WO2001037819A2 - Utilisation de derives d'indirubine pour la fabrication de medicaments - Google Patents
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- WO2001037819A2 WO2001037819A2 PCT/FR2000/003264 FR0003264W WO0137819A2 WO 2001037819 A2 WO2001037819 A2 WO 2001037819A2 FR 0003264 W FR0003264 W FR 0003264W WO 0137819 A2 WO0137819 A2 WO 0137819A2
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the subject of the invention is a new use in therapy of indirubin derivatives.
- indirubin belongs to the indigoids family.
- the term indigoide is used as the generic name for the dyes in the indigo group. These are bis-indoles, derived from various natural sources by fermentation, oxidation and dimerization in the presence of light.
- CDK inhibitory properties which cause a cell cycle arrest, give these derivatives of 1 indigoids an interest in the treatment of pathologies linked to the loss of proliferation control such as cancers, psoriasis, cardiovascular diseases, infectious diseases, nephrology, neurodegenerative diseases and viral infections.
- This kinase is an essential part of the WNT signal pathway. It is involved in multiple physiological processes: regulation of the cell cycle by controlling the levels of cyclin Dl and ⁇ -catenin, dorsoventral formation during development, action of insulin on glycogen synthesis, axonal outgrowth, neurotoxicity of HIV-1 mediated by Tat, et al.
- GSK-3 ⁇ and CDK5 are responsible for a good part of the abnormal hyperphosphorylation of the tau protein binding microtubules as observed in the helically paired filaments in Alzheimer's disease.
- the invention provides a solution to these problems with the use of high-efficiency indirubins with IC 50 of less than 10 ⁇ M, and more generally of the order of 5 to 50 nM, for the manufacture of GSK inhibitor drugs. -3 ⁇ .
- R and R identical or different, represent a hydrogen atom, a halogen atom; a hydroxy group; a methylenehydroxy group; an alkyl or alkyloxy or methylenealkoxy radical, with straight or branched chain, from C1 to C18; a cycloalkyl radical having 3 to 7 carbon atoms, optionally comprising one or more heteroatornes; a substituted or unsubstituted aryl, aralkyl or aryloxy radical, optionally comprising one or more heteroatoms; a mono-, di- or trialkylsilyl group having 1 to 6 carbon atoms, independently of each other, in each case, in the straight or branched chain alkyl group; a mono-, di- or triarylsilyl group, with substituted or unsubstituted aryl groups, independently of each other, in each case; a trifluoromethyl group; a -COM group; -COOM; or -CH 2 COOM, with
- one or more atoms of one or more benzene rings are replaced by nitrogen atoms.
- one or more aromatic or non-aromatic ring systems which may include one or more heteroatoms independently of one another, are condensed to the indirubin system.
- the indirubin derivatives of formula (I) are linked to a polyethylene glycol ester or to a polyethylene glycol ether by bonds, respectively, ester or ether.
- the invention relates more specifically to the indirubin derivatives having an IC 50 with respect to GSK-3 ⁇ of less than 10 ⁇ M and preferably of 1 ⁇ M, and in particular those with an IC 50 of less than 50 nM.
- R a hydrogen atom, halogen, alkyl, -S0 3 H, -S0 2 NH 2, -S0 2 -N (CH 3) 2, -S0 2 -NC 2 H 5 - OH, - S0 2 -N- (C 2 H 5 -OH) 2 , -S0 2 -NH-CH 3 ,
- R 4 and R 8 independently of one another: a hydrogen or halogen atom
- R an alkyl or aryl radical, the other substituents given in formula (I) representing a hydrogen atom.
- Derivatives of this family constituting high-efficiency GSK-3 ⁇ inhibitors with IC 50 of less than 5 ⁇ M, most generally of 1 ⁇ M, or even 50 nM, advantageously include substituents R 1 , R 3 , R 4 and R 8 with the following meanings:
- R 1 alkyl, in particular methyl, and phenyl,
- - R hydrogen, halogen (F, Cl, Br, I), N0 2, - S0 3 H, -S0 2 NH 2, -S0 2 -N (CH 3) 2, -S0 2 -NC 2 H 5 - 0H, -S0 2 -N- (C 2 H 5 -0H) 2 , -S0 2 -NHCH 3 ,
- halogen in particular I or Br, the other substituents given in formula (I) representing a hydrogen atom.
