WO2006011750A1 - Derives de tetrahydro-beta-carbolinone et procede permettant de les preparer - Google Patents

Derives de tetrahydro-beta-carbolinone et procede permettant de les preparer Download PDF

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Publication number
WO2006011750A1
WO2006011750A1 PCT/KR2005/002433 KR2005002433W WO2006011750A1 WO 2006011750 A1 WO2006011750 A1 WO 2006011750A1 KR 2005002433 W KR2005002433 W KR 2005002433W WO 2006011750 A1 WO2006011750 A1 WO 2006011750A1
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Prior art keywords
compound
tetrahydro
bromo
carbolin
disease
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PCT/KR2005/002433
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English (en)
Inventor
Jae-Ki Min
Bu-Young Choi
Mee-Hyun Lee
Bon-Am Koo
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C & C Research Laboratories
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Publication of WO2006011750A1 publication Critical patent/WO2006011750A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a new tetrahydro-beta-carbolinone derivative having antagonist effect for cyclin dependent kinase ('CDK 3 ' below) as well as an agonist effect for the expression of endogenous tumor suppressor protein.
  • the present invention also relates to a composition for the treatment of cancer, autoimmune disease, cardio-vascular disease, chemotherapy- induced alopecia and mucositis, infection disease, kidney disease, chronic and acute neurodegenerative disease, and viral infection, comprising the tetrahydro-beta-carbolinone derivative as an active ingredient.
  • the anticancer drugs According to the aging of modern society, the risk caused by cancer is getting more serious.
  • the anticancer drugs have not seemed to show any prominent improvements for tumorigenesis because most anticancer drugs except Taxol rely upon the spontaneous cell death mechanism evoked by the abnormality of DNA in cancer cells which can be induced by a direct injury of DNA or the perturbation of DNA replication process.
  • the most serious drawback of these anticancer drugs is that the cancer cells rapidly process to resistance against the drugs.
  • the radiotherapy or anticancer chemotherapy also relies on the same mechanism of DNA injury, the drug resistant cancer cells can resist to other anticancer therapies.
  • CDK is a major enzyme that regulates the eukaryotic cell cycle.
  • extracellular growth signal promotes the cell proliferation following the sequential cell cycle of Gl phase (gap 1 phase) ⁇ S phase (synthesis phase) ⁇ G2 phase (gap 2 phase) ⁇ M phase (mitosis phase).
  • CDK is activated by binding with specific cyclin, and regulate the cell cycle. For example, in Gl phase it is decided whether the cell is to proliferate or not. In a cell that is decided to proliferate, cyclin D/CDK4,6 complex phosphorylates pRB, and cyclin E/CDK2 complex hyperphosphorylates pRB.
  • a transcription factor E2F is dissociated from pRB and promotes the cell into S phase where DNA replication is carried out.
  • the transfer into G2 phase is stimulated by cyclin AJCDKl complex.
  • G2 phase the completion of DNA replication is confirmed and the timing of cell division is decided.
  • M phase equal distribution of completely replicated chromosomes and subsequent cell division is accomplished, and the cell returns to Gl phase again.
  • Most normal cells cease their division at Gl phase and enter the dormant GO phase where protein synthesis or energy metabolism is suspended, while the cancer cells maintain the rapid and anarchic cell cycle by the continual signal.
  • the present inventors have tried to develop a new anticancer agent which exhibits anticancer activity through a mechanism of inhibiting cell cycle regulators to overcome the drug resistance and various side effects of the existing inhibitors against DNA synthesis.
  • a tetrahydro-beta-carbolinone derivative of the formula (1) shows a selective and potent inhibitory activity against CDK and can be used as a new orally administrable CDK inhibitor, and completed the present invention.
  • the tetrahydro-beta-carbolinone derivative of the present invention has the effect of enhancing the expression of such endogenous tumor suppressor proteins as pi 6 and p21, as well as the inhibitory activity against CDK.
  • the compound of the present invention shows an improved anticancer effect (inhibitory effect against cell growth) compared with R-roscovitine, and can be used for the treatment of autoimmune disease, cardio-vascular disease, chemotherapy-induced alopecia and mucositis, infection disease, kidney disease, chronic and acute neurodegenerative disease, and viral infection, in addition to the cancer.
