[go: up one dir, main page]

WO2010064817A2 - Nouveaux composés à base de coumarine, procédé de préparation de ces derniers et compositions pharmaceutiques inhibant la résistance pléiotrope contenant ces nouveaux composés en tant qu'ingrédients actifs - Google Patents

Nouveaux composés à base de coumarine, procédé de préparation de ces derniers et compositions pharmaceutiques inhibant la résistance pléiotrope contenant ces nouveaux composés en tant qu'ingrédients actifs Download PDF

Info

Publication number
WO2010064817A2
WO2010064817A2 PCT/KR2009/007077 KR2009007077W WO2010064817A2 WO 2010064817 A2 WO2010064817 A2 WO 2010064817A2 KR 2009007077 W KR2009007077 W KR 2009007077W WO 2010064817 A2 WO2010064817 A2 WO 2010064817A2
Authority
WO
WIPO (PCT)
Prior art keywords
coumarin
formula
compound
enyl
methyl
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/KR2009/007077
Other languages
English (en)
Korean (ko)
Other versions
WO2010064817A3 (fr
Inventor
이경
민경훈
이기호
최용석
김영란
하연
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.)
Korea Research Institute of Bioscience and Biotechnology KRIBB
Original Assignee
Korea Research Institute of Bioscience and Biotechnology KRIBB
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 Korea Research Institute of Bioscience and Biotechnology KRIBB filed Critical Korea Research Institute of Bioscience and Biotechnology KRIBB
Publication of WO2010064817A2 publication Critical patent/WO2010064817A2/fr
Publication of WO2010064817A3 publication Critical patent/WO2010064817A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A61K31/37—Coumarins, e.g. psoralen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a coumarin compound, a preparation method thereof and a pharmaceutical composition for inhibiting multi-drug resistance containing the same as an active ingredient.
  • Surgical and radiation therapy is a useful method in the early stages of cancer development, so the dependence on chemotherapy is gradually increasing in cancers that are difficult to detect early, and the chemotherapy has a history of more than 50 years.
  • Hundreds of anticancer drugs have been developed and used in the clinic until now, but there are not many cases of obtaining clinically satisfactory effects.
  • MDR multidrug resistance
  • Cancer cells that have become resistant to one drug are structurally resistant to completely different anticancer compounds, which is called multi-drug resistance.
  • the development of such multi-drug resistance is the biggest obstacle in the treatment of metastatic cancer using chemotherapeutic agents.
  • Pgp P-glycoprotein
  • ABSC transporter ATP-dependent transporter
  • P-glycoprotein inhibitors can be explored and identified.
  • the P-glycoprotein is a membrane protein encoded by 170 kDa by human ABCB-1 (MDR1) gene, which is divided into six membranes and one. It belongs to the superfamily of ATP binding cassette (ABP) transport proteins consisting of 1,280 amino acids formed of two homologous hydrophobic sites having an ATP-binding site of
  • ABCB-1 ABCB-1
  • the expression of multidrug resistance is indicated by multidrug resistance through a mechanism of lowering drug concentration in cells by releasing the drug out of the cell by an energy dependent mechanism in which P-glycoprotein directly binds to the drug and consumes ATP.
  • most human tumors such as colon or kidney cancer, express P-glycoprotein and increase the expression rate, thereby exacerbating tumor deterioration.
  • Anticancer agents affected by P-glycoprotein include vinblastine, vincristine and navelbine of the vinca alkaloids family; Taxanes family paclitaxel (TAX), taxotere; Anthracyclines family of doxorubicin, daunorubicin, epirubicin and idarubicin; Epipodophyllotoxins family drugs etoposide and teniposide; Other drugs include colchicine, mitoxantrone, dactinomycin, topotecan, trimetrexate, mitramycin, mitomycin C Various drugs are known.
  • the first-generation drugs such as verapamil, calmodulin antagonists, steroid drugs, immunosuppressants (cyclosporine) and antimalarial drugs (quinine), which are calcium channel inhibitors, are being used for other therapeutic purposes.
  • the drugs are drugs that inhibit P-glycoprotein.
  • first-generation drugs have not been sufficiently inhibited, and their original pharmacological action has been a side effect and failed to be used in clinical practice.
  • Second-generation drugs compensate for the shortcomings of the first generation, but many second-generation drugs not only inhibit other types of transporters but also inhibit metabolism-related enzymes, which increases the blood concentration of anticancer drugs for a long time. Showed a problem of increasing.
  • Third-generation drugs are highly selective for other transporters, have a very high inhibitory effect on P-glycoproteins, and are not metabolized by CYP450 3A4, which does not change the pharmacokinetic characteristics of anticancer drugs administered in combination, resulting in side effects from anticancer drugs. I never do that. Despite these characteristics, many of the third generation drugs that have been developed so far (Tariquidar, Zosuquidar, VX-710, Laniquidar, ONT-093, etc.), except for those in clinical trials, are cells that are caused by P-glycoprotein inhibitors themselves. Unexpected side effects from toxicity are a problem.
  • the present inventors have studied to search for compounds having no self-cytotoxicity while inhibiting the overexpression of P-glycoprotein, which is a major cause of multi-drug resistance, and increasing the therapeutic efficiency of existing anticancer drugs,
  • the present invention was synthesized, and it was confirmed that some of these compounds and known coumarin-based compounds exhibited superior inhibitory activity in P-glycoprotein expression.
  • An object of the present invention is to provide a novel coumarin-based compound.
  • Another object of the present invention is to provide a method for preparing the novel coumarin compound.