- Particularly preferred derivatives are chosen from indirubin, 5-iodo-indirubin, 5-bromo-indirubin, 5-chloro-indirubin, 5-fluoro-indirubin, 5-methyl-indirubin, 5-nitro -indirubin, 5-SO 3 H-indirubin, 5'-bromo-indirubin, 5-5 '-dibromo-indirubin or 5'-bromo-indirubin 5-sulfonic acid.
- R 3 represents a halogen atom, in particular I, or a group -SO 3 Na.
- the corresponding derivatives advantageously have an IC 50 with respect to GSK-3 ⁇ of less than 100 nM, and even for many of them less than 50 nM.
- Preferred derivatives of this group are chosen from indirubin-3 '-monoxime, 5-iodo-indirubin-3' -monoxime and 5-SO 3 Na-indirubin-3 '-monoxime.
- the derivatives defined above have already been described as inhibitors of CDKs, as well as other indigoids derived, for example, from indigo or isoindigo.
- the indirubin derivatives also exert an inhibitory effect vis-à-vis GSK-3 ⁇ . This effect is most generally of the same order of magnitude with respect to CDKs and GSK-3 ⁇ .
- the drugs produced in accordance with the invention using the indirubin derivatives defined above can be used for the treatment of pathologies in which GSK-3 ⁇ is involved.
- GSK-3 ⁇ inhibitors can be used as insulin mimetics. It is recalled that insulin acts by a cascade of biochemical events leading to an inhibition of GSK-3 ⁇ and that this inhibition is responsible for the response of cells to 1 insulin.
- these drugs are of great interest for the treatment of neurodegenerative diseases.
- the hyperphosphorylation of the tau protein caused by CDK5 and GSK-3 ⁇ can indeed be inhibited by the indirubin derivatives.
- These drugs are also effective for the treatment of diseases caused by single-celled parasites such as malaria, trypanosomes, leishmanias, toxoplasmas, pneumocystis and others, or multi-cellular parasites, such as fungi and worms.
- the active ingredients used in therapeutically effective amounts, are mixed with the pharmaceutically acceptable vehicles for the chosen mode of administration.
- the drugs are prepared in the form of capsules, tablets, dragees, capsules, pills, drops and the like. Such drugs may contain from 1 to 100 mg of active ingredient per unit.
- the drugs come in the form of sterile or sterilizable solutions.
- the doses per unit of intake can vary from 1 to 50 mg of active ingredient.
- the daily dosage is chosen so as to obtain a final concentration of at most 100 ⁇ M of derivative of 1 indirubin in the blood of the treated patient.
- FIGS. 1 to 3 which respectively represent,
- the elementary analyzes were carried out using an elementary analysis apparatus of CHN Perkin-Elmer 2400.
- the spectra of RM ⁇ H were recorded at 400 MHz, of NMR 13 C at 100 MHz on a Bruker AMX apparatus. 400, with internal reference of tetramethylsilane. s denotes a singlet, d, a doublet and m, a multiplet.
- the mass spectra were taken according to the positive ion mode under electronic impact (El 70) and with a Finingan MAT 90 device.
- This compound is prepared as described Farb erke vorm. Meister
- a 25% aqueous ammonia solution (5.0 ml) is cooled beforehand to 0-5 ° C before adding a sample of
- the pads used have the following compositions:
- Homogenization buffer - 60 mM ⁇ -glycerophosphate, 15 mM p-nitrophenylphosphate, 25 mM Mops (pH 7.2), 15 mM EGTA, 15 mM MgCl 2 , 1 mM DTT, 1 mM sodium vanadate, 1 mM NaF, 1 mM phenylphosphate, 10 ⁇ g leupeptin / ml, 10 ⁇ g aprotinin / ml, 10 ⁇ g soybean trypsin inhibitor / ml and 100 ⁇ M benzamidine.