  • It is still another object of the present invention to provide a composition comprising the above compound as an active ingredient- together with a pharmaceutically acceptable carrier, for the treatment of cancer, autoimmune disease, cardio-vascular disease, chemotherapy-induced alopecia and mucositis, infection disease, kidney disease, chronic and acute neurodegenerative disease, and viral infection.
  • Figure 1 represents the Western blotting result showing the enhancing effect of the compound according to the present invention for the expression of pl6 and p21.
  • the present invention relates to a new tetrahydro-beta-carbolinone derivative of the following formula (1): [Formula 1] in which
  • R represents -(CH 2 ) H -R 1 , -(CO)-R 2 , or -(SO 2 )-R 3 , wherein n denotes an integer of 0 to 5, R 1 represents hydrogen, Q-C ⁇ -alkoxy, d-Ce-hydroxyalkyl, C 2 -C 6 -alkoxycarbonyl, carboxy, carbamoyl, or phenyl,
  • R 2 represents C 2 -C 6 -alkoxyalkyl, d-C 6 -alkyl, halogeno-Q-Ce-alkyl, d ⁇ C 6 -alkoxy, d-Q-alkylcarbonyloxyalkyl, C 3 -C 7 -cycloalkyl, or phenyl,
  • R 3 represents Ci-C 6 -alkyl
  • X represents halogen, d-C 6 -alkoxy, or aminosulfonyl, pharmaceutically acceptable salt, or stereoisomer thereof.
  • alkyl in the present invention may be linear or branched.
  • Preferred compounds among the compound of formula (1) above useful as inhibitory agent against CDK or enhancing agent for the expression of pi 6 and p21 are those wherein R represents -(CO)-R 2 , pharmaceutically acceptable salt, or stereoisomer thereof.
  • More preferred compounds are those wherein X represents bromine, pharmaceutically acceptable salt, or stereoisomer thereof.
  • Most preferred compounds are those wherein R represents -(CO)-R , wherein R represents d-C ⁇ -alkoxyalkyl or halogeno-d-C 6 -alkyl, and X represents bromine, pharmaceutically acceptable salt, or stereoisomer thereof.
  • Typical compounds among the compound of formula (1) are those selected from the group consisting of:
  • Particularly preferred compounds among the above typical compounds are those selected from the group consisting of: 6-Bromo-9-(2-chloro-acetyl)-2,3,4,9-tetrahydro- ⁇ -carbolin-l-one (Compound 3); 9-Acetyl-6-bromo-2,3,4,9-te1xahydro-/?-carbolm-l-one (Compound 6); 6-Bromo-9-(2-methoxy-acetyl)-2,3,4,9-tetrahydro- / 9-carbolin-l-one (Compound 12); and Acetic acid 2-(6-bromo-l-oxo-l,2,3,4-tetrahydro-/ ⁇ carbolm-9-yl)-2-oxo-ethyl ester (Compound 13).
  • the compound of formula (1) according to the present invention can also form a pharmaceutically acceptable salt.
  • Such salt includes non-toxic acid addition salt containing pharmaceutically acceptable anion, for example, a salt with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydriodic acid, etc., a salt with organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, etc., or a salt with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, etc.
  • a salt with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid,
  • the compound of formula (I) can also form a salt with alkaline metals such as sodium, potassium, etc., and a salt with other acids or bases which have been well-known and widely used in the technical field to which the tetrahydro-beta-carbolinone derivative belongs.
  • These salts can be prepared according to any of the conventional conversion methods.
  • the compound of the present invention may have asymmetric carbon atoms in the structure depending on the kind of substituents, and so may exist in the form of R or S isomer, or mixtures thereof including racemates.
  • the pure stereoisomers may be obtained by the conventional resolution method known in this field.
  • the present invention also includes all of these stereoisomers and their mixtures in its scope.
  • the compound of the present invention may be prepared according to the process explained below, and so the present invention also provides such process for preparing the compound of formula (1).
