WO2007091622A1 - 抗癌医薬組成物 - Google Patents
抗癌医薬組成物 Download PDFInfo
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- WO2007091622A1 WO2007091622A1 PCT/JP2007/052178 JP2007052178W WO2007091622A1 WO 2007091622 A1 WO2007091622 A1 WO 2007091622A1 JP 2007052178 W JP2007052178 W JP 2007052178W WO 2007091622 A1 WO2007091622 A1 WO 2007091622A1
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- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
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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
Definitions
- the present invention relates to an anticancer pharmaceutical composition
- an anticancer pharmaceutical composition comprising a thiazolidinedione compound having a peroxisome proliferator-activated receptor (PPAR) y activation ability as an active ingredient, and a PPAR ⁇ activation activity.
- PPAR peroxisome proliferator-activated receptor
- cancer, sarcoma, or hematopoietic cancer containing as an active ingredient a compound having an epidermal growth factor receptor (EGFR) inhibitor, a vascular endothelial growth factor receptor (VEGFR) inhibitor, or a Raf kinase inhibitor
- EGFR epidermal growth factor receptor
- VEGFR vascular endothelial growth factor receptor
- Raf kinase inhibitor Raf kinase inhibitor
- PPAR y activators are widely known to be useful as therapeutic agents for type 2 diabetes, as seen in examples such as rosiglitazone and pioglitazone.
- PPAR ⁇ is considered to have various physiological functions such as induction of differentiation into adipocytes and regulation of energy metabolism in the living body (for example, see Non-Patent Documents 1 and 2).
- Non-Patent Documents 1 and 2 it has been reported that PPAR ⁇ activators induce differentiation, cell cycle inhibition or apoptosis of certain cancer cells and cause cancer cell growth inhibition.
- Non-patent Document 3, 4 and 5 cancer cell growth inhibition
- —8- PPAR ⁇ 1 chromosomal translocation is frequently observed in thyroid cancer and PPAR ⁇ function is inactivated.
- anticancer agents used in these combination therapies include cell-killing cancer chemotherapeutic agents and various molecularly targeted drugs that have recently been introduced to the market.
- molecularly targeted drugs generally have fewer side effects than the former, and it is often necessary to reduce the amount of the former in order to prevent an increase in side effects in combined use. Therefore, in combination therapy, it is possible to enhance the effect by the efficacy of the molecular target drug while maximizing the effectiveness of the cell-killing cancer chemotherapeutic agent. Drug development is underway.
- Molecular targeting drugs that are currently attracting attention include bevacizumab (trade name: Avastin), an antibody drug with angiogenesis inhibitory activity, and gefitinib (trade name: Iressa), an epidermal growth factor receptor (EGFR) inhibitor.
- EGFR epidermal growth factor receptor
- chininib trade name Tarceno
- Sorafu-bu which has both vascular endothelial growth factor receptor (VE GFR) inhibitory activity and Raf kinase inhibitory activity, has been suggested in clinical trials.
- VE GFR vascular endothelial growth factor receptor
- the enhancement of the anticancer effect by combined administration is generally that the effect of combined administration is superior to the effect of each single agent (for example, non-administration). (See Patent Document 9), and even if a synergistic enhancement effect is not always obtained, it is regarded as having significant clinical significance.
- Japanese Patent No. 3488099 discloses a thiazolidinedione compound having a novel chemical structure.
- the compound represented by the general formula (I) contained as an active ingredient of the anticancer pharmaceutical composition of the present invention is a compound included in the compound range of the thiazolidindione compound disclosed in the publication.
- Japanese Patent No. 3488099 describes that it has the thiazolidinedione compound power PPAR y activity disclosed in the publication and can be used as an anticancer agent.
- this publication does not disclose any specific test data showing that this thiazolidindione compound actually has an anticancer activity.
- a pharmaceutical composition containing this thiazolidinedione compound and a MAP kinase inhibitor has been reported (see Patent Documents 3 and 4), and this pharmaceutical composition is particularly useful for stomach cancer, lung cancer, breast cancer. It is described as being useful as a prophylactic or therapeutic agent for cancer such as colon cancer, prostate cancer, spleen cancer, liver cancer, leukemia, head and neck cancer, and liposarcoma, or as a cytostatic agent.
- a pharmaceutical composition for preventing or treating cancer comprising a part of compounds within the above-mentioned thiazolidinedione compound range and an R XR (retinoid X receptor) active agent.
- R XR retinoid X receptor
- a pharmaceutical composition containing the thiazolidinedione compound and a fluorouracil antimetabolite or a platinum complex has been reported (see Patent Documents 7 and 8), and this pharmaceutical composition is particularly useful for gastric cancer. , Lung cancer, breast cancer, colon cancer, prostate cancer, spleen cancer, liver cancer, leukemia, head and neck cancer, cancer such as liposarcoma, or cell growth suppression .
- this pharmaceutical composition can prevent or treat side effects such as cardiac hypertrophy, edema, fluid retention, and pleural effusion that occur when a PPAR y activator is administered,
- side effects such as cardiac hypertrophy, edema, fluid retention, and pleural effusion that occur when a PPAR y activator is administered
- a prophylactic or therapeutic agent for cancer such as gastric cancer, lung cancer, breast cancer, colon cancer, prostate cancer, spleen cancer, liver cancer, leukemia, head and neck cancer, liposarcoma, or cell growth inhibitor.
- cancer such as gastric cancer, lung cancer, breast cancer, colon cancer, prostate cancer, spleen cancer, liver cancer, leukemia, head and neck cancer, liposarcoma, or cell growth inhibitor.
- a pharmaceutical composition containing the thiazolidinedione compound and a novel sulfamide derivative having MEK inhibitory activity has been reported (see Patent Documents 11 and 12), and this pharmaceutical composition is particularly useful for gastric cancer. It is described as being useful as a prophylactic or therapeutic agent for cancer such as lung cancer, breast cancer, colon cancer, prostate cancer, spleen cancer, liver cancer, leukemia, head and neck cancer, and liposarcoma, or as a cytostatic agent.
- Patent Document 1 US Pat. No. 6,432,993
- Patent Document 2 European Patent No. 1022272
- Patent Document 3 Japanese Patent Laid-Open No. 2003-192592
- Patent Document 4 Pamphlet of International Publication No. 03/032988
- Patent Document 5 Japanese Patent Laid-Open No. 2003-238406
- Patent Document 6 International Publication No. 03/053440 Pamphlet
- Patent Document 7 Japanese Unexamined Patent Application Publication No. 2004-83558
- Patent Document 8 International Publication No. 03/082865 Pamphlet
- Patent Document 9 Japanese Patent Application Laid-Open No. 2004-83574
- Patent Document 10 International Publication No. 2004/000356 Pamphlet
- Patent Document 11 Japanese Unexamined Patent Application Publication No. 2005-162727
- Patent Document 12 International Publication No. 2004/083167 Pamphlet
- Non-Patent Document 2 Lehmann JM, Moore LB et al.
