WO2002013864A1 - Preparation medicinale de prevention et traitement du cancer - Google Patents

Preparation medicinale de prevention et traitement du cancer Download PDF

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WO2002013864A1
WO2002013864A1 PCT/JP2001/007037 JP0107037W WO0213864A1 WO 2002013864 A1 WO2002013864 A1 WO 2002013864A1 JP 0107037 W JP0107037 W JP 0107037W WO 0213864 A1 WO0213864 A1 WO 0213864A1
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group
pharmaceutical composition
preventing
treating cancer
compound
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PCT/JP2001/007037
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English (en)
Japanese (ja)
Inventor
Shinichi Kurakata
Kosaku Fujiwara
Naomi Shimazaki
Takashi Fujita
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Sankyo Company, Limited
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Priority to AU2001278738A priority Critical patent/AU2001278738A1/en
Publication of WO2002013864A1 publication Critical patent/WO2002013864A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a method for activating one or more PPs (peroxisomes 'proliferatives', 'activitides', 'receptors') for preventing and treating cancers (particularly human cancers).
  • the present invention relates to a pharmaceutical composition, comprising using an agent and one or more agents for activating RXR (retinoid X receptor) simultaneously or sequentially.
  • W098 / 29120 discloses that piogliyuzone alone is administered as a PPARa activating agent!
  • An experiment on the effect of administration of LG100268 alone as an Offi activating agent and administration of both in combination on adipocyte filtration is described.
  • the effect of promoting cell division was measured, and the single dose of pioglisun was 1 zM and the single dose of LG100268 was 50 nM.
  • the dose of pioglisunzone was 5 zM and the dose of LG100268 was 50 nM, and it is not an experimental system that can measure the combined effect.
  • the publication also describes an experiment on the promotion of differentiation of liposarcoma cells by co-administration of pioglisuzone and LG100268, but this experiment only measures the promotion of differentiation.
  • the present invention clarifies the effect of the compound of the present invention on cancer as a cancer cell growth inhibitory effect by direct experiment, This shows that the effect of suppressing the growth of human cancer cells when used in combination with an agonist is remarkably superior to each of the individual administrations.
  • the gazette discloses that as a PPMa activating agent, specifically, oral diglyuzone ( BRL49653), troglisuzone and pioglisuzone are described, but the PPMa activating agent used in the present invention has a significantly stronger PPARa activating effect than these compounds.
  • the present inventors have found that the combined use of a PPARa activating agent and an MR activating agent enhances the cancer cell growth inhibitory effect. That is, the invention of a compound having an excellent PPARa activating effect was carried out, and by combining this PPARa activating agent and the MR activating agent, the tumor growth inhibitory effect of each single agent administration was obtained.
  • the present invention was completed as a pharmaceutical composition for preventing or treating cancer by the combined use thereof.
  • the present invention relates to a method for preventing and treating cancer (particularly human cancer), comprising simultaneously or simultaneously using one or more PPARa activating agents and one or more m-activating agents.
  • Pharmaceutical composition by sequential use.
  • a PPARa activating agent one of the active ingredients of the present invention, activates PPMa as a ligand of PPMa belonging to the nuclear receptor family, and is characterized by a thiazolidinedione structure. Conventionally, it has been used as a therapeutic agent for diabetes.
  • PPMa activating agent examples include, for example, JP-A-7-330728, JP-A-9-295970, JP-A-11-193276, W095 / 18125, Compounds described in JP-A-6-247945, W097 / 31907, and JP-A-9-48771 can be exemplified.
  • PPMa activating agent which is the active ingredient of the present invention.
  • X a is India Ichiru Hajime Tamaki (which may have 1 to 3 of substituents a a to be described later.) Indoline ⁇ (optionally having 1 to 3 substituents secretions a described later good.), Azai Ndoru Hajime Tamaki (which may have 1 to 3 substituents secretions a to be described later.) may have 1 to 3 of substituents a, which Azain polyhedrin Hajime Tamaki (described later .), Imidazopi lysine Hajime Tamaki (which may have 1 to 3 of substituents a described later.), or Imida Zopirimijin Hajime Tamaki (which may have 1 to 3 substituents secretions a described later ).
