WO2004066994A1 - Agent anticancereux - Google Patents

Agent anticancereux Download PDF

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Publication number
WO2004066994A1
WO2004066994A1 PCT/JP2004/000680 JP2004000680W WO2004066994A1 WO 2004066994 A1 WO2004066994 A1 WO 2004066994A1 JP 2004000680 W JP2004000680 W JP 2004000680W WO 2004066994 A1 WO2004066994 A1 WO 2004066994A1
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group
cancer
optionally substituted
compound
anticancer agent
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PCT/JP2004/000680
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English (en)
Japanese (ja)
Inventor
Shinya Kimura
Taira Maekawa
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Kansai Technology Licensing Organization Co. Ltd.
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Priority to JP2005504703A priority Critical patent/JPWO2004066994A1/ja
Publication of WO2004066994A1 publication Critical patent/WO2004066994A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to an anticancer agent and a method for treating cancer.
  • P-glycoprotein P-glycoprotein
  • cells become multidrug-resistant
  • the administration of an anticancer drug to such a patient, who often acquires MDR has a problem in that the drug concentration in the cancer cells is reduced and an effective effect cannot be obtained.
  • An object of the present invention is to provide an anticancer agent having a mechanism different from the conventional one, effective for multidrug-resistant cancer cells, and having a large safety margin.
  • Another object of the present invention is to provide a method for treating cancer.
  • FIG. 1 shows the structures of 15 compounds obtained from Calophyllmn Brasiliensis.
  • FIG. 2 shows the results of examining the inhibitory effect of 15 compounds shown in FIG. 1 on the growth of BV173 cells at concentrations of ⁇ , M, 5 ⁇ , ⁇ , and 30 ⁇ ! .
  • FIG. 3 shows the results of measuring the cytostatic effect of compound 7 (GUT-70) on five types of leukemia cell lines (BV173, SEM, NALM6, HL60, and K562).
  • ⁇ indicates 0 ⁇ M
  • (translation) is 0.5 ⁇
  • (mouth) is 1.0 ⁇
  • (5.0) is 5.0 ⁇
  • (X) is the measurement result at 10 10. .
  • FIG. 4 shows the results of morphological observation of apoptosis by compound 7.
  • FIG. 4 ⁇ shows the observation results before treatment with compound 7, and
  • FIG. 4 ⁇ shows the observation results after treatment with compound 7.
  • FIG. 5 shows the results of measuring the relationship between cell cycle and apoptosis using TUNEL Atssei.
  • Fig. 5 ⁇ shows the results for the induction of apoptosis when GUT-70 was not treated and Fig. 5 ⁇ shows the results when GUT-70 was treated for 5 ⁇ for 24 hours.
  • Figure 6 shows the leukemia cell line NALM6 cells and BV173 cells treated with compound 7, was examined the temporal change in the P21 WAF./CIP. ⁇ P27 K IPL, p53 and p57 results.
  • FIG. 7A shows the results of comparing the resistance of daunorubicin (DNR) to the P-glycoprotein high-expressing cell K562 / D1-9 and the parent strain 562 cells that do not express P-glycoprotein.
  • FIG. 7B shows the results of comparing the resistance of compound 7 to the P-glycoprotein overexpressing cell K562 / D1-9 and the parent strain K562 cell not overexpressing P-glycoprotein.
  • DNR daunorubicin
  • FIG. 8 shows the results of examining the toxicity of compound 7 on normal cells using normal hematopoietic progenitor cells CFU-GM and BFU-E.
  • FIG. 9 shows the results of examining the effect of compound 7 (GUT-70) on human small cell lung cancer.
  • the inventor of the present invention has made intensive studies with the main object of solving the above problems. As a result, a compound having a specific structure has a remarkable inhibitory effect on the growth of cancer cells. They also found that they are effective against drug-resistant cancer cells, and that they have a large safety margin. The present inventors have made further studies and completed the present invention.
  • the present invention relates to the following anticancer agents and methods for treating cancer.
