WO1991009034A1 - Indolocarbazols provenant de saccharothrix aerocolonigenes subsp. copiosa subsp. nov. scc 1951, atcc 53856 - Google Patents

Indolocarbazols provenant de saccharothrix aerocolonigenes subsp. copiosa subsp. nov. scc 1951, atcc 53856 Download PDF

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WO1991009034A1
WO1991009034A1 PCT/US1990/007174 US9007174W WO9109034A1 WO 1991009034 A1 WO1991009034 A1 WO 1991009034A1 US 9007174 W US9007174 W US 9007174W WO 9109034 A1 WO9109034 A1 WO 9109034A1
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compound
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taken together
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scc
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PCT/US1990/007174
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Ellen B. Barrabee
Ann C. Horan
Frank A. Gentile
Mahesh G. Patel
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Schering Corporation
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20—Bacteria; Culture media therefor
    • C12N1/205—Bacterial isolates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
    • C12P17/182—Heterocyclic compounds containing nitrogen atoms as the only ring heteroatoms in the condensed system
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales

Definitions

  • This invention relates to indolocarbazotes, e xciuding the N-alkanoylstaurosporine derivatives, isolated from an antimicrobial, eg. antibacterial/ant ⁇ fungal indolocarbazole com plex produced by
  • the indolocarbazoles of this invention exhibit selective pharmacological activities, for example in cardiovascular disorders; especially anti hypertensive activity, against proliferation of tumor cells, on inflammation as well as on microbial infections such as caused by bacteria or fungi.
  • staurosporin derivative including N-acetyl staurosporine are disclosed in WIPO 89/07105 by Murakata et al. of KYOWA HAKKO KOGYO Co. Ltd. on August 1989 as protein Kinase C inhibitors and cell growth inhibitors.
  • N-acetylstaurosporine is disclosed and in Australian Patent Application - 17571/88 by CIBA-Geigy on December 15, 1988 as a N-substituted derivative of staurosporine being capable of selective modification of the activity of protein kinase C and as such can be useful for the preventive or curative treatment of diseases in which the inhibition of protein kinase C is of importance in a warm blooded animal as well as can be employed as medicaments for tumor-inhibition, inflammation-inhibition, immunomodulation and also in preparations for combating bacterial infections, arteriosclerosis, as well as other diseases of the
  • cardiovascular system cardiovascular system and of the central nervous system.
  • novel indolocarbazoles of this invention have selective pharmacological properties which are distinguishable from those of the known indolocarbazoles.
  • R a and R b are each H or R a and R b taken together are
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a compound of formula I and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition of this invention may be administered to warm-blooded animals to inhibit myosin light chain kinase, protein kinase C or tumor cell proliferation or to produce an anti-hypertensive effect or an anti-inflammation effect.
  • the present invention still further provides a method of treating a warm-blooded animal afflicted by hypertension, which comprises administering to said animal a therapeutically effective amount of a compound represented by formula I sufficient to treat hypertension or a pharmaceutical composition thereof.
  • the present invention further provides a method of treating inflammation in a warm-blooded animal which comprising administering t ⁇ said animal an anti-inflammatory effective amount of a compound of formula I or a pharmaceutical composition thereof.
  • the compounds of this invention are novel
  • indolocarbazoles which are isolated. along with N-acetylstaurosporine and known indolocarbazoles such as staurosporine from an antibiotic complex produced by cultivating a strain of Saccharothrix
  • aerocolonigenes subsp. copiosa subsp. nov, SCC 1951 having the identifying characteristics of ATCC 53856 in a pH and temperature controlled aqueous nutrient medium having assimilable sources of carbon and nitrogen under controlled submerged aerobic conditions until a composition of matter having substantial inhibition at myosin light chain kinase (“MLCK”) activity is produced.
  • MLCK myosin light chain kinase
  • This invention also provides a process for producing th e indolocarbazole complex of this invention which comprises cultivating an antibiotic complex producing strain of Saccharathrix
  • indolocarbazoles of formula I is a biologically pure culture of the microorganisms Saccharothrix aerocolonigenes subsp. copiosa subsp. nov having the identifying characteristics of ATCC 53856, said culture being capable of producing an indolocarbazole complex in a
  • the indolocarbazole compounds of this invention were isolated trom an imdolocabazole complex obtained from a culture broth produced by a fermentation under controlled conditions of a biologically pure culture of the microorganism, Saccharothrix aerocolonigenes suhsp-copiosa subsp nov. SCC 1951,.ATCC 53856.
