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WO2017073706A1 - DÉRIVÉ DE DIHYDRONAPHTHO[2,3-b]BENZOFURANE - Google Patents

DÉRIVÉ DE DIHYDRONAPHTHO[2,3-b]BENZOFURANE Download PDF

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Publication number
WO2017073706A1
WO2017073706A1 PCT/JP2016/081988 JP2016081988W WO2017073706A1 WO 2017073706 A1 WO2017073706 A1 WO 2017073706A1 JP 2016081988 W JP2016081988 W JP 2016081988W WO 2017073706 A1 WO2017073706 A1 WO 2017073706A1
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compound
cancer
alkyl
pharmaceutically acceptable
acceptable salt
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Japanese (ja)
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正樹 富澤
広樹 西井
田中　浩
雅英 青木
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Chugai Pharmaceutical Co Ltd
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Chugai Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to novel dihydronaphtho [2,3-b] benzofuran derivatives and pharmaceuticals containing them as active ingredients.
  • molecular target drugs designed to elucidate the specific properties of cancer cells at the molecular level and to act efficiently on targets identified based on that knowledge. It is. Since the molecular target drug specifically acts on cancer cells, it is expected that a high therapeutic effect can be obtained with fewer side effects.
  • NSCLC non-small cell lung cancer
  • EGFR epidermal growth factor receptor
  • ALK anaplastic lymphoma kinase
  • Proteins encoded by the NTRK1, NTRK2, and NTRK3 genes, TRKA, TRKB, and TRKC, are receptor tyrosine kinases that have a binding domain with the ligand NGF (Nerve Growth Factor) family outside the cell and a kinase domain inside the cell. It is.
  • the NGF family of ligands consists of NGF, BDNF (Brain Derived Neurotrophic Factor), Neurotrophin-3 and Neurotrophin-4, which exist in the form of homodimers, but these homodimers are present in each receptor.
  • TRK Upon binding, TRK also dimerizes, thereby autophosphorylating many tyrosine residues in the intracellular domain and causing signal transduction into the cell.
  • Non-Patent Document 6 chromosomal translocation binds the intracellular kinase domain of NTRK1 to the amino terminal side of MRRIP or CD74 to form MPRIP-NTRK1 and CD74-NTRK1 fusion genes having active tyrosine kinase activity.
  • Non-Patent Document 6 In addition to NSCLC, in various cancer types such as colorectal cancer, breast cancer, thyroid cancer, glioblastoma, glioma, bile duct cancer, head and neck cancer, acute myeloid leukemia, Spitz tumor, Expression of a fusion gene of NTRK1, NTRK2 and NTRK3 has been reported (Non-patent Documents 7 and 8). Since the tyrosine kinase region of these fusion gene products is derived from TRKA, TRKB or TRKC, TRK kinase is considered to be involved in the development of NTRK fusion gene-positive cancer.
  • Non-Patent Documents 9 to 13 point mutations, partial deletions, splicing variants, and high expression of NTRK gene have been found in various cancer types, and their association with cancer has also been suggested (Non-Patent Documents 9 to 13). ).
  • KM12-Luc (cell number JCRB1389) is known as a human colon cancer cell line having a tropomyosin (TPM) -NTRK1 ⁇ ⁇ ⁇ fusion gene (Non-patent Document 6), and is used for screening of anticancer agents. ing.
  • Non-patent Documents 14- 19 Clinical trials of NGF antibodies and TRK inhibitors and non-clinical studies have revealed the involvement of TRK in osteoarthritis, rheumatoid arthritis, chronic low back pain, and cancer pain.
  • TRK functions also in inflammatory cells and immune cells such as mast cells, T cells, and B cells
  • inflammatory cells such as ulcerative colitis and allergic diseases
  • asthma and apito dermatitis have been reported (Non-patent Documents 16, 17 and 21 to 23).
  • TRK inhibitor can be created, it is expected that it can be used as a therapeutic drug for diseases such as epidemiologic and autoimmune diseases in addition to cancer.
  • Non-patent Document 24 a dihydronaphtho [2,3-b] benzofuran derivative (compound 2), which has a selective AXL inhibitory action and is effective in the treatment of kidney disease, to the academic society. ). The report states that the compound also exhibits TRKA, TRKB, TRKC inhibitory activity. The selective AXL inhibitory action of the compound has also been reported (Non-patent Document 25).
  • Patent Document 1 compounds described in WO2010 / 143664 (Patent Document 1) are known.
  • An object of the present invention is to provide a compound and a pharmaceutical composition applicable to prevention and treatment of NTRK fusion gene positive cancer (NSCLC and the like).
  • the dihydronaphtho [2,3-b] benzofuran derivative represented by (1) was found to be a compound having high antitumor activity, and the present invention was completed.
  • the present invention provides the following inventions.
  • R a is selected from a hydrogen atom and C 1-8 alkyl
  • R b represents a hydrogen atom, a halogen atom, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, formyl, (C 1-8 alkyl) carbonyl, hydroxy, C 1-8 alkoxy, (C 1 -8 alkyl) carbonyloxy, carboxy, (C 1-8 alkoxy) carbonyl, cyano, amino, nitro, carbamoyl, C 1-8 alkylthio, C 1-8 alkylsulfinyl, C 1-8 alkylsulfonyl and aminosulfonyl Is;
  • R c1 and R c2 each independently represent C 1-8 alkyl (wherein the C 1-8 alkyl may be substituted with one or more halogen atoms), C 2-8 alkenyl and C 2-8 Selected from alkynyl or, together with the carbon atom
  • R c1 and R c2 are C 1-8 alkyl (the C 1-8 alkyl may be substituted with one or more halogen atoms), C 2-8 alkenyl and C 2-8 alkynyl.
  • the compound represented by the formula (1) is N- (tert-butyl) -2-((6,6-dimethyl-8- (methylsulfonamido) -11-oxo-6,11-dihydronaphtho.
  • [2,3-b] benzofuran-3-yl) ethynyl) -6-methylisonicotinamide the compound according to any one of [1] to [7], a pharmaceutically acceptable salt thereof, or Their solvates.
  • a pharmaceutical composition comprising the compound according to any one of [1] to [8], a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.
  • a preventive or therapeutic agent for cancer comprising the compound according to any one of [1] to [8], a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.
  • the compound according to the present invention, a salt thereof, or a pharmaceutical composition containing them has an excellent TRK inhibitory action, and is extremely high in tumors against NTRK fusion gene-positive cancer in vivo compared with compound 2. Since it exhibits growth inhibitory activity, the present invention provides a novel preventive or therapeutic agent for cancer such as NSCLC.
  • crystallization (sample C) of the compound 23 taken at the 11th process of Example 3 is shown.
  • the horizontal axis is temperature (° C.), and the right vertical axis is the weight change (%) of the sample in thermogravimetric analysis.
  • the left vertical axis represents the heat flow observed in the differential thermal analysis.
  • crystallization (sample A) of the compound 23 obtained in Example 2 is shown.
  • the vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2 ⁇ (°).
  • Example B The result of the powder X-ray diffraction analysis of the hydrate crystal
  • the vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2 ⁇ (°).
  • crystallization (sample C) of the compound 23 taken at the 11th process of Example 3 is shown.
  • the vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2 ⁇ (°).
  • FIG. 2 shows the effect of administration of Compound 2 (dose: 50 mg / kg body weight) on tumor volume in an in vivo model in which KM12-Luc cells are transplanted.
  • FIG. The vertical axis represents the tumor volume (mm 3 ), and the horizontal axis represents the number of administration days.
  • the plot in a solvent group is shown as a control.
  • FIG. 2 shows the effect of administration of Compound 23 (dose: 1, 3, 10 and 30 mg / kg body weight) on tumor volume in an in vivo model in which KM12-Luc cells are transplanted.
