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WO1996004906A1 - Composes utiles pour le traitement de la restenose - Google Patents

Composes utiles pour le traitement de la restenose Download PDF

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Publication number
WO1996004906A1
WO1996004906A1 PCT/GB1995/001899 GB9501899W WO9604906A1 WO 1996004906 A1 WO1996004906 A1 WO 1996004906A1 GB 9501899 W GB9501899 W GB 9501899W WO 9604906 A1 WO9604906 A1 WO 9604906A1
Authority
WO
WIPO (PCT)
Prior art keywords
dione
carbazole
defined above
pyrrolo
indolo
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/GB1995/001899
Other languages
English (en)
Inventor
Robert William Bonser
Martin John Slater
George Stuart Cockerill
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wellcome Foundation Ltd
Original Assignee
Wellcome Foundation Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Wellcome Foundation Ltd filed Critical Wellcome Foundation Ltd
Priority to AU31875/95A priority Critical patent/AU3187595A/en
Publication of WO1996004906A1 publication Critical patent/WO1996004906A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • 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
    • A61K31/407—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 other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline

Definitions

  • the present invention is concerned with compounds having use in the prophylaxis or treatment of restenosis.
  • the invention relates to the use of these compounds in the manufacture of medicaments for the prophylaxis or treatment of restenosis, to medicaments obtained thereby, and to a method for treatment to prevent or alleviate restenosis using the compounds ofthe invention or a medicament containing said compounds.
  • Restenosis can occur following a number of surgical techniques, for example, transplant surgery, vein grafting, coronary by-pass grafting and, most commonly, following angioplasty.
  • Angioplasty is a surgical technique wherein atherosclerotic stenoses in the peripheral, renal and coronary vasculature are opened up by compressing and/or tearing the plaque on the vessel walls, typically by means of a pressurised balloon catheter.
  • a pressurised balloon catheter typically by means of a pressurised balloon catheter.
  • Alternatives to the balloon catheter such as pulsed lasers and rotary cutters, have been developed with a view to reducing or preventing restenosis following angioplasty, but have met with limited success.
  • a number of drugs including anti-coagulants and vasodilators have also been tried with disappointing or equivocal results.
  • vascular smooth muscle cells SMC
  • extracellular matrix material SMC
  • PDGF platelet-derived growth factor
  • Patent applications WO 93/18766 and WO 95/07910 disclose indole derivatives and their use in medical therapy. It is these compounds which we have now found to be useful in the prophylaxis or treatment of restenosis.
  • R.1 and R ⁇ are independently selected from:
  • R 6 is Cj_6 alkyl, C3.7 cycloalkyl, aryl (for example phenyl), arylalkyl (for example benzyl), C2-6 alkenyl, or H,
  • R 7 and R are independently selected from H, -COR 6 (where R 6 is as defined above), C3_7cycloalkyl, aryl, and arylalkyl, or R 7 and R** together with the N atom to which they are attached form a 3-, 4-, 5- or 6- membered heterocyclic ring (for example piperidine, pyrrolidine) in which from 1 to 3 ofthe carbon atoms are replaced by heteroatoms independently selected from O, N and S (for example, morpholino, piperazine) which ring may where possible be partially or completely unsaturated, and
  • alkyl, alkenyl or cycloalkyl moiety may be optionally substituted by one or more substituents selected from: halogen, cyano, nitro, azido,
  • R 8 are as defined above), heterocycle, -NH-heterocycle, heteroaryl, and aryl (for example phenyl, pyridyl, furyL, thienyl, pyrrole, naphthyl) optionally substituted by one or more substituents selected from -OR 6 , -NR 7 R 8 , -SR 6 , -SO2R 6 , -CO 2 R 6 , nitro, cyano, SCN, C ⁇ galkyl, C3_6cycloalkyl, haloalkyl (for example trifluoromethyl), hydroxylalkyl, -CONH2, halogen and methylenedioxy, (where
  • R 6 ,R 7 , and R 8 are each as defined above);
  • R 3 is selected from:
  • R 4 and R-> either together with the carbon atom to which they are attached form a carbonyl group (> O) or R 4 is H and R 5 is selected from H, -OR 6 ,and -SR 6 , (where R 6 is as defined above);
  • a and B which may be the same or different, together with the carbon atoms to which they are attached each represent a phenyl ring in which from 1 to 3 carbon atom(s) may be replaced by nitrogen atom(s), the nitrogen atom(s) being optionally substituted with an oxide group;
  • a and B are optionally substituted by one or more ring substituent(s) selected from:
  • -Ci.Qa&yl optionally substituted by -OR 6 (where R 6 is as defined above), halogen (for example trifluoromethyl), or -NR 7 R 8 (where R 7 and R 8 are as defined above),
  • R 3 is not -CH2OR 6 or -CH2N 7 R 8 and rings A and B are not substituted by -NHCOR 6 , (where R 6 , R 7 , and R 8 are as defined above);
  • Preferred compounds of formula (I) are as defined above wherein R 3 is hydrogen and R 4 and B ⁇ together with the carbon atom to which they are attached fo ⁇ n a carbonyl group; or a physiologically functional derivative thereof or a solvate of any thereof.
  • Preferred compounds of formula (I) include:
  • R 1 is H and R 2 is:
  • -C 2 -4alkyl optionally substituted by one or more substituents selected from: -OR 6 ', halogen, cyano, and -NR 7 ⁇ 8 ', where R 6 ' is Chalky., C2_6a*U ⁇ nyl, or H, where R 7 ' is H and R 8 ' is Chalky!; R 3 is H