  • a viable culture of this microorganism has been deposited on January 17, 1989 in the collection of the American Type Culture Collection (ATCC) in Rockville, Md., where it has been assigned accession num ber ATCC 53856 and found viable on January 23, 1989.
  • ATCC American Type Culture Collection
  • Inoculum for the biochemical and physiological tests was prepared by adding 1.0 mL of thawed culture suspension to 10 mL of clear broth in a testrtube which was placed on a rotary shaker (300 rpm) at 28-30°C for 3 to 5 days. The culture was harvested by centrifugation and washed three times with distilled water. The final pellet was resuspended in distilled water to 4 times the packed cell volume.
  • Incubation temperature for the biochemical and physiological tests was 28°C. Readings of the results were made at various times up to 21 days for the plate media. Most of the tubed media were read at weekly intervals for 4 to 6 weeks.
  • Strain SCC 1951 was isolated from a soil collected in Spain and is a filamentous organism that forms a well developed, moderately branching substrate mycelium with hyphae approximately 0.4 ⁇ m to 0.6 ⁇ m in diameter. The vegetative mycelium fragments into coccoid to bacillary elements.
  • Purified cell wall preparations of SCC 1951 analyzed by the method of Becker [Becker et al., Appl., Microbial.12, 421-423 (1964)] contain the meso-isomer of 2,-6-diaminopimelic acid, alanine, glutamic acid, glucosamine, muramic acid and galactose (Type III).
  • Lechevalier, M.P., J. Lab. Clin. Med. 71 , 934-944 (1968)] contain gatactose, glucose, mannose, ribose, rhamnose and a trace of madurose.
  • the method of Becker [Becker et al., Appl., Microbial.12, 421-423 (1964)] contain the meso-isomer of 2,-6-diaminopimelic acid, alanine, glutamic acid, glucosamine, muramic acid and galact
  • phospholipids present are diphosphatidylglycerol, phosphatidylinositol, phosphatidylinositol mannosides, phosphatidylethanolamine acylated to both hydroxy and branched chain fatty acids and a minor unknown (Type PII).
  • the substrate mycelium of SCC 1951 varies from cream to orange yellow to dark yellow brown to brownish black.
  • the aeriat mycelium is usually white and tends to be thin.
  • the white aerial mycelium turns yellow as it ages and:
  • SCC 1951 was placed in the genus Saccharothrix.
  • the description of SCC 1951 was compared with the descriptions of those Saccharothrix species listed on the Approved Lists of Bacterial Names or found in the patent literature: Saccharothrix australiensis. S. espanaensis., and S. aerocolonigenes.
  • SCC 1951 is easily differentiated from S. australiensis and S. espanaensis.
  • S. australiensis produces melanin, fails to grow on ISP 9 with any carbon source and does not hydrolyze starch or
  • SCC 1951 The description of SCC 1951 , however, closely resembles that of S. aerocolonigenes and SCC 1951 was compared directly with S. aerocolonigenes ATCC 23870, the type strain. SCC 1951 differs from ATCC 23870 in producing acid from erythritol and destroying the cttror ⁇ ophore in phenol reef. SCC 1951 also produces a reddish orange to brownish orange soluble pigment on carbon utilization medium ISP 9 with trehalose, galactose or ribose as the carbon source. These pigments were never observed on the ATCC 23870 plates.
  • Saccharothrix aerocolonigenes subsp. copiosa in reference to the large number of indolocarbazoles produced by this strain.
  • PKC Protein kinase C
  • Ca 2+ - and phospholipid-dependent protein kinase involved in mediating a wide variety of cellular responses to growth factors, hormones, oncogenes and other
  • staurosporine and related indolocarbazoles, K252a, and K252b are inhibitory to PKC (from rats' brains) with good potency, in the nanomoiar range. Staurosporine has also been shown to inhibit the growth of cells at concentrations which correlate with in vitro PKC inhibition and to have antitumor activity in-vivo.