- Buffer A 10 mM MgCl 2 , 1 mM EGTA, 1 mM DTT, 25 mM Tris-HCl pH 7.5, 50 ⁇ g heparin / ml.
- Buffer-C homogenization buffer, but containing 5 mM of EGTA, and devoid of NaF and protease inhibitors.
- Tween-20 salt tris buffer 50 mM Tris pH 7.4, 150 mM NaCl, 0.1% Tween-20 R.
- Hypotonic lysis buffer 50 mM Tris-HCl ph 7.4, 120 mM NaCl, 10% glycerol, 1% Nonidet-P40, 5 mM DTT, 1 mM EGTA, 20 mM NaF, 1 mM orthovanadate, 5 ⁇ M microcystin, 100 ⁇ g / ml of each of the following products: leupeptin, aprotinin, pepstatin.
- HLB Hypotonic lysis buffer
- the kinase activities were determined in buffer A or C (unless otherwise indicated), at 30 ° C, at a final ATP concentration of 15 ⁇ M.
- the values of the blank tests were subtracted and the activities calculated in pmoles of phosphate incorporated for a 10 min incubation.
- the values of the activities are generally expressed in% of the maximum activity, that is to say, in the absence of inhibitors.
- Control tests were carried out using appropriate dilutions of Me 2 SO. In some cases, as indicated below, the phosphorylation of the substrates is determined by autoradiography after SDS-PAGE.
- the GSK-3 ⁇ used is either the enzyme purified from rabbit muscle or expressed and purified from Sf9 insect cells (Hughes et al, 1992, Eur. J. Biochem., 203: 305,311). The determinations were carried out with a 1/100 dilution in 1 mg of BSA / ml of 10 mM DTT, with 5 ⁇ l of 40 ⁇ M GS-1 as substrate, in buffer A, in the presence of 15 ⁇ M [ ⁇ 32 P ] ATP (3000 Ci / moles; 1 mCi / ml) in a final volume of 30 ⁇ l.
- the CDK1 / cyclin B used was extracted with the aid of a homogenization buffer from oocytes of starfish (Marthasterias glacialis) and purified by affinity chromatography on p9 beads - Sepharose from oocytes of starfish (Marthasterias glacialis) and purified by affinity chromatography on p9 beads - Sepharose from oocytes of starfish (Marthasterias glacialis) and purified by affinity chromatography on p9 beads - Sepharose from
- the kinase activity was determined in buffer C, with 1 mg of histone Hl / ml, in the presence of 15 ⁇ M of [ ⁇ 32 P] ATP
- CDK5 / p25 was reconstituted by mixing equal amounts of recombinant mammalian CDKS and p25 expressed in E. coli as a GST fusion protein
- Glutathione-S-transferase and purified by affinity chromatography on glutathione-agarose p25 is a truncated version of p35, the CDK5 activator of 35kDa. Its activity was determined in buffer C as described for CDKl / cyclin B.
- Sf9 cells the Sf9 cells (InVitrogen, San Diego, CA) were cultured at 27 ° C. in a monolayer culture Grace medium (Gibco BRL, Gaithersburg, MD), supplemented with 10% fetal bovine serum and 50 ⁇ g of gentamycin / ml and 2.5 ⁇ g of amphotericin / ml.
- BaculoGold was obtained from PharMingen (San Diego, CA), and pVL1392 from InVitrogen.
- Tau transfection we excised, from a bacterial expression vector pNG2 (Biernat et al., 1993, Neuron 11: 153-163) and the gene coding for htau23, the shortest human tau isoform , with Xbal and BamHI. The gene was inserted into the baculovirus transfer vector pVL1392 cut with the same endonucleases.
- the BaculoGold system was used for the construction of the vector containing the baculovirus tau.
