WO2010061907A1 - Anti-cancer agent - Google Patents

Anti-cancer agent Download PDF

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WO2010061907A1
WO2010061907A1 PCT/JP2009/070001 JP2009070001W WO2010061907A1 WO 2010061907 A1 WO2010061907 A1 WO 2010061907A1 JP 2009070001 W JP2009070001 W JP 2009070001W WO 2010061907 A1 WO2010061907 A1 WO 2010061907A1
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substituted
component
agent
lower alkyl
compound
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PCT/JP2009/070001
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French (fr)
Japanese (ja)
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譲 阿部
行正 塩津
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協和発酵キリン株式会社
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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
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A61K31/69—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to an anti-cancer agent containing an isoindolinone derivative or a pharmacologically acceptable salt thereof, and a component selected from a chemotherapeutic agent, a hormonal therapeutic agent and a molecular target drug.
  • Patent Document 1 An isoindolinone derivative used in the present invention is known (Patent Document 1).
  • the isoindolinone derivative has Aurora, fibroblast growth factor receptor 3 (FGFR3) and hummus-like tyrosine kinase (Flt-3) inhibitory activity, and anticancer activity Has been.
  • FGFR3 fibroblast growth factor receptor 3
  • Flt-3 hummus-like tyrosine kinase
  • this compound has JAK inhibitory activity (Patent Document 2).
  • Non-Patent Document 1 compounds related to the isoindolinone derivative used in the present invention are known (Patent Documents 3 to 7, Non-Patent Document 1).
  • combination therapy is used in the treatment of many cancers. Examples of the purpose of the combination therapy include the following 1-3, etc. (Clinical Oncology 3rd Edition, Cancer and Chemotherapy). 1. Enhancement of antitumor effect by using multiple drugs 2. Expansion of the spectrum of anticancer effects (when multiple cancer cells are expressed, one drug is given to cancer cells for which one drug is ineffective, and other drugs that are effective against it) 3.
  • instalocarbazole derivatives such as restaltinib (Lestaurtinib, CEP-701) and PKC412 are used for chemotherapy or HDAC inhibitors and m-TOR against acute myeloid leukemia cells. It has been reported that combined use with an inhibitor [Clinical Cancer Reseach, 10, 4991 (2004); Blood, 104, 1145 ( 2004); Proceeding of the National Academy of Sciences of the United States of America, 101, 3130 (2004)].
  • Sunitinib (Sunitinib, SU011248), an indolinone derivative, has been reported to be effective in combination with chemotherapy or molecular targeted drugs in blood cancer and solid cancer [Blood, 104, 4202 (2004), WO06 / 120557].
  • An object of the present invention is to administer a first component comprising an isoindolinone derivative or a pharmacologically acceptable salt thereof, and a second component selected from a chemotherapeutic agent, a hormonal therapeutic agent and a molecular target agent simultaneously or separately.
  • An object of the present invention is to provide an anticancer agent and the like.
  • the present invention relates to the following (1) to (18).
  • R 1 and R 2 are the same or different and each is a hydrogen atom, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl , Substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group or —OR 4 [wherein R 4 is a hydrogen atom, substituted or unsubstituted lower alkyl or —S (O) 2 R 5 (wherein R 5 represents amino, mono or di (substituted or unsubstituted lower alkyl) amino, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic group)] , R 3 represents carboxy or a substituted or unsubstituted lower alkyl
  • R 3 is —CH 2 NR 6 R 7 (wherein R 6 and R 7 are the same or different and each represents a hydrogen atom or a substituted or unsubstituted lower alkyl, or R 6 and R 7 are adjacent to each other)
  • the chemotherapeutic agent is selected from tubulin agonists, deoxyribonucleic acid agonists and antimetabolites.
  • the second component is a hormone therapy agent.
  • the hormone therapy agent is selected from an anti-androgen agent, an anti-estrogen agent, an androgen preparation, an estrogen preparation, an LH-RH agonist, a progestin, an aromatase inhibitor, and a steroid sulfatase inhibitor.
  • the second component is a molecular target drug.
  • Molecular target drug selected from kinase inhibitor, kinesin Eg5 inhibitor, mTOR (mammalian target of rapamycin) inhibitor, proteasome inhibitor, histone deacetylase inhibitor, heat shock protein 90 inhibitor and farnesyl transferase inhibitor
  • the anticancer agent according to (10) above.
  • a first component comprising an isoindolinone derivative or a pharmacologically acceptable salt thereof, and a second component selected from a chemotherapeutic agent, a hormonal therapeutic agent and a molecular target drug are administered simultaneously or separately.
  • Anticancer agents and the like are provided.
  • FIG. 1 is a graph showing the antitumor effect of a combination of compound 19 and bortezomib in a mouse model transplanted with human multiple myeloma NCI-H929 cells.
  • the vertical axis shows the ratio of change in tumor volume (V / V0) when the tumor volume on day 0 is V0.
  • the horizontal axis indicates the number of days.
  • ⁇ indicates the negative control group (A)
  • ⁇ indicates the compound 19 alone group (B)
  • ⁇ indicates the bortezomib alone group (C)
  • ⁇ indicates the compound 19 / bortezomib combination group (D) (mean ⁇ standard) error).
  • FIG. 2 is a graph showing the antitumor effect of the combined use of Compound 19 and melphalan in a mouse model transplanted with human multiple myeloma KMS-11 cells.
  • FIG. 3 is a graph showing the antitumor effect of a combination of compound 19 and CPT-11 in a mouse model transplanted with human gastric cancer SNU-16 cell cells.
  • FIG. 4 is a graph showing the antitumor effect of a combination of Compound 19 and docetaxel in a mouse model transplanted with human gastric cancer SNU-16 cell cells.
  • the vertical axis shows the ratio of change in tumor volume (V / V0) when the tumor volume on day 0 is V0.
  • the horizontal axis indicates the number of days.
  • ⁇ indicates the negative control group (A)
  • ⁇ indicates the compound 19 alone group (B)
  • ⁇ indicates the docetaxel alone group (C)
  • ⁇ indicates the compound 19 / docetaxel combination group (D) (mean ⁇ standard) error).
  • Halogen includes fluorine, chlorine, bromine and iodine atoms.
  • Lower alkyl, and lower alkyl of lower alkoxy and mono- or di-lower alkylamino include, for example, alkyl having 1 to 10 carbon atoms, straight chain, branched chain, or a combination thereof, More specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, n- Nonyl, n-decyl and the like can be mentioned.
  • cycloalkyl examples include cycloalkyl having 3 to 10 carbon atoms, and more specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, noradamantyl, adamantyl, bicyclo [ 2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.3.0] octyl, bicyclo [3.3.1] nonyl and the like.
  • lower alkenyl examples include linear or branched alkenyl having 2 to 10 carbon atoms, and more specifically vinyl, allyl, 1-propenyl, 1-butenyl, 3-butenyl, 2-pentenyl, 4-pentenyl, 2-hexenyl, 5-hexenyl, 2-decenyl, 9-decenyl and the like can be mentioned.
  • lower alkynyl examples include straight-chain or branched alkynyl having 2 to 10 carbon atoms, and more specifically, ethynyl, 2-propynyl, 3-butynyl, 4-pentynyl, 5- Hexinyl, 9-decynyl and the like can be mentioned.
  • aryl for example, monocyclic or condensed condensed aryl having two or more rings condensed, more specifically, aryl having 6 to 14 ring carbon atoms, such as phenyl, naphthyl, indenyl , Anthranyl and the like.
  • heterocyclic group examples include an aromatic heterocyclic group and an alicyclic heterocyclic group.
  • aromatic heterocyclic group examples include monocyclic or condensed aromatic heterocyclic groups in which two or more rings are condensed, and heteroatoms contained in the aromatic heterocyclic group Is not particularly limited, and may contain, for example, one or more heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom, more specifically, the number of ring atoms 5 to 14 aromatic heterocyclic groups such as furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, indolyl, indazolyl, benzimi
  • Examples of the alicyclic heterocyclic group include monocyclic or condensed alicyclic heterocyclic groups in which two or more rings are condensed, and are included in the alicyclic heterocyclic group
  • the type and number of heteroatoms to be obtained are not particularly limited, and may include, for example, one or more heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom, and more specifically, for example, Pyrrolidinyl, 2,5-dioxopyrrolidinyl, thiazolidinyl, oxazolidinyl, piperidyl, 1,2-dihydropyridyl, piperazinyl, homopiperazinyl, morpholinyl, thiomorpholinyl, pyrazolinyl, oxazolinyl, dioxolanyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetra
  • Examples of the heterocyclic group formed together with the adjacent nitrogen atom include a 5-membered or 6-membered monocyclic heterocyclic group containing at least one nitrogen atom (the monocyclic heterocyclic group is , May contain other nitrogen atoms, oxygen atoms or sulfur atoms), a condensed bicyclic or tricyclic condensed 3- to 8-membered ring and containing at least one nitrogen atom
  • the condensed heterocyclic group may contain other nitrogen atom, oxygen atom or sulfur atom), and more specifically, pyrrolidinyl, piperidino, piperazinyl, morpholino, thiomorpholino, homopiperidino, homopiperazinyl, Tetrahydropyridyl, tetrahydroquinolyl, tetrahydroisoquinolyl and the like can be mentioned.
  • Substituents in substituted lower alkyl, substituted cycloalkyl, substituted lower alkoxy, substituted lower alkenyl, substituted lower alkynyl and mono- or di-substituted lower alkylamino are the same or different, for example, a halogen having 1 to 3 substituents , Hydroxy, oxo, lower alkoxy, carboxy, lower alkoxycarbonyl, substituted or unsubstituted aryl (the substituent in the substituted aryl is carboxy, lower alkoxy, lower alkoxycarbonyl, etc.), substituted or unsubstituted heterocyclic group (Substituents in the substituted heterocyclic group are carboxy, lower alkoxy, lower alkoxycarbonyl, etc.), NR 8 R 9 (wherein R 8 and R 9 are the same or different and are a hydrogen atom, substituted or unsubstituted Lower alkyl of [substituent in the substituted
  • a substituted or unsubstituted heterocyclic group together with a nitrogen atom are, for example, halogens having 1 to 3 substituents, amino, nitro , Hydroxy, oxo, cyano, carboxy, lower alkanoyl, lower alkoxycarbonyl, lower alkylsulfonyl, heterocyclic group, substituted or unsubstituted lower alkyl (the substituent in the substituted lower alkyl is, for example, amino having 1 to 3 substituents, Hydroxy, cyano, etc.), substituted or unsubstituted lower alkoxy (substituent
  • the halogen is as defined in the above (i), and the lower alkyl and the lower alkyl part of the lower alkoxy, lower alkoxycarbonyl, lower alkylsulfonyl and mono- or di-lower alkylamino are as defined in the above (ii).
  • cycloalkyl is as defined above (iii)
  • aryl is as defined above (vi)
  • a heterocyclic group is as defined above (vii) and is formed together with the adjacent nitrogen atom.
  • the heterocyclic group has the same meaning as the above (viii).
  • lower alkanoyl part of lower alkanoyl and lower alkanoylamino examples include linear or branched lower alkanoyl having 1 to 8 carbon atoms, and more specifically formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl. , Isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl and the like.
  • Substituents in the substituted aryl group formed together with the substituted aryl, substituted heterocyclic group and adjacent nitrogen atom are the same or different, for example, halogen, amino, Nitro, ureido, cyano, carboxy, aminocarbonyl, lower alkoxycarbonyl, lower alkylsulfonylamino, lower alkylsulfonyloxy, substituted or unsubstituted lower alkyl (the substituent in the substituted lower alkyl is, for example, a halogen having 1 to 3 substituents)
  • Substituted, unsubstituted lower alkoxy substituted lower alkoxy are, for example, halogen having 1 to 3 substituents, hydroxy, lower alkoxy, etc.
  • substituted or unsubstituted Lower alkanoyl (the substituent in the substituted lower alkanoyl is, for example, Examples thereof include halogen having 1 to 3 substituents,
  • the halogen is as defined in the above (i), and the lower alkyl, and the lower alkyl part of the lower alkoxy, lower alkoxycarbonyl, lower alkylsulfonylamino and lower alkylsulfonyloxy are as defined in the above (ii).
  • the lower alkanoyl include linear or branched lower alkanoyl having 1 to 8 carbon atoms, and more specifically, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, Examples include heptanoyl and octanoyl.
  • Examples of pharmacologically acceptable salts of compound (I) include pharmacologically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, and the like.
  • Acid addition salts include inorganic acid salts such as hydrochloride, sulfate and phosphate, organic salts such as acetate, maleate, fumarate, tartrate, citrate, lactate, aspartate and glutamate.
  • the metal salt examples include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt, zinc salt and the like, and ammonium salt includes ammonium, Examples include salts such as tetramethylammonium, examples of organic amine addition salts include addition salts such as morpholine and piperidine, and examples of amino acid addition salts include addition salts such as lysine, glycine, and phenylalanine.
  • a salt of compound (I) When it is desired to obtain a salt of compound (I), it can be purified as it is when the compound (I) is obtained in a salt form, and when it is obtained in a free form, the compound (I) is added to a suitable solvent. It may be dissolved or suspended, and an acid or base may be added to form a salt.
  • Compound (I) may have an isomer such as a positional isomer, a geometric isomer, or an optical isomer, but a possible isomer and a mixture of the isomers in any ratio are components of the pharmaceutical composition of the present invention. Can be used as
  • Compound (I) and pharmacologically acceptable salts thereof may exist in the form of adducts with water or various solvents, and these adducts are also used as components of the pharmaceutical composition of the present invention. be able to.
  • the chemotherapeutic agent, hormone therapy agent, and molecular target drug used as the second component include low molecular weight compounds, protein pharmaceuticals (eg, cytokines, antibodies, etc.), nucleic acid pharmaceuticals (eg, siRNA, antisense oligos, etc.) ) Etc. can be used.
  • cytokines include interleukin-2 (IL-2), IFN- ⁇ , IFN- ⁇ , GM-CSF, G-CSF, TNF- ⁇ , and IL-1 ⁇ .
  • IL-2 interleukin-2
  • IFN- ⁇ interleukin-2
  • IFN- ⁇ IFN- ⁇
  • GM-CSF GM-CSF
  • G-CSF TNF- ⁇
  • IL-1 ⁇ IL-1 ⁇
  • the antibody include anti-EGFR antibody (Cetuximab, Erbitux), anti-ErbB2 antibody [trastuzumab (genetical recombination), Herceptin], anti-CD20 antibody (Rituxan), anti-CD52 antibody (Campath) and the like.
  • chemotherapeutic agents include tubulin agonists, deoxyribonucleic acid (DNA) agonists, antimetabolites, and the like.
  • hormone therapy agents include antiandrogens, antiestrogens, androgens, estrogen, LH-RH agonists (chemical castrations), progestins, aromatase inhibitors, steroid sulfatase inhibitors, and the like.
  • molecular target drugs examples include Bcr-Abl inhibitors, EGFR inhibitors, multikinase inhibitors, kinesin Eg5 inhibitors, Flt-3 inhibitors, mTOR inhibitors, proteasome inhibitors, histone deacetylase (HDAC) inhibitors Heat shock protein 90 (Hsp90) inhibitor, farnesyltransferase inhibitor, and the like.
  • tubulin agonists include vinblastine, vindesine, vincristine, vinorelbine, paclitaxel (taxol), docetaxel (taxotere) and the like.
  • DNA agonists examples include chlorambucil, cyclophosphamide, melpharan, dacarbazine (DTIC), oxaloplatin, bleomycin, Doxorubicin (adriamycin) [doxorubicin ⁇ ⁇ lipooxo (doxil)], idarubicin, mitomycin, mitoxantrone, etoposide, etopocamp CPT-11,10-hydroxy-7-ethyl-camptothecin (SN38), topotecan and the like.
  • DTIC dacarbazine
  • oxaloplatin bleomycin
  • Doxorubicin (adriamycin) doxorubicin ⁇ ⁇ lipooxo (doxil)]
  • idarubicin idarubicin
  • mitomycin mitoxantrone
  • etoposide etopocamp CPT-11,10-hydroxy-7-ethyl-camptothe
  • antimetabolite examples include fludarabine, hydroxyurea, cytarabine, methotrexate and the like.
  • hormone therapy agents include, for example, leuprolide, goserelin, megestrol, tamoxifen, ICI182780, toremifene, fadrozole, letrozole, flutamide (Flutamide), bicalutamide, testolactone, mitotane, prednisolone, dexamethasone and the like.
  • molecular target drugs include, for example, Lapatinib (HKI-272, BIBW-2992, BMS-599626), imatinib (STI-571) [imatinib (STI571)], dasatinib (dasatinib, BMS-354825), nilotinib, AMN107), Sunitinib (Sutent) [sunitinib (SUTENT), SU11248], Sorafenib (Nexabar), BAY43-9006], CHIR-258, vatalanib (PTK-787), R-1155777 (tipifarnib, zarnestra) , Rapamycin, temsirolimus (CCI-779), bortezomib (Velcade), PS-341, asparaginase, pegaspargase and the like.
