WO2023149549A1 - Novel pharmaceutical composition - Google Patents

Novel pharmaceutical composition Download PDF

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Publication number
WO2023149549A1
WO2023149549A1 PCT/JP2023/003581 JP2023003581W WO2023149549A1 WO 2023149549 A1 WO2023149549 A1 WO 2023149549A1 JP 2023003581 W JP2023003581 W JP 2023003581W WO 2023149549 A1 WO2023149549 A1 WO 2023149549A1
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Prior art keywords
carbon atoms
pharmaceutical composition
cancer
compound
hydroxy
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PCT/JP2023/003581
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French (fr)
Japanese (ja)
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スレス アワレ
尚樹 豊岡
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国立大学法人富山大学
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Publication of WO2023149549A1 publication Critical patent/WO2023149549A1/en

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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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/80—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/83—Oxygen atoms

Definitions

  • the present invention relates to novel pharmaceutical compositions, particularly novel anticancer pharmaceutical compositions, and novel compounds used in the pharmaceutical compositions.
  • pancreatic (pancreatic) cancer has the lowest 5-year survival rate among all solid cancers, and is a cancer with an extremely poor prognosis.
  • Surgery is the most effective treatment for pancreatic cancer, but chemotherapeutic agents play a major role before and after surgery.
  • chemotherapeutic agents play a major role before and after surgery.
  • Non-Patent Document 1 FOLFIRINOX, which is used in combination with fluouracil, oxaliplatin, irinotecan, etc., and TS-1, which is an oral drug, is also used, although it is only applicable in Japan.
  • drug delivery systems such as nab-paclitaxel and onivyde, which aim to reduce side effects, are also utilized as liposome formulations (Non-Patent Document 4).
  • a chemotherapeutic agent for pancreatic cancer with sufficient therapeutic effect has not been obtained.
  • anticancer agents have a problem of side effects, and anticancer agents with less side effects are desired.
  • an object of the present invention is to provide a novel pharmaceutical composition, particularly a novel anticancer pharmaceutical composition, and a novel compound used in the pharmaceutical composition.
  • the technology of the present invention is a proposal for a novel anticancer pharmaceutical composition, etc., which has a mechanism of action different from that of existing anticancer agents for pancreatic cancer, and serious side effects unique to anticancer agents are hardly confirmed.
  • the present invention provides an epoch-making drug that exerts its effects when used alone or in combination with existing anticancer drugs.
  • the present invention is not only able to add a new piece to multidrug anticancer drugs, but is also thought to greatly improve the occurrence of side effects in single use.
  • a drug that is effective against pancreatic cancer that is resistant to Gemcitabine the first-choice drug for pancreatic cancer.
  • R 1 represents a hydrocarbon group having 1 to 20 carbon atoms which may have a substituent
  • R 2 to R 5 each independently represent hydrogen, a hydrocarbon group having 1 to 4 carbon atoms, an electron-donating group or an electron-withdrawing group
  • R 2 to R 5 combine with adjacent groups to form a ring
  • R 6 to R 10 are each independently hydrogen, hydroxy, halogen, alkoxy having 1 to 20 carbon atoms, alkoxy having 1 to 4 carbon atoms substituted with alkylamino having 1 to 4 carbon atoms, or 1 to 4 carbon atoms.
  • R 6 to R 10 may combine with adjacent groups to form a ring.
  • R 8 is hydroxy, hydrogen, alkoxy having 1 to 20 carbon atoms, or alkoxy having 1 to 4 carbon atoms substituted with alkylamino having 1 to 4 carbon atoms [1] to [3]
  • the electron-withdrawing group is halogen, halogenated alkyl having 1 to 4 carbon atoms, carboxylic acid ester having 1 to 10 carbon atoms, acyl having 1 to 4 carbon atoms, cyano (—CN), nitro (—NO 2 ), C 1-4 alkylthio (-SR; R represents alkyl), C 1-4 alkylsulfinyl (-SOR; R represents alkyl), or C 1-4 alkylsulfonyl (- SO 2 R; R represents alkyl); or aryl or heteroaryl having these electron-withdrawing groups as substituents.
  • [6] The pharmaceutical composition according to any one of [1] to [5], wherein the electron-donating group is hydroxy, alkoxy having 1 to 4 carbon atoms, or amino.
  • [8] The pharmaceutical composition according to any one of [1] to [7], which is for anticancer use.
  • the pharmaceutical composition of [8], wherein the cancer is pancreatic cancer.
  • composition of [11] The pharmaceutical composition according to any one of [1] to [10], which is for suppressing the development of cancer stem cells or for killing cancer stem cells.
  • Any one of [1] to [12] for use in combination with an anticancer compound other than the compound represented by formula (I) or a pharmacologically acceptable salt thereof The pharmaceutical composition according to .
  • R 1 ' represents an optionally substituted hydrocarbon group having 1 to 20 carbon atoms
  • R 2 ' to R 5 ' each independently represents hydrogen, a hydrocarbon group having 1 to 4 carbon atoms, an electron donating group or an electron withdrawing group
  • R 2 ' to R 5 ' are adjacent groups may be combined to form a ring
  • R 6 ' and R 10 ' are each independently hydrogen, hydroxy, halogen, alkoxy having 1 to 20 carbon atoms, alkoxy having 1 to 4 carbon atoms substituted with alkylamino having 1 to 4 carbon atoms, or alkoxy having 1 to 4 carbon atoms.
  • R 7 ' and R 9 ' each independently represent halogen or alkylsulfonyl having 1 to 4 carbon atoms
  • R 8 ' represents hydroxy, hydrogen, alkoxy having 1 to 20 carbon atoms, or alkoxy having 1 to 4 carbon atoms substituted with alkylamino having 1 to 4 carbon atoms
  • R 1 ' is C4 alkyl
  • at least one of R 2 '-R 5 ' is other than hydrogen.
  • the electron withdrawing group is halogen, halogenated alkyl having 1 to 4 carbon atoms, carboxylic acid ester having 1 to 10 carbon atoms, acyl having 1 to 4 carbon atoms, cyano (-CN), nitro (-NO 2 ), C 1-4 alkylthio (-SR; R represents alkyl), C 1-4 alkylsulfinyl (-SOR; R represents alkyl), or C 1-4 alkylsulfonyl (- SO 2 R; R represents alkyl); or aryl or heteroaryl having these electron-withdrawing groups as substituents, the compound according to [16].
  • [18] The compound of [16] or [17], wherein the electron-donating group is hydroxy, alkoxy having 1 to 4 carbon atoms, or amino.
  • An anticancer compound of any one of [16] to [18] or a pharmacologically acceptable salt thereof that suppresses the development of cancer stem cells or kills cancer stem cells Use as an agent.
  • a method for treating or preventing cancer which comprises administering the compound represented by the above formula (I) or a pharmacologically acceptable salt thereof to a subject.
  • the present invention provides novel pharmaceutical compositions, particularly novel anticancer pharmaceutical compositions, and novel compounds used in the pharmaceutical compositions.
  • FIG. 1 is a diagram (drawing-substituting photograph) showing the evaluation results of the in vitro inhibitory activity against PANC-1 of the benzoylbenzofuran derivative T-38.
  • A is an image observed by a live cell imaging device (control, T-38 treatment from the left in each figure).
  • B is an image observed with a microscope (each column is an AO-stained image, an EB-stained image, a phase-contrast image, and a merged image from the left).
  • FIG. 2 is a diagram (drawing-substituting photograph) showing evaluation results of the metastasis inhibitory activity against PANC-1 of the benzoylbenzofuran derivative T-38.
  • A is an image observed under a microscope (from left to right: control, T-38 5 ⁇ M treatment, T-38 40 ⁇ M treatment). The upper row is the image at the start, and the lower row is the image 24 hours after the start.
  • B is a graph showing the open area at each time.
  • Figure 3 shows the evaluation results of the in vivo antitumor effect of the benzoylbenzofuran derivative T-38 (*: P ⁇ 0.05, ** ⁇ 0.01, *** ⁇ 0.001, **** ⁇ 0.0001, Anova -test).
  • A is a graph showing the tumor size of each group.
  • B is a graph showing the tumor weight of each group.
  • C is a graph showing the body weight of each group.
  • FIG. 4 is a diagram (drawing-substituting photograph) showing the evaluation results of the in vivo antitumor effect of the benzoylbenzofuran derivative T-38 (excised tumor image).
  • Figure 5 shows the results of evaluating the in vivo antitumor effect of the benzoylbenzofuran derivative T-79 (*: P ⁇ 0.05, ** ⁇ 0.01, *** ⁇ 0.001, **** ⁇ 0.0001, Anova -test).
  • A is a graph showing the tumor size of each group.
  • B is a graph showing the tumor weight of each group.
  • C is a graph showing the body weight of each group.
  • FIG. 6 is a diagram (drawing-substituting photograph) showing the evaluation results of the in vivo antitumor effect of the benzoylbenzofuran derivative T-79 (excised tumor image).
  • Figure 7 shows the results of evaluating the in vivo antitumor effect of the benzoylbenzofuran derivative T-38 (*: P ⁇ 0.05, ** ⁇ 0.01, *** ⁇ 0.001, **** ⁇ 0.0001, Anova -test).
  • A is a graph showing the tumor size of each group.
  • B is a graph showing the tumor weight of each group.
  • C is a graph showing the body weight of each group.
  • FIG. 8 is a diagram (drawing-substituting photograph) showing the evaluation results of the in vivo antitumor effect of the benzoylbenzofuran derivative T-38 (excised tumor image).
  • FIG. 9 is a diagram (drawing-substituting photograph) showing the evaluation results of the Akt/mTOR activation inhibitory activity of the benzoylbenzofuran derivative T-38.
  • A shows the evaluation results of pAkt and pmTOR inhibitory activity in NDM and DMEM.
  • B shows the evaluation results of pAkt and pmTOR inhibitory activity (comparison or combined effect with Akt inhibitor and activator IGF-1).
  • FIG. 10 is a diagram (drawing-substituting photograph) showing the evaluation results of the AMPK/ULK1 pathway inhibitory activity of the benzoylbenzofuran derivative T-38.
  • A shows the evaluation results of pAMPK and pULK1 inhibitory activities in NDM and DMEM.
  • B shows the evaluation results of LC3 inhibitory activity (comparison or combined effect with autophagy inhibitors 3-MA and chloroquine (CQ)).
  • FIG. 11 is a diagram (drawing-substituting photograph) showing evaluation results of the SOX2, c-MYC, and OCT-4 inhibitory activity of the benzoylbenzofuran derivative T-38.
  • A shows results under stemness induction with Gemcitabine in DMEM.
  • B shows results in NDM and DMEM.
  • Figure 12 shows the experimental protocol for testing T-compounds for antitumor activity in a mouse orthotopic KPCY solid tumor implant model.
  • Figure 13 shows the results of the endpoint study.
  • A indicates the body weight of mice during the experiment. Body weight was measured daily until the end of the study. Administration of T-38 alone or in combination did not change the body weight of mice, suggesting that it is well tolerated.
  • B Tumor weight of mice treated with compound T-38 and/or gemcitabine in an orthotopic KPCY solid tumor implantation model in immunocompetent C57B1/6 mice.
  • the X-axis represents treatment groups including control, T-38, GEM, and the combination of T-38 and GEM, and the Y-axis represents tumor weight.
  • alkyl having 1 to 10 carbon atoms means a linear, branched or cyclic saturated hydrocarbon group having 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, i -propyl, n-butyl, sec-butyl, t-butyl, isobutyl, pentyl, isopentyl, 2,3-dimethylpropyl, hexyl, cyclohexyl and the like.
  • C1-4 alkyl means a linear or branched saturated hydrocarbon group having 1-4 carbon atoms, and includes methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl, isobutyl and the like.
  • C1-3 alkyl means a linear or branched saturated hydrocarbon group with 1-3 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl and the like.
  • aryl refers to an aromatic hydrocarbon group having carbon atoms, including benzene and naphthalene.
  • heteroaryl refers to a 3- to 10-membered monocyclic heterocyclic group or a 5- to 10-membered heterocyclic group containing at least one heteroatom selected from a nitrogen atom, an oxygen atom, and a sulfur atom. means a membered condensed heterocyclic group.
  • the heteroaryl may contain, for example, 1-5, 1-4, 1-3, 1-2, 2, 1 heteroatoms.
  • heterocyclic group containing one nitrogen atom a heterocyclic group containing two nitrogen atoms, a heterocyclic group containing three nitrogen atoms, a heterocyclic group containing one oxygen atom, a heterocyclic group containing two oxygen atoms heterocyclic groups containing one oxygen atom and one nitrogen atom, heterocyclic groups containing one sulfur atom, and the like.
  • Heterocyclic groups may be aromatic or non-aromatic.
  • Monocyclic heterocyclic groups are preferably 5- to 6-membered rings.
  • the fused heterocyclic group is preferably an 8- to 10-membered ring.
  • heteroaryl having 5 to 10 carbon atoms examples include piperidyl, piperazyl, morpholyl, quinuclidyl, pyrrolidyl, azetidyl, oxetyl, azetidin-2-one-yl, aziridinyl, tropanyl, furyl, tetrahydrofuryl, thienyl, pyrrolyl, pyrrolyl, pyrrolidinyl, dioxolanyl, oxazolyl, oxazolinyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxadiazolyl, furazanyl, thiadiazol
  • alkoxy having 1 to 20 carbon atoms is a group to which the aforementioned “alkyl having 1 to 20 carbon atoms” is bonded via an oxygen atom (O).
  • alkoxy having 1 to 4 carbon atoms is a group to which the aforementioned “alkyl having 1 to 4 carbon atoms” is bonded via an oxygen atom (O).
  • alkylamino having 1 to 4 carbon atoms is a group to which the aforementioned “alkyl having 1 to 4 carbon atoms” is bonded via a nitrogen atom (N).
  • Carboxylic acid ester having 1 to 10 carbon atoms as used herein means a group formed by dehydration condensation of alcohol and carboxylic acid, and may be simply referred to as "ester having 1 to 10 carbon atoms". Examples include methyl ester group, ethyl ester group, propyl ester group, butyl ester group, pentyl ester group, hexyl ester group and the like.
  • the acyl having 1 to 4 carbon atoms is formyl or a group to which alkyl, alkenyl or alkynyl having 1 to 3 carbon atoms is bonded via a carbonyl group.
  • the "carboxylic acid ester having 1 to 10 carbon atoms” may be a group to which acyl having 1 to 10 carbon atoms is bonded via an oxy group (--O--).
  • halogenated alkyl having 1 to 4 carbon atoms means alkyl having 1 to 4 carbon atoms substituted with halogen.
  • the number of substituted halogens can be, for example, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 3, 2, or 1.
  • alkylthio having 1 to 4 carbon atoms is a group to which the aforementioned “alkyl having 1 to 4 carbon atoms” is bonded via a sulfur atom (S).
  • composition of the present invention is a pharmaceutical composition containing, as an active ingredient, a compound represented by the following formula (I) or a pharmacologically acceptable salt thereof (hereinafter referred to as “pharmaceutical composition of the present invention” there is).
  • the present inventors have found a benzoylbenzofuran derivative, that is, a compound represented by the following formula (I), as a compound having anticancer activity. They also found that the same compound inhibited Akt, mTORC1, AMPK, ULK1, SOX2, c-MYC, and OCT-4. Based on this finding, a pharmaceutical composition containing a compound represented by the following formula (I) or a pharmacologically acceptable salt thereof as an active ingredient was developed.
  • the pharmaceutical composition includes anticancer agents (anticancer pharmaceutical compositions), multikinase inhibitors, Akt inhibitors, mTORC1 inhibitors, AMPK inhibitors, ULK1 inhibitors, SOX2 inhibitors, c-MYC inhibitors, OCT-4 inhibitors (medical compositions for treating diseases involving Akt, mTORC1, AMPK, ULK1, SOX2, c-MYC, and OCT-4), and the like.
  • anticancer agents anticancer pharmaceutical compositions
  • multikinase inhibitors Akt inhibitors, mTORC1 inhibitors, AMPK inhibitors, ULK1 inhibitors, SOX2 inhibitors, c-MYC inhibitors, OCT-4 inhibitors
  • Akt inhibitors Akt inhibitors
  • mTORC1 inhibitors AMPK inhibitors
  • ULK1 inhibitors ULK1 inhibitors
  • SOX2 inhibitors c-MYC inhibitors
  • OCT-4 inhibitors medical compositions for treating diseases involving Akt, mTORC1,
  • R 1 represents a hydrocarbon group having 1 to 20 carbon atoms which may have a substituent
  • R 2 to R 5 each independently represent hydrogen, a hydrocarbon group having 1 to 4 carbon atoms, an electron-donating group or an electron-withdrawing group
  • R 2 to R 5 combine with adjacent groups to form a ring
  • R 6 to R 10 are each independently hydrogen, hydroxy, halogen, alkoxy having 1 to 20 carbon atoms, alkoxy having 1 to 4 carbon atoms substituted with alkylamino having 1 to 4 carbon atoms, and 1 to 4 carbon atoms.
  • R 6 to R 10 may combine with adjacent groups to form a ring.
  • R 1 represents a hydrocarbon group having 1 to 20 carbon atoms which may have a substituent.
  • the hydrocarbon group has 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 2 to 7 carbon atoms, still more preferably 3 to 6 carbon atoms, particularly preferably 3 to 4 carbon atoms, and most preferably 4 carbon atoms.
  • the hydrocarbon group may be linear, branched or cyclic. Moreover, it may be saturated or may contain an unsaturated bond.
  • alkyl having 1 to 10 carbon atoms alkenyl having 2 to 10 carbon atoms, alkynyl having 2 to 10 carbon atoms, or aryl having 6 to 10 carbon atoms, preferably linear, branched or cyclic C 1 to It is 10 alkyl, more preferably linear alkyl having 4 carbon atoms.
  • Substituents of the hydrocarbon group are not limited, but examples include halogen, haloalkyl having 1 to 4 carbon atoms, hydroxy, carboxy, amino, alkylamino having 1 to 4 carbon atoms, alkyl having 1 to 4 carbon atoms, and Examples include aryl having 6 to 10 carbon atoms, alkoxy having 1 to 4 carbon atoms, acyl having 1 to 4 carbon atoms, and the like, preferably alkyl having 1 to 4 carbon atoms, or phenyl.
  • R 1 is linear, branched, or cyclic alkyl having 1 to 10 carbon atoms, or benzyl. In another aspect of compound (I), R 1 is alkyl having 4 carbon atoms.
  • R 2 to R 5 each independently represent hydrogen, a hydrocarbon group having 1 to 4 carbon atoms, an electron donating group or an electron withdrawing group.
  • R 2 to R 5 may combine with adjacent groups to form a ring.
  • R 2 and R 3 , R 3 and R 4 , or R 4 and R 5 may combine to form a saturated, unsaturated or heterocyclic ring.
  • the number of carbon atoms in the hydrocarbon group is 1-4, preferably 1-3, more preferably 1 or 2, still more preferably 1.
  • the hydrocarbon group may be linear, branched or cyclic. Moreover, it may be saturated or may contain an unsaturated bond.
  • alkyl having 1 to 4 carbon atoms alkenyl having 2 to 4 carbon atoms, or alkynyl having 2 to 4 carbon atoms.
  • An electron-donating group is a group that donates electrons to a substituted atomic group.
  • the electron-donating group donates electrons to the benzofuran ring.
  • the electron-donating group is not limited as long as it has such action. Examples of electron-donating groups include, but are not limited to, hydroxy, alkoxy having 1 to 4 carbon atoms, amino, and the like.
  • Electron-withdrawing groups are groups that withdraw electrons from a substituted atomic group. In the present invention, the electron withdrawing group withdraws electrons from the benzofuran ring.
  • the electron-withdrawing group is not limited as long as it has such action.
  • Electron-withdrawing groups include, but are not limited to, halogens (X) such as fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I), and halogenated groups having 1 to 4 carbon atoms.
  • Alkyl carboxylic acid ester having 1 to 10 carbon atoms, acyl having 1 to 4 carbon atoms, cyano (-CN), nitro (-NO 2 ), alkylthio (-SR) having 1 to 4 carbon atoms, 1 to 4 carbon atoms alkylsulfinyl (--SOR), or alkylsulfonyl (--SO 2 R) having 1 to 4 carbon atoms; or aryl having 6 to 10 carbon atoms or heteroaryl and the like.
  • R 2 to R 5 are preferably hydrogen, alkyl having 1 to 4 carbon atoms, hydroxy, alkoxy having 1 to 4 carbon atoms, halogen, halogenated alkyl having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, Examples include alkylsulfinyl having 1 to 4 carbon atoms, alkylsulfonyl having 1 to 4 carbon atoms, and the like.
  • R 2 to R 5 are hydrogen or halogen. In another aspect of compound (I), at least one of R 3 and R 4 is halogen and the others are hydrogen. In another aspect of compound (I), R 2 and R 5 are hydrogen.
  • R 6 to R 10 are each independently hydrogen, hydroxy, halogen, straight chain having 1 to 20 carbon atoms (preferably 1 to 10 carbon atoms, more preferably 1 to 3 carbon atoms, still more preferably 1 carbon atom, (branched or cyclic) alkoxy, alkoxy having 1 to 4 carbon atoms substituted with alkylamino having 1 to 4 carbon atoms, or alkylsulfonyl having 1 to 4 carbon atoms.
  • R 6 to R 10 may combine with adjacent groups to form a ring. Specifically, for example, R 6 and R 7 , R 7 and R 8 , R 8 and R 9 , or R 9 and R 10 may combine to form a saturated, unsaturated or heterocyclic ring.
  • R 8 is hydroxy, hydrogen, alkoxy having 1 to 20 carbon atoms, or alkoxy having 1 to 4 carbon atoms substituted with alkylamino having 1 to 4 carbon atoms. In a further aspect, R 8 is hydroxy.
  • R 7 and R 9 are each independently halogen or alkylsulfonyl having 1 to 4 carbon atoms. In a further aspect, R7 and R9 are halogen. In a further aspect, R 7 and R 9 are bromine or iodine.
  • R 6 and R 10 are hydrogen.
  • R 1 is optionally substituted alkyl having 1 to 10 carbon atoms
  • R 2 to R 5 are hydrogen or halogen
  • R 6 and R 10 is hydrogen
  • R 7 and R 9 are halogen and R 8 is hydroxy
  • R 1 is linear alkyl having 4 carbon atoms
  • R 2 and R 5 are hydrogen
  • at least one of R 3 and R 4 is halogen
  • the others are hydrogen and
  • R 6 and R 10 are hydrogen
  • R 7 and R 9 are halogen and R 8 is hydroxy.
  • R 1 is linear alkyl having 4 carbon atoms
  • R 2 is halogen, at least one of R 3 and R 4 is halogen, and the others are hydrogen
  • R5 is hydrogen
  • R6 and R10 are hydrogen
  • R7 and R9 are halogen
  • R8 is hydroxy.
  • Examples of compound (I) include, but are not limited to, the compounds shown in Examples below.
  • the compound (I) among them, a compound having a structure represented by the following formula is preferable.
  • compounds T-38, T-39 and T-79 are particularly preferable as compound (I).
  • Compound (I) can be synthesized by a known synthesis method with reference to Examples below.
  • salts with acidic groups such as carboxylic acid groups include alkali metal and alkaline earth metal salts such as lithium, sodium, potassium, magnesium, calcium; ammonia, methylamine, dimethylamine, ethylamine, methanolamine, ethanolamine, trimethylamine.
  • dicyclohexylamine tris(hydroxymethyl)aminomethane, N,N-bis(hydroxyethyl)piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine, amines such as L-glucamine or salts with basic amino acids such as lysine, ⁇ -hydroxylysine, arginine and the like.
  • basic groups salts with hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, boric acid, etc.
  • inorganic acid salts methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid , propionate, acetic acid, lactic acid, fumaric acid, malic acid, oxalic acid, benzoic acid, mandelic acid, cinnamic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, tosylic acid, glycolic acid, glucuronic acid , ascorbic acid, nicotinic acid, salicylic acid and the like (organic acid salts); and salts with acidic amino acids such as aspartic acid and glutamic acid.
  • cancer is interpreted broadly and used interchangeably with the term "malignant tumor”.
  • malignant tumor in the stage before the diagnosis is confirmed pathologically, that is, before the tumor is either benign or malignant, it may include benign tumors, benign-malignant borderline lesions, and malignant tumors collectively. could be.
  • cancers are called by the name of the organ from which they originated, or by the name of the originating tissue.
  • cancer salivary gland cancer, esophageal cancer, stomach cancer, small intestine cancer, colon cancer, rectal cancer, liver cancer, biliary tract cancer, gallbladder cancer, pancreatic cancer, lung cancer, breast cancer, thyroid cancer cancer, adrenal cancer, pituitary tumor, pineal tumor, uterine cancer, ovarian cancer, vaginal cancer, bladder cancer, kidney cancer, prostate cancer, urethral cancer, retinoblastoma, conjunctiva Cancer, neuroblastoma, glioma, glioblastoma, skin cancer, medulloblastoma, leukemia, malignant lymphoma, testicular tumor, osteosarcoma, rhabdomyosarcoma, leiomyosarcoma, angiosarcoma, liposarcoma , chondrosarcoma, and Ewing's sarcoma.
  • the site of the organ in which it develops can be classified as upper/middle/hypopharynx cancer, upper/middle/lower esophageal cancer, gastric cardia cancer, gastric pyloric cancer, cervical cancer, endometrial cancer, etc.
  • Subclassifications include, but are not limited to, the description of "cancer” in the present invention.
  • the anticancer pharmaceutical composition of the present invention is effective against “cancer” in general, but it can be particularly preferably used for pancreatic cancer and solid cancer of pancreatic cancer.
  • Pancreatic cancer is a malignant tumor that occurs in the pancreas, and can be classified into invasive pancreatic duct cancer, pancreatic neuroendocrine tumor, malignant intraductal papillary mucinous tumor, and malignant mucocystic tumor. It can be done, but pancreatic cancer generally refers to “invasive pancreatic duct cancer (common pancreatic cancer)”.
  • a "solid cancer” is a solid cancer that is observed as a clear mass in a specific organ, tissue, or the like.
  • Anti-cancer pharmaceutical composition refers to a pharmaceutical composition that exhibits a therapeutic or preventive effect on cancer, which is the target disease or condition.
  • Therapeutic effects include alleviation of symptoms characteristic of cancer or accompanying symptoms (mitigation), prevention or delay of exacerbation of symptoms, and the like. The latter can be regarded as one of preventive effects in terms of preventing aggravation.
  • the therapeutic effect and the prophylactic effect are partially overlapping concepts, and it is difficult to clearly distinguish between them, and there is little practical benefit from doing so.
  • a typical preventive effect is to prevent or delay the recurrence (development) of symptoms characteristic of cancer.
  • it corresponds to the anticancer pharmaceutical composition.
  • the therapeutic or preventive effect on cancer brought about by compound (I) or a combination drug thereof may include improvement of cancer complications (eg, cachexia). That is, "anti-cancer” and “cancer treatment” in the present specification mean that in addition to effects such as growth suppression and shrinkage on cancer tissue itself, complications (preferably, cachexia ).
  • composition of the present invention can be formulated according to conventional methods, except that compound (I), which is an active ingredient, or a pharmacologically acceptable salt thereof is added.
  • compound (I) or a pharmacologically acceptable salt thereof may be used singly or in any combination of two or more.
  • other pharmaceutically acceptable components e.g., carriers, excipients, disintegrants, buffers, emulsifiers, suspending agents, soothing agents, stabilizers, preservatives, preservatives, interfaces Active agents, lubricants, diluents, coating agents, sugar coating agents, flavoring agents, emulsifying/solubilizing/dispersing agents, pH adjusters, isotonic agents, solubilizing agents, fragrances, coloring agents, solubilizing agents, physiological saline solution, etc.).
  • the dosage form for formulation is also not particularly limited.
  • dosage forms include tablets, powders, fine granules, granules, capsules, syrups, solutions, suspensions, emulsions, jelly, injections, external preparations, inhalants, nasal drops, eye drops, and suppositories.
  • the anticancer agent of the present invention contains the active ingredient in an amount necessary to obtain the expected therapeutic effect (or preventive effect) (that is, a therapeutically effective amount).
  • the amount of the active ingredient in the pharmaceutical composition of the present invention generally varies depending on the dosage form, but the amount of the active ingredient can be adjusted, for example, in the range of about 0.01% by mass to about 99.9% by mass so as to achieve the desired dosage. can be set within
  • the pharmaceutical composition of the present invention can be administered orally or parenterally (intravenous, intraarterial, subcutaneous, intradermal, intramuscular, intraperitoneal injection, transdermal, nasal, transmucosal, etc.) depending on its dosage form. ) to the subject.
  • routes of administration are not mutually exclusive, and two or more arbitrarily selected routes can be used in combination (for example, intravenous injection or the like is performed at the same time as oral administration or after a predetermined period of time has elapsed).
  • Local administration may be used instead of systemic administration.
  • a drug delivery system (DDS) may be used to deliver the active ingredient in a target tissue-specific manner.
  • the "subject” here is not particularly limited, and includes humans and non-human mammals (pet animals, domestic animals, experimental animals) in need of cancer treatment or prevention. Specifically, for example, mice, rats, guinea pigs, hamsters, monkeys, cows, pigs, goats, sheep, dogs, cats, chickens, quail, etc.). In one preferred aspect, the subject is a human.
  • a method for treating or preventing cancer using the anticancer pharmaceutical composition of the present invention (hereinafter, these two methods are collectively referred to as "therapeutic method, etc.”).
  • the treatment method and the like of the present invention include the step of administering the anticancer pharmaceutical composition of the present invention to a patient suffering from cancer or showing symptoms of cancer.
  • the route of administration is not particularly limited, and examples thereof include oral, intravenous, intraarterial, intradermal, subcutaneous, intramuscular, intraperitoneal, transdermal, transnasal, and transmucosal routes. These administration routes are not mutually exclusive, and two or more arbitrarily selected routes can be used in combination.
  • the dosage of the anticancer pharmaceutical composition may generally vary depending on the patient's symptoms, age, sex, body weight, etc., a person skilled in the art can set an appropriate dosage as appropriate.
  • oral administration for example, about 0.01 mg to 1000 mg per day can be administered to adults once or in several divided doses.
  • parenteral administration for example, about 0.01 mg to 1000 mg can be administered by subcutaneous injection, intramuscular injection or intravenous injection.
  • an administration schedule for example, once to several times a day, once every two days, or once every three days can be adopted. In setting the administration schedule, the patient's symptoms, duration of effect of the active ingredient, etc. can be taken into consideration.
  • compound (I) has multikinase inhibitory activity that inhibits multiple kinases that are associated with cancer growth, nutritional starvation resistance, and the like. For this reason, it is thought that excellent therapeutic effects can be brought about against the growth of malignant tumors and resistance to nutritional starvation, for which conventional cytotoxic anticancer agents have little effect.
  • compound (I) since a single drug inhibits multiple kinases without using multiple drugs, it is possible to reduce the number of drugs to be administered in cancer treatment, thereby reducing side effects to patients. can be mitigated.
  • Akt, mTORC1, AMPK, and ULK1 which are extremely important molecules involved in malignant transformation of cancer and resistance to nutrient starvation. Furthermore, it can be expected that therapeutic agents for diseases involving Akt, mTORC1, AMPK, and ULK1 will be obtained.
  • a multikinase inhibitor containing compound (I) or a pharmacologically acceptable salt thereof as an active ingredient.
  • the multikinase inhibitor inhibits Akt.
  • the multikinase inhibitor inhibits mTORC1.
  • the multikinase inhibitor inhibits AMPK.
  • the multikinase inhibitor inhibits ULK1.
  • a pharmaceutical composition containing compound (I) or a pharmacologically acceptable salt thereof as an active ingredient for selectively killing nutrient-starved tumor cells. be done.
  • compound (I) has multikinase inhibitory activity that inhibits multiple kinases that are associated with cancer growth, nutritional starvation resistance, and the like.
  • the pharmaceutical composition utilizes the multikinase inhibitory activity of compound (I) or a pharmacologically acceptable salt thereof as one of the mechanisms for selectively killing nutrient-starved tumor cells. is.
  • Another further aspect of the present invention provides an anticancer agent containing the multikinase inhibitor as an active ingredient.
  • compound (I) inhibits SOX2, c-MYC, and OCT-4, which is considered to be closely associated with treatment resistance, recurrence, and metastasis of cancer. Inhibits stem cell expression (suppresses development) or kills cancer stem cells. Therefore, it is considered that excellent effects can be brought about against treatment resistance, recurrence, and metastasis of cancer.
  • anticancer compounds exhibiting cancer treatment resistance against pancreatic cancer, that is, resistance against pancreatic cancer, the compound used in the present invention, or the compound used in the present invention Combined use with other (other) anticancer compounds can provide excellent efficacy with little resistance to pancreatic cancer.
  • molecularly targeted therapeutic agents for SOX2, c-MYC, and OCT-4 which are extremely important molecules involved in treatment resistance, recurrence, and metastasis of cancer, can be obtained. Furthermore, it can be expected that therapeutic drugs for diseases involving SOX2, c-MYC, and OCT-4 will be obtained.
  • SOX2 inhibitors, c-MYC inhibitors and OCT-4 inhibitors containing compound (I) or a pharmacologically acceptable salt thereof as an active ingredient are provided. be done.
  • anticancer agents, cancer metastasis inhibitors, and cancer stem cell inhibitors containing the SOX2 inhibitor, c-MYC inhibitor, and OCT-4 inhibitor as active ingredients In one aspect, a cancer stem cell development inhibitor, a cancer stem cell-killing agent is provided.
  • anticancer compounds are conceivable as anticancer compounds that exhibit resistance to pancreatic cancer, particularly antimetabolites such as enocitabine, carmofur, capecitabine, tegafur, tegafur uracil, tegafur gimeracil, Oteracil potassium, gemcitabine, cytarabine, cytarabine ocphosphate, nerarabine, fluorouracil, fludarabine, pemetrexed, pentostatin, methotrexate, cladribine, doxifluridine, hydroxycarbamide, mercaptopurine, etc., especially gemcitabine is resistant to pancreatic cancer.
  • antimetabolites such as enocitabine, carmofur, capecitabine, tegafur, tegafur uracil, tegafur gimeracil, Oteracil potassium, gemcitabine, cytarabine, cytarabine ocphosphate, nerarabine, fluor
  • the content described in the above ⁇ Pharmaceutical composition for anticancer>> section is used as the multikinase inhibitor and the cancer stem cell. It can also be applied in suppressing the development of cancer stem cells or as a cancer stem cell-killing agent.
  • the above-mentioned multikinase inhibitors and cancer stem cell development inhibitors or cancer stem cell-killing agents can also be used as reagents. It can be carried out.
  • the present invention includes use of compound (I) for manufacturing a pharmaceutical composition for treating cancer.
  • the present invention includes use of compound (I) for the treatment or prevention of cancer.
  • the present invention relates to a method for treating or preventing cancer, comprising administering compound (I).
  • Compound (I) (including salts thereof; the same applies hereinafter in this paragraph) can be made into a pharmaceutical composition together with other anticancer compounds, and can be used in combination with other anticancer compounds. Thereby, it is also possible to exhibit a more improved effect. Therefore, the present invention provides a pharmaceutical composition for cancer treatment containing compound (I) and other anticancer agents, and a cancer treatment composition containing compound (I) for use together with other anticancer agents. It relates to pharmaceutical compositions. Alternatively, the present invention includes use of compound (I) for manufacturing a pharmaceutical composition for treating cancer for use with other anticancer agents.
  • the present invention provides the use of compound (I) for treating or preventing cancer, and compound (I) for treating or preventing cancer and Including the use of other anticancer agents. including. Furthermore, the present invention relates to a method for treating or preventing cancer comprising administering compound (I) together with other anticancer agents.
  • the compounding ratio and the like in the combined use can be set according to a conventional method.
  • "to be administered in combination” means that the above agents may be administered at the same time, in succession, or one of them may be administered first and then administered at a later time.