  • a and B together with the carbon atoms to which they are attached each represent a phenyl ring optionally substituted by one or more ring substituent(s) selected from:
  • R 2 is not ethyl or 2,3- dihydroxypropyl
  • Preferred compounds of formula (IA) are as defined above where at least one of the phenyl rings A and B is substituted by one or more substituents as defined above.
  • Preferred compounds of formula (IA) include:
  • alkyl as a group or part of a group means a straight or branched chain alkyl group. Such alkyl groups preferably have from 1 to 3 carbon atoms.
  • aryl as a group or part of a group includes phenyl, pyridyl, naphthyl, pyrrolo, thienyl, furyl
  • heteroaryl includes a 5- or 6- membered ring where from 1 to 3 atom(s) are selected from N, O, and S, optionally fused to an aryl ring (for example quinolyl, isoquinolyl, benzimidazolyl, benzotriazolyl, benzothienyl, benzoxazolyl, benzothiazolyl, etc.), and the term heterocycle includes a 5- or 6- membered ring where from 1 to 3 carbon atom(s) are replaced by atom(s) selected from N, O, and S (for example morph
  • Preferred esters in accordance with the invention include carboxylic acid esters in which the non-carbonyl moiety ofthe carboxylic acid portion ofthe ester grouping is selected from straight or branched chain alkyl (for example, methyl, n-propyl, t-butyl, or n- butyl), cycloalkyl, alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted by, for example, halogen, Cj_4 alkyl, or Cj_4 alkoxy), or amino; sulphonate esters, such as alkyl- or aralkylsulphonyl (for example, methanesulphonyl); amino acid esters (for example, L-valyl or L-isoleucyl); and mono-, di-, or tri-phosphate esters.
  • any alkyl moiety present advantageously contains from 1 to 18 carbon atoms, particularly from 1 to 6 carbon atoms, more particularly from 1 to 4 carbon atoms.
  • Any cycloalkyl moiety present in such esters advantageously contains from 3 to 6 carbon atoms.
  • Any aryl moiety present in such esters advantageously comprises a phenyl group.
  • Examples of pharmaceutically acceptable salts of the compounds of formula (I) and physiologically functional derivatives thereof include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium), ammonium and X4 + (wherein X is salts derived from an appropriate acid, for example, organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic and succinic acids, organic sulphonic acids, such as methanesulphonic, ethanesulphonic, benzenesulphonic and p-toluenesulphonic acids, and inorganic acids, such as hydrochloric, sulphuric, phosphoric and sulphamic acids.
  • an appropriate base such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium), ammonium and X4 +
  • X is salts derived from an appropriate acid, for example, organic carboxylic acids such as
  • physiologically functional derivative means a chemical derivative, for example a physiologically acceptable salt, ester, or salt of such ester, of a compound of formula (I) or (IA) which has the same physiological function as the free compound of formula (I) or (IA), for example, by being convertible in the body to the free compound of formula (I) or (IA) or an active metabolite or residue thereof.
  • the present invention further includes a method for the treatment of a mammal, such as a human, to prevent or alleviate restenosis, for example, restenosis following angioplasty which comprises the adrrjinistration of a therapeutically effective amount of a compound of formula (I) or (IA) or a physiologically functional derivative thereof or a solvate of any thereof.
  • a compound of the invention is used hereinafter to describe a compound of formula (I) or (IA) or any of its physiologically functional derivatives, or solvates of any thereof.
  • a suitable daily dose for a mammal is in the range 0.5 to 120mg of compound/kilogram bodyweight, the preferred daily dosage being 2 to 60mg kg, which may be administered as two or more sub-doses daily.
  • a compound of the invention While it is possible for a compound of the invention to be administered alone, it is preferable to present it as a pharmaceutical formulation comprising the compound of the invention in association with a pharmaceutically acceptable carrier or excipient and, optionally, one or more other therapeutic ingredients.
  • the present invention also provides pharmaceutical formulations for use in the prophylaxis or treatment of restenosis, for example, restenosis following angioplasty containing a compound of formula (I) or (IA) or a physiologically functional derivative thereof or a solvate of any thereof, at least one pharmaceutical carrier or excipient and, optionally, one or more other therapeutic ingredients.
  • the pharmaceutical carrier or excipient must, of course, be compatible with the other ingredients in the formulation and must not be detrimental to the patient.
  • the active ingredient may comprise from 0.1% to 99.9% by weight of the formulation.
  • Typical unit doses of a pharmaceutical formulation according to the invention contain from 1 to 1500mg and preferably from 10 to 700mg ofthe active ingredient.
  • compositions according to the invention may be adapted for administration by oral or parenteral (including intravenous, intradermal or intramuscular) routes, or may also be administered during the surgical procedure via an angioplasty cannula (for example, a l-50mg dose); by this means the formulated drug is introduced at the site of the angioplasty through perforations in the balloon catheter used to open up the atherosclerotic stenosis.
  • the resulting restenosis may be 'held open' by means of a tubular stent which may be impregnated with a compound of the invention which gradually leaches into the site of the angioplasty.