  • Y a represents an oxygen atom or a sulfur atom.
  • Z a is a chemical structural formula
  • R a is a hydrogen atom, C - C 4 alkyl group, - (4 alkoxy group, a halogen atom, water group may nitro group, which may have an amino group (to be described later substituent T), or C 7 -C represents an ⁇ aralkyl group.
  • n m a represents an integer of 1 to 5.
  • the substituent a is a CC 4 alkyl group,-( ⁇ alkoxy group, benzyloxy group, A halogen atom, a hydroxyl group, an acetyl group, a phenylthio group, an alkylthio group, a trifluoromethyl group, a nitro group, an amino group (which may have a substituent / a as described below), C 6 -C 1 ( 37 reel group (may have a substituent y a to be described later), and C?
  • -c ⁇ y represents a group selected from the group consisting of an aralkyl group (which may have a substituent ⁇ & described later).
  • Substituent 5 a is, C 8 alkyl group, (Cu Ararukiru group, C 6 -C 10 7 aryl group, C i - aliphatic Ashiru group, C 8 -C 12 aromatic aliphatic Ashiru group, and C 7 - Cu aromatic And represents a group selected from the group consisting of aromatic group.
  • Substituents ⁇ &, the ( ⁇ - (4 alkyl group, - c 4 alkoxy group, Tei has a halogen atom, a hydroxyl group, a nitro group, phenyl group, triflate Ruo Russia methyl group, and an amino group (substituent / a? And a group selected from the group consisting of:
  • X b represents a benzimidazole group (which may have 1 to 5 substituents b described below).
  • Y b represents an oxygen atom or a sulfur atom.
  • Z b is a chemical structural formula
  • R b is a hydrogen atom, C ⁇ C 4 alkyl groups, C "C 4 alkoxy group, a halogen atom, water group, a nitro group, an amino group (to be described later substituent 5 b may be in o Nl Yes H ) Or C 7 -C aralkyl.
  • n m b represents an integer of 1 to 5.
  • Substituent b is:-alkyl group, CC 4 alkoxy group, benzyloxy group, phenol, hydrogen atom, hydroxyl group, acetoxy group, phenylthio group, C factory C 4 alkylthio group, trifluoromethyl group, nitro group, amino group (which may have a substituent 5 b to be described later), -. Ariru group (which may have a substituent ⁇ 15 to be described later.), And is selected from the group consisting of (which may. Optionally having substituents 7 b to be described later) C 7 -Cu aralkyl group Represents a group.
  • Substituents b are -C 8 alkyl group, ( ⁇ -Cu aralkyl group, C 6 -C 10 aryl group, C aliphatic acyl group, C 8 -C 12 araliphatic acyl group, and (Cu aromatic acyl group) A group selected from the group consisting of groups is shown.
  • Substituents 7 b is, C ⁇ C 4 alkyl group, - an alkoxy group, a halogen atom, a hydroxyl group, a nitro group, phenyl group, triflate Ruo Russia methyl group, and amino group (which may have a substituent b?. ) Represents a group selected from the group consisting of: ] And a salt thereof.
  • R ei is a general formula
  • phenyl group which may have one to five of the substituents described below.
  • a pyridyl group which may have 1 to four substituents a e to be described later.
  • R e5 represents a hydrogen atom or a substituent described below.
  • R C6 are hydrogen atom, - alkyl, C 6 -C 10 7 aryl group (. Which may have 1 to 3 substituents min / ?. described later) or C 7 - 6 Ararukiru group (described later May have 1 to 3 substitutions /? 0 ).
  • De represents an oxygen atom or a sulfur atom.