  • the vertical axis represents the tumor volume (mm 3 ), and the horizontal axis represents the number of administration days.
  • the plot in a solvent group is shown as a control.
  • FIG. 6 shows the effect of administration of Compound 23a (dose: 0.3, 1, 3, 10 and 30 mg / kg body weight) on tumor volume in an in vivo model transplanted with KM12-Luc cells.
  • the vertical axis represents the tumor volume (mm 3 ), and the horizontal axis represents the number of administration days.
  • the plot in a solvent group is shown as a control.
  • halogen atom means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or the like.
  • halogen atom when the halogen atom is a substituent such as aryl (for example, R b in formula (1)), preferred halogen atoms include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • halogen atom when the halogen atom is a substituent such as alkyl (for example, the substituent when R c1 and R c2 in formula (I) are C 1-8 alkyl), a preferred halogen atom is a fluorine atom , Bromine atom and iodine atom.
  • C 1-8 alkyl having a halogen atom as a substituent include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2-chloroethyl, hepta Fluoropropyl, 3,3,3-trifluoropropyl, 2,3-dichloropropyl, 1-fluoro-3-bromopropyl, 4-bromobutyl, 3,3,3,4,4-pentafluorobutyl, 4,4 -Dichlorobutyl, 5-iodopentyl, 5,5-difluoropentyl, 6-chlorohexyl, 6,6,6-trifluorohexyl, 7-chloroheptyl, 7,7-dichloroheptyl, 7,7,7-tri Fluoroheptyl, 8-fluorooctyl, 8-chlorooo
  • C 1-8 alkyl is a linear or branched alkyl group having 1 to 8 carbon atoms. Specific examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, 1-methylpropyl, n-pentyl, isopentyl, 2-methylbutyl, 1,1 -Dimethylpropyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 2-ethylbutyl, n-heptyl, 5-methylhexyl, 1-propylbutyl, 2-ethyl-2-methylbutyl, n-octyl, 5- Examples include methylheptyl, 2,3-dimethylhexyl, 1-methyl-1-propylbutyl, 2,2-diethylbutyl and the like.
  • C 2-8 alkenyl is a linear or branched alkenyl group having 2 to 8 carbon atoms and having at least one double bond.
  • Specific examples include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3- Pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-1-butenyl, 1,1-dimethyl-2-propenyl, Examples include pentadienyl, 1-hexenyl, hexadienyl, heptenyl, heptadienyl, octenyl, octadienyl and the like.
  • C 2-8 alkynyl is a linear or branched alkenyl group having 2 to 8 carbon atoms and having at least one triple bond.
  • Specific examples include, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4- Pentynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 3-methyl-1-butynyl, 1,1-dimethyl-2-propynyl, 1-hexynyl, heptynyl, Examples include heptadiynyl, octynyl, octadiynyl and the like.
  • (C 1-8 alkyl) carbonyl means a (C 1-8 alkyl) -C (O) — group, where C 1-8 alkyl is as defined above.
  • Specific examples include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, i-propylcarbonyl, n-butylcarbonyl, i-butylcarbonyl, sec-butylcarbonyl, t-butylcarbonyl, 1-methylpropylcarbonyl, n-pentylcarbonyl.
  • C 1-8 alkoxy means a C 1-8 alkyl-O— group, wherein C 1-8 alkyl is as defined above.
  • Specific examples include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, t-butoxy, 1-methylpropoxy, n-pentyloxy, isopentyloxy, 2-methylbutoxy 1,1-dimethylpropoxy, 1-ethylpropoxy, n-hexyloxy, 4-methylpentyloxy, 2-ethylbutoxy, n-heptyloxy, 5-methylhexyloxy, 1-propylbutoxy, 2-ethyl-2 -Methylbutoxy, n-octyloxy, 5-methylheptyloxy, 2,3-dimethylhexyloxy, 1-methyl-1-propylbutoxy, 2,2-diethylbutoxy and the like.
  • (C 1-8 alkyl) carbonyloxy means a (C 1-8 alkyl) -C (O) —O— group, wherein C 1-8 alkyl is as defined above. is there. Specific examples include methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, i-propylcarbonyloxy, n-butylcarbonyloxy, i-butylcarbonyloxy, sec-butylcarbonyloxy, t-butylcarbonyloxy, 1- Methylpropylcarbonyloxy, n-pentylcarbonyloxy, isopentylcarbonyloxy, 2-methylbutylcarbonyloxy, 1,1-dimethylpropylcarbonyloxy, 1-ethylpropylcarbonyloxy, n-hexylcarbonyloxy, 4-methylpentylcarbonyl Oxy, 2-ethylbutylcarbonyloxy, n-
  • (C 1-8 alkoxy) carbonyl means a C 1-8 alkyl-O—C (O) — group, wherein C 1-8 alkyl is as already defined.
  • Specific examples include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl, i-butoxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl, 1-methylpropoxycarbonyl, n-pentyloxy.
  • Carbonyl isopentyloxycarbonyl, 2-methylbutoxycarbonyl, 1,1-dimethylpropoxycarbonyl, 1-ethylpropoxycarbonyl, hexyloxycarbonyl, 4-methylpentyloxycarbonyl, 2-ethylbutoxycarbonyl, n-heptyloxycarbonyl, 5-methylhexyloxycarbonyl, 1-propylbutoxycarbonyl, 2-ethyl-2-methylbutoxycarbonyl, n-octyloxycarbonyl, 5-methyl Le heptyloxycarbonyl, 2,3-dimethyl-hexyloxycarbonyl, 1-methyl-1-propyl-butoxycarbonyl, and 2,2-diethyl-butoxycarbonyl.
  • C 1-8 alkylthio means a C 1-8 alkyl-S— group, wherein C 1-8 alkyl is as defined above. Specific examples include methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, i-butylthio, sec-butylthio, t-butylthio, 1-methylpropylthio, n-pentylthio, isopentylthio, 2-methyl.
  • C 1-8 alkylsulfinyl means a C 1-8 alkyl-S (O) — group, wherein C 1-8 alkyl is as already defined.
  • Specific examples include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, i-propylsulfinyl, n-butylsulfinyl, i-butylsulfinyl, sec-butylsulfinyl, t-butylsulfinyl, 1-methylpropylsulfinyl, n-pentyl.
  • Sulfinyl isopentylsulfinyl, 2-methylbutylsulfinyl, 1,1-dimethylpropylsulfinyl, 1-ethylpropylsulfinyl, n-hexylsulfinyl, 4-methylpentylsulfinyl, 2-ethylbutylsulfinyl, n-heptylsulfinyl, 5- Methylhexylsulfinyl, 1-propylbutylsulfinyl, 2-ethyl-2-methylbutylsulfinyl, n-octylsulfinyl, 5-methylheptylsulfinyl , 2,3-dimethyl-hexyl-sulfinyl, 1-methyl-1-propyl-butylsulfinyl, and 2,2-diethyl-butylsulfinyl and the like.
  • C 1-8 alkylsulfonyl means a C 1-8 alkyl-S (O) 2 — group, wherein C 1-8 alkyl is as already defined.
  • Specific examples include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, i-propylsulfonyl, n-butylsulfonyl, i-butylsulfonyl, sec-butylsulfonyl, t-butylsulfonyl, 1-methylpropylsulfonyl, n-pentyl.