- An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator—activated receptor gamma. J Biol he m 1995; 270: 12953-6.
- Non-Patent Document 3 Mueller E, Sarraf P et al. Terminal differentiation of the human breast cancer through PPAR gamma. Mol Cell 1998; 1: 465—70.
- Non-Patent Document 4 Yoshizume T, Ohta T et al. Thiazolidinedione, a peroxisome proliferat or— activated receptor gamma ligana, inhibits growth and metastasis of HT— 29 human colon cancer cells through differentiation— promoting effects.
- Thiazolidinedione a peroxisome proliferat or— activated receptor gamma ligana, inhibits growth and metastasis of HT— 29 human colon cancer cells through differentiation— promoting effects.
- Non-Patent Document 5 Ray DM, Bernstein SH et al. Human multiple myeloma cells express p eroxisome proliferator— activated receptor y and undergo apoptosis upon exposure to PPAR y ligands. Clin Immunology, 2004; 113: 203-13.
- Patent Document 6 Dwight T, Thoppe SR, et al. Involvement of the PAX8 / peroxisome proliferator— activated receptor gamma reaarangement in follicular thyroid tumors. J C lin Endocrinol Metab 2003; 88: 4440-5.
- Non-Patent Document 7 Sarraf P, Mueller E et al. Loss— of— function mutations in PPAR gamma associated with human colon cancer.Mole Cell 1999; 3: 799-804.
- Non-Patent Document 8 Debrock G, Vanhentenrijk V et al. A phase II trial with rosiglitazone i n liposarcoma patients. Br J Cancer 2003; 89: 1409-12.
- Non-Patent Literature 9 Saito Tatsuo, Cancer pharmacotherapy development and effect assessment, Realize Inc., pl28-138, (1985)
- the present inventors select a compound represented by the general formula (I), which is an active ingredient of the anticancer pharmaceutical composition of the present invention, from the compound range of the above thiazolidinedione compound, The anticancer effect of the compound represented by the general formula (I) of the invention alone was examined.
- the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has an excellent anticancer effect in a specific cancer type.
- the inventors of the present invention have found that a compound having PPAR y activity (particularly, the general formula (I ) Or a pharmacologically acceptable salt thereof and epidermal growth factor receptor (EGFR) inhibitor, vascular endothelial growth factor receptor (VEGFR) inhibitor or Raf kinase inhibitor.
- EGFR epidermal growth factor receptor
- VEGFR vascular endothelial growth factor receptor
- Raf kinase inhibitor a compound having PPAR y activity
- the present inventors have found that the anticancer effect is enhanced as compared with the case where each is administered alone, thereby completing the present invention.
- R represents a phenyl group substituted with 1 to 5 groups selected from the substituent group a, X represents an oxygen atom or a sulfur atom.
- a cyclic group a 5- to 6-membered aromatic heterocyclic group containing a nitrogen atom; a nitro group; and a cyano group.
- Gastric cancer large intestine cancer, lung cancer, breast cancer, spleen cancer, kidney cancer, prostate cancer, medulloblastoma, rhabdomyosarcoma, Ewing's sarcoma
- Anti-cancer pharmaceutical composition for preventing or treating liposarcoma, multiple myeloma or leukemia,
- the scale is a phenenore group substituted with 1 to 5 substituents in which the substituent group ⁇ force is also selected
- a pharmaceutical composition which is a 5- to 6-membered aromatic heterocyclic group containing a cyclic group and a nitrogen atom, (3)
- R is an amino group which may be substituted with 1 to 2 substituents (the substituents may be the same or different, and may be C—C alkyl, C—C aryl, and C—C
- a phenyl group which may be substituted with 1 to 2 C C alkyls.
- the compound having the general formula (I) or a pharmacologically acceptable salt thereof is 5-(4— (6-(4 amino-3, 5 dimethylphenoxy) 1-methyl 1H benzoy A pharmaceutical composition that is midazol-2ylmethoxy) benzyl) thiazolidine 2,4 dione dihydrochloride,
- the compound having the general formula (I) or a pharmacologically acceptable salt thereof is 5- (4— (6- (3-isopropylamino-phenoxy) 1-methyl 1H benzimidazo 1-ru-2-ylmethoxy) benzyl) thiazolidine-2,4 dione dihydrochloride, a pharmaceutical composition,
- At least one anticancer agent selected from the group consisting of an epidermal growth factor receptor (EGFR) inhibitor, a vascular endothelial growth factor receptor (VEGF R) inhibitor, and a Raf kinase inhibitor, and the following general formula (I ):
- EGFR epidermal growth factor receptor
- VEGF R vascular endothelial growth factor receptor
- Raf kinase inhibitor Raf kinase inhibitor
- R represents a phenyl group substituted with 1 to 5 groups selected from the substituent group a, and X represents an oxygen atom or a sulfur atom.
- An anticancer pharmaceutical composition for preventing or treating cancer
- the anticancer agent is an epidermal growth factor receptor (EGFR) inhibitor (the agent is cetuximab, panitumumab, gefitib, erucibib or lapatib), vascular endothelium.
- EGFR epidermal growth factor receptor
- VEGFR Cell growth factor receptor
- a pharmaceutical composition which is at least one selected from the group consisting of:
- composition according to (9), wherein the anticancer agent is at least one selected from the group consisting of Gefitiv and Sorafu-buca,
- R force may be substituted with 1 or 2 substituents (the substituents may be the same or different and may be substituted with C — C alkyl , C — C
- c -c aralkyl group power is the group power selected.
- a phenyl group which may be substituted with 1 to 3 substituents (the substituent is a group selected from the group consisting of halogen, C C alkyl and halogeno C C alkyl groups).
- At least one compound selected from the group consisting of the compound having the general formula (I) and a pharmacologically acceptable salt thereof is 5- (4 1 (6- (4 amino-3 , 5 dimethylroofenoxy) 1-methyl 1H-benzimidazole-2-ylmethoxy) monobenzyl) thiazolidine 2, 4 dione dihydrochloride, pharmaceutical composition,
- At least one compound selected from the group consisting of the compound having the general formula (I) and a pharmacologically acceptable salt thereof is 5- (4 (6- (3 isopropylamino-phenoxy) 1-methyl 1H-benzimidazole 1-2-ylmethoxy) monobenzyl) -thiazolidine mono 2,4 dione dihydrochloride pharmaceutical composition
- the present invention provides a gastric cancer comprising the administration of a pharmaceutical composition according to any one of (1) to (8) above to a warm-blooded animal (preferably a human), Provided is a method for preventing or treating colorectal cancer, lung cancer, breast cancer, spleen cancer, kidney cancer, prostate cancer, medulloblastoma, rhabdomyosarcoma, Ewing sarcoma, liposarcoma, multiple myeloma or leukemia.