  • Anticancer compounds include, for example, alkylating agents, antimetabolites, microtubule inhibitors, antibiotic anticancer agents, topoisomerase inhibitors, platinum agents, molecular target drugs, hormone agents, biologics, etc., preferably. includes antimetabolites, antibiotic anticancer agents, platinum preparations and the like, more preferably antimetabolites.
  • gemcitabine is particularly preferable because its combined use with gemcitabine is not only effective against gemcitabine-resistant cancer but also exerts a synergistic effect against non-resistant cancer.
  • Antimetabolites include, for example, enocitabine, carmofur, capecitabine, tegafur, tegafur uracil, tegafur gimeracil oteracil potassium, gemcitabine, cytarabine, cytarabine octophosphate, nerarabine, fluorouracil, fludarabine, pemetrexed, pentostatin, methotrexate, Cladribine, doxifluridine, hydroxycarbamide, mercaptopurine and the like.
  • alkylating agents examples include cyclophosphamide, ifosfamide, nitrosourea, dacarbazine, temozolomide, nimustine, busulfan, melphalan, procarbazine, ranimustine and the like.
  • microtubule inhibitors examples include alkaloid anticancer agents such as vincristine, and taxane anticancer agents such as docetaxel and paclitaxel.
  • Antibiotic anticancer agents include, for example, mitomycin C, doxorubicin, epirubicin, daunorubicin, bleomycin, actinomycin D, aclarubicin, idarubicin, pirarubicin, peplomycin, mitoxantrone, amrubicin, and dinostatin stimaramer.
  • topoisomerase inhibitors examples include CPT-11, irinotecan, and topotecan, which have topoisomerase I inhibitory activity, and etoposide and sobuzoxan, which have topoisomerase II inhibitory activity.
  • platinum agents examples include cisplatin, nedaplatin, oxaliplatin, carboplatin, and the like.
  • Hormonal agents include, for example, dexamethasone, finasteride, tamoxifen, astrozole, exemestane, ethinylestradiol, chlormadinone, goserelin, bicalutamide, flutamide, brednisolone, leuprorelin, letrozole, estramustine, toremifene, fosfestrol, mitotane, Methyltestosterone, medroxyprogesterone, mepitiostane and the like.
  • biologics include interferon ⁇ , ⁇ and ⁇ , interleukin 2, ubenimex, dried BCG, and the like.
  • molecular targeted drugs examples include rituximab, alemtuzumab, trastuzumab, cetuximab, panitumumab, imatinib, dasatinib, nilotinib, gefitinib, erlotinib, temsirolimus, bevacizumab, VEGF trap, sunitinib, sorafenib, tocituzumab, bortezomib, gemtuzumab o Zogamicin, ibritumomab ozogamicin , ibritumomab tiuxetan, tamibarotene, tretinoin and the like.
  • Human epidermal growth factor receptor 2 inhibitors Human epidermal growth factor receptor 2 inhibitors, epidermal growth factor receptor inhibitors, Bcr-Abl tyrosine kinase inhibitors, epidermal growth factor tyrosine kinase inhibitors, mTOR inhibitors, in addition to those identified here.
  • Angiogenesis-targeted inhibitors such as vascular endothelial growth factor receptor 2 inhibitors ( ⁇ -VEGFR-2 antibodies), various tyrosine kinase inhibitors such as MAP kinase inhibitors, cytokine-targeted inhibitors, Molecularly targeted drugs such as proteasome inhibitors, antibody-anticancer drug combinations, and the like can also be included. These inhibitors also include antibodies.
  • the compound represented by formula (I)' is a novel compound developed by the present inventors. That is, another aspect of the present invention relates to compounds represented by the following formula (I)' and pharmacologically acceptable salts thereof.
  • the compound represented by formula (I)′ (hereinafter sometimes referred to as “compound of the present invention” or “compound (I)′”) and pharmacologically acceptable salts thereof are effective in treating starvation-starved tumors. It selectively kills cells, has anticancer activity, and can be used as an anticancer pharmaceutical composition.
  • the content described in the section ⁇ pharmaceutical composition for anticancer>> is applied to the compound represented by formula (I)′, Alternatively, it can be applied to an anticancer pharmaceutical composition containing a pharmacologically acceptable salt thereof as an active ingredient.
  • the present invention relates to the use of the compound of the present invention, or a pharmacologically acceptable salt thereof, as an anticancer agent that selectively kills nutrient-starved tumor cells.
  • Another aspect of the present invention is the use of the compound of the present invention or a pharmacologically acceptable salt thereof as an anticancer agent that suppresses the development of cancer stem cells or kills cancer stem cells.
  • R 1 ' represents an optionally substituted hydrocarbon group having 1 to 20 carbon atoms
  • R 2 ' to R 5 ' each independently represents hydrogen, a hydrocarbon group having 1 to 4 carbon atoms, an electron donating group or an electron withdrawing group
  • R 2 ' to R 5 ' are adjacent groups may be combined to form a ring
  • R 6 ' and R 10 ' are each independently hydrogen, hydroxy, halogen, alkoxy having 1 to 20 carbon atoms, alkoxy having 1 to 4 carbon atoms substituted with alkylamino having 1 to 4 carbon atoms, or alkoxy having 1 to 4 carbon atoms.
  • R 7 ' and R 9 ' each independently represent halogen or alkylsulfonyl having 1 to 4 carbon atoms
  • R 8 ' represents hydroxy, hydrogen, alkoxy having 1 to 20 carbon atoms, or alkoxy having 1 to 4 carbon atoms substituted with alkylamino having 1 to 4 carbon atoms
  • R 1 ' is C4 alkyl
  • at least one of R 2 '-R 5 ' is other than hydrogen.
  • compound (I)' Similar to compound (I), compounds T-38, T-39 and T-79 are preferable as compound (I)'.
  • Compound (I)' can be synthesized by a known synthesis method with reference to Examples below.
  • NDM nutrient-rich medium
  • NDM nutrient-deficient medium
  • compound T-38 exhibited particularly strong inhibitory activity with a nutrient starvation selective 50% cell inhibitory concentration (PC 50 ) value of 5 nM.
  • PC 50 cell inhibitory concentration
  • Compound T-39 also had a PC 50 value of ⁇ 10 nM
  • compound T-53 had a PC 50 value of 13 nM
  • compound T-67 had a PC 50 value of 25 nM
  • compound T-79 had a PC 50 value of 0.7 nM
  • Compound T-81 had a PC 50 value of 2.0 nM
  • compound T-82 had a PC 50 value of 1.5 nM, showing strong inhibitory activity.
  • FIG. 1A and FIG. 1B show the results of confirming the in vitro inhibitory activity of these T-compounds under nutrient starvation conditions from the traits of PANC-1 under NDM culture.
  • T-38-treated cells lost cell shape and increased staining with acridine orange (AO) and ethidium bromide (EB), which stain dead cells. That is, the T-compound, compound T-38, exhibited potent inhibitory activity against PANC-1 under NDM culture.
  • T-compounds have been shown to be useful as anti-austerity agents.
  • Figures 2A and 2B show the results of evaluating the metastasis inhibitory activity against PANC-1 under DMEM culture and confirming the activity of T-compounds against cancer cell metastasis. Control cells migrated significantly, whereas migration was suppressed in T-38-treated cells in a dose-dependent manner. That is, compound T-38, which is a T-compound, exhibited potent metastasis inhibitory activity against PANC-1 under DMEM culture. T-compounds have been shown to have metastatic potential.
  • T-38 Effect of T-38 on MIA PaCa-2 Tumor Growth in Nude Mice
  • Five-week-old male BALB/c nude mice CAnN, Cg-Fixbk ⁇ nu>/CrlCrlJ 5W males
  • MIA PaCa-2 tumor cells (10,000,000 cells/200 mL PBS) were implanted subcutaneously into the left and right flanks of all mice.
  • mice were injected intraperitoneally with T-compound or Gemcitabine (treatment group) or PBS (control group). All mice had free access to solid food and water. Body weight and tumor size were measured twice weekly using the following formula. On the 31st day after the start of the experiment, the tumor was excised, photographed, and weighed.
  • the T-38-administered group showed a remarkable suppressive effect on tumor size and weight (Fig. 3). The effect was concentration dependent. Groups treated with Gemcitabine and T-38 also showed significant tumor size and weight suppression.
  • FIG. 4 shows a photograph of the tumor excised on the 31st day after the start of the experiment. These results indicated that the T-compound alone and the combination of T-38 and Gemcitabine had anticancer activity. In particular, the combination administration of T-38 and Gemcitabine was more effective than administration of each compound alone. On the other hand, administration of T-38 did not affect the weight gain of mice, and no adverse effects on growth were observed.
  • T-79 also exhibited significant tumor size and weight suppression (FIGS. 5-6). The effect was concentration dependent. Groups treated with Gemcitabine and T-79 also showed significant tumor size and weight suppression. In addition, T-compounds alone and in combination with T-79 and Gemcitabine were shown to have anticancer activity. In particular, T-79 was more effective than T-38 when combined with lower doses of Gemcitabine than when each compound was administered alone. In addition, T-79 did not affect the weight gain of mice, and no side effects on growth were observed.
  • T-Compounds on KPCY Tumor Growth in C57BL/6 Mice The antitumor effect of T-38 was examined for in vivo antitumor effects on KPCY tumor growth in C57BL/6 mice.
  • Trials of T-38 (30 mg/kg) and GEM (60 mg/kg) alone (5 animals/group) were conducted using C57BL/6 mice with normal immune function and a mouse-derived KPCY cell line. , Example 5. above. was done in a similar way.
  • the number of cells used for transplantation was 1,000,000 cells/200 ⁇ L PBS.
  • the difference in the number of cells from 10,000,000 used for the above MIA PaCa-2 cells is due to the difference in growth rate of these cell lines.
  • the tumor was excised, photographed, and weighed.
  • FIG. 7 shows a photograph of the tumor excised on the 29th day after the start of the experiment. These results indicated that the T-compound had anticancer activity. On the other hand, T-38 did not affect the weight gain of mice, and no adverse effects on growth were observed.
  • T-compounds were further investigated.
  • Cells were isolated using RIPA buffer (Wako Pure Chemical Industries, Osaka, Japan) containing 0.5 mM phenylmethylsulfonyl fluoride (PMSF) (pH 7.4), cOmpleteTM protease inhibitor cocktail (Roche, Mannheim, Germany).
  • PMSF phenylmethylsulfonyl fluoride
  • cOmpleteTM protease inhibitor cocktail Roche, Mannheim, Germany.
  • Extracted protein samples were heated at 100° C. for 5 minutes in 2 ⁇ Laemmli sample buffer (Bio-Rad, Hercules, CA, USA). Equal amounts of protein were subjected to SDS-polyacrylamide gel electrophoresis on 8-15% acrylamide gels.
  • the gel was subsequently transferred to an Immobilon-P transfer polyvinylidene fluoride membrane (Millipore Corp, Bedford, Mass., USA).
  • the membrane was immediately immersed in blocking buffer [5% non-fat dry milk in TBS-Tween (TBS-T) buffer containing 10 mM Tris, 100 mM NaCl, 0.1% Tween 20, pH 7.5] for 1 hour at room temperature, followed by TBS. After washing with -T buffer for 30 minutes, they were incubated overnight at 4°C with appropriate specific primary antibodies commercially available.
  • Akt serine/threonine kinase B
  • mTOR is also a member of the PI3K-related protein kinase (PIKK) family and functions to propagate growth factor pathway signals, thereby supporting cell growth, proliferation, and survival. Upregulated mTOR signaling has been detected in various cancers.
  • mTOR is the core catalytic unit of two protein complexes, mTORC1 and mTORC2, the mTORC1 complex is rapamycin-sensitive and consists of mTOR, Raptor, and mLST8.
  • mTORC1 controls cell growth and proliferation. Other biological processes are also regulated by mTORC1, including various tumor cell-specific processes such as translation, ribosome biogenesis, autophagy, glucose metabolism, cellular response to hypoxia, and metastasis. Phosphorylation of ULK1 is also a major mechanism of regulation of autophagy, and the serine/threonine kinases AMPK and mTOR are two kinases that phosphorylate ULK1.
  • Cancer cells generally grow irregularly and rapidly, and often have fragile and disorganized vasculature that expose them to a stressful microenvironment such as glucose deprivation, hypoxia, and other nutrient deficiencies.
  • cancer cells exhibit an inherent ability to regulate energy metabolism and withstand harsh conditions such as low nutrition and low oxygen supply.
  • Autophagy is thought to be one such mechanism.
  • T-compounds have been shown to be useful as anti-austerity agents that inhibit autophagy.
  • T-compounds also inhibited SOX2, c-MYC and OCT-4 under nutrient starvation conditions.
  • Cancer stem cells are cells that have self-renewal ability, multipotency, and strong tumorigenic ability to form cancer at a high rate even from a small number of cells. Cancer stem cells are also thought to be deeply associated with treatment resistance, recurrence, and metastasis of cancer.
  • SOX2, c-MYC, and OCT-4 are known to promote dedifferentiation of cancer cells and confer stemness. It was shown that T-compounds promote dedifferentiation of cancer cells, inhibit the conferment of stemness, and are useful in suppressing treatment resistance, recurrence and metastasis of cancer.
  • the compound used in the present invention inhibits SOX2, c-MYC, and OCT-4, thereby exhibiting excellent efficacy against cancer treatment resistance, that is, pancreatic cancer, without showing almost any resistance. It was suggested that
  • KPCY mouse pancreatic cancer cells were first subcutaneously inoculated, and the host BALB/c-nu mice were subcutaneously inoculated for 2 to 2 days. Cultured for 3 weeks. On the day of implantation, tumors in host BALB/c-nu mice were excised and cut into pieces approximately 15 mg in size. Small pieces of this tumor were surgically implanted into the pancreas of C57B1/6 recipient mice. Mice were randomized on day 3 of surgery and were treated with T-38, GEM, or a combination of the two agents beginning on day 3. Mice were sacrificed on day 16 and tumors were excised and weighed.
  • results of the endpoint study are shown in FIG.
  • the graph shows that administration of T-38 alone significantly reduced tumor weight compared to the control group. In combination with gemcitabine, tumor weight is further reduced.
  • T-38 has potent antitumor activity in immunocompetent mice, and that the combination of T-38 and gemcitabine is more effective in inhibiting tumor growth than either agent alone. It was suggested that Importantly, the combination therapy did not change the body weight of the mice, suggesting that it was well tolerated.
  • T-compounds have the potential to overcome gemcitabine resistance in pancreatic cancer, and that combination therapy may provide a new and effective way to treat cancer, especially pancreatic cancer.
  • T-38 has superior in vivo antitumor activity compared to the clinically used anticancer drug gemcitabine, which was demonstrated in the above examples in which T-38 was administered to immunocompetent C57Bl/6 mice. has been proven in the tests of Also, the combination of T-38 and gemcitabine showed a strong tumor growth inhibitory effect as shown in the graph of tumor weight. Importantly, T-38 and related T-compounds were shown to inhibit tumor growth without altering body weight in both immunodeficient and immunocompetent mice. . T-38 and related T-compounds are therefore a promising new class of anti-tumor agents that may be used in the treatment of cancer.
  • T-compounds which are extremely unique compounds that exhibit little toxicity to cancer cells under nutrient-rich conditions and exhibit toxicity to cancer cells only under nutrient-starved conditions. This indicates that serious side effects peculiar to anticancer drugs can be avoided. T-compounds also inhibit multiple kinases involved in key mechanisms such as cancer growth and resistance to nutrient starvation. Therefore, it is thought to be effective not only against pancreatic cancer but also against pancreatic cancer showing resistance and cancer in general.
  • cancer stem cells the more they are in a state of nutritional starvation, the higher their proliferative ability, metastatic ability, and malignancy. This is thought to be closely related to cancer stem cells, and in fact, the expression of cancer stem cells is remarkably increased under conditions of nutritional starvation. If cancer stem cells are not effectively killed, the cancer will eventually recur, which is extremely serious.
  • the present invention is an approach that is specifically focused on cytotoxicity in the cancer microenvironment, i.e., nutrient starvation, and is highly likely to be effective in this cancer stem cell as well.
  • the present invention can be used as a pharmaceutical composition for cancer treatment.

Abstract

A purpose of the present invention is to provide a novel pharmaceutical composition, particularly a novel anti-cancer pharmaceutical composition, and a novel compound used for the anti-cancer agent.　The present invention provides a pharmaceutical composition including, as an active ingredient, a compound represented by the formula (I) below or a pharmacologically acceptable salt thereof.

Description

新規医薬組成物Novel pharmaceutical composition
　本発明は、新規医薬組成物、特に新規抗がん用医薬組成物、および同医薬組成物に用いられる新規化合物に関する。 The present invention relates to novel pharmaceutical compositions, particularly novel anticancer pharmaceutical compositions, and novel compounds used in the pharmaceutical compositions.
　がんの中でも膵(臓)がんは、全固形がん中で５年生存率が最も低く、極めて予後不良ながんである。膵臓がんの最も効果的な治療は外科手術であるが、術前および術後における化学療法剤の果たす役割は大きい。しかし、現在膵臓がん治療における効果的な化学療法剤は極めて少なく、またその効果も限定的である。 Among all cancers, pancreatic (pancreatic) cancer has the lowest 5-year survival rate among all solid cancers, and is a cancer with an extremely poor prognosis. Surgery is the most effective treatment for pancreatic cancer, but chemotherapeutic agents play a major role before and after surgery. However, there are currently very few effective chemotherapeutic agents in the treatment of pancreatic cancer, and their effects are limited.
　膵臓がんにおける化学療法剤として、以前はGemcitabine（ゲムシタビン）が第一選択薬として使用されていた。しかし、Gemcitabineに対して耐性を示す膵臓がんもある（非特許文献１）。また、近年では、Gemcitabineと他剤の併用療法が主流となっている（非特許文献２、３）。Fluorouracil、oxaliplatin、irinotecan等を併用するFOLFIRINOXや本邦のみに適用ではあるが、経口剤としてTS-1も用いられている。さらに、リポソーム製剤としてnab-paclitaxelやonivyde等副作用軽減を目指したドラッグデリバリーシステムも活用されている（非特許文献４）。しかしながら、十分な治療効果が得られる膵臓がんの化学療法剤は得られていない。 Gemcitabine was previously used as the first-line drug for pancreatic cancer as a chemotherapeutic agent. However, some pancreatic cancers show resistance to Gemcitabine (Non-Patent Document 1). Moreover, in recent years, combination therapy of Gemcitabine and other drugs has become mainstream (Non-Patent Documents 2 and 3). FOLFIRINOX, which is used in combination with fluouracil, oxaliplatin, irinotecan, etc., and TS-1, which is an oral drug, is also used, although it is only applicable in Japan. Furthermore, drug delivery systems such as nab-paclitaxel and onivyde, which aim to reduce side effects, are also utilized as liposome formulations (Non-Patent Document 4). However, a chemotherapeutic agent for pancreatic cancer with sufficient therapeutic effect has not been obtained.
　また、膵臓がん以外のがんについても、治療に決定的な化学療法剤は未だ見いだされておらず、新規抗がん剤の開発が求められている。また、抗がん剤には、副作用の問題もあり、副作用の少ない抗がん剤が求められている。 Also, for cancers other than pancreatic cancer, definitive chemotherapeutic agents have not yet been found, and there is a demand for the development of new anticancer agents. In addition, anticancer agents have a problem of side effects, and anticancer agents with less side effects are desired.
　前記の状況を鑑み、本発明は、新規医薬組成物、特に新規抗がん用医薬組成物、および同医薬組成物に用いられる新規化合物を提供することを課題とする。 In view of the above situation, an object of the present invention is to provide a novel pharmaceutical composition, particularly a novel anticancer pharmaceutical composition, and a novel compound used in the pharmaceutical composition.
　本発明の技術は、既存の膵臓がんに対する抗がん剤とは作用機序が異なる新規抗がん用医薬組成物等の提案であり、抗がん剤特有の深刻な副作用がほとんど確認されない。
　すなわち、本発明の抗がん用医薬組成物単独、および既存の抗がん剤との併用においても効果を発揮する画期的な薬剤を提供するものである。
　また、副作用軽減の観点からも、本発明は、抗がん剤多剤併用に新たなピースを加えることができるのみならず、単独使用においても副作用の発現を大きく改善できると考えられる。
　さらに、膵臓がんの第一選択薬であるGemcitabineに対して、耐性を示す膵臓がんにも効果がある薬剤を提供するものである。 The technology of the present invention is a proposal for a novel anticancer pharmaceutical composition, etc., which has a mechanism of action different from that of existing anticancer agents for pancreatic cancer, and serious side effects unique to anticancer agents are hardly confirmed. .
In other words, the present invention provides an epoch-making drug that exerts its effects when used alone or in combination with existing anticancer drugs.
In addition, from the viewpoint of reducing side effects, the present invention is not only able to add a new piece to multidrug anticancer drugs, but is also thought to greatly improve the occurrence of side effects in single use.
Furthermore, we will provide a drug that is effective against pancreatic cancer that is resistant to Gemcitabine, the first-choice drug for pancreatic cancer.
　すなわち、本発明の要旨は、以下のとおりである。
［１］　下記式（Ｉ）で示される化合物、またはその薬理学的に許容可能な塩を有効成分として含有する、医薬組成物： That is, the gist of the present invention is as follows.
[1] A pharmaceutical composition containing a compound represented by the following formula (I) or a pharmacologically acceptable salt thereof as an active ingredient:
Figure JPOXMLDOC01-appb-C000003
Figure JPOXMLDOC01-appb-C000003
　式中、
　Ｒ１は、置換基を有してもよい炭素数１～２０の炭化水素基を示し、
　Ｒ２～Ｒ５は、それぞれ独立に、水素、炭素数１～４の炭化水素基、電子供与性基または電子吸引性基を示し、Ｒ２～Ｒ５は、隣り合った基と結合し環を形成していてもよく、
　Ｒ６～Ｒ１０は、それぞれ独立に、水素、ヒドロキシ、ハロゲン、炭素数１～２０のアルコキシ、炭素数１～４のアルキルアミノで置換された炭素数１～４のアルコキシ、または炭素数１～４のアルキルスルホニル（－ＳＯ２Ｒ；Ｒはアルキルを示す）を示し、Ｒ６～Ｒ１０は、隣り合った基と結合し環を形成していてもよい。
［２］　前記Ｒ７およびＲ９が、それぞれ独立に、ハロゲン、または炭素数１～４のアルキルスルホニルである、［１］に記載の医薬組成物。
［３］　前記Ｒ１が、置換基を有してもよい炭素数１～１０のアルキルである、［１］または［２］に記載の医薬組成物。
［４］　前記Ｒ８が、ヒドロキシ、水素、炭素数１～２０のアルコキシ、または炭素数１～４のアルキルアミノで置換された炭素数１～４のアルコキシである、［１］～［３］のいずれかに記載の医薬組成物。
［５］　電子吸引性基が、ハロゲン、炭素数１～４のハロゲン化アルキル、炭素数１～１０のカルボン酸エステル、炭素数１～４のアシル、シアノ（－ＣＮ）、ニトロ（－ＮＯ2）、炭素数１～４のアルキルチオ（－ＳＲ；Ｒはアルキルを示す）、炭素数１～４のアルキルスルフィニル（－ＳＯＲ；Ｒはアルキルを示す）、もしくは炭素数１～４のアルキルスルホニル（－ＳＯ２Ｒ；Ｒはアルキルを示す）；またはこれらの電子吸引性基を置換基として有するアリールもしくはヘテロアリールである、［１］～［４］のいずれかに記載の医薬組成物。
［６］　電子供与性基がヒドロキシ、炭素数１～４のアルコキシ、またはアミノである、［１］～［５］のいずれかに記載の医薬組成物。
［７］　栄養飢餓状態の腫瘍細胞を選択的に死滅させるための、[１]～［６］のいずれかに記載の医薬組成物。
［８］　抗がん用である、［１］～［７］のいずれかに記載の医薬組成物。
［９］　前記がんが、膵臓がんである、［８］に記載の医薬組成物。
［１０］　前記膵臓がんが、式（Ｉ）で示される化合物、またはその薬理学的に許容可能な塩以外の抗がん化合物に対して耐性を示す膵臓がんである、［９］に記載の医薬組成物。
［１１］　がん幹細胞の発生抑制用、または、がん幹細胞の殺傷用である、［１］～［１０］のいずれかに記載の医薬組成物。
［１２］　さらに、式（Ｉ）で示される化合物、またはその薬理学的に許容可能な塩以外の抗がん化合物を含有する、［１］～［１１］のいずれかに記載の医薬組成物。
［１３］　式（Ｉ）で示される化合物、またはその薬理学的に許容可能な塩以外の抗がん化合物と併用投与されるように用いられるための、［１］～［１２］のいずれかに記載の医薬組成物。
［１４］　前記式（Ｉ）で示される化合物、またはその薬理学的に許容可能な塩以外の抗がん化合物が、代謝拮抗薬である、［１０］、［１２］または［１３］のいずれかに記載の医薬組成物。
［１５］　前記代謝拮抗薬が、ゲムシタビンである、［１４］に記載の医薬組成物。
［１６］　下記式（Ｉ）’で示される化合物、またはその薬理学的に許容可能な塩： During the ceremony,
R 1 represents a hydrocarbon group having 1 to 20 carbon atoms which may have a substituent,
R 2 to R 5 each independently represent hydrogen, a hydrocarbon group having 1 to 4 carbon atoms, an electron-donating group or an electron-withdrawing group, and R 2 to R 5 combine with adjacent groups to form a ring may form
R 6 to R 10 are each independently hydrogen, hydroxy, halogen, alkoxy having 1 to 20 carbon atoms, alkoxy having 1 to 4 carbon atoms substituted with alkylamino having 1 to 4 carbon atoms, or 1 to 4 carbon atoms. 4 alkylsulfonyl (--SO 2 R; R represents alkyl), and R 6 to R 10 may combine with adjacent groups to form a ring.
[2] The pharmaceutical composition according to [1], wherein R 7 and R 9 are each independently halogen or alkylsulfonyl having 1 to 4 carbon atoms.
[3] The pharmaceutical composition according to [1] or [2], wherein R 1 is optionally substituted alkyl having 1 to 10 carbon atoms.
[4] wherein R 8 is hydroxy, hydrogen, alkoxy having 1 to 20 carbon atoms, or alkoxy having 1 to 4 carbon atoms substituted with alkylamino having 1 to 4 carbon atoms [1] to [3] The pharmaceutical composition according to any one of
[5] The electron-withdrawing group is halogen, halogenated alkyl having 1 to 4 carbon atoms, carboxylic acid ester having 1 to 10 carbon atoms, acyl having 1 to 4 carbon atoms, cyano (—CN), nitro (—NO 2 ), C 1-4 alkylthio (-SR; R represents alkyl), C 1-4 alkylsulfinyl (-SOR; R represents alkyl), or C 1-4 alkylsulfonyl (- SO 2 R; R represents alkyl); or aryl or heteroaryl having these electron-withdrawing groups as substituents.
[6] The pharmaceutical composition according to any one of [1] to [5], wherein the electron-donating group is hydroxy, alkoxy having 1 to 4 carbon atoms, or amino.
[7] The pharmaceutical composition according to any one of [1] to [6], for selectively killing nutrient-starved tumor cells.
[8] The pharmaceutical composition according to any one of [1] to [7], which is for anticancer use.
[9] The pharmaceutical composition of [8], wherein the cancer is pancreatic cancer.
[10] The pancreatic cancer described in [9], wherein the pancreatic cancer is resistant to an anticancer compound other than the compound represented by formula (I) or a pharmacologically acceptable salt thereof. pharmaceutical composition of
[11] The pharmaceutical composition according to any one of [1] to [10], which is for suppressing the development of cancer stem cells or for killing cancer stem cells.
[12] The pharmaceutical composition of any one of [1] to [11], further comprising an anticancer compound other than the compound represented by formula (I) or a pharmacologically acceptable salt thereof. .
[13] Any one of [1] to [12] for use in combination with an anticancer compound other than the compound represented by formula (I) or a pharmacologically acceptable salt thereof The pharmaceutical composition according to .
[14] Any of [10], [12] or [13], wherein the anticancer compound other than the compound represented by formula (I) or a pharmacologically acceptable salt thereof is an antimetabolite A pharmaceutical composition according to
[15] The pharmaceutical composition of [14], wherein the antimetabolite is gemcitabine.
[16] A compound represented by the following formula (I)', or a pharmacologically acceptable salt thereof:
Figure JPOXMLDOC01-appb-C000004
Figure JPOXMLDOC01-appb-C000004
　式中、
　Ｒ１’は、置換基を有してもよい炭素数１～２０の炭化水素基を示し、
　Ｒ２’～Ｒ５’は、それぞれ独立に、水素、炭素数１～４の炭化水素基、電子供与性基または電子吸引性基を示し、Ｒ２’～Ｒ５’は、隣り合った基と結合し環を形成していてもよく、
　Ｒ６’およびＲ１０’は、それぞれ独立に、水素、ヒドロキシ、ハロゲン、炭素数１～２０のアルコキシ、炭素数１～４のアルキルアミノで置換された炭素数１～４のアルコキシ、または炭素数１～４のアルキルスルホニル（－ＳＯ２Ｒ；Ｒはアルキルを示す）を示し、
　Ｒ７’およびＲ９’は、それぞれ独立に、ハロゲン、または炭素数１～４のアルキルスルホニルを示し、
　Ｒ８’は、ヒドロキシ、水素、炭素数１～２０のアルコキシ、または炭素数１～４のアルキルアミノで置換された炭素数１～４のアルコキシを示し、
　Ｒ１’が炭素数４のアルキルである場合、Ｒ２’～Ｒ５’の少なくとも１つは水素以外である。
［１７］　電子吸引性基が、ハロゲン、炭素数１～４のハロゲン化アルキル、炭素数１～１０のカルボン酸エステル、炭素数１～４のアシル、シアノ（－ＣＮ）、ニトロ（－ＮＯ2）、炭素数１～４のアルキルチオ（－ＳＲ；Ｒはアルキルを示す）、炭素数１～４のアルキルスルフィニル（－ＳＯＲ；Ｒはアルキルを示す）、もしくは炭素数１～４のアルキルスルホニル（－ＳＯ２Ｒ；Ｒはアルキルを示す）；またはこれらの電子吸引性基を置換基として有するアリールもしくはヘテロアリールである、［１６］に記載の化合物。
［１８］　電子供与性基がヒドロキシ、炭素数１～４のアルコキシ、またはアミノである、［１６］または［１７］に記載の化合物。
［１９］　［１６］～［１８］のいずれかに記載の化合物、またはその薬理学的に許容可能な塩の、栄養飢餓状態の腫瘍細胞を選択的に死滅させる抗がん剤としての使用。
［２０］　［１６］～［１８］のいずれかに記載の化合物、またはその薬理学的に許容可能な塩の、がん幹細胞の発生を抑制させる、または、がん幹細胞を殺傷させる抗がん剤としての使用。
［２１］　上記式（Ｉ）で示される化合物、またはその薬理学的に許容可能な塩を対象に投与することを含む、がんの治療または予防方法。
［２２］　さらに、式（Ｉ）で示される化合物、またはその薬理学的に許容可能な塩以外の抗がん化合物を対象に投与することを含む、［２１］に記載の方法。
［２３］　前記抗がん化合物が、ゲムシタビンである、［２２］に記載の方法。
［２４］　上記式（Ｉ）で示される化合物、またはその薬理学的に許容可能な塩の、がんの治療または予防のための組成物の製造における使用。 During the ceremony,
R 1 ' represents an optionally substituted hydrocarbon group having 1 to 20 carbon atoms,
R 2 ' to R 5 ' each independently represents hydrogen, a hydrocarbon group having 1 to 4 carbon atoms, an electron donating group or an electron withdrawing group, and R 2 ' to R 5 ' are adjacent groups may be combined to form a ring,
R 6 ' and R 10 ' are each independently hydrogen, hydroxy, halogen, alkoxy having 1 to 20 carbon atoms, alkoxy having 1 to 4 carbon atoms substituted with alkylamino having 1 to 4 carbon atoms, or alkoxy having 1 to 4 carbon atoms. 1 to 4 alkylsulfonyl (--SO 2 R; R represents alkyl);
R 7 ' and R 9 ' each independently represent halogen or alkylsulfonyl having 1 to 4 carbon atoms,
R 8 ' represents hydroxy, hydrogen, alkoxy having 1 to 20 carbon atoms, or alkoxy having 1 to 4 carbon atoms substituted with alkylamino having 1 to 4 carbon atoms,
When R 1 ' is C4 alkyl, at least one of R 2 '-R 5 ' is other than hydrogen.
[17] The electron withdrawing group is halogen, halogenated alkyl having 1 to 4 carbon atoms, carboxylic acid ester having 1 to 10 carbon atoms, acyl having 1 to 4 carbon atoms, cyano (-CN), nitro (-NO 2 ), C 1-4 alkylthio (-SR; R represents alkyl), C 1-4 alkylsulfinyl (-SOR; R represents alkyl), or C 1-4 alkylsulfonyl (- SO 2 R; R represents alkyl); or aryl or heteroaryl having these electron-withdrawing groups as substituents, the compound according to [16].
[18] The compound of [16] or [17], wherein the electron-donating group is hydroxy, alkoxy having 1 to 4 carbon atoms, or amino.
[19] Use of the compound according to any one of [16] to [18] or a pharmacologically acceptable salt thereof as an anticancer agent that selectively kills nutrient-starved tumor cells.
[20] An anticancer compound of any one of [16] to [18] or a pharmacologically acceptable salt thereof that suppresses the development of cancer stem cells or kills cancer stem cells Use as an agent.
[21] A method for treating or preventing cancer, which comprises administering the compound represented by the above formula (I) or a pharmacologically acceptable salt thereof to a subject.
[22] The method of [21], further comprising administering to the subject an anticancer compound other than the compound represented by formula (I) or a pharmacologically acceptable salt thereof.
[23] The method of [22], wherein the anticancer compound is gemcitabine.
[24] Use of the compound represented by formula (I) or a pharmacologically acceptable salt thereof in the manufacture of a composition for treating or preventing cancer.
　本発明は、新規医薬組成物、特に新規抗がん用医薬組成物、および同医薬組成物に用いられる新規化合物を提供する。 The present invention provides novel pharmaceutical compositions, particularly novel anticancer pharmaceutical compositions, and novel compounds used in the pharmaceutical compositions.