  • staurosporine have high potency and thus are useful for biological studies but they have limited selectivity against protein kinases.
  • H. Nako et al. J. Antibiot., (1987) Vol. 40. pp. 706-708] disclose that staurosporine, for example, will inhibit cyclic AMP-dependent protein kinase, myosin light chain kinase (MLCK) and p60v-src tyrosine kinase with similar potencies.
  • MLCK myosin light chain kinase
  • N-acetylstaurosporines is a potent inhibitor of PKC with increased selectivity compared to staurosporine as evidenced by comparison of inhibition of PKC to that of MLCK.
  • Staurosporine and K- 252a have nanomolar potencies with MLCK to PKC ratios of 1.2 and 1.3 respectively.
  • N-aoetytstaurasporine also ex hibits selective inhibition of MLCK and PKC with IC 50 's in the nanomolar range and has a MLCK to PKC ratio of 4.7.
  • the PKC was partially purified fro m rat brain and assayed in the presence of its activators: Ca 2+ ; phosphatidyserine and 1-oleoyl-2-acetylglycerol. Histone lll-S was used as phosphate acceptor.
  • the MLCK was native enzyme from chicken gizzard fully activated by calm ⁇ dulin. Kemptamide was usedas phosphate acceptor.
  • the compounds with good potency for PKC inhibition as well as selectivity of PKC inhibition relative to other protein kinases indicate in vivo utility as potential antitumor agents.
  • the compounds of this invention are potent inhibitors of PKC with increased selectivity compared to staurosporine as evidenced by comparison of inhibition of PKC to that of MLCK.
  • Staurosporine and K-252a have nanomolar potencies with MLCK to PKC ratios of 1.2 and 1.3 respectively.
  • the compounds of this invention exhibit selective inhibition of MLCK with IC 50 's in the range of 138 to > 1000 nM and PKC with IC 50 's in the range of 19 to 854 nM and MLCK to PKC ratios 1.2 to 18.8.
  • the PKC was partially purified from rat brain and assayed in the presence of its activators: Ca 2+ , phosphatidylserine and 1-oleoyl-2- acetylglycerol.
  • Histone lll-S was used as phosphate acceptor.
  • the MLCK was native enzyme from chicken gizzard fully activated by calmodulin.
  • Kemptamide was used as phosphate acceptor.
  • the compounds with good potency for PKC inhibition as well as selectivity of PKC inhibition relative to other protein kinases indicate in vivo utility as potential antitumor agents.
  • the compounds of this invention inhibited (a) serotonin release in human platelets which were prelabelled with [ 3 H] serotonin. Serotonin release from human platelets (IC 50 ranged from 0.95 to >50 ⁇ M) was measured following stimulation for one min with various doses of thrombin or at various times following addition of 1 unit/ml of thrombin. [T. Tohmatsu et al. Thrombosis Research, (1987), Vol. 47, pp. 25-35], (b) phorbot ester induced c-fos expression in cultured mouse BALB/C 3T3 cells which were exposed to the compounds of this invention for 20 hours prior to serum stimulation. The IC 50 's ranged from 0.6 ⁇ M to 5.4 ⁇ M. [T.
  • the antibiotic complex of this invention as well as the individual indolocarbazoles of this invention isolated therefrom were shown to be myosin light chain kinase inhibitors and phosphodiesterase inhibitors and as such have utilation in treating cardiovascular disorders.
  • the compounds of this invention exhibit antimicrobial properties and like K-252 indolocarbazoles exhibit diuretic properties.
  • the compounds of this invention exhibit selective inhibition of MLCK and PKC and thus exhibit anti-proliferation activity against tumors cells.
  • the present invention also provides a method of inhibiting tumor cell proliferation, which comprises contacting said tumor ceils with an anti-tumor cell proliferation effective amount of a compound of this invention represented by formula I or a pharmaceutical composition thereof.
  • the present invention also provides a. method of treating a warm-blooded animal afflicted by hypertension which comprises administering to said animal a therapeutically effective amount of a compound represented by formula I sufficient to treat hypertension, or apharmaceutrcal com position of a com pound represented by formula I.