  • compositions of the invention may conveniently be presented in unit dosage form and may be prepared by any method known in the art of pharmacy. Such methods include the step of bringing the active ingredient into association with a carrier or excipient and, optionally, containing one or more accessory ingredients. In general, pharmaceutical formulations are prepared by uniformly and ultimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier, or both, and then, if desired, shaping the product into the required form.
  • compositions adapted for oral administration may be in the form of discrete units such as capsules, cachets, tablets, or lozenges, each containing a predetermined amount ofthe active ingredient; in the form of a powder or granules; in the form of a solution or suspension in an aqueous or non-aqueous liquid; edible foams or whips; or in the form of an oil-in-water or water-in-oil emulsion.
  • the formulation may also be in the form of a bolus, electuary, or paste.
  • a tablet may be made by compressing or moulding the active ingredient, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent and/or surface active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered active ingredient and a suitable carrier or excipient moistened with an inert liquid diluent.
  • compositions adapted for parenteral administration typically comprise a sterile aqueous or non-aqueous preparation of the active ingredient (where necessary, solubilised in a small amount of an appropriate organic solvent) which may contain anti ⁇ oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the patient.
  • Such formulations may also be in the form of aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition ofthe sterile liquid carrier, for example, water for injections, immediately prior to use.
  • sterile liquid carrier for example, water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.
  • compositions suitable for administration via an angjoplasty cannula are typically the same as those used for intravenous administration.
  • the formulations may include one or more additional ingredients conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
  • the compounds of the invention may be prepared by one or more of the methods described in WO 93/18766, WO 93/24491, and pending WO 95/07910 which are incorporated herein by reference.
  • the following compound was prepared by a similar method, replacing propyl iodide with 2-iodo- 1 , 1 , 1 -trifluoroethane.
  • Triethyloxonium tetrafluroborate (3.99g) was added to a suspension of indole-3- acetamide (3.48g, 20mmol) in dichloromethane (100ml) and the mixture warmed gently to effect dissolution. After stirring for 2 hours at room temperature, ethyldiisopropylamine (14ml) was added (solution A).
  • Example 2 (2.3g) in methanolic potassium hydroxide solution (0.1M, 400ml) was heated under reflux for 9.5 hours. The methanol was evaporated in vacuo. HC1 (2N, 200ml) added to give a solution of pH 1-2, the mixture extracted with ethyl acetate (300ml), the organic layer separated, washed with brine and dried (Na2SO4). Evaporation afforded the product as a red solid.
  • Example 7C 12-f 2.2.2-Trifluoroethvn- 12.13-dihvdro-5H-indolo[2.3 a]pyrrolor3 ,4c1carbazole- 5.7r6HVdione
  • the "active ingredient" in the following formulation example is a compound of the invention as defined above.
  • Confluent monolayers of rat aortic smooth muscle cells were incubated in Dulbecco's Modified Eagles Media (DMEM) plus 0.2% foetal calf serum for 24hrs. After this period the cells were stimulated with PDGF in the presence or absence of inhibitor. The assay was terminated by harvesting the cells on ice in a lysis buffer. (5mM Tris pH8.0, 1% NP40, 150mM NaCl).
  • the cell lysates were prepared for polyacrylamide gel electrophoresis by boiling with sodium dodecylsulphate (SDS) sample buffer (0.3125M Tris pH 6.8, 10% SDS, 50% glycerol 5mM dithiothreitol (DTT)) and separated using a discontinuous polyacrylamide gel electrophoresis system as described in Nature, 227, 680 (1970), Laemelli.
  • SDS sodium dodecylsulphate
  • DTT dithiothreitol
  • the separated phosphorylated proteins were transferred onto nitrocellulose membrane (Scheicher and Schuell. Anderman Comments, Surrey) using an eletrophoretic Western blotting technique based on a method described in Anal. Biochem., 112. 195, (1981),Burnette.
  • the phosphotyrosine proteins were detected immunocytochemically using a mouse anti- phosphotyrosine monoclonal 4G10 (UBI Lake Placid, NY) followed by a second sheep anti-mouse IgG monoclonal with a radioiodinated label (Amersham Int., Little Chalfont, Bucks). The proteins were then visualised and quantitated using a PhospholmagerTM (Molecular Dynamics Sevenoaks, Kent). When tested in this assay, representative compounds of the invention were found to significantly inhibit PDGFr tyrosine kinase at a concentration of l ⁇ M.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composés de formule (I) utilisés dans la prophylaxie ou le traitement de la resténose. Cette invention concerne plus particulièrement l'utilisation de ces composés dans la fabrication de médicaments destinés à la prophylaxie ou au traitement de la resténose; les médicaments obtenus de cette manière; ainsi qu'un procédé de traitement permettant de prévenir ou d'atténuer la resténose à l'aide des composés de cette invention ou d'un médicament contenant ces derniers.
PCT/GB1995/001899 1994-08-13 1995-08-11 Composes utiles pour le traitement de la restenose Ceased WO1996004906A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU31875/95A AU3187595A (en) 1994-08-13 1995-08-11 Compounds for the treatment of restenosis