  • Sulfonyl isopentylsulfonyl, 2-methylbutylsulfonyl, 1,1-dimethylpropylsulfonyl, 1-ethylpropylsulfonyl, n-hexylsulfonyl, 4-methylpentylsulfonyl, 2-ethylbutylsulfonyl, n-heptylsulfonyl, 5- Methylhexylsulfonyl, 1-propylbutylsulfonyl, 2-ethyl-2-methylbutylsulfonyl, n-octylsulfonyl, 5-methylheptylsulfonyl, 2,3-dimethylhexylsulfonyl, 1-methyl -L-propyl-butyl-sulfonyl, such as 2,2-diethyl-butylsulfonyl and the like.
  • C 3-8 cycloalkyl is a monovalent group derived by removing any one hydrogen atom from a cyclic saturated aliphatic hydrocarbon having 3 to 8 carbon atoms. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. When two groups are combined to form C 3-8 cycloalkyl, the group is a divalent group.
  • cyclopropyl-1,1-diyl cyclobutyl-1,1-diyl, cyclopentyl-1,1-diyl, cyclohexyl-1,1-diyl, cycloheptyl-1,1-diyl, and cyclooctyl. -1,1-diyl.
  • “4 to 10-membered heterocycloalkyl” refers to a saturated heterocyclic group composed of 4 to 10 ring members containing 1 to 3 heteroatoms selected from O, S, and N. means.
  • the heterocycloalkyl may be monocyclic or bicyclic or spirocyclic heterocycloalkyl.
  • “4-10 membered heterocycloalkyl” includes “5-10 membered heterocycloalkyl”, “5-8 membered heterocycloalkyl”, “6-8 membered heterocycloalkyl”, “5-6 membered heterocycloalkyl”. Is included.
  • “4- to 10-membered heterocycloalkyl” include oxetanyl, azetidinyl, 3,7-dioxa-9-azabicyclo [3.3.1] nonanyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, tetrahydropyranyl , Tetrahydrofuranyl, 2-oxa-6-azaspiro [3.3] heptyl, 2-azaspiro [3.3] heptyl, 2,6-diazaspiro [3.3] heptyl, 2-thia-6-azaspiro [3.
  • heptyl oxazolidinyl, thiazolidinyl, imidazolidinyl, pyrazolidinyl, thianyl, oxanyl, thioxanyl and the like.
  • the group is a divalent group.
  • Specific examples include pyrrolidine-2,2-diyl, tetrahydropyran-3,3-diyl, 1,4-dioxane-2.2-diyl, piperidine-4,4-diyl, piperazine-2,2-diyl, Examples include morpholine-2,2-diyl and indoline-3,3-diyl.
  • C 6-10 aryl is an aromatic carbocyclic group having 6 to 10 carbon atoms. Specific examples include phenyl, 1-naphthyl, 2-naphthyl and the like.
  • C 6-10 arylsulfonyl means a C 6-10 aryl-S (O) 2 — group, wherein C 6-10 aryl is as defined above. Specific examples include phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl and the like.
  • R a , R b , R c1 , R c2 , and R d are as defined above, Hal represents a halogen atom, and P 1 represents methyl, ethyl, n-propyl, i-propyl, t-butyl.
  • P 2 and P 3 independently represent C 1 Represents a carboxy protecting group such as -6 alkyl.
  • the target product of that process is obtained by, for example, protecting and deprotecting a functional group.
  • protecting groups see for example T.W. W. Greene, P.M. G. M.M. Wuts, Protective Groups in Organic Synthesis, Fourth Edition, John Wiley & Sons, Inc. , New York (2007).
  • Some of the protection and deprotection of functional groups are also described in the following scheme.
  • Step 1 Compound b can be obtained by reacting compound a with a base and further reacting with R c1 -Hal and R c2 -Hal.
  • compound b in which R c1 and R c2 are the same group can be obtained by using one kind of halide.
  • the base examples include sodium hydride, potassium hydride, lithium bis (trimethylsilyl) amide (hereinafter also referred to as “LiHMDS”), sodium bis (trimethylsilyl) amide (hereinafter also referred to as “NaHMDS”), and the like. Preferably, it is NaHMDS.
  • reaction solvent examples include ether solvents such as tetrahydrofuran (hereinafter also referred to as “THF”) and diethyl ether; and chlorine solvents such as methylene chloride, preferably THF.
  • ether solvents such as tetrahydrofuran (hereinafter also referred to as “THF”) and diethyl ether
  • chlorine solvents such as methylene chloride, preferably THF.
  • the reaction temperature can be appropriately selected depending on the kind of the reaction solvent, and the like, but during the reaction of compound a and the base, for example, -20 ° C to 40 ° C, preferably -10 ° C to 30 ° C, and R c1
  • the reaction temperature is, for example, 0 ° C to 60 ° C, preferably 15 ° C to 35 ° C.
  • the reaction time can be appropriately selected depending on the reaction temperature and the like, but the reaction time between compound a and the base is, for example, 5 minutes to 3 hours, preferably 10 minutes to 1 hour, R c1 -Hal and / or R
  • the reaction time with c2 -Hal is, for example, 2 hours to 20 hours, preferably 5 hours to 15 hours.
  • a base may be added as appropriate, and R c1 -Hal and R c2 -Hal may be added as appropriate.
  • a C 3-8 cycloalkyl or 4-10 membered heterocycloalkyl (the C 3-8 cycloalkyl and 4-10 membered heterocycloalkyl are C 6
  • the compound b which is optionally substituted with -10 arylsulfonyl, and C 6-10 aryl in the C 6-10 arylsulfonyl may be substituted with C 1-8 alkyl) is R It can be prepared by using a dihalide corresponding to the formation of the ring structure instead of c1 -Hal and / or R c2 -Hal.
  • dihalide used for ring formation examples include 1,3-dichloropropane, 1,4-dichlorobutane, 1,5-dichloropentane, 1,3-dibromopropane, 1,4-dibromobutane, 1,5- Examples include dibromopentane, 1,3-diiodopropane, 1,4-diiodobutane, 1,5-diiodopentane, and the like.
  • step 1 For the implementation of step 1, see, for example, J. Org. Chem. 72 (25), 9541-9549 (2007).
  • Compound a can be purchased as a commercially available reagent (manufactured by Tokyo Chemical Industry Co., Ltd., catalog No. M1331).
  • Step 2 Compound c can be obtained by reacting compound b with a compound represented by CH 3 CO 2 P 3 in the presence of a base.
  • Examples of the base include LiHMDS, NaHMDS, potassium bis (trimethylsilyl) amide (hereinafter also referred to as “KHMDS”), lithium diisopropylamide (hereinafter also referred to as “LDA”), and lithium 2,2,6,6.
  • KHMDS potassium bis (trimethylsilyl) amide
  • LDA lithium diisopropylamide
  • 2,2,6,6 lithium 2,2,6,6.
  • -Metal hydrides such as tetramethylpyrrolidide, etc., and LiHMDS is preferred.
  • reaction solvent examples include ether solvents such as THF, diethyl ether, and dioxane, and preferably THF.
  • the reaction temperature is, for example, ⁇ 20 ° C. to 20 ° C., preferably ⁇ 10 ° C. to 10 ° C.
  • the reaction time is, for example, 5 minutes to 3 hours, preferably 10 minutes to 1 hour.
  • Step 3 Compound e can be obtained by reacting compound c and compound d in the presence of a base.
  • the base examples include inorganic bases such as sodium phosphate, potassium phosphate, sodium carbonate, potassium carbonate, and cesium carbonate, and preferably cesium carbonate.
  • reaction solvent examples include aprotic polar solvents such as dimethyl sulfoxide, dimethylformamide, dimethylacetamide, and 1-methyl-2-pyrrolidinone, and preferably 1-methyl-2-pyrrolidinone.
  • the reaction temperature is, for example, 30 ° C. to 200 ° C., preferably 50 ° C. to 150 ° C.
  • the reaction time is, for example, 10 hours to 30 hours, preferably 15 hours to 25 hours.