  • Another object of the present invention to provide a pharmaceutical composition for inhibiting multi-drug resistance containing the novel coumarin-based compound as an active ingredient.
  • the present invention provides a novel coumarin-based compound.
  • the present invention also provides a method for producing the novel coumarin compound.
  • the present invention provides a pharmaceutical composition for inhibiting multi-drug resistance containing the novel coumarin-based compound as an active ingredient.
  • novel coumarin-based compounds according to the present invention exhibit an inhibitory activity against overexpression of P-glycoprotein, which is a major cause of multi-drug resistance, and an increase in anti-cancer activity upon co-administration with anti-cancer agents, thereby overcoming multi-drug resistance over-the-counter, therapeutic or It can be used as a modulator, enhance the effectiveness of anticancer drugs, increase the survival rate of cancer patients, reduce the dose of anticancer drugs administered in combination, reduce side effects on normal cells, and can provide economic benefits as well. It can be usefully used for treatment.
  • the present invention provides a novel coumarin compound represented by the following formula (1).
  • R is -X-Y
  • X is C 1 -C 6 alkylene or carbonyl
  • Y is phenyl or pyridyl, wherein the phenyl or pyridyl may be unsubstituted or substituted with one or more nitriles, trifluoromethyl, halogen, C 1 -C 6 alkoxy or phenyl.
  • X is C 1 -C 2 alkylene or carbonyl
  • Y is wherein Y is phenyl or pyridyl, wherein the phenyl or pyridyl may be unsubstituted or substituted with one or more nitro, trifluoromethyl, halogen, C 1 -C 6 alkoxy or phenyl.
  • X is C 1 -C 2 alkylene
  • Y is phenyl or pyridyl, wherein phenyl or pyridyl may be unsubstituted or substituted with one or more nitro or phenyl.
  • Table 1 below shows the structures of specific examples of the coumarin-based compound of Formula 1 according to the present invention.
  • the present invention includes all of the novel coumarin-based compounds represented by Formula 1, as well as pharmaceutically acceptable salts, possible solvates or hydrates and prodrugs that can be prepared therefrom.
  • the present invention is also a group consisting of known coumarin-based compounds such as marmesin, decursinol, decursinol, decursin, decursinol angelate and marmesin angelate. It provides a pharmaceutical composition for inhibiting multi-drug resistance, containing a coumarin-based compound selected from the above as an active ingredient.
  • memesin (marmesin), decursinol (decursinol), decursin (decursin), decursinol angelate (decursinol angelate) and mamesin angelate (marmesin angelate) are each represented by the following formulas 2 to 6,
  • the compounds may be prepared or purchased according to known production methods.
  • the present invention provides a method for producing a novel coumarin compound of formula (1).
  • It comprises the step of preparing a coumarin-based compound of Formula 1a through the esterification reaction of the starting material dimethylsuberosin (dimethylsuberosin) of the formula (7).
  • the esterification reaction of Scheme 1 may be completed using a reagent for a conventional esterification reaction.
  • the esterification reaction of Scheme 1 is achieved using acyl halide and base, or carboxylic anhydride.
  • esterification reaction of Scheme 1 can also be achieved by reacting the carboxylic acid with dimethyl subsurosine of the formula (7) in the presence of a condensing agent and an amine catalyst.
  • dicyclohexylcarbodiimide DCC
  • 1,1-carbonyldiimidazole etc.
  • amine catalyst trialkyl including pyridine, dimethylaminopyridine (DMAP), and triethylamine An amine etc.
  • dicyclohexyl carbodiimide can be used as a condensing agent
  • dimethylamino pyridine can be used as an amine catalyst.
  • Dichloromethane, chloroform, tetrahydrofuran, etc. may be used as a reaction solvent of the esterification reaction of Scheme 1, and preferably dichloromethane may be used.
  • the esterification reaction of Scheme 1 may be achieved by stirring at room temperature for 12 hours to 24 hours.
  • Hal is one of the halogen elements
  • X is alkylene of C 1 -C 6
  • Y is as defined in formula (1).
  • an aprotic polar solvent such as DMF or DMSO may be used as the reaction solvent, and preferably DMF may be used.
  • sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide and the like can be used as the base in Scheme 2.
  • the reaction can be made by stirring at room temperature for 12 to 24 hours.
  • dimethyl suverosine which is a starting material of Scheme 1 or 2
  • Scheme 3 dimethyl suverosine
  • Hal is one of the halogen elements
  • Bn represents benzyl
  • Boc represents t-butyloxycarbonyl.
  • Step 1 Preparing a protected benzaldehyde of Chemical Formula 9 by reacting di-t-butyl dicarbonate in the presence of a base with benzaldehyde of Chemical Formula 8 as a starting material (Step 1);
  • step 2 Reducing the protected benzaldehyde of Formula 9 obtained in step 1 with a reducing agent to prepare a protected benzyl alcohol of Formula 10 (step 2);
  • step 4 Preparing a compound of formula 12 by reacting the compound of formula 11 obtained in step 3 with the benzyl halide reagent in the presence of a base (step 4);
  • step 5 Treating the compound of Formula 12 obtained in step 4 under acidic conditions to remove the protective group Boc to prepare a compound of Formula 13 (step 5);
  • step 6 Reacting the compound of formula 13 obtained in step 5 with triehtylorthoformate (CH (OEt) 3 ) in the presence of AlCl 3 catalyst to obtain a compound of formula 14 (step 6);
  • the compound of Formula 15 obtained in step 7 is prepared using a reducing agent capable of removing the benzyl group to prepare dimethylsuberosine of formula 7 (step 8).
  • Step 1 is a step of preparing a protected benzaldehyde of Chemical Formula 9 by reacting di-t-butyl daacarbonate (Boc 2 O) with benzaldehyde of Chemical Formula 8 in the presence of a base.