図１は、ベンゾイルベンゾフラン誘導体T-38のPANC-1に対するin vitro阻害活性の評価結果を示す図（図面代用写真）である。Ａは、ライブセルイメージング装置による観察像（各図は、左からコントロール、T-38処置）である。Ｂは、顕微鏡による観察像（各列は、左からAO染色像、EB染色像、位相差像、マージ画像）である。FIG. 1 is a diagram (drawing-substituting photograph) showing the evaluation results of the in vitro inhibitory activity against PANC-1 of the benzoylbenzofuran derivative T-38. A is an image observed by a live cell imaging device (control, T-38 treatment from the left in each figure). B is an image observed with a microscope (each column is an AO-stained image, an EB-stained image, a phase-contrast image, and a merged image from the left). 図２は、ベンゾイルベンゾフラン誘導体T-38のPANC-1に対する転移阻害活性の評価結果を示す図（図面代用写真）である。Ａは、顕微鏡による観察像（各図は、左からコントロール、T-38 5μM処置、T-38 40μM処置）である。上段は、開始時、下段は、開始24時間後の像である。Ｂは、各時間の開口領域を示すグラフである。FIG. 2 is a diagram (drawing-substituting photograph) showing evaluation results of the metastasis inhibitory activity against PANC-1 of the benzoylbenzofuran derivative T-38. A is an image observed under a microscope (from left to right: control, T-38 5 μM treatment, T-38 40 μM treatment). The upper row is the image at the start, and the lower row is the image 24 hours after the start. B is a graph showing the open area at each time. 図３は、ベンゾイルベンゾフラン誘導体T-38のin vivo抗腫瘍効果の評価結果を示す図である（*: P<0.05, **<0.01, ***<0.001, ****<0.0001, Anova-test）。Ａは、各群の腫瘍サイズを示すグラフである。Ｂは、各群の腫瘍重量を示すグラフである。Ｃは、各群の体重を示すグラフである。Figure 3 shows the evaluation results of the in vivo antitumor effect of the benzoylbenzofuran derivative T-38 (*: P<0.05, **<0.01, ***<0.001, ****<0.0001, Anova -test). A is a graph showing the tumor size of each group. B is a graph showing the tumor weight of each group. C is a graph showing the body weight of each group. 図４は、ベンゾイルベンゾフラン誘導体T-38のin vivo抗腫瘍効果の評価結果（摘出腫瘍画像）を示す図（図面代用写真）である。FIG. 4 is a diagram (drawing-substituting photograph) showing the evaluation results of the in vivo antitumor effect of the benzoylbenzofuran derivative T-38 (excised tumor image). 図５は、ベンゾイルベンゾフラン誘導体T-79のin vivo抗腫瘍効果の評価結果を示す図である（*: P<0.05, **<0.01, ***<0.001, ****<0.0001, Anova-test）。Ａは、各群の腫瘍サイズを示すグラフである。Ｂは、各群の腫瘍重量を示すグラフであるを示す。Ｃは、各群の体重を示すグラフである。Figure 5 shows the results of evaluating the in vivo antitumor effect of the benzoylbenzofuran derivative T-79 (*: P<0.05, **<0.01, ***<0.001, ****<0.0001, Anova -test). A is a graph showing the tumor size of each group. B is a graph showing the tumor weight of each group. C is a graph showing the body weight of each group. 図６は、ベンゾイルベンゾフラン誘導体T-79のin vivo抗腫瘍効果の評価結果（摘出腫瘍画像）を示す図（図面代用写真）である。FIG. 6 is a diagram (drawing-substituting photograph) showing the evaluation results of the in vivo antitumor effect of the benzoylbenzofuran derivative T-79 (excised tumor image). 図７は、ベンゾイルベンゾフラン誘導体T-38のin vivo抗腫瘍効果の評価結果を示す図である（*: P<0.05, **<0.01, ***<0.001, ****<0.0001, Anova-test）。Ａは、各群の腫瘍サイズを示すグラフである。Ｂは、各群の腫瘍重量を示すグラフであるを示す。Ｃは、各群の体重を示すグラフである。Figure 7 shows the results of evaluating the in vivo antitumor effect of the benzoylbenzofuran derivative T-38 (*: P<0.05, **<0.01, ***<0.001, ****<0.0001, Anova -test). A is a graph showing the tumor size of each group. B is a graph showing the tumor weight of each group. C is a graph showing the body weight of each group. 図８は、ベンゾイルベンゾフラン誘導体T-38のin vivo抗腫瘍効果の評価結果（摘出腫瘍画像）を示す図（図面代用写真）である。FIG. 8 is a diagram (drawing-substituting photograph) showing the evaluation results of the in vivo antitumor effect of the benzoylbenzofuran derivative T-38 (excised tumor image). 図９は、ベンゾイルベンゾフラン誘導体T-38のAkt/mTOR活性化阻害活性の評価結果を示す図（図面代用写真）である。Ａは、NDMおよびDMEMにおけるpAktおよびpmTOR阻害活性の評価結果を示す。Ｂは、pAktおよびpmTOR阻害活性の評価結果（Akt阻害剤および活性化剤IGF-1との比較または併用効果）を示す。FIG. 9 is a diagram (drawing-substituting photograph) showing the evaluation results of the Akt/mTOR activation inhibitory activity of the benzoylbenzofuran derivative T-38. A shows the evaluation results of pAkt and pmTOR inhibitory activity in NDM and DMEM. B shows the evaluation results of pAkt and pmTOR inhibitory activity (comparison or combined effect with Akt inhibitor and activator IGF-1). 図１０は、ベンゾイルベンゾフラン誘導体T-38のAMPK/ULK1 pathway阻害活性の評価結果を示す図（図面代用写真）である。Ａは、NDMおよびDMEMにおけるpAMPKおよびpULK1阻害活性の評価結果を示す。Ｂは、LC3阻害活性の評価結果（オートファジー阻害剤3-MAおよびchloroquine (CQ)との比較または併用効果）を示す。FIG. 10 is a diagram (drawing-substituting photograph) showing the evaluation results of the AMPK/ULK1 pathway inhibitory activity of the benzoylbenzofuran derivative T-38. A shows the evaluation results of pAMPK and pULK1 inhibitory activities in NDM and DMEM. B shows the evaluation results of LC3 inhibitory activity (comparison or combined effect with autophagy inhibitors 3-MA and chloroquine (CQ)). 図１１は、ベンゾイルベンゾフラン誘導体T-38のSOX2、c-MYC、OCT-4阻害活性の評価結果を示す図（図面代用写真）である。Ａは、DMEMにおけるGemcitabineによる幹細胞性誘導下における結果を示す。Ｂは、NDMおよびDMEMにおける結果を示す。FIG. 11 is a diagram (drawing-substituting photograph) showing evaluation results of the SOX2, c-MYC, and OCT-4 inhibitory activity of the benzoylbenzofuran derivative T-38. A shows results under stemness induction with Gemcitabine in DMEM. B shows results in NDM and DMEM. 図１２は、T-化合物のマウス同所性KPCY固形腫瘍移植モデルにおける抗腫瘍活性についての試験の実験プロトコールを示す図である。Figure 12 shows the experimental protocol for testing T-compounds for antitumor activity in a mouse orthotopic KPCY solid tumor implant model. 図１３は、エンドポイント試験の結果を示す図である。Ａは、実験中のマウスの体重を示す。体重は、試験終了まで毎日測定した。T-38のみを投与しても、併用投与しても、マウスの体重に変化はなく、忍容性が高いことが示唆される。Ｂは、免疫コンピテントC57Bl／6マウスの同所性KPCY固形腫瘍移植モデルにおいて、化合物T-38および／またはゲムシタビンで処理したマウスの腫瘍重量を示す。X軸は対照、T-38、GEM、およびT-38とGEMとの組み合わせを含む治療群を、Y軸は腫瘍重量を表す。統計解析はBrown-Forsythe and Welch ANOVA testを用いて行い（n=8）、有意性は**P<0.01および***P<0.001と表記した。Figure 13 shows the results of the endpoint study. A indicates the body weight of mice during the experiment. Body weight was measured daily until the end of the study. Administration of T-38 alone or in combination did not change the body weight of mice, suggesting that it is well tolerated. B, Tumor weight of mice treated with compound T-38 and/or gemcitabine in an orthotopic KPCY solid tumor implantation model in immunocompetent C57B1/6 mice. The X-axis represents treatment groups including control, T-38, GEM, and the combination of T-38 and GEM, and the Y-axis represents tumor weight. Statistical analysis was performed using the Brown-Forsythe and Welch ANOVA test (n=8), and significance was expressed as **P<0.01 and ***P<0.001.
　以下、本発明の実施の形態について、説明する。ただし、本発明は、以下の好ましい実施形態に限定されず、本発明の範囲内で自由に変更することができるものである。なお、本明細書において、数値範囲を「下限～上限」で表現するものに関しては、上限は「以下」であっても「未満」であってもよく、下限は「以上」であっても「超」であってもよい。 Embodiments of the present invention will be described below. However, the present invention is not limited to the following preferred embodiments, and can be freely modified within the scope of the present invention. In this specification, regarding the numerical range expressed as "lower limit to upper limit", the upper limit may be "less than" or "less than", and the lower limit may be "more than" or " It may be "super".
　本明細書において「炭素数１～１０のアルキル」とは、直鎖、分岐または環状の炭素数が１～１０個の飽和炭化水素基を意味し、例えば、メチル、エチル、ｎ－プロピル、ｉ－プロピル、ｎ－ブチル、ｓｅｃ－ブチル、ｔ－ブチル、イソブチル、ペンチル、イソペンチル、２，３－ジメチルプロピル、ヘキシル、およびシクロヘキシル等が挙げられる。
　「炭素数１～４のアルキル」とは、直鎖または分岐状の炭素数が１～４個の飽和炭化水素基を意味し、メチル、エチル、ｎ－プロピル、ｉ－プロピル、ｎ－ブチル、ｓｅｃ－ブチル、ｔ－ブチル、イソブチル等が挙げられる。
　「炭素数１～３のアルキル」とは、直鎖または分岐状の炭素数が１～３個の飽和炭化水素基を意味し、メチル、エチル、ｎ－プロピル、ｉ－プロピル等が挙げられる。 As used herein, "alkyl having 1 to 10 carbon atoms" means a linear, branched or cyclic saturated hydrocarbon group having 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, i -propyl, n-butyl, sec-butyl, t-butyl, isobutyl, pentyl, isopentyl, 2,3-dimethylpropyl, hexyl, cyclohexyl and the like.
"C1-4 alkyl" means a linear or branched saturated hydrocarbon group having 1-4 carbon atoms, and includes methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl, isobutyl and the like.
"C1-3 alkyl" means a linear or branched saturated hydrocarbon group with 1-3 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl and the like.
　本明細書において「アリール」とは、炭素原子を有する芳香族炭化水素基のことであり、ベンゼンおよびナフタレンを包含する。 As used herein, the term "aryl" refers to an aromatic hydrocarbon group having carbon atoms, including benzene and naphthalene.
　本明細書において「ヘテロアリール」とは、窒素原子、酸素原子、および硫黄原子から選択される１種類以上のヘテロ原子を少なくとも１個含む３～１０員の単環式複素環基または５～１０員の縮合複素環基を意味する。ヘテロアリールが含有するヘテロ原子の数は、例えば、１～５個、１～４個、１～３個、１～２個、２個、１個であってよい。例えば、窒素原子を１個含む複素環基、窒素原子を２個含む複素環基、窒素原子を３個含む複素環基、酸素原子１個を含む複素環基、酸素原子を２個含む複素環基、酸素原子１個と窒素原子１個を含む複素環基、硫黄原子を１個含む複素環基等様々な組み合わせが存在する。複素環基は、芳香族性であっても、非芳香族性であってもよい。単環式複素環基は、好ましくは、５～６員環である。縮合複素環基は、好ましくは、８～１０員環である。炭素数５～１０のヘテロアリールとしては、例えば、ピペリジル、ピペラジル、モルホリル、キヌクリジル、ピロリジル、アゼチジル、オキセチル、アゼチジン－２－オン－イル、アジリジニル、トロパニル、フリル、テトラヒドロフリル、チエニル、ピロリル、ピロリニル、ピロリジニル、ジオキソラニル、オキサゾリル、オキサゾリニル、イソオキサゾリル、チアゾリル、チアゾリニル、イソチアゾリル、イミダゾリル、イミダゾリニル、イミダゾリジニル、オキサゾリジニル、チアゾリジニル、ピラゾリル、ピラゾリニル、ピラゾリジニル、オキサジアゾリル、フラザニル、チアジアゾリル、１,２,３－トリアゾリル、１,２,４－トリアゾリル、テトラゾリル、ピラニル、ピリジル、ピペリジニル、ピリダジニル、ピリミジニル、ピラジニル、ピペラジニル、ジオキサニル、オキサジニル、モルホリニル、チアジニル、トリアジニル、ベンゾフラニル、イソベンゾフラニル、ジヒドロベンゾフラニル、ジヒドロイソベンゾフラニル、ベンゾチエニル、イソベンゾチエニル、ジヒドロベンゾチエニル、ジヒドロイソベンゾチエニル、テトラヒドロベンゾチエニル、キノリル、イソキノリル、キナゾリニル、フタラジニル、プテリジニル、クマリル、クロモニル、１，４－ベンゾジアゼピニル、インドリル、イソインドリル、ベンズイミダゾイル、ベンゾフリル、プリニル、アクリジニル、フェノキサジニル、フェノチアジニル、ベンゾオキサゾリル、ベンゾチアゾリル、インダゾリル、ベンズイミダゾリル、ベンゾジオキソラニル、ベンゾジオキサニルクロメニル、クロマニル、イソクロマニル、クロマノニル、シンノリニル、キノキサリニル、インドリジニル、キノリジニル、イミダゾピリジル、ナフチリジニル、ジヒドロベンゾオキサジニル、ジヒドロベンゾオキサゾリノニル、ジヒドロベンゾオキサジノニル、およびベンゾチオキサニルを挙げることができる。 As used herein, the term “heteroaryl” refers to a 3- to 10-membered monocyclic heterocyclic group or a 5- to 10-membered heterocyclic group containing at least one heteroatom selected from a nitrogen atom, an oxygen atom, and a sulfur atom. means a membered condensed heterocyclic group. The heteroaryl may contain, for example, 1-5, 1-4, 1-3, 1-2, 2, 1 heteroatoms. For example, a heterocyclic group containing one nitrogen atom, a heterocyclic group containing two nitrogen atoms, a heterocyclic group containing three nitrogen atoms, a heterocyclic group containing one oxygen atom, a heterocyclic group containing two oxygen atoms heterocyclic groups containing one oxygen atom and one nitrogen atom, heterocyclic groups containing one sulfur atom, and the like. Heterocyclic groups may be aromatic or non-aromatic. Monocyclic heterocyclic groups are preferably 5- to 6-membered rings. The fused heterocyclic group is preferably an 8- to 10-membered ring. Examples of heteroaryl having 5 to 10 carbon atoms include piperidyl, piperazyl, morpholyl, quinuclidyl, pyrrolidyl, azetidyl, oxetyl, azetidin-2-one-yl, aziridinyl, tropanyl, furyl, tetrahydrofuryl, thienyl, pyrrolyl, pyrrolyl, pyrrolidinyl, dioxolanyl, oxazolyl, oxazolinyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxadiazolyl, furazanyl, thiadiazolyl, 1,2,3-triazolyl, 1,2, 4-triazolyl, tetrazolyl, pyranyl, pyridyl, piperidinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, dioxanyl, oxazinyl, morpholinyl, thiazinyl, triazinyl, benzofuranyl, isobenzofuranyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, benzothienyl , isobenzothienyl, dihydrobenzothienyl, dihydroisobenzothienyl, tetrahydrobenzothienyl, quinolyl, isoquinolyl, quinazolinyl, phthalazinyl, pteridinyl, coumaryl, chromonyl, 1,4-benzodiazepinyl, indolyl, isoindolyl, benzimidazolyl, benzofuryl , purinyl, acridinyl, phenoxazinyl, phenothiazinyl, benzoxazolyl, benzothiazolyl, indazolyl, benzimidazolyl, benzodioxolanyl, benzodioxanylchromenyl, chromanyl, isochromanyl, chromanonyl, cinnolinyl, quinoxalinyl, indolizinyl, quinolidinyl, imidazopyridyl , naphthyridinyl, dihydrobenzoxazinyl, dihydrobenzoxazolinonyl, dihydrobenzoxazinonyl, and benzothioxanyl.
　本明細書において「炭素数１～２０のアルコキシ」とは、前述の「炭素数１～２０のアルキル」が酸素原子（Ｏ)を介して結合する基である。 As used herein, "alkoxy having 1 to 20 carbon atoms" is a group to which the aforementioned "alkyl having 1 to 20 carbon atoms" is bonded via an oxygen atom (O).
　本明細書において「炭素数１～４のアルコキシ」とは、前述の「炭素数１～４のアルキル」が酸素原子（Ｏ)を介して結合する基である。 As used herein, "alkoxy having 1 to 4 carbon atoms" is a group to which the aforementioned "alkyl having 1 to 4 carbon atoms" is bonded via an oxygen atom (O).
　本明細書において「炭素数１～４のアルキルアミノ」とは、前述の「炭素数１～４のアルキル」が窒素原子（Ｎ)を介して結合する基である。 As used herein, "alkylamino having 1 to 4 carbon atoms" is a group to which the aforementioned "alkyl having 1 to 4 carbon atoms" is bonded via a nitrogen atom (N).
　本明細書において「炭素数１～１０のカルボン酸エステル」とは、アルコールとカルボン酸が脱水縮合してできた基を意味し、単に「炭素数１～１０のエステル」という場合もある。例えば、メチルエステル基、エチルエステル基、プロピルエステル基、ブチルエステル基、ペンチルエステル基、ヘキシルエステル基等が挙げられる。 "Carboxylic acid ester having 1 to 10 carbon atoms" as used herein means a group formed by dehydration condensation of alcohol and carboxylic acid, and may be simply referred to as "ester having 1 to 10 carbon atoms". Examples include methyl ester group, ethyl ester group, propyl ester group, butyl ester group, pentyl ester group, hexyl ester group and the like.
　本明細書において「アシル」とは、ホルミル、またはアルキル、アルケニル、アルキニル、アリール、またはヘテロアリールがカルボニル基（＞Ｃ＝Ｏ）を介して結合する基である。炭素数１～４のアシルとは、ホルミル、または炭素数１～３のアルキル、アルケニルまたはアルキニルがカルボニル基を介して結合する基である。「炭素数１～１０のカルボン酸エステル」は、炭素数１～１０のアシルがオキシ基（－Ｏ－）を介して結合する基であってもよい。 As used herein, "acyl" is formyl or a group to which alkyl, alkenyl, alkynyl, aryl, or heteroaryl is bonded via a carbonyl group (>C=O). The acyl having 1 to 4 carbon atoms is formyl or a group to which alkyl, alkenyl or alkynyl having 1 to 3 carbon atoms is bonded via a carbonyl group. The "carboxylic acid ester having 1 to 10 carbon atoms" may be a group to which acyl having 1 to 10 carbon atoms is bonded via an oxy group (--O--).
　本明細書において「炭素数１～４のハロゲン化アルキル」とは、ハロゲンで置換された炭素数１～４のアルキルを意味する。置換するハロゲンの数としては、例えば、１～６個、１～５個、１～４個、１～３個、３個、２個、または１個とすることができる。例えば、クロロメチル、ジクロロメチル、トリクロロメチル、フルオロメチル、ジフルオロメチル、トリフルオロメチル、ブロモメチル、ジブロモメチル、トリブロモメチル、イオドメチル、ジイオドメチル、トリイオドメチル、クロロエチル、ジクロロエチル、トリクロロエチル、フルオロエチル、ジフルオロエチル、トリフルオロエチル、ブロモエチル、ジブロモエチル、トリブロモエチル、イオドエチル、ジイオドエチル、トリイオドエチル、クロロメチル、ジクロロメチル、トリクロロメチル、フルオロメチル、ジフルオロメチル、トリフルオロメチル、ブロモメチル、ジブロモメチル、トリブロモメチル、イオドメチル、ジイオドメチル、トリイオドメチル、クロロプロピル、ジクロロプロピル、トリクロロプロピル、フルオロプロピル、ジフルオロプロピル、トリフルオロプロピル、ブロモプロピル、ジブロモプロピル、トリブロモプロピル、イオドプロピル、ジイオドプロピル、トリイオドプロピル、クロロメチル、ジクロロメチル、トリクロロメチル、フルオロメチル、ジフルオロメチル、トリフルオロメチル、ブロモメチル、ジブロモメチル、トリブロモメチル、イオドメチル、ジイオドメチル、トリイオドメチル、クロロブチル、ジクロロブチル、トリクロロブチル、フルオロブチル、ジフルオロブチル、トリフルオロブチル、ブロモブチル、ジブロモブチル、トリブロモブチル、イオドブチル、ジイオドブチル、およびトリイオドブチル等を挙げることができる。 As used herein, "halogenated alkyl having 1 to 4 carbon atoms" means alkyl having 1 to 4 carbon atoms substituted with halogen. The number of substituted halogens can be, for example, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 3, 2, or 1. For example, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, bromomethyl, dibromomethyl, tribromomethyl, iodomethyl, diiodomethyl, triiodomethyl, chloroethyl, dichloroethyl, trichloroethyl, fluoroethyl, difluoro ethyl, trifluoroethyl, bromoethyl, dibromoethyl, tribromoethyl, iodoethyl, diiodoethyl, triiodoethyl, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, bromomethyl, dibromomethyl, tribromomethyl , iodomethyl, diiodomethyl, triiodomethyl, chloropropyl, dichloropropyl, trichloropropyl, fluoropropyl, difluoropropyl, trifluoropropyl, bromopropyl, dibromopropyl, tribromopropyl, iodopropyl, diiodopropyl, triiodopropyl, chloromethyl, dichloro methyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, bromomethyl, dibromomethyl, tribromomethyl, iodomethyl, diiodomethyl, triiodomethyl, chlorobutyl, dichlorobutyl, trichlorobutyl, fluorobutyl, difluorobutyl, trifluorobutyl, Bromobutyl, dibromobutyl, tribromobutyl, iodobutyl, diiodobutyl, triiodobutyl and the like can be mentioned.
　本明細書において「炭素数１～４のアルキルチオ」とは、前述の「炭素数１～４のアルキル」が硫黄原子（Ｓ)を介して結合する基である。「炭素数１～４のアルキルスルフィニル」とは、前述の「炭素数１～４のアルキルチオ」における硫黄原子が１個の酸素原子（＝Ｏ)と結合している基である。「炭素数１～４のアルキルスルホニル（－ＳＯ２Ｒ）」とは、前述の「炭素数１～４のアルキルチオ」における硫黄原子が２個の酸素原子（＝Ｏ)と結合している基である。 As used herein, the term "alkylthio having 1 to 4 carbon atoms" is a group to which the aforementioned "alkyl having 1 to 4 carbon atoms" is bonded via a sulfur atom (S). "C1-C4 alkylsulfinyl" is a group in which the sulfur atom in the aforementioned "C1-C4 alkylthio" is bonded to one oxygen atom (=O). “C1-4 alkylsulfonyl (—SO 2 R)” is a group in which the sulfur atom in the aforementioned “C1-4 alkylthio” is bound to two oxygen atoms (=O). be.
＜医薬組成物＞
　本発明の一態様は、下記式（Ｉ）で示される化合物、またはその薬理学的に許容可能な塩を有効成分として含有する、医薬組成物（以下、「本発明の医薬組成物」ということがある）に関する。 <Pharmaceutical composition>
One aspect of the present invention is a pharmaceutical composition containing, as an active ingredient, a compound represented by the following formula (I) or a pharmacologically acceptable salt thereof (hereinafter referred to as "pharmaceutical composition of the present invention" there is).
　本発明者らは、抗がん活性を有する化合物として、ベンゾイルベンゾフラン誘導体、すなわち、下記式（Ｉ）で示される化合物を見出した。また、同化合物が、Akt、mTORC1、AMPK、ULK1、SOX2、c-MYC、OCT-4を阻害することを知見した。同知見に基づいて、下記式（Ｉ）で示される化合物、またはその薬理学的に許容可能な塩を有効成分として含有する、医薬組成物を開発した。すなわち、医薬組成物としては、抗がん剤（抗がん用医薬組成物）、マルチキナーゼ阻害剤、Akt阻害剤、mTORC1阻害剤、AMPK阻害剤、ULK1阻害剤、SOX2阻害剤、c-MYC阻害剤、OCT-4阻害剤（Akt、mTORC1、AMPK、ULK1、SOX2、c-MYC、OCT-4が関わる疾患治療用医薬組成物）等である。本発明はこのようにして完成されたものである。 The present inventors have found a benzoylbenzofuran derivative, that is, a compound represented by the following formula (I), as a compound having anticancer activity. They also found that the same compound inhibited Akt, mTORC1, AMPK, ULK1, SOX2, c-MYC, and OCT-4. Based on this finding, a pharmaceutical composition containing a compound represented by the following formula (I) or a pharmacologically acceptable salt thereof as an active ingredient was developed. That is, the pharmaceutical composition includes anticancer agents (anticancer pharmaceutical compositions), multikinase inhibitors, Akt inhibitors, mTORC1 inhibitors, AMPK inhibitors, ULK1 inhibitors, SOX2 inhibitors, c-MYC inhibitors, OCT-4 inhibitors (medical compositions for treating diseases involving Akt, mTORC1, AMPK, ULK1, SOX2, c-MYC, and OCT-4), and the like. The present invention is thus completed.
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000005
　式中、
　Ｒ１は、置換基を有してもよい炭素数１～２０の炭化水素基を示し、
　Ｒ２～Ｒ５は、それぞれ独立に、水素、炭素数１～４の炭化水素基、電子供与性基または電子吸引性基を示し、Ｒ２～Ｒ５は、隣り合った基と結合し環を形成していてもよく、
　Ｒ６～Ｒ１０は、それぞれ独立に、水素、ヒドロキシ、ハロゲン、炭素数１～２０のアルコキシ、炭素数１～４のアルキルアミノで置換された炭素数１～４のアルコキシ、炭素数１～４のアルキルスルホニル（－ＳＯ２Ｒ；Ｒはアルキルを示す）を示し、Ｒ６～Ｒ１０は、隣り合った基と結合し環を形成していてもよい。 During the ceremony,
R 1 represents a hydrocarbon group having 1 to 20 carbon atoms which may have a substituent,
R 2 to R 5 each independently represent hydrogen, a hydrocarbon group having 1 to 4 carbon atoms, an electron-donating group or an electron-withdrawing group, and R 2 to R 5 combine with adjacent groups to form a ring may form
R 6 to R 10 are each independently hydrogen, hydroxy, halogen, alkoxy having 1 to 20 carbon atoms, alkoxy having 1 to 4 carbon atoms substituted with alkylamino having 1 to 4 carbon atoms, and 1 to 4 carbon atoms. is alkylsulfonyl (--SO 2 R; R represents alkyl), and R 6 to R 10 may combine with adjacent groups to form a ring.
≪式（Ｉ）で示される化合物、またはその薬理学的に許容可能な塩≫
　以下、式（I）で示される化合物（以下、「本発明に用いられる化合物」または「化合物（I）」ということがある。）について説明する。 <<Compound represented by Formula (I), or a pharmacologically acceptable salt thereof>>
The compound represented by formula (I) (hereinafter sometimes referred to as "compound used in the present invention" or "compound (I)") is described below.
　Ｒ１は、置換基を有してもよい炭素数１～２０の炭化水素基を示す。
　炭化水素基の炭素数は１～２０であり、好ましくは１～１０、より好ましくは２～７、さらに好ましくは３～６、特に好ましくは３～４、最も好ましくは４である。炭化水素基は、直鎖、分岐鎖、および環状のいずれであってもよい。また、飽和でもよく、不飽和結合を含んでいてもよい。例えば、炭素数１～１０のアルキル、炭素数２～１０のアルケニル、炭素数２～１０のアルキニル、または炭素数６～１０のアリール、好ましくは直鎖、分岐鎖、または環状の炭素数１～１０のアルキルであり、より好ましくは直鎖の炭素数４のアルキルである。 R 1 represents a hydrocarbon group having 1 to 20 carbon atoms which may have a substituent.
The hydrocarbon group has 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 2 to 7 carbon atoms, still more preferably 3 to 6 carbon atoms, particularly preferably 3 to 4 carbon atoms, and most preferably 4 carbon atoms. The hydrocarbon group may be linear, branched or cyclic. Moreover, it may be saturated or may contain an unsaturated bond. For example, alkyl having 1 to 10 carbon atoms, alkenyl having 2 to 10 carbon atoms, alkynyl having 2 to 10 carbon atoms, or aryl having 6 to 10 carbon atoms, preferably linear, branched or cyclic C 1 to It is 10 alkyl, more preferably linear alkyl having 4 carbon atoms.
　炭化水素基の置換基としては、限定されないが、例えば、ハロゲン、炭素数１～４のハロアルキル、ヒドロキシ、カルボキシ、アミノ、炭素数１～４のアルキルアミノ、炭素数１～４のアルキル、炭素数６～１０のアリール、炭素数１～４のアルコキシ、または炭素数１～４のアシル等が挙げられ、好ましくは、炭素数１～４のアルキル、またはフェニルである。 Substituents of the hydrocarbon group are not limited, but examples include halogen, haloalkyl having 1 to 4 carbon atoms, hydroxy, carboxy, amino, alkylamino having 1 to 4 carbon atoms, alkyl having 1 to 4 carbon atoms, and Examples include aryl having 6 to 10 carbon atoms, alkoxy having 1 to 4 carbon atoms, acyl having 1 to 4 carbon atoms, and the like, preferably alkyl having 1 to 4 carbon atoms, or phenyl.
　化合物（Ｉ）の一態様では、Ｒ１が、直鎖、分岐鎖、または環状の炭素数１～１０のアルキル、またはベンジルである。
　化合物（Ｉ）の別の一態様では、Ｒ１が、炭素数４のアルキルである。 In one aspect of compound (I), R 1 is linear, branched, or cyclic alkyl having 1 to 10 carbon atoms, or benzyl.
In another aspect of compound (I), R 1 is alkyl having 4 carbon atoms.
　Ｒ２～Ｒ５は、それぞれ独立に、水素、炭素数１～４の炭化水素基、電子供与性基または電子吸引性基を示す。Ｒ２～Ｒ５は、隣り合った基と結合し環を形成していてもよい。具体的には、例えば、Ｒ２とＲ３、Ｒ３とＲ４、またはＲ４とＲ５が結合し、飽和、不飽和またはヘテロ環を形成していてもよい。
　炭化水素基の炭素数は１～４であり、好ましくは１～３、より好ましくは１または２、さらに好ましくは１である。炭化水素基は、直鎖、分岐鎖、および環状のいずれであってもよい。また、飽和でもよく、不飽和結合を含んでいてもよい。例えば、炭素数１～４のアルキル、炭素数２～４のアルケニル、または炭素数２～４のアルキニルである。 R 2 to R 5 each independently represent hydrogen, a hydrocarbon group having 1 to 4 carbon atoms, an electron donating group or an electron withdrawing group. R 2 to R 5 may combine with adjacent groups to form a ring. Specifically, for example, R 2 and R 3 , R 3 and R 4 , or R 4 and R 5 may combine to form a saturated, unsaturated or heterocyclic ring.
The number of carbon atoms in the hydrocarbon group is 1-4, preferably 1-3, more preferably 1 or 2, still more preferably 1. The hydrocarbon group may be linear, branched or cyclic. Moreover, it may be saturated or may contain an unsaturated bond. For example, alkyl having 1 to 4 carbon atoms, alkenyl having 2 to 4 carbon atoms, or alkynyl having 2 to 4 carbon atoms.
　電子供与性基は、置換した原子団に、電子を与える基である。本発明において、電子供与性基は、ベンゾフラン環に電子を供与する。電子供与性基は、このような作用を有するものであれば限定されない。電子供与性基は、限定されないが、例えば、ヒドロキシ、炭素数１～４のアルコキシ、またはアミノ等が挙げられる。 An electron-donating group is a group that donates electrons to a substituted atomic group. In the present invention, the electron-donating group donates electrons to the benzofuran ring. The electron-donating group is not limited as long as it has such action. Examples of electron-donating groups include, but are not limited to, hydroxy, alkoxy having 1 to 4 carbon atoms, amino, and the like.
　電子吸引性基は、置換した原子団から、電子を吸引する基である。本発明において、電子吸引性基は、ベンゾフラン環より電子を吸引する。電子吸引性基は、このような作用を有するものであれば限定されない。電子吸引性基は、限定されないが、例えば、フッ素（－Ｆ）、塩素（－Ｃｌ）、臭素（－Ｂｒ）、ヨウ素（－Ｉ）等のハロゲン（Ｘ）、炭素数１～４のハロゲン化アルキル、炭素数１～１０のカルボン酸エステル、炭素数１～４のアシル、シアノ（－ＣＮ）、ニトロ（－ＮＯ2）、炭素数１～４のアルキルチオ（－ＳＲ）、炭素数１～４のアルキルスルフィニル（－ＳＯＲ）、もしくは炭素数１～４のアルキルスルホニル（－ＳＯ２Ｒ）；またはこれらの電子吸引性基を置換基として有する炭素数６～１０のアリールもしくは炭素数３～１０のヘテロアリール等が挙げられる。 Electron-withdrawing groups are groups that withdraw electrons from a substituted atomic group. In the present invention, the electron withdrawing group withdraws electrons from the benzofuran ring. The electron-withdrawing group is not limited as long as it has such action. Electron-withdrawing groups include, but are not limited to, halogens (X) such as fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I), and halogenated groups having 1 to 4 carbon atoms. Alkyl, carboxylic acid ester having 1 to 10 carbon atoms, acyl having 1 to 4 carbon atoms, cyano (-CN), nitro (-NO 2 ), alkylthio (-SR) having 1 to 4 carbon atoms, 1 to 4 carbon atoms alkylsulfinyl (--SOR), or alkylsulfonyl (--SO 2 R) having 1 to 4 carbon atoms; or aryl having 6 to 10 carbon atoms or heteroaryl and the like.
　Ｒ２～Ｒ５として、好ましくは、水素、炭素数１～４のアルキル、ヒドロキシ、炭素数１～４のアルコキシ、ハロゲン、炭素数１～４のハロゲン化アルキル、炭素数１～４のアルキルチオ、炭素数１～４のアルキルスルフィニル、または炭素数１～４のアルキルスルホニル等が挙げられる。 R 2 to R 5 are preferably hydrogen, alkyl having 1 to 4 carbon atoms, hydroxy, alkoxy having 1 to 4 carbon atoms, halogen, halogenated alkyl having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, Examples include alkylsulfinyl having 1 to 4 carbon atoms, alkylsulfonyl having 1 to 4 carbon atoms, and the like.
　化合物（Ｉ）の一態様では、Ｒ２～Ｒ５が、水素、またはハロゲンである。
　化合物（Ｉ）の別の一態様では、Ｒ３およびＲ４の少なくとも一方が、ハロゲン、それ以外が水素である。
　化合物（Ｉ）の別の一態様では、Ｒ２およびＲ５が、水素である。 In one aspect of compound (I), R 2 to R 5 are hydrogen or halogen.
In another aspect of compound (I), at least one of R 3 and R 4 is halogen and the others are hydrogen.
In another aspect of compound (I), R 2 and R 5 are hydrogen.
　Ｒ６～Ｒ１０は、それぞれ独立に、水素、ヒドロキシ、ハロゲン、炭素数１～２０（好ましくは炭素数１～１０、より好ましくは炭素数１～３、さらに好ましくは炭素数１の直鎖、分岐鎖、または環状）のアルコキシ、炭素数１～４のアルキルアミノで置換された炭素数１～４のアルコキシ、または炭素数１～４のアルキルスルホニルを示す。Ｒ６～Ｒ１０は、隣り合った基と結合し環を形成していてもよい。具体的には、例えば、Ｒ６とＲ７、Ｒ７とＲ８、Ｒ８とＲ９、またはＲ９とＲ１０が結合し、飽和、不飽和またはヘテロ環を形成していてもよい。 R 6 to R 10 are each independently hydrogen, hydroxy, halogen, straight chain having 1 to 20 carbon atoms (preferably 1 to 10 carbon atoms, more preferably 1 to 3 carbon atoms, still more preferably 1 carbon atom, (branched or cyclic) alkoxy, alkoxy having 1 to 4 carbon atoms substituted with alkylamino having 1 to 4 carbon atoms, or alkylsulfonyl having 1 to 4 carbon atoms. R 6 to R 10 may combine with adjacent groups to form a ring. Specifically, for example, R 6 and R 7 , R 7 and R 8 , R 8 and R 9 , or R 9 and R 10 may combine to form a saturated, unsaturated or heterocyclic ring.
　化合物（Ｉ）の一態様では、Ｒ８が、ヒドロキシ、水素、炭素数１～２０のアルコキシ、または炭素数１～４のアルキルアミノで置換された炭素数１～４のアルコキシである。さらなる一態様では、Ｒ８が、ヒドロキシである。 In one aspect of compound (I), R 8 is hydroxy, hydrogen, alkoxy having 1 to 20 carbon atoms, or alkoxy having 1 to 4 carbon atoms substituted with alkylamino having 1 to 4 carbon atoms. In a further aspect, R 8 is hydroxy.
　化合物（Ｉ）の別の一態様では、Ｒ７およびＲ９が、それぞれ独立に、ハロゲン、または炭素数１～４のアルキルスルホニルである。さらなる一態様では、Ｒ７およびＲ９が、ハロゲンである。さらなる一態様では、Ｒ７およびＲ９が、臭素、またはヨウ素である。 In another aspect of compound (I), R 7 and R 9 are each independently halogen or alkylsulfonyl having 1 to 4 carbon atoms. In a further aspect, R7 and R9 are halogen. In a further aspect, R 7 and R 9 are bromine or iodine.