  • R 3 and R 4 each independently represent a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, an alkyl group, a cycloalkyl group, an optionally substituted aryl group, an alkoxy group, an acyl group, a propyloxyl group, an alkoxy group, A carboxyl group, an amino group, a monoalkylamino group, a dialkylamino group or a quinoline: a diamino group;
  • R 5 , R 8 and R 9 each independently represent a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, an alkyl group, a cycloalkyl group, an optionally substituted aryl group, an alkoxy group, an acyl group, a carboxyl group , Alkoxycarbonyl group, optionally substituted aryloxy group, thiol group, alkylthio group, optionally substituted arylthio group, alkylsulfonyl group, optionally substituted arylsulfur group, alkylaminocarbonyl Group, an optionally substituted arylaminosulfonyl group, an alkylaminosulfoyl group, an optionally substituted arylaminosulfonyl group, an alkoxycarbonyl group, an optionally substituted aryloxycarbonyl Group, amino group, monoalkylamino group, dialquinoleamino group, acylamino
  • R 6 represents an alkyl group, a cycloalkyl group, an optionally substituted aryl group, an alkoxy group, an acyl group, a carboxyl group, an alkoxycarbol group, or a compound represented by the following general formula (2)
  • R 7 represents 0, NH or NR 13 ;
  • R 1 Represents a hydrogen atom, an alkyl group, a cycloalkyl group or an aryl group which may be substituted;
  • R u and R 12 each independently represent a hydrogen atom, an alkyl group, a cycloalkyl group, or a substituted or unsubstituted aryl group;
  • R 13 represents an alkyl group, a cycloalkyl group or an aryl group which may be substituted) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • anticancer agent according to claim 1 which is R 5 force S methoxy group.
  • R 9 is an alkyl group or an optionally substituted aryl group.
  • R 6 is the following general formula (2)
  • R 1G , R 11 and R 12 are as defined above.
  • a method for treating cancer which comprises administering an effective amount of the compound according to any one of Items 1 to 7.
  • the cancer is acute myeloid leukemia, acute lymphocytic leukemia, malignant lymphoma, choriocarcinoma, multiple myeloma, soft tissue tumor, small cell lung cancer, chronic myelogenous leukemia, medullary thyroid carcinoma, osteosarcoma, head and neck Item 9.
  • cancer selected from the group consisting of acute myeloid leukemia, acute lymphocytic leukemia, malignant lymphoma, chronic myeloid leukemia, and small cell lung cancer.
  • the present invention relates to an anticancer agent preferably containing a compound represented by the general formula (3) as an active ingredient, and a method for treating cancer by administering the compound to a cancer patient.
  • the present invention relates to an anticancer agent containing a compound represented by the formula (3) as an active ingredient. Further, the present invention preferably relates to a method for treating cancer, which comprises administering an anticancer effective amount of a compound represented by the general formula (3).
  • acute antimyelogenous leukemia acute lymphocytic leukemia, malignant lymphoma, choriocarcinoma, multiple myeloma, characterized in that an anticancer effective amount of the compound represented by the general formula (3) is administered.
  • Soft tissue tumor small cell lung cancer, chronic myeloid leukemia, medullary thyroid cancer, osteosarcoma, head and neck cancer, esophageal cancer, non-small cell lung cancer, colorectal cancer, gastric cancer, biliary tract cancer, brain tumor, malignant melanoma, kidney
  • the present invention relates to a method for treating a disease selected from the group consisting of cancer, victory cancer, and liver cancer.
  • the active ingredient of the anticancer agent of the present invention has a structure represented by the following general formula (1).
  • the alkyl group includes a substituted or unsubstituted linear or branched one, and usually has 1 to 18, preferably 1 to 8, and more preferably 1 to 3, for example, Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutynole, tert-butynole, n-pentyl, isopentyl, hexyl, heptyl, octyl, nonyl and decyl.