  • STI-571 imatinib
  • dasatinib dasatinib (dasatinib, BMS-354825
  • Flt-3 inhibitors examples include CEP-701, PKC412, MLN518, CHIR-258, indazole derivatives described in Tables 1-1 and 1-2 (WO2005 / 012258), and the like.
  • HDAC inhibitors include Vorinostat (suberanilohydroxamic acid, SAHA, Zolinza), valproic acid, MS-275, and the like.
  • Hsp90 inhibitors include, for example, radicicol, geldanamycin, 17-AAG, herbimycin A, novobiocin, benzoyl compounds described in Tables 2-1 and 2-2 (WO2005 / 000778) and the like.
  • Compound (I) or a pharmacologically acceptable salt thereof can also be used in combination with a differentiation inducer, a bone resorption inhibitor and the like.
  • a differentiation inducer include, for example, all-trans retinoic acid, thalidomide, lenalidomide, bexarotene (targretin) and the like.
  • the bone resorption inhibitor examples include bisphosphonate (Zoledronic acid, Zometa).
  • the above compounds may not be able to obtain a sufficient therapeutic effect when administered alone, or may cause side effects when administered at a high dose.
  • a high therapeutic effect can be obtained as compared with each single administration. Can be used at low doses. Therefore, in addition to a sufficient therapeutic effect, side effects can be reduced.
  • Compound (I) used in the present invention can be synthesized, for example, according to the method described in WO2006 / 112479. Specific examples of the compound (I) used in the present invention are shown in the following Tables 3-1 to 3-3, but the present invention is not limited thereto. In the table, Me and Et represent methyl and ethyl, respectively. Compounds 1 to 29 are the same as those in Examples 188, 215, 218, 222, 227, 229, 231, 241, 261, 297, 305, 323, 325, 327, 338, 346, 349, and 359 of WO2006 / 112479, respectively. 362, 365, 382, 406, 409, 424, 426, 462, 466, 375 and 456.
  • Examples of the anticancer agent of the present invention include cancer caused by hematopoietic tumor (eg, acute myeloid leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, lymphoma, etc.), breast cancer, endometrial cancer, uterus
  • hematopoietic tumor eg, acute myeloid leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, lymphoma, etc.
  • breast cancer eg, endometrial cancer, uterus
  • breast cancer eg., endometrial cancer, uterus
  • breast cancer eg., endometrial cancer, uterus
  • breast cancer eg, endometrial cancer, uterus
  • breast cancer eg, endometrial cancer, uterus
  • breast cancer eg
  • the pharmaceutical composition of the present invention may be used as a single agent, as long as it is formulated so as to contain compound (I) or a pharmacologically acceptable salt thereof and at least one compound for use in combination therewith. It can be used, administered or manufactured as a combination of a plurality of preparations. These pharmaceutical compositions are preferably in a unit dosage form suitable for oral or parenteral administration such as injection. Further, when used or administered as a combination of a plurality of preparations, they can be used or administered simultaneously or separately.
  • the dose ratio (weight / weight) of compound (I), which is the first component, or a pharmacologically acceptable salt thereof, and the second component is the combination of the second component used and the second component used. It may be appropriately adjusted according to the efficacy, etc., and specifically, for example, a ratio between 1/300 to 1000/1, preferably 1/200 to 500/1, more preferably 1/100 to 100/1. is there.
  • a kit can be prepared, and each component can be administered to the same subject by the same route or different routes simultaneously or separately using the kit.
  • kits There are no particular limitations on the material, shape, etc. of the kit as long as it is a container that does not show, for example, denaturation of components that are contents by external temperature or light during storage, elution of chemical components from the container, etc. Consists of the above containers (eg, vials, bags, etc.) and contents, and the contents of the first component and the second component can be administered via separate routes (eg, tubes) or the same route Is used.
  • routes eg, tubes
  • preparations are pharmaceutically acceptable diluents, excipients, disintegrants, lubricants, binders, surfactants, plasticizers, water, physiological saline, vegetable oils, solvents. , Solubilizers, tonicity agents, preservatives, antioxidants, etc.
  • excipients such as lactose, disintegrants such as starch, lubricants such as magnesium stearate, binders such as hydroxypropylcellulose, surfactants such as fatty acid esters, plasticizers such as glycerin Etc. may be used according to a conventional method.
  • water, physiological saline, vegetable oil, solvent, solubilizer, tonicity agent, preservative, antioxidant and the like may be used in a conventional manner.
  • Compound (I) or a pharmacologically acceptable salt thereof can be administered orally or parenterally as an injection or the like when used for the above-mentioned purposes, and the effective dose and the number of administrations are the administration form.
  • Test Example 1 Combined effect of compound 19 and dexamethasone in multiple myeloma cell line KMS-11 TC MICROWELL 96U plate was used for multiple myeloma cell line KMS-11 prepared at 0.75 ⁇ 10 5 cells / mL in a normal culture medium. [Catalog number 163320, Nargenung (Rochester, NY, USA)] was seeded at 80 ⁇ L each and cultured at 37 ° C. for 24 hours in a 5% carbon dioxide incubator.
  • DMSO dimethyl sulfoxide
  • the relative growth rate (%) of wells cultured for 72 hours was calculated, and the value obtained by subtracting the value from 100 was taken as the cell growth inhibition rate (%) of the test compound.
  • Bliss independence analysis was used [Cancer Cell, Vol. 9, page 133 (2006)].
  • the lowest inhibition rate (minimum inhibition rate) expected to be more than the additive effect when two agents with different action points were used in combination was calculated by the following formula.
  • Test Example 2 Anti-tumor effect of combined use of compound 19 and bortezomib in a mouse model transplanted with human multiple myeloma NCI-H929 cells Anti -Asialo GM1 in Fox CB-17 / Icr-scidJcl mice (Clea Japan) 2 days before transplantation Antibody (about 10 mg protein / 1 mL vial) (Wako Pure Chemical Industries) was intraperitoneally administered at 0.3 mg / mouse. NCI-H929 cells, in RPMI1640 medium containing 10% fetal calf serum (FCS), 5% in a carbon dioxide incubator to culture grown at 37 ° C., subcutaneously, ventrally 1 ⁇ 10 7 cells per mouse Transplanted. The major axis and minor axis of the tumor grown subcutaneously with calipers 8 days after the transplantation were measured, and the tumor volume was determined according to the following formula.
  • FCS fetal calf serum
  • mice were divided into the following administration groups with 5 mice per group so that the average tumor volume and the average body weight were uniform.
  • Compound 19 is dissolved in a 5% sugar solution (Otsuka Pharmaceutical Co., Ltd.) at a concentration of 2.5 mg / mL, and once a day on the 0th, 7th, and 14th days of administration, 0.01 mL (25 mg / kg) was administered intravenously from the tail vein.
  • Bortezomib was suspended in physiological saline (manufactured by Otsuka Pharmaceutical Co., Ltd.) at a concentration of 0.075 mg / mL, and once a day on the 0th, 3rd, 7th, and 10th days of administration, 0.01 mL (0.75 mg / kg) was administered intravenously from the tail vein.
  • Compound 19 alone group 25 mg / kg (once daily / administered on days 0, 7, 14)
  • Bortezomib alone group 0.75 mg / kg (once daily / administered on days 0, 3, 7, 10)
  • D D.
  • Compound 19 / bortezomib combination group Compound 19 is 25 mg / kg (once daily / 0, 7 and 14 days), bortezomib is 0.75 mg / kg (once daily / 0, 3, 7 On day 10) From day 0, tumor volume was measured twice a week. The determination of the antitumor effect was performed by calculating the average value of the tumor volumes of each group and comparing the change in tumor volume (V / V0) when the tumor volume on day 0 was V0.
  • FIG. 1 shows V / V0 of each group measured over time.
  • Table 5 shows values (T / C) obtained by dividing V / V0 of each group on day 21 by V / V0 of the negative control group. Compared to the theoretical value of T / C when the efficacy of both compound 19 and bortezomib is simply added, that is, the value obtained by multiplying the T / C of each compound alone group, the T / C ( D) in the table showed a value (0.022) lower than the theoretical value of 0.11 on the 14th day.
  • Test Example 3 Anti-tumor effect of combined use of Compound 19 and melphalan in a mouse model transplanted with human multiple myeloma KMS-11 cells Anti -Asialo GM1 in Fox CB-17 / Icr-scidJcl mice (CLEA Japan) the day before cancer Antibody (about 10 mg protein / 1 mL vial) (Wako Pure Chemical Industries) was intraperitoneally administered at 0.3 mg / mouse. KMS-11 cells in RPMI1640 medium containing 10% fetal calf serum (FCS), 5% in a carbon dioxide incubator to culture grown at 37 ° C., subcutaneously, ventrally 1 ⁇ 10 7 cells per mouse Transplanted. Ten days after transplantation, the major axis and minor axis of the tumor grown subcutaneously with calipers were measured, and the tumor volume was determined according to the following formula.
  • FCS fetal calf serum
  • mice were divided into the following administration groups with 5 mice per group so that the average tumor volume and the average body weight were uniform.
  • Compound 19 is dissolved in 5% sugar solution (manufactured by Otsuka Pharmaceutical Co., Ltd.) at a concentration of 1.25 mg / mL, and once a day on the 0th, 7th, and 14th days of administration, 0.01 mL (12.5 mg / g mouse body weight) / kg) was administered intravenously from the tail vein.
  • Compound 19 / melphalan combination group Compound 19 is 12.5 mg / kg (once a day / 0, administered on days 7 and 14), melphalan is 3 mg / kg (once a day / day 0) Administered) From day 0, tumor volume was measured twice a week. The determination of the antitumor effect was performed by calculating the average value of the tumor volumes of each group and comparing the change in tumor volume (V / V0) when the tumor volume on day 0 was V0. FIG. 2 shows V / V0 of each group measured over time.
  • Table 6 shows values (T / C) obtained by dividing V / V0 of each group on day 17 by V / V0 of the negative control group. Compared to the theoretical value of T / C when the efficacy of both compound 19 and melphalan is simply added, that is, the value obtained by multiplying the T / C of each compound alone group, the T / C of the actual combination group (D in the table) showed a value (0.095) lower than the theoretical value of 0.24 on the 17th day.
  • Test Example 4 Anti-tumor effect of combined use of compound 19 and CPT-11 in a mouse model transplanted with human gastric cancer
  • SNU-16 cells Anti -Asialo GM1 antibody was administered to Fox CB-17 / Icr-scidJcl mice (Claire Japan) on the day before cancer cell transplantation ( About 10 mg protein / 1 mL vial) (Wako Pure Chemical Industries) was administered intraperitoneally at 0.3 mg / mouse.
  • SNU-16 cells were cultured and grown in RPMI1640 medium containing 10% fetal calf serum (FCS) in a 5% carbon dioxide incubator at 37 ° C and ventral subcutaneously at 0.5 x 10 7 cells per mouse. Transplanted. Seven days after transplantation, the major axis and minor axis of the tumor grown subcutaneously with calipers were measured, and the tumor volume was determined according to the following formula.
  • FCS fetal calf serum
  • mice were divided into the following administration groups with 5 mice per group so that the average tumor volume and the average body weight were uniform.
  • Compound 19 is dissolved in a 5% sugar solution (manufactured by Otsuka Pharmaceutical Co., Ltd.) at a concentration of 1 mg / mL, and once a day on days 0, 7, and 14 of administration, 0.01 mL (10 mg / kg) was administered intravenously from the tail vein.
  • CPT-11 was suspended in physiological saline (manufactured by Otsuka Pharmaceutical Co., Ltd.) at a concentration of 1 mg / mL, and once daily on the 0th and 7th day of administration, 0.01 mL (10 mg / mg kg) was administered intravenously from the tail vein.
  • CPT-11 alone group 10 mg / kg (once a day / 0, administered on day 7)
  • D D.
  • Test compound / CPT-11 combination group Test compound is 10 mg / kg (once a day / 0, administered on days 7 and 14), CPT-11 is 10 mg / kg (once a day / 0 On day 7) From day 0, tumor volume was measured twice a week. The determination of the antitumor effect was performed by calculating the average value of the tumor volumes of each group and comparing the change in tumor volume (V / V0) when the tumor volume on day 0 was V0.
  • FIG. 3 shows V / V0 of each group measured over time.
  • Table 7 shows values (T / C) obtained by dividing V / V0 of each group on day 32 by V / V0 of the negative control group. Compared to the theoretical value of T / C when the efficacy of both compounds 19 and CPT-11 was simply added, that is, the value obtained by multiplying the T / C of each compound alone group, the T / C of the actual combination group C (D in the table) showed a value (0.246) lower than the theoretical value of 0.247 on the 32nd day.
  • Test Example 5 Anti-tumor effect of combined use of compound 19 and docetaxel in a mouse model transplanted with human gastric cancer SNU-16 cells Anti -Asialo GM1 antibody (about 10) to Fox CB-17 / Icr-scidJcl mice (CLEA Japan) on the day before cancer cell transplantation mg protein / 1 mL vial) (Wako Pure Chemical Industries, Ltd.) was intraperitoneally administered at a dose of 0.3 mg / mouse.
  • SNU-16 cells were cultured and grown in RPMI1640 medium containing 10% fetal calf serum (FCS) in a 5% carbon dioxide incubator at 37 ° C and ventral subcutaneously at 0.5 x 10 7 cells per mouse. Transplanted. Seven days after transplantation, the major axis and minor axis of the tumor grown subcutaneously with calipers were measured, and the tumor volume was determined according to the following formula.
  • FCS fetal calf serum
  • mice were divided into the following administration groups with 5 mice per group so that the average tumor volume and the average body weight were uniform.
  • Compound 19 is dissolved in a 5% sugar solution (manufactured by Otsuka Pharmaceutical Co., Ltd.) at a concentration of 1 mg / mL, and once a day on days 0, 7, and 14 of administration, 0.01 mL (10 mg / kg) was administered intravenously from the tail vein.
  • Docetaxel is suspended in physiological saline (manufactured by Otsuka Pharmaceutical Co., Ltd.) at a concentration of 0.2 mg / mL, and once a day on the 0th and 7th day of administration, 0.01 mL / g body weight of the mouse (2 mg / kg) Was administered intravenously from the tail vein.
  • Compound 19 alone group 10 mg / kg (once daily / administered on days 0, 7, 14)
  • Docetaxel alone group 2 mg / kg (once a day / 0, administered on day 7)
  • Compound 19 / Docetaxel combination group Compound 19 is 10 mg / kg (once daily / 0, 7 and 14 days), docetaxel is 2 mg / kg (once daily / 0, 7 days) Administered) From day 0, tumor volume was measured twice a week. The determination of the antitumor effect was performed by calculating the average value of the tumor volumes of each group and comparing the change in tumor volume (V / V0) when the tumor volume on day 0 was V0. FIG. 4 shows V / V0 of each group measured over time.
  • Table 8 shows values (T / C) obtained by dividing V / V0 of each group on day 28 by V / V0 of the negative control group. Compared to the theoretical value of T / C when the efficacy of both compound 19 and docetaxel is simply added, that is, the value obtained by multiplying the T / C of each compound alone group, the T / C ( D) in the table showed a value (0.25) lower than the theoretical value of 0.28 on the 28th day.
  • Formulation Example 1 A tablet having the following composition is prepared by a conventional method.
  • Compound 1 5 mg Lactose 60 mg Potato starch 30 mg Polyvinyl alcohol 2 mg Magnesium stearate 1 mg Tar pigment Trace amount
  • Formulation Example 2 A tablet having the following composition is prepared by a conventional method.
  • Formulation Example 3 An injection having the following composition is prepared by a conventional method. Compound 19 2 mg D-mannitol 10 mg Hydrochloric acid aqueous solution Appropriate amount Sodium hydroxide aqueous solution Appropriate amount Distilled water for injection Appropriate amount
  • Formulation Example 4 An injection having the following composition is prepared by a conventional method. Dexamethasone 2 mg D-mannitol 10 mg Hydrochloric acid aqueous solution Appropriate amount Sodium hydroxide aqueous solution Appropriate amount Distilled water for injection Appropriate amount
  • a first component comprising an isoindolinone derivative or a pharmacologically acceptable salt thereof, and a second component selected from a chemotherapeutic agent, a hormonal therapeutic agent and a molecular target drug are administered simultaneously or separately.
  • Anticancer agents and the like are provided.