- the active ingredients of the pharmaceutical composition described in any one of the above (9) to (21) are selected at the same time or each active ingredient is administered at a time.
- Consisting of carcinoma especially stomach cancer, colon cancer, lung cancer, breast cancer, spleen cancer, kidney cancer or prostate cancer
- sarcoma especially medulloblastoma, rhabdomyosarcoma, Ewing sarcoma or liposarcoma
- hematopoietic cancer especially multiple myeloma or leukemia.
- the “norogen atom” in the definitions of the substituent groups ⁇ and j8 is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom, Preferable is a fluorine atom.
- "C — C alkyl group” in the definition of substituent groups ⁇ and j8 is a group having 1 to 6 carbon atoms.
- Straight chain or branched chain alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sbutyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1 ethylpropyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3 dimethylbutyl, 2,2 dimethylbutyl, 1,1-dimethylbutyl, 1,2 dimethylbutyl, 1,3 dimethylbutyl, 2,3 dimethylbutyl Or in the substituent group ⁇ , preferably a methyl or t-butyl group, and in the substituent group j8, preferably a CC alkyl group, more preferably a methyl group. Or it is an ethyl group.
- 1 6 1 represents a group in which 1 to 3 halogen atoms are bonded to an alkyl group, for example, trifluoro
- 1 6 1 6 Indicates a group in which an alkyl group is bonded to an oxygen atom.
- Particularly preferred is a methoxy group.
- C 1 -C 4 alkylthio group in the definition of substituent group ⁇ is the above-mentioned C 1 -C 6 alkyl alkyl.
- 1 6 1 6 represents a group in which a sulfur group is bonded to a sulfur atom, for example, methylthio, ethylthio, propylthiol O, Isopropylthio, Butylthio, Isobutylthio, S Butylthio, t-Butylthio
- Pentylthio isopentylthio, 2-methylbutylthio, neopentylthio, 1-ethylpropylthio, hexylthio, 4-methylpentylthio, 3-methylpentylthio, 2 methylpentylthio, 1 methylpentylthio, 3, 3 Dimethylbutylthio, 2,2-dimethylbutylthio, 1,1 dimethylbutylthio, 1,2-dimethylbutylthio, 1,3 dimethylenobutinoretio, 2,3 dimethylenobutinoretio or 2-ethinolevylthio group And is preferably a C 1 -C alkylthio group, more preferably C
- C is an alkylthio group, particularly preferably a methylthio group.
- an amino group which may be substituted with one or two groups selected from substituent group y includes a C — C alkyl group, a C — C aryl group, C — C
- Tyl 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1-propylbutyl, 4,4 dimethylpentyl, octyl, 1-methylheptyl, 2-methylheptyl , 3 methylheptyl, 4 methylheptinole, 5-methinoleheptinole, 6-methinoreheptinole, 1 propinolepentinole, 2 ethinorehexyl, 5,5-dimethylhexyl, noel, 3-methyloctyl, 4-methyloctyl , 5-Methyloctyl, 6-Methyloctyl, 1-propylhexyl, 2-Ethylhexyl, 6,6 Dimethylheptyl, Decyl, 1-Methylnoel, 3-Methylnoel, 8-Methylnonyl, 3-Ethyloc
- aromatic hydrocarbon groups include, for example, phenol
- —C aryl group represents a group bonded to the C 1 -C alkyl group, for example, benzyl
- 14 is an aralkyl group bonded to an alkyl group, and more preferably a benzyl group.
- a carbonyl, 2-indanecarbol or 1 or 2-naphthoyl group preferably a benzoyl or naphthoyl group.
- Group " is a C-C cycloalkyl group (optionally condensed 3- to 10-membered saturated cyclic hydrocarbon
- Cycloheptyl, norbornyl or adamantyl group preferably C C cycl
- the “5- to 6-membered aromatic heterocyclic carbonyl group containing a nitrogen atom” includes at least one nitrogen atom, and further includes a nitrogen atom, an oxygen atom, and a sulfur atom.
- Heteroatomic group forces that also contain nuclear power 5 to 6-membered aromatic heterocycles that may contain selected heteroatoms e.g., pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrazyl, pyrimidinyl, pyridazin- , A thiazolyl, an oxazolyl, an oxadiazolyl or a thiadiazolyl group), a carbocyclic group bonded to), for example, pyrrolylcarboxyl, imidazolylcarbol, pyrazolylcarbol, triazolylcarbonyl, tetrazolyl Carbonyl, nicotinol, isonicotinoyl, pyrazole carbonyl, pyrimidyl carbonate, Pyridazylcarbonyl, thiazolylcarbonyl, oxazolylcarbonyl, oxazi
- amino group optionally substituted by 1 or 2 groups selected from the substituent group ⁇ is preferably an amino group, 1 or 2
- An amino group substituted with a substituent of the above (the substituents may be the same or different and may be a C—C alkyl group, a C—C aryl group,
- C C aralkyl group power is also selected group. And more preferably
- 3 is a cycloalkyl group, more preferably halogen, hydroxy, c-c alkyl and
- Binologeno c -C alkyl force group force may be substituted with one selected group
- Iji C cycloalkyl group more preferably fluorine, chlorine, hydroxy, methyl,
- An adamantyl group which may be substituted by one by ethyl, t-butyl, trifluoromethyl, methoxy, amino, methylamino or dimethylamino, particularly preferably an adamantyl group.
- the C aryl moiety has the same meaning as described above, preferably from the substituent group j8.
- a c -c aryl group which may be substituted one by the selected group, more preferably halo.
- a substituent group ⁇ force is a C 1 -C aryl group which may be substituted by 1 or 2 with a selected group, or may be substituted with 1 amino, more preferably fluorine, chlorine , Hydroxy
- a phenyl group which may be substituted by one of cis, methyl, ethyl, t-butyl, trifluoromethyl, methoxy, amide-containing methylamino or dimethylamino, particularly preferably a phenyl or 4-hydroxyphenol. Group.
- a benzyl group which may be substituted with an optionally substituted amino, more preferably fluorine, chlorine, hydroxy, methyl, ethyl, t-butyl, trifluoromethyl, methoxy, amino
- Benzyl group which may be substituted by one with methylamino or dimethylamino, particularly preferred Is a benzyl group.