  • the cycloalkyl group may be substituted or unsubstituted, and the number of carbon atoms is not particularly limited, but is usually 3 to 10, preferably 3 to 7. Specific examples of the cycloalkyl group include cyclopropanol, cyclobutyl, cyclopentyl, cyclohexynole, and cycloheptyl.
  • the term "aryl group” means a monocyclic or polycyclic group composed of a 5- or 6-membered aromatic hydrocarbon ring, and specific examples include phenyl, naphthyl, fluorenyl, and anthrenyl. , Biphenyl, tetrahydronaphthyl, chromanyl, 2,3-dihydro-1,4-dioxanaphthalenyl, indanyl and phenanthryl.
  • the number of substituents of the aryl group having a substituent is 1 to 3, preferably 1 or 2, and the substituent includes methyl, ethyl, methoxy, ethoxy, amino, methylamino, dimethinoleamino, cyano, nitro, Examples include fluorine, chlorine, bromine, trifluoromethyl, hydroxy, carboxyl, methoxycarbonyl, ethoxycarbol, propoxylproponyl, butoxycarbonyl, CONH2, acetyl.
  • substituted aryl group examples include phenyl, 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-chlorophenol, 2_, 3- or 4-bromophenyl, 2,4- Difluorophenyl, 2, 3_, 2, 4-, 3, 4-, 3, 5- or 2,6-dichlorophenyl, 3-chloro-1-phenylphenyl, 4-isopropylphenyl, 2,6- Dimethynophenyl, 2-, 3- or 4-trifluoromethylphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 2-, 3- or 4-dimethylaminophenyl, 2_ , 3- or 4-1-trophenyl, and 4-sulfamoylphenyl.
  • alkoxy group examples include groups represented by ⁇ R ′ (R ′ is the above-mentioned alkyl group).
  • R ′ is the above-mentioned alkyl group.
  • acyl group examples include a group represented by one COR ′ ′ (R ′′ is the above-mentioned alkyl group or the above-mentioned optionally substituted aryl group), and examples thereof include acetyl, propionyl, and benzoyl. Is done.
  • halogen atom examples include fluorine, chlorine, bromine, and iodine.
  • Examples of the asinoleamino group include a group represented by one NHCOR ′ ′ (R ′′ is the above-mentioned alkyl group or the above-mentioned optionally substituted aryl group).
  • R ′′ is the above-mentioned alkyl group or the above-mentioned optionally substituted aryl group.
  • alkoxycarbonyl group examples include a group represented by one CO ⁇ R ′ (R ′ is the aforementioned alkyl group), for example, methoxycarbyl, ethoxycarbonyl, n-propoxycarbinole, isopropoxycarbonyl, Examples are n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl and t-butoxycarbonyl. You may be replaced!
  • Examples of the / aryloxy group include a group represented by -0- (substituted or substituted aryl group), and examples include phenyloxy and naphthyloxy.
  • alkylthio group examples include a group represented by -S- (alkyl group), and examples thereof include methylthio, ethylthio, n -propynolethio, isopropylthio, n-butylthio, isobutylthio, and tert-butylthio.
  • Examples of the / and arylthio groups include groups represented by -S- (substituted or substituted aryl groups), such as phenylthio and naphthylthio.
  • Examples of the monoalkylamino group include an amino group mono-substituted with the above alkyl, such as methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, and isobutylamino.
  • an amino group mono-substituted with the above alkyl such as methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, and isobutylamino.
  • Examples of the dianolequinole amino group include amino groups di-substituted with the above alkyl, such as dimethylaminocarbonyl, getylaminocarbonyl, di-n-propylaminocarbonyl, diisopropylaminocarbonyl, di-n-butylaminoamino, Examples thereof include diisobutylaminocarbonyl, ditert-butylaminocarbonyl, di-n-pentylaminocarbonyl, diisopentylaminocarbonyl, and dihexylaminocarbonyl.