  • the present invention provides a method of treating a warm-blooded animal afflicted with diseases wherein the inhibition of protein kinase C is of importance which comprises administering to said animal a therapeutically effective amount of a compound represented by formula I or a pharmaceutical composition thereof.
  • the present invention provides a method of treating inflammation (arthritis, bursitis, tendonitis, gout as well as other inflammatory conditions) in a warm-blooded animal by administering to such an animal an anti-inflammatory effective amount of a compound of formula I or a pharmaceutical composition thereof.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of this invention represented by formula I or a pharmaceutically acceptable salt thereof, in racemic or optically active form and an inert pharmaceutically acceptable carrier or diluent.
  • Typical suitable pharmaceutically acceptable salts are acid addition salts formed by adding to the compounds of this invention an equivalent of a mineral acid such as HCl, HF, HNO 3 , H 2 SO 4 or H 3 PO 4 or an organic acid, such as acetic, propionic, oxalic, valeric, oleic, palmitic, stearic, lauric, benzole, lactic, para-toluenesulfonic, methane sulfonic, citric, maleic, fumaric, succinic and the like.
  • a mineral acid such as HCl, HF, HNO 3 , H 2 SO 4 or H 3 PO 4
  • organic acid such as acetic, propionic, oxalic, valeric, oleic, palmitic, stearic, lauric, benzole, lactic, para-toluenesulfonic, methane sulfonic, citric, maleic, fumaric, succinic and the
  • compositions may be made up by combining the compounds of this invention or a pharmaceutically acceptable salt thereof with any suitable, i.e., inert pharmaceutical carrier or diluent and administered orally, parentally or topically in a variety of formulations.
  • suitable pharmaceutical co mpositions include solid compositions for oral administration such as tablets, capsules, pills, powders and granules, liquid compositions for oral administration such as solutions, suspensions or emulsions. They may also be
  • the actual preferred dosages of the compounds of this invention or pharmaceutically acceptable salts thereof will vary according to the particular compound being used, the particular composition formulated, the mode of application and the particular situs, host and disease being treated. Many factors that modify the action of the drug will be taken into account by the attending clinician, e.g. age, body weight, sex, diet, time of administration, rate of excretion, condition of the host, drug combinations, reaction sensitivities and severity of the disease. Administration can be carried out
  • Solvent used for column chromatography, and high pressure liquid chromatography (“HLPC”) were HPLC grade and not redistilled.
  • Water refers to in-house deionized water passed through a Millipore Milli-Q purification system.
  • the CHP-20P resin was purchased from Mitsubishi. Thin layer chromatography was carried out on
  • anisaldehyde spray reagent High pressure liquid chromatography was carried out using Waters model 510 HPLC pumps controlled by a Waters automated gradient controller: Compounds were monitored at 300 nm using a Hewlett Packard 1040A photodiode array ultraviolet (UV) detector. Ultraviolet spectra were measured on the Hewlett Packard 1040A photodiode array detector or on a Hewlett Packard 8450A UV/Vis spectrophotometer; infrared spectra were measured on a Nicolet 10-MX instrument. 1 H and 13 C NMR spectra were measured on a Varian 400 instrument at 400 and 100 mHz, respectively.
  • UV Hewlett Packard 1040A photodiode array ultraviolet
  • the indolocarbazoles of this invention were isolated from an indolocarbazole complex which was produced by fermentation of a biologically pure culture of Saccharothrix aerocolonigenes subsp.
  • the fermentation which produces the complex, was started using two or more inoculum stages.
  • Medium for the inoculum stages are listed below.
  • the inoculum and fermentation stages were conducted at a pH from about 6.4 to about 8.5, preferably about 7.0 for the inoculum stage and 7.5 for the fermentation stage.
  • a temperature of about 27°C to 35°C was used to grow the inoculum stages, and to conduct the fermentation stage a temperature of about 27°C-35oC: was used
  • Inoculum preparation was carried out in two stages for large scale fermentations (10L to 100L). Suitable nutrients for preparing the inocula are listed below:
  • Five liters of the second stage inoculu m were used to inoculate 100L of the fermentation medium. The fermentation was conducted for 66 hours at 30°C in a 150L NBS Fermatron with agitation and aeration at 270 rpm and 1.8 cfm, respectively.