- 6 10 6 10 6 10 represents a group in which aryl is bonded to an oxygen atom, for example, phenoxy, 1 indenyloxy, 2 induroxy, 3 induroxy, 1 naphthyloxy or 2 naphthyloxy group, preferably a phenoxy group.
- the C — C aralkyloxy portion of the “C — C aralkyloxy group which may be substituted with 1 to 3 substituents selected by the substituent group ⁇ force” in the definition of the substituent group a is the C ⁇
- C represents a aralkyl group bonded to an oxygen atom, such as benzyloxy, naphthyl
- the C C aryl thio moiety of the “substituent group ⁇ force optionally substituted by 1 to 3 C C aryl thio groups” in the definition of the substituent group a is the C C aryl
- 6 10 6 10 6 10 represents a group in which a sulfur group is bonded to a sulfur atom, for example, phenylthio, 1 indenylthio, 2 indenylthio, 3 indenylthio, 1 naphthylthio or 2 naphthylthio group, preferably a phenylthio group It is.
- the "CC aliphatic acyloxy group" in the definition of the substituent group a represents a group in which an oxygen atom is bonded to the CC aliphatic acyl group, and includes, for example, formyloxy, acetoxy, pionyloxy, butyryloxy, isobutyryloxy.
- "4- to 7-membered saturated heterocyclic group containing nitrogen atom" in the definition of substituent group a is nitrogen A heteroatom group force comprising at least one elemental atom and further comprising a nitrogen atom, an oxygen atom and a sulfur atom; a 4- to 7-membered saturated heterocyclic group which may contain a selected heteroatom, such as azetidul, Pyrrolidyl, imidazolidinyl, thiazolidyl, bisazolidyl, piperidinyl, monoreforinole, thiomonoreforinole, piperazinyl, homopiperazinyl, preferably pyrrolidyl, piperidyl, or morpholinyl.
- a pyrrolidine 1-yl, piperidine 1-yl or morpholine-4-yl group is a selected heteroatom, such as azetidul, Pyrrolidyl, imidazolidinyl, thiazolidyl
- the "5- to 6-membered aromatic heterocyclic group containing a nitrogen atom" in the definition of the substituent group a has the same meaning as described above, and is preferably an imidazolyl, tetrazolyl or pyridinyl group, Preferred is a pyridine-2-yl or pyridine-3-yl group.
- R is preferably a halogen atom, a C C alkyl group, or a halogeno C C alkyl group.
- a substituent group ⁇ force an amino group which may be substituted by 1 or 2 groups, a 4- to 7-membered saturated heterocyclic group containing a nitrogen atom and a 5- to 6-membered aromatic heterocyclic group containing a nitrogen atom
- a phenyl group substituted with 1 to 5 groups selected from the group consisting of
- R is more preferably an amino or an amino substituted with 1 to 2 substituents (the substituents may be the same or different and each represents a C 1 -C alkyl group, a C 1 -C aryl group, and a C 2- C
- the group power that consists of rukirka is also the group that is selected.
- a phenyl group which may be further substituted with 1 to 3 substituents (the substituent is a halogen atom, C — C alkyl)
- R is more preferably a single amino or mono- or di-C C alkylamino group.
- phenyl group which may be further substituted with 1 or 2 C C alkyl.
- the present invention provides at least one anticancer agent selected from the group consisting of an epidermal growth factor receptor (EGFR) inhibitor, a vascular endothelial growth factor receptor (VEGFR) inhibitor, and a Raf kinase inhibitor, and peroxisome proliferator activity.
- EGFR epidermal growth factor receptor
- VEGFR vascular endothelial growth factor receptor
- Raf kinase inhibitor a Raf kinase inhibitor
- PPAR peroxisome proliferator activity.
- Receptor (PPAR) Containing ⁇ -activating ability and at least one compound selected from the group consisting of pharmacologically acceptable salt strengths as active ingredients, simultaneously or separately with time
- an anticancer pharmaceutical composition for preventing or treating carcinoma, sarcoma or hematopoietic cancer for administration.
- Epidermal growth factor receptor refers to epidermal growth factor. It is a receptor protein that exists on the cell surface. This receptor is a transmembrane protein, and has a region having tyrosine kinase activity in the cell. It has been clarified that this receptor is expressed on the surface of many cancer cells, and overexpression is frequently observed particularly in lung cancer, breast cancer, colon cancer, spleen cancer and the like.
- Examples of drugs that inhibit the function of epidermal growth factor receptor (EGFR) include cetuximab (trade name: Lubitux) and panitumumab as antibodies that bind to the extracellular region.
- Examples of the inhibitor for tyrosine kinase activity include Gefitiv (trade name Iressa), L-mouth (trade name Tarceva), and Lapatib. The L mouth tube (trade name Tarceno is preferred).
- Vascular endothelial cell growth factor receptor is a receptor protein present on the cell surface for vascular endothelial cell growth factor.
- This receptor is a transmembrane protein and has a region having tyrosine kinase activity in the cell.
- This receptor is known to be mainly expressed in vascular endothelial cells, and stimulates the proliferation of vascular endothelial cells upon stimulation by vascular endothelial growth factor secreted by cancer cells. As a result, angiogenesis around the cancer tissue is enhanced and the growth of the cancer tissue is promoted.
- bevacizumab (trade name Avastin), which is a neutralizing antibody against vascular endothelial growth factor itself, and as an inhibitor of tyrosine kinase activity , Solaf Enib, SU11248, Batarab (PTK787). Solafunib is preferred.
- Raf kinase is a kind of serine threonine kinase that is deeply involved in cell proliferation signals and is known to play a part in the cascade that transmits proliferation signals from Ras protein, a low molecular weight G protein, into the nucleus.
- a drug that inhibits the kinase activity of Raf is Sorafenib.
- the compound having PPAR ⁇ activation ability which is one of the active ingredients of the anticancer pharmaceutical composition of the present invention, may be any compound that activates human PPARy by any acceptable activity. Or any compound generally recognized as a PPAR y activator or PPAR y agent. Such a PPAR y activator may be an activator of two or more PPAR subtypes.
- Preferred PPAR activator One is non-thiazolidinedione compounds such as thiazolidinedione compounds known to be useful in the treatment of diabetes and those disclosed in US Pat. No. 6,294,580. PPAR y tactics can also be mentioned.
- Preferred thiazolidinedione compounds include rosiglitazone and pioglitazone, which are currently commercially available, in addition to the compound having the general formula (I) of the present invention, and Japanese Patent No. 2976885 (US5886014) and Japanese Patent No. 3488099. (US6432993, EP1022272) and JP 2000 351779 (WO00 / 61581) can be mentioned.
- Preferable non-thiazolidinedione compounds include compounds under development such as the GlaxoSmithKline compound GI262570 (farglitazar).