- BaculoGold DNA is a modified type of baculovirus containing a lethal deletion. Co-transfection of BaculoGold DNA with a complementary baculovirus transfer vector makes it possible to recover the lethal deletion of this viral DNA and to reconstitute viable virus particles carrying the sequence coding for htau23.
- the plasmid DNA used for the transfections was purified using QIAGEN cartridges (Hilden,
- Sf9 cells cultured in monolayers (2 ⁇ 10 6 cells in a 60 mm cell culture vessel) were co-transfected with baculovirus DNA (0.5 ⁇ g of BaculoGold DNA) and with derivatives of pVL1392 ( 2 ⁇ g) using the calcium phosphate co-precipitation method.
- the presence of recombinant protein was examined in infected cells 5 days after infection with SDS-
- the Sf9 cells infected with the baculovirus expressing htau23 were treated 36 hours after infection, with 50 ⁇ M of indirubin-3 '-monoxime for 5 hours before to be collected.
- Sf9 cells expressing htau23 were treated with 0.2 ⁇ M okadaic acid for 5 hours before harvest.
- Sf9 cells were infected with a recombinant virus at an MOI of 1 to 5.
- HLB hypotonic lysis buffer
- the kinase activities were determined with an appropriate substrate (GSK-3 ⁇ : GS1 peptide; CDKs: histone Hl) in the presence of 15 ⁇ M of ATP and at increasing concentrations of the derivatives tested.
- the IC 50 values were calculated from the dose / response curves and are given in Table 1.
- Figures 1A to 1D give the dose-response curves for 5-iodo-indirubin-3 '-monoxime (A), 5,5'- dibromoindirubine (B), 5-sulfonic acid indirubine-3' - monoxime (C) and 1 'indirubin- 3' -monoxime (D). Inhibition of
- GSK-3 ⁇ and CDKs is determined as indicated above.
- the activity is expressed in% of the maximum activity (without inhibitors).
- ATP concentrations in the reaction mixture vary from 0 to 2 ⁇ M, the concentration of GS-1 being kept constant at 6.7 ⁇ M. It is found that indirubin-3 '-monoxime acts in competition with ATP to bind.
- the linearity of the slope in the box in the figure shows that it is a linear inhibitor.
- FIG. 3A gives the results obtained and shows that phosphorylation is inhibited in a dose-dependent manner by 1 'indirubin-3' -monoxime, with an IC 50 around 100 nM.
- FIG. 3B gives the% of phosphorylation of tau as a function of the concentration of indirubin-3 '-monoxine (nM).
- K9JA pan-tau antibody recognizes all preparations containing tau.
- AT8 and PHF1 are specific for various phosphorylated units SP or TP, namely, respectively, Ser 202; Thr 205, Thr 231; Ser 235 and Ser 396; Ser 404 (numbering in htau 40, which corresponds to the longest isoform of the human tau protein).
- AT 100 recognizes the tau protein phosphorylee at T 212 and S214 (very specific reaction of the tau protein in Alzheimer's disease, but which also occurs in Sf9 cells, if the 2 sites are phosphorylated).
- FIG. 3D represents the diagram of tau isoforms, epitopes recognized by antibodies and preferred phosphorylation sites: (a) htau 23, (b) htau 40, the smallest and largest of the 6 isoforms generated by the assembly alternative (residues 352 and 441).
- the htau 23 protein lacks the N-terminal inserts and the second repeat. The repetitions are shown in gray and the adjacent regions are shaded. Some epitopes are indicated.
- Example 4 Study of the inhibition by indirubins, in vitro and in vivo, of the phosphorylation of DARPP-32 by CDK5 / p25
- the neural protein DARPP-32 has been identified as a physiological substrate for CDK5 / p25. DARPP-32 becomes a cAMP-dependent kinase inhibitor (PKA) when it is phosphorylated by CDK5 / p25 on Thr 75.
- PKA cAMP-dependent kinase inhibitor
- This protein was used as a substrate for in vitro phosphorylation by CDK5 / p25.