  • the culture produced small quantities of a very complex mixture of indolocarbazoles.
  • an analytical HPLC chromatogram of a partially purified sample of the complex mixture about 20
  • indolocarbazole components including N-acetyl staurosporine were detected.
  • the isolation of the indolocarbazole complex was accompllshed through a series of silica gel and reverse-phase chromatographies.
  • the individual components were then obtained using size exclusion and reverse-phase semi-preparative HPLC. An exemplary procedure followed for various batch sizes is given hereinbelow.
  • the oil was then subjected to a second silica gel column (6-7L) using 5% methanol in dichloromethane (v/v) as eluant; 1L cuts were taken and analyzed as above.
  • the active fractions were then passed through a CHP-20P (IL) reverse-phase column and then eluted with 30, 50, 75 and 100% aq. ACN, the activity was found in the 50 and 75% fractions.
  • the material in the active fractions were subjected to chromatography using a second CHP-20P column using a continuous gradient of 30 to 100% aqueous acetonitrile as solvent to produce partially purified material.
  • the isolation of 2-3 component mixtures were achieved using LH-20 chromatography with 1 :1 dichloromethane/acetcnitrile as solvent.
  • HPLC HPLC.
  • the final step in purification was semi-preparative HPLC which was carried out on a YMC, C 18 reverse-phase column (15 ⁇ , 120 A, 30 x 500 mm) using a 30-40% aqueous acetonitrile gradient (UV at 375 nm, 35 mL/min flow rate). From 1000L batches, the indolocarbazole components (150 mg total) were isolated varying in weight from 1-30 mg including about 20 mg of N-acetyl-staurosporine.
  • UV MEOH 207 (26,000), 239 (19,000), 292 (sh, 24,000 ⁇ , 301 (30,000), 330
  • UV (MEOH); 206 (31,000), 238 (21,000), 293 (sh, 31,500), 300 (37,000), 340
  • UV (MEOH) 208 (29,000) , 239 (25,000), 232 (sh, 26,000), 301 (49,000) , 340
  • IR ( KBR) 3390, 1690, 1680, 1650, 1630, 1450, 1350, 1325, 1115, 1090, 1055
  • N-acetylstaurosporine was prepared from staurosporine and a stoichiometric excess acetic anhydride in pyridine. The solution was stirred overnight at room temperature. The solvent was removed. The resulting solid was partitioned between ethyl acetate and water. The organic layer was washed with water then dried with anhydrous Na 2 SO 4 . Solvent was removed yielding N- acetylstaurosporine.
  • N-substituted staurosporines may be prepared using the procedure of Example 2.
  • N-propanoyl staurosporine N-propanoyl staurosporine

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Abstract

L'invention concerne les indolocarbozols représentés par la formule (I), dans laquelle Ra et Rb représente chacun H ou Ra et Rb pris ensemble représentent A ou B, dans lesquelles R1 et R2 représentent indépendemment H ou OH ou OCH3 et R3 représente OH, NHCH3, NCH3COCH3 ou NHCOCH3 et R4 représente OH ou H, et leurs isomères stéréochimiques ou leurs compositions pharmaceutiques utiles pour inhiber la kinase à chaînes légères de myosine, la kinase C protéique ou la prolifération de cellules tumorales, ainsi que pour produire un effet antihypertensif et un effet antiinflammatoire chez les animaux à sang chaud et chez l'homme, aux conditions que (1) lorsque Ra et Rb repreésentent ensemble A, et R1=H ou OH, R3 ne représente pas NHCH3; (2) lorsque Ra et Rb représentent ensemble B, alors R1=R4=H; (3) lorsque Ra=Rb=H R1=-OCH3, et (4) lorsque Ra et Rb représentent ensemble A, et R1=H, R3 ne représente pas (II).