　化合物（Ｉ）の別の一態様では、Ｒ６およびＲ１０が、水素である。 In another aspect of compound (I), R 6 and R 10 are hydrogen.
　化合物（Ｉ）の別の一態様では、Ｒ１が置換基を有してもよい炭素数１～１０のアルキルであり、Ｒ２～Ｒ５が水素、またはハロゲンであり、Ｒ６およびＲ１０が水素であり、Ｒ７およびＲ９がハロゲンであり、Ｒ８がヒドロキシである。
　化合物（Ｉ）の別の一態様では、Ｒ１が直鎖の炭素数４のアルキルであり、Ｒ２およびＲ５が水素であり、Ｒ３およびＲ４の少なくとも一方がハロゲン、それ以外が水素であり、Ｒ６およびＲ１０が水素であり、Ｒ７およびＲ９がハロゲンであり、Ｒ８がヒドロキシである。
　化合物（Ｉ）の別の一態様では、Ｒ１が直鎖の炭素数４のアルキルであり、Ｒ２がハロゲンであり、Ｒ３およびＲ４の少なくとも一方がハロゲン、それ以外が水素であり、Ｒ５が水素であり、Ｒ６およびＲ１０が水素であり、Ｒ７およびＲ９がハロゲンであり、Ｒ８がヒドロキシである。
　化合物（I）として、限定されないが、例えば、後記実施例に示される化合物が挙げられる。化合物（I）としては、それらのうち、下記式で示される構造の化合物が好ましい。化合物（I）としては、それらのうち、化合物T-38、T-39、T-79が特に好ましい。 In another aspect of compound (I), R 1 is optionally substituted alkyl having 1 to 10 carbon atoms, R 2 to R 5 are hydrogen or halogen, and R 6 and R 10 is hydrogen, R 7 and R 9 are halogen and R 8 is hydroxy.
In another aspect of compound (I), R 1 is linear alkyl having 4 carbon atoms, R 2 and R 5 are hydrogen, at least one of R 3 and R 4 is halogen, and the others are hydrogen and R 6 and R 10 are hydrogen, R 7 and R 9 are halogen and R 8 is hydroxy.
In another embodiment of compound (I), R 1 is linear alkyl having 4 carbon atoms, R 2 is halogen, at least one of R 3 and R 4 is halogen, and the others are hydrogen; R5 is hydrogen, R6 and R10 are hydrogen, R7 and R9 are halogen and R8 is hydroxy.
Examples of compound (I) include, but are not limited to, the compounds shown in Examples below. As the compound (I), among them, a compound having a structure represented by the following formula is preferable. Among them, compounds T-38, T-39 and T-79 are particularly preferable as compound (I).
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006
　化合物（I）は、後記実施例を参照し、公知の合成方法により合成することができる。 Compound (I) can be synthesized by a known synthesis method with reference to Examples below.
　本明細書における「薬理学的に許容可能な塩」とは、無機または有機の塩基または酸と結合して形成した塩であって、医薬として体内に投与することが許容可能な塩のことである。このような塩は、例えば、Ｂｅｒｇｅら、Ｊ．Ｐｈａｒｍ．Ｓｃｉ．６６：１－１９（１９７７）等に記載されている。カルボン酸基等の酸性基との塩としては、リチウム、ナトリウム、カリウム、マグネシウム、カルシウム等のアルカリ金属およびアルカリ土類金属塩；アンモニア、メチルアミン、ジメチルアミン、エチルアミン、メタノールアミン、エタノールアミン、トリメチルアミン、ジシクロヘキシルアミン、トリス（ヒドロキシメチル）アミノメタン、Ｎ，Ｎ－ビス（ヒドロキシエチル）ピペラジン、２－アミノ－２－メチル－１－プロパノール、エタノールアミン、Ｎ－メチルグルカミン、Ｌ－グルカミン等のアミンの塩；またはリジン、δ－ヒドロキシリジン、アルギニン等の塩基性アミノ酸との塩を形成することができる。塩基性基が存在する場合には、塩酸、臭化水素酸、リン酸、硫酸、硝酸、ホウ酸等との塩（無機酸塩）；メタンスルホン酸、ベンゼンスルホン酸、パラトルエンスルホン酸、ギ酸、プロピオン酸塩、酢酸、乳酸、フマル酸、リンゴ酸、シュウ酸、安息香酸、マンデル酸、ケイ皮酸、マレイン酸、酒石酸、クエン酸、コハク酸、マロン酸、トシル酸、グリコール酸、グルクロン酸、アスコルビン酸、ニコチン酸、サリチル酸等との塩（有機酸塩）；またはアスパラギン酸、グルタミン酸等の酸性アミノ酸との塩等を挙げることができる。これらの塩の調製は慣用手段によって行なうことができる。なお、以上の例示は、「薬理学的に許容可能な塩」が限定解釈されるために用いられるべきではない。即ち、「薬理学的に許容可能な塩」は、広義に解釈されるべきであり、各種の塩を含む用語である。本明細書における化合物は、それが明らかに適さない場合を除き、明示されていない場合にも、当該化合物またはその塩の水和物または溶媒和物をも含む。 The term "pharmacologically acceptable salt" as used herein means a salt formed by combining with an inorganic or organic base or acid, and is acceptable for administration into the body as a pharmaceutical. be. Such salts are described, for example, in Berge et al., J. Am. Pharm. Sci. 66:1-19 (1977). Salts with acidic groups such as carboxylic acid groups include alkali metal and alkaline earth metal salts such as lithium, sodium, potassium, magnesium, calcium; ammonia, methylamine, dimethylamine, ethylamine, methanolamine, ethanolamine, trimethylamine. , dicyclohexylamine, tris(hydroxymethyl)aminomethane, N,N-bis(hydroxyethyl)piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine, amines such as L-glucamine or salts with basic amino acids such as lysine, δ-hydroxylysine, arginine and the like. When basic groups are present, salts with hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, boric acid, etc. (inorganic acid salts); methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid , propionate, acetic acid, lactic acid, fumaric acid, malic acid, oxalic acid, benzoic acid, mandelic acid, cinnamic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, tosylic acid, glycolic acid, glucuronic acid , ascorbic acid, nicotinic acid, salicylic acid and the like (organic acid salts); and salts with acidic amino acids such as aspartic acid and glutamic acid. Preparation of these salts can be carried out by conventional means. In addition, the above examples should not be used to restrict interpretation of "pharmacologically acceptable salts". That is, "pharmacologically acceptable salt" should be interpreted broadly and is a term that includes various salts. Reference to compounds herein also includes hydrates or solvates of such compounds or salts thereof, unless explicitly indicated otherwise.
≪抗がん用医薬組成物≫
　本発明において、用語「がん」は広義に解釈され、用語「悪性腫瘍」と互換的に使用される。また、病理学的に診断が確定される前の段階、すなわち腫瘍としての良性、悪性のどちらかが確定される前には、良性腫瘍、良性悪性境界病変、悪性腫瘍を総括的に含む場合もあり得る。一般に、がんはその発生の母体となった臓器の名、もしくは発生母組織の名で呼ばれ、主なものを列記すると、舌がん、歯肉がん、咽頭がん、上顎がん、喉頭がん、唾液腺がん、食道がん、胃がん、小腸がん、大腸がん、直腸がん、肝臓がん、胆道がん、胆嚢がん、膵（臓）がん、肺がん、乳がん、甲状腺がん、副腎がん、脳下垂体腫瘍、松果体腫瘍、子宮がん、卵巣がん、膣がん、膀胱がん、腎臓がん、前立腺がん、尿道がん、網膜芽細胞腫、結膜がん、神経芽腫、神経膠腫、神経膠芽細胞腫、皮膚がん、髄芽種、白血病、悪性リンパ腫、睾丸腫瘍、骨肉腫、横紋筋肉腫、平滑筋肉腫、血管肉腫、脂肪肉腫、軟骨肉腫、ユーイング肉腫等である。そして、さらに発生臓器の部位の特徴によって、上・中・下咽頭がん、上部・中部・下部食道がん、胃噴門がん、胃幽門がん、子宮頚がん、子宮体がん等と細分類されているが、これらが限定的ではなく本発明の「がん」としての記載に含まれる。本発明の抗がん用医薬組成物は、「がん」全般に効果を奏するものであるが、特に膵臓がん、膵臓がんの固形がんに好ましく用いられ得る。膵臓がんとは、膵臓にできた悪性腫瘍のことであり、浸潤性膵管がんや、膵神経内分泌腫瘍、悪性の膵管内乳頭粘液性腫瘍、悪性の粘液嚢胞性腫瘍等に分類することができるが、一般的に膵臓がんと言えば、「浸潤性膵管がん（通常型膵臓がん）」をあらわす。また、「固形がん」とは、特定の臓器や組織等に、明らかな塊として認められる充実性のがんである。 ≪Anticancer pharmaceutical composition≫
In the present invention, the term "cancer" is interpreted broadly and used interchangeably with the term "malignant tumor". In addition, in the stage before the diagnosis is confirmed pathologically, that is, before the tumor is either benign or malignant, it may include benign tumors, benign-malignant borderline lesions, and malignant tumors collectively. could be. In general, cancers are called by the name of the organ from which they originated, or by the name of the originating tissue. cancer, salivary gland cancer, esophageal cancer, stomach cancer, small intestine cancer, colon cancer, rectal cancer, liver cancer, biliary tract cancer, gallbladder cancer, pancreatic cancer, lung cancer, breast cancer, thyroid cancer cancer, adrenal cancer, pituitary tumor, pineal tumor, uterine cancer, ovarian cancer, vaginal cancer, bladder cancer, kidney cancer, prostate cancer, urethral cancer, retinoblastoma, conjunctiva Cancer, neuroblastoma, glioma, glioblastoma, skin cancer, medulloblastoma, leukemia, malignant lymphoma, testicular tumor, osteosarcoma, rhabdomyosarcoma, leiomyosarcoma, angiosarcoma, liposarcoma , chondrosarcoma, and Ewing's sarcoma. Furthermore, depending on the characteristics of the site of the organ in which it develops, it can be classified as upper/middle/hypopharynx cancer, upper/middle/lower esophageal cancer, gastric cardia cancer, gastric pyloric cancer, cervical cancer, endometrial cancer, etc. Subclassifications include, but are not limited to, the description of "cancer" in the present invention. The anticancer pharmaceutical composition of the present invention is effective against "cancer" in general, but it can be particularly preferably used for pancreatic cancer and solid cancer of pancreatic cancer. Pancreatic cancer is a malignant tumor that occurs in the pancreas, and can be classified into invasive pancreatic duct cancer, pancreatic neuroendocrine tumor, malignant intraductal papillary mucinous tumor, and malignant mucocystic tumor. It can be done, but pancreatic cancer generally refers to “invasive pancreatic duct cancer (common pancreatic cancer)”. A "solid cancer" is a solid cancer that is observed as a clear mass in a specific organ, tissue, or the like.
　「抗がん用医薬組成物」とは、標的の疾病ないし病態である、がんに対する治療的または予防的効果を示す医薬組成物のことをいう。治療的効果には、がんに特徴的な症状または随伴症状を緩和すること（軽症化）、症状の悪化を阻止ないし遅延すること等が含まれる。後者については、重症化を予防するという点において予防的効果の一つと捉えることができる。このように、治療的効果と予防的効果は一部において重複する概念であり、明確に区別して捉えることは困難であり、またそうすることの実益は少ない。なお、予防的効果の典型的なものは、がんに特徴的な症状の再発発現（発症）を阻止ないし遅延することである。なお、がんに対して何らかの治療的効果または予防的効果、あるいはこの両者を示す限り、抗がん用医薬組成物に該当する。また、化合物（I)またはその併用剤がもたらす癌に対する治療的または予防的効果は、がんの合併症（例えば、悪液質）の改善を含んでいてもよい。すなわち、本明細書における「抗がん」や「がん治療」とは、がん組織そのものに対して増殖抑制や縮小等の効果を奏することに加えて、合併症（好ましくは、悪液質）を改善することを含んでいてもよい。 "Anti-cancer pharmaceutical composition" refers to a pharmaceutical composition that exhibits a therapeutic or preventive effect on cancer, which is the target disease or condition. Therapeutic effects include alleviation of symptoms characteristic of cancer or accompanying symptoms (mitigation), prevention or delay of exacerbation of symptoms, and the like. The latter can be regarded as one of preventive effects in terms of preventing aggravation. Thus, the therapeutic effect and the prophylactic effect are partially overlapping concepts, and it is difficult to clearly distinguish between them, and there is little practical benefit from doing so. A typical preventive effect is to prevent or delay the recurrence (development) of symptoms characteristic of cancer. In addition, as long as it shows some therapeutic effect or preventive effect, or both, against cancer, it corresponds to the anticancer pharmaceutical composition. In addition, the therapeutic or preventive effect on cancer brought about by compound (I) or a combination drug thereof may include improvement of cancer complications (eg, cachexia). That is, "anti-cancer" and "cancer treatment" in the present specification mean that in addition to effects such as growth suppression and shrinkage on cancer tissue itself, complications (preferably, cachexia ).
　本発明の医薬組成物の製剤化は、有効成分である化合物（Ｉ）、またはその薬理学的に許容可能な塩を配合すること以外は、常法に従って行うことができる。化合物（Ｉ）、またはその薬理学的に許容可能な塩は、１種のみまたは任意の２種以上を組み合わせて用いられ得る。
　製剤化する場合には、製剤上許容される他の成分（例えば、担体、賦形剤、崩壊剤、緩衝剤、乳化剤、懸濁剤、無痛化剤、安定剤、保存剤、防腐剤、界面活性剤、滑沢剤、稀釈剤、被覆剤、糖衣剤、矯味矯臭剤、乳化・可溶化・分散剤、pH調製剤、等張剤、可溶化剤、香料、着色剤、溶解補助剤、生理食塩水等）を含有させることができる。製剤化する場合の剤形も特に限定されない。剤形の例は錠剤、散剤、細粒剤、顆粒剤、カプセル剤、シロップ剤、液剤、懸濁剤、乳剤、ゼリー剤、注射剤、外用剤、吸入剤、点鼻剤、点眼剤および座剤である。本発明の抗がん剤には、期待される治療効果（または予防効果）を得るために必要な量（即ち治療上有効量）の有効成分が含有される。本発明の医薬組成物中の有効成分量は一般に剤形によって異なるが、所望の投与量を達成できるように有効成分量を、例えば、約０．０１質量％～約９９．９質量％の範囲内で設定し得る。 The pharmaceutical composition of the present invention can be formulated according to conventional methods, except that compound (I), which is an active ingredient, or a pharmacologically acceptable salt thereof is added. Compound (I) or a pharmacologically acceptable salt thereof may be used singly or in any combination of two or more.
When formulating, other pharmaceutically acceptable components (e.g., carriers, excipients, disintegrants, buffers, emulsifiers, suspending agents, soothing agents, stabilizers, preservatives, preservatives, interfaces Active agents, lubricants, diluents, coating agents, sugar coating agents, flavoring agents, emulsifying/solubilizing/dispersing agents, pH adjusters, isotonic agents, solubilizing agents, fragrances, coloring agents, solubilizing agents, physiological saline solution, etc.). The dosage form for formulation is also not particularly limited. Examples of dosage forms include tablets, powders, fine granules, granules, capsules, syrups, solutions, suspensions, emulsions, jelly, injections, external preparations, inhalants, nasal drops, eye drops, and suppositories. is an agent. The anticancer agent of the present invention contains the active ingredient in an amount necessary to obtain the expected therapeutic effect (or preventive effect) (that is, a therapeutically effective amount). The amount of the active ingredient in the pharmaceutical composition of the present invention generally varies depending on the dosage form, but the amount of the active ingredient can be adjusted, for example, in the range of about 0.01% by mass to about 99.9% by mass so as to achieve the desired dosage. can be set within
　本発明の医薬組成物は、その剤形に応じて、経口投与または非経口投与（静脈内、動脈内、皮下、皮内、筋肉内、または腹腔内注射、経皮、経鼻、経粘膜等）によって対象に適用される。これらの投与経路は互いに排他的なものではなく、任意に選択される二つ以上を併用することもできる（例えば、経口投与と同時にまたは所定時間経過後に静脈注射等を行う等）。全身投与によらず、局所投与することにしてもよい。ドラッグデリバリーシステム（ＤＤＳ）を利用して標的組織特異的に有効成分が送達されるように投与してもよい。ここでの「対象」は特に限定されず、がんの治療または予防が必要なヒトおよびヒト以外の哺乳動物（ペット動物、家畜、実験動物を含む。具体的には例えばマウス、ラット、モルモット、ハムスター、サル、ウシ、ブタ、ヤギ、ヒツジ、イヌ、ネコ、ニワトリ、ウズラ等である）を含む。好ましい一態様では、適用対象はヒトである。 The pharmaceutical composition of the present invention can be administered orally or parenterally (intravenous, intraarterial, subcutaneous, intradermal, intramuscular, intraperitoneal injection, transdermal, nasal, transmucosal, etc.) depending on its dosage form. ) to the subject. These routes of administration are not mutually exclusive, and two or more arbitrarily selected routes can be used in combination (for example, intravenous injection or the like is performed at the same time as oral administration or after a predetermined period of time has elapsed). Local administration may be used instead of systemic administration. A drug delivery system (DDS) may be used to deliver the active ingredient in a target tissue-specific manner. The "subject" here is not particularly limited, and includes humans and non-human mammals (pet animals, domestic animals, experimental animals) in need of cancer treatment or prevention. Specifically, for example, mice, rats, guinea pigs, hamsters, monkeys, cows, pigs, goats, sheep, dogs, cats, chickens, quail, etc.). In one preferred aspect, the subject is a human.
　本発明のさらなる態様として、本発明の抗がん用医薬組成物を使用した、がんに対する治療方法または予防方法（以下、これら二つの方法をまとめて「治療方法等」という）が提供される。本発明の治療方法等は、上記本発明の抗がん用医薬組成物を、がんを罹患するまたはがんの兆候を認める患者に投与するステップを含む。投与経路は特に限定されず、例えば、経口、静脈内、動脈内、皮内、皮下、筋肉内、腹腔内、経皮、経鼻、経粘膜等を挙げることができる。これらの投与経路は互いに排他的なものではなく、任意に選択される二つ以上を併用することもできる。抗がん用医薬組成物の投与量は一般に、患者の症状、年齢、性別、および体重等によって変動し得るが、当業者であれば適宜適当な投与量を設定することが可能である。限定されないが、例えば、経口投与では、成人に対して、例えば、1日約0.01mg～1000mgを1回、または数回に分けて投与することができる。また、非経口投与では、例えば、1回約0.01mg～1000mgを皮下注射、筋肉注射または静脈注射によって投与することができる。投与スケジュールとしては例えば１日１回～数回、２日に１回、あるいは３日に１回等を採用できる。投与スケジュールの設定においては、患者の症状や有効成分の効果持続時間等を考慮することができる。 As a further aspect of the present invention, there is provided a method for treating or preventing cancer using the anticancer pharmaceutical composition of the present invention (hereinafter, these two methods are collectively referred to as "therapeutic method, etc."). . The treatment method and the like of the present invention include the step of administering the anticancer pharmaceutical composition of the present invention to a patient suffering from cancer or showing symptoms of cancer. The route of administration is not particularly limited, and examples thereof include oral, intravenous, intraarterial, intradermal, subcutaneous, intramuscular, intraperitoneal, transdermal, transnasal, and transmucosal routes. These administration routes are not mutually exclusive, and two or more arbitrarily selected routes can be used in combination. Although the dosage of the anticancer pharmaceutical composition may generally vary depending on the patient's symptoms, age, sex, body weight, etc., a person skilled in the art can set an appropriate dosage as appropriate. Although not limited, for oral administration, for example, about 0.01 mg to 1000 mg per day can be administered to adults once or in several divided doses. In parenteral administration, for example, about 0.01 mg to 1000 mg can be administered by subcutaneous injection, intramuscular injection or intravenous injection. As an administration schedule, for example, once to several times a day, once every two days, or once every three days can be adopted. In setting the administration schedule, the patient's symptoms, duration of effect of the active ingredient, etc. can be taken into consideration.
≪マルチキナーゼ阻害剤およびがん幹細胞の発生抑制またはがん幹細胞殺傷剤≫
　後記実施例に記載のとおり、化合物（Ｉ）は、がんの増殖や栄養飢餓耐性等に関連するとされる複数のキナーゼを阻害するマルチキナーゼ阻害活性を有する。このため、従来の細胞障害性抗がん剤では効果がほとんどなかった悪性腫瘍の増殖や栄養飢餓耐性に対して優れた治療効果をもたらすことができると考えられる。また、本発明によれば、複数の薬剤を使用せずに、単一の薬剤により複数のキナーゼを阻害するため、がん治療において投与する薬剤を少なくすることができ、これにより患者に対する副作用を軽減することができる。また、本発明によれば、栄養飢餓状態においてのみ細胞に毒性を示すため、がんに特異的に作用することを可能とし、これにより抗がん剤特有の深刻な副作用を回避することができる。また、本発明によれば、がんの悪性化や栄養飢餓耐性に関与する極めて重要な分子であるAkt、mTORC1、AMPK、ULK1に対する分子標的治療薬が得られる。更に、Akt、mTORC1、AMPK、ULK1が関わる疾患の治療薬が得られると予測できる。 ≪Multi-kinase inhibitors and cancer stem cell development inhibitors or cancer stem cell-killing agents≫
As described in Examples below, compound (I) has multikinase inhibitory activity that inhibits multiple kinases that are associated with cancer growth, nutritional starvation resistance, and the like. For this reason, it is thought that excellent therapeutic effects can be brought about against the growth of malignant tumors and resistance to nutritional starvation, for which conventional cytotoxic anticancer agents have little effect. In addition, according to the present invention, since a single drug inhibits multiple kinases without using multiple drugs, it is possible to reduce the number of drugs to be administered in cancer treatment, thereby reducing side effects to patients. can be mitigated. In addition, according to the present invention, since it exhibits toxicity to cells only in a state of nutrient starvation, it is possible to act specifically on cancer, thereby avoiding serious side effects peculiar to anticancer agents. . Moreover, according to the present invention, molecularly targeted therapeutic agents for Akt, mTORC1, AMPK, and ULK1, which are extremely important molecules involved in malignant transformation of cancer and resistance to nutrient starvation, can be obtained. Furthermore, it can be expected that therapeutic agents for diseases involving Akt, mTORC1, AMPK, and ULK1 will be obtained.
　したがって、本発明の別のさらなる態様として、化合物（Ｉ）、またはその薬理学的に許容可能な塩を有効成分として含有する、マルチキナーゼ阻害剤が提供される。
　一態様では、前記マルチキナーゼ阻害剤は、Aktを阻害する。
　別の一態様では、前記マルチキナーゼ阻害剤は、mTORC1を阻害する。
　別の一態様では、前記マルチキナーゼ阻害剤は、AMPKを阻害する。
　別の一態様では、前記マルチキナーゼ阻害剤は、ULK1を阻害する。
　本発明の別の態様として、栄養飢餓状態の腫瘍細胞を選択的に死滅させるための、化合物（Ｉ）、またはその薬理学的に許容可能な塩を有効成分として含有する、医薬組成物が提供される。上記のとおり、化合物（Ｉ）は、がんの増殖や栄養飢餓耐性等に関連するとされる複数のキナーゼを阻害するマルチキナーゼ阻害活性を有する。上記医薬組成物は、栄養飢餓状態の腫瘍細胞を選択的に死滅させるためのメカニズムの１つとして、化合物（Ｉ）、またはその薬理学的に許容可能な塩のマルチキナーゼ阻害活性を利用するものである。
　本発明の別のさらなる態様として、前記マルチキナーゼ阻害剤を有効成分として含有する、抗がん剤が提供される。 Therefore, as another further aspect of the present invention, there is provided a multikinase inhibitor containing compound (I) or a pharmacologically acceptable salt thereof as an active ingredient.
In one aspect, the multikinase inhibitor inhibits Akt.
In another aspect, the multikinase inhibitor inhibits mTORC1.
In another aspect, the multikinase inhibitor inhibits AMPK.
In another aspect, the multikinase inhibitor inhibits ULK1.
As another aspect of the present invention, there is provided a pharmaceutical composition containing compound (I) or a pharmacologically acceptable salt thereof as an active ingredient for selectively killing nutrient-starved tumor cells. be done. As described above, compound (I) has multikinase inhibitory activity that inhibits multiple kinases that are associated with cancer growth, nutritional starvation resistance, and the like. The pharmaceutical composition utilizes the multikinase inhibitory activity of compound (I) or a pharmacologically acceptable salt thereof as one of the mechanisms for selectively killing nutrient-starved tumor cells. is.
Another further aspect of the present invention provides an anticancer agent containing the multikinase inhibitor as an active ingredient.
　また、後記実施例に記載のとおり、化合物（Ｉ）はSOX2、c-MYC、OCT-4を阻害することで、がんの治療抵抗性、再発・転移と深く結び付いているとされるがん幹細胞の発現を阻害（発生を抑制）、または、がん幹細胞を殺傷する。このため、がんの治療抵抗性、再発・転移に対して優れた効果をもたらすことができると考えられる。特に、膵臓がんに対してがんの治療抵抗性、すなわち膵臓がんに対して耐性を示す抗がん化合物が存在する中で、本発明に用いられる化合物、あるいは本発明に用いられる化合物とそれ以外の（他の）抗がん化合物を併用することによって、膵臓がんに対してほとんど耐性を示すことなく、優れた効果をもたらすことができる。また、本発明によれば、がんの治療抵抗性、再発・転移に関与する極めて重要な分子であるSOX2、c-MYC、OCT-4に対する分子標的治療薬が得られる。更に、SOX2、c-MYC、OCT-4が関わる疾患の治療薬が得られると予測できる。 In addition, as described in Examples below, compound (I) inhibits SOX2, c-MYC, and OCT-4, which is considered to be closely associated with treatment resistance, recurrence, and metastasis of cancer. Inhibits stem cell expression (suppresses development) or kills cancer stem cells. Therefore, it is considered that excellent effects can be brought about against treatment resistance, recurrence, and metastasis of cancer. In particular, among the existence of anticancer compounds exhibiting cancer treatment resistance against pancreatic cancer, that is, resistance against pancreatic cancer, the compound used in the present invention, or the compound used in the present invention Combined use with other (other) anticancer compounds can provide excellent efficacy with little resistance to pancreatic cancer. Moreover, according to the present invention, molecularly targeted therapeutic agents for SOX2, c-MYC, and OCT-4, which are extremely important molecules involved in treatment resistance, recurrence, and metastasis of cancer, can be obtained. Furthermore, it can be expected that therapeutic drugs for diseases involving SOX2, c-MYC, and OCT-4 will be obtained.
　したがって、本発明の別のさらなる態様として、化合物（Ｉ）、またはその薬理学的に許容可能な塩を有効成分として含有する、SOX2阻害剤、c-MYC阻害剤、OCT-4阻害剤が提供される。
　本発明の別のさらなる態様として、前記SOX2阻害剤、c-MYC阻害剤、OCT-4阻害剤を有効成分として含有する、抗がん剤、がん転移抑制剤、およびがん幹細胞阻害剤（一態様では、がん幹細胞の発生抑制剤、がん幹細胞の殺傷剤）が提供される。 Therefore, as another further aspect of the present invention, SOX2 inhibitors, c-MYC inhibitors and OCT-4 inhibitors containing compound (I) or a pharmacologically acceptable salt thereof as an active ingredient are provided. be done.
As another further aspect of the present invention, anticancer agents, cancer metastasis inhibitors, and cancer stem cell inhibitors containing the SOX2 inhibitor, c-MYC inhibitor, and OCT-4 inhibitor as active ingredients ( In one aspect, a cancer stem cell development inhibitor, a cancer stem cell-killing agent) is provided.
　膵臓がんに対して耐性を示す抗がん化合物としては、様々な抗がん化合物が考えられるが、特に代謝拮抗剤、例えば、エノシタビン、カルモフール、カペシタビン、テガフール、テガフール・ウラシル、テガフール・ギメラシル・オテラシルカリウム、ゲムシタビン、シタラビン、シタラビンオクホスファート、ネララビン、フルオロウラシル、フルダラビン、ペメトレキセド、ペントスタチン、メトトレキサート、クラドリビン、ドキシフルリジン、ヒドロキシカルバミド、メルカプトプリン等が挙げられ、特にゲムシタビンが膵臓がんに対して耐性を示すことがある。 Various anticancer compounds are conceivable as anticancer compounds that exhibit resistance to pancreatic cancer, particularly antimetabolites such as enocitabine, carmofur, capecitabine, tegafur, tegafur uracil, tegafur gimeracil, Oteracil potassium, gemcitabine, cytarabine, cytarabine ocphosphate, nerarabine, fluorouracil, fludarabine, pemetrexed, pentostatin, methotrexate, cladribine, doxifluridine, hydroxycarbamide, mercaptopurine, etc., especially gemcitabine is resistant to pancreatic cancer. may indicate
　なお、任意成分、投与量、対象となるがん、予防または治療対象等については、上記≪抗がん用医薬組成物≫の項で説明した内容を、前記マルチキナーゼ阻害剤、およびがん幹細胞の発生抑制またはがん幹細胞殺傷剤においても適用することができる。また、前記マルチキナーゼ阻害剤、およびがん幹細胞の発生抑制またはがん幹細胞殺傷剤は、試薬としても使用可能であり、試薬の製造、使用等は、分子生物学分野における常法に基づいて、行うことができる。 Regarding the optional ingredient, dosage, target cancer, preventive or therapeutic target, etc., the content described in the above <<Pharmaceutical composition for anticancer>> section is used as the multikinase inhibitor and the cancer stem cell. It can also be applied in suppressing the development of cancer stem cells or as a cancer stem cell-killing agent. In addition, the above-mentioned multikinase inhibitors and cancer stem cell development inhibitors or cancer stem cell-killing agents can also be used as reagents. It can be carried out.
　なお、本発明に用いられる化合物は、単独で、上記効果等を発揮し得る。そのため、本発明の薬剤は、これらの効果および／または作用を有する他の成分を含まなくとも、その所望の効果を発揮することができるが、薬理作用を有する他の成分が含有されていてもよい。よって、本発明は、がん治療用医薬組成物を製造するための、化合物（I）の使用を含む。あるいは、本発明は、がんの治療若しくは予防のための化合物（I）の使用を含む。更に、本発明は、化合物（I）を投与することを含む、がんの治療方法若しくは予防方法に関する。 It should be noted that the compound used in the present invention can exhibit the above effects and the like by itself. Therefore, the agent of the present invention can exert its desired effect without containing other ingredients having these effects and/or actions, but even if it contains other ingredients having pharmacological action, good. Accordingly, the present invention includes use of compound (I) for manufacturing a pharmaceutical composition for treating cancer. Alternatively, the present invention includes use of compound (I) for the treatment or prevention of cancer. Furthermore, the present invention relates to a method for treating or preventing cancer, comprising administering compound (I).
≪併用のための医薬組成物≫
　化合物（I）（その塩も含む。本段落において以下同様。）は、他の抗がん化合物とともに医薬組成物とすることができ、また、他の抗がん化合物と併用することができる。これにより、より向上した効果を発揮することも可能である。よって、本発明は、化合物（I）および他の抗癌剤を含有するがん治療用医薬組成物、および、他の抗がん剤と共に使用するための、化合物（I）を含有するがん治療用医薬組成物に関する。あるいは、本発明は、他の抗がん剤と共に使用するためのがん治療用医薬組成物を製造するための、化合物（I）の使用を含む。あるいは、本発明は、他の抗がん剤と共に投与されるための、がんの治療若しくは予防のための化合物（I）の使用、およびがんの治療若しくは予防のための化合物（I）および他の抗癌剤の使用を含む。を含む。更に、本発明は、他の抗がん剤と共に化合物（I）を投与することを含む、がんの治療方法若しくは予防方法に関する。併用における配合比等は、常法に基づいて、設定することができる。なお、本発明において「併用して投与する」とは、上記薬剤を同時に、連続して、あるいは、一方を先に投与した後、時間をおいて投与してもよい。 <<Pharmaceutical composition for combined use>>
Compound (I) (including salts thereof; the same applies hereinafter in this paragraph) can be made into a pharmaceutical composition together with other anticancer compounds, and can be used in combination with other anticancer compounds. Thereby, it is also possible to exhibit a more improved effect. Therefore, the present invention provides a pharmaceutical composition for cancer treatment containing compound (I) and other anticancer agents, and a cancer treatment composition containing compound (I) for use together with other anticancer agents. It relates to pharmaceutical compositions. Alternatively, the present invention includes use of compound (I) for manufacturing a pharmaceutical composition for treating cancer for use with other anticancer agents. Alternatively, the present invention provides the use of compound (I) for treating or preventing cancer, and compound (I) for treating or preventing cancer and Including the use of other anticancer agents. including. Furthermore, the present invention relates to a method for treating or preventing cancer comprising administering compound (I) together with other anticancer agents. The compounding ratio and the like in the combined use can be set according to a conventional method. In the present invention, "to be administered in combination" means that the above agents may be administered at the same time, in succession, or one of them may be administered first and then administered at a later time.
　他の抗がん化合物としては、特に制限されず、各種抗がん化合物を用いることができる。抗がん化合物としては、例えばアルキル化剤、代謝拮抗剤、微小管阻害剤、抗生物質抗がん剤、トポイソメラーゼ阻害剤、白金製剤、分子標的薬、ホルモン剤、生物製剤等が挙げられ、好ましくは代謝拮抗剤、抗生物質抗がん剤、白金製剤等が挙げられ、より好ましくは代謝拮抗剤である。これらの化合物のうち、ゲムシタビン（Gemcitabine）との併用は、ゲムシタビン耐性がんに効果があるのみならず、非耐性がんに対しても相乗効果を発揮することから、特に好ましくはゲムシタビンである。 Other anticancer compounds are not particularly limited, and various anticancer compounds can be used. Anticancer compounds include, for example, alkylating agents, antimetabolites, microtubule inhibitors, antibiotic anticancer agents, topoisomerase inhibitors, platinum agents, molecular target drugs, hormone agents, biologics, etc., preferably. includes antimetabolites, antibiotic anticancer agents, platinum preparations and the like, more preferably antimetabolites. Among these compounds, gemcitabine is particularly preferable because its combined use with gemcitabine is not only effective against gemcitabine-resistant cancer but also exerts a synergistic effect against non-resistant cancer.
　代謝拮抗剤としては、例えば、エノシタビン、カルモフール、カペシタビン、テガフール、テガフール・ウラシル、テガフール・ギメラシル・オテラシルカリウム、ゲムシタビン、シタラビン、シタラビンオクホスファート、ネララビン、フルオロウラシル、フルダラビン、ペメトレキセド、ペントスタチン、メトトレキサート、クラドリビン、ドキシフルリジン、ヒドロキシカルバミド、メルカプトプリン等が挙げられる。 Antimetabolites include, for example, enocitabine, carmofur, capecitabine, tegafur, tegafur uracil, tegafur gimeracil oteracil potassium, gemcitabine, cytarabine, cytarabine octophosphate, nerarabine, fluorouracil, fludarabine, pemetrexed, pentostatin, methotrexate, Cladribine, doxifluridine, hydroxycarbamide, mercaptopurine and the like.
　アルキル化剤としては、例えばシクロホスファミド、イホスファミド、ニトロソウレア、ダカルバジン、テモゾロミド、ニムスチン、ブスルファン、メルファラン、プロカルバジン、ラニムスチン等が挙げられる。 Examples of alkylating agents include cyclophosphamide, ifosfamide, nitrosourea, dacarbazine, temozolomide, nimustine, busulfan, melphalan, procarbazine, ranimustine and the like.
　微小管阻害剤としては、例えば、ビンクリスチン等のアルカロイド系抗がん剤、ドセタキセル、パクリタキセル等のタキサン系抗がん剤が挙げられる。 Examples of microtubule inhibitors include alkaloid anticancer agents such as vincristine, and taxane anticancer agents such as docetaxel and paclitaxel.