  • the compound of formula (1) defined above, pharmaceutically acceptable salt, or stereoisomer thereof may be prepared by the process which comprises
  • the above process (a) of reacting the compound of formula (2) with the compound of formula (3) is preferably carried out in a solvent and in the presence of a base.
  • a solvent one or more can be selected from the group consisting of acetonitrile, dimethylsulfoxide, N,N-dimethylforrnamide, and tetrahydrofuran
  • the base one or more can be selected from the group consisting of sodium hydroxide, potassium fluoride, potassium carbonate, and sodium hydride.
  • reaction aids as aluminum oxide may be further used. It is economic in the aspect of yield, etc.
  • the compound of formula (1) according to the present invention may be advantageously used as an anticancer agent due to its excellent inhibitory activity against CDKs. Therefore, the present invention relates to an anticancer composition comprising the compound of formula (1), pharmaceutically acceptable salt, or stereoisomer thereof as an active ingredient together with the pharmaceutically acceptable carrier.
  • the compound of the present invention may also be advantageously used for the preparation of therapeutic agents for treating autoimmune disease, cardio-vascular disease, chemotherapy-induced alopecia and mucositis, infection disease, kidney disease, chronic and acute neurodegenerative disease, and viral infection besides cancer.
  • the cancer is defined as solid tumor and leukemia;
  • the autoimmune disease is defined as psoriasis, alopecia, and multiple sclerosis;
  • the cardio-vascular disease is defined as stenosis, arteriosclerosis, and recurrent stricture;
  • the infection disease is defined as those caused by unicellular parasites;
  • the kidney disease is defined as glomerulonephritis;
  • the chronic neurodegenerative disease is defined as Huntington's disease, amyotrophic lateral sclerosis, Parkinson's disease, AIDS, dementia, and Alzheimer's disease;
  • the acute neurodegenerative disease is defined as cerebral ischemia and neurotrauma;
  • the viral infection is defined as the infections by giant cell, herpes, hepatitis B or C, and HIV.
  • the compound of the present invention When the compound of the present invention is used for clinical purpose, it is preferable to administer it to the subject patient in an amount ranging from 0.5 to lOOOmg, preferably 50 to 200mg, per day.
  • the total daily dosage may be administered once or over several times.
  • specific administration dosage for an individual patient can be varied depending on specific compound used, body weight, gender, hygienic condition, diet of subject patient, time or method of administration, excretion rate, mixing ratio of agent, severity of disease to be treated, etc.
  • composition according to the present invention As a result of administering the composition according to the present invention in the amount of lOOmg/kg to 10 rats and observing their conditions in 1 day, there was no rat which died or showed serious disease. Thus, it was identified that the compound of the present invention is not toxic.
  • the compound of the present invention may be formulated as a parenteral injection or oral preparation, depending on its application purpose.
  • aqueous or oily suspension for sterilized injection can be prepared according to the known procedure using suitable dispersing agent, wetting agent, or suspending agent.
  • Solvents that can be used for preparing injections include water, Ringer's fluid, and isotonic NaCl solution, and also sterilized fixing oil may be conveniently used as the solvent or suspending media. Any non-irritating fixing oil including mono- or di-glyceride may be used for this purpose.
  • Fatty acid such as oleic acid may also be used for injections.
  • the orally administrable solid preparations include capsules, tablets, pills, powders, and granules, capsules and tablets among which are preferable. It is desirable for tablets and pills to be formulated into enteric-coated preparation.
  • the solid preparations are prepared by mixing the active compound of formula (1) with one or more carriers selected from inert diluents such as sucrose, lactose, starch, etc., lubricants such as magnesium stearate, disintegrating agents, and binding agents.
  • the active compound of formula (1) may be administered together with one or more known anticancer agents.
  • the anticancer agents to be mixed and administered together with the compound of the present invention in this manner include 5-fluorouracil, cisplatin, doxorubicin, taxol, Gemcitabine, etc.
  • the preparations comprising the compound of the present invention which expect several pharmacological effects including the anticancer activity, are not restricted to those explained above, but may include any preparations useful for the prevention and treatment of diseases.
  • the extract was dried over MgSO 4 , filtered, and distilled under reduced pressure.