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Abstract

An anti-cancer agent comprising a first component and a second component as active ingredients and is adapted to administer the first component and the second component simultaneously or separately, wherein the first component comprises an isoindolinone derivative represented by formula (I) [wherein R1 and R2 independently represent a hydrogen atom, a substituted or unsubstituted lower alkyl group, -OR4 [wherein R4 represents a hydrogen atom, a substituted or unsubstituted lower alkyl group, or -S(O)2R5 (wherein R5 represents an amino group, a mono- or di-(lower alkylamino) group, a substituted or unsubstituted lower alkyl group, or the like)], or the like; and R3 represents a substituted or unsubstituted lower alkyl group, or the like] or a pharmacologically acceptable salt thereof and the second component is selected from a chemotherapeutic agent, a hormonal therapeutic agent and a molecular targeting agent; and others.

Description

抗癌剤Anticancer drug
　本発明は、イソインドリノン誘導体またはその薬理学的に許容される塩、ならびに化学療法剤、ホルモン療法剤及び分子標的薬から選ばれる成分を含有する抗癌剤等に関する。 The present invention relates to an anti-cancer agent containing an isoindolinone derivative or a pharmacologically acceptable salt thereof, and a component selected from a chemotherapeutic agent, a hormonal therapeutic agent and a molecular target drug.
　本発明で用いられるイソインドリノン誘導体が知られている（特許文献1）。同文献中にて、該イソインドリノン誘導体がオーロラ（Aurora）、繊維芽細胞増殖因子受容体3（FGFR3）及びフムス様チロシンキナーゼ（Flt-3）阻害活性、ならびに抗癌活性を有することが開示されている。さらに、同化合物がJAK阻害活性を有することも知られている（特許文献2）。 An isoindolinone derivative used in the present invention is known (Patent Document 1). In the same document, it is disclosed that the isoindolinone derivative has Aurora, fibroblast growth factor receptor 3 (FGFR3) and hummus-like tyrosine kinase (Flt-3) inhibitory activity, and anticancer activity Has been. Furthermore, it is also known that this compound has JAK inhibitory activity (Patent Document 2).
　また、本発明で用いられるイソインドリノン誘導体に関連する化合物が知られている（特許文献3～7、非特許文献1）。
　現在、多くの癌の治療において多剤併用療法が用いられている。併用療法の目的としては、例えば以下の1～3等が挙げられる（臨床腫瘍学第3版、癌と化学療法社）。
1. 複数の薬剤を用いることによる抗腫瘍効果の増強
2. 抗癌作用のスペクトラムの拡大（複数の癌細胞が発現している場合、1種の薬剤が無効な癌細胞に対し、それに対して有効な他の薬剤を投与する）
3. 耐性細胞の出現の回避、または遅延
　例えばインドロカルバゾール誘導体である、レスタルチニブ（Lestaurtinib、CEP-701）やPKC412等は急性骨髄性白血病細胞に対して、化学療法あるいはHDAC阻害剤やm-TOR阻害剤と併用することで併用効果を示すことが報告されている[クリニカル・キャンサー・リサーチ（Clinical Cancer Reseach）、10巻、4991頁（2004年）；ブラッド（Blood）、104巻、1145頁（2004年）；プロシーディング・オブ・ザ・ナショナル・アカデミー・オブ・サイエンシーズ・オブ・ジ・ユナイテッド・ステイツ・オブ・アメリカ（Proceeding of the national academy of sciences of the united states of America）、101巻、3130頁（2004年）]。インドリノン誘導体であるスニチニブ（Sunitinib、SU011248）は血液癌及び固形癌における化学療法あるいは分子標的薬との併用の有効性が報告されている[ブラッド（Blood）、104巻、4202頁（2004年）、WO06/120557］。 In addition, compounds related to the isoindolinone derivative used in the present invention are known (Patent Documents 3 to 7, Non-Patent Document 1).
Currently, combination therapy is used in the treatment of many cancers. Examples of the purpose of the combination therapy include the following 1-3, etc. (Clinical Oncology 3rd Edition, Cancer and Chemotherapy).
1. Enhancement of antitumor effect by using multiple drugs
2. Expansion of the spectrum of anticancer effects (when multiple cancer cells are expressed, one drug is given to cancer cells for which one drug is ineffective, and other drugs that are effective against it)
3. Avoidance or delay of emergence of resistant cells For example, instalocarbazole derivatives such as restaltinib (Lestaurtinib, CEP-701) and PKC412 are used for chemotherapy or HDAC inhibitors and m-TOR against acute myeloid leukemia cells. It has been reported that combined use with an inhibitor [Clinical Cancer Reseach, 10, 4991 (2004); Blood, 104, 1145 ( 2004); Proceeding of the National Academy of Sciences of the United States of America, 101, 3130 (2004)]. Sunitinib (Sunitinib, SU011248), an indolinone derivative, has been reported to be effective in combination with chemotherapy or molecular targeted drugs in blood cancer and solid cancer [Blood, 104, 4202 (2004), WO06 / 120557].
国際公開第2006/112479号パンフレットInternational Publication No. 2006/112479 Pamphlet 国際公開第2008/047831号パンフレットInternational Publication No. 2008/047831 Pamphlet 国際公開第2004/108672号パンフレットInternational Publication No. 2004/108672 Pamphlet 国際公開第2004/021532号パンフレットInternational Publication No. 2004/021532 Pamphlet 国際公開第2005/039564号パンフレットInternational Publication No. 2005/039564 Pamphlet 国際公開第2005/051300号パンフレットInternational Publication No. 2005/051300 Pamphlet 米国特許出願公開第2005/0026976号明細書US Patent Application Publication No. 2005/0026976
　本発明の目的は、イソインドリノン誘導体またはその薬理学的に許容される塩からなる第1成分、ならびに化学療法剤、ホルモン療法剤及び分子標的薬から選ばれる第2成分を同時にまたは別々に投与するための抗癌剤等を提供することにある。 An object of the present invention is to administer a first component comprising an isoindolinone derivative or a pharmacologically acceptable salt thereof, and a second component selected from a chemotherapeutic agent, a hormonal therapeutic agent and a molecular target agent simultaneously or separately. An object of the present invention is to provide an anticancer agent and the like.
　本発明は、以下の（1）～（18）に関する。
（1）式（I） The present invention relates to the following (1) to (18).
(1) Formula (I)
Figure JPOXMLDOC01-appb-C000002
Figure JPOXMLDOC01-appb-C000002
｛式中、R1及びR2は同一または異なって水素原子、ハロゲン、置換もしくは非置換の低級アルキル、置換もしくは非置換のシクロアルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級アルキニル、置換もしくは非置換のアリール、置換もしくは非置換の複素環基または-OR4［式中、R4は水素原子、置換もしくは非置換の低級アルキルまたは-S(O)2R5（式中、R5はアミノ、モノもしくはジ(置換もしくは非置換の低級アルキル)アミノ、置換もしくは非置換の低級アルキル、置換もしくは非置換のアリールまたは置換もしくは非置換の複素環基を表す）を表す］を表し、
R3はカルボキシまたは置換もしくは非置換の低級アルキルを表す｝で表されるイソインドリノン誘導体またはその薬理学的に許容される塩からなる第1成分、ならびに化学療法剤、ホルモン療法剤及び分子標的薬から選ばれる第2成分を有効成分とする、該第1成分と該第2成分を同時にまたは別々に投与するための抗癌剤。 {Wherein R 1 and R 2 are the same or different and each is a hydrogen atom, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl , Substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group or —OR 4 [wherein R 4 is a hydrogen atom, substituted or unsubstituted lower alkyl or —S (O) 2 R 5 (wherein R 5 represents amino, mono or di (substituted or unsubstituted lower alkyl) amino, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic group)] ,
R 3 represents carboxy or a substituted or unsubstituted lower alkyl}, a first component consisting of an isoindolinone derivative represented by: or a pharmacologically acceptable salt thereof, and a chemotherapeutic agent, hormone therapeutic agent and molecular target An anticancer agent for administering the first component and the second component simultaneously or separately, comprising a second component selected from drugs as an active ingredient.
（2）R1が-OS(O)2R5（式中、R5は前記と同義である）である前記（1）記載の抗癌剤。
（3）R1が-OS(O)2R5a（式中、R5aは置換もしくは非置換の低級アルキルを表す）である前記（1）記載の抗癌剤。
（4）R2が置換もしくは非置換の低級アルコキシである前記（1）～（3）のいずれかに記載の抗癌剤。
（5）R3が-CH2NR6R7（式中、R6及びR7は同一または異なって水素原子または置換もしくは非置換の低級アルキルを表すか、またはR6及びR7が隣接する窒素原子と一緒になって置換もしくは非置換の複素環基を形成する）である前記（1）～（4）のいずれかに記載の抗癌剤。 (2) The anticancer agent according to (1), wherein R 1 is —OS (O) 2 R 5 (wherein R 5 has the same meaning as described above).
(3) The anticancer agent according to (1), wherein R 1 is —OS (O) 2 R 5a (wherein R 5a represents a substituted or unsubstituted lower alkyl).
(4) The anticancer agent according to any one of (1) to (3), wherein R 2 is substituted or unsubstituted lower alkoxy.
(5) R 3 is —CH 2 NR 6 R 7 (wherein R 6 and R 7 are the same or different and each represents a hydrogen atom or a substituted or unsubstituted lower alkyl, or R 6 and R 7 are adjacent to each other) The anticancer agent according to any one of (1) to (4) above, which forms a substituted or unsubstituted heterocyclic group together with a nitrogen atom.
（6）第2成分が化学療法剤である前記（1）～（5）のいずれかに記載の抗癌剤。
（7）化学療法剤がチューブリン作用薬、デオキシリボ核酸作用薬及び代謝拮抗剤から選ばれる前記（6）記載の抗癌剤。
（8）第2成分がホルモン療法剤である前記（1）～（5）のいずれかに記載の抗癌剤。
（9）ホルモン療法剤が抗アンドロゲン剤、抗エストロゲン剤、アンドロゲン製剤、エストロゲン製剤、LH-RH作動薬、プロゲスチン、アロマターゼ阻害剤及びステロイドサルファターゼ阻害剤から選ばれる前記（8）記載の抗癌剤。
（10）第2成分が分子標的薬である前記（1）～（5）のいずれかに記載の抗癌剤。 (6) The anticancer agent according to any one of (1) to (5), wherein the second component is a chemotherapeutic agent.
(7) The anticancer agent according to (6), wherein the chemotherapeutic agent is selected from tubulin agonists, deoxyribonucleic acid agonists and antimetabolites.
(8) The anticancer agent according to any one of (1) to (5), wherein the second component is a hormone therapy agent.
(9) The anticancer agent according to (8), wherein the hormone therapy agent is selected from an anti-androgen agent, an anti-estrogen agent, an androgen preparation, an estrogen preparation, an LH-RH agonist, a progestin, an aromatase inhibitor, and a steroid sulfatase inhibitor.
(10) The anticancer agent according to any one of (1) to (5), wherein the second component is a molecular target drug.
（11）分子標的薬がキナーゼ阻害剤、キネシンEg5阻害剤、mTOR（mammalian target of rapamycin）阻害剤、プロテアソーム阻害剤、ヒストンデアセチラーゼ阻害剤、ヒートショック蛋白質90阻害剤及びファルネシルトランスフェラーゼ阻害剤から選ばれる前記（10）記載の抗癌剤。
（12）前記（1）～（5）のいずれかに記載のイソインドリノン誘導体またはその薬理学的に許容される塩からなる第1成分、ならびに化学療法剤、ホルモン療法剤及び分子標的薬から選ばれる第2成分を含有する、医薬組成物。 (11) Molecular target drug selected from kinase inhibitor, kinesin Eg5 inhibitor, mTOR (mammalian target of rapamycin) inhibitor, proteasome inhibitor, histone deacetylase inhibitor, heat shock protein 90 inhibitor and farnesyl transferase inhibitor The anticancer agent according to (10) above.
(12) From the first component comprising the isoindolinone derivative or the pharmacologically acceptable salt thereof according to any one of (1) to (5) above, and the chemotherapeutic agent, hormone therapeutic agent and molecular target drug A pharmaceutical composition comprising a selected second component.
（13）前記（1）～（5）のいずれかに記載のイソインドリノン誘導体またはその薬理学的に許容される塩からなる第1成分、ならびに化学療法剤、ホルモン療法剤及び分子標的薬から選ばれる第2成分を有するキット。
（14）癌の治療のための前記（13）記載のキット。
（15）化学療法剤、ホルモン療法剤及び分子標的薬から選ばれる薬剤と同時にまたは別々に投与するための、前記（1）～（5）のいずれかに記載のイソインドリノン誘導体またはその薬理学的に許容される塩。
（16）前記（1）～（5）のいずれかに記載のイソインドリノン誘導体またはその薬理学的に許容される塩からなる第1成分、ならびに化学療法剤、ホルモン療法剤及び分子標的薬から選ばれる第2成分を含有する抗癌剤。 (13) From the first component comprising the isoindolinone derivative or the pharmacologically acceptable salt thereof according to any one of (1) to (5) above, and the chemotherapeutic agent, hormone therapeutic agent and molecular target drug A kit having a second component selected.
(14) The kit according to the above (13) for treating cancer.
(15) The isoindolinone derivative or the pharmacology thereof according to any one of (1) to (5) above, which is administered simultaneously or separately with a drug selected from a chemotherapeutic agent, a hormonal therapeutic agent and a molecular target drug Acceptable salt.
(16) From the first component comprising the isoindolinone derivative or the pharmacologically acceptable salt thereof according to any one of (1) to (5) above, and a chemotherapeutic agent, hormone therapeutic agent and molecular target drug An anticancer agent comprising a selected second component.
（17）前記（1）～（5）のいずれかに記載のイソインドリノン誘導体またはその薬理学的に許容される塩からなる第1成分、ならびに化学療法剤、ホルモン療法剤及び分子標的薬から選ばれる第2成分の有効量を投与する工程を含む、癌の治療方法。
（18）癌の治療のための、前記（1）～（5）のいずれかに記載のイソインドリノン誘導体またはその薬理学的に許容される塩からなる第1成分、ならびに化学療法剤、ホルモン療法剤及び分子標的薬から選ばれる第2成分の使用。 (17) From the first component comprising the isoindolinone derivative or the pharmacologically acceptable salt thereof according to any one of (1) to (5) above, and a chemotherapeutic agent, hormone therapeutic agent and molecular target drug A method for treating cancer, comprising a step of administering an effective amount of a selected second component.
(18) A first component comprising the isoindolinone derivative or a pharmacologically acceptable salt thereof according to any one of (1) to (5), and a chemotherapeutic agent or hormone for the treatment of cancer Use of a second component selected from therapeutic agents and molecular targeted drugs.
　本発明により、イソインドリノン誘導体またはその薬理学的に許容される塩からなる第1成分、ならびに化学療法剤、ホルモン療法剤及び分子標的薬から選ばれる第2成分を同時にまたは別々に投与するための抗癌剤等が提供される。 According to the present invention, a first component comprising an isoindolinone derivative or a pharmacologically acceptable salt thereof, and a second component selected from a chemotherapeutic agent, a hormonal therapeutic agent and a molecular target drug are administered simultaneously or separately. Anticancer agents and the like are provided.
図1は、ヒト多発性骨髄腫NCI-H929細胞移植マウスモデルにおける化合物19とボルテゾミブの併用による抗腫瘍効果を示す図である。　縦軸は0日目の腫瘍体積をV0としたときの腫瘍体積変化の比（V/V0）を示す。横軸は日数を示す。○は陰性対照群（A）、●は化合物19単独群（B）、▲はボルテゾミブ単独群（C）、×は化合物19／ボルテゾミブ併用群（D）における増殖阻害効果を示す（平均値±標準誤差）。FIG. 1 is a graph showing the antitumor effect of a combination of compound 19 and bortezomib in a mouse model transplanted with human multiple myeloma NCI-H929 cells. The vertical axis shows the ratio of change in tumor volume (V / V0) when the tumor volume on day 0 is V0. The horizontal axis indicates the number of days. ○ indicates the negative control group (A), ● indicates the compound 19 alone group (B), ▲ indicates the bortezomib alone group (C), and × indicates the compound 19 / bortezomib combination group (D) (mean ± standard) error). 図2は、ヒト多発性骨髄腫KMS-11細胞移植マウスモデルにおける化合物19とメルファランの併用による抗腫瘍効果を示す図である。FIG. 2 is a graph showing the antitumor effect of the combined use of Compound 19 and melphalan in a mouse model transplanted with human multiple myeloma KMS-11 cells.