　抗生物質抗がん剤としては、例えば、マイトマイシンC、ドキソルビシン、エピルビシン、ダウノルビシン、ブレオマイシン、アクチノマイシンD、アクラルビシン、イダルビシン、ピラルビシン、ペプロマイシン、ミトキサントロン、アムルビシン、ジノスタチンスチマラマー等が挙げられる。 Antibiotic anticancer agents include, for example, mitomycin C, doxorubicin, epirubicin, daunorubicin, bleomycin, actinomycin D, aclarubicin, idarubicin, pirarubicin, peplomycin, mitoxantrone, amrubicin, and dinostatin stimaramer.
　トポイソメラーゼ阻害剤としてはトポイソメラーゼI阻害作用を有するCPT-11、イリノテカン、ノギテカン、トポイソメラーゼII阻害作用をもつエトポシド、ソブゾキサンが挙げられる。 Examples of topoisomerase inhibitors include CPT-11, irinotecan, and topotecan, which have topoisomerase I inhibitory activity, and etoposide and sobuzoxan, which have topoisomerase II inhibitory activity.
　白金製剤としては、例えば、シスプラチン、ネダプラチン、オキサリプラチン、カルボプラチン等が挙げられる。 Examples of platinum agents include cisplatin, nedaplatin, oxaliplatin, carboplatin, and the like.
　ホルモン剤としては、例えば、デキサメタゾン、フィナステリド、タモキシフェン、アストロゾール、エキセメスタン、エチニルエストラジオール、クロルマジノン、ゴセレリン、ビカルタミド、フルタミド、ブレドニゾロン、リュープロレリン、レトロゾール、エストラムスチン、トレミフェン、ホスフェストロール、ミトタン、メチルテストステロン、メドロキシプロゲステロン、メピチオスタン等が挙げられる。 Hormonal agents include, for example, dexamethasone, finasteride, tamoxifen, astrozole, exemestane, ethinylestradiol, chlormadinone, goserelin, bicalutamide, flutamide, brednisolone, leuprorelin, letrozole, estramustine, toremifene, fosfestrol, mitotane, Methyltestosterone, medroxyprogesterone, mepitiostane and the like.
　生物製剤としては、例えば、インターフェロンα、βおよびγ、インターロイキン2、ウベニメクス、乾燥BCG等が挙げられる。 Examples of biologics include interferon α, β and γ, interleukin 2, ubenimex, dried BCG, and the like.
　分子標的薬としては、例えば、リツキシマブ、アレムツズマブ、トラスツズマブ、セツキシマブ、パニツムマブ、イマチニブ、ダサチニブ、ニロチニブ、ゲフィチニブ、エルロチニブ、テムシロリムス、ベバシズマブ、VEGF trap、スニチニブ、ソラフェニブ、トシツズマブ、ボルテゾミブ、ゲムツズマブ・オゾガマイシン、イブリツモマブ・オゾガマイシン、イブリツモマブチウキセタン、タミバロテン、トレチノイン等が挙げられる。ここに特定する分子標的薬以外にも、ヒト上皮性増殖因子受容体2阻害剤、上皮性増殖因子受容体阻害剤、Bcr-Ablチロシンキナーゼ阻害剤、上皮性増殖因子チロシンキナーゼ阻害剤、mTOR阻害剤、血管内皮増殖因子受容体2阻害剤（α-VEGFR-2抗体）等の血管新生を標的にした阻害剤、MAPキナーゼ阻害剤等の各種チロシンキナーゼ阻害剤、サイトカインを標的とした阻害剤、プロテアソーム阻害剤、抗体－抗がん剤配合体等の分子標的薬等も含めることができる。これら阻害剤には抗体も含む。 Examples of molecular targeted drugs include rituximab, alemtuzumab, trastuzumab, cetuximab, panitumumab, imatinib, dasatinib, nilotinib, gefitinib, erlotinib, temsirolimus, bevacizumab, VEGF trap, sunitinib, sorafenib, tocituzumab, bortezomib, gemtuzumab o Zogamicin, ibritumomab ozogamicin , ibritumomab tiuxetan, tamibarotene, tretinoin and the like. Human epidermal growth factor receptor 2 inhibitors, epidermal growth factor receptor inhibitors, Bcr-Abl tyrosine kinase inhibitors, epidermal growth factor tyrosine kinase inhibitors, mTOR inhibitors, in addition to those identified here. Angiogenesis-targeted inhibitors such as vascular endothelial growth factor receptor 2 inhibitors (α-VEGFR-2 antibodies), various tyrosine kinase inhibitors such as MAP kinase inhibitors, cytokine-targeted inhibitors, Molecularly targeted drugs such as proteasome inhibitors, antibody-anticancer drug combinations, and the like can also be included. These inhibitors also include antibodies.
＜新規化合物＞
　式（Ｉ）で示される化合物のうち、式（Ｉ）’で示される化合物は、本発明者らによって開発された新規化合物である。すなわち、本発明の別の一態様は、下記式（Ｉ）’で示される化合物、およびその薬理学的に許容可能な塩に関する。式（Ｉ）’で示される化合物（以下、「本発明の化合物」、または「化合物（Ｉ）’」ということがある）、およびその薬理学的に許容可能な塩は、栄養飢餓状態の腫瘍細胞を選択的に死滅させ、また、抗がん活性を有し、抗がん用医薬組成物として用いることができる。なお、任意成分、投与量、対象となるがん、予防または治療対象等については、上記≪抗がん用医薬組成物≫の項で説明した内容を、式（Ｉ）’で示される化合物、またはその薬理学的に許容可能な塩を有効成分として含有する、抗がん用医薬組成物においても適用することができる。さらに、別の態様として、本発明は、本発明の化合物、またはその薬理学的に許容可能な塩の、栄養飢餓状態の腫瘍細胞を選択的に死滅させる抗がん剤としての使用に関する。別の態様として、本発明は、本発明の化合物、またはその薬理学的に許容可能な塩の、がん幹細胞の発生を抑制させる、または、がん幹細胞を殺傷させる抗がん剤としての使用に関する。 <New compound>
Among the compounds represented by formula (I), the compound represented by formula (I)' is a novel compound developed by the present inventors. That is, another aspect of the present invention relates to compounds represented by the following formula (I)' and pharmacologically acceptable salts thereof. The compound represented by formula (I)′ (hereinafter sometimes referred to as “compound of the present invention” or “compound (I)′”) and pharmacologically acceptable salts thereof are effective in treating starvation-starved tumors. It selectively kills cells, has anticancer activity, and can be used as an anticancer pharmaceutical composition. Regarding optional ingredients, doses, target cancers, preventive or therapeutic targets, etc., the content described in the section <<pharmaceutical composition for anticancer>> is applied to the compound represented by formula (I)′, Alternatively, it can be applied to an anticancer pharmaceutical composition containing a pharmacologically acceptable salt thereof as an active ingredient. Furthermore, in another aspect, the present invention relates to the use of the compound of the present invention, or a pharmacologically acceptable salt thereof, as an anticancer agent that selectively kills nutrient-starved tumor cells. Another aspect of the present invention is the use of the compound of the present invention or a pharmacologically acceptable salt thereof as an anticancer agent that suppresses the development of cancer stem cells or kills cancer stem cells. Regarding.
Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000007
　式中、
　Ｒ１’は、置換基を有してもよい炭素数１～２０の炭化水素基を示し、
　Ｒ２’～Ｒ５’は、それぞれ独立に、水素、炭素数１～４の炭化水素基、電子供与性基または電子吸引性基を示し、Ｒ２’～Ｒ５’は、隣り合った基と結合し環を形成していてもよく、
　Ｒ６’およびＲ１０’は、それぞれ独立に、水素、ヒドロキシ、ハロゲン、炭素数１～２０のアルコキシ、炭素数１～４のアルキルアミノで置換された炭素数１～４のアルコキシ、または炭素数１～４のアルキルスルホニル（－ＳＯ２Ｒ）を示し、
　Ｒ７’およびＲ９’は、それぞれ独立に、ハロゲン、または炭素数１～４のアルキルスルホニルを示し、
　Ｒ８’は、ヒドロキシ、水素、炭素数１～２０のアルコキシ、または炭素数１～４のアルキルアミノで置換された炭素数１～４のアルコキシを示し、
　Ｒ１’が炭素数４のアルキルである場合、Ｒ２’～Ｒ５’の少なくとも１つは水素以外である。 During the ceremony,
R 1 ' represents an optionally substituted hydrocarbon group having 1 to 20 carbon atoms,
R 2 ' to R 5 ' each independently represents hydrogen, a hydrocarbon group having 1 to 4 carbon atoms, an electron donating group or an electron withdrawing group, and R 2 ' to R 5 ' are adjacent groups may be combined to form a ring,
R 6 ' and R 10 ' are each independently hydrogen, hydroxy, halogen, alkoxy having 1 to 20 carbon atoms, alkoxy having 1 to 4 carbon atoms substituted with alkylamino having 1 to 4 carbon atoms, or alkoxy having 1 to 4 carbon atoms. 1-4 alkylsulfonyl (—SO 2 R),
R 7 ' and R 9 ' each independently represent halogen or alkylsulfonyl having 1 to 4 carbon atoms,
R 8 ' represents hydroxy, hydrogen, alkoxy having 1 to 20 carbon atoms, or alkoxy having 1 to 4 carbon atoms substituted with alkylamino having 1 to 4 carbon atoms,
When R 1 ' is C4 alkyl, at least one of R 2 '-R 5 ' is other than hydrogen.
　Ｒ１’～Ｒ１０’のそれぞれの基の具体例は、化合物（Ｉ）におけるＲ１～Ｒ１０で説明されたものと同様である。 Specific examples of each group of R 1 ' to R 10 ' are the same as those explained for R 1 to R 10 in compound (I).
　化合物（I）’の好ましい化合物としては、化合物（Ｉ）と同様に、化合物T-38、T-39、T-79である。
　化合物（I）’は、後記実施例を参照し、公知の合成方法により、合成することができる。 Similar to compound (I), compounds T-38, T-39 and T-79 are preferable as compound (I)'.
Compound (I)' can be synthesized by a known synthesis method with reference to Examples below.
　以下、実施例により、本発明をさらに具体的に説明するが、本発明はその要旨を超えない限り、これらの実施例に限定されるものではない。 The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples as long as it does not exceed the gist thereof.
＜方法＞
１．化合物の合成
　T-化合物を、以下のようにして合成した。 <Method>
1. Synthesis of Compounds T-compounds were synthesized as follows.
　参考文献：
1から2の合成：M. F. Wempe, et al. J. Med. Chem., 2011, 54, 2701-2713.
2から3の合成：M. F. Wempe, et al. J. Med. Chem., 2011, 54, 2701-2713.
3から4の合成：(a) B. Bhushan, et al. Bioorg. Med. Chem., 2018, 26, 2984-2991. (AlCl3) (b) M. F. Wempe, et al.J. Med. Chem., 2011, 54, 2701-2713. (SnCl4)
4から5の合成：W. Huang, et al. J. Org. Chem., 2019, 84, 2941-2950. References:
Synthesis of 1 to 2: M. F. Wempe, et al. J. Med. Chem., 2011, 54, 2701-2713.
Synthesis of 2 to 3: M. F. Wempe, et al. J. Med. Chem., 2011, 54, 2701-2713.
Synthesis of 3 to 4: (a) B. Bhushan, et al. Bioorg. Med. Chem., 2018, 26, 2984-2991. ( AlCl3 ) (b) M. F. Wempe, et al.J. Med. Chem. , 2011, 54, 2701-2713. ( SnCl4 )
Synthesis of 4 to 5: W. Huang, et al. J. Org. Chem., 2019, 84, 2941-2950.
　参考文献：
5から6の合成：B. Bhushan, et al. Bioorg. Med. Chem., 2018, 26, 2984-2991. References:
Synthesis of 5 to 6: B. Bhushan, et al. Bioorg. Med. Chem., 2018, 26, 2984-2991.
　参考文献：
5から7の合成：M. F. Wempe, et al. J. Med. Chem., 2011, 54, 2701-2713. References:
Synthesis of 5 to 7: M. F. Wempe, et al. J. Med. Chem., 2011, 54, 2701-2713.
　参考文献：
5から8の合成：W. Ou, et al. Angew. Chem. Int. Ed., 2020, 60, 6357-6361. References:
Synthesis of 5 to 8: W. Ou, et al. Angew. Chem. Int. Ed., 2020, 60, 6357-6361.
　参考文献：
9から10の合成：N. A. Paras, et al. J. Am. Chem. Soc., 2002, 124, 7894-7895.
10から11の合成：W. Huang, et al. J. Org. Chem., 2019, 84, 2941-2950.
11から12の合成：J. H. Han, et al. Tetrahedron, 2010, 66, 1673-1677.
12から13の合成：W. Kirmse, et al. J. Am. Chem. Soc., 1989, 111, 1465-1473.
12からT-64の合成：S. H. M. Mehr, et al. J. Org. Chem., 2015, 80, 5144-5150. References:
Synthesis of 9 to 10: N. A. Paras, et al. J. Am. Chem. Soc., 2002, 124, 7894-7895.
Synthesis of 10-11: W. Huang, et al. J. Org. Chem., 2019, 84, 2941-2950.
Synthesis of 11-12: J. H. Han, et al. Tetrahedron, 2010, 66, 1673-1677.
Synthesis of 12-13: W. Kirmse, et al. J. Am. Chem. Soc., 1989, 111, 1465-1473.
Synthesis of T-64 from 12: S. H. M. Mehr, et al. J. Org. Chem., 2015, 80, 5144-5150.
　参考文献：
14から15の合成：M. F. Wempe, et al. J. Med. Chem., 2011, 54, 2701-2713.
15から16の合成：M. F. Wempe, et al. J. Med. Chem., 2011, 54, 2701-2713.
16から17の合成：B. Bhushan, et al. Bioorg. Med. Chem., 2018, 26, 2984-2991.
17から18の合成：M. Wempe, et al. PCT Int. Appl., 2012048058, 12 Apr 2012.
18からT-93の合成：R. Heald, et al. J. Med. Chem., 2005, 48, 2993-3004.
T-93からT-94の合成：W. Huang, et al. J. Org. Chem., 2019, 84, 2941-2950. References:
Synthesis of 14-15: M. F. Wempe, et al. J. Med. Chem., 2011, 54, 2701-2713.
Synthesis of 15-16: M. F. Wempe, et al. J. Med. Chem., 2011, 54, 2701-2713.
Synthesis of 16-17: B. Bhushan, et al. Bioorg. Med. Chem., 2018, 26, 2984-2991.
Synthesis of 17-18: M. Wempe, et al. PCT Int. Appl., 2012048058, 12 Apr 2012.
Synthesis of T-93 from 18: R. Heald, et al. J. Med. Chem., 2005, 48, 2993-3004.
Synthesis of T-94 from T-93: W. Huang, et al. J. Org. Chem., 2019, 84, 2941-2950.
＜結果＞
　予備的に見出した抗がん活性を有するベンゾイルベンゾフラン骨格を有する化合物をリード化合物とし、構造最適化研究を行った。合成した化合物のNMRスペクトル値を以下に示す。 <Results>
A compound having a benzoylbenzofuran skeleton with anti-cancer activity, which was preliminarily discovered, was used as a lead compound, and structural optimization studies were conducted. The NMR spectrum values of the synthesized compound are shown below.
(2-Butylbenzofuran-3-yl)(phenyl)methanone (T-1)
1H-NMR (400 MHz, CDCl3) δ: 0.88 (3H, t, J = 7.2 Hz), 1.34 (2H, sext, J = 7.2 Hz), 1.75 (2H, quint, J = 7.2 Hz), 2.89 (2H, t, J = 7.2 Hz, 2H), 7.18 (1H, t, J = 7.6 Hz), 7.28 (1H, d, J = 7.6 Hz), 7.34 (1H, d, J =7.6 Hz), 7.48 (3H, t, J = 7.6 Hz), 7.60 (1H, t, J = 7.6 Hz), 7.81 (2H, d, J = 7.6 Hz) (2-Butylbenzofuran-3-yl)(phenyl)methanone (T-1)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.88 (3H, t, J = 7.2 Hz), 1.34 (2H, sext, J = 7.2 Hz), 1.75 (2H, quint, J = 7.2 Hz), 2.89 (2H, t, J = 7.2 Hz, 2H), 7.18 (1H, t, J = 7.6 Hz), 7.28 (1H, d, J = 7.6 Hz), 7.34 (1H, d, J = 7.6 Hz), 7.48 (3H, t, J = 7.6 Hz), 7.60 (1H, t, J = 7.6 Hz), 7.81 (2H, d, J = 7.6 Hz)
(2-Butylbenzofuran-3-yl)(4-methoxyphenyl)methanone (T-2)
既報に従い合成した (2-Butylbenzofuran-3-yl)(4-methoxyphenyl)methanone (T-2)
Synthesized according to a previous report
(2-Butylbenzofuran-3-yl)(4-hydroxyphenyl)methanone (T-3)
既報に従い合成した (2-Butylbenzofuran-3-yl)(4-hydroxyphenyl)methanone (T-3)
Synthesized according to a previous report
(4-Butoxyphenyl)(2-butylbenzofuran-3-yl)methanone (T-4)
1H-NMR (400 MHz, CDCl3) δ: 0.89 (3H, t, J = 7.2 Hz), 1.00 (3H, t, J = 7.2 Hz), 1.31-1.38 (2H, m), 1.47-1.55 (2H, m), 1.71-1.83 (4H, m), 2.91 (2H, t, J = 7.2 Hz), 4.05 (2H, t, J = 7.2 Hz), 6.94 (2H, d, J = 8.2 Hz), 7.18 (1H, t, J = 7.6 Hz), 7.27 (1H, t, J = 7.6 Hz), 7.36 (1H, d, J = 7.6 Hz), 7.47 (1H, d, J = 7.6 Hz), 7.83 (2H, d, J = 8.2 Hz) (4-Butoxyphenyl)(2-butylbenzofuran-3-yl)methanone (T-4)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.89 (3H, t, J = 7.2 Hz), 1.00 (3H, t, J = 7.2 Hz), 1.31-1.38 (2H, m), 1.47-1.55 ( 2H, m), 1.71-1.83 (4H, m), 2.91 (2H, t, J = 7.2 Hz), 4.05 (2H, t, J = 7.2 Hz), 6.94 (2H, d, J = 8.2 Hz), 7.18 (1H, t, J = 7.6 Hz), 7.27 (1H, t, J = 7.6 Hz), 7.36 (1H, d, J = 7.6 Hz), 7.47 (1H, d, J = 7.6 Hz), 7.83 ( 2H, d, J = 8.2Hz)
(2-Butylbenzofuran-3-yl)(4-((3-ethylpentyl)oxy)phenyl)methanone (T-5)
1H-NMR (400 MHz, CDCl3) δ: 0.88-0.92 (9H, m), 1.31-1.49 (7H, m), 1.72-1.81 (4H, m), 2.91 (2H, t, J = 7.6 Hz), 4.07 (2H, t, J = 7.6 Hz), 6.94 (2H, d, J = 8.8 Hz), 7.18 (1H, td, J = 7.6, 1.2 Hz), 7.27 (1H, td, J = 7.6, 1.2 Hz), 7.36 (1H, dd, J = 7.6, 1.2 Hz), 7.47 (1H, dd, J = 7.6, 1.2 Hz), 7.83 (2H, d, J = 8.8 Hz) (2-Butylbenzofuran-3-yl)(4-((3-ethylpentyl)oxy)phenyl)methanone (T-5)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.88-0.92 (9H, m), 1.31-1.49 (7H, m), 1.72-1.81 (4H, m), 2.91 (2H, t, J = 7.6 Hz ), 4.07 (2H, t, J = 7.6 Hz), 6.94 (2H, d, J = 8.8 Hz), 7.18 (1H, td, J = 7.6, 1.2 Hz), 7.27 (1H, td, J = 7.6, 1.2 Hz), 7.36 (1H, dd, J = 7.6, 1.2 Hz), 7.47 (1H, dd, J = 7.6, 1.2 Hz), 7.83 (2H, d, J = 8.8 Hz)
(2-Butylbenzofuran-3-yl)(4-(2-cyclopentylethoxy)phenyl)methanone (T-6)
1H-NMR (400 MHz, CDCl3) δ: 0.89 (3H, t, J = 7.2 Hz), 1.14-2.05 (15H, m), 2.91 (2H, t, J = 7.2 Hz), 4.07 (2H, t, J = 7.2 Hz), 6.94 (2H, d, J = 8.8 Hz), 7.18 (1H, t, J = 7.6 Hz), 7.27 (1H, t, J = 7.6 Hz), 7.36 (1H, d, J = 7.6 Hz), 7.47 (1H, d, J = 7.6 Hz), 7.83 (2H, d, J = 8.8 Hz) (2-Butylbenzofuran-3-yl)(4-(2-cyclopentylethoxy)phenyl)methanone (T-6)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.89 (3H, t, J = 7.2 Hz), 1.14-2.05 (15H, m), 2.91 (2H, t, J = 7.2 Hz), 4.07 (2H, t, J = 7.2 Hz), 6.94 (2H, d, J = 8.8 Hz), 7.18 (1H, t, J = 7.6 Hz), 7.27 (1H, t, J = 7.6 Hz), 7.36 (1H, d, J = 7.6Hz), 7.47 (1H, d, J = 7.6Hz), 7.83 (2H, d, J = 8.8Hz)
(2-Butylbenzofuran-3-yl)(4-(2-cyclohexylethoxy)phenyl)methanone (T-7)
1H-NMR (400 MHz, CDCl3) δ: 0.85-1.79 (20H, m), 2.91 (2H, t, J = 7.2 Hz), 4.08 (2H, t, J = 7.2 Hz), 6.94 (2H, d, J = 8.4 Hz), 7.18 (1H, t, J = 7.5 Hz), 7.25-7.29 (1H, m), 7.36 (1H, d, J = 7.5 Hz), 7.47 (1H, d, J = 7.5 Hz), 7.83 (2H, d, J = 8.4 Hz) (2-Butylbenzofuran-3-yl)(4-(2-cyclohexylethoxy)phenyl)methanone (T-7)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.85-1.79 (20H, m), 2.91 (2H, t, J = 7.2 Hz), 4.08 (2H, t, J = 7.2 Hz), 6.94 (2H, d, J = 8.4 Hz), 7.18 (1H, t, J = 7.5 Hz), 7.25-7.29 (1H, m), 7.36 (1H, d, J = 7.5 Hz), 7.47 (1H, d, J = 7.5 Hz) Hz), 7.83 (2H, d, J = 8.4 Hz)
(2-Butylbenzofuran-3-yl)(4-(2-(dimethylamino)ethoxy)phenyl)methanone (T-8)
1H-NMR (400 MHz, CDCl3) δ: 0.89 (3H, t, J = 7.4 Hz), 1.35 (2H, sext, J = 7.4 Hz), 1.75 (2H, quint, J = 7.4 Hz), 2.37 (6H, s), 2.78 (2H, t, J = 5.6 Hz), 2.91 (2H, t, J = 7.4 Hz), 4.16 (2H, t, J = 5.6 Hz), 6.97 (2H, d, J = 8.6 Hz), 7.18 (1H, td, J = 8.0, 1.2 Hz, 1H), 7.26 (1H, td, J = 8.0, 1.2 Hz, 1H), 7.34 (1H, d, J = 8.0 Hz), 7.46 (1H, d, J = 8.0 Hz), 7.83 (2H, d, J = 8.6 Hz) (2-Butylbenzofuran-3-yl)(4-(2-(dimethylamino)ethoxy)phenyl)methanone (T-8)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.89 (3H, t, J = 7.4 Hz), 1.35 (2H, sext, J = 7.4 Hz), 1.75 (2H, quint, J = 7.4 Hz), 2.37 (6H, s), 2.78 (2H, t, J = 5.6 Hz), 2.91 (2H, t, J = 7.4 Hz), 4.16 (2H, t, J = 5.6 Hz), 6.97 (2H, d, J = 8.6 Hz), 7.18 (1H, td, J = 8.0, 1.2 Hz, 1H), 7.26 (1H, td, J = 8.0, 1.2 Hz, 1H), 7.34 (1H, d, J = 8.0 Hz), 7.46 ( 1H, d, J = 8.0 Hz), 7.83 (2H, d, J = 8.6 Hz)
(2-Butylbenzofuran-3-yl)(4-(2-(diethylamino)ethoxy)phenyl)methanone (T-9)
既報に従い合成した (2-Butylbenzofuran-3-yl)(4-(2-(diethylamino)ethoxy)phenyl)methanone (T-9)
Synthesized according to a previous report
(2-Butylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-10)
既報に従い合成した (2-Butylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-10)
Synthesized according to a previous report
(2-Butylbenzofuran-3-yl)(4-hydroxy-3-iodophenyl)methanone (T-11)
既報に従い合成した (2-Butylbenzofuran-3-yl)(4-hydroxy-3-iodophenyl)methanone (T-11)
Synthesized according to a previous report
(2-Butylbenzofuran-3-yl)(2-hydroxyphenyl)methanone (T-12)
1H-NMR (400 MHz, CDCl3) δ: 0.92 (3H, t, J = 7.4 Hz), 1.38 (2H, sext, J = 7.4 Hz), 1.79 (2H, quint, J = 7.4 Hz), 2.93 (2H, t, J = 7.4 Hz), 6.86 (1H, td, J = 7.8, 1.2 Hz), 7.09 (1H, dd, J = 7.8, 1.2 Hz), 7.23 (1H, td, J = 7.5, 1.2 Hz, 1H), 7.31 (1H, td, J = 7.5, 1.2 Hz), 7.40 (1H, dd, J = 7.5, 1.2 Hz), 7.50 (1H, dd, J = 7.5, 1.2 Hz), 7.52 (1H, td, J = 7.8, 1.2 Hz), 7.68 (1H, dd, J = 7.8, 1.2 Hz), 12.1 (1H, s) (2-Butylbenzofuran-3-yl)(2-hydroxyphenyl)methanone (T-12)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.92 (3H, t, J = 7.4 Hz), 1.38 (2H, sext, J = 7.4 Hz), 1.79 (2H, quint, J = 7.4 Hz), 2.93 (2H, t, J = 7.4 Hz), 6.86 (1H, td, J = 7.8, 1.2 Hz), 7.09 (1H, dd, J = 7.8, 1.2 Hz), 7.23 (1H, td, J = 7.5, 1.2 Hz) Hz, 1H), 7.31 (1H, td, J = 7.5, 1.2 Hz), 7.40 (1H, dd, J = 7.5, 1.2 Hz), 7.50 (1H, dd, J = 7.5, 1.2 Hz), 7.52 (1H , td, J = 7.8, 1.2 Hz), 7.68 (1H, dd, J = 7.8, 1.2 Hz), 12.1 (1H, s)
(2-Butylbenzofuran-3-yl)(3-hydroxyphenyl)methanone (T-13)
1H-NMR (400 MHz, CDCl3) δ: 0.89 (3H, t, J = 7.0 Hz), 1.34 (2H, sext, J = 7.0 Hz), 1.75 (2H, quint, J = 7.0 Hz), 2.89 (2H, t, J = 7.0 Hz), 7.07-7.12 (1H, m), 7. 19 (1H, t, J = 7.9 Hz), 7.29 (1H, d, J = 7.9 Hz), 7.32-7.36 (3H, m), 7.38 (1H, d, J = 7.9 Hz), 7.47 (1H, d, J = 7.9 Hz) (2-Butylbenzofuran-3-yl)(3-hydroxyphenyl)methanone (T-13)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.89 (3H, t, J = 7.0 Hz), 1.34 (2H, sext, J = 7.0 Hz), 1.75 (2H, quint, J = 7.0 Hz), 2.89 (2H, t, J = 7.0 Hz), 7.07-7.12 (1H, m), 7. 19 (1H, t, J = 7.9 Hz), 7.29 (1H, d, J = 7.9 Hz), 7.32-7.36 ( 3H, m), 7.38 (1H, d, J = 7.9 Hz), 7.47 (1H, d, J = 7.9 Hz)
(2-Ethylbenzofuran-3-yl)(4-hydroxyphenyl)methanone (T-14)
既報に従い合成した (2-Ethylbenzofuran-3-yl)(4-hydroxyphenyl)methanone (T-14)
Synthesized according to a previous report
(2-Ethylbenzofuran-3-yl)(2-hydroxyphenyl)methanone (T-15)
既報に従い合成した (2-Ethylbenzofuran-3-yl)(2-hydroxyphenyl)methanone (T-15)
Synthesized according to a previous report
(2-Ethylbenzofuran-3-yl)(3-hydroxyphenyl)methanone (T-16)
既報に従い合成した (2-Ethylbenzofuran-3-yl)(3-hydroxyphenyl)methanone (T-16)
Synthesized according to a previous report
(2-(Cyclohexylmethyl)benzofuran-3-yl)(4-hydroxyphenyl)methanone (T-17)
1H-NMR (400 MHz, CDCl3) δ: 0.86-1.27 (5H, m), 1.62-1.67 (5H, m), 1.79-1.90 (1H, m), 2.83 (2H, d, J = 7.6 Hz), 5.98 (1H, s), 6.90 (2H, d, J = 8.4 Hz), 7.17 (1H, td, J = 7,7, 1.2 Hz), 7.27 (1H, td, J = 7.7, 1.2 Hz), 7.23 (1H, dd, J = 7.7, 1. 2 Hz), 7.47 (1H, dd, J = 7.7, 1.2 Hz), 7.79 (2H, d, J = 8.4 Hz) (2-(Cyclohexylmethyl)benzofuran-3-yl)(4-hydroxyphenyl)methanone (T-17)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.86-1.27 (5H, m), 1.62-1.67 (5H, m), 1.79-1.90 (1H, m), 2.83 (2H, d, J = 7.6 Hz ), 5.98 (1H, s), 6.90 (2H, d, J = 8.4 Hz), 7.17 (1H, td, J = 7,7, 1.2 Hz), 7.27 (1H, td, J = 7.7, 1.2 Hz) , 7.23 (1H, dd, J = 7.7, 1.2 Hz), 7.47 (1H, dd, J = 7.7, 1.2 Hz), 7.79 (2H, d, J = 8.4 Hz)
(2-(Cyclohexylmethyl)benzofuran-3-yl)(2-hydroxyphenyl)methanone (T-18)
1H-NMR (400 MHz, CDCl3) δ: 0.87-1.28 (5H, m), 1.63-1.69 (5H, m), 1.82-1.93 (1H, m), 2.83 (2H, d, J = 7.6 Hz), 6.85 (1H, td, J = 8.0, 1.2 Hz), 7.08 (1H, dd, J = 8.0, 1.2 Hz), 7.22 (1H, td, J = 7.8, 1.2 Hz), 7.30 (1H, td, J = 7.8, 1.2 Hz), 7.36 (1H, dd, J = 7.8, 1.2 Hz), 7.50 (1H, dd, J = 7.8, 1.2 Hz), 7.52 (1H, td, J = 8.0, 1.2 Hz), 7.66 (1H, dd, J = 8.0, 1.2 Hz), 12.1 (s, 1H) (2-(Cyclohexylmethyl)benzofuran-3-yl)(2-hydroxyphenyl)methanone (T-18)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.87-1.28 (5H, m), 1.63-1.69 (5H, m), 1.82-1.93 (1H, m), 2.83 (2H, d, J = 7.6 Hz ), 6.85 (1H, td, J = 8.0, 1.2 Hz), 7.08 (1H, dd, J = 8.0, 1.2 Hz), 7.22 (1H, td, J = 7.8, 1.2 Hz), 7.30 (1H, td, J = 7.8, 1.2 Hz), 7.36 (1H, dd, J = 7.8, 1.2 Hz), 7.50 (1H, dd, J = 7.8, 1.2 Hz), 7.52 (1H, td, J = 8.0, 1.2 Hz), 7.66 (1H, dd, J = 8.0, 1.2Hz), 12.1 (s, 1H)
(2-(Cyclohexylmethyl)benzofuran-3-yl)(3-hydroxyphenyl)methanone (T-19)
1H-NMR (400 MHz, CDCl3) δ: 0.88-1.28 (5H, m), 1.64-1.67 (5H, m), 1.80-1.89 (1H, m), 2.82 (2H, d, J = 7.2 Hz), 5.5 (1H, s), 7.07-7.12 (1H, m), 7.18 (1H, t, J = 8.0 Hz), 7.27 (1H, t, J = 8.0 Hz), 7.32-7.36 (4H, m), 7.48 (1H, d, J = 8.0 Hz) (2-(Cyclohexylmethyl)benzofuran-3-yl)(3-hydroxyphenyl)methanone (T-19)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.88-1.28 (5H, m), 1.64-1.67 (5H, m), 1.80-1.89 (1H, m), 2.82 (2H, d, J = 7.2 Hz ), 5.5 (1H, s), 7.07-7.12 (1H, m), 7.18 (1H, t, J = 8.0 Hz), 7.27 (1H, t, J = 8.0 Hz), 7.32-7.36 (4H, m) , 7.48 (1H, d, J = 8.0Hz)
(2-Benzylbenzofuran-3-yl)(4-hydroxyphenyl)methanone (T-20)
既報に従い合成した (2-Benzylbenzofuran-3-yl)(4-hydroxyphenyl)methanone (T-20)
Synthesized according to a previous report
(2-Benzylbenzofuran-3-yl)(2-hydroxyphenyl)methanone (T-21)
1H-NMR (400 MHz, CDCl3) δ: 4.24 (2H, s), 6.80 (1H, td, J = 8.0, 1.5 Hz), 7.05 (1H, dd, J = 8.0, 1.5Hz), 7.16-7.22 (2H, m), 7.24-7.31 (5H, m), 7.35 (1H, d, J = 8.0 Hz), 7.65 (1H, dd, J = 8.0, 1.5 Hz) (2-Benzylbenzofuran-3-yl)(2-hydroxyphenyl)methanone (T-21)
1 H-NMR (400 MHz, CDCl 3 ) δ: 4.24 (2H, s), 6.80 (1H, td, J = 8.0, 1.5 Hz), 7.05 (1H, dd, J = 8.0, 1.5Hz), 7.16- 7.22 (2H, m), 7.24-7.31 (5H, m), 7.35 (1H, d, J = 8.0Hz), 7.65 (1H, dd, J = 8.0, 1.5Hz)
(2-Benzylbenzofuran-3-yl)(3-hydroxyphenyl)methanone (T-22)
1H-NMR (400 MHz, CDCl3) δ: 4.23 (2H, s), 5.36 (1H, s), 7.05 (1H, dd, J = 8.0, 1.2 Hz), 7.14 (1H, td, J = 8.0, 1.2 Hz), 7.17-7.26 (5H, m), 7.27-7.35 (5H, m), 7. 41 (1H, dd, J = 8.0, 1.2 Hz) (2-Benzylbenzofuran-3-yl)(3-hydroxyphenyl)methanone (T-22)
1 H-NMR (400 MHz, CDCl 3 ) δ: 4.23 (2H, s), 5.36 (1H, s), 7.05 (1H, dd, J = 8.0, 1.2 Hz), 7.14 (1H, td, J = 8.0 , 1.2 Hz), 7.17-7.26 (5H, m), 7.27-7.35 (5H, m), 7. 41 (1H, dd, J = 8.0, 1.2 Hz)
(2-Butylbenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone (T-23)
既報に従い合成した (2-Butylbenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone (T-23)
Synthesized according to a previous report
(2-Butyl-5-chlorobenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-24)
1H-NMR (400 MHz, CDCl3) δ: 0.91 (3H, t, J = 7.6 Hz), 1.35 (2H, sext, J = 7.6 Hz), 1.76 (2H, quint, J = 7.6 Hz), 2.82 (2H, t, J = 7.6 Hz), 6.21 (1H, s), 7.27 (1H, dd, J = 9.0, 2.4 Hz), 7.41 (1H, d, J = 9.0 Hz), 7.46 (1H, d, J = 2.4 Hz, 1H), 8.11 (2H, s) (2-Butyl-5-chlorobenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-24)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.91 (3H, t, J = 7.6 Hz), 1.35 (2H, sext, J = 7.6 Hz), 1.76 (2H, quint, J = 7.6 Hz), 2.82 (2H, t, J = 7.6 Hz), 6.21 (1H, s), 7.27 (1H, dd, J = 9.0, 2.4 Hz), 7.41 (1H, d, J = 9.0 Hz), 7.46 (1H, d, J = 2.4Hz, 1H), 8.11 (2H, s)
(2-Butyl-5-chlorobenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone (T-25)
1H-NMR (400 MHz, CDCl3) δ: 0.90 (3H, t, J = 7.2 Hz), 1.35 (2H, sext, J = 7.2 Hz), 1.75 (2H, quint, J = 7.2 Hz), 2.82 (2H, t, J = 6.4 Hz), 6.18 (1H, br), 7.27 (1H, d, J = 2.0 Hz), 7.40 (1H, d, J = 7.2 Hz), 7.46 (1H, d, J = 2.0 Hz), 8.16 (2H, s) (2-Butyl-5-chlorobenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone (T-25)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.90 (3H, t, J = 7.2 Hz), 1.35 (2H, sext, J = 7.2 Hz), 1.75 (2H, quint, J = 7.2 Hz), 2.82 (2H, t, J = 6.4 Hz), 6.18 (1H, br), 7.27 (1H, d, J = 2.0 Hz), 7.40 (1H, d, J = 7.2 Hz), 7.46 (1H, d, J = 2.0Hz), 8.16 (2H, s)
(5-Bromo-2-butylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-26)
1H-NMR (400 MHz, CDCl3) δ: 0.91 (3H, t, J = 7.6 Hz), 1.35 (2H, sext, J = 7.6 Hz), 1.76 (2H, quint, J = 7.6 Hz), 2.82 (2H, t, J = 7.6 Hz), 6.21 (1H, s, 1H), 7.36 (1H, d, J = 8.8 Hz), 7.41 (1H, dd, J = 8.8, 2.0 Hz), 7.62 (1H, d, J = 2.0 Hz), 8.16 (2H, s) (5-Bromo-2-butylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-26)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.91 (3H, t, J = 7.6 Hz), 1.35 (2H, sext, J = 7.6 Hz), 1.76 (2H, quint, J = 7.6 Hz), 2.82 (2H, t, J = 7.6 Hz), 6.21 (1H, s, 1H), 7.36 (1H, d, J = 8.8 Hz), 7.41 (1H, dd, J = 8.8, 2.0 Hz), 7.62 (1H, d, J = 2.0Hz), 8.16 (2H, s)
(5-Bromo-2-butylbenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone (T-27)
1H-NMR (400 MHz, CDCl3) δ: 0.90 (3H, t, J = 7.6 Hz), 1.34 (2H, sext, J = 7.6 Hz), 1.76 (2H, quint, J = 7.6 Hz), 2.83 (2H, t, J = 7.6 Hz), 7.36 (1H, d, J = 9.0 Hz), 7.41 (1H, dd, J = 9.0, 2.0 Hz), 7.60 (1H, d, J = 2.0 Hz), 7.96 (2H, s) (5-Bromo-2-butylbenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone (T-27)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.90 (3H, t, J = 7.6 Hz), 1.34 (2H, sext, J = 7.6 Hz), 1.76 (2H, quint, J = 7.6 Hz), 2.83 (2H, t, J = 7.6 Hz), 7.36 (1H, d, J = 9.0 Hz), 7.41 (1H, dd, J = 9.0, 2.0 Hz), 7.60 (1H, d, J = 2.0 Hz), 7.96 (2H, s)
(2-(Cyclohexylmethyl)benzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-28)