  • the residue was dissolved in dichloromethane (1OmA), and trifluoroacetic acid (0.032mA, 0.411mmol) was slowly added at 0 ° C, and stirred for 1 h.
  • the reaction mixture was distilled under reduced pressure, diluted with water, neutralized with aqueous NaHCO 3 solution, and extracted twice with ethyl acetate (3OmA).
  • the extract was dried over MgSO 4 , filtered, and distilled under reduced pressure.
  • the extract was dried over MgSO 4 , filtered, and distilled under reduced pressure.
  • the residue was dissolved in dichloromethane (10m£), and trifluoroacetic acid (0.032m£, 0.411mmol) was slowly added at 0 ° C, and stirred for 1 h.
  • the reaction mixture was distilled under reduced pressure, diluted with water, neutralized with saturated aqueous NaHCO 3 solution, and extracted twice with ethyl acetate (30ml).
  • the extract was dried over MgSO 4 , filtered, and distilled under reduced pressure.
  • the reaction mixture was distilled under reduced pressure, diluted with water, neutralized with saturated aqueous NaHCO 3 solution, and extracted twice with ethyl acetate (40m£).
  • the extract was dried over MgSO 4 , filtered, and distilled under reduced pressure.
  • n-hexane 5in£, which was stirred for 10 min at room temperature and filtered to give the title compound (80mg, 86.9%) as white solid.
  • the reaction mixture was diluted with water (5ra£), saturated aqueous NaHCO 3 solution was added, and the mixture was extracted twice with ethyl acetate (20m£).
  • the extract was dried over MgSO 4 , filtered, and distilled under reduced pressure.
  • the residue was dissolved in dichloromethane (5m£), and trifluoroacetic acid (0.032m£, 0.411mmol) was slowly added at 0 ° C, and stirred for 1 h.
  • the reaction mixture was distilled under reduced pressure, diluted with water, neutralized with saturated aqueous NaHCO 3 solution, and extracted twice with ethyl acetate (20m ⁇ ).
  • the extract was dried over MgSO 4 , filtered, and distilled under reduced pressure.
  • the reaction mixture was diluted with water (5ml), saturated aqueous NaHCO 3 solution was added, and the mixture was extracted twice with ethyl acetate (20ml). The extract was dried over MgSO 4 , filtered, and distilled under reduced pressure. The residue was dissolved in dichloromethane (5ml), and trifluoroacetic acid (0.032m£, 0.411mmol) was slowly added at 0 ° C, and stirred for 1 h. The reaction mixture was distilled under reduced pressure, diluted with water, neutralized with saturated aqueous NaHCO 3 solution, and extracted twice with ethyl acetate (20M). The extract was dried over MgSO 4 , filtered, and distilled under reduced pressure.
  • CDK2/cyclin A and CDK2/cyclin E complexes were prepared by using Baculovirus recombinant system and insect cell S£21 purchased from Invitrogen Co.
  • the substrate Histone (Cat. # 382150) was purchased from Calbiochem Co.
  • Test samples (0 ⁇ M and 0.032 ⁇ M-IOO ⁇ M) diluted in various concentrations in 2X reaction buffer [2OmM Tris/HCl (pH8.0), 1OmM MgCl 2 , lOO ⁇ M NaVO 3 , 5mM glycerophosphate, ImM DTT] were added to a 96-well filter plate (Cat. # MHVBN4550, Millipore).
  • 2X reaction buffer 2OmM Tris/HCl (pH8.0), 1OmM MgCl 2 , lOO ⁇ M NaVO 3 , 5mM glycerophosphate, ImM DTT
  • the mixture of substrate and ATP [3 ⁇ M cold ATP/well (0.3/ ⁇ /well, stock ImM), 0.3 ⁇ Ci [ ⁇ - 32 P]ATP/well (0.03/ ⁇ /well, stock 10 ⁇ Ci/ ' ⁇ ), Histone (10/ ⁇ /well, stock lmgM), 20/ ⁇ dH 2 O] was added and subjected to enzymatic reaction for 30 min at 30 ° C.
  • the reaction was stopped by adding 100 ⁇ i of 70% ice-cold TCA.