  • Step 4 Compound f can be obtained by subjecting compound e to a deprotection reaction.
  • the protecting group P 3 is preferably a group that can be removed under mild conditions that do not affect the protecting group P 1.
  • t-butyl that can be removed with an acid or a Lewis acid is preferred.
  • the acid include inorganic acids such as hydrochloric acid, organic acids such as trifluoroacetic acid, and Lewis acids include silyl halides such as trimethylsilyl chloride, with trimethylsilyl chloride being preferred.
  • the reaction solvent include alcohol solvents such as methanol, ethanol, isopropanol, ethylene glycol, fluoroethanol, and trifluoroethanol, and 2,2,2-trifluoroethanol is preferable.
  • the reaction temperature is, for example, ⁇ 10 ° C. to 60 ° C., preferably 0 ° C. to 30 ° C.
  • the reaction time is, for example, 30 minutes to 30 hours, preferably 1 to 2 hours.
  • the protecting group P 3 it is possible to select a protecting group other than t-butyl, and it is also possible to select an appropriate deprotection reaction according to the protecting group.
  • Step 5 Compound g can be obtained by subjecting compound f to a Friedel-Crafts reaction using an acid as a catalyst.
  • Examples of the acid include sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid, and trifluoromethanesulfonic acid is preferable.
  • sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid, and trifluoromethanesulfonic acid is preferable.
  • an acid anhydride such as acetic anhydride or trifluoroacetic anhydride
  • acetic anhydride or trifluoroacetic anhydride it is preferable to add an acid anhydride such as acetic anhydride or trifluoroacetic anhydride to the compound f to prepare a mixed acid anhydride to promote the reaction.
  • an acid may be added as appropriate, and an acid anhydride may be added as appropriate.
  • reaction solvent acetonitrile is preferable.
  • the reaction temperature is, for example, ⁇ 10 ° C. to 50 ° C., preferably ⁇ 5 ° C. to 30 ° C.
  • the reaction time is, for example, 5 minutes to 50 hours, preferably 10 minutes to 30 hours.
  • Step 6 Compound h can be obtained by deprotecting compound g with an acid.
  • the protecting group P 1 for the phenolic hydroxyl group it is necessary to select a group that cannot be removed even under the reaction conditions in Steps 1 to 5. For example, methyl that can be removed by an acid or a Lewis acid can be selected.
  • acids used for deprotection include inorganic acids such as hydrogen chloride, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid; formic acid, acetic acid, oxalic acid, maleic acid, fumaric acid, succinic acid, and malon.
  • inorganic acids such as hydrogen chloride, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid
  • formic acid acetic acid, oxalic acid, maleic acid, fumaric acid, succinic acid, and malon.
  • Carboxylic acids such as acid, citric acid, gluconic acid, mandelic acid, benzoic acid, salicylic acid, trifluoroacetic acid, tartaric acid, propionic acid, glutaric acid; methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, pyridinium p-toluene
  • sulfonic acids such as sulfonate
  • Lewis acids such as thionyl halide, boron tribromide, and trimethylsilyl iodide, and boron tribromide is preferable.
  • reaction solvent examples include halogen solvents such as methylene chloride, chloroform, and carbon tetrachloride, and methylene chloride is preferable.
  • the reaction temperature can be appropriately selected depending on the type of the reaction solvent, and is, for example, ⁇ 78 ° C. to 100 ° C., preferably ⁇ 5 ° C. to 50 ° C.
  • the reaction time can be appropriately selected depending on the reaction temperature and the like, and is, for example, 30 minutes to 150 hours, preferably 1 hour to 90 hours.
  • Step 7 Compound j can be obtained by reacting compound i with an amine represented by (H 3 C) 3 CNHR a in the presence of a base and a condensing agent.
  • Examples of the base include triethylamine, N-methylmorpholine, diisopropylethylamine, diazabicycloundecene (hereinafter, also referred to as “DBU”), and 1,4-diazabicyclo [2.2.2] octane (hereinafter, “ Tertiary amines such as “DABCO”).), Preferably triethylamine.
  • the condensing agent examples include N, N′-dicyclohexylcarbodiimide, benzotriazol-1-yloxy-trisdimethylaminophosphonium salt, and 1-propanephosphonic acid cyclic anhydride. Is preferred.
  • the reaction temperature is, for example, ⁇ 10 ° C. to 60 ° C., preferably 20 ° C. to 50 ° C.
  • the reaction time is, for example, 5 minutes to 24 hours, preferably 1 hour to 2 hours.
  • Compound i can be purchased as a commercially available general reagent (for example, catalog No. C2486 manufactured by Tokyo Chemical Industry Co., Ltd.).
  • Step 8 Compound k can be obtained by Sonogashira coupling between compound j and a compound represented by HC ⁇ C—Si (CH 3 ) 3 using a base, a palladium catalyst and a copper catalyst.
  • Examples of the base include tertiary amines such as triethylamine, N-methylmorpholine, diisopropylethylamine, DBU, and DABCO, with triethylamine being preferred.
  • tertiary amines such as triethylamine, N-methylmorpholine, diisopropylethylamine, DBU, and DABCO, with triethylamine being preferred.
  • the palladium catalyst a complex formed in the system by separately adding a palladium compound and a ligand can be used. Further, the complex prepared separately may be used as it is. Examples of the palladium catalyst that can be used in this step include [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex.
  • Examples of the copper catalyst include copper iodide, and copper (I) iodide is preferable.
  • reaction solvent examples include acetates such as methyl acetate, ethyl acetate, and t-butyl acetate, and ethyl acetate is preferable.
  • the reaction temperature is, for example, 5 ° C to 45 ° C, preferably 15 ° C to 35 ° C when the base is added.
  • the copper catalyst and the palladium catalyst for example, 20 ° C. to 90 ° C., preferably 20 ° C. to 70 ° C.
  • the reaction time is, for example, 5 minutes to 5 hours, preferably 30 minutes to 4 hours.
  • Step 9 Compound l can be obtained by deprotecting compound k with a fluoride salt and then performing Sonogashira coupling with compound h using a base and a palladium catalyst.
  • fluoride salt examples include sodium fluoride, potassium fluoride, and cesium fluoride, and cesium fluoride is preferable.
  • base examples include weakly basic inorganic salts such as sodium carbonate, potassium carbonate, and cesium carbonate, and cesium carbonate is preferable.
  • the palladium catalyst As the palladium catalyst, a complex formed in the system by separately adding a palladium compound and a ligand can be used. Further, the complex prepared separately may be used as it is. Examples of the palladium catalyst that can be used in this step include a complex formed of di- ⁇ -chlorobis [( ⁇ -allyl) palladium (II)] and tri-tert-butylphosphonium tetrafluoroborate. It is done.
  • reaction solvent examples include aprotic polar solvents such as dimethyl sulfoxide, dimethylformamide, dimethylacetamide, and 1-methyl-2-pyrrolidinone methylpyrrolidinone, and preferably 1-methyl-2-pyrrolidinone (methylpyrrolidinone).
  • the reaction temperature is, for example, 5 ° C. to 50 ° C., preferably 10 ° C. to 45 ° C. when the reagent and catalyst are added. After the addition of the reagent and the catalyst, for example, 40 ° C to 120 ° C, preferably 60 ° C to 100 ° C.
  • the reaction time is, for example, 15 minutes to 4 hours, preferably 30 minutes to 2 hours.
  • Deprotection and Sonogami coupling may be performed at the same time.
  • Step 10 Compound m can be obtained by adding a trifluoromethanesulfonylating agent to compound l in the presence of a base.
  • Examples of the base include organic amines such as pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine, DBU, and DABCO, with triethylamine being preferred.