  • a base an inorganic base can be used preferably.
  • Inorganic bases include potassium carbonate, sodium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide and the like.
  • reaction solvent diethyl ether, tetrahydrofuran, dichloromethane, chloroform and the like can be used.
  • Step 2 is a step of reducing the protected benzaldehyde of Formula 9 obtained in Step 1 with a reducing agent to prepare a protected benzyl alcohol of Formula 10.
  • the reducing agent may be any kind of reducing agent capable of reducing aldehyde to alcohol, and PCC, LAH, NaBH 4 , a metal catalyst in the presence of hydrogen, sodium in the presence of alcohol, and the like are preferable.
  • the reducing agent include NaBH 4
  • the reaction solvent may be a mixture of tetrahydrofuran, diethyl ether, tetrahydrofuran and water.
  • Step 3 is a step of preparing a compound of Formula 11 by reacting the Grignard reagent of 2-methyl-1-propenyl with the protected benzyl halide of Formula 10 obtained in Step 2.
  • a Grignard reagent of 2-methyl-1-propenyl 2-methyl-1-propenyl magnesium bromide or 2-methyl-1-propenyl magnesium chloride is preferably used, and as reaction solvent, diethyl ether or Tetrahydrofuran can be used preferably.
  • Step 4 is a step of preparing a compound of formula 12 by reacting the compound of formula 11 obtained in step 3 with the benzyl halide reagent in the presence of a base.
  • Benzyl halide reagents are preferably benzyl bromide and benzyl chloride, and inorganic bases may be used as the base, and inorganic bases include potassium carbonate, sodium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide and the like.
  • Step 5 is a step of preparing a compound of Formula 13 by removing the Boc group as a protective group by treating the compound of Formula 12 obtained in step 4 under acidic conditions.
  • Any acidic condition capable of removing the Boc group is possible, and preferably, an acidic condition including hydrochloric acid is used.
  • Step 6 is a step of obtaining a compound of Formula 14 by reacting the compound of Formula 13 obtained in step 5 with triethylorthoformate (CH (OEt) 3 ) in the presence of AlCl 3 catalyst.
  • the reaction solvent benzene, toluene, xylene or the like can be preferably used.
  • Step 7 is a step of obtaining a compound of Formula 15 by reacting (carbethoxymethylene) triphenylphosphorane with the compound of Formula 14 obtained in Step 6.
  • the reaction solvent N, N-diethylaniline can be preferably used.
  • Step 8 is a step of preparing dimethyl suverosine of the formula (7) using a reducing agent capable of removing the benzyl group of the compound of formula (15) obtained in step 7.
  • a metal catalyst such as Raney Ni may be used in the presence of hydrogen.
  • novel coumarin-based compound according to the present invention is not limited to the above-mentioned preparation method, and may be used as long as it is a method capable of synthesizing the new coumarin-based compound even in a known method as well as an unknown method.
  • novel coumarin-based compound prepared according to the present invention may be separated and purified by high-performance liquid chromatography after preparation, and then the molecular structure may be confirmed by nuclear magnetic resonance.
  • the present invention provides a pharmaceutical composition for inhibiting multi-drug resistance, which contains a coumarin-based compound of Formula 1 as an active ingredient.
  • Compounds of Formula 1 of the present invention can control or treat multi-drug resistance by inhibiting overexpression of a protein that induces multi-drug resistance to anticancer drugs, wherein the protein that induces multi-drug resistance is a P-glycoprotein expressed in cancer cells To be the target.
  • the pharmaceutical composition containing the coumarin-based compound of the present invention as an active ingredient inhibits the induction of multi-drug resistance by coadministration with an anticancer agent, thereby enhancing the anticancer effect of the anticancer agent, and also reducing the dose of the anticancer agent coadministered with the anticancer agent alone. Reduce side effects on normal cells
  • Multidrug resistance is mainly due to overexpression of P-glycoprotein by MDR1 in the cell membrane of cancer cells, which directly binds to anticancer drugs, resulting in the release of the drug out of the cell and reducing intracellular drug accumulation. As the drug concentration inside the cancer cells is reduced. Therefore, compounds that inhibit the overexpression of P-glycoprotein have the effect of inhibiting multi-drug resistance.
  • Compounds of the present invention enhance the cytotoxicity of paclitaxel against MES-SA / DX5 cancer cell line, a P-glycoprotein expressing cell line treated with paclitaxel, inhibit the expression of P-glycoprotein (see Table 2), Compared to the IC 50 values measured with anti-cancer agents alone when combined with paclitaxel, the IC 50 values were lowered by up to 36-fold for the MES-SA / DX5 cell line. This shows superior multi-drug resistance inhibitory activity than verapamil used as a conventional multi-drug resistance inhibitor (see Table 2). Therefore, the compounds of the present invention effectively inhibit P-glycoprotein that causes multi-drug resistance, and thus can be usefully used to treat or modulate multi-drug resistance.
  • the compounds of the present invention are not only cancers in which P-glycoprotein is normally expressed, such as colon cancer, rectal cancer, bladder cancer, menstrual cancer, breast cancer, lung cancer, etc., but also acute myeloid leukemia (AML) in which the expression of P-glycoprotein is not high. ), And can be used to treat or regulate multi-drug resistance by anticancer agents in malignant lymphomas and the like.
  • cancers in which P-glycoprotein is normally expressed such as colon cancer, rectal cancer, bladder cancer, menstrual cancer, breast cancer, lung cancer, etc.