- Slices of striatum from the brain of an adult mouse are prepared by operating according to standard methodology. After equilibration in a pad of oxygenated Krebs bicarbonate by continuous aeration (95% 0 2 /5% C0 2 ), the sections are treated with different concentrations of indirubin-3 '-monoxime, or with 10 ⁇ m of roscovitine for 60 min. , or are left in the Krebs bicarbonate pad for the same time. The sections are homogenized by sonication in SDS
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Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002387591A CA2387591A1 (fr) | 1999-11-23 | 2000-11-23 | Utilisation de derives d'indirubine pour la fabrication de medicaments |
EP00985309A EP1231916A2 (fr) | 1999-11-23 | 2000-11-23 | Utilisation de derives d'indirubine pour la fabrication de medicaments |
AU21770/01A AU2177001A (en) | 1999-11-23 | 2000-11-23 | Use of indirubine derivatives for making medicines |
JP2001539434A JP2003514850A (ja) | 1999-11-23 | 2000-11-23 | 薬剤を調製するためのインジルビン誘導体の使用 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR9914749A FR2801216A1 (fr) | 1999-11-23 | 1999-11-23 | Utilisation de derives d'indirubine pour la fabrication de medicaments |
FR99/14749 | 1999-11-23 |
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Publication Number | Publication Date |
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WO2001037819A2 true WO2001037819A2 (fr) | 2001-05-31 |
WO2001037819A3 WO2001037819A3 (fr) | 2002-06-13 |
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PCT/FR2000/003264 WO2001037819A2 (fr) | 1999-11-23 | 2000-11-23 | Utilisation de derives d'indirubine pour la fabrication de medicaments |
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EP (1) | EP1231916A2 (fr) |
JP (1) | JP2003514850A (fr) |
AU (1) | AU2177001A (fr) |
CA (1) | CA2387591A1 (fr) |
FR (1) | FR2801216A1 (fr) |
WO (1) | WO2001037819A2 (fr) |
Cited By (20)
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WO2002030410A3 (fr) * | 2000-10-10 | 2002-07-11 | Univ Texas | Suppression de l'activite de kinase cycline-dependante pour la prevention et le traitement des infections |
WO2002092079A1 (fr) * | 2001-05-17 | 2002-11-21 | Schering Aktiengesellschaft | Utilisation de derives d'indirubine selectifs en tant qu'inhibiteurs du vegf-r |
WO2002100401A1 (fr) * | 2001-06-11 | 2002-12-19 | Schering Aktiengesellschafat | Derives d'indirubine inhibiteurs de cdk solubles |
WO2002074742A3 (fr) * | 2001-03-16 | 2003-02-20 | Schering Ag | Derives d'indirubine inhibiteurs de cdk ayant une solubilite elevee |
WO2003027275A1 (fr) | 2001-09-27 | 2003-04-03 | Alcon, Inc. | Inhibiteurs de la glycogene synthase kinase-3 (gsk-3) pour le traitement du glaucome |
WO2004039797A1 (fr) * | 2002-10-29 | 2004-05-13 | Jingcai Cheng | Composes d'indole de type special, leur preparation et leur utilisation pour le traitement et la prevention de maladies telles que le cancer |
WO2004091663A1 (fr) * | 2003-04-18 | 2004-10-28 | Kyowa Hakko Kogyo Co., Ltd. | Medicament pour la regeneration des nerfs |
WO2005070416A1 (fr) * | 2004-01-27 | 2005-08-04 | Anygen Co., Ltd. | Derives d'indirubine possedant une propriete anti-cancer contre la lignee cellulaire du cancer humain |