PCT/US1990/007174 1989-12-14 1990-12-12 Indolocarbazols provenant de saccharothrix aerocolonigenes subsp. copiosa subsp. nov. scc 1951, atcc 53856 WO1991009034A1 (fr)

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US45148789A 1989-12-14 1989-12-14
US45127189A 1989-12-14 1989-12-14
US451,487 1989-12-14
US451,271 1989-12-14

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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993007153A1 (fr) * 1991-10-10 1993-04-15 Schering Corporation Derives de staurosporine 4'-(n-substituee-n-oxydee)
EP0541486A1 (fr) * 1991-11-07 1993-05-12 Ciba-Geigy Ag Conjugates polycycliques
EP0575955A1 (fr) * 1992-06-22 1993-12-29 Kyowa Hakko Kogyo Co., Ltd. Procédé pour la préparation de dérivés de staurosporine
WO1994016706A1 (fr) 1993-01-28 1994-08-04 Neorx Corporation Inhibiteur therapeutique de cellules de muscles vasculaires lisses
WO1995000520A1 (fr) * 1993-06-17 1995-01-05 Ciba-Geigy Ag Compose d'indolocarbazole utilise comme inhibiteur de proteine-kinase c
US5382675A (en) * 1993-05-07 1995-01-17 Ciba-Geigy Corporation Polycyclic compounds and processes for the preparation thereof
WO1996013506A1 (fr) * 1994-10-26 1996-05-09 Cephalon, Inc. Inhibiteurs de la proteine-kinase pour le traitement de troubles neurologiques
US5547976A (en) * 1992-03-20 1996-08-20 Burroughs Wellcome Co. Further indole derivatives with antiviral activity
WO1999047522A1 (fr) * 1998-03-13 1999-09-23 The University Of British Columbia Derives de granulatimide utilises dans le traitement du cancer
US6184217B1 (en) 1996-06-25 2001-02-06 Cephalon, Inc. Use of K-252a derivative
US6291447B1 (en) 1998-03-13 2001-09-18 The University Of British Columbia Granulatimide compounds and uses thereof
US6306849B1 (en) 1996-06-03 2001-10-23 Cephalon, Inc. Selected derivatives of K-252a
WO2003037347A1 (fr) * 2001-10-30 2003-05-08 Novartis Ag Derives de staurosporine inhibiteurs de l'activite tyrosine kinase du recepteur flt3
US6875865B1 (en) 1996-06-03 2005-04-05 Cephalon, Inc. Selected derivatives of K-252a
EP2098230A1 (fr) 1997-03-31 2009-09-09 Boston Scientific Scimed Limited Utlisation des inhibiteurs cytosquelettiques en forme cristalline pour l'inhibition ou la prévention de la resténose
ES2326459A1 (es) * 2008-04-08 2009-10-09 Universidad De Oviedo Indolocarbazoles glicosilados, su procedimiento de obtencion y sus usos.
EP2292225A1 (fr) 1997-03-31 2011-03-09 Boston Scientific Scimed Limited Forme de dosage comprénant du taxol en forme cristalline
CN106831898A (zh) * 2016-12-27 2017-06-13 杭州科兴生物化工有限公司 具有蛋白激酶抑制活性的化合物及其制备方法和应用
CN107417751A (zh) * 2017-06-15 2017-12-01 杭州科兴生物化工有限公司 吲哚咔唑类化合物及其制备方法和应用

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EP0303697A1 (fr) * 1987-03-09 1989-02-22 Kyowa Hakko Kogyo Co., Ltd. Derives de la substance physiologiquement active k-252
WO1989007105A1 (fr) * 1988-02-04 1989-08-10 Kyowa Hakko Kogyo Co., Ltd. Derives de staurosporine
EP0328000A2 (fr) * 1988-02-06 1989-08-16 Gödecke Aktiengesellschaft Dérivés d'indolocarbazole, procédé pour leur préparation et médicaments les contenant

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WO1993007153A1 (fr) * 1991-10-10 1993-04-15 Schering Corporation Derives de staurosporine 4'-(n-substituee-n-oxydee)
EP0540185A1 (fr) * 1991-10-10 1993-05-05 Schering Corporation Dérivés de staurosporine-N-oxide N-substitués
EP0541486A1 (fr) * 1991-11-07 1993-05-12 Ciba-Geigy Ag Conjugates polycycliques
US5264431A (en) * 1991-11-07 1993-11-23 Ciba-Geigy Corp. Polycyclic conjugates