  • AML acute myeloid leukemia
  • the compounds of the present invention include vinblastine, vincristine and navelbine of the vinca alkaloids family; Taxanes family of paclitaxel (TAX), taxotere; Anthracyclines family of doxorubicin, daunorubicin, epirubicin and idarubicin; Epipodophyllotoxins family drugs etoposide and teniposide; Other drugs include colchicine, mitoxantrone, dactinomycin, topotecan, trimetrexate, mitramycin, mitomycin C It can be used to treat or control multi-drug resistance to anticancer agents.
  • the pharmaceutical composition containing the coumarin-based compound represented by Formula 1 as an active ingredient may be formulated and administered in various oral or parenteral dosage forms as described below during clinical administration. It is not limited to this.
  • Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, and the like.
  • Rose sucrose, mannitol, sorbitol, cellulose and / or glycine
  • lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols.
  • Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and optionally such as starch, agar, alginic acid or its sodium salt.
  • Disintegrant or boiling mixtures and / or absorbents, colorants, flavors, and sweeteners include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixir
  • compositions comprising the compound represented by Formula 1 as an active ingredient may be administered parenterally, and parenteral administration may be by injecting subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.
  • the salt of the coumarin-based compound of Formula 1 may be prepared as a solution or a suspension by mixing with a stabilizer or a buffer in water to formulate into a formulation for parenteral administration, it may be prepared in ampule or vial unit dosage form.
  • the compositions may contain sterile and / or preservatives, stabilizers, hydrating or emulsifying accelerators, auxiliaries such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, and conventional methods of mixing, granulating It may be formulated according to the formulation or coating method.
  • the dosage of the compound of the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and generally based on an adult patient having a weight of 70 kg. It is 30-120 mg / day, Preferably it is 40-80 mg / day, It can also divide and administer once a day to several times at regular time intervals according to the judgment of a doctor or a pharmacist.
  • Silica gel 60 (230-400 mesh Kieselgel 60) was used for flash column chromatography, unless otherwise specified in the present preparations and examples, and in preparative thin layer chromatography (TLC), a silica gel plate of a glass substrate ( 1 mm thick), and a 0.25 mm thick silica plate (E. Merck, silica gel 60 F254) was used for TLC to confirm the progress of the reaction.
  • TLC preparative thin layer chromatography
  • Step 3 Preparation of t-butyl 3-hydroxy-4- (3-methylbut-2-enyl) phenyl carbonate
  • Step 4 Preparation of t-butyl 3-benzyloxy-4- (3-methylbut-2-enyl) phenyl carbonate
  • Step 7 Preparation of 7-benzyloxy-6- (3-methylbut-2-enyl) -2H-chromen-2-one
  • the MES-SA / DX5 (ATCC Number: CRL-1977) cell line was purchased from ATCC and used and cultured based on the culture method described by ATCC.
  • MES-SA / DX5 cell lines were cultured in DMEM (or RPMI-1640) containing 10% FBS and passaged from 1: 6 to 1:10 every 2-3 days.
  • MES-SA / DX5 cell lines were dispensed into 96-well plates and precultured for 24 hours to allow cells to adhere to the plate bottom face.
  • the attached cells were treated with the control group (without multidrug resistance inhibitor) and the compound prepared in Examples 4, 5, and 8 (5.0 ⁇ M) according to the serial dilution concentration of the anticancer agent paclitaxel (Taxol), and Mamesine represented by the general formula (6).
  • Angelate compounds and verapamil (5.0 ⁇ M) were added as a control group and incubated for 72 hours.
  • coumarin-based compounds and verapamil according to the present invention can be seen to enhance the cytotoxicity of paclitaxel against the MES-SA / DX5 cancer cell line P-glycoprotein expressing cell line. That is, in the case of the coumarin-based compound according to the present invention when 5.0 ⁇ M in combination with paclitaxel, it is shown that the IC 50 value is lower than the paclitaxel alone treatment group for the MES-SA / DX5 cell line. In particular, in the case of the compound of Example 8, the IC 50 value is lowered by 36 times compared with the paclitaxel alone treatment group, which shows superior drug resistance inhibitory activity than verapamil used as a conventional drug resistance inhibitor.
  • the coumarin compound according to the present invention effectively inhibits P-glycoprotein that causes multi-drug resistance, and thus can be usefully used for treating or controlling multi-drug resistance.
  • the side effects of self-cytotoxicity which is a major problem of P-glycoprotein inhibitors, will be minimized.
  • the coumarin compound of Formula 1 according to the present invention can be formulated in various forms according to the purpose.
  • the following are some examples of formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.
  • the above ingredients were added to the indicated contents, uniformly mixed, stirred and granulated. After drying, tablets were prepared using a tablet press.
  • the desired components were prepared by adding the above components in the amounts shown in the present invention, mixing them uniformly, and filling the gelatine capsules with an appropriate size.
  • the above components are dissolved in boiling water with a given content, stirred, filled, cooled, and filled into a 2 ml sterile vial, and supplemented with an appropriate amount of injectable purified water to 2 ml. Prepared.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (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