　縦軸は0日目の腫瘍体積をV0としたときの腫瘍体積変化の比（V/V0）を示す。横軸は日数を示す。○は陰性対照群（A）、●は化合物19単独群（B）、▲はメルファラン単独群（C）、×は化合物19／メルファラン併用群（D）における増殖阻害効果を示す（平均値±標準偏差）。
図3は、ヒト胃癌SNU-16細胞細胞移植マウスモデルにおける化合物19とCPT-11の併用による抗腫瘍効果を示す図である。 The vertical axis shows the ratio of change in tumor volume (V / V0) when the tumor volume on day 0 is V0. The horizontal axis indicates the number of days. ○ indicates negative control group (A), ● indicates compound 19 alone group (B), ▲ indicates melphalan alone group (C), × indicates compound 19 / melphalan combination group (D) (average value) ± standard deviation).
FIG. 3 is a graph showing the antitumor effect of a combination of compound 19 and CPT-11 in a mouse model transplanted with human gastric cancer SNU-16 cell cells.
　縦軸は0日目の腫瘍体積をV0としたときの腫瘍体積変化の比（V/V0）を示す。横軸は日数を示す。○は陰性対照群（A）、●は化合物19単独群（B）、▲はCPT-11単独群（C）、×は化合物19／CPT-11併用群（D）における増殖阻害効果を示す（平均値±標準誤差）。
図4は、ヒト胃癌SNU-16細胞細胞移植マウスモデルにおける化合物19とドセタキセルの併用による抗腫瘍効果を示す図である。 The vertical axis shows the ratio of change in tumor volume (V / V0) when the tumor volume on day 0 is V0. The horizontal axis indicates the number of days. ○ indicates a negative control group (A), ● indicates a compound 19 alone group (B), ▲ indicates a CPT-11 alone group (C), and × indicates a growth inhibitory effect in the compound 19 / CPT-11 combination group (D) ( Average value ± standard error).
FIG. 4 is a graph showing the antitumor effect of a combination of Compound 19 and docetaxel in a mouse model transplanted with human gastric cancer SNU-16 cell cells.
　縦軸は0日目の腫瘍体積をV0としたときの腫瘍体積変化の比（V/V0）を示す。横軸は日数を示す。○は陰性対照群（A）、●は化合物19単独群（B）、▲はドセタキセル単独群（C）、×は化合物19／ドセタキセル併用群（D）における増殖阻害効果を示す（平均値±標準誤差）。 The vertical axis shows the ratio of change in tumor volume (V / V0) when the tumor volume on day 0 is V0. The horizontal axis indicates the number of days. ○ indicates the negative control group (A), ● indicates the compound 19 alone group (B), ▲ indicates the docetaxel alone group (C), and × indicates the compound 19 / docetaxel combination group (D) (mean ± standard) error).
　以下、式（I）で表される化合物を化合物（I）という。他の式番号の化合物についても同様である。
　式（I）の各基の定義において、
（i）ハロゲンとしてはフッ素、塩素、臭素、ヨウ素の各原子が挙げられる。
（ii）低級アルキル、ならびに低級アルコキシ及びモノもしくはジ低級アルキルアミノの低級アルキル部分としては、例えば炭素原子数1から10の直鎖状、分枝鎖状またはこれらの組み合わせからなるアルキルが挙げられ、より具体的には、メチル、エチル、n-プロピル、イソプロピル、n-ブチル、イソブチル、sec-ブチル、tert-ブチル、n-ペンチル、ネオペンチル、n-ヘキシル、n-ヘプチル、n-オクチル、n-ノニル、n-デシル等が挙げられる。なお、ジ低級アルキルアミノにおける2つの低級アルキル部分は同一でも異なっていてもよい。
（iii）シクロアルキルとしては、炭素原子数3～10のシクロアルキルが挙げられ、より具体的にはシクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル、シクロデシル、ノルアダマンチル、アダマンチル、ビシクロ[2.2.1]ヘプチル、ビシクロ[2.2.2]オクチル、ビシクロ[3.3.0]オクチル、ビシクロ[3.3.1]ノニル等が挙げられる。 Hereinafter, the compound represented by formula (I) is referred to as compound (I). The same applies to the compounds of other formula numbers.
In the definition of each group of formula (I):
(I) Halogen includes fluorine, chlorine, bromine and iodine atoms.
(Ii) Lower alkyl, and lower alkyl of lower alkoxy and mono- or di-lower alkylamino include, for example, alkyl having 1 to 10 carbon atoms, straight chain, branched chain, or a combination thereof, More specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, n- Nonyl, n-decyl and the like can be mentioned. The two lower alkyl moieties in the di-lower alkylamino may be the same or different.
(Iii) Examples of cycloalkyl include cycloalkyl having 3 to 10 carbon atoms, and more specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, noradamantyl, adamantyl, bicyclo [ 2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.3.0] octyl, bicyclo [3.3.1] nonyl and the like.
（iv）低級アルケニルとしては、例えば炭素原子数2から10の直鎖または分枝鎖状のアルケニルが挙げられ、より具体的にはビニル、アリル、1-プロペニル、1-ブテニル、3-ブテニル、2-ペンテニル、4-ペンテニル、2-ヘキセニル、5-ヘキセニル、2-デセニル、9-デセニル等が挙げられる。
（v）低級アルキニルとしては、例えば炭素原子数2から10の直鎖または分枝鎖状のアルキニルが挙げられ、より具体的にはエチニル、2-プロピニル、3-ブチニル、4-ペンチニル、5-ヘキシニル、9-デシニル等が挙げられる。
（vi）アリールとしては、例えば単環性または2つ以上の環が縮合した縮環性のアリール、より具体的には、環構成炭素原子数が6から14のアリール、例えばフェニル、ナフチル、インデニル、アントラニル等が挙げられる。 (Iv) Examples of lower alkenyl include linear or branched alkenyl having 2 to 10 carbon atoms, and more specifically vinyl, allyl, 1-propenyl, 1-butenyl, 3-butenyl, 2-pentenyl, 4-pentenyl, 2-hexenyl, 5-hexenyl, 2-decenyl, 9-decenyl and the like can be mentioned.
Examples of (v) lower alkynyl include straight-chain or branched alkynyl having 2 to 10 carbon atoms, and more specifically, ethynyl, 2-propynyl, 3-butynyl, 4-pentynyl, 5- Hexinyl, 9-decynyl and the like can be mentioned.
(Vi) As aryl, for example, monocyclic or condensed condensed aryl having two or more rings condensed, more specifically, aryl having 6 to 14 ring carbon atoms, such as phenyl, naphthyl, indenyl , Anthranyl and the like.
（vii）複素環基としては、例えば芳香族複素環基、脂環式複素環基等が挙げられる。
（vii-i）芳香族複素環基としては、例えば単環性または2つ以上の環が縮合した縮環性の芳香族複素環基等が挙げられ、芳香族複素環基に含まれるヘテロ原子の種類及び数は特に限定されないが、例えば窒素原子、硫黄原子及び酸素原子からなる群から選ばれるヘテロ原子を1つまたは2つ以上含んでいてもよく、より具体的には、環構成原子数5から14の芳香族複素環基、例えばフリル、チエニル、ピロリル、イミダゾリル、ピラゾリル、トリアゾリル、テトラゾリル、オキサゾリル、オキサジアゾリル、チアゾリル、ピリジル、ピラジニル、ピリミジニル、ピリダジニル、トリアジニル、インドリル、インダゾリル、ベンゾイミダゾリル、ベンゾオキサゾリル、ベンゾチアゾリル、キノリル、イソキノリル、フタラジニル、ナフチリジニル、キノキサリニル、キナゾリニル、シンノリニル、プリニル、クマリニル等が挙げられる。
（vii-ii）脂環式複素環基としては、例えば単環性または2つ以上の環が縮合した縮環性の脂環式複素環基等が挙げられ、脂環式複素環基に含まれるヘテロ原子の種類及び数は特に限定されないが、例えば窒素原子、硫黄原子及び酸素原子からなる群から選ばれるヘテロ原子を1つまたは2つ以上含んでいてもよく、より具体的には、例えばピロリジニル、2,5-ジオキソピロリジニル、チアゾリジニル、オキサゾリジニル、ピペリジル、1,2-ジヒドロピリジル、ピペラジニル、ホモピペラジニル、モルホリニル、チオモルホリニル、ピラゾリニル、オキサゾリニル、ジオキソラニル、テトラヒドロピラニル、テトラヒドロチオピラニル、テトラヒドロフリル、テトラヒドロキノリル、テトラヒドロイソキノリル、テトラヒドロキノキサリニル、オクタヒドロキノリル、ジヒドロインドリル、1,3-ジオキソイソインドリニル等が挙げられる。 (Vii) Examples of the heterocyclic group include an aromatic heterocyclic group and an alicyclic heterocyclic group.
Examples of the (vii-i) aromatic heterocyclic group include monocyclic or condensed aromatic heterocyclic groups in which two or more rings are condensed, and heteroatoms contained in the aromatic heterocyclic group Is not particularly limited, and may contain, for example, one or more heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom, more specifically, the number of ring atoms 5 to 14 aromatic heterocyclic groups such as furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, indolyl, indazolyl, benzimidazolyl, benzoxazolyl , Benzothiazolyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, Kisariniru, quinazolinyl, cinnolinyl, purinyl, coumarinyl and the like.
(Vii-ii) Examples of the alicyclic heterocyclic group include monocyclic or condensed alicyclic heterocyclic groups in which two or more rings are condensed, and are included in the alicyclic heterocyclic group The type and number of heteroatoms to be obtained are not particularly limited, and may include, for example, one or more heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom, and more specifically, for example, Pyrrolidinyl, 2,5-dioxopyrrolidinyl, thiazolidinyl, oxazolidinyl, piperidyl, 1,2-dihydropyridyl, piperazinyl, homopiperazinyl, morpholinyl, thiomorpholinyl, pyrazolinyl, oxazolinyl, dioxolanyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuryl , Tetrahydroquinolyl, tetrahydroisoquinolyl, tetrahydroquinoxalinyl, octa Dorokinoriru, dihydroindolyl, 1,3-dioxo-isoindolinylcarbonyl like.
（viii）隣接する窒素原子と一緒になって形成される複素環基としては、例えば少なくとも1つの窒素原子を含む5員または6員の単環性複素環基（該単環性複素環基は、他の窒素原子、酸素原子または硫黄原子を含んでいてもよい）、3～8員の環が縮合した二環または三環性で少なくとも1つの窒素原子を含む縮環性複素環基（該縮環性複素環基は、他の窒素原子、酸素原子または硫黄原子を含んでいてもよい）等が挙げられ、より具体的にはピロリジニル、ピペリジノ、ピペラジニル、モルホリノ、チオモルホリノ、ホモピペリジノ、ホモピペラジニル、テトラヒドロピリジル、テトラヒドロキノリル、テトラヒドロイソキノリル等が挙げられる。 (Viii) Examples of the heterocyclic group formed together with the adjacent nitrogen atom include a 5-membered or 6-membered monocyclic heterocyclic group containing at least one nitrogen atom (the monocyclic heterocyclic group is , May contain other nitrogen atoms, oxygen atoms or sulfur atoms), a condensed bicyclic or tricyclic condensed 3- to 8-membered ring and containing at least one nitrogen atom The condensed heterocyclic group may contain other nitrogen atom, oxygen atom or sulfur atom), and more specifically, pyrrolidinyl, piperidino, piperazinyl, morpholino, thiomorpholino, homopiperidino, homopiperazinyl, Tetrahydropyridyl, tetrahydroquinolyl, tetrahydroisoquinolyl and the like can be mentioned.
（ix）置換低級アルキル、置換シクロアルキル、置換低級アルコキシ、置換低級アルケニル、置換低級アルキニル及びモノもしくはジ置換低級アルキルアミノにおける置換基としては、同一または異なって、例えば置換数1～3の、ハロゲン、ヒドロキシ、オキソ、低級アルコキシ、カルボキシ、低級アルコキシカルボニル、置換もしくは非置換のアリール（該置換アリールにおける置換基は、カルボキシ、低級アルコキシ、低級アルコキシカルボニル等である）、置換もしくは非置換の複素環基（該置換複素環基における置換基は、カルボキシ、低級アルコキシ、低級アルコキシカルボニル等である）、NR8R9｛式中、R8及びR9は同一または異なって、水素原子、置換もしくは非置換の低級アルキル［該置換低級アルキルにおける置換基は、例えば置換数1～3のハロゲン、アミノ、モノもしくはジ低級アルキルアミノ、ニトロ、ヒドロキシ、オキソ、シアノ、カルボキシ、低級アルカノイル、低級アルコキシカルボニル、アリール、複素環基、置換もしくは非置換の低級アルコキシ（該置換低級アルコキシにおける置換基は、例えば置換数1～3のヒドロキシ等である）等である］、置換もしくは非置換のシクロアルキル［該置換シクロアルキルにおける置換基は、例えば置換数1～3のハロゲン、ヒドロキシ、置換もしくは非置換の低級アルキル（該置換低級アルキルにおける置換基は、例えば置換数1～3のハロゲン、ヒドロキシ等である）等である］または置換もしくは非置換のアリール［該置換アリールにおける置換基は、例えば置換数1～3のハロゲン、アミノ、ヒドロキシ、低級アルカノイルアミノ、低級アルコキシ、置換もしくは非置換の低級アルキル（該置換低級アルキルにおける置換基は、例えば置換数1～3のハロゲン、ヒドロキシ等である）］を表すか、またはR8及びR9が隣接する窒素原子と一緒になって置換もしくは非置換の複素環基［該隣接する窒素原子と一緒になって形成される置換複素環基における置換基は、例えば置換数1～3のハロゲン、アミノ、ニトロ、ヒドロキシ、オキソ、シアノ、カルボキシ、低級アルカノイル、低級アルコキシカルボニル、低級アルキルスルホニル、複素環基、置換もしくは非置換の低級アルキル（該置換低級アルキルにおける置換基は、例えば置換数1～3のアミノ、ヒドロキシ、シアノ等である）、置換もしくは非置換の低級アルコキシ（該置換低級アルコキシにおける置換基は、例えば置換数1～3のヒドロキシ等である）等である］を形成する｝、N(O)R8aR9a（式中、R8a及びR9aはそれぞれ前記R8及びR9と同義である）等が挙げられる。 (Ix) Substituents in substituted lower alkyl, substituted cycloalkyl, substituted lower alkoxy, substituted lower alkenyl, substituted lower alkynyl and mono- or di-substituted lower alkylamino are the same or different, for example, a halogen having 1 to 3 substituents , Hydroxy, oxo, lower alkoxy, carboxy, lower alkoxycarbonyl, substituted or unsubstituted aryl (the substituent in the substituted aryl is carboxy, lower alkoxy, lower alkoxycarbonyl, etc.), substituted or unsubstituted heterocyclic group (Substituents in the substituted heterocyclic group are carboxy, lower alkoxy, lower alkoxycarbonyl, etc.), NR 8 R 9 (wherein R 8 and R 9 are the same or different and are a hydrogen atom, substituted or unsubstituted Lower alkyl of [substituent in the substituted lower alkyl is an example For example, halogen having 1 to 3 substituents, amino, mono- or di-lower alkylamino, nitro, hydroxy, oxo, cyano, carboxy, lower alkanoyl, lower alkoxycarbonyl, aryl, heterocyclic group, substituted or unsubstituted lower alkoxy Substituted in lower alkoxy is, for example, hydroxy having 1 to 3 substituents) and the like], substituted or unsubstituted cycloalkyl [substituent in the substituted cycloalkyl is, for example, halogen having 1 to 3 substituents , Hydroxy, substituted or unsubstituted lower alkyl (the substituent in the substituted lower alkyl is, for example, halogen having 1 to 3 substituents, hydroxy, etc.) or the like] or substituted or unsubstituted aryl [in the substituted aryl Examples of the substituent include halogen, amino, hydroxy, lower alkyl having 1 to 3 substituents. Represents canoylamino, lower alkoxy, substituted or unsubstituted lower alkyl (the substituent in the substituted lower alkyl is, for example, halogen having 1 to 3 substituents, hydroxy, etc.), or R 8 and R 9 are adjacent to each other A substituted or unsubstituted heterocyclic group together with a nitrogen atom [substituents in a substituted heterocyclic group formed together with the adjacent nitrogen atom are, for example, halogens having 1 to 3 substituents, amino, nitro , Hydroxy, oxo, cyano, carboxy, lower alkanoyl, lower alkoxycarbonyl, lower alkylsulfonyl, heterocyclic group, substituted or unsubstituted lower alkyl (the substituent in the substituted lower alkyl is, for example, amino having 1 to 3 substituents, Hydroxy, cyano, etc.), substituted or unsubstituted lower alkoxy (substituent in the substituted lower alkoxy) , For example, is formed which is] a a hydroxy or the like as) such as 1 to 3 substituents}, in N (O) R 8a R 9a ( wherein, R 8a and R 9a are each the same meanings as defined above R 8 and R 9 And the like.
　前記（ix）において、ハロゲンは前記（i）と同義であり、低級アルキル、ならびに低級アルコキシ、低級アルコキシカルボニル、低級アルキルスルホニル及びモノもしくはジ低級アルキルアミノの低級アルキル部分は前記（ii）と同義であり、シクロアルキルは前記（iii）と同義であり、アリールは前記（vi）と同義であり、複素環基は前記（vii）と同義であり、隣接する窒素原子と一緒になって形成される複素環基は前記（viii）と同義である。低級アルカノイル及び低級アルカノイルアミノの低級アルカノイル部分としては、例えば炭素数1～8の直鎖または分枝鎖状の低級アルカノイルが挙げられ、より具体的にはホルミル、アセチル、プロピオニル、ブチリル、イソブチリル、バレリル、イソバレリル、ピバロイル、ヘキサノイル、ヘプタノイル、オクタノイル等が挙げられる。
