• the enzyme was purified from a homogenate of starfish oocytes (Marthasterias glacialis) in M phase as described in Ewr. J. Biochem, 1997, 243. 527-536 and J Biol.
• the IC 50 values are estimated from the dose-response curves. During this test, the compound of Example 1 has an IC 50 greater than 5 ⁇ M, thus demonstrating its weak capacity to inhibit this cyclin dependent protein kinase.
• CDK5 was expressed in E. coli as a GST (Glutathione-S-transferase) fusion protein and purified on a glutathione-agarose affinity column. CDK5 is then activated by p25 (1/1 mixture), prepared in the same way. The enzymatic activity of the CDK5 / p25 complex is measured as described above for CDK1 / cyclin B. The IC 50 values are estimated from the dose-response curves.
• Example 1 has an IC 5 o greater than 5 ⁇ M, thus demonstrating its weak ability to inhibit this cyclin dependent protein kinase.
• Example 10 Pharmaceutical composition for 1000 tablets dosed at 10 mg

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