La présente invention concerne de nouveaux composés à base de coumarine, un procédé de préparation de ces derniers et des compositions pharmaceutiques inhibant la résistance pléiotrope contenant ces nouveaux composés en tant qu'ingrédients actifs. Les composés à base de coumarine selon l'invention présentent des activités d'inhibition s'opposant à la surexpression de la glycoprotéine P (Pgp) qui est la cause majeure de résistance pléiotrope et augmentent les activités anticancer lorsqu'ils sont administrés en combinaison avec des médicaments anticancéreux. Par conséquent, les composés à base de coumarine selon l'invention peuvent être utilisés en tant qu'agents pour vaincre, traiter ou gérer la résistance pléiotrope contre les médicaments anticancéreux. Les composés à base de coumarine selon l'invention augmentent les effets des médicaments anticancéreux pour faire monter le taux de survie des patients cancéreux. Les composés à base de coumarine selon l'invention réduisent la dose des médicaments anticancéreux administrés en combinaison avec les composés à base de coumarine afin de réduire les effets secondaires contre les cellules normales et sont par conséquent utiles dans les traitements anticancéreux.
PCT/KR2009/007077 2008-12-01 2009-11-30 Nouveaux composés à base de coumarine, procédé de préparation de ces derniers et compositions pharmaceutiques inhibant la résistance pléiotrope contenant ces nouveaux composés en tant qu'ingrédients actifs Ceased WO2010064817A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2008-0120497 2008-12-01
KR1020080120497A KR101039750B1 (ko) 2008-12-01 2008-12-01 신규 쿠마린계 화합물, 이의 제조방법 및 이를 유효성분으로 함유하는 다약제내성 억제용 약학적 조성물