（x）置換アリール、置換複素環基及び隣接する窒素原子と一緒になって形成される置換複素環基における置換基としては、同一または異なって、例えば置換数1～3の、ハロゲン、アミノ、ニトロ、ウレイド、シアノ、カルボキシ、アミノカルボニル、低級アルコキシカルボニル、低級アルキルスルホニルアミノ、低級アルキルスルホニルオキシ、置換もしくは非置換の低級アルキル（該置換低級アルキルにおける置換基は、例えば置換数1～3のハロゲン、ヒドロキシ、低級アルコキシ等である）、置換もしくは非置換の低級アルコキシ（該置換低級アルコキシにおける置換基は、例えば置換数1～3のハロゲン、ヒドロキシ、低級アルコキシ等である）、置換もしくは非置換の低級アルカノイル（該置換低級アルカノイルにおける置換基は、例えば置換数1～3のハロゲン、ヒドロキシ、低級アルコキシ等である）等が挙げられる。置換複素環基及び隣接する窒素原子と一緒になって形成される置換複素環基における置換基は、前記に加えオキソであってもよい。 In the above (ix), the halogen is as defined in the above (i), and the lower alkyl and the lower alkyl part of the lower alkoxy, lower alkoxycarbonyl, lower alkylsulfonyl and mono- or di-lower alkylamino are as defined in the above (ii). And cycloalkyl is as defined above (iii), aryl is as defined above (vi), and a heterocyclic group is as defined above (vii) and is formed together with the adjacent nitrogen atom. The heterocyclic group has the same meaning as the above (viii). Examples of the lower alkanoyl part of lower alkanoyl and lower alkanoylamino include linear or branched lower alkanoyl having 1 to 8 carbon atoms, and more specifically formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl. , Isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl and the like.
(X) Substituents in the substituted aryl group formed together with the substituted aryl, substituted heterocyclic group and adjacent nitrogen atom are the same or different, for example, halogen, amino, Nitro, ureido, cyano, carboxy, aminocarbonyl, lower alkoxycarbonyl, lower alkylsulfonylamino, lower alkylsulfonyloxy, substituted or unsubstituted lower alkyl (the substituent in the substituted lower alkyl is, for example, a halogen having 1 to 3 substituents) Substituted, unsubstituted lower alkoxy (substituents in the substituted lower alkoxy are, for example, halogen having 1 to 3 substituents, hydroxy, lower alkoxy, etc.), substituted or unsubstituted Lower alkanoyl (the substituent in the substituted lower alkanoyl is, for example, Examples thereof include halogen having 1 to 3 substituents, hydroxy, lower alkoxy and the like. In addition to the above, the substituent in the substituted heterocyclic group formed together with the substituted heterocyclic group and the adjacent nitrogen atom may be oxo.
　前記（x）において、ハロゲンは前記（i）と同義であり、低級アルキル、ならびに低級アルコキシ、低級アルコキシカルボニル、低級アルキルスルホニルアミノ及び低級アルキルスルホニルオキシの低級アルキル部分は前記（ii）と同義であり、低級アルカノイルとしては、例えば炭素数1～8の直鎖または分枝鎖状の低級アルカノイルが挙げられ、より具体的にはホルミル、アセチル、プロピオニル、ブチリル、イソブチリル、バレリル、イソバレリル、ピバロイル、ヘキサノイル、ヘプタノイル、オクタノイル等が挙げられる。 In the above (x), the halogen is as defined in the above (i), and the lower alkyl, and the lower alkyl part of the lower alkoxy, lower alkoxycarbonyl, lower alkylsulfonylamino and lower alkylsulfonyloxy are as defined in the above (ii). Examples of the lower alkanoyl include linear or branched lower alkanoyl having 1 to 8 carbon atoms, and more specifically, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, Examples include heptanoyl and octanoyl.
　化合物（I）の薬理学的に許容される塩としては、例えば薬理学的に許容される酸付加塩、金属塩、アンモニウム塩、有機アミン付加塩、アミノ酸付加塩等が挙げられる。酸付加塩としては塩酸塩、硫酸塩、リン酸塩等の無機酸塩、酢酸塩、マレイン酸塩、フマル酸塩、酒石酸塩、クエン酸塩、乳酸塩、アスパラギン酸塩、グルタミン酸塩等の有機酸塩が挙げられ、金属塩としてはナトリウム塩、カリウム塩等のアルカリ金属塩、マグネシウム塩、カルシウム塩等のアルカリ土類金属塩、アルミニウム塩、亜鉛塩等が挙げられ、アンモニウム塩としてはアンモニウム、テトラメチルアンモニウム等の塩が挙げられ、有機アミン付加塩としてはモルホリン、ピペリジン等の付加塩が挙げられ、アミノ酸付加塩としてはリジン、グリシン、フェニルアラニン等の付加塩が挙げられる。 Examples of pharmacologically acceptable salts of compound (I) include pharmacologically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, and the like. Acid addition salts include inorganic acid salts such as hydrochloride, sulfate and phosphate, organic salts such as acetate, maleate, fumarate, tartrate, citrate, lactate, aspartate and glutamate. Examples of the metal salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt, zinc salt and the like, and ammonium salt includes ammonium, Examples include salts such as tetramethylammonium, examples of organic amine addition salts include addition salts such as morpholine and piperidine, and examples of amino acid addition salts include addition salts such as lysine, glycine, and phenylalanine.
　化合物（I）の塩を取得したい場合には、化合物（I）が塩の形で得られるときはそのまま精製すればよく、また遊離の形で得られるときは適当な溶媒に化合物（I）を溶解または懸濁し、酸または塩基等を加えて塩を形成させればよい。
　化合物（I）には、位置異性体、幾何異性体または光学異性体等の異性体が存在し得るが、可能な異性体及び該異性体のいかなる比率における混合物も本発明の医薬組成物の成分として用いることができる。 When it is desired to obtain a salt of compound (I), it can be purified as it is when the compound (I) is obtained in a salt form, and when it is obtained in a free form, the compound (I) is added to a suitable solvent. It may be dissolved or suspended, and an acid or base may be added to form a salt.
Compound (I) may have an isomer such as a positional isomer, a geometric isomer, or an optical isomer, but a possible isomer and a mixture of the isomers in any ratio are components of the pharmaceutical composition of the present invention. Can be used as
　また、化合物（I）及びその薬理学的に許容される塩は、水または各種溶媒との付加物の形で存在することもあるが、それら付加物も本発明の医薬組成物の成分として用いることができる。
　本発明の抗癌剤において、第2成分として用いられる化学療法剤、ホルモン療法剤及び分子標的薬としては、低分子化合物、蛋白質医薬品（例えばサイトカイン、抗体等）、核酸医薬品（例えばsiRNA、アンチセンスオリゴ等）等を用いることができる。 Compound (I) and pharmacologically acceptable salts thereof may exist in the form of adducts with water or various solvents, and these adducts are also used as components of the pharmaceutical composition of the present invention. be able to.
In the anticancer agent of the present invention, the chemotherapeutic agent, hormone therapy agent, and molecular target drug used as the second component include low molecular weight compounds, protein pharmaceuticals (eg, cytokines, antibodies, etc.), nucleic acid pharmaceuticals (eg, siRNA, antisense oligos, etc.) ) Etc. can be used.
　サイトカインとしては、例えばインターロイキン-2（IL-2）、IFN-α、IFN-γ、GM-CSF、G-CSF、TNF-α、IL-1β等が挙げられる。
　抗体としては、例えば抗EGFR抗体（Cetuximab、Erbitux）、抗ErbB2抗体［trastuzumab（geneticalrecombination）、Herceptin］、抗CD20抗体（Rituxan）、抗CD52抗体（Campath）等が挙げられる。 Examples of cytokines include interleukin-2 (IL-2), IFN-α, IFN-γ, GM-CSF, G-CSF, TNF-α, and IL-1β.
Examples of the antibody include anti-EGFR antibody (Cetuximab, Erbitux), anti-ErbB2 antibody [trastuzumab (genetical recombination), Herceptin], anti-CD20 antibody (Rituxan), anti-CD52 antibody (Campath) and the like.
　化学療法剤としては、例えばチューブリン作用薬、デオキシリボ核酸（DNA）作用薬、代謝拮抗剤等が挙げられる。
　ホルモン療法剤としては、例えば抗アンドロゲン剤、抗エストロゲン剤、アンドロゲン製剤、エストロゲン製剤、LH-RH作動薬（化学的去勢薬）、プロゲスチン、アロマターゼ阻害剤、ステロイドサルファターゼ阻害剤等が挙げられる。 Examples of chemotherapeutic agents include tubulin agonists, deoxyribonucleic acid (DNA) agonists, antimetabolites, and the like.
Examples of hormone therapy agents include antiandrogens, antiestrogens, androgens, estrogen, LH-RH agonists (chemical castrations), progestins, aromatase inhibitors, steroid sulfatase inhibitors, and the like.
　分子標的薬としては、例えばBcr-Abl阻害剤、EGFR阻害剤、マルチキナーゼ阻害剤、キネシンEg5阻害剤、Flt-3阻害剤、mTOR阻害剤、プロテアソーム阻害剤、ヒストンデアセチラーゼ（HDAC）阻害剤、ヒートショック蛋白質90（Hsp90）阻害剤、ファルネシルトランスフェラーゼ阻害剤等が挙げられる。
　チューブリン作用薬の例としては、例えばビンブラスチン（vinblastine）、ビンデシン（vindesine）、ビンクリスチン（vincristine）、ビノレルビン（vinorelbine）、パクリタキセル（タキソール）、ドセタキセル（タキソテア）等が挙げられる。 Examples of molecular target drugs include Bcr-Abl inhibitors, EGFR inhibitors, multikinase inhibitors, kinesin Eg5 inhibitors, Flt-3 inhibitors, mTOR inhibitors, proteasome inhibitors, histone deacetylase (HDAC) inhibitors Heat shock protein 90 (Hsp90) inhibitor, farnesyltransferase inhibitor, and the like.
Examples of tubulin agonists include vinblastine, vindesine, vincristine, vinorelbine, paclitaxel (taxol), docetaxel (taxotere) and the like.
　DNA作用薬の例としては、例えばクロラムブシル（chlorambucil）、シクロフォスファミド（cyclophosphamide）、メルファラン（melpharan）、ダカルバジン（DTIC）［dacarbazine (DTIC)］、オキザロプラチン（oxaloplatin）、ブレオマイシン（bleomycin）、ドキソルビシン（アドリアマイシン）［doxorubicin (adriamycin)］、ドキソルビシンリポ（ドキシル）［doxorubicin lipo (doxil)］、イダルビシン（idarubicin）、マイトマイシン（mitomycin）、ミトキサントロン（mitoxantrone）、エトポシド（etoposide）、カンプトテシン（camptothecin）、CPT-11,10-ヒドロキシ-7-エチル-カンプトテシン（SN38）、トポテカン（topotecan）等が挙げられる。 Examples of DNA agonists include chlorambucil, cyclophosphamide, melpharan, dacarbazine (DTIC), oxaloplatin, bleomycin, Doxorubicin (adriamycin) [doxorubicin リ ポ lipooxo (doxil)], idarubicin, mitomycin, mitoxantrone, etoposide, etopocamp CPT-11,10-hydroxy-7-ethyl-camptothecin (SN38), topotecan and the like.
　代謝拮抗剤の例としては、例えばフルダラビン（fludarabine）、ヒドロキシウレア（hydroxyurea）、シタラビン（cytarabine）、メトトレキセート（methotrexate）等が挙げられる。
　ホルモン療法剤の例としては、例えばロイプロリド（leuprolide）、ゴセレリン（goserelin）、メゲストロール（megestrol）、タモキシフェン（tamoxifen）、ICI182780、トレミフェン（Tremifene）、ファドロゾール（fadrozole）、レトロゾール（letrozole）、フルタミド（flutamide）、ビカルタミド(bicalutamide)、テストラクトン（testolactone）、ミトタン（mitotane）、プレドニゾロン（prednisolone）、デキサメタゾン（dexamethasone）等が挙げられる。 Examples of the antimetabolite include fludarabine, hydroxyurea, cytarabine, methotrexate and the like.
Examples of hormone therapy agents include, for example, leuprolide, goserelin, megestrol, tamoxifen, ICI182780, toremifene, fadrozole, letrozole, flutamide (Flutamide), bicalutamide, testolactone, mitotane, prednisolone, dexamethasone and the like.
　分子標的薬の例としては、例えばLapatinib（HKI-272、BIBW-2992、BMS-599626）、イマチニブ（STI-571）［imatinib (STI571)］、ダサチニブ（dasatinib、BMS-354825）、ニロチニブ（nilotinib、AMN107）、スニチニブ（スーテント）[sunitinib (SUTENT）、SU11248]、ソラフェニブ（ネクサバール）[sorafenib (Nexabar)、BAY43-9006]、CHIR-258、vatalanib（PTK-787）、R-1155777（tipifarnib、zarnestra）、ラパマイシン（rapamycin）、temsirolimus（CCI-779）、ボルテゾミブ（ベルケード）[bortezomib (Velcade)、PS-341]、アスパラギナーゼ（asparaginase）、ペガスパラガーゼ（pegaspargase）等が挙げられる。 Examples of molecular target drugs include, for example, Lapatinib (HKI-272, BIBW-2992, BMS-599626), imatinib (STI-571) [imatinib (STI571)], dasatinib (dasatinib, BMS-354825), nilotinib, AMN107), Sunitinib (Sutent) [sunitinib (SUTENT), SU11248], Sorafenib (Nexabar), BAY43-9006], CHIR-258, vatalanib (PTK-787), R-1155777 (tipifarnib, zarnestra) , Rapamycin, temsirolimus (CCI-779), bortezomib (Velcade), PS-341, asparaginase, pegaspargase and the like.
　Flt-3阻害剤の例としては、例えばCEP-701、PKC412、MLN518、CHIR-258、表1-1及び1-2記載のインダゾール誘導体（WO2005/012258）等が挙げられる。 Examples of Flt-3 inhibitors include CEP-701, PKC412, MLN518, CHIR-258, indazole derivatives described in Tables 1-1 and 1-2 (WO2005 / 012258), and the like.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
　HDAC阻害剤の例としては、例えばVorinostat（suberanilohydroxamic acid、SAHA、Zolinza）、バルプロ酸、MS-275等が挙げられる。
　Hsp90阻害剤の例としては、例えばラディシコール（Radicicol）、ゲルダナマイシン（Geldanamycin）、17-AAG、ハービマイシン（Herbimycin）A、ノボビオシン（Novobiocin）、表2-1及び2-2記載のベンゾイル化合物（WO2005/000778）等が挙げられる。 Examples of HDAC inhibitors include Vorinostat (suberanilohydroxamic acid, SAHA, Zolinza), valproic acid, MS-275, and the like.
Examples of Hsp90 inhibitors include, for example, radicicol, geldanamycin, 17-AAG, herbimycin A, novobiocin, benzoyl compounds described in Tables 2-1 and 2-2 (WO2005 / 000778) and the like.
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006
　化合物（I）またはその薬理学的に許容される塩は、分化誘導剤、骨吸収阻害剤等と組み合わせて用いることもできる。
　分化誘導剤の例としては、例えばオール－トランスレチノイン酸（all-trans retinoic acid）、サリドマイド（thalidomide）、レナリドマイド（lenalidomide）、ベキサロテン（ターグレチン）［bexarotene (targretin)］等が挙げられる。 Compound (I) or a pharmacologically acceptable salt thereof can also be used in combination with a differentiation inducer, a bone resorption inhibitor and the like.
Examples of the differentiation inducer include, for example, all-trans retinoic acid, thalidomide, lenalidomide, bexarotene (targretin) and the like.
　骨吸収阻害剤の例としては、例えばビスフォスフォナート（Zoledronic acid, Zometa）が挙げられる。
　上記の化合物は、単独投与では十分な治療効果が得られない場合や、高用量投与では副作用が懸念される場合がある。しかしながら、本発明においては、上記の化合物と、化合物（I）またはその薬理学的に許容される塩とを組み合わせることにより、それぞれの単独投与に比べて、高い治療効果が得られ、上述の化合物を低用量で用いることができる。従って、十分な治療効果に加えて、副作用を軽減することができる。 Examples of the bone resorption inhibitor include bisphosphonate (Zoledronic acid, Zometa).
The above compounds may not be able to obtain a sufficient therapeutic effect when administered alone, or may cause side effects when administered at a high dose. However, in the present invention, by combining the above compound with the compound (I) or a pharmacologically acceptable salt thereof, a high therapeutic effect can be obtained as compared with each single administration. Can be used at low doses. Therefore, in addition to a sufficient therapeutic effect, side effects can be reduced.
　本発明で用いられる化合物（I）は、例えばWO2006/112479記載の方法に従って合成することができる。
　本発明で用いられる化合物（I）の具体例を以下の表3-1～3-3に示すが、本発明はこれらに限定されるものではない。表中、Me及びEtはそれぞれメチル及びエチルを表す。
　なお、化合物1～29は、それぞれWO2006/112479の実施例188、215、218、222、227、229、231、241、261、297、305、323、325、327、338、346、349、359、362、365、382、406、409、424、426、462、466、375及び456に従って合成することができる。 Compound (I) used in the present invention can be synthesized, for example, according to the method described in WO2006 / 112479.
Specific examples of the compound (I) used in the present invention are shown in the following Tables 3-1 to 3-3, but the present invention is not limited thereto. In the table, Me and Et represent methyl and ethyl, respectively.
Compounds 1 to 29 are the same as those in Examples 188, 215, 218, 222, 227, 229, 231, 241, 261, 297, 305, 323, 325, 327, 338, 346, 349, and 359 of WO2006 / 112479, respectively. 362, 365, 382, 406, 409, 424, 426, 462, 466, 375 and 456.
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000008
Figure JPOXMLDOC01-appb-T000008
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000009