US5547976A (en) * 1992-03-20 1996-08-20 Burroughs Wellcome Co. Further indole derivatives with antiviral activity
US5344926A (en) * 1992-06-22 1994-09-06 Kyowa Hakko Kogyo Co., Ltd. Process for producing staurosporine derivatives
EP0575955A1 (fr) * 1992-06-22 1993-12-29 Kyowa Hakko Kogyo Co., Ltd. Procédé pour la préparation de dérivés de staurosporine
US5741808A (en) * 1992-07-24 1998-04-21 Cephalon, Inc. Protein kinase inhibitors for treatmen of neurological disorders
US5756494A (en) * 1992-07-24 1998-05-26 Cephalon, Inc. Protein kinase inhibitors for treatment of neurological disorders
WO1994016706A1 (fr) 1993-01-28 1994-08-04 Neorx Corporation Inhibiteur therapeutique de cellules de muscles vasculaires lisses
EP2324829A1 (fr) 1993-01-28 2011-05-25 Boston Scientific Limited Inhibiteur therapeutique de cellules de muscles
EP2298310A2 (fr) 1993-01-28 2011-03-23 Boston Scientific Limited Inhibiteur thérapeutique de cellules de muscles vasculaires lisses
US5382675A (en) * 1993-05-07 1995-01-17 Ciba-Geigy Corporation Polycyclic compounds and processes for the preparation thereof
US5455241A (en) * 1993-05-07 1995-10-03 Ciba-Geigy Corporation Polycyclic compounds and processes for the preparation thereof
WO1995000520A1 (fr) * 1993-06-17 1995-01-05 Ciba-Geigy Ag Compose d'indolocarbazole utilise comme inhibiteur de proteine-kinase c
EP1125938A1 (fr) * 1994-10-26 2001-08-22 Cephalon, Inc. Inhibiteurs de la proteine-kinase pour le traitement de troubles neurologiques
WO1996013506A1 (fr) * 1994-10-26 1996-05-09 Cephalon, Inc. Inhibiteurs de la proteine-kinase pour le traitement de troubles neurologiques
US6875865B1 (en) 1996-06-03 2005-04-05 Cephalon, Inc. Selected derivatives of K-252a
US6306849B1 (en) 1996-06-03 2001-10-23 Cephalon, Inc. Selected derivatives of K-252a
US6184217B1 (en) 1996-06-25 2001-02-06 Cephalon, Inc. Use of K-252a derivative
EP2292225A1 (fr) 1997-03-31 2011-03-09 Boston Scientific Scimed Limited Forme de dosage comprénant du taxol en forme cristalline
EP2098230A1 (fr) 1997-03-31 2009-09-09 Boston Scientific Scimed Limited Utlisation des inhibiteurs cytosquelettiques en forme cristalline pour l'inhibition ou la prévention de la resténose
WO1999047522A1 (fr) * 1998-03-13 1999-09-23 The University Of British Columbia Derives de granulatimide utilises dans le traitement du cancer
US6291447B1 (en) 1998-03-13 2001-09-18 The University Of British Columbia Granulatimide compounds and uses thereof
US7973031B2 (en) 2001-10-30 2011-07-05 Novartis Ag Staurosporine derivatives as inhibitors of FLT3 receptor tyrosine kinase activity
WO2003037347A1 (fr) * 2001-10-30 2003-05-08 Novartis Ag Derives de staurosporine inhibiteurs de l'activite tyrosine kinase du recepteur flt3
US8222244B2 (en) 2001-10-30 2012-07-17 Novartis Ag Staurosporine derivatives as inhibitors of FLT3 receptor tyrosine kinase activity
US8445479B2 (en) 2001-10-30 2013-05-21 Novartis Ag Staurosporine derivatives as inhibitors of FLT3 receptor tyrosine kinase activity
WO2009125042A1 (fr) * 2008-04-08 2009-10-15 Universidad De Oviedo Indolocarbazoles glycosylés, leur procédé d'obtention et leurs utilisations
ES2326459A1 (es) * 2008-04-08 2009-10-09 Universidad De Oviedo Indolocarbazoles glicosilados, su procedimiento de obtencion y sus usos.
US8598132B2 (en) 2008-04-08 2013-12-03 Universidad De Oviedo Glycosylated indolocarbazoles, method for obtaining same and uses thereof
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