Publications (2)

Publication Number Publication Date
WO2010064817A2 true WO2010064817A2 (fr) 2010-06-10
WO2010064817A3 WO2010064817A3 (fr) 2010-09-30

Family

ID=42233715

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2009/007077 Ceased WO2010064817A2 (fr) 2008-12-01 2009-11-30 Nouveaux composés à base de coumarine, procédé de préparation de ces derniers et compositions pharmaceutiques inhibant la résistance pléiotrope contenant ces nouveaux composés en tant qu'ingrédients actifs

Country Status (2)

Country Link
KR (1) KR101039750B1 (fr)
WO (1) WO2010064817A2 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9532938B2 (en) 2010-07-29 2017-01-03 Eastman Chemical Company Esters of O-substituted hydroxy carboxylic acids and preparations thereof
CN109111419A (zh) * 2017-06-23 2019-01-01 复旦大学 7，8-含取代基香豆素衍生物及其制备方法和用途
CN114671844A (zh) * 2022-04-06 2022-06-28 浙江工业大学 一种分离制备4-o-甲基苏木素的方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100829122B1 (ko) 2006-12-05 2008-05-13 한국과학기술연구원 당귀 추출물 또는 이로부터 분리한 쿠마린계 화합물을 유효성분으로 함유하는 폐암 예방용 조성물

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9532938B2 (en) 2010-07-29 2017-01-03 Eastman Chemical Company Esters of O-substituted hydroxy carboxylic acids and preparations thereof
CN109111419A (zh) * 2017-06-23 2019-01-01 复旦大学 7，8-含取代基香豆素衍生物及其制备方法和用途
CN109111419B (zh) * 2017-06-23 2022-07-08 复旦大学 7，8-含取代基香豆素衍生物及其制备方法和用途
CN114671844A (zh) * 2022-04-06 2022-06-28 浙江工业大学 一种分离制备4-o-甲基苏木素的方法

Also Published As

Publication number Publication date
WO2010064817A3 (fr) 2010-09-30
KR101039750B1 (ko) 2011-06-09
KR20100062072A (ko) 2010-06-10