  • R G2 represents a hydrogen atom or a substituent e described later.
  • R e3 is a chemical structural formula
  • a c is - represents an alkylene group.
  • B c represents an oxygen atom or a sulfur atom.
  • Substitution are a halogen atom, a hydroxyl group, a C 6 alkyl group, a halogeno-alkyl group, a C 6 alkoxy group, a CrCe alkylthio group, an amino group (which may have a substituent described later), C 3 -C 10 cycloalkyl (may have 1 to 3 substitutions ⁇ described below), C 6 -C 10 7 reel (1 to 3 substitutions /? Described below) and may be), C 7 -. the C 10 7 Riruokishi (described later substituent / ?. -?. C 16 Ararukiru (substituents to be described later may have 1 to 3), C 6.
  • C 7 -C 16 arylalkyloxy may have 1 to 3 substituents described below
  • C 6 -C 10 arylthio group which may have 1 to 3 substituents min / ?. described later.
  • C 6 aliphatic Ashiruokishi group the nitrogen atom a 4- to 7-membered saturated heterocyclic group containing, ChissoHara 5 or 6-membered aromatic heterocyclic group containing, represents a group selected from the group consisting of nitro group, and shea ⁇ cyano group.
  • Replacement / 5 Represents a halogen atom, a hydroxyl group, C ⁇ C 6 alkyl group, halogeno -.. Which (] 6 Al kill groups, C ⁇ C 6 alkoxy group, an amino group (which may have a later-described substituent ⁇ ), C And a group selected from the group consisting of a 6- Ci0 aryl group and a nitro group.
  • the substituent in “may be substituted” is a halogen atom, a hydroxyl group, Ci
  • -c 6 alkyl group halogeno - alkyl, - alkoxy group, and - c 6 is 1 to 3 substituents selected from the group consisting ⁇ alkylthio group.
  • the following compounds are also suitable as the PPARa activating agent as the active ingredient of the present invention.
  • W represents a hydrogen atom, a -C 6 alkyl group, a C 6 -C 10 aryl group (which may have 1 to 5 substituents described below), a monocyclic heteroaromatic group (substituted Or a C 7 -C 12 aralkyl group (which may have 1 to 5 substituents described later on the aryl).
  • the “monocyclic heteroaromatic group” refers to a 5- or 6-membered monocyclic aromatic heterocyclic group having one or two nitrogen atoms, for example, pyridyl, virazyl, pyrimidinyl , Pyridazinyl, pivalyl, imidazolyl, and pyrazolyl.
  • substitutions may be the same or different.
  • W indicates "C 6 -C 1 0 7 aryl group (which may have one to five of the substituents.)"
  • the group for example phenyl, methylphenyl, 2,3,4-trimethyl Phenyl, t-butylphenyl, di-1-butylphenyl, methoxyphenyl, dimethoxyphenyl, fluorophenyl, difluorophenyl, penfluorofluorophenyl, chlorophenyl, dichlorophenyl, 2-, 3- and 4-hydroxyphenyl Enyl, 4-hydroxy-2-methylphenyl, 4-hydroxy-3-methylphenyl, 2-1-butyl-4-hydroxyphenyl, 3-t-butyl-4-hydroxyphenyl, 4-hydroxy-2,3- Dimethylphenyl, 4-hydroxy-3,5-dimethylphenyl, 4-hydroxy-3,6-dimethylphenyl, 3,5-di-t-butyl-4-hydroxyphenyl, 3,6-di-t -
  • the group include pendyl, methylbenzyl, t- Butylpentyl, methoxypentyl, hydroxypentyl, fluorobenzyl, chlorobenzyl, hydroxybenzyl, 4-hydroxy-3,5-dimethylbenzyl, 3,5-di-t-butyl-4-hydroxybenzyl, phenethyl, methylphenethyl, t -Butyl phenyl, methoxyphenyl, hydroxyphenyl, fluorophenyl, chlorophenyl, hydroxyphenyl, 4-phenylbutyl, 4- (methylphenyl) butyl, 4- (hydroxyphenyl) butyl, 6 -(Methylphenyl) hexyl, 6-phenylhexyl, and 6- (hydroxyphenyl) hexyl
  • W is a C factory C 4 alkyl group, a C 6 -C 10 aryl group (which may have 1 to 5 substituents), a monocyclic heteroaromatic group (substituents Or a thiazolidinedione conjugate or a C?- ⁇ 2 aralkyl group (which may have 1 to 5 substituents on the aryl). Its pharmacologically acceptable salts.