  • organic amines such as pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine, DBU, and DABCO, with triethylamine being preferred.
  • trifluoromethanesulfonylating agent examples include trifluoromethanesulfonic anhydride, 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl) sulfonyl) methanesulfonamide, and the like. Is 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl) sulfonyl) methanesulfonamide.
  • reaction solvent examples include aprotic polar solvents such as dimethyl sulfoxide, dimethylformamide, dimethylacetamide, and N-methylpyrrolidone, with N-methylpyrrolidone being preferred.
  • aprotic polar solvents such as dimethyl sulfoxide, dimethylformamide, dimethylacetamide, and N-methylpyrrolidone, with N-methylpyrrolidone being preferred.
  • the reaction temperature can be appropriately selected depending on the type of reaction solvent, and is, for example, 0 ° C. to 70 ° C., preferably 10 ° C. to 45 ° C.
  • the reaction time can be appropriately selected depending on the reaction temperature and the like, and is, for example, 5 minutes to 6 hours, preferably 15 minutes to 4 hours.
  • Step 11 A compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is obtained by reacting a compound m and a sulfonamide represented by R d NHSO 2 CH 3 in the presence of a palladium catalyst and a base. Can do.
  • a complex formed in the system by separately adding a palladium compound and a ligand can be used. Further, the complex prepared separately may be used as it is.
  • the ligand include 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene, trimethylenebis (diphenylphosphine), 2- (di-tert-butylphosphino) biphenyl, and 2-dicyclohexylphosphino.
  • the palladium compound to be combined with the ligand for example, di- ⁇ -chlorobis [( ⁇ -allyl) palladium (II)], tetrakis (triphenylphosphine) palladium (0), or the like can be used.
  • Examples of the palladium catalyst that can be used in this step include tris (dibenzylideneacetone) dipalladium (0), 5,10,15,20-tetraphenyl-21H, 23H-porphinecobalt (II), palladium acetate (II ), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane adduct, dichlorobis (triphenylphosphine) palladium (II), palladium hydroxide, tetrakis (triphenylphosphine) palladium (0) And di- ⁇ -chlorobis [( ⁇ -allyl) palladium (II)].
  • Step 11 di- ⁇ -chlorobis [( ⁇ -allyl) palladium (II)] is used as a palladium compound, and 2- (di-tert-butylphosphino) -2 ′, 4 ′, 6′-triisopropyl- A complex formed using 1,1′-biphenyl as a ligand is preferably used as a catalyst.
  • the base examples include inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, trisodium phosphate, and tripotassium phosphate, and tripotassium phosphate is preferable.
  • reaction solvent examples include ether solvents such as diethyl ether, THF, dimethoxyethane, and dioxane, preferably THF.
  • the reaction temperature can be appropriately selected depending on the type of the reaction solvent, and is, for example, 0 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C.
  • the reaction time can be appropriately selected depending on the reaction temperature and the like, and is, for example, 1 minute to 2 hours, preferably 3 minutes to 1 hour.
  • ORGANIC LETTERS 13 (24), 6354-6357 (2011) can be referred to.
  • the compound represented by the formula (1) obtained in the step 11 can be obtained by contacting or reacting an acid or base that can be used for the production of a pharmaceutical product, so that the compound represented by the formula (1) is pharmaceutically acceptable.
  • Such salts include inorganic acid salts (hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc.), sulfonate (methanesulfonate, benzenesulfonate, etc.) , Toluenesulfonate, etc.), carboxylates (formate, acetate, oxalate, maleate, fumarate, citrate, malate, succinate, malonate, gluconate, Mandelate, benzoate, salicylate, fluoroacetate, trifluoroacetate, tartrate, propionate, glutarate, etc., alkali metal salts (lithium, sodium, potassium, cesium, rubidium) Salts), alkaline earth
  • the free form is suspended or dissolved in an alcohol such as methanol or ethanol, and a basic aqueous solution containing sodium ions such as sodium hydroxide is added to the sodium salt of the compound represented by formula (1) Can be obtained.
  • the reaction temperature is, for example, 0 ° C. to 50 ° C., preferably 10 ° C. to 40 ° C.
  • the reaction time is, for example, 1 minute to 1 hour, preferably 3 minutes to 10 minutes.
  • the compound represented by the formula (1) and a pharmaceutically acceptable salt thereof may be a solvate or a non-solvate.
  • the solvent contained in the solvate may be either water or an organic solvent.
  • alcohol eg, methanol, ethanol, n-propanol
  • dimethylformamide and the like can be used.
  • the compound represented by the formula (1) and a pharmaceutically acceptable salt thereof are preferably used in the form of a hydrate, and are also preferably used in the form of a non-solvate.
  • the ratio of the solvent molecule (preferably water molecule) to one molecule of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is, for example, 0.05 to 5, more preferably 0.1 to 3 preferable. A specific example of a preferable ratio is 1. Further, this ratio may vary depending on humidity, manufacturing method, manufacturing time, and the like.
  • Solvates of the compound represented by the formula (1) and pharmaceutically acceptable salts thereof for example, precipitate the compound represented by the formula (1) and pharmaceutically acceptable salts thereof from the solvent. It can be obtained by a conventional method. Hydrates can also be obtained by precipitating the compound represented by formula (1) and pharmaceutically acceptable salts thereof from a water-containing organic solvent.
  • the solvate of the compound represented by the formula (1) and a pharmaceutically acceptable salt thereof is obtained by a conventional method such as heating under reduced pressure, for example, the compound represented by the formula (1) and a pharmaceutically acceptable salt thereof. To an acceptable salt.
  • the compound used as a medicine As the compound used as a medicine, the compound itself (free form) represented by the formula (1), its sodium salt and free form hydrate are preferable, and the free form and its hydrate are more preferable.
  • the compound represented by the formula (1) or a salt thereof or a solvate thereof may be used in the form of crystals, or may be used in an amorphous state.
  • the present invention includes all stereoisomers (for example, enantiomers, diastereomers (including cis and trans geometric isomers)) of the compound represented by formula (1), racemates of the isomers, and other A mixture is included.
  • compounds of the present invention may have formula (1) having one or more asymmetric points, and the present invention includes racemic mixtures, diastereomeric mixtures, and enantiomers of such compounds. .
  • the present invention includes all isotopes of the compound represented by the formula (1).
  • the isotope of the compound of the present invention is one in which at least one atom is substituted with an atom having the same atomic number (number of protons) and a different mass number (sum of the number of protons and neutrons).
  • Examples of isotopes contained in the compounds of the present invention include a hydrogen atom, a carbon atom, a nitrogen atom, an oxygen atom, a phosphorus atom, a sulfur atom, a fluorine atom, a chlorine atom, and the like. 2 H, 3 H, 13 C respectively , 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, and the like.
  • radioactive isotopes such as 3 H and 14 C that decay by emitting radioactivity are useful in pharmaceutical tissue or compound tissue distribution tests and the like. Stable isotopes can be used safely because they do not decay, their abundances are almost unchanged, and there is no radioactivity.
  • the isotope of the compound of the present invention can be converted according to a conventional method by replacing the reagent used in the synthesis with a reagent containing the corresponding isotope.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof or a solvate thereof is administered as it is or in the form of a pharmaceutical composition to a patient in a pharmaceutically effective amount by an appropriate administration method. It can be used to treat cell proliferative diseases, especially cancer. Administration methods include oral administration, rectal administration, intravenous administration, intramuscular administration, subcutaneous administration, intracisternal administration, intravaginal administration, intraperitoneal administration, intravesical administration, and inhalation administration, and ointments, Any of topical administration such as gels and creams may be used.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof or a solvate thereof is used in the form of a pharmaceutical composition, it is usually used after being formulated into a certain preparation (dosage form).