1H-NMR (400 MHz, CDCl3) δ: 0.97-1.28 (5H, m), 1.61-1.70 (5H, m), 1.83-1.88 (1H, m), 2.80 (2H, d, J = 7.2 Hz), 6.19 (1H, s), 7.23 (1H, td, J = 7.6, 1.2 Hz), 7.28 (1H, td, J = 7.6, 1.2 Hz), 7.34 (1H, dd, J = 7.6, 1.2 Hz), 7.49 (1H, dd, J = 7.6, 1.2 Hz), 8.18 (2H, s) (2-(Cyclohexylmethyl)benzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-28)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.97-1.28 (5H, m), 1.61-1.70 (5H, m), 1.83-1.88 (1H, m), 2.80 (2H, d, J = 7.2 Hz ), 6.19 (1H, s), 7.23 (1H, td, J = 7.6, 1.2 Hz), 7.28 (1H, td, J = 7.6, 1.2 Hz), 7.34 (1H, dd, J = 7.6, 1.2 Hz) , 7.49 (1H, dd, J = 7.6, 1.2 Hz), 8.18 (2H, s)
(5-Chloro-2-(cyclohexylmethyl)benzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-29)
1H-NMR (400 MHz, CDCl3) δ: 0.83-1.29 (5H, m), 1.62-1.70 (5H, m), 1.79-1.89 (1H, m), 2.75 (2H, d, J = 7.6 Hz), 6.23 (1H, s), 7.27 (1H, dd, J = 8.2, 2.4 Hz), 7.39 (1H, d, J = 2.4 Hz), 7.41 (1H, d, J = 8.2 Hz), 8.16 (2H, s) (5-Chloro-2-(cyclohexylmethyl)benzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-29)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.83-1.29 (5H, m), 1.62-1.70 (5H, m), 1.79-1.89 (1H, m), 2.75 (2H, d, J = 7.6 Hz ), 6.23 (1H, s), 7.27 (1H, dd, J = 8.2, 2.4 Hz), 7.39 (1H, d, J = 2.4 Hz), 7.41 (1H, d, J = 8.2 Hz), 8.16 (2H , s)
(2-(Cyclohexylmethyl)-5-fluorobenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-30)
1H-NMR (400 MHz, CDCl3) δ: 0.95-1.28 (5H, m), 1.62-1.69 (5H, m), 1.80-1.90 (1H, m), 2.76 (2H, d, J = 7.2 Hz), 6.22 (1H, br), 7.02 (1H, td, J = 8.7, 2.8 Hz), 7. 05 (1H, dd, J = 8.7, 2.8 Hz), 7.42 (1H, d, J = 8.7 Hz), 8.15 (2H, s) (2-(Cyclohexylmethyl)-5-fluorobenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-30)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.95-1.28 (5H, m), 1.62-1.69 (5H, m), 1.80-1.90 (1H, m), 2.76 (2H, d, J = 7.2 Hz ), 6.22 (1H, br), 7.02 (1H, td, J = 8.7, 2.8 Hz), 7. 05 (1H, dd, J = 8.7, 2.8 Hz), 7.42 (1H, d, J = 8.7 Hz) , 8.15 (2H, s)
(2-(Cyclohexylmethyl)-5-fluorobenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone (T-31)
1H-NMR (400 MHz, CDCl3) δ: 0.90-1.33 (5H, m), 1.60-1.67 (5H, m), 1.82-1.98 (1H, m), 2.81 (2H, d, J = 6.8 Hz), 6.24 (1H, br), 7.07 (1H, td, J = 9.2, 2.8 Hz), 7. 0 31(1H, dd, J = 9.2, 2.8 Hz), 7.40 (1H, d, J = 9.2 Hz), 7.94 (2H, s) (2-(Cyclohexylmethyl)-5-fluorobenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone (T-31)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.90-1.33 (5H, m), 1.60-1.67 (5H, m), 1.82-1.98 (1H, m), 2.81 (2H, d, J = 6.8 Hz ), 6.24 (1H, br), 7.07 (1H, td, J = 9.2, 2.8 Hz), 7. 0 31 (1H, dd, J = 9.2, 2.8 Hz), 7.40 (1H, d, J = 9.2 Hz ), 7.94 (2H, s)
(5-Bromo-2-(cyclohexylmethyl)benzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-32)
1H-NMR (400 MHz, CDCl3) δ: 0.92-1.28 (5H, m), 1.61-1.70 (5H, m), 1.79-1.90 (1H, m), 2.75 (2H, d, J = 7.6 Hz), 6.23 (1H, s), 7.36 (1H, d, J = 8.9 Hz), 7.41 (1H, dd, J = 8.9, 2.0 Hz), 7.56 (1H, d, J = 2.0 Hz), 8.16 (2H, s) (5-Bromo-2-(cyclohexylmethyl)benzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-32)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.92-1.28 (5H, m), 1.61-1.70 (5H, m), 1.79-1.90 (1H, m), 2.75 (2H, d, J = 7.6 Hz ), 6.23 (1H, s), 7.36 (1H, d, J = 8.9 Hz), 7.41 (1H, dd, J = 8.9, 2.0 Hz), 7.56 (1H, d, J = 2.0 Hz), 8.16 (2H , s)
(5-Bromo-2-(cyclohexylmethyl)benzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone (T-33)
1H-NMR (400 MHz, CDCl3) δ: 0.86-1.27 (5H, m), 1.61-1.69 (5H, m), 1.80-1.87 (1H, m), 2.76 (2H, d, J = 7.2 Hz), 6.37 (1H, br), 7.37 (1H, d, J = 9.0 Hz), 7.41 (1H, dd, J = 9.0, 2.0 Hz), 7.54 (1H, d, J = 2.0 Hz), 7.96 (s, 2H) (5-Bromo-2-(cyclohexylmethyl)benzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone (T-33)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.86-1.27 (5H, m), 1.61-1.69 (5H, m), 1.80-1.87 (1H, m), 2.76 (2H, d, J = 7.2 Hz ), 6.37 (1H, br), 7.37 (1H, d, J = 9.0 Hz), 7.41 (1H, dd, J = 9.0, 2.0 Hz), 7.54 (1H, d, J = 2.0 Hz), 7.96 (s , 2H)
(2-(Cyclohexylmethyl)-5-methylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-34)
1H-NMR (400 MHz, CDCl3) δ: 0.92-1.28 (5H, m), 1.61-1.68 (5H, m), 1.81-1.90 (1H, m), 2.39 (3H, s), 2.76 (2H, d, J = 6.4 Hz), 6.19 (1H, s), 7.11 (1H, dd, J = 8.1, 2.0 Hz), 7.17 (1H, d, J = 2.0 Hz), 7.36 (1H, d, J = 8.1 Hz), 8.19 (2H, s) (2-(Cyclohexylmethyl)-5-methylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-34)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.92-1.28 (5H, m), 1.61-1.68 (5H, m), 1.81-1.90 (1H, m), 2.39 (3H, s), 2.76 (2H , d, J = 6.4 Hz), 6.19 (1H, s), 7.11 (1H, dd, J = 8.1, 2.0 Hz), 7.17 (1H, d, J = 2.0 Hz), 7.36 (1H, d, J = 8.1Hz), 8.19 (2H, s)
(2-(Cyclohexylmethyl)benzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone (T-36)
1H-NMR (400 MHz, CDCl3) δ: 0.97-1.28 (5H, m), 1.59-1.68 (5H, m), 1.77-1.84 (1H, m), 2.81 (2H, d, J = 7.2 Hz), 6.20 (1H, s), 7.25 (1H, td, J = 8.0, 1.6 Hz), 7.31 (1H, td, J = 8.0, 1.6 Hz), 7.30 (1H, dd, J = 8.0, 1.6 Hz), 7.55 (1H, dd, J = 8.0, 1.6 Hz), 7.93 (2H, s) (2-(Cyclohexylmethyl)benzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone (T-36)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.97-1.28 (5H, m), 1.59-1.68 (5H, m), 1.77-1.84 (1H, m), 2.81 (2H, d, J = 7.2 Hz ), 6.20 (1H, s), 7.25 (1H, td, J = 8.0, 1.6 Hz), 7.31 (1H, td, J = 8.0, 1.6 Hz), 7.30 (1H, dd, J = 8.0, 1.6 Hz) , 7.55 (1H, dd, J = 8.0, 1.6 Hz), 7.93 (2H, s)
(5-Chloro-2-(cyclohexylmethyl)benzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone (T-37)
1H-NMR (400 MHz, CDCl3) δ: 0.86-1.30 (5H, m), 1.61-1.69 (5H, m), 1.80-1.89 (1H, m), 2.76 (2H, d, J = 6.8 Hz), 6.39 (1H, s), 7.26 (1H, dd, J = 8.8, 1.6 Hz), 7.37 (1H, d, J = 1.6 Hz), 7.41 (1H, d, J = 8.8 Hz), 7.95 (2H, s) (5-Chloro-2-(cyclohexylmethyl)benzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone (T-37)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.86-1.30 (5H, m), 1.61-1.69 (5H, m), 1.80-1.89 (1H, m), 2.76 (2H, d, J = 6.8 Hz ), 6.39 (1H, s), 7.26 (1H, dd, J = 8.8, 1.6 Hz), 7.37 (1H, d, J = 1.6 Hz), 7.41 (1H, d, J = 8.8 Hz), 7.95 (2H , s)
(2-Butyl-6-chlorobenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-38)
1H-NMR (400 MHz, CDCl3) δ: 0.91 (3H, t, J = 7.6 Hz), 1.35 (2H, sext, J = 7.6 Hz), 1.76 (2H, quint, J = 7.6 Hz), 2.85 (2H, t, J = 7.6 Hz), 6.30 (1H, br), 7.22 (1H, d, J = 8.4 Hz), 7.33 (1H, d, J = 8.4 Hz), 7.50 (1H, s), 8.15 (2H, s) (2-Butyl-6-chlorobenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-38)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.91 (3H, t, J = 7.6 Hz), 1.35 (2H, sext, J = 7.6 Hz), 1.76 (2H, quint, J = 7.6 Hz), 2.85 (2H, t, J = 7.6 Hz), 6.30 (1H, br), 7.22 (1H, d, J = 8.4 Hz), 7.33 (1H, d, J = 8.4 Hz), 7.50 (1H, s), 8.15 (2H, s)
(2-Butyl-6-chlorobenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone (T-39)
1H-NMR (400 MHz, CDCl3) δ: 0.91 (3H, t, J = 7.6 Hz), 1.36 (2H, sext, J = 7.6 Hz), 1.76 (2H, quint, J = 7.6 Hz), 2.86 (2H, t, J = 7.6 Hz), 6.38 (1H, br), 7.22 (1H, dd, J = 8.2, 2.0 Hz), 7.31 (1H, d, J = 8.2 Hz), 7.50 (1H, d, J = 2.0 Hz), 7. 95 (2H, s) (2-Butyl-6-chlorobenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone (T-39)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.91 (3H, t, J = 7.6 Hz), 1.36 (2H, sext, J = 7.6 Hz), 1.76 (2H, quint, J = 7.6 Hz), 2.86 (2H, t, J = 7.6 Hz), 6.38 (1H, br), 7.22 (1H, dd, J = 8.2, 2.0 Hz), 7.31 (1H, d, J = 8.2 Hz), 7.50 (1H, d, J = 2.0Hz), 7.95 (2H, s)
(6-Chloro-2-(cyclohexylmethyl)benzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-40)
1H-NMR (400 MHz, CDCl3) δ: 0.88-1.28 (5H, m), 1.62-1.70 (5H, m), 1.83-1.88 (1H, m), 2.77 (2H, d, J = 8.4 Hz), 6.20 (1H, s), 7.21 (1H, dd, J = 8.4, 2.0 Hz), 7.27 (1H, d, J = 8.4 Hz), 7.51 (1H, d, J = 2.0 Hz), 8.15 (2H, s) (6-Chloro-2-(cyclohexylmethyl)benzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-40)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.88-1.28 (5H, m), 1.62-1.70 (5H, m), 1.83-1.88 (1H, m), 2.77 (2H, d, J = 8.4 Hz ), 6.20 (1H, s), 7.21 (1H, dd, J = 8.4, 2.0 Hz), 7.27 (1H, d, J = 8.4 Hz), 7.51 (1H, d, J = 2.0 Hz), 8.15 (2H , s)
(6-Chloro-2-(cyclohexylmethyl)benzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone (T-41)
1H-NMR (400 MHz, CDCl3) δ: 0.92-1.30 (5H, m), 1.54-1.72 (5H, m), 1.76-1.90 (1H, m), 2.76 (2H, d, J= 7.6 Hz), 6.40 (1H, br), 7.21 (1H, dd, J= 8.4, 2.0 Hz), 7.27 (1H, d, J= 8.4 Hz), 7.51 (1H, d, J = 2.0 Hz), 7.95 (2H, s) (6-Chloro-2-(cyclohexylmethyl)benzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone (T-41)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.92-1.30 (5H, m), 1.54-1.72 (5H, m), 1.76-1.90 (1H, m), 2.76 (2H, d, J = 7.6 Hz ), 6.40 (1H, br), 7.21 (1H, dd, J = 8.4, 2.0 Hz), 7.27 (1H, d, J = 8.4 Hz), 7.51 (1H, d, J = 2.0 Hz), 7.95 (2H , s)
(2-Butyl-5-fluorobenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-42)
1H-NMR (400 MHz, CDCl3) δ: 0.92 (3H, t, J = 7.6 Hz), 1.36 (2H, sext, J = 7.6 Hz), 1.77 (2H, quint, J = 7.6 Hz), 2.84 (2H, t, J = 7.6 Hz), 6.21 (1H, s), 7.02 (1H, td, J = 8.8, 2.4 Hz), 7.13 (1H, dd, J = 8.8, 2.4 Hz), 7.41 (1H, dd, J = 8.8, 2.4 Hz), 8.16 (2H, s) (2-Butyl-5-fluorobenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-42)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.92 (3H, t, J = 7.6 Hz), 1.36 (2H, sext, J = 7.6 Hz), 1.77 (2H, quint, J = 7.6 Hz), 2.84 (2H, t, J = 7.6 Hz), 6.21 (1H, s), 7.02 (1H, td, J = 8.8, 2.4 Hz), 7.13 (1H, dd, J = 8.8, 2.4 Hz), 7.41 (1H, dd, J = 8.8, 2.4Hz), 8.16 (2H, s)
(2-Butyl-5-fluorobenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone (T-43)
1H-NMR (400 MHz, CDCl3) δ: 0.91 (3H, t, J = 7.6 Hz), 1.36 (2H, sext, J = 7.6 Hz), 1.76 (2H, quint, J = 7.6 Hz), 2.85 (2H, t, J = 7.6 Hz), 6.37 (1H, s), 7.02 (1H, td, J = 8.8, 2.8 Hz), 7.10 (1H, d, J = 8.8 Hz), 7.42 (1H, dd, J = 8.8, 2.8 Hz), 7.96 (2H, s) (2-Butyl-5-fluorobenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone (T-43)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.91 (3H, t, J = 7.6 Hz), 1.36 (2H, sext, J = 7.6 Hz), 1.76 (2H, quint, J = 7.6 Hz), 2.85 (2H, t, J = 7.6 Hz), 6.37 (1H, s), 7.02 (1H, td, J = 8.8, 2.8 Hz), 7.10 (1H, d, J = 8.8 Hz), 7.42 (1H, dd, J = 8.8, 2.8Hz), 7.96 (2H, s)
(4-Hydroxy-3,5-diiodophenyl)(2-octylbenzofuran-3-yl)methanone (T-44)
1H-NMR (400 MHz, CDCl3) δ: 0.86 (3H, t, J = 7.2 Hz), 1.16-1.34 (10H, m), 1.78 (2H, quint, J = 7.2 Hz), 2.86 (2H, t, J = 7.2 Hz), 6.34 (1H, br), 7.23 (1H, td, J = 7.8, 1.2 Hz), 7.31 (1H, td, J = 7.8, 1.2 Hz), 7.39 (1H, d, J = 7.8 Hz) 7.49 (1H, d, J = 7.8 Hz), 8.18 (s, 2H) (4-Hydroxy-3,5-diiodophenyl)(2-octylbenzofuran-3-yl)methanone (T-44)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.86 (3H, t, J = 7.2 Hz), 1.16-1.34 (10H, m), 1.78 (2H, quint, J = 7.2 Hz), 2.86 (2H, t, J = 7.2 Hz), 6.34 (1H, br), 7.23 (1H, td, J = 7.8, 1.2 Hz), 7.31 (1H, td, J = 7.8, 1.2 Hz), 7.39 (1H, d, J = 7.8 Hz) 7.49 (1H, d, J = 7.8 Hz), 8.18 (s, 2H)
(4-Hydroxy-3,5-diiodophenyl)(2-octylbenzofuran-3-yl)methanone (T-45)
1H-NMR (400 MHz, CDCl3) δ: 0.90 (3H, t, J = 7.2 Hz), 1.16-1.34 (10H, m), 1.77 (2H, quint, J =7.2 Hz), 2.86 (2H, t, J = 7.2 Hz), 6.29 (1H, brs), 7.22 (1H, td, J = 7.2, 1.2 Hz), 7.31 (1H, td, J = 7.2, 1.2 Hz), 7.39 (1H, d, J = 7.2 Hz) 7.49 (1H, d, J = 7.2 Hz), 7.98 (s, 2H) (4-Hydroxy-3,5-diiodophenyl)(2-octylbenzofuran-3-yl)methanone (T-45)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.90 (3H, t, J = 7.2 Hz), 1.16-1.34 (10H, m), 1.77 (2H, quint, J =7.2 Hz), 2.86 (2H, t, J = 7.2 Hz), 6.29 (1H, brs), 7.22 (1H, td, J = 7.2, 1.2 Hz), 7.31 (1H, td, J = 7.2, 1.2 Hz), 7.39 (1H, d, J = 7.2 Hz) 7.49 (1H, d, J = 7.2 Hz), 7.98 (s, 2H)
(4-Hydroxy-3,5-diiodophenyl)(2-isopentylbenzofuran-3-yl)methanone (T-46)
1H-NMR (400 MHz, CDCl3) δ 0.91 (6H, d, J = 6.8 Hz), 1.59 (1H, sept, J = 6.8 Hz), 1.69 (2H, q, J = 6.8 Hz), 2.89 (2H, t, J = 6.8 Hz), 6.19 (1H, br), 7.24 (1H, t, J = 7.2, Hz), 7.30 (1H, t, J = 7.2 Hz), 7.41 (1H, d, J = 7.2 Hz), 7.49 (1H, d, J = 7.2 Hz), 8.18 (2H, s) (4-Hydroxy-3,5-diiodophenyl)(2-isopentylbenzofuran-3-yl)methanone (T-46)
1 H-NMR (400 MHz, CDCl 3 ) δ 0.91 (6H, d, J = 6.8 Hz), 1.59 (1H, sept, J = 6.8 Hz), 1.69 (2H, q, J = 6.8 Hz), 2.89 ( 2H, t, J = 6.8 Hz), 6.19 (1H, br), 7.24 (1H, t, J = 7.2, Hz), 7.30 (1H, t, J = 7.2 Hz), 7.41 (1H, d, J = 7.2Hz), 7.49 (1H, d, J = 7.2Hz), 8.18 (2H, s)
(3,5-Dibromo-4-hydroxyphenyl)(2-isopentylbenzofuran-3-yl)methanone (T-47)
1H-NMR (400 MHz, CDCl3) δ: 0.91 (6H, d, J = 6.8 Hz), 1.59 (1H, sept, J = 6.8 Hz), 1.69 (2H, q, J = 6.8 Hz), 2.89 (2H, t, J = 6.8 Hz), 6.37 (1H, br), 7.23 (1H, t, J = 7.6 Hz), 7.30 (1H, t, J = 7.6 Hz), 7.39 (1H, d, J = 7.6 Hz), 7.49 (1H, d, J = 7.6 Hz), 7.98 (2H, s) (3,5-Dibromo-4-hydroxyphenyl)(2-isopentylbenzofuran-3-yl)methanone (T-47)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.91 (6H, d, J = 6.8 Hz), 1.59 (1H, sept, J = 6.8 Hz), 1.69 (2H, q, J = 6.8 Hz), 2.89 (2H, t, J = 6.8 Hz), 6.37 (1H, br), 7.23 (1H, t, J = 7.6 Hz), 7.30 (1H, t, J = 7.6 Hz), 7.39 (1H, d, J = 7.6Hz), 7.49 (1H, d, J = 7.6Hz), 7.98 (2H, s)
(2-(3,3-Dimethylbutyl)benzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-50)
1H-NMR (400 MHz, CDCl3) δ: 0.93 (9H, s), 1.67-1.76 (2H, m), 2.82-2.87 (2H, m), 6.18 (1H, br), 7.24 (1H, td, J = 7.2, 1,2 Hz), 7.30 (1H, td, J = 7.2, 1,2 Hz), 7.40 (1H, dd, J = 7.2, 1.2 Hz), 7.49 (1H, d, J = 7.2 Hz), 8.18 (2H, s) (2-(3,3-Dimethylbutyl)benzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-50)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.93 (9H, s), 1.67-1.76 (2H, m), 2.82-2.87 (2H, m), 6.18 (1H, br), 7.24 (1H, td , J = 7.2, 1,2 Hz), 7.30 (1H, td, J = 7.2, 1,2 Hz), 7.40 (1H, dd, J = 7.2, 1.2 Hz), 7.49 (1H, d, J = 7.2 Hz), 8.18 (2H, s)
(2-(2,2-Dimethylbutyl)benzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-52)
1H-NMR (400 MHz, CDCl3) δ: 0.86 (3H, t, J = 7.2 Hz), 0.92 (6H, s), 1.33 (2H, q, J = 7.2 Hz), 2.89 (2H, t, J = 7.2 Hz), 6.20 (1H, br), 2.91 (2H, s), 7.19-7.25 (2H, m) 7.30 (1H, td, J= 7.8, 1.2 Hz), 7.51 (1H, d, J= 7.8 Hz), 8.18 (2H, s) (2-(2,2-Dimethylbutyl)benzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-52)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.86 (3H, t, J = 7.2 Hz), 0.92 (6H, s), 1.33 (2H, q, J = 7.2 Hz), 2.89 (2H, t, J = 7.2 Hz), 6.20 (1H, br), 2.91 (2H, s), 7.19-7.25 (2H, m) 7.30 (1H, td, J = 7.8, 1.2 Hz), 7.51 (1H, d, J = 7.8Hz), 8.18 (2H, s)
(2-(2,2-Dimethylbutyl)benzofuran-3-yl)(4-hydroxy-3,5-dibromophenyl)methanone (T-53)
1H-NMR (400 MHz, CDCl3) δ: 0.88 (3H. t, J = 7.2 Hz), 0.95 (6H, s), 1.33 (2H, q, J = 7.2 Hz), 2.91 (2H, t, J = 7.2 Hz), 6.22 (1H, br), 7.19-7.26 (2H, m), 7.30 (1H, td, J = 8.4, 1.2 Hz), 7.54 (1H, d, J = 8.4 Hz), 7.98 (2H, s) (2-(2,2-Dimethylbutyl)benzofuran-3-yl)(4-hydroxy-3,5-dibromophenyl)methanone (T-53)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.88 (3H. t, J = 7.2 Hz), 0.95 (6H, s), 1.33 (2H, q, J = 7.2 Hz), 2.91 (2H, t, J = 7.2 Hz), 6.22 (1H, br), 7.19-7.26 (2H, m), 7.30 (1H, td, J = 8.4, 1.2 Hz), 7.54 (1H, d, J = 8.4 Hz), 7.98 ( 2H, s)
(6-Chloro-2-(3,3-dimethylbutyl)benzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-54)
1H-NMR (400 MHz, CDCl3) δ: 0.91 (9H, s), 1.53-1.73 (2H, m), 2.75-2.84 (2H, m), 6.18 (1H, br), 7.22 (1H, dd, J = 8.4, 2.0 Hz), 7.32 (1H, d, J = 8.4 Hz), 7.50 (1H, d, J = 2.0 Hz), 8.15 (2H, s) (6-Chloro-2-(3,3-dimethylbutyl)benzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-54)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.91 (9H, s), 1.53-1.73 (2H, m), 2.75-2.84 (2H, m), 6.18 (1H, br), 7.22 (1H, dd , J = 8.4, 2.0 Hz), 7.32 (1H, d, J = 8.4 Hz), 7.50 (1H, d, J = 2.0 Hz), 8.15 (2H, s)
(6-Chloro-2-(3,3-dimethylbutyl)benzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone (T-55)
1H-NMR (400 MHz, CDCl3) δ: 0.92 (9H, s), 1.65-1.70 (2H, m), 2.80-2.85 (2H, m), 6.33 (1H, br), 7.22 (1H, dd, J = 8.4, 2.0 Hz), 7.31 (1H, d, J = 8.4 Hz), 7.50 (1H, d, J = 2.0 Hz), 7.96 (2H, s) (6-Chloro-2-(3,3-dimethylbutyl)benzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone (T-55)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.92 (9H, s), 1.65-1.70 (2H, m), 2.80-2.85 (2H, m), 6.33 (1H, br), 7.22 (1H, dd , J = 8.4, 2.0 Hz), 7.31 (1H, d, J = 8.4 Hz), 7.50 (1H, d, J = 2.0 Hz), 7.96 (2H, s)
(2-Butyl-7-chlorobenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-56)
1H-NMR (400 MHz, CDCl3) δ: 0.93 (3H, t, J = 7.2 Hz), 1.38 (2H, sext, J = 7.2 Hz), 1.80 (2H, quint, J = 7.2 Hz), 2.88 (2H, t, J = 7.0 Hz), 6.20 (1H, br), 7.17 (1H, t, J = 7.6 Hz), 7.30-7.32 (2H, m), 8.16 (2H, s) (2-Butyl-7-chlorobenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-56)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.93 (3H, t, J = 7.2 Hz), 1.38 (2H, sext, J = 7.2 Hz), 1.80 (2H, quint, J = 7.2 Hz), 2.88 (2H, t, J = 7.0 Hz), 6.20 (1H, br), 7.17 (1H, t, J = 7.6 Hz), 7.30-7.32 (2H, m), 8.16 (2H, s)
(2-Butyl-7-chlorobenzofuran-3-yl)(4-hydroxy-3,5-dibromophenyl)methanone (T-57)
1H-NMR (400 MHz, CDCl3) δ: 0.93 (3H, t, J = 7.2 Hz), 1.38 (2H, sext, J = 7.2 Hz), 1.80 (2H, quint, J =7.2 Hz), 2.88 (2H, t, J = 7.2 Hz), 6.24 (1H, br), 7.17 (1H, t, J = 7.6 Hz), 7.30-7.32 (2H, m), 7.96 (2H, s) (2-Butyl-7-chlorobenzofuran-3-yl)(4-hydroxy-3,5-dibromophenyl)methanone (T-57)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.93 (3H, t, J = 7.2 Hz), 1.38 (2H, sext, J = 7.2 Hz), 1.80 (2H, quint, J = 7.2 Hz), 2.88 (2H, t, J = 7.2 Hz), 6.24 (1H, br), 7.17 (1H, t, J = 7.6 Hz), 7.30-7.32 (2H, m), 7.96 (2H, s)
(2-Butyl-4-chlorobenzofuran-3-yl)(3,5-diiodo-4-hydroxyphenyl)methanone (T-58)
1H-NMR (400 MHz, CDCl3) δ 0.89 (3H, t, J = 7.4 Hz), 1.33 (2H, sext, J = 7.4 Hz), 1.72 (2H, quint, J = 7.6 Hz), 2.74 (2H, t, J = 7.4 Hz), 6.36 (1H, brs), 7.27-7.21 (2H, m), 7.43 (1H, dd, J = 8.8, 1.2 Hz), 7.99 (2H, s) (2-Butyl-4-chlorobenzofuran-3-yl)(3,5-diiodo-4-hydroxyphenyl)methanone (T-58)
1 H-NMR (400 MHz, CDCl 3 ) δ 0.89 (3H, t, J = 7.4 Hz), 1.33 (2H, sext, J = 7.4 Hz), 1.72 (2H, quint, J = 7.6 Hz), 2.74 ( 2H, t, J = 7.4 Hz), 6.36 (1H, brs), 7.27-7.21 (2H, m), 7.43 (1H, dd, J = 8.8, 1.2 Hz), 7.99 (2H, s)
(2-Butyl-4-chlorobenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone (T-59)
1H-NMR (400 MHz, CDCl3) δ: 0.89 (3H, t, J = 7.4 Hz), 1.33 (2H, sext, J = 7.4 Hz), 1.72 (2H, quint, J = 7.6 Hz), 2.72 (2H, t, J = 7.4 Hz), 6.22 (1H, brs), 7.28-7.20 (2H, m), 7.43 (1H, dd, J = 8.8, 1.2 Hz), 8.20 (2H, s) (2-Butyl-4-chlorobenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone (T-59)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.89 (3H, t, J = 7.4 Hz), 1.33 (2H, sext, J = 7.4 Hz), 1.72 (2H, quint, J = 7.6 Hz), 2.72 (2H, t, J = 7.4 Hz), 6.22 (1H, brs), 7.28-7.20 (2H, m), 7.43 (1H, dd, J = 8.8, 1.2 Hz), 8.20 (2H, s)
(7-Chloro-2-(3,3-dimethylbutyl)benzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-60)
1H-NMR (400 MHz, CDCl3) δ: 0.93 (9H, s), 1.69-1.73 (2H, m), 2.84-2.89 (2H, m), 6.20 (1H, br), 7.17 (1H, t, J = 8.0 Hz), 7.30 (2H, d, J = 8.0 Hz), 8.16 (2H, s) (7-Chloro-2-(3,3-dimethylbutyl)benzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-60)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.93 (9H, s), 1.69-1.73 (2H, m), 2.84-2.89 (2H, m), 6.20 (1H, br), 7.17 (1H, t , J = 8.0 Hz), 7.30 (2H, d, J = 8.0 Hz), 8.16 (2H, s)
(7-Chloro-2-(3,3-dimethylbutyl)benzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone (T-61)
1H-NMR (400 MHz, CDCl3) δ: 0.91 (9H, s), 1.70-1.75 (2H, m), 2.80-2.84 (2H, m), 6.20 (1H, br), 7.14 (1H, t, J = 8.0 Hz), 7.25 (2H, d, J = 8.0 Hz), 7.94 (2H, s) (7-Chloro-2-(3,3-dimethylbutyl)benzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone (T-61)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.91 (9H, s), 1.70-1.75 (2H, m), 2.80-2.84 (2H, m), 6.20 (1H, br), 7.14 (1H, t , J = 8.0 Hz), 7.25 (2H, d, J = 8.0 Hz), 7.94 (2H, s)
(4-Chloro-2-(3,3-dimethylbutyl)benzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-62)
1H-NMR (400 MHz, CDCl3) δ: 0.89 (9H, s), 1.63-1.67 (2H, m), 2.65-2.70 (2H, m), 6.25 (1H, br), 7.21-7.27 (2H, m), 7.42 (1H, dd, J = 7.6 Hz, 2.0 Hz), 8.20 (2H, s) (4-Chloro-2-(3,3-dimethylbutyl)benzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-62)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.89 (9H, s), 1.63-1.67 (2H, m), 2.65-2.70 (2H, m), 6.25 (1H, br), 7.21-7.27 (2H , m), 7.42 (1H, dd, J = 7.6 Hz, 2.0 Hz), 8.20 (2H, s)
(4-Chloro-2-(3,3-dimethylbutyl)benzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone (T-63)
1H-NMR (400 MHz, CDCl3) δ: 0.89 (9H, s), 1.62-1.66 (2H, m), 2.66-2.73 (2H, m), 6.25 (1H, br), 7.20-7.28 (2H, m), 7.45 (1H, dd, J = 7.6 Hz, 2.0 Hz), 7.92 (2H, s) (4-Chloro-2-(3,3-dimethylbutyl)benzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone (T-63)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.89 (9H, s), 1.62-1.66 (2H, m), 2.66-2.73 (2H, m), 6.25 (1H, br), 7.20-7.28 (2H , m), 7.45 (1H, dd, J = 7.6 Hz, 2.0 Hz), 7.92 (2H, s)
(4-Hydroxy-3,5-diiodophenyl)(2-(2-methoxyethyl)benzofuran-3-yl)methanone (T-64) 1H-NMR (400 MHz, CDCl3) δ: 3.14 (2H, t, J = 6.8 Hz), 3.23 (3H, s), 3.77 (2H, t, J = 6.8 Hz), 6.20 (1H, br), 7.23-7.26 (1H, m), 7.32 (1H, td, J= 8.0, 1.2 Hz), 7.38 (1H, d, J= 8.0 Hz), 7.49 (1H, d, J = 8.0 Hz), 8.00 (2H, s) (4-Hydroxy-3,5-diiodophenyl)(2-(2-methoxyethyl)benzofuran-3-yl)methanone (T-64) 1 H-NMR (400 MHz, CDCl 3 ) δ: 3.14 (2H, t, J = 6.8 Hz), 3.23 (3H, s), 3.77 (2H, t, J = 6.8 Hz), 6.20 (1H, br), 7.23-7.26 (1H, m), 7.32 (1H, td, J = 8.0 , 1.2 Hz), 7.38 (1H, d, J = 8.0 Hz), 7.49 (1H, d, J = 8.0 Hz), 8.00 (2H, s)
(2-Ethyl-6-fluorobenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-65)
1H-NMR (400 MHz, CDCl3) δ: 1.32 (3H, t, J = 7.4 Hz), 2.82 (2H, q, J = 7.4 Hz), 6.25 (1H, br), 6.99 (1H, td, J = 8.8, 2.4 Hz), 7.19 (1H, dd, J = 8.8, 2.4 Hz), 7.36 (1H, dd, J = 8.8, 4.8 Hz, 1H), 8.14 (2H, s) (2-Ethyl-6-fluorobenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-65)
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.32 (3H, t, J = 7.4 Hz), 2.82 (2H, q, J = 7.4 Hz), 6.25 (1H, br), 6.99 (1H, td, J = 8.8, 2.4 Hz), 7.19 (1H, dd, J = 8.8, 2.4 Hz), 7.36 (1H, dd, J = 8.8, 4.8 Hz, 1H), 8.14 (2H, s)
(2-Ethyl-6-fluorobenzofuran-3-yl)(4-hydroxy-3,5-dibromophenyl)methanone (T-66)
1H-NMR (400 MHz, CDCl3) δ: 1.35 (3H, t, J = 7.4 Hz), 2.83 (2H, q, J = 7.4 Hz), 6.46 (1H, br), 6.99 (1H, td, J = 8.4, 2.4 Hz), 7.19 (1H, dd, J = 8.4, 2.4 Hz), 7.35 (dd, J = 8.4, 4.8 Hz, 1H), 7.94 (s, 2H) (2-Ethyl-6-fluorobenzofuran-3-yl)(4-hydroxy-3,5-dibromophenyl)methanone (T-66)
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.35 (3H, t, J = 7.4 Hz), 2.83 (2H, q, J = 7.4 Hz), 6.46 (1H, br), 6.99 (1H, td, J = 8.4, 2.4 Hz), 7.19 (1H, dd, J = 8.4, 2.4 Hz), 7.35 (dd, J = 8.4, 4.8 Hz, 1H), 7.94 (s, 2H)
(2-Butyl-6-fluorobenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-67)
1H-NMR (400 MHz, CDCl3) δ: 0.91 (3H, t, J = 7.4 Hz), 1.35 (2H, sext, J = 7.4 Hz), 1.76 (2H, quint, J = 7.4 Hz), 2.82 (2H, t, J = 7.4 Hz), 6.26 (1H, br), 7.01 (1H, td, J = 8.8, 2.4 Hz), 7.21 (1H, dd, J = 8.8, 2.4 Hz), 7.38 (1H, dd, J = 8.8, 4.8 Hz), 8.16 (2H, s) (2-Butyl-6-fluorobenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-67)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.91 (3H, t, J = 7.4 Hz), 1.35 (2H, sext, J = 7.4 Hz), 1.76 (2H, quint, J = 7.4 Hz), 2.82 (2H, t, J = 7.4 Hz), 6.26 (1H, br), 7.01 (1H, td, J = 8.8, 2.4 Hz), 7.21 (1H, dd, J = 8.8, 2.4 Hz), 7.38 (1H, dd, J = 8.8, 4.8Hz), 8.16 (2H, s)
(2-Butyl-6-fluorobenzofuran-3-yl)(4-hydroxy-3,5-dibromophenyl)methanone (T-68)
1H-NMR (400 MHz, CDCl3) δ: 0.91 (3H, t, J = 7.4 Hz), 1.35 (2H, sext, J = 7.4 Hz), 1.76 (2H, quint, J = 7.4 Hz), 2.82 (2H, t, J = 7.4 Hz), 6.26 (1H, br), 7.01 (1H, td, J = 9.2, 2.4 Hz), 7.21 (1H, dd, J = 9.2, 2.4 Hz), 7.36 (1H, dd, J = 9.2, 4.8 Hz), 7.96 (2H, s) (2-Butyl-6-fluorobenzofuran-3-yl)(4-hydroxy-3,5-dibromophenyl)methanone (T-68)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.91 (3H, t, J = 7.4 Hz), 1.35 (2H, sext, J = 7.4 Hz), 1.76 (2H, quint, J = 7.4 Hz), 2.82 (2H, t, J = 7.4 Hz), 6.26 (1H, br), 7.01 (1H, td, J = 9.2, 2.4 Hz), 7.21 (1H, dd, J = 9.2, 2.4 Hz), 7.36 (1H, dd, J = 9.2, 4.8Hz), 7.96 (2H, s)
(2-Butyl-6-methylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-70)
1H-NMR (400 MHz, CDCl3) δ: 0.92 (4H, t, J = 7.4 Hz), 1.37 (2H, sext, J = 7.4 Hz), 1.76 (2H, quint, J = 7.4 Hz), 2.47 (3H, s), 2.86 (2H, t, J = 7.4 Hz), 6.20 (1H, s), 7.05 (1H, dd, J = 8.0, 0.6 Hz), 7.23-7.27 (1H, m), 7.29 (1H, d, J = 0.6 Hz), 8.18 (2H, s) (2-Butyl-6-methylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-70)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.92 (4H, t, J = 7.4 Hz), 1.37 (2H, sext, J = 7.4 Hz), 1.76 (2H, quint, J = 7.4 Hz), 2.47 (3H, s), 2.86 (2H, t, J = 7.4 Hz), 6.20 (1H, s), 7.05 (1H, dd, J = 8.0, 0.6 Hz), 7.23-7.27 (1H, m), 7.29 ( 1H, d, J = 0.6 Hz), 8.18 (2H, s)
(6-Bromo-2-butylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-72)
1H-NMR (400 MHz, CDCl3) δ: 0.92 (3H, t, J = 7.4 Hz), 1.36 (2H, sext, J = 7.4 Hz), 1.76 (2H, quint, J = 7.4 Hz), 2.84 (2H, t, J= 7.4 Hz), 6.23 (1H, br), 7.28 (1H, d, J= 8.4 Hz), 7.36 (1H, dd, J = 8.4, 1.6 Hz), 7.66 (1H, d, J = 1.6 Hz), 8.15 (2H, s) (6-Bromo-2-butylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-72)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.92 (3H, t, J = 7.4 Hz), 1.36 (2H, sext, J = 7.4 Hz), 1.76 (2H, quint, J = 7.4 Hz), 2.84 (2H, t, J = 7.4 Hz), 6.23 (1H, br), 7.28 (1H, d, J = 8.4 Hz), 7.36 (1H, dd, J = 8.4, 1.6 Hz), 7.66 (1H, d, J = 1.6Hz), 8.15 (2H, s)