  • W is a -C 4 alkyl group, a phenyl group (which may have 1 to 5 substituent (s)), a pyridyl group (which may have 1 to 3 substituent (s)), or A thiazolidinedione compound showing a benzyl group (which may have 1 to 3 substituent (s) on the aryl) or a pharmacologically acceptable salt thereof.
  • a thiazolidinedione compound in which X represents a sulfur atom or a pharmacologically acceptable salt thereof is a thiazolidinedione compound in which X represents a sulfur atom or a pharmacologically acceptable salt thereof.
  • a thiazolidinedione compound or a pharmacologically acceptable salt thereof, wherein Y represents one group CH.
  • W represents a phenyl group (which may have 1 to 5 substituents).
  • X represents an oxygen atom
  • the substituent represents a group selected from the group consisting of a CfC fi alkyl group and a hydroxyl group.
  • the PPMa-activating agent of the present invention includes the following compounds, but the PPARa-activating agent of the present invention is not limited to these compounds.
  • An RXR activating agent which is one of the active ingredients of the present invention, is a compound having an action of enhancing the action of a compound having retinoic acid-retinoic acid-like physiological activity (retinoide) by binding to RXR. It is.
  • RXR activating agent as an active ingredient of the present invention, typical examples include, for example, J. Thiboimet et al, Synlett, 1, ppl41-143 (1999), JP-A-6-107542, and The compounds described in W094 / 15901 can be exemplified.
  • the structural formula of a typical compound as an active ingredient of the present invention as an RXR activation agent is shown below.
  • the compound name of ATRA is (E, E, E, E) -3,7-dimethyl-9- [2,6,6-trimethyl-1-cyclohexene-1-yl] -2,4,6 , 8-Nonatetraenoic acid (all-trans-retinoic acid).
  • the method of producing ATRA is described in J. Thibonnet et al, Synlett, 1, ppl4 143 (1999), and ATRA acts on RXR by itself or part of it is converted to 9-cis-retinoic acid. This is described in Japanese Patent Publication No. 10-511948.
  • 9-cis-retinoic acid is described in JP-A-6-107542, and its compound name is (E, E, E) -3,7-dimethyl-9- [2,6,6-trimethyl-1 -Cyclohexene-1-yl]-2,4,6,8-nonatetraenoic acid (9-cis-retinoic acid).
  • the preparation of 9-cis-retinoic acid and the fact that 9-cis-retinoic acid is et al, J. Med. Chem., 37, pp. 408-414 (1994).
  • LG100268 is described in W094 / 15901, and its compound name is 6- [1- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthylene-2) -Yl) cyclopropyl] nicotinic acid.
  • the method for producing the compound and the fact that the compound is an RXR activating agent are described in W094 / 15901.
  • Lugretin is described in W094 / 15901, and its compound name is 6- [1- (3,5,5,8,8-dimethyl-5,6,7,8-tetrahydronaphthylene). -2-yl) ethenyl] is benzoic acid.
  • the method for producing the compound and the fact that the compound is an RXR activating agent are described in W094 / 15901.
  • the PPARa activating agent and the RXR activating agent which are the active ingredients of the present invention, can be converted into a salt according to a conventional method.