  • the alkylsulfonyl group, - S0 2 - include groups represented by (alkyl), for example, methylcarbamoyl Roh less Honoré Honi Honoré, E Chino less Honoré Honi Honoré, n- pro Pinot less Honoré Honi Honoré, isopropylidene Roh-less And norfoninole, n-butylsulfonyl, isoptylsulfonyl, and tert-butylsulfonyl.
  • the optionally substituted ⁇ reel sulfonyl group, _S0 2 - include groups represented by (optionally substituted ⁇ aryl group), for example Fuenirusuruho - Le include naphthylsulfonyl El.
  • alkylaminocarbo group examples include an aminocarbonyl group mono- or di-substituted with the alkyl.
  • the amino group mono-substituted with the alkyl include methylaminocanoleponinole, ethylaminocarbonyl, and the like. n-propylaminocarbonyl, isopropylaminocarboel, n-butylaminocarbonyl, isobutylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, isopentylaminocarbonyl, and hexinoleaminocarbonyl.
  • amino-disubstituted di-substituted alkyl Dimethylaminopropyl, diethylaminocarbonyl, di-n-propylaminocarbonyl, diisopropylaminocarbonyl, di-n-butylaminocarbonyl, diisobutylaminocarbonyl, di-tert-butylaminocarbonyl, di-n-pentyla Examples include minocarbonyl, diisopentylaminocarbonyl, and dihexylaminocarbonyl.
  • optionally substituted arylaminocarbonyl group examples include a group represented by -CONH- (optionally substituted arylylcarbonyl), such as phenylaminoaminocarbonyl and naphthylaminocarbonyl. No.
  • alkylaminosulfonyl group examples include an aminosulfonyl group mono- or di-substituted with the alkyl.
  • amino group mono-substituted with the alkyl examples include methylaminosulfonyl, ethylaminosulfonyl, and n-propylamino.
  • Sulfonyl isopropylamino sulfoel, n-butylaminosulfonyl, isobutylaminosulfonyl, tert-butynoleaminosulfonyl, n-pentylaminosulfonyl, isopentylaminosulfonyl, hexylaminosulfonyl, and the aminosulfonyl di-substituted with the alkyl.
  • methyl group examples include dimethylaminosulfonyl, getylaminosulfonyl, di-n-propylaminosulfonyl, diisopropylaminosulfonyl, di-n-butylaminosulfonyl, Two Honoré, di tert- heptyl aminosulfonyl, di n- pentyl aminosulfonyl, Jiisopenchirua Minosuruhoniru include carboxymethyl Honoré aminosulfonyl to di.
  • substituents on these ⁇ reel aminosulfonyl group, - S0 2 NH- include groups represented by (substituted Moyoi Ariru group), like for example phenylalanine amino sulfonyl, naphthyl aminosulfonyl Can be
  • the substituted or unsubstituted aryloxycarbonyl group includes a group represented by -COO- (substituted or unsubstituted aryl group), for example, phenylcarboxy group. And naphthyloxycarbonyl.
  • Alkylsulfonyl ⁇ amino group, - NHS0 2 - et include groups represented by (alkyl) is, for example, methylsulfonyl ⁇ Mino, E chill sulfonyl ⁇ amino, n- propylsulfonyl amino, isopropylsulfonyl - Ruamino, n-butylsulfonylamino-containing isobutylsulfonylamino, tert-butylsnolephonylamino, n-pentylsulfonylamino, isopentylsulfonynonamino, hexylsulfonylamino, Substituted by Les, be good Le, as a ⁇ reel sulfonyl ⁇ amino group, - NHS0 2 - include groups (! Substituted / ⁇ also good I Ariru group) represented by, e.g.
  • R 7 is preferably an oxygen atom ( ⁇ ).
  • R 5 is preferably a methoxy group (_OCH 3 ).
  • R 9 is preferably an alkyl group or an aryl group, particularly preferably an n-propyl group.
  • R 6 is a general formula (2)
  • R 1 (3 , R 11 and R 12 are as defined above)
  • the compound of the general formula (3) has a particularly excellent cancer cell growth inhibitory action.