  • a certain preparation include, for example, tablets, capsules, granules, powders, fine granules, pills, and aqueous or non-aqueous solutions and suspensions.
  • the above-mentioned compounds or salts can also be used in the form of various controlled-release preparations. Examples of such controlled-release preparations are those that are implanted in the body and those that are applied to the oral mucosa or nasal mucosa. Is mentioned.
  • the solution and suspension can be filled and stored in a container suitable for subdividing into individual doses.
  • the above-mentioned various preparations can be produced by a known method by mixing the compound or salt and a pharmaceutically acceptable additive.
  • additives include excipients, lubricants (coating agents), binders, disintegrants, stabilizers, flavoring agents, bases, dispersants, diluents, surfactants, and emulsifiers. Etc.
  • excipients examples include starch (starch, potato starch, corn starch, etc.), lactose, crystalline cellulose, and calcium hydrogen phosphate.
  • lubricant examples include ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, shellac, talc, carnauba wax, and paraffin.
  • binder examples include compounds similar to the above excipients, in addition to polyvinylpyrrolidone and macrogol.
  • disintegrant examples include chemical modified starches such as croscarmellose sodium, sodium carboxymethyl starch, and crosslinked polyvinylpyrrolidone, and celluloses, and the same compounds as the above excipients.
  • the stabilizer examples include paraoxybenzoates such as methylparaben and propylparaben; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid.
  • flavoring agents include commonly used sweeteners, acidulants, and fragrances.
  • Bases include, for example, fats such as lard, vegetable oils such as olive oil and sesame oil, higher alcohols such as stearyl alcohol and cetanol, animal oils, lanolinic acid, petrolatum, paraffin, bentonite, glycerin, and glycol oil .
  • dispersant examples include cellulose derivatives (such as gum arabic, tragacanth, and methylcellulose), stearic acid polyesters, sorbitan sesquioleate, aluminum monostearate, sodium alginate, polysorbates, and sorbitan fatty acid esters.
  • cellulose derivatives such as gum arabic, tragacanth, and methylcellulose
  • stearic acid polyesters such as stearic acid polyesters
  • sorbitan sesquioleate such as gum arabic, tragacanth, and methylcellulose
  • aluminum monostearate such as sodium alginate
  • polysorbates such as sodium alginate
  • sorbitan fatty acid esters examples include sorbitan fatty acid esters.
  • solvent or diluent in the liquid preparation examples include phenol, chlorocresol, purified water, and distilled water.
  • surfactant or emulsifier examples include polysorbate 80, polyoxyl 40 stearate, and lauromacrogol.
  • the content of the compound of the present invention or a pharmaceutically acceptable salt thereof or a solvate thereof in the preparation varies depending on the dosage form, but is generally 0.01 to 100% by weight.
  • the preparation may contain only one type of the compound of the present invention or a pharmaceutically acceptable salt thereof or a solvate thereof, or may contain two or more types.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof or a solvate thereof is used as a prophylactic agent for cancer
  • its dosage is the symptom severity, age, body weight, relative health condition, combination drug It can be determined appropriately according to the presence or absence, administration method, and the like.
  • the daily dose per kg body weight is, for example, 0.03 to 4 mg, preferably 0.07 to 1 mg, more preferably, in oral administration. 0.1-1 mg.
  • parenteral administration it is, for example, 0.07 to 9 mg, preferably 0.2 to 3 mg, more preferably 0.3 to 3 mg.
  • the above dose may be administered once per day to several weeks or divided into two or more per day.
  • the dosage is the severity of symptoms, age, body weight, relative health condition, combination drug It can be determined appropriately according to the presence or absence, administration method, and the like.
  • the dose per day per kg of body weight is, for example, 0.08 to 11 mg, preferably 0.2 to 3 mg, more preferably 0 for oral administration. .3 to 3 mg.
  • parenteral administration it is, for example, 0.2 to 28 mg, preferably 0.5 to 8 mg, more preferably 0.8 to 8 mg.
  • the above dose may be administered once per day to several weeks or divided into two or more per day.
  • the effective amount of the compound of formula (1) means a therapeutically effective amount or a prophylactically effective amount, and is appropriately determined according to the severity of symptoms, age, weight, relative health, presence or absence of concomitant drugs, administration method, and the like. be able to.
  • cancer includes leukemia (acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, etc.), malignant lymphoma (Hodgkin disease, non-Hodgkin lymphoma, etc.), multiple myeloma, bone marrow Blood and lymph cancers such as dysplasia syndrome, brain tumors, glioma, head and neck cancer (pharyngeal cancer, laryngeal cancer, tongue cancer, etc.), esophageal cancer, stomach cancer, colon cancer, Lung cancer (small cell cancer, non-small cell cancer, etc.), thyroid cancer, breast cancer, biliary tract cancer, pancreatic cancer, liver cancer, prostate cancer, ovarian cancer,
  • leukemia acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, etc.
  • malignant lymphoma Hodgkin disease, non-Hodgkin
  • These cancers include NTRK fusion gene-positive cancers.
  • the pharmaceutical composition of the present invention is particularly suitable for the treatment or prevention of non-small cell lung cancer, colon cancer, brain tumor, thyroid cancer and the like.
  • NTRK fusion gene positive cancer is preferable.
  • non-small cell lung cancer, colon cancer, thyroid cancer, and brain tumor are preferable.
  • Mass spectrometry was measured using a mass spectrometer, SQD (manufactured by Waters), 2020 (manufactured by Shimadzu), and 2010 EV (manufactured by Shimadzu).
  • SQD manufactured by Waters
  • 2020 manufactured by Shimadzu
  • 2010 EV manufactured by Shimadzu
  • Room temperature refers to a temperature in the range of 5-30 ° C.
  • Second step tert-butyl 4- (3-methoxyphenyl) -4-methyl-3-oxopentanoate (compound 13) Tetrahydrofuran of methyl 2- (3-methoxyphenyl) -2-methylpropanoate (compound 12, 2 g, 9.60 mmol) and lithium bis (trimethylsilyl) amide (1.3 M tetrahydrofuran solution) (18.47 mL, 24.01 mmol) To a (20 mL) solution, a solution of tert-butyl acetate (1.553 mL, 11.52 mmol) in tetrahydrofuran (2 mL) was added at 0 ° C. over 10 minutes.
  • Step 5 3-Bromo-8-methoxy-6,6-dimethylnaphtho [2,3-b] benzofuran-11 (6H) -one (Compound 16) 6-Bromo-2- (2- (3-methoxyphenyl) propan-2-yl) benzofuran-3-carboxylic acid (Compound 15, 20 mg, 0.051 mmol) and trifluoromethanesulfonic acid (9.09 ⁇ L, 0.103 mmol) ) In acetonitrile (400 ⁇ L) was added trifluoroacetic anhydride (14.51 ⁇ L, 0.103 mmol) at 0 ° C. After stirring for 30 minutes, the reaction mixture was warmed to 25 ° C.
  • Step 6 3-Bromo-8-hydroxy-6,6-dimethylnaphtho [2,3-b] benzofuran-11 (6H) -one (Compound 17)
  • methylene chloride 250 ⁇ L
  • Boron tribromide 1M methylene chloride solution, 0.27 mL, 0.27 mmol
  • Step 7 N- (tert-butyl) -2-chloro-6-methylisonicotinamide (Compound 19) To a suspension of 2-chloro-6-methylisonicotinic acid (compound 18, 5.00 g, 29.1 mmol) in ethyl acetate (25 mL) was added 2-amino-2-methylpropane (4.77 mL, 43.7 mmol). And triethylamine (8.12 mL, 58.3 mmol) was gradually added so that the internal temperature was 40 ° C. or lower.