- these compounds having PPARy activity particularly preferably A compound having the general formula (I) of the invention or a pharmacologically acceptable salt thereof.
- EGFR epidermal growth factor receptor
- vascular endothelial cell growth factor receptor which is an active ingredient of the pharmaceutical composition of the present invention
- Body (VEGFR) inhibitors and Raf kinase inhibitors that form salts can be converted into salts according to conventional methods, if desired, and such salts are also included in the present invention.
- salts with acids for example, salts of inorganic acids such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate; acetate, fumarate, Carboxylic acid salts such as maleate, oxalate, malonate, succinate, succinate, malate; methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, etc. And salts of amino acids such as glutamate and aspartate.
- inorganic acids such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate; acetate, fumarate, Carboxylic acid salts such as maleate, oxalate, malonate, succinate, succinate, malate; methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, etc.
- Examples of the salt with a base include a salt with an alkali metal such as a lithium salt, a sodium salt, or a potassium salt; a salt with an alkaline earth metal such as a calcium salt or a magnesium salt; And salts with organic bases such as dimethyl salt, triethylamine salt, diisopropylamine salt and cyclohexylamine salt.
- an alkali metal such as a lithium salt, a sodium salt, or a potassium salt
- a salt with an alkaline earth metal such as a calcium salt or a magnesium salt
- salts with organic bases such as dimethyl salt, triethylamine salt, diisopropylamine salt and cyclohexylamine salt.
- EGFR epidermal growth factor receptor
- vascular endothelial cell growth factor which is an active ingredient of the pharmaceutical composition of the present invention
- Each of the child receptor (VEGFR) inhibitor and the Raf kinase inhibitor may have an optical isomer, and any of them or a mixture thereof is included in the present invention.
- Such optical isomers can be obtained by synthesizing each isomer raw material compound or by dividing the synthesized compound using a conventional resolution method or separation method as desired.
- EGFR epidermal growth factor receptor
- vascular endothelial cell growth factor receptor which is an active ingredient of the pharmaceutical composition of the present invention
- the body (VEGFR) inhibitor and the Raf kinase inhibitor are each included in the present invention in terms of the forces that may exist as hydrates or solvates, respectively, or a mixture thereof.
- the present invention relates to carcinoma (especially stomach cancer, colon cancer, lung cancer, breast cancer, spleen cancer, kidney cancer or prostate cancer), sarcoma (especially medulloblastoma, rhabdomyosarcoma, Ewing sarcoma or Or a method of preventing or treating hematopoietic cancer (especially multiple myeloma or leukemia).
- carcinoma especially stomach cancer, colon cancer, lung cancer, breast cancer, spleen cancer, kidney cancer or prostate cancer
- sarcoma especially medulloblastoma, rhabdomyosarcoma, Ewing sarcoma or Or a method of preventing or treating hematopoietic cancer (especially multiple myeloma or leukemia).
- EGFR epidermal growth factor receptor
- VEGFR vascular endothelial growth factor receptor
- “combination” refers to the use of two or more kinds of drugs.
- a form in which each drug is administered simultaneously a form in which each drug is administered separately separately over time, a mixture
- a form in which it is physically administered as a single composition there may be mentioned a form in which it is physically administered as a single composition.
- administered simultaneously is not particularly limited as long as it is an administration form that can be administered at approximately the same time, but it is preferably administered as a single composition.
- EGFR epidermal growth factor receptor
- a harmful agent, a vascular endothelial growth factor receptor (VEGFR) inhibitor or a Raf kinase inhibitor is administered, and then, after a predetermined time, a compound having PPAR y activity or its ability Administering a pharmacologically acceptable salt.
- EGFR epidermal growth factor receptor
- VEGFR vascular endothelial growth factor receptor
- Raf kinase inhibitor Administering a pharmacologically acceptable salt.
- the anticancer pharmaceutical composition of the present invention containing a compound having the general formula (I) as an active ingredient includes gastric cancer, colon cancer, lung cancer, breast cancer, spleen cancer, kidney cancer, prostate cancer, medulloblastoma, It is useful as a prophylactic or therapeutic agent for rhabdomyosarcoma, Ewing sarcoma, liposarcoma, multiple myeloma or leukemia.
- EGFR epidermal growth factor receptor
- An anticancer pharmaceutical composition containing a compound as an active ingredient and administered separately at the same time or at intervals is an anticancer agent (such as stomach cancer, colon cancer, lung cancer, breast cancer, spleen cancer, kidney cancer, prostate cancer).
- hematopoietic cancers such as sarcomas such as neoplastic carcinoma, medulloblastoma, rhabdomyosarcoma, Ewing sarcoma, liposarcoma or multiple myeloma .
- Roziglitazone can be easily produced according to the method described in US5741803, and pioglitazone can be produced according to the method described in US4687777.
- Fargritazar can be easily produced according to the method described in WO00Z08002.
- EGFR epidermal growth factor receptor
- Gefitiv is obtained from AstraZeneca can do.
- Cetuximab is EP359282, Panitumumab is W096Z33735, L-Tube is WO96Z30347, Lapatib is W099Z35146, a vascular endothelial growth factor receptor (VEGFR) inhibitor Among them, bevacizumab is EP13 25932 publication, Sorafu is W099Z35146 publication, SU11248 is WO2001 / 060814 publication, Notaranifu Sakuma, WO98 / 035958 publication [the method described in this subsection! /, It can be manufactured easily.
- VEGFR vascular endothelial growth factor receptor
- the compound having the general formula (I) or the pharmacologically acceptable salt thereof, which is an active ingredient of the pharmaceutical composition of the present invention is used as a therapeutic agent 'ameliorating agent or prophylactic agent, itself or an appropriate Mix with pharmacologically acceptable excipients, diluents, etc., for example, orally by tablets, capsules, granules, powders or syrups, or parenterally by injections or suppositories, etc. Can be administered.
- excipients for example, sugar derivatives such as lactose, sucrose, sucrose, mannitol, sorbitol; starch derivatives such as corn starch, potato starch, alpha starch, dextrin; crystalline cellulose Cellulose derivatives; gum arabic; dextran; organic excipients such as pullulan: and silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, magnesium metasilicate aluminate; hydrogen phosphate Inorganic fillers such as phosphates such as calcium carbonates; sulfates such as calcium sulfates), lubricants (for example, stearic acid, calcium stearate, Metal stearates such as magnesium stearate; talc; colloidal silica; Waxes; boric acid; adipic acid; sulfates such as sodium sulfate; glycols; fumaric acid; sodium benzoate;
- excipients for example,
- Disintegrants eg, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, cellulose derivatives such as internally crosslinked sodium carboxymethyl cellulose; carboxymethyl starch, sodium carboxymethyl starch, Chemically modified denpene such as celluloses), stabilizers (paraoxybenzoates such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol, and phenylethyl alcohol) Benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid.), Flavoring agents (for example, common May be mentioned are used, sweetener, acidulant, perfume, etc .;.), It is prepared in a known manner by using additives such as diluents.