  • Such salts include, for example, alkali metal salts such as sodium, potassium and lithium salts; alkaline earth metal salts such as calcium and magnesium salts; aluminum salts, iron salts, zinc salts, copper salts, Metal salts such as nickel salts and cobalt salts; inorganic salts such as ammonium salts; t-octylamine salts, dipendylamine salts, morpholine salts, glucosamine salts, phenylglycine alkylester salts, ethylenediamine salts, N-methylglucamine salts, Guanidine salt, getylamine salt, triethylamine salt, dicyclohexylamine salt, ⁇ , ⁇ '-dibenzylethylenediamine salt, black mouth pro-force salt, pro-force salt, diethanolamine salt
  • Fonates salts of amino acids such as glutamic acid, aspartic acid, etc .; fumaric acid, Organic acids such as salts of carboxylic acids such as succinic acid, citric acid, tartaric acid, oxalic acid, and maleic acid; and amino acids such as ortinate, glutamate, and aspartate.
  • the salt of the PPM active agent is preferably a hydrohalide or an organic acid salt, and more preferably a hydrochloride.
  • the compound of the present invention may be left in the air or recrystallized to absorb water, adsorb water, or form a hydrate. When formed, these are all included in the present invention.
  • the compounds of the present invention may absorb certain other solvents and form solvates, which are also included in the present invention.
  • thiazolidine ring of the thiazolidinedione compound having the structure of the general formula (I) contains an asymmetric carbon, and has an optical isomer because an asymmetric carbon may be present on the substituent.
  • each of these isomers, or any proportion thereof, are encompassed by the present invention.
  • Such isomers can be obtained by synthesizing the compound of the present invention using the starting conjugate of each isomer or, if desired, resolving the compound of the present invention by a conventional resolution method or separation method. Can be obtained.
  • the present invention includes all compounds that are metabolized in vivo and converted into the compound of the present invention or a pharmacologically acceptable salt, so-called prodrugs.
  • prodrugs for example, when the compound having the general formula (I) of the present invention has a phenolic hydroxyl group, a protecting group which can be cleaved in vivo by a biological method such as hydrolysis in a living body. Refers to a protected compound.
  • a protecting group that can be cleaved in vivo by a biological method such as hydrolysis means a free phenolic hydroxyl group or a salt thereof that is cleaved in a human body by a biological method such as hydrolysis. Means a protective group that produces such a derivative or not, Can be determined by administering the compound to an experimental animal by intravenous injection, examining the body fluid of the animal thereafter, and detecting the original compound or a pharmacologically acceptable salt thereof.
  • Such protecting groups include, for example, formyloxymethyl, acetoxymethyl, dimethylaminoacetoxymethyl, propionyloxymethyl, ptyryloxymethyl, bivaloyloxymethyl, 1-formyloxetyl, 1-acetoxethyl, 1- 1- (lower aliphatic acyloxy) lower alkyl groups such as propionyloxyl, 1-butyryloxyl, 1-piparyloxyl, methoxycarbonyloxyloxymethyl, ethoxycarbonyloxyloxymethyl, propoxycarbonyloxyloxymethyl, iso Propoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl, 1- (methoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, 1- (propoxycarbonyloxy) 1- (such as 1- (isopropoxycarbonyloxy) ethyl, 1- (butoxycarbonyloxy) ethyl, 1-
  • the prevention and treatment of cancer in the present invention is performed by using a PPy activating agent and an RXR activating agent in combination. That is, by using one or more PPMa activating agents and one or more RXR activating agents simultaneously or sequentially, the superior effect compared to each single agent It shows.
  • “simultaneously” means that one or more PPARa activating agents and one or more RXR activating agents are combined in the form of a combination drug or these agents are physically combined. When it is not preferable to mix these drugs, it means that these drugs are administered individually and simultaneously.
  • ⁇ simultaneously or sequentially '' May be administered simultaneously or sequentially, with two or more being administered simultaneously and the remaining drug being administered sequentially, or two or more being being administered sequentially and the remaining being being administered simultaneously. It may be administered.