　本発明の抗癌剤は、例えば造血器腫瘍による癌（例えば急性骨髄性白血病、慢性骨髄性白血病、急性リンパ性白血病、慢性リンパ性白血病、多発性骨髄腫、リンパ腫等）、乳癌、子宮体癌、子宮頚癌、前立腺癌、膀胱癌、腎癌、胃癌、食道癌、肝癌、胆道癌、大腸癌、直腸癌、膵癌、肺癌、口頭頚部癌、骨肉腫、メラノーマまたは脳腫瘍による癌の治療に用いることができる。中でも、多発性骨髄腫の治療に用いるのが好ましい。 Examples of the anticancer agent of the present invention include cancer caused by hematopoietic tumor (eg, acute myeloid leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, lymphoma, etc.), breast cancer, endometrial cancer, uterus Can be used to treat cancer caused by cervical cancer, prostate cancer, bladder cancer, renal cancer, gastric cancer, esophageal cancer, liver cancer, biliary tract cancer, colon cancer, rectal cancer, pancreatic cancer, lung cancer, oral neck cancer, osteosarcoma, melanoma or brain tumor it can. Among them, it is preferable to use it for the treatment of multiple myeloma.
　本発明の医薬組成物は、化合物（I）またはその薬理学的に許容される塩と、それと併用するための少なくとも1つの化合物を含有するように製剤化したものであれば、単剤としてでも複数の製剤の組み合わせとしてでも使用、投与または製造することができる。これらの医薬組成物は、経口的または注射剤等の非経口的投与に対して適する単位服用形態にあることが望ましい。また、複数の製剤の組み合わせとして使用または投与する際には、同時にまたは別々に使用または投与することができる。 The pharmaceutical composition of the present invention may be used as a single agent, as long as it is formulated so as to contain compound (I) or a pharmacologically acceptable salt thereof and at least one compound for use in combination therewith. It can be used, administered or manufactured as a combination of a plurality of preparations. These pharmaceutical compositions are preferably in a unit dosage form suitable for oral or parenteral administration such as injection. Further, when used or administered as a combination of a plurality of preparations, they can be used or administered simultaneously or separately.
　第1成分である化合物（I）またはその薬理学的に許容される塩と、第2成分との用量比（重量／重量）は、使用する第2成分との組み合わせ、使用する第2成分の効力等に応じて適宜調整すればよいが、具体的には例えば1/300～1000/1、好ましくは1/200～500/1、より好ましくは1/100～100/1の間の比である。
　複数の製剤の組み合わせとして投与する際には、例えば化合物（I）またはその薬理学的に許容される塩を含有する第1成分と、第2成分とを、それぞれ上記のように別途製剤化し、キットとして作成しておき、このキットを用いてそれぞれの成分を同時にまたは別々に、同一対象に対して同一経路または異なった経路で投与することができる。 The dose ratio (weight / weight) of compound (I), which is the first component, or a pharmacologically acceptable salt thereof, and the second component is the combination of the second component used and the second component used. It may be appropriately adjusted according to the efficacy, etc., and specifically, for example, a ratio between 1/300 to 1000/1, preferably 1/200 to 500/1, more preferably 1/100 to 100/1. is there.
When administered as a combination of a plurality of preparations, for example, the first component containing Compound (I) or a pharmacologically acceptable salt thereof, and the second component are separately formulated as described above, A kit can be prepared, and each component can be administered to the same subject by the same route or different routes simultaneously or separately using the kit.
　該キットとしては、例えば保存する際に外部の温度や光による内容物である成分の変性、容器からの化学成分の溶出等が見られない容器であれば材質、形状等は特に限定されない2つ以上の容器（例えばバイアル、バッグ等）と内容物からなり、内容物である第1成分と第2成分が別々の経路（例えばチューブ等）または同一の経路を介して投与可能な形態を有するものが用いられる。 There are no particular limitations on the material, shape, etc. of the kit as long as it is a container that does not show, for example, denaturation of components that are contents by external temperature or light during storage, elution of chemical components from the container, etc. Consists of the above containers (eg, vials, bags, etc.) and contents, and the contents of the first component and the second component can be administered via separate routes (eg, tubes) or the same route Is used.
　これら製剤は、それぞれ有効成分の他に製剤学的に許容される希釈剤、賦形剤、崩壊剤、滑沢剤、結合剤、界面活性剤、可塑剤、水、生理食塩水、植物油、溶剤、可溶化剤、等張化剤、保存剤、抗酸化剤等を用いて常法により作成することができる。
　錠剤の調製にあたっては、例えば乳糖等の賦形剤、澱粉等の崩壊剤、ステアリン酸マグネシウム等の滑沢剤、ヒドロキシプロピルセルロース等の結合剤、脂肪酸エステル等の界面活性剤、グリセリン等の可塑剤等を常法に従って用いればよい。 These preparations are pharmaceutically acceptable diluents, excipients, disintegrants, lubricants, binders, surfactants, plasticizers, water, physiological saline, vegetable oils, solvents. , Solubilizers, tonicity agents, preservatives, antioxidants, etc.
In preparing tablets, for example, excipients such as lactose, disintegrants such as starch, lubricants such as magnesium stearate, binders such as hydroxypropylcellulose, surfactants such as fatty acid esters, plasticizers such as glycerin Etc. may be used according to a conventional method.
　注射剤の調製にあたっては、水、生理食塩水、植物油、溶剤、可溶化剤、等張化剤、保存剤、抗酸化剤等を常法により用いればよい。
　化合物（I）またはその薬理学的に許容される塩は、上記の目的で用いる場合、通常、経口的または注射剤等として非経口的に投与可能であり、その有効用量及び投与回数は投与形態、患者の年齢、体重、症状等により異なるが、通常一日当たり、0.01～20 mg/kgを投与するのが好ましい。 In preparing the injection, water, physiological saline, vegetable oil, solvent, solubilizer, tonicity agent, preservative, antioxidant and the like may be used in a conventional manner.
Compound (I) or a pharmacologically acceptable salt thereof can be administered orally or parenterally as an injection or the like when used for the above-mentioned purposes, and the effective dose and the number of administrations are the administration form. Depending on the age, weight, symptoms, etc. of the patient, it is usually preferable to administer 0.01 to 20 mg / kg per day.
　次に、本発明の抗癌剤の薬理作用について試験例でより具体的に説明する。
試験例1：多発性骨髄腫細胞株KMS-11における化合物19及びデキサメサゾンの併用効果
　通常培養用培地で0.75×105個/mLに調製した多発性骨髄腫細胞株KMS-11をTC MICROWELL 96U plate［カタログ番号163320、ナルジェヌンク社（Rochester, NY, USA）］に80 μLずつ播種し、37 ℃で24時間、5%炭酸ガスインキュベーター内において培養した。最終濃度が8 nmol/Lとなるように調製した化合物19のジメチルスルホキシド（DMSO）溶液を10 μLずつ添加した。同様に、最終濃度が18.8 nmol/Lとなるように調製したデキサメサゾンのDMSO溶液を10 μLずつ添加した。コントロールウェルとブランクプレートには、最終濃度が0.1%となるようにDMSOを10 μLずつ添加した。ブランクプレート以外は、試験化合物添加後、5%炭酸ガスインキュベーター内で37 ℃で72時間培養した。WST-1試薬｛4-[3-(4-Iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate sodium salt｝（カタログ番号1644807、ロシュ・ダイアグノスティックス社）を10 μL加え、37 ℃で2時間インキュベートした後に、マイクロプレート分光光度計SPECTRA max 340PC［モレキュラーデバイス社（Sunnyvale, CA, USA）］を用い、450 nm（対照波長690 nm）の吸光度を測定した。 Next, the pharmacological action of the anticancer agent of the present invention will be described more specifically with test examples.
Test Example 1: Combined effect of compound 19 and dexamethasone in multiple myeloma cell line KMS-11 TC MICROWELL 96U plate was used for multiple myeloma cell line KMS-11 prepared at 0.75 × 10 5 cells / mL in a normal culture medium. [Catalog number 163320, Nargenung (Rochester, NY, USA)] was seeded at 80 μL each and cultured at 37 ° C. for 24 hours in a 5% carbon dioxide incubator. 10 μL of a dimethyl sulfoxide (DMSO) solution of compound 19 prepared to a final concentration of 8 nmol / L was added. Similarly, 10 μL of a dexamethasone DMSO solution prepared to a final concentration of 18.8 nmol / L was added. 10 μL of DMSO was added to the control well and the blank plate at a final concentration of 0.1%. Except for the blank plate, the cells were cultured at 37 ° C. for 72 hours in a 5% carbon dioxide incubator after adding the test compound. WST-1 Reagent {4- [3- (4-Iodophenyl) -2- (4-nitrophenyl) -2H-5-tetrazolio] -1,3-benzene disulfonate sodium salt} (Catalog No. 1644807, Roche Diagnostics) After incubating for 2 hours at 37 ° C, the absorbance at 450 nm (control wavelength: 690 nm) was measured using a microplate spectrophotometer SPECTRA max 340PC [Molecular Devices (Sunnyvale, CA, USA)]. Was measured.
　試験化合物を添加せずDMSOのみを加え72時間KMS-11細胞を培養したウェル（コントロール）の値を100%、細胞を播種せず培地のみのウェル（ブランク）の値を0%として、試験化合物を加え72時間培養したウェルの相対増殖率（%）を算出し、その値を100から引いた値を試験化合物の細胞増殖阻害率（%）とした。
　併用効果の判定については、Bliss independence analysisを用いた［キャンサー・セル（Cancer Cell）、9巻、133頁（2006年）］。作用点の異なる2剤を併用した際の相加効果以上の効果があると期待される最低の阻害率（最低阻害率）は、以下の式により算出した。 Test compound with the value of well (control) without culture compound added to DMSO alone and cultured for 72 hours for KMS-11 cells as 100%, well with medium only without cell seeding (blank) as 0% The relative growth rate (%) of wells cultured for 72 hours was calculated, and the value obtained by subtracting the value from 100 was taken as the cell growth inhibition rate (%) of the test compound.
Regarding the determination of the combined effect, Bliss independence analysis was used [Cancer Cell, Vol. 9, page 133 (2006)]. The lowest inhibition rate (minimum inhibition rate) expected to be more than the additive effect when two agents with different action points were used in combination was calculated by the following formula.
Figure JPOXMLDOC01-appb-M000010
Figure JPOXMLDOC01-appb-M000010
　KMS-11細胞株の増殖に対して化合物19（8 nmol/L）とデキサメサゾン（18.8 nmol/L）はそれぞれ単独で39.0及び37.3%の阻害率を示したが、それらの併用により、78.3%の阻害率が観察された。これはBliss independence anaylsisから算出される最低阻害率61.8%よりも大きく、この結果から化合物19とデキサメサゾンの併用効果が支持される。
　上記の結果から、本発明の抗癌剤の併用効果が示された。 Compound 19 (8 nmol / L) and dexamethasone (18.8 nmol / L) alone showed an inhibition rate of 39.0 and 37.3% for the growth of the KMS-11 cell line, respectively. An inhibition rate was observed. This is greater than the lowest inhibition rate calculated from Bliss independence anaylsis of 61.8%, and this result supports the combined effect of Compound 19 and dexamethasone.
From the above results, the combined effect of the anticancer agent of the present invention was shown.
Figure JPOXMLDOC01-appb-T000011
Figure JPOXMLDOC01-appb-T000011
試験例2：ヒト多発性骨髄腫NCI-H929細胞移植マウスモデルにおける化合物19とボルテゾミブの併用による抗腫瘍効果
　癌細胞移植2日前にFox C.B-17/Icr-scidJclマウス（日本クレア）に抗アシアロGM1抗体（約10 mg蛋白／1 mLバイアル）（和光純薬工業）を0.3 mg/マウスずつ腹腔内投与した。NCI-H929細胞は、10%牛胎児血清（FCS）を含むRPMI1640培地中、5%炭酸ガスインキュベーター内で37 ℃にて培養し増殖させ、マウス1匹あたり1×107細胞にて腹側皮下に移植した。移植8日後にノギスにて皮下で増殖した腫瘍の長径、短径を測定し以下の式に従って腫瘍体積を求めた。 Test Example 2: Anti-tumor effect of combined use of compound 19 and bortezomib in a mouse model transplanted with human multiple myeloma NCI-H929 cells Anti -Asialo GM1 in Fox CB-17 / Icr-scidJcl mice (Clea Japan) 2 days before transplantation Antibody (about 10 mg protein / 1 mL vial) (Wako Pure Chemical Industries) was intraperitoneally administered at 0.3 mg / mouse. NCI-H929 cells, in RPMI1640 medium containing 10% fetal calf serum (FCS), 5% in a carbon dioxide incubator to culture grown at 37 ° C., subcutaneously, ventrally 1 × 10 7 cells per mouse Transplanted. The major axis and minor axis of the tumor grown subcutaneously with calipers 8 days after the transplantation were measured, and the tumor volume was determined according to the following formula.
Figure JPOXMLDOC01-appb-M000012
Figure JPOXMLDOC01-appb-M000012
　同時に各マウスの体重も測定し、平均腫瘍体積と平均体重が均一になるように1群5匹ずつ以下のような投与群に分け、この日を投与試験開始0日として投与を開始した。
　化合物19は5%糖液（大塚製薬社製）に2.5 mg/mLの濃度で溶解させ、投与開始0、7、14日目にそれぞれ1日1回、マウス体重1 gあたり0.01 mL（25 mg/kg）の用量で、尾静脈より静脈内投与した。 At the same time, the body weight of each mouse was also measured, and the mice were divided into the following administration groups with 5 mice per group so that the average tumor volume and the average body weight were uniform.
Compound 19 is dissolved in a 5% sugar solution (Otsuka Pharmaceutical Co., Ltd.) at a concentration of 2.5 mg / mL, and once a day on the 0th, 7th, and 14th days of administration, 0.01 mL (25 mg / kg) was administered intravenously from the tail vein.
　ボルテゾミブは生理食塩水（大塚製薬社製）で0.075 mg/ mLの濃度で懸濁させ、投与開始0、3、7、10日目にそれぞれ1日1回、マウス体重1 gあたり0.01 mL（0.75 mg/kg）の用量で、尾静脈より静脈内投与した。
A. 陰性対照群（Control）：化合物19及びボルテゾミブ非投与
B. 化合物19単独群：25 mg/kg（1日1回／0、7、14日目に投与）
C. ボルテゾミブ単独群：0.75 mg/kg（1日1回／0、3、7、10日目に投与）
D. 化合物19／ボルテゾミブ併用群：化合物19は25 mg/kg（1日1回／0、7、14日目に投与）、ボルテゾミブは0.75 mg/kg（1日1回／0、3、7、10日目に投与）
　0日目以降、週に2回腫瘍体積の測定を行った。抗腫瘍効果の判定は各群の腫瘍体積の平均値を算出し、0日目の腫瘍体積をV0としたときの腫瘍体積変化（V/V0）の比較で行った。経日測定した各群のV/V0を図1に示す。 Bortezomib was suspended in physiological saline (manufactured by Otsuka Pharmaceutical Co., Ltd.) at a concentration of 0.075 mg / mL, and once a day on the 0th, 3rd, 7th, and 10th days of administration, 0.01 mL (0.75 mg / kg) was administered intravenously from the tail vein.
A. Negative control group (Control): Compound 19 and bortezomib not administered
B. Compound 19 alone group: 25 mg / kg (once daily / administered on days 0, 7, 14)
C. Bortezomib alone group: 0.75 mg / kg (once daily / administered on days 0, 3, 7, 10)
D. Compound 19 / bortezomib combination group: Compound 19 is 25 mg / kg (once daily / 0, 7 and 14 days), bortezomib is 0.75 mg / kg (once daily / 0, 3, 7 On day 10)
From day 0, tumor volume was measured twice a week. The determination of the antitumor effect was performed by calculating the average value of the tumor volumes of each group and comparing the change in tumor volume (V / V0) when the tumor volume on day 0 was V0. FIG. 1 shows V / V0 of each group measured over time.
　図1に示したように、化合物19とボルテゾミブとの併用投与は、化合物19単独あるいはボルテゾミブ単独よりも高い増殖抑制効果を示した。
　21日目の各群のV/V0を陰性対照群のV/V0で除した値（T/C）を表5に示す。化合物19、ボルテゾミブ両化合物の薬効が単純に加算された時のT/Cの理論値、すなわち各化合物単独群のT/Cを掛け合わせた値と比べると、実際の併用群のT/C（表中のD）は、14日目において理論値である0.11よりも低い値（0.022）を示した。 As shown in FIG. 1, the combined administration of compound 19 and bortezomib showed a higher growth inhibitory effect than compound 19 alone or bortezomib alone.
Table 5 shows values (T / C) obtained by dividing V / V0 of each group on day 21 by V / V0 of the negative control group. Compared to the theoretical value of T / C when the efficacy of both compound 19 and bortezomib is simply added, that is, the value obtained by multiplying the T / C of each compound alone group, the T / C ( D) in the table showed a value (0.022) lower than the theoretical value of 0.11 on the 14th day.
Figure JPOXMLDOC01-appb-T000013
Figure JPOXMLDOC01-appb-T000013
　以上より、化合物19とボルテゾミブの併用投与は、それぞれ単独投与より高い抗腫瘍効果を有し、相乗効果を示すことが明らかとなった。この結果から、化合物（I）とボルテゾミブの併用投与は、それぞれの単独投与より高い抗腫瘍活性を有し、相乗効果を示すことが示唆された。