Similar Documents

Publication Publication Date Title
WO2011083999A2 (fr) Dérivé de biguanide, son procédé de préparation, et composition pharmaceutique contenant ce dérivé en tant que principe actif
WO2017026718A1 (fr) Nouveau composé 3-(isoxazol-3-yl)-pyrazolo[3,4-d]pyrimidin-4-amine, qui est un inhibiteur de la kinase ret
WO2009139576A2 (fr) Dérivés de pyridine substitués avec de nouveaux benzoxazoles ou des sels pharmaceutiquement acceptables de ces composés, procédé de préparation de ces composés et compositions pharmaceutiques contenant ces composés comme principes actifs destinées à la prévention et au traitement d'une maladie à croissance cellulaire anormale
WO2019112344A1 (fr) Nouveau dérivé de pyrimidine ayant pour effet d'inhiber la croissance de cellules cancéreuses, et composition pharmaceutique contenant celui-ci
WO2018004258A1 (fr) Nouveau dérivé hétérocyclique et son utilisation
WO2014171801A1 (fr) Dérivé d'amidopyridinol ou sel pharmaceutiquement acceptable correspondant et composition pharmaceutique le comprenant comme constituant actif
WO2021107656A2 (fr) Nouveau dérivé d'oxydo-réduction de la quercétine et son utilisation en tant qu'inhibiteur de bet
WO2020040582A1 (fr) Nouveau dérivé de benzopyrane ou sel pharmaceutiquement acceptable de celui-ci et composition pharmaceutique le comprenant en tant que principe actif
WO2019168237A1 (fr) Nouveau composé et composition pour la prévention, l'amélioration ou le traitement de la fibrose ou de la stéatohépatite non alcoolique le comprenant en tant que principe actif
WO2012053768A2 (fr) Composé à base d'aryloxyphénoxyacétyl présentant une activité inhibitrice du hif-1, son procédé de préparation, et composition pharmaceutique le contenant en tant que principe actif
WO2010064817A2 (fr) Nouveaux composés à base de coumarine, procédé de préparation de ces derniers et compositions pharmaceutiques inhibant la résistance pléiotrope contenant ces nouveaux composés en tant qu'ingrédients actifs
WO2021149900A1 (fr) Dérivé d'adamantyle disubstitué ou son sel pharmaceutiquement acceptable, et composition pharmaceutique pour empêcher la croissance du cancer le contenant comme principe actif
WO2011014009A2 (fr) Nouveau composé à base de phénoxyacétyle disubstitué ou son sel pharmaceutiquement acceptable, son procédé de fabrication, et composition pharmaceutique de suppression de multirésistance aux médicaments qui contient ce composé en tant que principe actif
WO2022177307A1 (fr) Composition de stimulateur de gène d'interféron comprenant un dérivé de benzimidazole en tant que principe actif
WO2023287128A1 (fr) Dérivé d'indazole yl benzimidazole ou sel pharmaceutiquement acceptable de celui-ci et son utilisation
WO2016111523A2 (fr) Antagoniste de hnf4-a et utilisation associée
WO2021235812A1 (fr) Composition pharmaceutique pour la prévention ou le traitement du cancer du poumon non à petites cellules associé à une mutation ron, et méthode l'utilisant
WO2021235811A1 (fr) Composition pharmaceutique pour la prévention ou le traitement du cancer du poumon à petites cellules associé à des mutants de ron et méthode l'utilisant
WO2012148140A2 (fr) Dérivés d'alcaloïdes à base d'imidazole ayant des effets d'inhibition de l'angiogenèse et antioxydants et leur procédé de préparation
WO2017099424A1 (fr) Nouveaux dérivés de la dihydropyranopyrimidinone et leur utilisation
WO2021029450A1 (fr) Nouveau dérivé de pyrimidine sulfonamide et composition pharmaceutique pour prévenir ou traiter le cancer le comprenant en tant que principe actif
WO2019231261A1 (fr) Nouveau composé dérivé de biphényle et utilisation associée
WO2023080652A1 (fr) Agents de dégradation du récepteur des androgènes pour traiter le cancer de la prostate résistant à la castration et leur utilisation
WO2019182322A1 (fr) Nouveau sel, son procédé de préparation et composition pharmaceutique le comprenant
WO2019231262A1 (fr) Nouveau composé dérivé de biphényle et son utilisation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09830555

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09830555

Country of ref document: EP

Kind code of ref document: A2