  • Pharmaceutically acceptable salts of the compounds represented by the general formula (I) of the present invention may be any one of -R 6 , R 8 , R 9 in which a carboxyl group (COOH) or an amino group, a mono- or di-alkylamino group. If the compound has a phenyl group, a pharmaceutically acceptable salt can be prepared.
  • Examples of pharmaceutically acceptable salts of carboxy groups include alkali metal salts (sodium salt, potassium salt, lithium salt), and pharmaceutically acceptable salts of amino, mono- or dialkylamino groups.
  • Inorganic salts such as sulfate, hydrochloride, hydrobromide, lead nitrate and phosphate, fumarate, maleate, succinate, methanesulfonate, toluenesulfonate And other organic acid salts.
  • Such pharmaceutically acceptable salts can be obtained by reacting a compound of the present invention with an alkali metal carbonate or carbonate, an alkali metal hydroxide, or an inorganic or organic acid.
  • the above compounds can be appropriately prepared by various methods, may be chemically synthesized, or may be separated from an appropriate plant by extraction or the like.
  • R 8 and R 9 are as defined above.
  • R ⁇ R 5 , R 8 and R 9 are as defined above.
  • a compound having a structure wherein R 6 is represented by the general formula (2) is a compound represented by the following general formula (10) as a compound represented by the general formula (9).
  • the Friedel 'Crafts (Friede preparative Crafts) catalysts include, for example, A1C1 3, BF 3, ZnCl 2 , Sn Cl 4.
  • the compound of the present invention thus obtained is usually dissolved, extracted, separated, gradient, filtered, concentrated, thin-layer chromatography, column chromatography, gas chromatography, high-performance liquid chromatography, distillation, sublimation, crystal Purification is carried out as appropriate by using a method such as chemical conversion alone or in combination.
  • various conjugates can be obtained by using an intermediate having a desired substituent or by appropriately introducing an appropriate functional group.
  • R 1 and R 2 are methyl groups, R 3 and R 4 are hydrogen, and R 5 is —OCH 3 group, and in the general formula (6), R 8 is hydrogen
  • R 9 is a —CH 2 CH 2 CH 3 group
  • R 10 a compound in which R 1C) is hydrogen, R ′′ and R 12 is a methyl group
  • the compound serving as an active ingredient of the pharmaceutical composition of the present invention can be obtained by extracting an appropriate plant power.
  • the plant include a plant of the family Cucurbitaceae (Guttiferae).
  • plants of the family Tortaceae those belonging to the genus Calophyllum, such as Calophyllum Brasiliensis or Calophyllum inophyllum, are preferred, and Calophyllum Brasiliensis is particularly preferred.
  • the method for obtaining the compound by extracting the compound from the plant can be appropriately selected from known methods, and is not particularly limited.
  • a method in which the bark of a plant is powder-framed and extracted with an organic solvent is used. Can be.
  • the desired compound is obtained by performing appropriate separation and purification such as chromatography, filtration and extraction.
  • an appropriate organic solvent for example, a lower alcohol such as acetone, hexane, methanol, ethanol, etc.
  • the compound of the general formula (3) can be obtained by separating and purifying a plant extract of Calophyllum Brasiliensis (Guttiferae).
  • composition (pharmaceutical formulation)
  • the compound of the general formula (1) or a salt thereof is mixed with a pharmaceutically acceptable carrier, and solid preparations such as tablets, capsules, granules and powders; liquid preparations such as syrups and injections, and patches It can be appropriately formulated as a transdermal absorbent such as an ointment and a plaster, an inhalant, and a suppository.
  • the pharmaceutical composition of the present invention is orally or parenterally administered, and the above compounds may be used alone or in combination of two or more.