- additives such as diluents.
- the dose may vary greatly depending on various conditions such as the activity of the drug, the symptoms of the patient (warm-blooded animals, particularly humans), age, weight, etc. For example, once in the case of oral administration Per day, 0.0005 mg / kg body weight as the lower limit, 50 mg / kg body weight as the upper limit, and once for intravenous administration, 0.0005 mg / kg body weight as the lower limit, 50 mg / kg body weight as the upper limit, 1 day It is desirable to administer several times depending on the symptoms.
- a compound having PPAR ⁇ activation ability preferably a compound having the above general formula (I)
- a pharmacologically acceptable salt thereof an epidermal growth factor receptor (EGFR) inhibitor, Vascular endodermal growth factor receptor (VEGFR) inhibitors or Raf kinase inhibitors
- EGFR epidermal growth factor receptor
- VEGFR Vascular endodermal growth factor receptor
- Raf kinase inhibitors can be individually adjusted to separate unit dosage forms or mixed to form a physically single dosage form.
- EGFR epidermal growth factor receptor
- VEGFR vascular endothelial growth factor receptor
- Raf kinase inhibitor each itself or mixed with appropriate pharmacologically acceptable excipients, diluents, etc.
- excipients for example, lactose, sucrose, sucrose, mannitol, sorbitol Sugar derivatives such as maize starch, potato starch, alpha starch, starch derivatives such as dextrin; cellulose derivatives such as crystalline cellulose; gum arabic; dextrane; organic excipients such as pullulan; and light anhydrous Silicate derivatives such as silicic acid, synthetic aluminum silicate, calcium silicate, magnesium metasilicate aluminate; hydrogen phosphate power phosphate such as calcium; carbonate such as calcium carbonate; inorganic such as sulfate such as calcium sulfate Excipients), lubricants (eg, stearic acid, calcium stearate, magnesium stearate such as magnesium stearate; talc; colloidal silica; beeswax, Waxes; boric acid; adipic acid; sulfates such as sodium sulfate
- excipients for example
- Binders for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polybutylpyrrolidone, macrogol, and compounds similar to the above excipients
- disintegrants for example, low substitution Cellulose derivatives such as hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, internally cross-linked sodium carboxymethylcellulose; chemically modified such as carboxymethyl starch, carboxymethyl starch sodium, cross-linked polyvinyl pyrrolidone Starches (can include celluloses), emulsifiers (eg colloidal clays such as bentonite and bee gum); metal hydroxides such as magnesium hydroxide and aluminum hydroxide; sodium lauryl sulfate , Anionic surfactants such as calcium stearate; cationic surfactants such as salt benzalkonium; and non-oxygen surfactants such as polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, sucrose fatty acid esters Ionic sur
- EGFR epidermal growth factor receptor
- VEGFR vascular endothelial growth factor receptor
- Raf kinase inhibitor a compound having PPAR y activation ability or a pharmacologically acceptable salt thereof, an epidermal growth factor receptor (EGFR) inhibitor, a vascular endothelial growth factor receptor (VEGFR) inhibitor, a Raf kinase inhibitor
- the dose ratio may vary depending on various conditions such as individual drug activity, patient symptoms, age, weight, and the like.
- the dose depends on the activity of the drug, the symptoms of the patient (warm-blooded animals, especially humans), age, weight, etc.
- the lower limit is 0.1 mg / kg each time.
- Upper limit lOOmg / kg (preferably 20mg / kg)
- lower limit 0.01mg per dose upper limit 100mg / kg (preferably 10mg / kg) 1 to 6 times per day, depending on the symptoms, at the same time or separately at different times.
- the ratio of the dose of the compound having the ability to activate PPAR ⁇ and the epidermal growth factor receptor (EGFR) inhibitor, vascular endothelial growth factor receptor (VEGFR) inhibitor, or Raf kinase inhibitor is also as follows:
- EGFR epidermal growth factor receptor
- VEGFR vascular endothelial growth factor receptor
- Raf kinase inhibitors can be in the range of 1: 1000 to 1000: 1 by weight ratio.
- a mixture of sodium borohydride and 200 ml of anhydrous tetrahydrofuran was stirred at room temperature for 4 days.
- the reaction mixture was concentrated, water was added and extracted with ethyl acetate.
- N (5— (3 Bromophenoxy) -2-trophenol) obtained in Reference Example 3 of Omg —N-methylcarbamic acid t-butyl ester, 0.2 ml of isobutylmethylamine, 151.
- Omg of Tris Suspend (dibenzylideneacetone) dipalladium, 115.7 mg 2- (dicyclohexylphosphino) biphenol and 277.7 mg potassium t-butoxide in 4 ml water-free toluene at 100 ° C. Stir for 5 hours. Add water to the reaction mixture and add acetate. Extracted with chill.
- Human gastric cancer cell lines (MKN74, MKN28) purchased from Immunobiological Research Institute, Inc.
- MKN7 4, MKN28, ZR-75-1, SBC-1 and AsPC-1 are 10% fetal bovine serum (Neuklon Laboratories)-RPMI (Invitrogen), RD-ES is 15% fetal bovine serum (Necrolon Laboratories)-RPMI (Invitrogen), D341 Med uses 10% fetal calf serum (High clone Laboratories)-MEM ⁇ (Invitrogen), ACHN uses 10% fetal calf serum (Neugen) (Iclone Laboratories)-Using ⁇ - ⁇ (Invitrogen), SW872 using 10% fetal calf serum (Neuclonal Laboratories)-L15 (Invitrogen), ⁇ -204 using 10% fetal calf serum (Noi Clone Laboratories)-McCoy's 5A U266 was cultured using 0.5% fetal calf serum (Neuclonal Laboratories)-2 ng / mL IL-6 (Genzyme)-
- U266 cells were cultured for 4 days. After completion of the culture, a 50% triclonal acetic acid (Wako Pure Chemical Industries) solution was added to the cell culture solution so that the final concentration was 10%, and the cells were fixed by leaving at 4 ° C for 1 hr. Thereafter, each well was washed 5 times with distilled water, and then 100 ⁇ L of 0.4% sulforhodamine B (Molecular Probes) -1% acetic acid solution was added to each well and allowed to stand for 30 minutes to stain the cells. Each well was then washed 5 times with 1% acetic acid solution and air-dried.