  • the reaction mixture was washed five times with 200 ⁇ of 25% ice-cold TCA and dried for 1 h at 60 ° C.
  • MTS one solution was purchased from Promega, and PA-I (ovarian) and HeLa(cervix) cells were purchased from ATCC. The cells were cultured in MEM media containing 10% FBS at 37 "C in a CO 2 incubator.
  • the cells cultured in T75 flask were diluted with growth media and distributed into a plate in a population of 5000 cells per well in 100 ⁇ l of media. After incubating for 24 h in a CO 2 incubator at 37 "C, 100 ⁇ i of test samples diluted with growth media in various concentrations (0 ⁇ M and 0.5 ⁇ M-100 ⁇ M; the final concentration of DMSO was
  • Thermo-MAX Microplate Reader (Molecular Devices Co.).
  • the absorbance data were treated on Microsoft Excel, with using the value from the well treated only by MTS one solution as blanc, and adopting the value from 0 ⁇ M well as 100% activity.
  • the relative values were calculated for each well, and the IC 50 values were determined as presented in Table 2 below.
  • the antibody against pl6 was purchased from NeoMarkers Co.; the antibodies against p21 (C-19, sc-397) and actin (1-19, sc-1616) were from Santacruz Co.; the secondary antibodies, HRP-goat-anti-mouse IgG, HRP-goat-anti-rabbit IgG, and HRP-donkey-anti-goat IgG, were from ZYMED Co. and Santacruz Co.; and Chemiluminscent ECL plus detection reagent (RPN2132) was from Amersharm biosciences Co.
  • HeLa cells were distributed into 60mm dishes in a population of 2x10 5 cells per dish in 5ml of MEM containing 10% FBS, and cultured at 37 "C for about 24 h in a CO 2 incubator. The media was replaced with fresh one (5ml), and the test samples were added in various concentrations (0 ⁇ M and 0.5 ⁇ M-IO ⁇ M). The cells were incubated for 48 h, lysis buffer was added in order to obtain cell lysate, and the amount of protein was determined.
  • the membrane to which the protein was transferred was blocked with the blocking solution [5% Non-fat dry milk in IX TBS-T (Tris buffered saline, 1OmM Tris-Cl, pH 7.6, 15OmM NaCl)-0.1% T(Tween-20)] for 1 h, washed three times with IX 0.1% TBS-T for 10 min, and treated with 4 ⁇ g of the primary antibody (pl6, p21, actin) diluted with 10ml of IX TBS-T.
  • the blocking solution [5% Non-fat dry milk in IX TBS-T (Tris buffered saline, 1OmM Tris-Cl, pH 7.6, 15OmM NaCl)-0.1% T(Tween-20)] for 1 h, washed three times with IX 0.1% TBS-T for 10 min, and treated with 4 ⁇ g of the primary antibody (pl6, p21, actin) diluted with 10ml of IX TBS-T.
  • the membrane was washed three times with IX TBS-T, and treated with the secondary antibody (HRP-goat-anti-mouse IgG, HRP-goat-anti-rabbit IgG, HRP-donkey-anti-goat IgG) diluted with 10mA of IX TBS-T for the ratio of 1:5000. After 1 hrs incubation, the membrane was washed four times with IX TBS-T for 10 min. Each band was visualized on a X-ray film using Chemiluminescent ECL plus detection reagent, and the results are presented in Figure 1.
  • the new tetrahydro-beta-carboline derivative provided by the present invention shows the inhibitory activity against cyclin dependent kinases as well as the activity for enhancing the expression of endogenous tumor suppressive proteins, and so can be used for the treatment of cancer, autoimmune disease, cardio-vascular disease, chemotherapy-induced alopecia and mucositis, infection disease, kidney disease, chronic and acute neurodegenerative disease, and viral infection.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention concerne un nouveau dérivé de tetrahydro-beta-carbolinone ayant un effet antagoniste pour une kinase dépendante des cyclines, ainsi qu'un effet antagoniste pour l'expression de protéines 'suppresseurs' de tumeurs endogènes. Cette invention concerne également une composition permettant de traiter un cancer, une maladie auto-immune, une maladie cardiovasculaire, une mucosité et une alopécie entraînées par une chimiothérapie, une maladie infectieuse, une maladie des reins, une maladie neurogénérante aiguë et chronique, une infection virale; laquelle composition contient, en tant que principe actif, le dérivé de tetrahydro-beta-carbolinone.