  • various organic or inorganic carrier substances commonly used as pharmaceutical materials can be used as the pharmaceutically acceptable carrier. Specifically, excipients, lubricants, binders, disintegrants in solid preparations, solvents, dissolution aids, suspending agents, isotonic agents, buffers, soothing agents, etc. in liquid preparations Can be blended. If necessary, pharmaceutical additives such as preservatives, antioxidants, coloring agents and sweeteners can also be used.
  • excipient examples include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light caffeic anhydride and the like.
  • Preferred examples of the lubricant include, for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like.
  • Suitable examples of the binder include, for example, crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylsenorellose, hydroxypropylmethylcellulose, polyvinylinolepyrrolidone and the like.
  • Preferred examples of the disintegrant include starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethyl starch sodium and the like.
  • Preferred examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like.
  • dissolution aid examples include, for example, polyethylene glycol, propylene dalicol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; polybutyl alcohol , Polyvinylpyrrolidone, sodium carboxymethinolate cellulose, methinoresenololose, hydroxymethylsenorelose, Examples include hydrophilic polymers such as droxicetyl cellulose and hydroxypropyl cellulose.
  • surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate
  • polybutyl alcohol Polyvinylpyrrolidone, sodium carboxymethinolate cellulose, methinoresenololose, hydroxymethylsenor
  • the tonicity agent include sodium chloride, glycerin, D-mannitol and the like.
  • buffers such as phosphate, acetate, carbonate, and citrate.
  • Preferable examples of the painless darting agent include, for example, benzyl alcohol.
  • Preferable examples of the preservative include, for example, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • the antioxidant include, for example, sulfite, ascorbic acid and the like.
  • the anticancer agent of the present invention can be applied to the treatment of various cancers.
  • the type of cancer is not particularly limited, for example, acute myeloid leukemia, acute lymphocytic leukemia, malignant lymphoma, choriocarcinoma, multiple myeloma, soft tissue tumor, small cell lung cancer, chronic myeloid leukemia, medullary thyroid cancer Osteosarcoma, head and neck cancer, esophageal cancer, non-small cell lung cancer, colorectal cancer, stomach cancer, biliary tract cancer, brain tumor, malignant melanoma, kidney cancer, knee cancer, and liver cancer.
  • the anticancer agent of the present invention is particularly effective for acute myeloid leukemia, acute lymphocytic leukemia, and small cell lung cancer. Among them, it is suitably used for acute myeloid leukemia, acute lymphocytic leukemia, and small cell lung cancer.
  • the administration conditions and administration method of the anticancer agent of the present invention can be appropriately set according to the type of the disease, the condition of the patient, the application site, and the like.
  • the dose is appropriately adjusted according to the type, size (or weight), symptoms, etc. of the animal.
  • the administration method can also be adjusted appropriately to obtain the optimal therapeutic effect.For example, it can be administered in several divided doses daily, and if a dangerous condition occurs during treatment, the dose may be adjusted according to the condition. And the number of administrations can be reduced as appropriate.
  • the anticancer agent of the present invention can be administered alone to obtain a desired effect. It can also be used in appropriate combination with an anticancer agent, a chemotherapeutic agent, an anti-inflammatory agent or an immunotherapeutic agent.
  • anticancer agents used in combination with the anticancer agent of the present invention include, for example, antimetabolites, alkylating agents, platinum-based anticancer agents, topoisomerase inhibitors, anticancer antibiotics, tyrosine kinase inhibitors, human Antibodies.
  • Human leukemia cells BV173, SUPB15, NAL6, HL60 and SEM were obtained from the American Type Culture Collection.
  • human small cell lung cancer cell lines SBC-1, SBC-3, SBC_5, 25N427, N69, LUT_130, H82, NCI345, LUT134B were used in the experiments.
  • Human leukemia cell lines BV173, SUPB15, NALM6, HL60 and SEM, and human small cell lung cancer cell lines SBC-1, SBC-3, SBC-5, N427, N69, LUT-130, H82, NCI345, LUT134B are non- inactivated the 10% FCS (Hyclone) RPMI- 1640 medium supplemented with in (GibcoBRL), and maintained at 37 ° C, in 5% C0 2 moisture culture Yoshita.