- a 50% triclonal acetic acid (Wako Pure Chemical Industries) solution was added to the cell culture solution so that the final concentration was 10%, and the cells were fixed by leaving at 4 ° C for 1 hr. Thereafter, each well was washed 5 times with distilled water, and then 100 ⁇ L of 0.4% sulforhodamine B (Molecular Probes) -
- Compound X exhibited significant growth inhibitory activity against any cancer cell. From this, compound X is human gastric cancer cell, human breast cancer cell, small cell lung cancer, spleen cancer cell, prostate cancer cell, kidney cancer cell, medulloblastoma, human sarcoma cell (rhabdomyosarcoma, Ewing sarcoma, liposarcoma) ) Strongly suggested the possibility of antitumor activity against multiple myeloma.
- Compound X Human white of the compound described in Production Example 8 having PPAR ⁇ activation activity
- the cells were cultured for 5 days at 37 ° C in the presence of 5% carbon dioxide. Thereafter, Cell Titer 96 Aqueous One Solution Reagent (Promega Corp.) was added at 40 ⁇ l / well, and after incubation for 2 hours, the absorbance A490 of each well was measured using MICROPLATE READER (BIO RAD). The average absorbance of the control group treated with DMSO was defined as 100%, and the average absorbance of each concentration-treated group of Compound X was expressed as a percentage. By subtracting 100% of this value, the cancer cell proliferation inhibitory activity of Compound X was examined.
- Cell Titer 96 Aqueous One Solution Reagent Promega Corp.
- the subcultured tumor was cut into 5 mm pieces and transplanted subcutaneously into the right axilla of BALB / cA JcHiu mice using a trocar (CLEA Japan).
- a trocar CLCA Japan
- DMA was adjusted to a final concentration of 2.5%.
- the cells were cultured for 7 days at 37 ° C in the presence of 5% carbon dioxide. Thereafter, Cell Titer 96 Aqueous One Solution Reagent (Promega Corp.) was added to each 40 ⁇ L / well, cultured for 2 hours, and the absorbance A490 of each well was measured using MICROPLATE ATE READER (BIO RAD).
- the average absorbance of the non-compound-supplemented (DMSO-treated only) control group was defined as 100%, and the average absorbance of each of the compound X and gefitinib-treated groups was expressed as a percentage. By subtracting 100% of this value, the cancer cell growth inhibitory activity of Compound X, Gefitibe, and a combination of both was examined.
- human non-small cell lung cancer strain A549 (purchased from American Type Culture Collection), which was confirmed not to detect mouse pathogenic microorganisms by quarantine, was subcutaneously applied to the axilla of nude mouse BALB / cA JcHiu (Claire Japan).
- the transplanted and subcultured tumor was cut into small pieces of 5 mm in size and transplanted subcutaneously into the right axilla of BALB / cA JcHiu mice using a trocar (CLEA Japan).
- Compound X and the epidermal growth factor receptor (EGFR) inhibitor gefitib are weighed in the required amount, and the compound described in Production Example 8 having PPAR y activity
- the compound X) is suspended in a 0.5% -methylcellulose solution to a final concentration of 1 mg / mL, and gefiib is added to a final concentration of 10 mg / mL. It was prepared in a Tween 80 (Tokyo Chemical Industry Co., Ltd.) solution.
- the evaluation of antitumor activity by each drug administration group was determined by the tumor volume inhibition rate. Ma The statistical significance test was performed by performing the Students' t test on the tumor volume of the non-administered control group and the drug-administered group on day 63 after transplantation. When the p-value was less than 0.05, it was considered that there was a significant difference between the two groups.
- Gefitiv also showed significant antitumor activity with a tumor volume inhibition rate of 56%.
- the tumor volume inhibition rate was 73%, and the antitumor activity was significantly different between the compound X monotherapy group and the gefitinib monotherapy group. An increase was observed.
- Compound X has antitumor activity against human non-small cell lung cancer and that antitumor activity is enhanced by combined administration with an epidermal growth factor receptor (EGFR) inhibitor. It became clear.
- EGFR epidermal growth factor receptor
- V EGFR vascular endothelial growth factor receptor kinase
- a compound described in Production Example 8 having PPAR y activity against human non-small cell lung cancer strain A549 (referred to as compound X), a vascular endothelial growth factor receptor kinase (VEGFR) inhibitor, Raf kinase inhibition
- compound X a compound described in Production Example 8 having PPAR y activity against human non-small cell lung cancer strain A549
- VEGFR vascular endothelial growth factor receptor kinase
- Raf kinase inhibition The effect of combined use with drugs was examined using cell growth inhibitory activity as an index
- Human non-small cell lung cancer strain A549 cells were seeded at 5 ⁇ 10 2 cells / well in a 96-well plate, and various concentrations of drugs dissolved in DMSO were added at a DMSO concentration of 0.1%.
- V EGFR vascular endothelial growth factor receptor kinase
- the evaluation of antitumor activity by each drug administration group was determined by the tumor volume inhibition rate.
- the statistical significance test was performed by performing the Students' t test on the tumor volume of the non-administered control group and the drug-administered group 59 days after transplantation. When the p-value was less than 0.05, it was considered that there was a significant difference between the two groups.
- FIG. 1 On the vertical axis, the absorbance (%) of each cell after addition of Compound X to various cancer cells is plotted with the concentration (M) of Compound X added on the horizontal axis.
- 3 is a graph showing the relationship between the concentration of compound X and cancer cell growth inhibitory activity.
- FIG. 2 On the vertical axis, the absorbance (%) of each cell after adding Compound X to various cancer cells is plotted with the concentration (M) of Compound X added on the horizontal axis.
- 3 is a graph showing the relationship between the concentration of compound X and cancer cell growth inhibitory activity.
- FIG. 3 On the vertical axis, the absorbance (%) of each cell after addition of Compound X to various cancer cells is plotted with the concentration (M) of Compound X added on the horizontal axis. 3 is a graph showing the relationship between the concentration of compound X and cancer cell growth inhibitory activity.
- FIG. 4 The vertical axis shows the tumor volume (mm 3 ) when compound X, getivib alone or both agents are used together with the transplanted cancer cells, and the horizontal axis shows the number of days after transplantation (day). This is a graph showing the relationship between the number of days of transplantation and the tumor volume.
- FIG. 5 The vertical axis represents the tumor volume (mm 3 ) when Compound X, Sorafave alone or both were used in transplanted cancer cells, and the horizontal axis represents the number of days after transplantation (day). This is a graph showing the relationship between the number of days of transplantation and the tumor volume.