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9416467.0 1994-08-13
GB9416467A GB9416467D0 (en) 1994-08-13 1994-08-13 Compounds for use in medicine

Publications (1)

Publication Number Publication Date
WO1996004906A1 true WO1996004906A1 (fr) 1996-02-22

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PCT/GB1995/001899 Ceased WO1996004906A1 (fr) 1994-08-13 1995-08-11 Composes utiles pour le traitement de la restenose

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AU (1) AU3187595A (fr)
GB (1) GB9416467D0 (fr)
WO (1) WO1996004906A1 (fr)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6313143B1 (en) * 1999-12-16 2001-11-06 Hoffmann-La Roche Inc. Substituted pyrroles
FR2826653A1 (fr) * 2001-06-29 2003-01-03 Servier Lab Nouveaux derives de pyrido-pyrido-pyrrolo[3,2-g]pyrrolo [3,4-e]-indole et pyrido-pyrrolo[2,3-a]pyrrolo[3,4-c] carbazole, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
JP2003507480A (ja) * 1999-08-20 2003-02-25 セフアロン・インコーポレーテツド 異性体の縮合ピロロカルバゾール類およびイソインドロン類
WO2003027275A1 (fr) 2001-09-27 2003-04-03 Alcon, Inc. Inhibiteurs de la glycogene synthase kinase-3 (gsk-3) pour le traitement du glaucome
ES2189597A1 (es) * 2000-07-18 2003-07-01 Fundacion Universitaria San Pablo-Ceu Derivados de 12,13-dihidro-5h-indolo(2,3-a)pirrolo(3,4-c)carbazol-5,7(6h)-diona como agentes antineoplasicos.
DE10161940A1 (de) * 2001-12-17 2003-07-03 Nad Ag N-Carbacyclus-monosubstitutierte Indolocarbazole als Proteinkinase-inhibitoren
US6641611B2 (en) 2001-11-26 2003-11-04 Swaminathan Jayaraman Therapeutic coating for an intravascular implant
US7202266B2 (en) * 2003-07-17 2007-04-10 Plexxikon, Inc. PPAR active compounds
US7348338B2 (en) 2003-07-17 2008-03-25 Plexxikon, Inc. PPAR active compounds
US7531568B2 (en) 2004-11-30 2009-05-12 Plexxikon, Inc. PPAR active compounds
US8053463B2 (en) 2007-03-08 2011-11-08 Plexxikon Inc. PPAR active compounds
WO2016008966A1 (fr) 2014-07-17 2016-01-21 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés pour le traitement de maladies liées à la jonction neuromusculaire
WO2016207366A1 (fr) 2015-06-26 2016-12-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes et compositions pharmaceutiques de traitement d'infections virales