WO2006117212A2 (fr) | 2005-05-04 | 2006-11-09 | Develogen Aktiengesellschaft | Utilisation des inhibiteurs gsk-3 dans la prevention et le traitement des maladies auto-immunes pancreatiques |
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WO2011063115A1 (fr) | 2009-11-19 | 2011-05-26 | Braincells Inc. | Combinaison d'un agent nootropique avec un ou plusieurs agents neurogènes ou à effet neurogène par synergie pour stimuler ou intensifier la neurogenèse |
WO2011091033A1 (fr) | 2010-01-20 | 2011-07-28 | Braincells, Inc. | Modulation de la neurogenèse par des agents ppar |
EP2377531A2 (fr) | 2006-05-09 | 2011-10-19 | Braincells, Inc. | Neurogénèse par modulation de l'angiotensine |
EP2377530A2 (fr) | 2005-10-21 | 2011-10-19 | Braincells, Inc. | Modulation de neurogénèse par inhibition PDE |
US8084621B2 (en) | 2006-12-04 | 2011-12-27 | Jiangsu Simcere Pharmaceutical R&D Co. Ltd. | 3-Pyrrolo[b]cyclohexylene-2-dihydroindolinone derivatives and uses thereof |
US10703718B2 (en) | 2014-03-14 | 2020-07-07 | City Of Hope | 5-bromo-indirubins |
US11306072B2 (en) | 2013-03-14 | 2022-04-19 | City Of Hope | 5-bromo-indirubins |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007099402A2 (fr) * | 2005-12-23 | 2007-09-07 | Centre National De La Recherche Scientifique (Cnrs) | Nouvelles indirubines substituees en 3' et 7 et leurs applications |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997041854A1 (fr) * | 1996-05-07 | 1997-11-13 | The Trustees Of The University Of Pennsylvania | Inhibiteurs de glycogene synthetase kinase-3 et procedes d'identification et d'utilisation de ces inhibiteurs |
EP0966963A1 (fr) * | 1998-05-29 | 1999-12-29 | Gerhard Prof. Dr. Eisenbrand | Utilisation des bisindole indigoides comme inhibiteurs de CDK1 |
-
1999
- 1999-11-23 FR FR9914749A patent/FR2801216A1/fr active Pending
-
2000
- 2000-11-23 EP EP00985309A patent/EP1231916A2/fr not_active Withdrawn
- 2000-11-23 JP JP2001539434A patent/JP2003514850A/ja active Pending
- 2000-11-23 CA CA002387591A patent/CA2387591A1/fr not_active Abandoned
- 2000-11-23 WO PCT/FR2000/003264 patent/WO2001037819A2/fr not_active Application Discontinuation
- 2000-11-23 AU AU21770/01A patent/AU2177001A/en not_active Abandoned
Cited By (29)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2002030410A3 (fr) * | 2000-10-10 | 2002-07-11 | Univ Texas | Suppression de l'activite de kinase cycline-dependante pour la prevention et le traitement des infections |
WO2002074742A3 (fr) * | 2001-03-16 | 2003-02-20 | Schering Ag | Derives d'indirubine inhibiteurs de cdk ayant une solubilite elevee |
WO2002092079A1 (fr) * | 2001-05-17 | 2002-11-21 | Schering Aktiengesellschaft | Utilisation de derives d'indirubine selectifs en tant qu'inhibiteurs du vegf-r |
WO2002100401A1 (fr) * | 2001-06-11 | 2002-12-19 | Schering Aktiengesellschafat | Derives d'indirubine inhibiteurs de cdk solubles |
DE10129028A1 (de) * | 2001-06-11 | 2003-01-02 | Schering Ag | Lösliche Cdk-inhibitorische Indirubinderivate |
RU2297243C2 (ru) * | 2001-09-27 | 2007-04-20 | Алькон, Инк. | Ингибиторы киназы-3 гликогенсинтазы (gsk-3) для лечения глаукомы |
WO2003027275A1 (fr) | 2001-09-27 | 2003-04-03 | Alcon, Inc. | Inhibiteurs de la glycogene synthase kinase-3 (gsk-3) pour le traitement du glaucome |