  • N- (tert-butyl) -2-methyl-6-((trimethylsilyl) ethynyl) isonicotinamide (Compound 20)
  • N- (tert-butyl) -2-chloro-6-methylisonicotinamide (Compound 19, 1.000 g, 4.41 mmol) in ethyl acetate (6.00 mL) triethylamine (1.537 mL, 11.03 mmol) was added at 25 ° C.
  • the reaction mixture was heated to 80 ° C. over 20 minutes under a nitrogen atmosphere and stirred at 80 ° C. for 1 hour. After returning to room temperature, the reaction mixture was filtered through celite, and the celite was washed with methanol (9.8 mL). The obtained filtrate was combined with the washing solution and concentrated under reduced pressure. Acetic acid (1.122 mL, 19.60 mmol) and methanol (23 mL) were added to the resulting residue, and then water (37 mL) was slowly added dropwise. Filtered.
  • Step 10 3-((4- (tert-butylcarbamoyl) -6-methylpyridin-2-yl) ethynyl) -6,6-dimethyl-11-oxo-6,11-dihydronaphtho [trifluoromethanesulfonic acid [ 2,3-b] benzofuran-8-yl (Compound 22) N- (tert-butyl) -2-((8-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydronaphtho [2,3-b] benzofuran-3-yl) ethynyl) -6- To a solution of methylisonicotinamide (compound 21, 3.262 g, 6.62 mmol) and triethylamine (1.846 mL, 13.24 mmol) in N-methylpyrrolidone (26 mL), 1,1,1-trifluoro-N-phenyl -N-((trifluor
  • Step 11 N- (tert-butyl) -2-((6,6-dimethyl-8- (methylsulfonamido) -11-oxo-6,11-dihydronaphtho [2,3-b] benzofuran-3 -Yl) ethynyl) -6-methylisonicotinamide
  • the reaction mixture was bubbled with nitrogen gas for 30 seconds and then stirred at 60 ° C. for 15 minutes under a nitrogen atmosphere. After cooling the reaction mixture to room temperature, a metal scavenger SiliaMetS (registered trademark) DMT (manufactured by SiliCycle) (27.13 mg, 20 mol%) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, and the celite was washed successively with N-methylpyrrolidone (0.4 mL) and ethyl acetate.
  • SiliaMetS registered trademark
  • DMT manufactured by SiliCycle
  • the filtrate was combined with the washing solution and concentrated under reduced pressure, 50% aqueous acetic acid (0.2 mL) was added to the residue, water (0.2 mL) was further slowly added, and the precipitate was collected by filtration.
  • the obtained solid was dissolved in tetrahydrofuran (0.76 mL), n-heptane was added, and the precipitate was collected by filtration.
  • Step 12 Sodium (3-((4- (tert-butylcarbamoyl) -6-methylpyridin-2-yl) ethynyl) -6,6-dimethyl-11-oxo-6,11-dihydronaphtho [2, 3-b] benzofuran-8-yl) (methylsulfonyl) amide
  • compound 23a N- (tert-butyl) -2-((6,6-dimethyl-8- (methylsulfonamido) -11-oxo-6,11-dihydronaphtho [2,3-b] benzofuran-3-yl) ethynyl ) -6-methylisonicotinamide (Compound 23, 1014 mg, 1.780 mmol) in ethanol (1.78 mL) suspension was added 1M aqueous sodium hydroxide solution (1.78 mL, 1.780 mmol) at room temperature.
  • Example 2 N- (tert-butyl) -2-((6,6-dimethyl-8- (methylsulfonamido) -11-oxo-6,11-dihydronaphtho [2,3-b] benzofuran- Preparation of hydrate crystals of 3-yl) ethynyl) -6-methylisonicotinamide (Compound 23) N- (tert-butyl) -2-((6,6-dimethyl-8) obtained in Example 1 -(Methylsulfonamide) -11-oxo-6,11-dihydronaphtho [2,3-b] benzofuran-3-yl) ethynyl) -6-methylisonicotinamide (Compound 23, 51.8 mg) was added to DMSO ( 0.259 mL).
  • a solution of tert-butyl acetate (1.93 kg, 16.6 mol) in tetrahydrofuran (3.34 kg) was added and stirred at 10 ° C. for 2 hours.
  • 20% aqueous ammonium chloride solution (37.5 kg) was added and stirred, and then ethyl acetate (16.9 kg) and n-heptane (12.8 kg) were added.
  • Step 6 tert-butyl 2- (2- (3- (bis (methylsulfonyl) amino) phenyl) propan-2-yl) -6-iodo-1-benzofuran-3-carboxylate
  • Compound 36 Tert-butyl 2- (2- (3-aminophenyl) propan-2-yl) -6-iodobenzofuran-3-carboxylate (compound 35, 5.44 kg, 11.4 mol) and diisopropylethylamine (5.89 kg, To a solution of 45.6 mol) in acetonitrile (21.4 kg), methanesulfonyl chloride (3.00 kg, 26.2 mol) was added at 5 ° C.
  • Part 2 2- (2- (3- (bis (methylsulfonyl) amino) phenyl) propan-2-yl) -6-iodo-1-benzofuran-3-carboxylic acid tert-butyl (compound 36, 7.22 kg, 11. 4 mol) was dissolved in ethyl acetate (15.6 kg), formic acid (44.1 kg) was added, and the mixture was stirred at 50 ° C. for 2 hours. Seed crystals (0.72 g) were added to the reaction mixture, and the mixture was further stirred at 50 ° C. for 4 hours. The precipitated solid was collected by filtration and washed with water (36.1 kg).
  • N- (tert-butyl) -2-methyl-6-((trimethylsilyl) ethynyl) isonicotinamide (compound 20) (part 2)
  • N- (tert-butyl) -2-chloro-6-methylisonicotinamide (Compound 19, 10 g, 44.1 mmol) in cyclopentyl methyl ether (75 mL) was added triethylamine (15.37 mL, 110 mmol) at 25 ° C. added.
  • the activated carbon was removed by filtration and washed with cyclopentyl methyl ether (15 mL). After separating the aqueous layer, the organic layer was washed with a 10% aqueous sodium chloride solution (50 mL). Heptane (90 mL) was added to the organic layer at 50 ° C. Further, seed crystals (10 mg) and heptane (180 mL) were added, and the mixture was stirred at 25 ° C. for 5 hours and further at 0 ° C. for 1 hour.
  • Step 10 N- (tert-butyl) -2-((6,6-dimethyl-8- (methylsulfonamido) -11-oxo-6,11-dihydronaphtho [2,3-b] benzofuran-3 -Il ) ethynyl) -6-methylisonicotinamide (Compound 23) hydrate crystals N- (3-iodo-6,6-dimethyl-11-oxo-6,11-dihydronaphtho [2,3-b ] To a solution of benzofuran-8-yl) -N- (methylsulfonyl) methanesulfonamide (Compound 38, 1.10 kg, 1.97 mol) in 1-methyl-2-pyrrolidinone (3.3 L) was added 5M water under a nitrogen atmosphere.
  • benzofuran-8-yl) -N- (methylsulfonyl) methanesulfonamide Compound 38, 1.10 kg, 1.97
  • Aqueous sodium oxide (0.98 L, 4.92 mmol) was added at 25 ° C. After stirring for 30 minutes, the reaction mixture was charged with N- (tert-butyl) -2-methyl-6-((trimethylsilyl) ethynyl) isonicotinamide (Compound 20, 681 g, 2.36 mol), bis (triphenylphosphine) palladium.
  • (II) Dichloride (4.14 g, 5.90 mol) and copper (I) iodide (1.12 g, 5.90 mmol) were added. 25% aqueous ammonia (1.06 L) was added to the reaction mixture at 29-40 ° C., and the mixture was stirred at 40 ° C. for 2 hr.