PCT/KR2005/002433 2004-07-27 2005-07-27 Derives de tetrahydro-beta-carbolinone et procede permettant de les preparer WO2006011750A1 (fr)

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KR20040058686 2004-07-27

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006082409A3 (fr) * 2005-02-03 2006-12-14 Hunter Fleming Ltd Composes cytoprotecteurs tricycliques
WO2009078423A1 (fr) 2007-12-18 2009-06-25 National University Corporation University Of Toyama Composé tricyclique fusionné ayant une activité inhibitrice d'aldose réductase
JP2011157332A (ja) * 2010-02-03 2011-08-18 Toyama Univ ＰＰＡＲγアゴニスト
EP2480079A1 (fr) * 2009-09-23 2012-08-01 Medivation Technologies, Inc. Pyrido(3,4-b)indoles et leurs méthodes d'utilisation
WO2012157744A1 (fr) * 2011-05-19 2012-11-22 国立大学法人 富山大学 DÉRIVÉ DE 1-THIOXO-1,2,3,4-TÉTRAHYDRO-β-CARBOLINE ET AGENT ANTICANCÉREUX COMPRENANT CELUI-CI
US9260429B2 (en) 2008-03-24 2016-02-16 Medivation Technologies, Inc. Pyrido[3,4-B]indoles and methods of use
CN108623585A (zh) * 2018-05-22 2018-10-09 中国人民解放军第二军医大学 β-四氢咔啉类抗真菌药物及其制备方法和应用

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2006210727B2 (en) * 2005-02-03 2011-10-13 Hunter-Fleming Limited Tricyclic cytoprotective compounds
WO2006082409A3 (fr) * 2005-02-03 2006-12-14 Hunter Fleming Ltd Composes cytoprotecteurs tricycliques
JP5366211B2 (ja) * 2007-12-18 2013-12-11 国立大学法人富山大学 アルドース還元酵素阻害活性を有する縮合三環化合物
WO2009078423A1 (fr) 2007-12-18 2009-06-25 National University Corporation University Of Toyama Composé tricyclique fusionné ayant une activité inhibitrice d'aldose réductase
US8198447B2 (en) 2007-12-18 2012-06-12 National University Corporation University Of Toyama Fused tricyclic compound having aldose reductase inhibitory activity
US9469641B2 (en) 2008-03-24 2016-10-18 Medivation Technologies, Inc. Pyrido[3,4-B]indoles and methods of use
US9260429B2 (en) 2008-03-24 2016-02-16 Medivation Technologies, Inc. Pyrido[3,4-B]indoles and methods of use
EP2480079A4 (fr) * 2009-09-23 2015-04-08 Medivation Technologies Inc Pyrido(3,4-b)indoles et leurs méthodes d'utilisation
AU2010298167B2 (en) * 2009-09-23 2015-12-24 Medivation Technologies, Inc. Pyrido(3,4-b)indoles and methods of use
EP2480079A1 (fr) * 2009-09-23 2012-08-01 Medivation Technologies, Inc. Pyrido(3,4-b)indoles et leurs méthodes d'utilisation
JP2011157332A (ja) * 2010-02-03 2011-08-18 Toyama Univ ＰＰＡＲγアゴニスト
JPWO2012157744A1 (ja) * 2011-05-19 2014-07-31 国立大学法人富山大学 １−チオキソ−１，２，３，４−テトラヒドロ−β−カルボリン誘導体およびそれらを含有する抗がん剤
WO2012157744A1 (fr) * 2011-05-19 2012-11-22 国立大学法人 富山大学 DÉRIVÉ DE 1-THIOXO-1,2,3,4-TÉTRAHYDRO-β-CARBOLINE ET AGENT ANTICANCÉREUX COMPRENANT CELUI-CI
CN108623585A (zh) * 2018-05-22 2018-10-09 中国人民解放军第二军医大学 β-四氢咔啉类抗真菌药物及其制备方法和应用

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