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993018766A1 (fr) * 1992-03-20 1993-09-30 The Wellcome Foundation Limited Autres derives d'indole presentant une action antivirale

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WO1993018766A1 (fr) * 1992-03-20 1993-09-30 The Wellcome Foundation Limited Autres derives d'indole presentant une action antivirale

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Title
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CHEMICAL ABSTRACTS, vol. 107, no. 3, Columbus, Ohio, US; abstract no. 17329q, H. NAKANO ET AL.: "Staurosporine inhibits tyrosine-specific protein kinase activity of Rous sarcoma virus transforming protein" page 27; *
CHEMICAL ABSTRACTS, vol. 112, no. 21, Columbus, Ohio, US; abstract no. 191499h, R. OLSEN ET AL.: "Staurosporine inhibition of intracellular free calcium transients in mitogen-stimulated Swiss 3T3 fibroblasts" page 31; *
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Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003507480A (ja) * 1999-08-20 2003-02-25 セフアロン・インコーポレーテツド 異性体の縮合ピロロカルバゾール類およびイソインドロン類
JP4776842B2 (ja) * 1999-08-20 2011-09-21 セフアロン・インコーポレーテツド 異性体の縮合ピロロカルバゾール類およびイソインドロン類
US6313143B1 (en) * 1999-12-16 2001-11-06 Hoffmann-La Roche Inc. Substituted pyrroles
ES2189597A1 (es) * 2000-07-18 2003-07-01 Fundacion Universitaria San Pablo-Ceu Derivados de 12,13-dihidro-5h-indolo(2,3-a)pirrolo(3,4-c)carbazol-5,7(6h)-diona como agentes antineoplasicos.
US7001906B2 (en) 2001-06-29 2006-02-21 Les Laboratoires Servier Pyrido-pyrido-pyrrolo pyrrolo-indole and pyrido-pyrrolo pyrrolo carbazole derivatives, method for the production thereof and pharmaceutical compositions containing said derivatives
FR2826653A1 (fr) * 2001-06-29 2003-01-03 Servier Lab Nouveaux derives de pyrido-pyrido-pyrrolo[3,2-g]pyrrolo [3,4-e]-indole et pyrido-pyrrolo[2,3-a]pyrrolo[3,4-c] carbazole, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
WO2003002563A1 (fr) * 2001-06-29 2003-01-09 Les Laboratoires Servier Derives de pyrido-pyrido-pyrrolo pyrrolo-indole et pyrido-pyrrolo pyrrolo carbazole, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
US7598288B2 (en) 2001-09-27 2009-10-06 Alcon, Inc. Inhibitors of glycogen synthase kinase-3 (GSK-3) for treating glaucoma
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
US6641611B2 (en) 2001-11-26 2003-11-04 Swaminathan Jayaraman Therapeutic coating for an intravascular implant
DE10161940A1 (de) * 2001-12-17 2003-07-03 Nad Ag N-Carbacyclus-monosubstitutierte Indolocarbazole als Proteinkinase-inhibitoren
US7262215B2 (en) 2001-12-17 2007-08-28 Nad Ag N-carbacycle monosubstituted indolocarbazoles as protein kinase inhibitors
US7348338B2 (en) 2003-07-17 2008-03-25 Plexxikon, Inc. PPAR active compounds
US7491831B2 (en) 2003-07-17 2009-02-17 Plexxikon, Inc. PPAR active compounds
US7723374B2 (en) 2003-07-17 2010-05-25 Plexxikon, Inc. PPAR active compounds
US7476746B2 (en) 2003-07-17 2009-01-13 Plexxikon, Inc. PPAR active compounds
US7202266B2 (en) * 2003-07-17 2007-04-10 Plexxikon, Inc. PPAR active compounds
US8367828B2 (en) 2003-07-17 2013-02-05 Plexxikon Inc. PPAR active compounds
US7531568B2 (en) 2004-11-30 2009-05-12 Plexxikon, Inc. PPAR active compounds
US8053463B2 (en) 2007-03-08 2011-11-08 Plexxikon Inc. PPAR active compounds
WO2016008966A1 (fr) 2014-07-17 2016-01-21 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés pour le traitement de maladies liées à la jonction neuromusculaire
WO2016207366A1 (fr) 2015-06-26 2016-12-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes et compositions pharmaceutiques de traitement d'infections virales

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