  • cancer refers to sarcomas, carcinomas, leukemias, etc. These include fibrosarcoma, liposarcoma, osteosarcoma, angiosarcoma, lung cancer, stomach cancer, colon cancer, breast cancer, prostate cancer, kidney cancer. -Includes liver cancer, lenticular cancer, esophageal cancer, tongue cancer, brain tumor, laryngeal cancer, bladder cancer, ovarian cancer, acute leukemia, chronic leukemia and lymphoma.
  • the agent of the present invention which is a PPARa-activating agent and an RXR-activating agent, can be used as such or mixed with an appropriate pharmacologically acceptable excipient, lubricant, etc. -It can be administered orally by tablets or capsules or parenterally by injection or suppository.
  • excipients include, for example, sugar derivatives such as lactose, sucrose, glucose, mannitol and sorbitol; starch derivatives such as corn starch, potato starch, ⁇ -starch and dextrin; Cellulose derivatives such as arabia; dextran; organic excipients such as pullulan; silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, magnesium magnesium silicate; calcium hydrogen phosphate Inorganic excipients such as phosphates, carbonates such as calcium carbonate, and sulfates such as calcium sulfate.
  • sugar derivatives such as lactose, sucrose, glucose, mannitol and sorbitol
  • starch derivatives such as corn starch, potato starch, ⁇ -starch and dextrin
  • Cellulose derivatives such as arabia
  • dextran such as pullulan
  • silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate,
  • lubricants include metal salts of stearic acid such as stearic acid, calcium stearate, and magnesium stearate; talc; colloidal silica; waxes such as bi-gum and gay dandelion; boric acid; adipic acid; Like sodium Sodium sulfate, glycol; fumaric acid; sodium benzoate; DL leucine; sodium salt of fatty acid; radium sulfate such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as silicic anhydride and silicic acid hydrate; Derivatives may be mentioned.
  • the dosage form of the PPARa activating agent and the agent that is the MR activating agent used in the present invention is preferably oral administration. Therefore, the two types of drugs can be adjusted individually into separate unit dosage forms, or mixed and physically adjusted into one unit dosage form.
  • the dosage and the administration ratio of the PPMa activating agent and the RXR activating agent used in the present invention may vary depending on the activity of each drug, the symptoms of patients (warm-blooded animals, especially humans), age, body weight, etc. However, in general, the oral dose of each of the PPMa activating agent and the RXR activating agent per dose is 0.005 mg / kg as a lower limit.
  • Body weight (preferably 0.05 mg / kg body weight), upper limit of 50 Omg / k body weight (preferably 5 mg / kg body weight) 0.001 mg / kg body weight (preferably 0.01 mg / kg body weight) and up to 5 O mg / k body weight (preferably 5 mg / kg body weight) from 1 to It is desirable to administer several times depending on the symptoms.
  • the administration ratio of the PPMa activating agent to the MR activating agent can vary greatly, but can generally be in the range of 1: 200 to 200: 1 by weight.
  • aP2-12 Cells were seeded 2 x l0 4 cell / Ueru to 96 ⁇ El plate was added test compound at various concentrations dissolved in DMS0 at the same time so that DMS0 concentration of 0.1%.
  • the concentration of the test compound was lnM, IOIIMS lOnOnMs 1 ⁇ M, 10 zM.
  • the cells are cultured for 24 hours, washed with PBS (phosphate buffered saline), and then lysed with a 30 ⁇ 1 pitkadin cell lysate (Toyo Inki). It was adjusted.
  • the PPARa activating agent of the present invention also shows excellent PPARa activating action in the oral gizzinozone, the oral diglyuzone and the pioglizanzone.
  • the agent of the present invention comprising the combination of the PPMa-activating agent and the RXR-activating agent is a combination of troglisuzone, oral diglyuzone or pioglisuzone and the RXR-activating agent. It is suggested that it has a better cancer cell growth inhibitory effect than any other drug.