  • SEM is an Iscove culture (GibcoBRL) supplemented with inactivated 10% FCS.
  • MDR K562 / D1-9 cells were maintained in RPMI-1640 culture medium supplemented with inactivated 10% FCS and 0.1 ⁇ M daunorubicin (DNR).
  • DNR daunorubicin
  • Cell proliferation was determined using a count of cells using the trypan blue dye exclusion method and a modified MTT assay using a SF reagent (Nacalai Tesque).
  • Leukemia cells were cultured in flat-bottom 96-well plates (HGreiner labortechnik) at 2 ⁇ 10 4 cells / well in 100 ⁇ l medium and cultured for 72 hours with various concentrations of compound. ⁇ ⁇ ⁇
  • GUT-70 digestion compound 7
  • K562 / D1-9 cells were cultured at various concentrations for GUT-70 or DNR for 72 hours under the same conditions. Cultured. The average of each of the six data was used. There was a linear relationship between TT assay and cell number.
  • Protein samples were separated by SDS / PAGE and nitrocellulose membrane (Amersham
  • the membrane was saturated with a solution of 5% non-fat dry milk in TBST (25 mM Tris-HCl pH 7.8, 140 mM NaCl, 0.1% (vol / vol) Tween20) and persimmon polyclonal p21 w AFI / CIP1 , p27Kipl , Incubated overnight with p53 antibody (diluted to 1000 min). Then, the plate was washed thoroughly with TBST and incubated for 1 hour with donkey anti-Peacock IgG conjugated with horseradish peroxidase (Santa Cruz Biotech.). Detection was performed at Amersham Biosciences;
  • Apoptosis induction was examined for untreated NALM6 and NALM6 cells treated with GUT-70 for 12 hours and 24 hours. May-Giemsa staining was used to study the overall morphology, and a terminal deoxynucleotidyl transferase (TUNEL) assay was used to detect apoptosis. After drug treatment, the 5 X 10 4 cells were washed with PBS (P H7.3), and resuspended in the same buffer. The cytospin preparation of the cell suspension was fixed and stained with May-Giemsa stain. Cell morphology was determined by light microscopy.
  • TUNEL assay was performed using an apoptosis detection kit (R & D systems, Wiesbaden, Germany) according to the instructions. Briefly, NAL 6 cells were resuspended in PBS containing 3.7% formaldehyde on ice for 10 minutes and rinsed with PBS. Then fixed fine The cells were incubated in cytonin for 30 minutes at room temperature and washed with labeling buffer. Cells are labeled using a 25 1 labeling mix (dNTPMix, Mn 2+ , TdT, TdT labeling buffer).
  • the cells were rinsed with PBS, counterstained with 2 ⁇ g / ml propidium iodide for 30 minutes, and subjected to flow analysis using flow cytometry (FACScan; Becton Dickinson. NJ).
  • the sensitivity of normal hematopoietic progenitor cells to GUT-70 was examined by a standard methylcellulose culture assay containing GM-CSF, IL_3, and G-SCF.
  • Normal hematopoietic progenitor cells used were bone marrow cells from a healthy volunteer with informed consent. The cells (1 ⁇ 10 5 ) were cultured in methylcellulose for 12 days at 37 ° C. in a 5% CO 2 incubator at a GUT-70 concentration of 0.20 or 50. The number of CFU-GM and BFU-E colonies was counted under a microscope. Three tissues were tested for each gnorape and the average was determined.
  • Compound 7 having a propyl group showed a more remarkable effect (FIG. 2).
  • the compounds ⁇ and The IC50 value (halHnaximal inhibitory concentrations) of the compound 8 was 3 ⁇ M and 9 ⁇ M, respectively.
  • Compound 7 also exhibited concentration-dependent and time-dependent cell growth inhibitory effects on the other five leukemia cell lines (K562, HL60, SEM, NALM6, and SUPB15) (FIG. 3).
