WO2010061907A1

WO2010061907A1 - Anti-cancer agent

Info

Publication number: WO2010061907A1
Application number: PCT/JP2009/070001
Authority: WO
Inventors: 譲阿部; 行正塩津
Original assignee: 協和発酵キリン株式会社
Priority date: 2008-11-28
Filing date: 2009-11-27
Publication date: 2010-06-03

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

Anticancer drug

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.

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).

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].

International Publication No. 2006/112479 Pamphlet International Publication No. 2008/047831 Pamphlet International Publication No. 2004/108672 Pamphlet International Publication No. 2004/021532 Pamphlet International Publication No. 2005/039564 Pamphlet International Publication No. 2005/051300 Pamphlet US Patent Application Publication No. 2005/0026976

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).
(1) Formula (I)

{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) 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) 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) 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) 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) 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.

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.

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). 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.

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.

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.

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).

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) 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) 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) 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) 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.

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.

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.

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.

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.
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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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 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.

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.
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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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 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.

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.

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.

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.

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.

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.

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

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

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

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

Claims

Formula (I)

{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. The anticancer agent according to claim 1, wherein R 1 is —OS (O) 2 R 5 (wherein R 5 is as defined above).
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).
The anticancer agent according to any one of claims 1 to 3, wherein R 2 is substituted or unsubstituted lower alkoxy.
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. The anticancer agent according to claim 1, wherein the second component is a chemotherapeutic agent.
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.
6. The anticancer agent according to claim 1, wherein the second component is a hormone therapy agent.
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.
6. The anticancer agent according to claim 1, wherein the second component is a molecular target drug.
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.
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.
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. A kit according to claim 13 for the treatment of cancer.
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 .
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.