  • Example 2 Enhancement of antitumor effect on human acute promyelocytic leukemia cell line HL-60 cells 9 human BALB / c nude mice (female, 6 weeks old) A tumor piece (5 awake x 5 angle) of the HL-60 hematopoietic cell line was transplanted. The test compound was suspended in a 5% saline solution containing 2.5% dimethylacetamide and orally administered once a day on the following day, 4 to 7, 7 to 11, and 14 to 18 days after transplantation, a total of 14 times.
  • the short diameter (thigh) and long diameter (fiber) of the tumor were measured with an electronic digital caliper, and the tumor growth inhibition rate (GI%) 21 days after transplantation was evaluated by the following formula.
  • Tumor volume means 1/2 X [tumor major axis] X [tumor minor axis] 2 .
  • mice Ten BALB / c nude mice (female, 6 weeks of age) per group were subcutaneously implanted with tumor pieces (5 ⁇ 5 thigh angle) of human gastric cancer cell line St-40.
  • the test compound was suspended in 2.5% dimethylacetamide-containing 5% Emalphor saline, and the following day after transplantation: 1 to 4 days, 7 to 11 days, 14 to 18 days, 21 to 25 days 1 day Oral administration was performed 19 times in total.
  • the short diameter (thigh) and long diameter (recommended) of the tumor were measured with an electronic digital caliper, and the tumor growth inhibition rate (GI%) on day 28 after transplantation was calculated as in Example 1.
  • Example 4 Increase in cancer cell growth inhibitory activity against human acute promyelocytic leukemia cells HL-60
  • HL-60 cells were seeded at 1 ⁇ 10 3 cells / well in a 96-well plate, and at the same time, various concentrations of drugs dissolved in DMS0 were added to the solution so that the DMS0 concentration was 0.1%.
  • Cancer cell growth inhibition rate (%) [1-(Average absorbance (cell + drug)-Average absorbance (medium))
  • LG100268 Table 5 shows that the proliferation of human acute promyelocytic leukemia cells is a PPMa activator. It was revealed that the combined administration of Compound 18 and the RXR activator, LG100268, was significantly suppressed by the combined administration of both compounds, as compared to the single administration. Example 5 Enhancement of cancer cell growth inhibitory activity against human colon cancer cells C0L-2-JCK
  • COL-2-JCK cells were seeded at 4 ⁇ 10 3 cells / well in a 96-well plate, and at the same time, various concentrations of drugs dissolved in the image were added so that the DMS0 concentration was 0.1%.
  • Cancer cell growth inhibition rate (%) [1-(Average absorbance (cells + drug)-Average absorbance (medium))] (Average absorbance (cells + MS0)-Average absorbance (medium))] X 100
  • a drug containing the compound of the present invention as an active ingredient can be produced, for example, by the following method.
  • the pharmaceutical composition of the present invention obtained by simultaneously or sequentially using one or more PPMa activating agents and one or two or more RXR activating agents can be used for cancer (particularly, It is useful in preventing and treating human cancer.
  • the present invention provides a method for simultaneously or sequentially using one or more PPMa activating agents and one or more RXR activating agents as a novel antitumor substance. Which provides a pharmaceutical composition.

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Abstract

L'invention porte sur une préparation médicinale de prévention et traitement du cancer dans laquelle: on utilise simultanément ou successivement un ou plusieurs agonistes d'activation de la PPARη ou un ou plusieurs agonistes d'activation du RXR.