  • Step 11 N- (tert-butyl) -2-((6,6-dimethyl-8- (methylsulfonamido) -11-oxo-6,11-dihydronaphtho [2,3-b] benzofuran-3 Purification of hydrate crystals of -yl) ethynyl) -6-methylisonicotinamide (Compound 23) N- (tert-butyl) -2-((6,6-dimethyl-8- ( Methylsulfonamide) -11-oxo-6,11-dihydronaphtho [2,3-b] benzofuran-3-yl) ethynyl) -6-methylisonicotinamide (Compound 23) hydrate crystals (500 g, 0 .809 mol) was dissolved in dimethyl sulfoxide (1.38 L) and acetone (4.15 L) at 25 ° C.
  • Example 4 Thermogravimetric / Differential Thermal Analysis of Compound 23 Hydrate Crystal
  • the compound 23 crystal (sample C) taken in Step 11 of Example 3 was subjected to thermogravimetric / differential measurement by the following measurement method. Subjected to thermal analysis. The results are shown in FIG. Compound 23 did not melt at around 130 ° C., melted at around 180 ° C., crystallized at around 215 ° C., and melted (decomposed) at 300 ° C. or higher.
  • Measuring device EXSTAR TG / DTA6200R (Seiko Instruments (current name: Hitachi High-Tech Science)) Measurement range: 30-350 ° C Temperature increase rate: 10 ° C / min Atmosphere: nitrogen
  • Example 5 Measurement of moisture contained in hydrate crystal of compound 23
  • the water content contained in the hydrate crystal (sample C) of compound 23 taken in the eleventh step of Example 3 was determined by coulometric titration. Measured by a Karl Fischer moisture measuring device (CA200 manufactured by Mitsubishi Chemical Analytech). The result was 3.1%.
  • Example 4 From the results of Example 4 and Example 5, it was confirmed that the water contained in the sample C was mainly crystal water, and the sample C was almost monohydrate.
  • Example 6 Powder X-Ray Diffraction of Compound 23 Hydrate Crystal Compound 23 hydrate crystal obtained in Example 2 (Sample A), Compound 23 taken in Step 10 of Example 3
  • the hydrate crystal (sample B) and the hydrate crystal (sample C) of compound 23 taken in the eleventh step of Example 3 were each subjected to powder X-ray diffraction analysis by the following measurement method. .
  • the results are shown in FIGS. 2-1 to 2-3.
  • Measuring device D8 Discover with GADDS CS diffractometer (manufactured by Bruker AXS) Counter cathode: Cu Tube voltage: 40 kV Tube current: 40 mA Scanning range: 5 to 25.3 ° Sampling width: 0.02 °
  • Samples A, B, and C showed the same diffraction pattern, Samples A and B were the same as Sample C, N- (tert-butyl) -2-((6,6-dimethyl-8- ( Methylsulfonamide) -11-oxo-6,11-dihydronaphtho [2,3-b] benzofuran-3-yl) ethynyl) -6-methylisonicotinamide (Compound 23) confirmed.
  • the water content in the hydrate crystals of compound 23 varies depending on the preparation method, storage method, and the like.
  • Example 7 Preparation of monohydrate crystal of compound 23 and preparation of single crystal X-ray structural analysis single crystal: N- (tert-butyl) -2-((6,6-dimethyl-8- (methylsulfonamido) -11-oxo-6,11-dihydronaphtho [2, obtained in Step 11 of Example 1 3-b] benzofuran-3-yl) ethynyl) -6-methylisonicotinamide (Compound 23, 48.3 mg) was dissolved in DMSO (0.469 mL) and 2M hydrochloric acid (0.051 mL) at 70 ° C. 0.03 mL of this lysate was lyophilized at ⁇ 20 ° C.
  • Measuring device Rigaku R-AXIS RAPID II with a VariMax Cu diffractometer (manufactured by Rigaku)
  • Counter cathode Cu Tube voltage: 40 kV Tube current: 30 mA Measurement temperature: -180 ° C
  • Structural analysis The structure was determined by the direct method, and the structure was refined by the least square method. All non-hydrogen atoms were refined with anisotropic temperature factors, and all hydrogen atoms were geometrically arranged.
  • Human colorectal cancer line KM12-Luc (obtained from JCRB cell bank, catalog No. JCRB1389) is a medium in which Dulbecco's modified Eagle medium is supplemented with 10% fetal calf serum and 1 mM sodium pyruvate so as to be 5000 cells / 95 ⁇ L. A cell suspension was prepared.
  • Tumor growth inhibitory activity in an in vivo model transplanted with KM12-Luc cells A cell suspension of human colorectal cancer strain KM12-Luc was prepared in Hanks' solution, and 6.0 ⁇ 10 6 cells were obtained from female nude mice Transplanted subcutaneously in the neck. When the tumor volume reached about 200 mm 3 , a test compound dissolved in 10% DMSO / 10% Cremophor EL / 15% PEG400 / 15% HPCD at a concentration according to the dose was once a day for 10 days. Orally at 20 mL / kg.
  • the tumor volume was calculated by a formula of 0.5 ⁇ minor axis 2 ⁇ major axis, and the tumor growth inhibition rate was calculated from the ratio of tumor growth of the test compound administration group to the tumor growth of the solvent group (1-test compound administration)
  • the tumor growth amount of the group / tumor growth amount of the solvent group) ⁇ 100 (%) was calculated.
  • the results of this study are shown in FIGS. 4-1 to 4-3, and the dose in this study and the tumor growth inhibition rate on the day after the last administration are shown in Table 2.

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Abstract

La présente invention concerne un dérivé de dihydronaphtho [2,3-b]benzofurane représenté par la formule (1) et pouvant être utilisé dans la prévention et le traitement des cancers du gène de fusion NTRK (tel que le cancer du poumon non à petites cellules), un sel pharmacologiquement acceptable de celui-ci, des solvates de ceux-ci, et une composition pharmaceutique contenant ceux-ci en tant que principe actif.
PCT/JP2016/081988 2015-10-30 2016-10-28 DÉRIVÉ DE DIHYDRONAPHTHO[2,3-b]BENZOFURANE Ceased WO2017073706A1 (fr)

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WO2020050241A1 (fr) * 2018-09-04 2020-03-12 中外製薬株式会社 Procédé de production de composé tétracyclique
CN112585126A (zh) * 2018-09-04 2021-03-30 中外制药株式会社 四环化合物的制备方法
JPWO2020050241A1 (ja) * 2018-09-04 2021-08-30 中外製薬株式会社 ４環性化合物の製造方法
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CN115340523A (zh) * 2021-05-12 2022-11-15 盛世泰科生物医药技术(苏州)有限公司 一种具有alk抑制活性的化合物及其制备方法和用途
WO2022237813A1 (fr) * 2021-05-12 2022-11-17 盛世泰科生物医药技术(苏州)有限公司 Composé ayant une activité inhibitrice d'alk, son procédé de préparation et son utilisation
CN115340523B (zh) * 2021-05-12 2023-12-15 盛世泰科生物医药技术(苏州)股份有限公司 一种具有alk抑制活性的化合物及其制备方法和用途
JP2024518783A (ja) * 2021-05-12 2024-05-02 シージーンテック （スーチョウ， チャイナ） カンパニー リミテッド Ａｌｋ阻害活性を有する化合物及びその製造方法と用途
JP7752700B2 (ja) 2021-05-12 2025-10-10 シージーンテック （スーチョウ， チャイナ） カンパニー リミテッド Ａｌｋ阻害活性を有する化合物及びその製造方法と用途

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