(2-Butyl-4-fluorobenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone (T-73)
1H-NMR (400 MHz, CDCl3) δ: 0.92 (3H, t, J = 7.4 Hz), 1.37 (2H, sext, J = 7.4 Hz), 1.76 (2H, quint, J = 7.6 Hz), 2.83 (2H, t, J= 7.6 Hz), 6.22 (1H, s), 6.93 (1H, ddd, J= 10.0, 8.0, 0.9 Hz), 7.26 (1H, td, J= 8.0, 5.0 Hz), 7.32 (1H, dd, J= 8., 0.9 Hz), 7.99 (2H, s) (2-Butyl-4-fluorobenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone (T-73)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.92 (3H, t, J = 7.4 Hz), 1.37 (2H, sext, J = 7.4 Hz), 1.76 (2H, quint, J = 7.6 Hz), 2.83 (2H, t, J = 7.6 Hz), 6.22 (1H, s), 6.93 (1H, ddd, J = 10.0, 8.0, 0.9 Hz), 7.26 (1H, td, J = 8.0, 5.0 Hz), 7.32 ( 1H, dd, J = 8., 0.9Hz), 7.99 (2H, s)
(2-Butyl-4-fluorobenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-74)
1H-NMR (400 MHz, CDCl3) δ: 0.92 (3H, t, J = 7.4 Hz), 1.37 (2H, sext, J = 7.4 Hz), 1.76 (2H, quint, J = 7.4 Hz), 2.83 (2H, t, J= 7.4 Hz), 6.22 (1H, s), 6.93 (1H, ddd, J= 9.8, 8.0, 0.8 Hz), 7.26 (1H, td, J= 8.0, 5.0 Hz), 7.32 (1H, dd, J= 8.0, 0.8 Hz), 8.20 (1H, s) (2-Butyl-4-fluorobenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-74)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.92 (3H, t, J = 7.4 Hz), 1.37 (2H, sext, J = 7.4 Hz), 1.76 (2H, quint, J = 7.4 Hz), 2.83 (2H, t, J= 7.4 Hz), 6.22 (1H, s), 6.93 (1H, ddd, J= 9.8, 8.0, 0.8 Hz), 7.26 (1H, td, J= 8.0, 5.0 Hz), 7.32 ( 1H, dd, J = 8.0, 0.8Hz), 8.20 (1H, s)
(2-Butyl-7-fluorobenzofuran-3-yl)(4-hydroxy-3,5-dibromophenyl)methanone (T-75)
1H-NMR (400 MHz, CDCl3) δ: 0.92 (3H, t, J = 7.3 Hz), 1.38 (2H, sext, J = 7.3 Hz), 1.80 (2H, quint, J = 7.3 Hz), 2.90 (2H, t, J= 7.6 Hz), 6.38 (1H, br), 7.05 (1H, ddd, J= 10.4, 5.8, 3.3 Hz), 7.15-7.19 (2H, m), 7.97 (2H, s) (2-Butyl-7-fluorobenzofuran-3-yl)(4-hydroxy-3,5-dibromophenyl)methanone (T-75)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.92 (3H, t, J = 7.3 Hz), 1.38 (2H, sext, J = 7.3 Hz), 1.80 (2H, quint, J = 7.3 Hz), 2.90 (2H, t, J = 7.6 Hz), 6.38 (1H, br), 7.05 (1H, ddd, J = 10.4, 5.8, 3.3 Hz), 7.15-7.19 (2H, m), 7.97 (2H, s)
(2-Butyl-7-fluorobenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-76)
1H-NMR (400 MHz, CDCl3) δ: 0.92 (3H, t, J = 7.3 Hz), 1.38 (2H, sext, J = 7.3 Hz), 1.80 (2H, quint, J = 7.3 Hz), 2.88 (2H, t, J= 7.6 Hz), 6.22 (1H, s), 7.05 (1H, ddd, J= 10.4, 5.8, 3.3 Hz), 7.11-7.21 (2H, m), 8.17 (2H, s) (2-Butyl-7-fluorobenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-76)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.92 (3H, t, J = 7.3 Hz), 1.38 (2H, sext, J = 7.3 Hz), 1.80 (2H, quint, J = 7.3 Hz), 2.88 (2H, t, J = 7.6 Hz), 6.22 (1H, s), 7.05 (1H, ddd, J = 10.4, 5.8, 3.3 Hz), 7.11-7.21 (2H, m), 8.17 (2H, s)
(2-Butyl-7-methylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-77)
1H-NMR (400 MHz, CDCl3) δ: 0.93 (3H, t, J = 7.4 Hz), 1.39 (2H, sext, J = 7.4 Hz), 1.78 (2H, quint, J = 7.4 Hz), 2.55 (3H, s), 2.89 (2H, t, J = 7.4 Hz), 6.19 (1H, s), 7.06-7.16 (2H, m), 7.18-7.23 (1H, m), 8.18 (2H, s) (2-Butyl-7-methylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-77)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.93 (3H, t, J = 7.4 Hz), 1.39 (2H, sext, J = 7.4 Hz), 1.78 (2H, quint, J = 7.4 Hz), 2.55 (3H, s), 2.89 (2H, t, J = 7.4 Hz), 6.19 (1H, s), 7.06-7.16 (2H, m), 7.18-7.23 (1H, m), 8.18 (2H, s)
(2-Butyl-6,7-difluorobenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone (T-78)
1H-NMR (400 MHz, CDCl3) δ: 0.92 (3H, t, J = 7.4 Hz), 1.36 (2H, sext, J = 7.4 Hz), 1.79 (2H, quint, J = 7.4 Hz), 2.85 (2H, t, J= 7.4 Hz), 6.53 (1H, br), 7.05-7. 16, 2H, m), 7.95 (2H, s) (2-Butyl-6,7-difluorobenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone (T-78)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.92 (3H, t, J = 7.4 Hz), 1.36 (2H, sext, J = 7.4 Hz), 1.79 (2H, quint, J = 7.4 Hz), 2.85 (2H, t, J = 7.4 Hz), 6.53 (1H, br), 7.05-7.16, 2H, m), 7.95 (2H, s)
(2-Butyl-6,7-difluorobenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-79)
1H-NMR (400 MHz, CDCl3) δ: 0.92 (3H, t, J = 7.4 Hz), 1.36 (2H, sext, J = 7.4 Hz), 1.79 (2H, quint, J = 7.4 Hz), 2.84 (2H, t, J= 7.4 Hz), 6.25 (1H, br), 6.98-7. 17 (2H, m), 8.15 (2H, s) (2-Butyl-6,7-difluorobenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-79)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.92 (3H, t, J = 7.4 Hz), 1.36 (2H, sext, J = 7.4 Hz), 1.79 (2H, quint, J = 7.4 Hz), 2.84 (2H, t, J = 7.4 Hz), 6.25 (1H, br), 6.98-7.17 (2H, m), 8.15 (2H, s)
(2-Butyl-7-methylbenzofuran-3-yl)(4-hydroxy-3,5-dibromophenyl)methanone (T-80)
1H-NMR (400 MHz, CDCl3) δ: 0.93 (3H, t, J = 7.4 Hz), 1.39 (2H, sext, J = 7.4 Hz), 1.78 (2H, quint, J = 7.4 Hz), 2.55 (3H, s), 2.90 (2H, t, J = 7.4 Hz), 6.32 (1H, s), 7.09-7.19 (3H, m), 7.98 (2H, s) (2-Butyl-7-methylbenzofuran-3-yl)(4-hydroxy-3,5-dibromophenyl)methanone (T-80)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.93 (3H, t, J = 7.4 Hz), 1.39 (2H, sext, J = 7.4 Hz), 1.78 (2H, quint, J = 7.4 Hz), 2.55 (3H, s), 2.90 (2H, t, J = 7.4 Hz), 6.32 (1H, s), 7.09-7.19 (3H, m), 7.98 (2H, s)
(2-Butyl-7-chloro-5-fluorobenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone (T-81)
1H-NMR (400 MHz, CDCl3) δ: 0.92 (3H, t, J = 7.3 Hz), 1.37 (2H, sext, J = 7.3 Hz), 1.79 (2H, quint, J = 7.3 Hz), 2.86 (2H, t, J= 7.3 Hz), 6.45 (1H, br), 7.05 (1H, dd, J = 8.4, 2.8 Hz), 7.09 (1H, dd, J = 8.4, 2.8 Hz), 7.94 (2H, s) (2-Butyl-7-chloro-5-fluorobenzofuran-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone (T-81)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.92 (3H, t, J = 7.3 Hz), 1.37 (2H, sext, J = 7.3 Hz), 1.79 (2H, quint, J = 7.3 Hz), 2.86 (2H, t, J = 7.3 Hz), 6.45 (1H, br), 7.05 (1H, dd, J = 8.4, 2.8 Hz), 7.09 (1H, dd, J = 8.4, 2.8 Hz), 7.94 (2H, s)
(2-Butyl-7-chloro-5-fluorobenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-82)
1H-NMR (400 MHz, CDCl3) δ: 0.92 (3H, t, J = 7.6 Hz), 1.37 (2H, sext, J = 7.6 Hz), 1.79 (2H, quint, J = 7.6 Hz), 2.85 (2H, t, J= 7.6 Hz), 6.27 (1H, br), 7.06-7. 10 (2H, m), 8.14 (2H, s) (2-Butyl-7-chloro-5-fluorobenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-82)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.92 (3H, t, J = 7.6 Hz), 1.37 (2H, sext, J = 7.6 Hz), 1.79 (2H, quint, J = 7.6 Hz), 2.85 (2H, t, J = 7.6 Hz), 6.27 (1H, br), 7.06-7.10 (2H, m), 8.14 (2H, s)
(2-Butyl-5-(methylthio)benzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-83)
1H-NMR (400 MHz, CDCl3) δ: 0.91 (3H, t, J = 7.4 Hz), 1.36 (2H, sext, J = 7.4 Hz), 1.78 (2H, quint, J = 7.4 Hz), 2.74 (3H, s), 2.90 (2H, t, J = 7.4 Hz), 7.64-7. 68 (2H, m), 7.73 (1H, s), 7.97 (2H, s) (2-Butyl-5-(methylthio)benzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-83)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.91 (3H, t, J = 7.4 Hz), 1.36 (2H, sext, J = 7.4 Hz), 1.78 (2H, quint, J = 7.4 Hz), 2.74 (3H, s), 2.90 (2H, t, J = 7.4 Hz), 7.64-7.68 (2H, m), 7.73 (1H, s), 7.97 (2H, s)
(2-Butyl-5-(methylthio)benzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-84)
1H-NMR (400 MHz, CDCl3) δ: 0.92 (3H, t, J = 7.4 Hz), 1.36 (2H, sext, J = 7.4 Hz), 1.76 (2H, quint, J = 7.4 Hz), 2.46 (3H, s), 2.85 (2H, t, J = 7.4 Hz), 6.20 (1H, s), 7.28 (1H, dd, J = 8.6, 1.9 Hz), 7.37 (1H, d, J = 1.9 Hz), 7.40 (1H, d, J= 8.6 Hz), 8.19 (2H, s) (2-Butyl-5-(methylthio)benzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-84)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.92 (3H, t, J = 7.4 Hz), 1.36 (2H, sext, J = 7.4 Hz), 1.76 (2H, quint, J = 7.4 Hz), 2.46 (3H, s), 2.85 (2H, t, J = 7.4 Hz), 6.20 (1H, s), 7.28 (1H, dd, J = 8.6, 1.9 Hz), 7.37 (1H, d, J = 1.9 Hz) , 7.40 (1H, d, J = 8.6 Hz), 8.19 (2H, s)
(2-Butyl-5-(methylsulfinyl)benzofuran-3-yl)(4-hydroxy-3,5-dibromophenyl)methanone (T-85)
1H-NMR (400 MHz, CDCl3) δ: 0.90 (3H, t, J = 7.3 Hz), 1.36 (2H, sext J = 7.3 Hz), 1.79 (2H, quint, J = 7.3 Hz), 2.75 (3H, s), 2.90 (2H, t, J = 7.3 Hz), 7.64-7.75 (3H, m), 7.95 (2H, s) (2-Butyl-5-(methylsulfinyl)benzofuran-3-yl)(4-hydroxy-3,5-dibromophenyl)methanone (T-85)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.90 (3H, t, J = 7.3 Hz), 1.36 (2H, sext J = 7.3 Hz), 1.79 (2H, quint, J = 7.3 Hz), 2.75 ( 3H, s), 2.90 (2H, t, J = 7.3 Hz), 7.64-7.75 (3H, m), 7.95 (2H, s)
(2-Butyl-5-(methylsulfinyl)benzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-86)
1H-NMR (400 MHz, CDCl3) δ: 0.93 (3H, t, J = 7.4 Hz), 1.38 (2H, sext, J = 7.4 Hz), 1.79 (2H, quint, J = 7.4 Hz), 2.74 (3H, s), 2.89 (2H, t, J = 7.4 Hz), 6.36 (1H, s), 7.64-7.73 (3H, m), 8.18 (2H, s) (2-Butyl-5-(methylsulfinyl)benzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-86)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.93 (3H, t, J = 7.4 Hz), 1.38 (2H, sext, J = 7.4 Hz), 1.79 (2H, quint, J = 7.4 Hz), 2.74 (3H, s), 2.89 (2H, t, J = 7.4 Hz), 6.36 (1H, s), 7.64-7.73 (3H, m), 8.18 (2H, s)
(2-Butyl-5-(methylsulfonyl)benzofuran-3-yl)(4-hydroxy-3,5-dibromophenyl)methanone (T-87)
1H-NMR (400 MHz, CDCl3) δ: 0.90 (3H, t, J = 7.3 Hz), 1.36 (2H, sext, J = 7.3 Hz), 1.78 (2H, quint, J = 7.3 Hz), 2.89 (2H, t, J= 7.3 Hz), 3.06 (3H, s), 7.66 (1H, dd, J= 8.6, 1.5 Hz), 7.93 (dd, J = 8.6, 1.5 Hz), 7.97 (2H, s), 8.09 (1H, d,J = 1.5 Hz) (2-Butyl-5-(methylsulfonyl)benzofuran-3-yl)(4-hydroxy-3,5-dibromophenyl)methanone (T-87)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.90 (3H, t, J = 7.3 Hz), 1.36 (2H, sext, J = 7.3 Hz), 1.78 (2H, quint, J = 7.3 Hz), 2.89 (2H, t, J = 7.3 Hz), 3.06 (3H, s), 7.66 (1H, dd, J = 8.6, 1.5 Hz), 7.93 (dd, J = 8.6, 1.5 Hz), 7.97 (2H, s) , 8.09 (1H, d,J = 1.5Hz)
(2-Butyl-5-(methylsulfonyl)benzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-88)
1H-NMR (400 MHz, CDCl3) δ: 0.93 (3H, t, J = 7.6 Hz), 1.38 (2H, sext, J = 7.6 Hz), 1.79 (2H, quint, J = 7.6 Hz), 2.90 (2H, t, J= 7.6 Hz), 3.08 (3H, s), 6.27 (1H, s), 7.66 (1H, dd, J = 8.6, 0.5 Hz), 7.93 (1H, dd, J = 8.6, 1.9 Hz), 8.06-8.16 (1H, m), 8.18 (2H, s) (2-Butyl-5-(methylsulfonyl)benzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-88)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.93 (3H, t, J = 7.6 Hz), 1.38 (2H, sext, J = 7.6 Hz), 1.79 (2H, quint, J = 7.6 Hz), 2.90 (2H, t, J = 7.6 Hz), 3.08 (3H, s), 6.27 (1H, s), 7.66 (1H, dd, J = 8.6, 0.5 Hz), 7.93 (1H, dd, J = 8.6, 1.9 Hz), 8.06-8.16 (1H, m), 8.18 (2H, s)
(2-Butyl-6-(methylthio)benzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-89)
1H-NMR (500 MHz, CDCl3) δ: 0.92 (3H, t, J = 7.4 Hz), 1.29-1.43 (2H, m), 1.76 (2H, quint, J = 7.4 Hz), 2.54 (3H, s), 2.82-2.89 (2H, m), 6.19 (1H, s), 7.17 (1H, dd, J= 8.3, 1.6 Hz), 7.29 (1H, d, J= 8.3 Hz), 7.39 (1H, d, J = 1.6 Hz), 8.17 (2H, s) (2-Butyl-6-(methylthio)benzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-89)
1 H-NMR (500 MHz, CDCl 3 ) δ: 0.92 (3H, t, J = 7.4 Hz), 1.29-1.43 (2H, m), 1.76 (2H, quint, J = 7.4 Hz), 2.54 (3H, s), 2.82-2.89 (2H, m), 6.19 (1H, s), 7.17 (1H, dd, J = 8.3, 1.6 Hz), 7.29 (1H, d, J = 8.3 Hz), 7.39 (1H, d , J = 1.6 Hz), 8.17 (2H, s)
(2-Butyl-6-(methylsulfinyl)benzofuran-3-yl)(4-hydroxy-3,5-diio:dophenyl)methanone (T-90)
1H-NMR (500 MHz, CDCl3) δ: 0.93 (3H, t, J = 7.4 Hz), 1.22-1.44 (2H, m), 1.79 (2H, quint, J = 7.4 Hz), 2.77 (3H, s), 2.85-2.92 (2H, m), 7.44 (1H, dd, J = 8.2, 1.5 Hz), 7.58 (1H, d, J = 8.2 Hz), 7.91 (1H, d, J= 1.5 Hz), 8.17 (2H, s) (2-Butyl-6-(methylsulfinyl)benzofuran-3-yl)(4-hydroxy-3,5-diio:dophenyl)methanone (T-90)
1 H-NMR (500 MHz, CDCl 3 ) δ: 0.93 (3H, t, J = 7.4 Hz), 1.22-1.44 (2H, m), 1.79 (2H, quint, J = 7.4 Hz), 2.77 (3H, s), 2.85-2.92 (2H, m), 7.44 (1H, dd, J = 8.2, 1.5 Hz), 7.58 (1H, d, J = 8.2 Hz), 7.91 (1H, d, J = 1.5 Hz), 8.17 (2H, s)
(2-Butyl-6-(methylsulfonyl)benzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-91)
1H-NMR (500 MHz, CDCl3) δ: 0.93 (3H, t, J = 7.4 Hz), 1.38 (2H, sext, J = 7.4 Hz), 1.80 (2H, quint, J = 7.4 Hz), 2.87-2.99 (2H, m), 3.11 (3H, s), 7.62 (1H, d, J = 8.3 Hz), 7.82 (1H, dd, J = 8.3, 1.6 Hz), 8.12 (1H, d, J = 1.6 Hz), 8.16 (2H, s) (2-Butyl-6-(methylsulfonyl)benzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-91)
1 H-NMR (500 MHz, CDCl 3 ) δ: 0.93 (3H, t, J = 7.4 Hz), 1.38 (2H, sext, J = 7.4 Hz), 1.80 (2H, quint, J = 7.4 Hz), 2.87 -2.99 (2H, m), 3.11 (3H, s), 7.62 (1H, d, J = 8.3 Hz), 7.82 (1H, dd, J = 8.3, 1.6 Hz), 8.12 (1H, d, J = 1.6 Hz), 8.16 (2H, s)
(2-Butyl-6,7,8,9-tetrahydronaphtho[1,2-b]furan-3-yl)(4-hydroxy-3,5-diiodophenyl) methanone (T-92)
1H-NMR (400 MHz, CDCl3) δ: 0.92 (3H, t, J = 7.4 Hz), 1.38 (2H, sext, J = 7.4 Hz), 1.76 (2H, quint, J = 7.4 Hz), 1.81-1.95 (4H, m), 2.72-2.91 (4H, m), 2.98 (2H, t, J = 7.4 Hz), 6.16 (1H, s), 6.95 (1H, d, J = 8.0 Hz), 7.07 (1H, d, J = 8.0 Hz), 8.18 (2H, s) (2-Butyl-6,7,8,9-tetrahydronaphtho[1,2-b]furan-3-yl)(4-hydroxy-3,5-diiodophenyl) methanone (T-92)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.92 (3H, t, J = 7.4 Hz), 1.38 (2H, sext, J = 7.4 Hz), 1.76 (2H, quint, J = 7.4 Hz), 1.81 -1.95 (4H, m), 2.72-2.91 (4H, m), 2.98 (2H, t, J = 7.4 Hz), 6.16 (1H, s), 6.95 (1H, d, J = 8.0 Hz), 7.07 ( 1H, d, J = 8.0 Hz), 8.18 (2H, s)
(2-Butyl-6-methoxybenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-93)
1H-NMR (400 MHz, CDCl3) δ: 0.92 (3H, t, J = 7.4 Hz), 1.36 (2H, sext, J = 7.4 Hz), 1.75 (2H, quint, J = 7.4 Hz), 2.83 (2H, t, J= 7.4 Hz), 3.86 (3H, s), 6.86 (1H, dd, J= 8.7, 2.3 Hz), 7.02 (1H, d, J= 2.3 Hz), 7.28 (1H, d, J = 8.7 Hz), 8.17 (2H, s) (2-Butyl-6-methoxybenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-93)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.92 (3H, t, J = 7.4 Hz), 1.36 (2H, sext, J = 7.4 Hz), 1.75 (2H, quint, J = 7.4 Hz), 2.83 (2H, t, J = 7.4 Hz), 3.86 (3H, s), 6.86 (1H, dd, J = 8.7, 2.3 Hz), 7.02 (1H, d, J = 2.3 Hz), 7.28 (1H, d, J = 8.7Hz), 8.17 (2H, s)
(2-Butyl-6-hydroxybenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-94)
1H-NMR (400 MHz, acetone-d6) δ: 0.90 (3H, t, J = 7.4 Hz), 1.30-1.41 (2H, m), 1. 75 (2H, quint, J = 7.4 Hz), 2.09 (1H, s), 2.77-2.86 (2H, m), 6.84 (1H, dd, J = 8.5, 2.2 Hz), 6.99 (1H, d, J = 2.2 Hz), 7.28 (1H, d, J= 8.5 Hz), 8.21 (2H, s) (2-Butyl-6-hydroxybenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-94)
1 H-NMR (400 MHz, acetone-d 6 ) δ: 0.90 (3H, t, J = 7.4 Hz), 1.30-1.41 (2H, m), 1.75 (2H, quint, J = 7.4 Hz), 2.09 (1H, s), 2.77-2.86 (2H, m), 6.84 (1H, dd, J = 8.5, 2.2 Hz), 6.99 (1H, d, J = 2.2 Hz), 7.28 (1H, d, J = 8.5Hz), 8.21 (2H, s)
(2-Butyl-6-chlorobenzofuran-3-yl)(4-hydroxy-3-iodophenyl)methanone (T-95)
1H-NMR (400 MHz, CDCl3) δ: 0.90 (3H, t, J = 7.3 Hz), 1.35 (2H, sext, J = 7.3 Hz), 1.70-1.82 (2H, quint, J = 7.3 Hz), 2.86 (2H, t, J = 7.3 Hz), 6.02 (1H, s), 7. 05 (1H, d, J = 8.4 Hz), 7.20 (1H, dd, J = 8.4, 1.8 Hz), 7.30 (1H, d, J = 8.4 Hz), 7.49 (1H, d, J= 1.8 Hz), 7.74 (1H, dd, J = 8.5, 2.1 Hz), 8.19 (1H, d, J = 2.1 Hz) (2-Butyl-6-chlorobenzofuran-3-yl)(4-hydroxy-3-iodophenyl)methanone (T-95)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.90 (3H, t, J = 7.3 Hz), 1.35 (2H, sext, J = 7.3 Hz), 1.70-1.82 (2H, quint, J = 7.3 Hz) , 2.86 (2H, t, J = 7.3 Hz), 6.02 (1H, s), 7. 05 (1H, d, J = 8.4 Hz), 7.20 (1H, dd, J = 8.4, 1.8 Hz), 7.30 ( 1H, d, J = 8.4 Hz), 7.49 (1H, d, J = 1.8 Hz), 7.74 (1H, dd, J = 8.5, 2.1 Hz), 8.19 (1H, d, J = 2.1 Hz)
(2-Butyl-5-methylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-96)
1H-NMR (500 MHz, CDCl3) δ: 0.91 (3H, t, J = 7.5 Hz), 1.35 (2H, sext, J = 7.5 Hz), 1.75 (2H, quint, J = 7.5 Hz), 2.39 (3H, s), 2.81 (2H, t, J = 7.5 Hz), 6.18 (1H, br), 7.11 (1H, dd, J= 8.0, 1.5 Hz), 7.23 (1H, s), 7.35 (1H, d, J = 8.0 Hz), 8.19 (2H, s) (2-Butyl-5-methylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-96)
1 H-NMR (500 MHz, CDCl 3 ) δ: 0.91 (3H, t, J = 7.5 Hz), 1.35 (2H, sext, J = 7.5 Hz), 1.75 (2H, quint, J = 7.5 Hz), 2.39 (3H, s), 2.81 (2H, t, J = 7.5 Hz), 6.18 (1H, br), 7.11 (1H, dd, J = 8.0, 1.5 Hz), 7.23 (1H, s), 7.35 (1H, d, J = 8.0 Hz), 8.19 (2H, s)
(2-Butyl-6-(trifluoromethyl)benzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-97)
1H-NMR (400 MHz, CDCl3) δ: 0.93 (3H, t, J = 7.6 Hz), 1.39 (2H, sext, J = 7.6 Hz), 1.78 (2H, quint, J = 7.6 Hz), 2.89 (2H, t, J = 7.6 Hz), 6.22 (1H, br), 7.51-7.52 (2H, m), 7.77 (1H, s), 8.16 (2H, s) (2-Butyl-6-(trifluoromethyl)benzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-97)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.93 (3H, t, J = 7.6 Hz), 1.39 (2H, sext, J = 7.6 Hz), 1.78 (2H, quint, J = 7.6 Hz), 2.89 (2H, t, J = 7.6 Hz), 6.22 (1H, br), 7.51-7.52 (2H, m), 7.77 (1H, s), 8.16 (2H, s)
(2-Butyl-7,8-dihydro-6H-indeno[4,5-b]furan-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-98)
1H-NMR (400 MHz, CDCl3) δ: 0.92 (3H, t, J = 7.4 Hz), 1.38 (2H, sext, J = 7.4 Hz), 1.77 (2H, quint, J = 7.4 Hz), 2.87 (2H, t,J = 7.4 Hz), 3.03 (2H, t, J= 7.4 Hz), 3.16 (2H, t, J = 7.4 Hz), 6.23 (1H, s), 7.11 (1H, d, J= 8.0 Hz), 7.15 (1H, d, J = 8.0 Hz), 8.19 (2H, s) (2-Butyl-7,8-dihydro-6H-indeno[4,5-b]furan-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-98)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.92 (3H, t, J = 7.4 Hz), 1.38 (2H, sext, J = 7.4 Hz), 1.77 (2H, quint, J = 7.4 Hz), 2.87 (2H, t, J = 7.4 Hz), 3.03 (2H, t, J = 7.4 Hz), 3.16 (2H, t, J = 7.4 Hz), 6.23 (1H, s), 7.11 (1H, d, J = 8.0Hz), 7.15 (1H, d, J = 8.0Hz), 8.19 (2H, s)
(2-Butyl-6-chlorobenzofuran-3-yl)(4-hydroxy-3-(methylsulfonyl)phenyl)methanone (T-99)
1H-NMR (400 MHz, CDCl3) δ: 0.89 (3H, t, J = 7.4 Hz), 1.34 (2H, sext, J = 7.4 Hz), 1.75 (2H, quint, J = 7.4 Hz), 2.88 (2H, t, J= 7.4 Hz), 3.15 (3H, s), 7.14-7.26 (3H, m), 7.50 (1H, s), 8.02 (1H, d, J = 6.4 Hz), 8.20 (1H, s), 9.52 (1H, s) (2-Butyl-6-chlorobenzofuran-3-yl)(4-hydroxy-3-(methylsulfonyl)phenyl)methanone (T-99)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.89 (3H, t, J = 7.4 Hz), 1.34 (2H, sext, J = 7.4 Hz), 1.75 (2H, quint, J = 7.4 Hz), 2.88 (2H, t, J = 7.4 Hz), 3.15 (3H, s), 7.14-7.26 (3H, m), 7.50 (1H, s), 8.02 (1H, d, J = 6.4 Hz), 8.20 (1H, s), 9.52 (1H, s)
(2-Butyl-6,7-dimethylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-100)
1H-NMR (400 MHz, CDCl3) δ: 0.93 (3H, t, J = 7.4 Hz), 1.39 (2H, sext, J = 7.4 Hz), 1.78 (2H, quint, J =7.4 Hz), 2.38 (3H, s), 2.45 (3H, s), 2.90 (2H, t, J = 7.4 Hz), 6.26 (1H, br), 7.03 (1H, d, J = 6.4 Hz), 7.07 (1H, d, J = 6.4 Hz), 8.19 (2H, s) (2-Butyl-6,7-dimethylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-100)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.93 (3H, t, J = 7.4 Hz), 1.39 (2H, sext, J = 7.4 Hz), 1.78 (2H, quint, J = 7.4 Hz), 2.38 (3H, s), 2.45 (3H, s), 2.90 (2H, t, J = 7.4 Hz), 6.26 (1H, br), 7.03 (1H, d, J = 6.4 Hz), 7.07 (1H, d, J = 6.4Hz), 8.19 (2H, s)
(2-Butyl-4,7-dimethylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-101)
1H-NMR (400 MHz, CDCl3) δ: 0.93 (3H, t, J = 7.4 Hz), 1.30 (2H, sext, J = 7.4 Hz), 1.71 (2H, quint, J = 7.4 Hz), 2.17 (3H, s), 2.51 (3H, s), 2.65 (2H, t, J = 7. 4 Hz), 6.29 (1H, br), 6.92 (1H, d, J = 7.4 Hz), 7.02 (1H, d, J = 7.4 Hz), 8.24 (2H, s) (2-Butyl-4,7-dimethylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-101)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.93 (3H, t, J = 7.4 Hz), 1.30 (2H, sext, J = 7.4 Hz), 1.71 (2H, quint, J = 7.4 Hz), 2.17 (3H, s), 2.51 (3H, s), 2.65 (2H, t, J = 7.4 Hz), 6.29 (1H, br), 6.92 (1H, d, J = 7.4 Hz), 7.02 (1H, d, J = 7.4Hz), 8.24 (2H, s)
(2-Butyl-4,6-dimethylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-102)
1H-NMR (400 MHz, CDCl3) δ: 0.86 (3H, t, J = 7.2 Hz), 1.28 (2H, sext, J = 7.2 Hz), 1.68 (2H, quint, J = 7.2 Hz), 2.17 (3H, s), 2.43 (3H, s), 2.61 (2H, t, J = 7. 2 Hz), 6.21 (1H, s), 6.86 (1H, s), 7.14 (1H, s), 8.24 (2H, s) (2-Butyl-4,6-dimethylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-102)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.86 (3H, t, J = 7.2 Hz), 1.28 (2H, sext, J = 7.2 Hz), 1.68 (2H, quint, J = 7.2 Hz), 2.17 (3H, s), 2.43 (3H, s), 2.61 (2H, t, J = 7.2 Hz), 6.21 (1H, s), 6.86 (1H, s), 7.14 (1H, s), 8.24 ( 2H, s)
(7-Bromo-2-butyl-5-methylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-103)
1H-NMR (500 MHz, CDCl3) δ: 0.92 (3H, t, J = 7.5 Hz), 1.36 (2H, sext, J = 7.5 Hz), 1.77 (2H, quint, J = 7.5 Hz), 2.84 (2H, t, J = 7.5 Hz), 6.19 (1H, br), 7.18 (1H, s), 7.30 (1H, s), 8.17 (2H, s) (7-Bromo-2-butyl-5-methylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-103)
1 H-NMR (500 MHz, CDCl 3 ) δ: 0.92 (3H, t, J = 7.5 Hz), 1.36 (2H, sext, J = 7.5 Hz), 1.77 (2H, quint, J = 7.5 Hz), 2.84 (2H, t, J = 7.5 Hz), 6.19 (1H, br), 7.18 (1H, s), 7.30 (1H, s), 8.17 (2H, s)
(2-Butyl-5-chloro-7-iodobenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-104)
1H-NMR (400 MHz, CDCl3) δ: 0.92 (3H, t, J = 7.2 Hz), 1.36 (2H, sext, J = 7.2 Hz), 1.78 (2H, quint, J = 7.2 Hz), 2.83 (2H, t, J = 7.2 Hz), 6.22 (1H, br), 7.45 (1H, d, J = 2.4 Hz), 7.96 (1H, d, J = 2.4 Hz), 8.14 (s, 2H) (2-Butyl-5-chloro-7-iodobenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-104)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.92 (3H, t, J = 7.2 Hz), 1.36 (2H, sext, J = 7.2 Hz), 1.78 (2H, quint, J = 7.2 Hz), 2.83 (2H, t, J = 7.2 Hz), 6.22 (1H, br), 7.45 (1H, d, J = 2.4 Hz), 7.96 (1H, d, J = 2.4 Hz), 8.14 (s, 2H)
(2-Butyl-5-iodobenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-105)
1H-NMR (400 MHz, CDCl3) δ: 0.91 (3H, t, J = 7.2 Hz), 1.34 (2H, sext, J = 7.2 Hz), 1.73 (2H, quint, J = 7.2 Hz), 2.81 (2H, t, J = 7.2 Hz), 6.21 (1H, br), 7.25-7.27 (1H, m), 7.59 (1H, dd, J= 8.8, 1.6 Hz), 7.83 (1H, d, J= 1.6 Hz), 8.16 (2H, s) (2-Butyl-5-iodobenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-105)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.91 (3H, t, J = 7.2 Hz), 1.34 (2H, sext, J = 7.2 Hz), 1.73 (2H, quint, J = 7.2 Hz), 2.81 (2H, t, J = 7.2 Hz), 6.21 (1H, br), 7.25-7.27 (1H, m), 7.59 (1H, dd, J = 8.8, 1.6 Hz), 7.83 (1H, d, J = 1.6 Hz), 8.16 (2H, s)
(5-Bromo-2-butyl-7-chlorobenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-106)
1H-NMR (400 MHz, CDCl3) δ: 0.92 (3H, t, J = 7.2 Hz), 1.36 (2H, sext, J = 7.2 Hz), 1.78 (2H, quint, J = 7.2 Hz), 2.83 (2H, t, J = 7.2 Hz), 6.23 (1H, br), 7.46 (1H, d, J = 1.2 Hz), 7.54 (1H, d, J = 1.2 Hz), 8.15 (2H, s) (5-Bromo-2-butyl-7-chlorobenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-106)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.92 (3H, t, J = 7.2 Hz), 1.36 (2H, sext, J = 7.2 Hz), 1.78 (2H, quint, J = 7.2 Hz), 2.83 (2H, t, J = 7.2 Hz), 6.23 (1H, br), 7.46 (1H, d, J = 1.2 Hz), 7.54 (1H, d, J = 1.2 Hz), 8.15 (2H, s)
(2-Butyl-6,7-dichlorobenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-107)
1H-NMR (400 MHz, CDCl3) δ: 0.92 (3H, t, J = 7.2 Hz), 1.37 (2H, sext, J = 7.2 Hz), 1.79 (2H, quint, J = 7.2 Hz), 2.87 (2H, t, J = 7.2 Hz), 6.23 (1H, br), 7.25 (1H, d, J = 8.8 Hz), 7.33 (1H, d, J = 8.8 Hz), 8.15 (2H, s) (2-Butyl-6,7-dichlorobenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-107)
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.92 (3H, t, J = 7.2 Hz), 1.37 (2H, sext, J = 7.2 Hz), 1.79 (2H, quint, J = 7.2 Hz), 2.87 (2H, t, J = 7.2 Hz), 6.23 (1H, br), 7.25 (1H, d, J = 8.8 Hz), 7.33 (1H, d, J = 8.8 Hz), 8.15 (2H, s)
(2-Butyl-5,7-diiodobenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-108) 1H-NMR (400 MHz, CDCl3) δ: 0.90 (3H, t, J = 7.2 Hz), 1.36 (2H, sext, J = 7.2 Hz), 1.76 (2H, quint, J = 7.2 Hz), 2.82 (2H, t, J = 7.2 Hz), 6.23 (1H, br), 7.80 (1H, d, J = 1.6 Hz), 7.96 (1H, d, J = 1.6 Hz), 8.15 (2H, s) (2-Butyl-5,7-diiodobenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone (T-108) 1 H-NMR (400 MHz, CDCl 3 ) δ: 0.90 (3H, t , J = 7.2 Hz), 1.36 (2H, sext, J = 7.2 Hz), 1.76 (2H, quint, J = 7.2 Hz), 2.82 (2H, t, J = 7.2 Hz), 6.23 (1H, br), 7.80 (1H, d, J = 1.6Hz), 7.96 (1H, d, J = 1.6Hz), 8.15 (2H, s)
２．ヒト膵臓がん由来細胞株PANC-1に対するin vitro阻害活性の評価
　PANC-1に対するin vitroにおけるT-化合物の阻害活性を栄養豊富な培地（DMEM）と栄養欠乏培地（NDM）と比較しながら試験することにより評価した。具体的には、以下のようにして試験した。
　PANC-1（RBRC-RCB2095）ヒト膵臓がん細胞株は、理研BRC細胞バンクから購入し、10％FBSを補充した標準的なDMEMで維持し、5％CO2と95％空気の加湿雰囲気下で37℃で保存した。ヒト膵臓がん細胞を96ウェルプレート（1.5×104/ウェル）に播種し、新鮮なDMEMを用いて、5% CO2および95%空気の下、37℃で24時間培養した。細胞をPBSで2回洗浄した後、培地を栄養豊富な培地（DMEM）と栄養欠乏培地（NDM）のそれぞれで連続的に希釈した試験用培地に変更し、各試験プレートにコントロールとブランクを入れた。NDMの組成は以下の通りであった。0.1 mg L-1 Fe（NO3）3（9 H2O）、265 mg L-1 CaCl2（2 H2O）、400 mg L-1 KCl、200 mg L-1 MgSO4（7 H2O）、6400 mg L-1 NaCl、700 mg L-1 NaHCO3、125 mg L-1 NaH2PO4、15 mg L-1フェノールレッド、25 mM L-1 HEPES緩衝液（pH 7.4）、MEMビタミン液（Life Technologies, Inc）、 最終的なpHは10％のNaHCO3水溶液で7.4に調整した。DMEMおよびNDM中で各試験化合物と24時間インキュベートした後、PBSで2回洗浄し、10％ WST-8細胞計数キット溶液を含む100μLのDMEMに交換した。3時間インキュベートした後、EnSpireマルチモードプレートリーダー（PerkinElmer, Inc.、Waltham, MA, USA）で450nmの吸光度を測定した。細胞生存率は、3つのウェルの平均値から以下の式を用いて算出した。 2. Evaluation of in vitro inhibitory activity against the human pancreatic cancer-derived cell line PANC-1 Testing the in vitro inhibitory activity of T-compounds against PANC-1 in nutrient rich medium (DMEM) versus nutrient deficient medium (NDM) It was evaluated by Specifically, the test was performed as follows.