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AU2007213028A AU2007213028C1 (en) | 2006-02-09 | 2007-02-08 | Anti-cancer pharmaceutical composition |
EP07708202A EP1982718A4 (en) | 2006-02-09 | 2007-02-08 | ANTICANCER PHARMACEUTICAL COMPOSITION |
NZ570381A NZ570381A (en) | 2006-02-09 | 2007-02-08 | Anti-cancer pharmaceutical composition |
CN2007800124996A CN101415422B (zh) | 2006-02-09 | 2007-02-08 | 抗癌药用组合物 |
JP2007557880A JP5133071B2 (ja) | 2006-02-09 | 2007-02-08 | 抗癌医薬組成物 |
BRPI0707671-1A BRPI0707671A2 (pt) | 2006-02-09 | 2007-02-08 | composiÇço farmacÊutica anti-cÂncer |
CA2642665A CA2642665C (en) | 2006-02-09 | 2007-02-08 | Anti-cancer pharmaceutical composition |
US12/221,019 US8263631B2 (en) | 2006-02-09 | 2008-07-30 | Anti-cancer pharmaceutical compositions and methods for treating patients with cancer |
IL193243A IL193243A0 (en) | 2006-02-09 | 2008-08-05 | Pharmaceutical compositions containing a thiazolidinedione derivative |
NO20083822A NO20083822L (no) | 2006-02-09 | 2008-09-08 | Farmasoytisk antikreftpreparat |
US13/525,932 US20120258991A1 (en) | 2006-02-09 | 2012-06-18 | Method of treating a cancer by administering a specified drug |
US13/527,002 US20120263716A1 (en) | 2006-02-09 | 2012-06-19 | Method of treating cancers and a pharmaceutical composition that may be used in practicing said method |
US13/776,997 US20130183297A1 (en) | 2006-02-09 | 2013-02-26 | Method of treating cancers and a pharmaceutical composition that may be used in practicing said method |
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EP (1) | EP1982718A4 (ja) |
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KR (1) | KR20080101888A (ja) |
CN (1) | CN101415422B (ja) |
AU (1) | AU2007213028C1 (ja) |
BR (1) | BRPI0707671A2 (ja) |
CA (1) | CA2642665C (ja) |
IL (1) | IL193243A0 (ja) |
NO (1) | NO20083822L (ja) |
NZ (1) | NZ570381A (ja) |
RU (1) | RU2419430C2 (ja) |
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US10118959B2 (en) | 2005-10-14 | 2018-11-06 | Chugai Seiyaku Kabushiki Kaisha | Anti-glypican-3 antibody |
US8263631B2 (en) | 2006-02-09 | 2012-09-11 | Daiichi Sankyo Company, Limited | Anti-cancer pharmaceutical compositions and methods for treating patients with cancer |
WO2008099944A1 (en) * | 2007-02-08 | 2008-08-21 | Daiichi Sankyo Company, Limited | Crystalline forms of thiazolidinedione derivative and its manufacturing method |
US8497355B2 (en) | 2007-09-28 | 2013-07-30 | Chugai Seiyaku Kabushiki Kaisha | Anti-glypican-3 antibody having improved kinetics in plasma |
CN102046200A (zh) * | 2008-04-04 | 2011-05-04 | 中外制药株式会社 | 肝癌治疗剂 |
AU2009233301B2 (en) * | 2008-04-04 | 2014-01-23 | Chugai Seiyaku Kabushiki Kaisha | Liver cancer drug |
WO2009122667A1 (ja) * | 2008-04-04 | 2009-10-08 | 中外製薬株式会社 | 肝癌治療剤 |
JPWO2010013768A1 (ja) * | 2008-07-31 | 2012-01-12 | 第一三共株式会社 | チアゾリジンジオン化合物の結晶及びその製造方法 |
WO2010013769A1 (ja) | 2008-07-31 | 2010-02-04 | 第一三共株式会社 | チアゾリジンジオン化合物の結晶及びその製造方法 |
WO2010013768A1 (ja) | 2008-07-31 | 2010-02-04 | 第一三共株式会社 | チアゾリジンジオン化合物の結晶及びその製造方法 |
WO2011065420A1 (ja) | 2009-11-26 | 2011-06-03 | 第一三共株式会社 | 6-置換-1-メチル-1h-ベンズイミダゾール誘導体の製造法及びその製造中間体 |
JP2015502958A (ja) * | 2011-12-09 | 2015-01-29 | オンコメッド ファーマシューティカルズ インコーポレイテッド | がんの処置のための併用療法 |
US11096947B2 (en) | 2012-04-03 | 2021-08-24 | Novartis Ag | Combination products with tyrosine kinase inhibitors and their use |
US9975966B2 (en) | 2014-09-26 | 2018-05-22 | Chugai Seiyaku Kabushiki Kaisha | Cytotoxicity-inducing theraputic agent |
US11001643B2 (en) | 2014-09-26 | 2021-05-11 | Chugai Seiyaku Kabushiki Kaisha | Cytotoxicity-inducing therapeutic agent |
RU2692129C1 (ru) * | 2018-03-19 | 2019-06-21 | Федеральное государственное бюджетное научное учреждение "Томский национальный исследовательский медицинский центр Российской академии наук" (Томский НИМЦ) | Способ прогнозирования лимфогенного метастазирования у больных при аденокарциноме прямой кишки |
Also Published As
Publication number | Publication date |
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CA2642665C (en) | 2013-01-08 |
TW200800181A (en) | 2008-01-01 |
JPWO2007091622A1 (ja) | 2009-07-02 |
US20120258991A1 (en) | 2012-10-11 |
BRPI0707671A2 (pt) | 2011-05-10 |
RU2008136188A (ru) | 2010-03-20 |
JP5133071B2 (ja) | 2013-01-30 |
CA2642665A1 (en) | 2007-08-16 |
AU2007213028B2 (en) | 2010-10-28 |
CN101415422A (zh) | 2009-04-22 |
EP1982718A1 (en) | 2008-10-22 |
IL193243A0 (en) | 2009-02-11 |
US20120263716A1 (en) | 2012-10-18 |
EP1982718A4 (en) | 2010-05-12 |
NO20083822L (no) | 2008-11-05 |
AU2007213028A1 (en) | 2007-08-16 |
ZA200807721B (en) | 2010-02-24 |
US20130183297A1 (en) | 2013-07-18 |
US8263631B2 (en) | 2012-09-11 |
RU2419430C2 (ru) | 2011-05-27 |
KR20080101888A (ko) | 2008-11-21 |
US20090028868A1 (en) | 2009-01-29 |
NZ570381A (en) | 2011-02-25 |
CN101415422B (zh) | 2012-11-07 |
JP2012255042A (ja) | 2012-12-27 |
AU2007213028C1 (en) | 2011-05-19 |
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