  • GUT-70 also steadily inhibited the growth of human small cell lung cancer cell lines SBC-1, SBC-3, LUT134B, and H82 (IC50 value of 5 ⁇ to 8 ⁇ , FIG. 9).
  • compound 7 (GUT- 70) of exposing the c NALM-6 cells examined the relationship between leukemia cytostatic and apoptosis by changing the concentration of the compound 7 24 hours, morphological techniques and flow in the induction of apoptosis Measured by cytometry. After 24 hours of exposure to compound 7 at a concentration of 5 ⁇ , significant cell apoptosis was observed morphologically (FIG. 4).
  • Compound 7 induces TUNEL-positive (i.e., apoptosis) cells significant number, reduced the percentage of cells in G 2 / M phase.
  • Compound 7 was accumulated in Gi-phase cells by TUNEL-Assy using double-stained piumumoxide staining, and apoptotic cells mainly appeared near the G-S phase (FIG. 5 ).
  • Daunorubicin is generally used as an anticancer drug, and is expressed by P-glycoprotein in contrast to K562 / D1-9, which is a cell that expresses P-glycoprotein. It was about 75 times more resistant than the parent strain K562. On the other hand, the sensitivity of compound 7 was not reduced even for K562 / D1_-9, which overexpresses P-glycoprotein, as compared with the parent strain K562, which does not express P-glycoprotein (Fig. 7). ). These findings indicate that compound 7 (GUT-70) is not involved in the P-glycoprotein-related MDR system.
  • Compound 7 (GUT-70) appears to be a good candidate component to overcome the induction of MDR. Patients with relapse have MDR that induces P-glycoprotein, which is an anticancer drug efflux pump, and clinical trials of compound 7 as an anticancer drug that often shows multidrug resistance are initially applied to patients with relapsed or refractory disease It is thought that it is done.
  • the anticancer agent of the present invention has an action mechanism different from the conventional one, and suppresses cancer cell growth in a p53-independent manner. Therefore, the present invention can be expected to have an effective effect on cancers and the like which could not be expected with conventional anticancer agents. In addition, it is possible to treat a wider variety of cancers and reduce side effects by using them in combination with drugs having different mechanisms.
  • the pharmaceutical composition of the present invention maintains an excellent effect on multidrug-resistant cancer cells in which P-glycoprotein has been induced. Therefore, it can be effectively used for patients whose other anticancer drugs have stopped responding or for patients who need multiple drug combination therapy.
  • the present invention is suitable for clinical use with a large safety margin.
  • the present invention has various requirements that have been eagerly sought in the treatment of cancer and provides an excellent means for treating those diseases.

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  • Nitrogen Condensed Heterocyclic Rings (AREA)
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Abstract

L'invention concerne un agent anticancéreux qui contient en tant qu'ingrédient actif un composé représenté par la formule générale (1), dans laquelle R1 à R9 sont tels que définis dans le descriptif, ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/JP2004/000680 2003-01-28 2004-01-27 Agent anticancereux WO2004066994A1 (fr)

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WO2009060835A1 (fr) * 2007-11-05 2009-05-14 Kyoto University Nouvelle petite molécule de liaison de l'ubiquitine
JP5622856B2 (ja) * 2010-09-16 2014-11-12 株式会社エコリソース研究所 キサントン誘導体およびその用途
CN112409368A (zh) * 2020-11-23 2021-02-26 昆明医科大学 一类c-4位取代香豆素类化合物及其制备方法和应用

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009060835A1 (fr) * 2007-11-05 2009-05-14 Kyoto University Nouvelle petite molécule de liaison de l'ubiquitine
JP5622856B2 (ja) * 2010-09-16 2014-11-12 株式会社エコリソース研究所 キサントン誘導体およびその用途
CN112409368A (zh) * 2020-11-23 2021-02-26 昆明医科大学 一类c-4位取代香豆素类化合物及其制备方法和应用

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