試験例3：ヒト多発性骨髄腫KMS-11細胞移植マウスモデルにおける化合物19とメルファランの併用による抗腫瘍効果
　癌細胞移植前日にFox C.B-17/Icr-scidJclマウス（日本クレア）に抗アシアロGM1抗体（約10 mg蛋白／1 mLバイアル）（和光純薬工業）を0.3 mg/マウスずつ腹腔内投与した。KMS-11細胞は、10%牛胎児血清（FCS）を含むRPMI1640培地中、5%炭酸ガスインキュベーター内で37 ℃にて培養し増殖させ、マウス1匹あたり1×107細胞にて腹側皮下に移植した。移植10日後にノギスにて皮下で増殖した腫瘍の長径、短径を測定し以下の式に従って腫瘍体積を求めた。 From the above, it has been clarified that the combined administration of Compound 19 and bortezomib has a higher antitumor effect and a synergistic effect, respectively, compared to single administration. From these results, it was suggested that the combined administration of compound (I) and bortezomib has a higher antitumor activity than each single administration and shows a synergistic effect.

Test Example 3: Anti-tumor effect of combined use of Compound 19 and melphalan in a mouse model transplanted with human multiple myeloma KMS-11 cells Anti -Asialo GM1 in Fox CB-17 / Icr-scidJcl mice (CLEA Japan) the day before cancer Antibody (about 10 mg protein / 1 mL vial) (Wako Pure Chemical Industries) was intraperitoneally administered at 0.3 mg / mouse. KMS-11 cells in RPMI1640 medium containing 10% fetal calf serum (FCS), 5% in a carbon dioxide incubator to culture grown at 37 ° C., subcutaneously, ventrally 1 × 10 7 cells per mouse Transplanted. Ten days after transplantation, the major axis and minor axis of the tumor grown subcutaneously with calipers were measured, and the tumor volume was determined according to the following formula.
Figure JPOXMLDOC01-appb-M000014
Figure JPOXMLDOC01-appb-M000014
　同時に各マウスの体重も測定し、平均腫瘍体積と平均体重が均一になるように1群5匹ずつ以下のような投与群に分け、この日を投与試験開始0日として投与を開始した。
　化合物19は5%糖液（大塚製薬社製）に1.25 mg/mLの濃度で溶解させ、投与開始0、7、14日目にそれぞれ1日1回、マウス体重1 gあたり0.01 mL（12.5 mg/kg）の用量で、尾静脈より静脈内投与した。 At the same time, the body weight of each mouse was also measured, and the mice were divided into the following administration groups with 5 mice per group so that the average tumor volume and the average body weight were uniform.
Compound 19 is dissolved in 5% sugar solution (manufactured by Otsuka Pharmaceutical Co., Ltd.) at a concentration of 1.25 mg / mL, and once a day on the 0th, 7th, and 14th days of administration, 0.01 mL (12.5 mg / g mouse body weight) / kg) was administered intravenously from the tail vein.
　メルファランは生理食塩水（大塚製薬社製）で0.3 mg/ mLの濃度で懸濁させ、投与開始0日目に1回、マウス体重1 gあたり0.01 mL（3 mg/kg）の用量で、尾静脈より静脈内投与した。
A. 陰性対照群（Control）：化合物19及びメルファラン非投与
B. 化合物19単独群：12.5 mg/kg（1日1回／0、7、14日目に投与）
C. メルファラン単独群：3 mg/kg（1日1回／0日目に投与）
D. 化合物19／メルファラン併用群：化合物19は12.5 mg/kg（1日1回／0、7、14日目に投与）、メルファランは3 mg/kg（1日1回／0日目に投与）
　0日目以降、週に2回腫瘍体積の測定を行った。抗腫瘍効果の判定は各群の腫瘍体積の平均値を算出し、0日目の腫瘍体積をV0としたときの腫瘍体積変化（V/V0）の比較で行った。経日測定した各群のV/V0を図2に示す。 Melphalan is suspended in physiological saline (manufactured by Otsuka Pharmaceutical Co., Ltd.) at a concentration of 0.3 mg / mL, and once at day 0 of administration, at a dose of 0.01 mL (3 mg / kg) per gram of mouse body weight, It was administered intravenously from the tail vein.
A. Negative control group (Control): Compound 19 and melphalan not administered
B. Compound 19 alone group: 12.5 mg / kg (once daily / administered on days 0, 7, 14)
C. Melphalan alone group: 3 mg / kg (once daily / on day 0)
D. Compound 19 / melphalan combination group: Compound 19 is 12.5 mg / kg (once a day / 0, administered on days 7 and 14), melphalan is 3 mg / kg (once a day / day 0) Administered)
From day 0, tumor volume was measured twice a week. The determination of the antitumor effect was performed by calculating the average value of the tumor volumes of each group and comparing the change in tumor volume (V / V0) when the tumor volume on day 0 was V0. FIG. 2 shows V / V0 of each group measured over time.
　図2に示したように、化合物19とメルファランとの併用投与は、化合物19単独あるいはメルファラン単独よりも高い増殖抑制効果を示した。
　17日目の各群のV/V0を陰性対照群のV/V0で除した値（T/C）を表6に示す。化合物19、メルファラン両化合物の薬効が単純に加算された時のT/Cの理論値、すなわち各化合物単独群のT/Cを掛け合わせた値と比べると、実際の併用群のT/C（表中のD）は、17日目において理論値である0.24よりも低い値（0.095）を示した。 As shown in FIG. 2, combined administration of compound 19 and melphalan showed a higher growth inhibitory effect than compound 19 alone or melphalan alone.
Table 6 shows values (T / C) obtained by dividing V / V0 of each group on day 17 by V / V0 of the negative control group. Compared to the theoretical value of T / C when the efficacy of both compound 19 and melphalan is simply added, that is, the value obtained by multiplying the T / C of each compound alone group, the T / C of the actual combination group (D in the table) showed a value (0.095) lower than the theoretical value of 0.24 on the 17th day.
Figure JPOXMLDOC01-appb-T000015
Figure JPOXMLDOC01-appb-T000015
　以上より、化合物19とメルファランの併用投与は、それぞれ単独投与より高い抗腫瘍効果を有し、相乗効果を示すことが明らかとなった。この結果から、化合物（I）とメルファランの併用投与は、それぞれの単独投与より高い抗腫瘍活性を有し、相乗効果を示すことが示唆された。

試験例4：ヒト胃癌SNU-16細胞移植マウスモデルにおける化合物19とCPT-11の併用による抗腫瘍効果
　癌細胞移植前日にFox C.B-17/Icr-scidJclマウス（日本クレア）に抗アシアロGM1抗体（約10 mg蛋白／1 mLバイアル）（和光純薬工業）を0.3 mg/マウスずつ腹腔内投与した。SNU-16細胞は、10%牛胎児血清（FCS）を含むRPMI1640培地中、5%炭酸ガスインキュベーター内で37 ℃にて培養し増殖させ、マウス1匹あたり0.5×107細胞にて腹側皮下に移植した。移植7日後にノギスにて皮下で増殖した腫瘍の長径、短径を測定し以下の式に従って腫瘍体積を求めた。 From the above, it has been clarified that the combined administration of Compound 19 and melphalan has a higher antitumor effect and a synergistic effect than the single administration. From these results, it was suggested that the combined administration of Compound (I) and melphalan has a higher antitumor activity than each single administration and shows a synergistic effect.

Test Example 4: Anti-tumor effect of combined use of compound 19 and CPT-11 in a mouse model transplanted with human gastric cancer SNU-16 cells Anti -Asialo GM1 antibody was administered to Fox CB-17 / Icr-scidJcl mice (Claire Japan) on the day before cancer cell transplantation ( About 10 mg protein / 1 mL vial) (Wako Pure Chemical Industries) was administered intraperitoneally at 0.3 mg / mouse. SNU-16 cells were cultured and grown in RPMI1640 medium containing 10% fetal calf serum (FCS) in a 5% carbon dioxide incubator at 37 ° C and ventral subcutaneously at 0.5 x 10 7 cells per mouse. Transplanted. Seven days after transplantation, the major axis and minor axis of the tumor grown subcutaneously with calipers were measured, and the tumor volume was determined according to the following formula.
Figure JPOXMLDOC01-appb-M000016
Figure JPOXMLDOC01-appb-M000016
　同時に各マウスの体重も測定し、平均腫瘍体積と平均体重が均一になるように1群5匹ずつ以下のような投与群に分け、この日を投与試験開始0日として投与を開始した。
　化合物19は5%糖液（大塚製薬社製）に1 mg/mLの濃度で溶解させ、投与開始0、7、14日目にそれぞれ1日1回、マウス体重1 gあたり0.01 mL（10 mg/kg）の用量で、尾静脈より静脈内投与した。 At the same time, the body weight of each mouse was also measured, and the mice were divided into the following administration groups with 5 mice per group so that the average tumor volume and the average body weight were uniform.
Compound 19 is dissolved in a 5% sugar solution (manufactured by Otsuka Pharmaceutical Co., Ltd.) at a concentration of 1 mg / mL, and once a day on days 0, 7, and 14 of administration, 0.01 mL (10 mg / kg) was administered intravenously from the tail vein.
　CPT-11は生理食塩水（大塚製薬社製）で1 mg/ mLの濃度で懸濁させ、投与開始0、7日目にそれぞれ1日1回、マウス体重1 gあたり0.01 mL（10 mg/kg）の用量で、尾静脈より静脈内投与した。
A. 陰性対照群（Control）：試験化合物及びCPT-11非投与
B. 化合物19単独群：10 mg/kg（1日1回／0、7、14日目に投与）
C. CPT-11単独群：10 mg/kg（1日1回／0、7日目に投与）
D. 試験化合物／CPT-11併用群：試験化合物は10 mg/kg（1日1回／0、7、14日目に投与）、CPT-11は10 mg/kg（1日1回／0、7日目に投与）
　0日目以降、週に2回腫瘍体積の測定を行った。抗腫瘍効果の判定は各群の腫瘍体積の平均値を算出し、0日目の腫瘍体積をV0としたときの腫瘍体積変化（V/V0）の比較で行った。経日測定した各群のV/V0を図3に示す。 CPT-11 was suspended in physiological saline (manufactured by Otsuka Pharmaceutical Co., Ltd.) at a concentration of 1 mg / mL, and once daily on the 0th and 7th day of administration, 0.01 mL (10 mg / mg kg) was administered intravenously from the tail vein.
A. Negative control group (Control): Test compound and CPT-11 non-administration
B. Compound 19 alone group: 10 mg / kg (once daily / administered on days 0, 7, 14)
C. CPT-11 alone group: 10 mg / kg (once a day / 0, administered on day 7)
D. Test compound / CPT-11 combination group: Test compound is 10 mg / kg (once a day / 0, administered on days 7 and 14), CPT-11 is 10 mg / kg (once a day / 0 On day 7)
From day 0, tumor volume was measured twice a week. The determination of the antitumor effect was performed by calculating the average value of the tumor volumes of each group and comparing the change in tumor volume (V / V0) when the tumor volume on day 0 was V0. FIG. 3 shows V / V0 of each group measured over time.
　図3に示したように、化合物19とCPT-11との併用投与は、化合物19単独あるいはCPT-11単独よりも高い増殖抑制効果を示した。
　32日目の各群のV/V0を陰性対照群のV/V0で除した値（T/C）を表7に示す。化合物19、CPT-11両化合物の薬効が単純に加算された時のT/Cの理論値、すなわち各化合物単独群のT/Cを掛け合わせた値と比べると、実際の併用群のT/C（表中のD）は、32日目において理論値である0.247よりも低い値（0.246）を示した。 As shown in FIG. 3, the combined administration of Compound 19 and CPT-11 showed a higher growth inhibitory effect than Compound 19 alone or CPT-11 alone.
Table 7 shows values (T / C) obtained by dividing V / V0 of each group on day 32 by V / V0 of the negative control group. Compared to the theoretical value of T / C when the efficacy of both compounds 19 and CPT-11 was simply added, that is, the value obtained by multiplying the T / C of each compound alone group, the T / C of the actual combination group C (D in the table) showed a value (0.246) lower than the theoretical value of 0.247 on the 32nd day.
Figure JPOXMLDOC01-appb-T000017
Figure JPOXMLDOC01-appb-T000017
　以上より、化合物19とCPT-11の併用投与は、それぞれ単独投与より高い抗腫瘍効果を有することが明らかとなった。この結果から化合物（I）とCPT-11の併用投与は、それぞれの単独投与より高い抗腫瘍活性を有することが示唆された。

試験例5：ヒト胃癌SNU-16細胞移植マウスモデルにおける化合物19とドセタキセルの併用による抗腫瘍効果
　癌細胞移植前日にFox C.B-17/Icr-scidJclマウス（日本クレア）に抗アシアロGM1抗体（約10 mg蛋白／1 mLバイアル）（和光純薬工業）を0.3 mg/マウスずつ腹腔内投与した。SNU-16細胞は、10%牛胎児血清（FCS）を含むRPMI1640培地中、5%炭酸ガスインキュベーター内で37 ℃にて培養し増殖させ、マウス1匹あたり0.5×107細胞にて腹側皮下に移植した。移植7日後にノギスにて皮下で増殖した腫瘍の長径、短径を測定し以下の式に従って腫瘍体積を求めた。 From the above, it was revealed that the combined administration of Compound 19 and CPT-11 has a higher antitumor effect than the single administration. From these results, it was suggested that the combined administration of Compound (I) and CPT-11 has higher antitumor activity than each single administration.