PCT/JP2001/007037 2000-08-16 2001-08-15 Preparation medicinale de prevention et traitement du cancer WO2002013864A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003033494A1 (fr) * 2001-10-17 2003-04-24 Sankyo Company, Limited Derive de benzimidazole
WO2003053440A1 (fr) * 2001-12-11 2003-07-03 Sankyo Company, Limited Composition medicinale
WO2004000356A1 (fr) * 2002-06-25 2003-12-31 Sankyo Company, Limited Composition medicale contenant un diuretique et un activateur du recepteur $g(g) active par la proliferation des peroxisomes (ppar)
US6716842B2 (en) 2002-04-05 2004-04-06 Warner-Lambert Company, Llc Antidiabetic agents
WO2007069669A1 (fr) * 2005-12-16 2007-06-21 Daiichi Sankyo Company, Limited Composition pharmaceutique destinee a augmenter la production d’adiponectine
WO2007100027A1 (fr) * 2006-03-02 2007-09-07 Daiichi Sankyo Company, Limited Derive de thiazolidinedione optiquement actif

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994015901A1 (fr) * 1993-01-11 1994-07-21 Ligand Pharmaceuticals Inc. Composes activant selectivement les recepteurs de retinoides x
WO1997031907A1 (fr) * 1996-02-28 1997-09-04 Glaxo Group Limited Derives d'acide 4-hydroxy-phenylalcanoique substitue possedant une activite agoniste envers ppar-gamma
WO1998025598A2 (fr) * 1996-12-11 1998-06-18 Dana-Farber Cancer Institute Procedes et compositions pharmaceutiques inhibant la proliferation de cellules tumorales
WO1998029113A1 (fr) * 1996-12-31 1998-07-09 The Salk Institute For Biological Studies Traitement des etats pathologiques generes par la proliferation cellulaire neoplasique au moyen d'activateurs ppar-gamma et compositions utiles a cet effet
WO1999018081A1 (fr) * 1997-10-08 1999-04-15 Sankyo Company, Limited Composes heterocycliques condenses substitues
WO2000030628A2 (fr) * 1998-11-20 2000-06-02 Genentech, Inc. Methode d'inhibition de l'angiogenese

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994015901A1 (fr) * 1993-01-11 1994-07-21 Ligand Pharmaceuticals Inc. Composes activant selectivement les recepteurs de retinoides x
WO1997031907A1 (fr) * 1996-02-28 1997-09-04 Glaxo Group Limited Derives d'acide 4-hydroxy-phenylalcanoique substitue possedant une activite agoniste envers ppar-gamma
WO1998025598A2 (fr) * 1996-12-11 1998-06-18 Dana-Farber Cancer Institute Procedes et compositions pharmaceutiques inhibant la proliferation de cellules tumorales
WO1998029113A1 (fr) * 1996-12-31 1998-07-09 The Salk Institute For Biological Studies Traitement des etats pathologiques generes par la proliferation cellulaire neoplasique au moyen d'activateurs ppar-gamma et compositions utiles a cet effet
WO1999018081A1 (fr) * 1997-10-08 1999-04-15 Sankyo Company, Limited Composes heterocycliques condenses substitues
WO2000030628A2 (fr) * 1998-11-20 2000-06-02 Genentech, Inc. Methode d'inhibition de l'angiogenese

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003033494A1 (fr) * 2001-10-17 2003-04-24 Sankyo Company, Limited Derive de benzimidazole
WO2003053440A1 (fr) * 2001-12-11 2003-07-03 Sankyo Company, Limited Composition medicinale
US6716842B2 (en) 2002-04-05 2004-04-06 Warner-Lambert Company, Llc Antidiabetic agents
WO2004000356A1 (fr) * 2002-06-25 2003-12-31 Sankyo Company, Limited Composition medicale contenant un diuretique et un activateur du recepteur $g(g) active par la proliferation des peroxisomes (ppar)
WO2007069669A1 (fr) * 2005-12-16 2007-06-21 Daiichi Sankyo Company, Limited Composition pharmaceutique destinee a augmenter la production d’adiponectine
WO2007100027A1 (fr) * 2006-03-02 2007-09-07 Daiichi Sankyo Company, Limited Derive de thiazolidinedione optiquement actif

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