EP2281560A1 (fr) | 2001-09-27 | 2011-02-09 | Alcon, Inc. | Inhibiteurs de la glycogène synthase kinase-3 (GSK-3) pour traiter la neuropathie optique du glaucome |
US7598288B2 (en) | 2001-09-27 | 2009-10-06 | Alcon, Inc. | Inhibitors of glycogen synthase kinase-3 (GSK-3) for treating glaucoma |
WO2004039797A1 (fr) * | 2002-10-29 | 2004-05-13 | Jingcai Cheng | Composes d'indole de type special, leur preparation et leur utilisation pour le traitement et la prevention de maladies telles que le cancer |
WO2004091663A1 (fr) * | 2003-04-18 | 2004-10-28 | Kyowa Hakko Kogyo Co., Ltd. | Medicament pour la regeneration des nerfs |
WO2005070416A1 (fr) * | 2004-01-27 | 2005-08-04 | Anygen Co., Ltd. | Derives d'indirubine possedant une propriete anti-cancer contre la lignee cellulaire du cancer humain |
WO2006117212A2 (fr) | 2005-05-04 | 2006-11-09 | Develogen Aktiengesellschaft | Utilisation des inhibiteurs gsk-3 dans la prevention et le traitement des maladies auto-immunes pancreatiques |
EP2258358A2 (fr) | 2005-08-26 | 2010-12-08 | Braincells, Inc. | Neurogenèse avec un inhibiteur de l'acetylcholinestérase |
EP2258359A2 (fr) | 2005-08-26 | 2010-12-08 | Braincells, Inc. | Neurogenèse par modulation des récepteurs muscariniques avec sabcomeline |
EP2258357A2 (fr) | 2005-08-26 | 2010-12-08 | Braincells, Inc. | Neurogenèse avec inhibiteur de l'acetylcholinestérase |
EP2275095A2 (fr) | 2005-08-26 | 2011-01-19 | Braincells, Inc. | Neurogenese par modulation des recepteurs muscariniques |
EP2275096A2 (fr) | 2005-08-26 | 2011-01-19 | Braincells, Inc. | Neurogenese par modulation des recepteurs muscariniques |
EP2377530A2 (fr) | 2005-10-21 | 2011-10-19 | Braincells, Inc. | Modulation de neurogénèse par inhibition PDE |
EP2314289A1 (fr) | 2005-10-31 | 2011-04-27 | Braincells, Inc. | Modulation de la neurogenese dont la médiation est assurée par récepteur gaba |
EP2377531A2 (fr) | 2006-05-09 | 2011-10-19 | Braincells, Inc. | Neurogénèse par modulation de l'angiotensine |
EP2382975A2 (fr) | 2006-05-09 | 2011-11-02 | Braincells, Inc. | Neurogénèse par modulation d'angiotensine |
US8084621B2 (en) | 2006-12-04 | 2011-12-27 | Jiangsu Simcere Pharmaceutical R&D Co. Ltd. | 3-Pyrrolo[b]cyclohexylene-2-dihydroindolinone derivatives and uses thereof |
WO2010099217A1 (fr) | 2009-02-25 | 2010-09-02 | Braincells, Inc. | Modulation de neurogenèse à l'aide de combinaisons de d-cyclosérine |
WO2011063115A1 (fr) | 2009-11-19 | 2011-05-26 | Braincells Inc. | Combinaison d'un agent nootropique avec un ou plusieurs agents neurogènes ou à effet neurogène par synergie pour stimuler ou intensifier la neurogenèse |
WO2011091033A1 (fr) | 2010-01-20 | 2011-07-28 | Braincells, Inc. | Modulation de la neurogenèse par des agents ppar |
US11306072B2 (en) | 2013-03-14 | 2022-04-19 | City Of Hope | 5-bromo-indirubins |
US10703718B2 (en) | 2014-03-14 | 2020-07-07 | City Of Hope | 5-bromo-indirubins |
US11964941B2 (en) | 2014-03-14 | 2024-04-23 | City Of Hope | 5-Bromo-indirubins |
Also Published As
Publication number | Publication date |
---|---|
FR2801216A1 (fr) | 2001-05-25 |
WO2001037819A3 (fr) | 2002-06-13 |
EP1231916A2 (fr) | 2002-08-21 |
JP2003514850A (ja) | 2003-04-22 |
CA2387591A1 (fr) | 2001-05-31 |
AU2177001A (en) | 2001-06-04 |
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