Test Example 5: Anti-tumor effect of combined use of compound 19 and docetaxel in a mouse model transplanted with human gastric cancer SNU-16 cells Anti -Asialo GM1 antibody (about 10) to Fox CB-17 / Icr-scidJcl mice (CLEA Japan) on the day before cancer cell transplantation mg protein / 1 mL vial) (Wako Pure Chemical Industries, Ltd.) was intraperitoneally administered at a dose of 0.3 mg / mouse. SNU-16 cells were cultured and grown in RPMI1640 medium containing 10% fetal calf serum (FCS) in a 5% carbon dioxide incubator at 37 ° C and ventral subcutaneously at 0.5 x 10 7 cells per mouse. Transplanted. Seven days after transplantation, the major axis and minor axis of the tumor grown subcutaneously with calipers were measured, and the tumor volume was determined according to the following formula.
Figure JPOXMLDOC01-appb-M000018
Figure JPOXMLDOC01-appb-M000018
　同時に各マウスの体重も測定し、平均腫瘍体積と平均体重が均一になるように1群5匹ずつ以下のような投与群に分け、この日を投与試験開始0日として投与を開始した。
　化合物19は5%糖液（大塚製薬社製）に1 mg/mLの濃度で溶解させ、投与開始0、7、14日目にそれぞれ1日1回、マウス体重1 gあたり0.01 mL（10 mg/kg）の用量で、尾静脈より静脈内投与した。 At the same time, the body weight of each mouse was also measured, and the mice were divided into the following administration groups with 5 mice per group so that the average tumor volume and the average body weight were uniform.
Compound 19 is dissolved in a 5% sugar solution (manufactured by Otsuka Pharmaceutical Co., Ltd.) at a concentration of 1 mg / mL, and once a day on days 0, 7, and 14 of administration, 0.01 mL (10 mg / kg) was administered intravenously from the tail vein.
　ドセタキセルは生理食塩水（大塚製薬社製）で0.2 mg/ mLの濃度で懸濁させ、投与開始0、7日目にそれぞれ1日1回、マウス体重1 gあたり0.01 mL（2 mg/kg）の用量で、尾静脈より静脈内投与した。
A. 陰性対照群（Control）：試験化合物及びドセタキセル非投与
B. 化合物19単独群：10 mg/kg（1日1回／0、7、14日目に投与）
C. ドセタキセル単独群：2 mg/kg（1日1回／0、7日目に投与）
D. 化合物19／ドセタキセル併用群：化合物19は10 mg/kg（1日1回／0、7、14日目に投与）、ドセタキセルは2 mg/kg（1日1回／0、7日目に投与）
　0日目以降、週に2回腫瘍体積の測定を行った。抗腫瘍効果の判定は各群の腫瘍体積の平均値を算出し、0日目の腫瘍体積をV0としたときの腫瘍体積変化（V/V0）の比較で行った。経日測定した各群のV/V0を図4に示す。 Docetaxel is suspended in physiological saline (manufactured by Otsuka Pharmaceutical Co., Ltd.) at a concentration of 0.2 mg / mL, and once a day on the 0th and 7th day of administration, 0.01 mL / g body weight of the mouse (2 mg / kg) Was administered intravenously from the tail vein.
A. Negative control group (Control): Test compound and docetaxel not administered
B. Compound 19 alone group: 10 mg / kg (once daily / administered on days 0, 7, 14)
C. Docetaxel alone group: 2 mg / kg (once a day / 0, administered on day 7)
D. Compound 19 / Docetaxel combination group: Compound 19 is 10 mg / kg (once daily / 0, 7 and 14 days), docetaxel is 2 mg / kg (once daily / 0, 7 days) Administered)
From day 0, tumor volume was measured twice a week. The determination of the antitumor effect was performed by calculating the average value of the tumor volumes of each group and comparing the change in tumor volume (V / V0) when the tumor volume on day 0 was V0. FIG. 4 shows V / V0 of each group measured over time.
　図4に示したように、化合物19とドセタキセルとの併用投与は、化合物19単独あるいはドセタキセル単独よりも高い増殖抑制効果を示した。
　28日目の各群のV/V0を陰性対照群のV/V0で除した値（T/C）を表8に示す。化合物19、ドセタキセル両化合物の薬効が単純に加算された時のT/Cの理論値、すなわち各化合物単独群のT/Cを掛け合わせた値と比べると、実際の併用群のT/C（表中のD）は、28日目において理論値である0.28よりも低い値（0.25）を示した。 As shown in FIG. 4, the combined administration of Compound 19 and docetaxel showed a higher growth inhibitory effect than Compound 19 alone or docetaxel alone.
Table 8 shows values (T / C) obtained by dividing V / V0 of each group on day 28 by V / V0 of the negative control group. Compared to the theoretical value of T / C when the efficacy of both compound 19 and docetaxel is simply added, that is, the value obtained by multiplying the T / C of each compound alone group, the T / C ( D) in the table showed a value (0.25) lower than the theoretical value of 0.28 on the 28th day.
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-T000019
　以上より、化合物19とドセタキセルの併用投与は、それぞれ単独投与より高い抗腫瘍効果を有することが明らかとなった。この結果から化合物（I）とドセタキセルの併用投与は、それぞれの単独投与より高い抗腫瘍活性を有することが示唆された。

　以下、実施例により本発明をより具体的に説明するが、本発明はこれらに限定されるものではない。 From the above, it was revealed that the combined administration of Compound 19 and docetaxel has a higher antitumor effect than the single administration. From these results, it was suggested that the combined administration of Compound (I) and docetaxel has higher antitumor activity than each single administration.

EXAMPLES Hereinafter, although an Example demonstrates this invention more concretely, this invention is not limited to these.
製剤例1（錠剤）
　常法により、次の組成からなる錠剤を調製する。
化合物1　　　　　　　　　 　5 mg
乳糖　　　　　　　　　　　 60 mg
馬鈴薯澱粉　　　　　　　　 30 mg
ポリビニルアルコール　　　　2 mg
ステアリン酸マグネシウム　　1 mg
タール色素　　　　　　　　　微量 Formulation Example 1 (tablet)
A tablet having the following composition is prepared by a conventional method.
Compound 1 5 mg
Lactose 60 mg
Potato starch 30 mg
Polyvinyl alcohol 2 mg
Magnesium stearate 1 mg
Tar pigment Trace amount
製剤例2（錠剤）
　常法により、次の組成からなる錠剤を調製する。
化合物10　　　　　　　　　  5 mg
バルプロ酸　　　　　　　　 10 mg
乳糖　　　　　　　　　　　 60 mg
馬鈴薯澱粉　　　　　　　　 30 mg
ポリビニルアルコール　　　　2 mg
ステアリン酸マグネシウム　　1 mg
タール色素　　　　　　　　　微量 Formulation Example 2 (tablet)
A tablet having the following composition is prepared by a conventional method.
Compound 10 5 mg
Valproic acid 10 mg
Lactose 60 mg
Potato starch 30 mg
Polyvinyl alcohol 2 mg
Magnesium stearate 1 mg
Tar pigment Trace amount
製剤例3（注射剤）
　常法により、次の組成からなる注射剤を調製する。
化合物19　　　　　　　　 　 2 mg
D-マンニトール　　　　　　 10 mg
塩酸水溶液　　　　　　　　　適量
水酸化ナトリウム水溶液　　　適量
注射用蒸留水　　　　　　　　適量 Formulation Example 3 (Injection)
An injection having the following composition is prepared by a conventional method.
Compound 19 2 mg
D-mannitol 10 mg
Hydrochloric acid aqueous solution Appropriate amount Sodium hydroxide aqueous solution Appropriate amount Distilled water for injection Appropriate amount
製剤例4（注射剤）
　常法により、次の組成からなる注射剤を調製する。
デキサメサゾン　　　　　　　2 mg
D-マンニトール　　　　　　 10 mg
塩酸水溶液　　　　　　　　　適量
水酸化ナトリウム水溶液　　　適量
注射用蒸留水　　　　　　　　適量 Formulation Example 4 (Injection)
An injection having the following composition is prepared by a conventional method.
Dexamethasone 2 mg
D-mannitol 10 mg
Hydrochloric acid aqueous solution Appropriate amount Sodium hydroxide aqueous solution Appropriate amount Distilled water for injection Appropriate amount
　本発明により、イソインドリノン誘導体またはその薬理学的に許容される塩からなる第1成分、ならびに化学療法剤、ホルモン療法剤及び分子標的薬から選ばれる第2成分を同時にまたは別々に投与するための抗癌剤等が提供される。 According to the present invention, a first component comprising an isoindolinone derivative or a pharmacologically acceptable salt thereof, and a second component selected from a chemotherapeutic agent, a hormonal therapeutic agent and a molecular target drug are administered simultaneously or separately. Anticancer agents and the like are provided.

Claims (16)

  1. 式（I）
    Figure JPOXMLDOC01-appb-C000001
     ｛式中、R1及びR2は同一または異なって水素原子、ハロゲン、置換もしくは非置換の低級アルキル、置換もしくは非置換のシクロアルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級アルキニル、置換もしくは非置換のアリール、置換もしくは非置換の複素環基または-OR4［式中、R4は水素原子、置換もしくは非置換の低級アルキルまたは-S(O)2R5（式中、R5はアミノ、モノもしくはジ(置換もしくは非置換の低級アルキル)アミノ、置換もしくは非置換の低級アルキル、置換もしくは非置換のアリールまたは置換もしくは非置換の複素環基を表す）を表す］を表し、
    R3はカルボキシまたは置換もしくは非置換の低級アルキルを表す｝で表されるイソインドリノン誘導体またはその薬理学的に許容される塩からなる第1成分、ならびに化学療法剤、ホルモン療法剤及び分子標的薬から選ばれる第2成分を有効成分とする、該第1成分と該第2成分を同時にまたは別々に投与するための抗癌剤。     Formula (I)
    Figure JPOXMLDOC01-appb-C000001
     {Wherein R 1 and R 2 are the same or different and each is a hydrogen atom, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl , Substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group or —OR 4 [wherein R 4 is a hydrogen atom, substituted or unsubstituted lower alkyl or —S (O) 2 R 5 (wherein R 5 represents amino, mono or di (substituted or unsubstituted lower alkyl) amino, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic group)] ,
    R 3 represents carboxy or a substituted or unsubstituted lower alkyl}, a first component consisting of an isoindolinone derivative represented by: or a pharmacologically acceptable salt thereof, and a chemotherapeutic agent, hormone therapeutic agent and molecular target An anticancer agent for administering the first component and the second component simultaneously or separately, comprising a second component selected from drugs as an active ingredient.
  2. R1が-OS(O)2R5（式中、R5は前記と同義である）である請求項1記載の抗癌剤。 2. The anticancer agent according to claim 1, wherein R 1 is —OS (O) 2 R 5 (wherein R 5 is as defined above).
  3. R1が-OS(O)2R5a（式中、R5aは置換もしくは非置換の低級アルキルを表す）である請求項1記載の抗癌剤。 2. The anticancer agent according to claim 1, wherein R 1 is —OS (O) 2 R 5a (wherein R 5a represents a substituted or unsubstituted lower alkyl).
  4. R2が置換もしくは非置換の低級アルコキシである請求項1～3のいずれかに記載の抗癌剤。 The anticancer agent according to any one of claims 1 to 3, wherein R 2 is substituted or unsubstituted lower alkoxy.
  5. R3が-CH2NR6R7（式中、R6及びR7は同一または異なって水素原子または置換もしくは非置換の低級アルキルを表すか、またはR6及びR7が隣接する窒素原子と一緒になって置換もしくは非置換の複素環基を形成する）である請求項1～4のいずれかに記載の抗癌剤。 R 3 is —CH 2 NR 6 R 7 (wherein R 6 and R 7 are the same or different and each represents a hydrogen atom or a substituted or unsubstituted lower alkyl, or R 6 and R 7 are adjacent to the adjacent nitrogen atom, 5. The anticancer agent according to any one of claims 1 to 4, which forms a substituted or unsubstituted heterocyclic group together.
  6. 第2成分が化学療法剤である請求項1～5のいずれかに記載の抗癌剤。 6. The anticancer agent according to claim 1, wherein the second component is a chemotherapeutic agent.
  7. 化学療法剤がチューブリン作用薬、デオキシリボ核酸作用薬及び代謝拮抗剤から選ばれる請求項6記載の抗癌剤。 7. The anticancer agent according to claim 6, wherein the chemotherapeutic agent is selected from a tubulin agonist, a deoxyribonucleic acid agonist and an antimetabolite.
  8. 第2成分がホルモン療法剤である請求項1～5のいずれかに記載の抗癌剤。 6. The anticancer agent according to claim 1, wherein the second component is a hormone therapy agent.
  9. ホルモン療法剤が抗アンドロゲン剤、抗エストロゲン剤、アンドロゲン製剤、エストロゲン製剤、LH-RH作動薬、プロゲスチン、アロマターゼ阻害剤及びステロイドサルファターゼ阻害剤から選ばれる請求項8記載の抗癌剤。 9. The anticancer agent according to claim 8, wherein the hormone therapy agent is selected from an anti-androgen agent, an anti-estrogen agent, an androgen preparation, an estrogen preparation, an LH-RH agonist, a progestin, an aromatase inhibitor, and a steroid sulfatase inhibitor.
  10. 第2成分が分子標的薬である請求項1～5のいずれかに記載の抗癌剤。 6. The anticancer agent according to claim 1, wherein the second component is a molecular target drug.
  11. 分子標的薬がキナーゼ阻害剤、キネシンEg5阻害剤、mTOR（mammalian target of rapamycin）阻害剤、プロテアソーム阻害剤、ヒストンデアセチラーゼ阻害剤、ヒートショック蛋白質90阻害剤及びファルネシルトランスフェラーゼ阻害剤から選ばれる請求項10記載の抗癌剤。 The claim wherein the molecular target drug is selected from a kinase inhibitor, a kinesin Eg5 inhibitor, an mTOR (mammalian target of rapamycin) inhibitor, a proteasome inhibitor, a histone deacetylase inhibitor, a heat shock protein 90 inhibitor and a farnesyl transferase inhibitor 10. The anticancer agent according to 10.
  12. 請求項1～5のいずれかに記載のイソインドリノン誘導体またはその薬理学的に許容される塩からなる第1成分、ならびに化学療法剤、ホルモン療法剤及び分子標的薬から選ばれる第2成分を含有する、医薬組成物。 A first component comprising the isoindolinone derivative according to any one of claims 1 to 5 or a pharmacologically acceptable salt thereof, and a second component selected from a chemotherapeutic agent, a hormonal therapeutic agent and a molecular target drug. A pharmaceutical composition comprising.
  13. 請求項1～5のいずれかに記載のイソインドリノン誘導体またはその薬理学的に許容される塩からなる第1成分、ならびに化学療法剤、ホルモン療法剤及び分子標的薬から選ばれる第2成分を有するキット。 A first component comprising the isoindolinone derivative according to any one of claims 1 to 5 or a pharmacologically acceptable salt thereof, and a second component selected from a chemotherapeutic agent, a hormonal therapeutic agent and a molecular target drug. Kit with.
  14. 癌の治療のための請求項13記載のキット。 14. A kit according to claim 13 for the treatment of cancer.
  15. 化学療法剤、ホルモン療法剤及び分子標的薬から選ばれる薬剤と同時にまたは別々に投与するための、請求項1～5のいずれかに記載のイソインドリノン誘導体またはその薬理学的に許容される塩。 The isoindolinone derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 5, for administration simultaneously or separately with a drug selected from a chemotherapeutic agent, a hormonal therapeutic agent and a molecular target drug .
  16. 請求項1～5のいずれかに記載のイソインドリノン誘導体またはその薬理学的に許容される塩からなる第1成分、ならびに化学療法剤、ホルモン療法剤及び分子標的薬から選ばれる第2成分を含有する抗癌剤。 A first component comprising the isoindolinone derivative according to any one of claims 1 to 5 or a pharmacologically acceptable salt thereof, and a second component selected from a chemotherapeutic agent, a hormonal therapeutic agent and a molecular target drug. Contains anticancer agent.
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