PANC-1 (RBRC-RCB2095) human pancreatic cancer cell line was purchased from the Riken BRC Cell Bank and maintained in standard DMEM supplemented with 10% FBS under a humidified atmosphere of 5% CO and 95% air. and stored at 37°C. Human pancreatic cancer cells were seeded in 96-well plates (1.5×10 4 /well) and cultured with fresh DMEM for 24 hours at 37° C. under 5% CO 2 and 95% air. After washing the cells twice with PBS, the medium was changed to test media serially diluted in nutrient-rich medium (DMEM) and nutrient-deficient medium (NDM), respectively, and controls and blanks were added to each test plate. rice field. The composition of NDM was as follows. 0.1 mg L-1 Fe( NO3 ) 3 ( 9H2O ), 265 mg L-1 CaCl2 ( 2H2O ), 400 mg L-1 KCl, 200 mg L-1 MgSO4 ( 7H2O) O), 6400 mg L-1 NaCl, 700 mg L-1 NaHCO3 , 125 mg L-1 NaH2PO4 , 15 mg L-1 phenol red, 25 mM L-1 HEPES buffer (pH 7.4), MEM Vitamin solution (Life Technologies, Inc), final pH adjusted to 7.4 with 10% NaHCO 3 aqueous solution. After 24 hours of incubation with each test compound in DMEM and NDM, they were washed twice with PBS and replaced with 100 μL of DMEM containing 10% WST-8 cell counting kit solution. After incubation for 3 hours, absorbance at 450 nm was measured with an EnSpire multimode plate reader (PerkinElmer, Inc., Waltham, Mass., USA). Cell viability was calculated from the average value of 3 wells using the following formula.
Cellviability(%)=[Abs(test sample)-Abs(blank)/Abs(control)-Abs(blank)]x100 Cellviability(%)=[Abs (test sample) -Abs (blank) /Abs (control) -Abs (blank) ]x100
＜結果＞
　がん細胞は低栄養・低酸素といった極限状態におかれると、エネルギー代謝を変えることで生存する特有の耐性機構を示す。特に、PANC-1のようなヒト膵臓がん細胞は、このような耐性を獲得しており、低栄養・低酸素といった厳しい環境下においても長期間の生存が可能となっている。したがって、がん細胞の栄養飢餓耐性を解除する化合物（antiausterity agent）は、新たな抗がん剤探索の標的となる。
　上記のとおり、T-化合物を合成し、PANC-1に対するin vitro阻害活性を評価した。
　T-化合物は、膵臓がん由来細胞に対する細胞傷害性活性を示した（表１）。中でも、化合物T-38は栄養飢餓選択的50%細胞阻害濃度（PC50）値が5 nMと特に強力な阻害活性を示した。また、化合物T-39はPC50値が<10nM、化合物T-53はPC50値が13 nM、化合物T-67はPC50値が25 nM、化合物T-79はPC50値が0.7 nM、化合物T-81はPC50値が2.0 nM、化合物T-82はPC50値が1.5 nMであり、強力な阻害活性を示した。 <Results>
When exposed to extreme conditions such as malnutrition and hypoxia, cancer cells exhibit a unique resistance mechanism that allows them to survive by altering their energy metabolism. In particular, human pancreatic cancer cells such as PANC-1 have acquired such resistance and are able to survive for a long period of time even under harsh environments such as low nutrition and low oxygen. Therefore, antiausterity agents that release resistance to nutrient starvation in cancer cells are targets for searching for new anticancer drugs.
As described above, T-compounds were synthesized and evaluated for in vitro inhibitory activity against PANC-1.
T-compounds exhibited cytotoxic activity against pancreatic cancer-derived cells (Table 1). Among them, compound T-38 exhibited particularly strong inhibitory activity with a nutrient starvation selective 50% cell inhibitory concentration (PC 50 ) value of 5 nM. Compound T-39 also had a PC 50 value of <10 nM, compound T-53 had a PC 50 value of 13 nM, compound T-67 had a PC 50 value of 25 nM, compound T-79 had a PC 50 value of 0.7 nM, Compound T-81 had a PC 50 value of 2.0 nM, and compound T-82 had a PC 50 value of 1.5 nM, showing strong inhibitory activity.
Figure JPOXMLDOC01-appb-T000014
Figure JPOXMLDOC01-appb-T000014
３．栄養欠乏培地（NDM）培養下のPANC-1に対する阻害活性の評価
　上記試験におけるコントロール、およびT-38処置（1μM）の細胞を光学顕微鏡で観察した。また、コントロール、およびT-38処置（0.1μM, 1μM）の細胞を、Acridine orange（AO）染色、Ethidium bromide (EB)染色し、蛍光顕微鏡で観察した。 3. Evaluation of inhibitory activity against PANC-1 under nutrient deficient medium (NDM) culture Control and T-38 treated (1 μM) cells in the above test were observed under a light microscope. In addition, control and T-38-treated (0.1 μM, 1 μM) cells were stained with acridine orange (AO) and Ethidium bromide (EB) and observed under a fluorescence microscope.
＜結果＞
　栄養飢餓状態におけるこれらT-化合物のin vitro阻害活性を、NDM培養下のPANC-1の形質から確認した結果を図１Ａ、図１Ｂに示す。すなわち、T-38処置細胞では、細胞形状が崩れ、死細胞を染色するAcridine orange（AO）、Ethidium bromide (EB)による染色が増加した。すなわち、T-化合物である化合物T-38は、NDM培養下のPANC-1に対して強力な阻害活性を示した。T-化合物は、anti-austerity agentとして有用であることが示された。 <Results>
FIG. 1A and FIG. 1B show the results of confirming the in vitro inhibitory activity of these T-compounds under nutrient starvation conditions from the traits of PANC-1 under NDM culture. In other words, T-38-treated cells lost cell shape and increased staining with acridine orange (AO) and ethidium bromide (EB), which stain dead cells. That is, the T-compound, compound T-38, exhibited potent inhibitory activity against PANC-1 under NDM culture. T-compounds have been shown to be useful as anti-austerity agents.
４．栄養豊富培地（DMEM）培養下のPANC-1に対する転移阻害活性の評価
　PANC-1細胞懸濁液70μl（3×105cells/mL）を35mm μ-dishのCulture-Insert 2 Wellの各ウェルに播種し、37℃、5% CO2で24時間以上インキュベートして細胞を接着させた。その後、Culture-Insert 2ウェルを滅菌したピンセットで静かに取り除き、細胞層をPBSで洗浄した。μ-DishにDMEM単独（コントロール）または試験化合物（T-38）を含むDMEMをそれぞれ2mL入れ、CO2インキュベーター内に設置したCytoSMARTデバイスに載せた。画像は15分ごとに自動的に撮影された。各画像の開創面積はImageJソフトウェアを用いて算出し、データはGraphPad Prism 7を用いて処理した。 4. Evaluation of metastasis inhibitory activity against PANC-1 under nutrient-rich medium (DMEM) culture PANC-1 cell suspension 70 μl (3×10 5 cells/mL) was added to each well of a 35 mm μ-dish Culture-Insert 2 Well. Plated and incubated at 37° C., 5% CO 2 for >24 hours to allow cell attachment. Culture-Insert 2 wells were then gently removed with sterile forceps, and the cell layer was washed with PBS. A μ-Dish was filled with 2 mL each of DMEM alone (control) or DMEM with test compound (T-38) and placed on the CytoSMART device placed in a CO 2 incubator. Images were taken automatically every 15 minutes. The wound area of each image was calculated using ImageJ software and the data were processed using GraphPad Prism 7.
＜結果＞
　DMEM培養下のPANC-1に対する転移阻害活性を評価してT-化合物のがん細胞転移能に対する活性を確認した結果を図２Ａ、図２Ｂに示す。
　コントロールでは、細胞が大幅に移動したのに対し、T-38処置細胞では、濃度依存的に移動が抑制された。すなわち、T-化合物である化合物T-38は、DMEM培養下のPANC-1に対して強力な転移阻害活性を示した。T-化合物は、転移能を有することが示された。 <Results>
Figures 2A and 2B show the results of evaluating the metastasis inhibitory activity against PANC-1 under DMEM culture and confirming the activity of T-compounds against cancer cell metastasis.
Control cells migrated significantly, whereas migration was suppressed in T-38-treated cells in a dose-dependent manner. That is, compound T-38, which is a T-compound, exhibited potent metastasis inhibitory activity against PANC-1 under DMEM culture. T-compounds have been shown to have metastatic potential.
５．ヌードマウスにおけるMIA PaCa-2腫瘍の増殖に対するT-38の効果
　in vitro検討において強力な阻害活性を示したT-38の抗腫瘍効果について、in vivo抗腫瘍効果を検討した。5週齢の雄BALB/cヌードマウス（CAnN, Cg-Fixbk<nu>/CrlCrlJ 5Wオス）を1週間、動物舎で馴化させた。MIA PaCa-2腫瘍細胞（10,000,000 細胞/200 mL PBS）を全マウスの左右の脇腹に皮下注射して移植した。腫瘍細胞接種後4日目に、マウス（n＝8／群）を（i）対照群、（ii）低用量T-38投与群(T-38(L)）（10mg / kg /日; 低用量; 週5回）、（iii）高用量T-38投与群(T-38(H)）30mg / kg /日; 高用量; 5回/週）、（iv）Gemcitabine （GEM）投与群（150mg / kg /週; 1回/週）、（v）T-38とGemcitabineの併用投与群(T-38(H)+GEM)[Gemcitabine150mg / kg /週; 1回/週+ T-化合物、30mg / kg /日, 5 times/week]の5群に無作為に分けた。 5. Effect of T-38 on MIA PaCa-2 Tumor Growth in Nude Mice The in vivo antitumor effect of T-38, which showed strong inhibitory activity in in vitro studies, was investigated. Five-week-old male BALB/c nude mice (CAnN, Cg-Fixbk<nu>/CrlCrlJ 5W males) were acclimated in the animal house for one week. MIA PaCa-2 tumor cells (10,000,000 cells/200 mL PBS) were implanted subcutaneously into the left and right flanks of all mice. Four days after tumor cell inoculation, mice (n = 8/group) were divided into (i) control group, (ii) low-dose T-38 administration group (T-38(L)) (10 mg/kg/day; low 5 times a week), (iii) high dose T-38 group (T-38(H)) 30 mg/kg/day; high dose; 5 times/week), (iv) Gemcitabine (GEM) group ( 150 mg/kg/week; once/week), (v) combination administration group of T-38 and Gemcitabine (T-38(H)+GEM) [Gemcitabine 150 mg/kg/week; once/week + T-compound, 30mg/kg/day, 5 times/week] and divided into 5 groups at random.
　T-化合物またはGemcitabine(処理群)またはPBS(対照群)をマウスの腹腔内に注射した。すべてのマウスは、固形の食物と水を自由に摂取できる状態とした。体重と腫瘍の大きさを週に2回、以下の計算式を用いて測定した。また、実験開始31日目に腫瘍を摘出して写真を撮影し、重量を測定した。 Mice were injected intraperitoneally with T-compound or Gemcitabine (treatment group) or PBS (control group). All mice had free access to solid food and water. Body weight and tumor size were measured twice weekly using the following formula. On the 31st day after the start of the experiment, the tumor was excised, photographed, and weighed.
推定腫瘍体積（週2回の測定）＝（π×長さ×幅2）／6  Estimated tumor volume (measured twice weekly) = (π x length x width2 )/6
＜結果＞
　T-38を投与した群では、顕著な腫瘍サイズおよび重量の抑制効果が示された（図３）。効果は濃度依存的であった。GemcitabineおよびT-38を投与した群でも、顕著な腫瘍サイズおよび重量の抑制効果が示された。実験開始31日目に摘出した腫瘍の写真を図４に示す。これらの結果から、T-化合物単独、およびT-38およびGemcitabineの多剤併用において、抗がん活性を有することが示された。特に、T-38およびGemcitabineの多剤併用投与の場合、それぞれの化合物を単独で投与するよりも、より優れた効果が認められた。一方、T-38の投与は、マウス体重の増加に影響せず、生育への副作用は認められなかった。 <Results>
The T-38-administered group showed a remarkable suppressive effect on tumor size and weight (Fig. 3). The effect was concentration dependent. Groups treated with Gemcitabine and T-38 also showed significant tumor size and weight suppression. FIG. 4 shows a photograph of the tumor excised on the 31st day after the start of the experiment. These results indicated that the T-compound alone and the combination of T-38 and Gemcitabine had anticancer activity. In particular, the combination administration of T-38 and Gemcitabine was more effective than administration of each compound alone. On the other hand, administration of T-38 did not affect the weight gain of mice, and no adverse effects on growth were observed.
６．ヌードマウスにおけるMIA PaCa-2腫瘍の増殖に対するT-79の効果
　T-化合物をT-79とし、併用するGemcitabineを60mg / kg /週; 1回/週とした以外は、上記実施例５．と同様にして試験した。 6. Effect of T-79 on MIA PaCa-2 Tumor Growth in Nude Mice Example 5. above except that the T-compound was T-79 and the concomitant Gemcitabine was 60 mg/kg/week; once/week. tested in the same manner.
＜結果＞
　T-79においても、顕著な腫瘍サイズおよび重量の抑制効果が示された（図５～６）。効果は濃度依存的であった。GemcitabineおよびT-79を投与した群でも、顕著な腫瘍サイズおよび重量の抑制効果が示された。さらに、T-化合物単独、およびT-79およびGemcitabineの多剤併用において、抗がん活性を有することが示された。特に、T-79は、T-38より低用量のGemcitabineの多剤併用投与でも、それぞれの化合物を単独で投与するより、より優れた効果が認められた。また、T-79は、マウス体重増加に影響せず、生育への副作用は認められなかった。 <Results>
T-79 also exhibited significant tumor size and weight suppression (FIGS. 5-6). The effect was concentration dependent. Groups treated with Gemcitabine and T-79 also showed significant tumor size and weight suppression. In addition, T-compounds alone and in combination with T-79 and Gemcitabine were shown to have anticancer activity. In particular, T-79 was more effective than T-38 when combined with lower doses of Gemcitabine than when each compound was administered alone. In addition, T-79 did not affect the weight gain of mice, and no side effects on growth were observed.
７．C57BL/6マウスにおけるKPCY腫瘍の増殖に対するT-化合物の効果
　T-38の抗腫瘍効果について、C57BL/6マウスにおけるKPCY腫瘍の増殖に対するin vivo抗腫瘍効果を検討した。免疫機能が正常なC57BL/6マウスと、マウス由来のKPCY細胞株を用いた、T-38（30mg／kg）とGEM（60mg／kg）のそれぞれ単独投与群（5匹／群）の試験を、上記実施例５．と同様の方法で行った。移植に用いた細胞数は1,000,000個/200μL PBSとした。上記MIA PaCa-2細胞で用いた10,000,000個との細胞数の違いは、これらの細胞株の増殖率の違いによるものである。実験開始29日目に腫瘍を摘出し、写真を撮影して重量を測定した。 7. Effect of T-Compounds on KPCY Tumor Growth in C57BL/6 Mice The antitumor effect of T-38 was examined for in vivo antitumor effects on KPCY tumor growth in C57BL/6 mice. Trials of T-38 (30 mg/kg) and GEM (60 mg/kg) alone (5 animals/group) were conducted using C57BL/6 mice with normal immune function and a mouse-derived KPCY cell line. , Example 5. above. was done in a similar way. The number of cells used for transplantation was 1,000,000 cells/200 μL PBS. The difference in the number of cells from 10,000,000 used for the above MIA PaCa-2 cells is due to the difference in growth rate of these cell lines. On the 29th day after the start of the experiment, the tumor was excised, photographed, and weighed.
＜結果＞
　T-38を投与した群では、顕著な腫瘍サイズおよび重量の抑制効果が示された（図７）。実験開始29日目に摘出した腫瘍の写真を図８に示す。これらの結果から、T-化合物において、抗がん活性を有することが示された。一方、T-38は、マウス体重増加に影響せず、生育への副作用は認められなかった。 <Results>
The T-38-administered group exhibited a remarkable suppressive effect on tumor size and weight (Fig. 7). FIG. 8 shows a photograph of the tumor excised on the 29th day after the start of the experiment. These results indicated that the T-compound had anticancer activity. On the other hand, T-38 did not affect the weight gain of mice, and no adverse effects on growth were observed.
８．T-化合物の機能の検討
　T-化合物の機能をさらに検討した。0.5 mMフェニルメチルスルホニルフルオリド（PMSF）（pH 7.4）、cOmplete（商標）プロテアーゼ阻害剤カクテル（Roche、マンハイム、ドイツ）を含むRIPAバッファー（和光純薬、大阪、日本）を使用して、細胞から抽出したタンパク質サンプルを、2x Laemmliサンプルバッファー（Bio-Rad、Hercules、カリフォルニア、米国）中、100℃で5分間加熱した。等量のタンパク質を8～15％のアクリルアミドゲル上でSDS-ポリアクリルアミドゲル電気泳動にかけた。続いて、ゲルをImmobilon-P転写ポリフッ化ビニリデン膜（Millipore Corp, Bedford, MA, USA）に転写した。メンブレンを直ちにブロッキングバッファー［10mM Tris, 100mM NaCl, 0.1% Tween 20, pH7.5を含むTBS-Tween（TBS-T）バッファー中に5%脱脂粉乳を含む］に室温で1時間浸し、次にTBS-Tバッファーで30分洗浄した後、市販の適切な特異的一次抗体と4℃で一晩インキュベートした。その後、TBS-Tバッファーで30分洗浄した後、二次抗体（DakoCytomation, Glostrup, Denmark）と室温で1時間インキュベートし、さらにTBS-Tバッファーで40分洗浄した後、ImageQuant LAS 4000を用いて強化化学発光溶液（Bio-Rad, Hercules, CA, USA）でバンドを検出した。 8. Investigation of the function of T-compounds The function of T-compounds was further investigated. Cells were isolated using RIPA buffer (Wako Pure Chemical Industries, Osaka, Japan) containing 0.5 mM phenylmethylsulfonyl fluoride (PMSF) (pH 7.4), cOmplete™ protease inhibitor cocktail (Roche, Mannheim, Germany). Extracted protein samples were heated at 100° C. for 5 minutes in 2× Laemmli sample buffer (Bio-Rad, Hercules, CA, USA). Equal amounts of protein were subjected to SDS-polyacrylamide gel electrophoresis on 8-15% acrylamide gels. The gel was subsequently transferred to an Immobilon-P transfer polyvinylidene fluoride membrane (Millipore Corp, Bedford, Mass., USA). The membrane was immediately immersed in blocking buffer [5% non-fat dry milk in TBS-Tween (TBS-T) buffer containing 10 mM Tris, 100 mM NaCl, 0.1% Tween 20, pH 7.5] for 1 hour at room temperature, followed by TBS. After washing with -T buffer for 30 minutes, they were incubated overnight at 4°C with appropriate specific primary antibodies commercially available. Then washed with TBS-T buffer for 30 minutes, incubated with secondary antibody (DakoCytomation, Glostrup, Denmark) for 1 hour at room temperature, washed with TBS-T buffer for 40 minutes and enhanced using ImageQuant LAS 4000. Bands were detected with a chemiluminescent solution (Bio-Rad, Hercules, Calif., USA).
＜結果＞
　T-38処置細胞では、栄養飢餓条件下で、濃度依存的にpAKt、pmTOR、pAMPK、pULK、SOX-2、c-MYC、OCT-4の減少が認められた（図９～１１）。
　すなわち、T-化合物は、栄養飢餓条件下で、Akt/mTOR活性化、およびAMPK/ULK1 pathwayを阻害した。 <Results>
In T-38-treated cells, concentration-dependent decreases in pAKt, pmTOR, pAMPK, pULK, SOX-2, c-MYC, and OCT-4 were observed under nutrient starvation conditions (FIGS. 9-11).
Thus, T-compounds inhibited Akt/mTOR activation and the AMPK/ULK1 pathway under nutrient starvation conditions.
　セリン/スレオニンキナーゼAkt（プロテインキナーゼBとも呼ばれる）は、細胞シグナル伝達における中心的役割を果たし、これらのシグナル伝達の異常はがんおよび糖尿病から神経変性に至る広範囲の疾患に影響を及ぼす。
　また、mTORは、PI3K関連プロテインキナーゼ（PIKK）ファミリーのメンバーで、増殖因子経路のシグナルを伝播する機能を持ち、それによって細胞の成長、増殖、および生存をサポートする。さまざまながんにおいて、上方制御されているmTORシグナル伝達が検出されている。mTORは、２種類のタンパク質複合体mTORC1およびmTORC2のコア触媒ユニットで、mTORC1複合体は、ラパマイシン感受性で、mTOR、Raptor、およびmLST8から構成される。mTORC1は、細胞の成長および増殖を制御する。翻訳、リボソーム生合成、オートファジー、グルコース代謝、低酸素に対する細胞反応、および転移等のさまざまな腫瘍細胞特異的なプロセスを含むその他の生物学的プロセスもmTORC1によって制御される。
　また、ULK1のリン酸化は、オートファジーの制御の主な機構であり、セリン/スレオニンキナーゼAMPKとmTORが、ULK1をリン酸化する２つのキナーゼである。 The serine/threonine kinase Akt (also called protein kinase B) plays a central role in cell signaling, and abnormalities in these signaling affect a wide range of diseases from cancer and diabetes to neurodegeneration.
mTOR is also a member of the PI3K-related protein kinase (PIKK) family and functions to propagate growth factor pathway signals, thereby supporting cell growth, proliferation, and survival. Upregulated mTOR signaling has been detected in various cancers. mTOR is the core catalytic unit of two protein complexes, mTORC1 and mTORC2, the mTORC1 complex is rapamycin-sensitive and consists of mTOR, Raptor, and mLST8. mTORC1 controls cell growth and proliferation. Other biological processes are also regulated by mTORC1, including various tumor cell-specific processes such as translation, ribosome biogenesis, autophagy, glucose metabolism, cellular response to hypoxia, and metastasis.
Phosphorylation of ULK1 is also a major mechanism of regulation of autophagy, and the serine/threonine kinases AMPK and mTOR are two kinases that phosphorylate ULK1.
　がん細胞は一般に不規則かつ急速に増殖し、多くの場合、脆弱で無秩序に血管系が形成されるためグルコース欠乏や低酸素、その他栄養素の不足等ストレスの多い微小環境にさらされている。しかしながら、がん細胞はエネルギー代謝を調節して、低栄養・低酸素供給のような苛酷な条件に耐える固有の能力を示す。オートファジーは、その一機構と考えられる。T-化合物は、オートファジーを阻害するanti-austerity agentとして有用であることが示された。 Cancer cells generally grow irregularly and rapidly, and often have fragile and disorganized vasculature that expose them to a stressful microenvironment such as glucose deprivation, hypoxia, and other nutrient deficiencies. However, cancer cells exhibit an inherent ability to regulate energy metabolism and withstand harsh conditions such as low nutrition and low oxygen supply. Autophagy is thought to be one such mechanism. T-compounds have been shown to be useful as anti-austerity agents that inhibit autophagy.
　また、T-化合物は、栄養飢餓条件下で、SOX2、c-MYC、OCT-4を阻害した。
　がん幹細胞は、自己複製能と、多分化能を有し、少数の細胞からでも高率にがんを形成する強い造腫瘍能を有する細胞である。がん幹細胞は、がんの治療抵抗性、再発・転移と深く結び付いているとも考えられる。SOX2、c-MYC、OCT-4はがん細胞の脱分化を促進し、幹細胞性を付与することが知られる。T-化合物は、がん細胞の脱分化を促進し、幹細胞性を付与を阻害し、がんの治療抵抗性、再発・転移の抑制に有用であることが示された。特に、本発明に用いられる化合物は、SOX2、c-MYC、OCT-4を阻害することによって、がんの治療抵抗性、すなわち、膵臓がんに対してほとんど耐性を示すことなく、優れた効果をもたらすことが示唆された。 T-compounds also inhibited SOX2, c-MYC and OCT-4 under nutrient starvation conditions.
Cancer stem cells are cells that have self-renewal ability, multipotency, and strong tumorigenic ability to form cancer at a high rate even from a small number of cells. Cancer stem cells are also thought to be deeply associated with treatment resistance, recurrence, and metastasis of cancer. SOX2, c-MYC, and OCT-4 are known to promote dedifferentiation of cancer cells and confer stemness. It was shown that T-compounds promote dedifferentiation of cancer cells, inhibit the conferment of stemness, and are useful in suppressing treatment resistance, recurrence and metastasis of cancer. In particular, the compound used in the present invention inhibits SOX2, c-MYC, and OCT-4, thereby exhibiting excellent efficacy against cancer treatment resistance, that is, pancreatic cancer, without showing almost any resistance. It was suggested that
９．T-化合物のマウス同所性KPCY固形腫瘍移植モデルにおける抗腫瘍活性
　本発明の実験プロトコール（図１２）では、まずKPCYマウス膵臓がん細胞を皮下接種し、宿主BALB/c-nuマウスで2～3週間培養した。移植日に、宿主BALB/c-nuマウスの腫瘍を摘出し、約15mgの大きさの小片に切断した。この腫瘍の小片を、外科手術によってC57Bl/6レシピエントマウスの膵臓に移植した。マウスは手術3日目にランダム化され、3日目からT-38、GEM、または2つの薬剤の組み合わせで治療された。16日目にマウスを犠牲にし、腫瘍を摘出し、体重を測定した。 9. Antitumor activity of T-compounds in mouse orthotopic KPCY solid tumor transplantation model In the experimental protocol of the present invention (Fig. 12), KPCY mouse pancreatic cancer cells were first subcutaneously inoculated, and the host BALB/c-nu mice were subcutaneously inoculated for 2 to 2 days. Cultured for 3 weeks. On the day of implantation, tumors in host BALB/c-nu mice were excised and cut into pieces approximately 15 mg in size. Small pieces of this tumor were surgically implanted into the pancreas of C57B1/6 recipient mice. Mice were randomized on day 3 of surgery and were treated with T-38, GEM, or a combination of the two agents beginning on day 3. Mice were sacrificed on day 16 and tumors were excised and weighed.
＜結果＞
　エンドポイント試験の結果を図１３に示す。グラフから、T-38単独投与では、対照群に比べ、腫瘍重量が有意に減少していることがわかる。ゲムシタビンとの併用で、腫瘍重量はさらに減少する。これらの結果から、T-38は免疫コンピテントマウスにおいて強力な抗腫瘍活性を有し、T-38とゲムシタビンの併用は、どちらか一方の薬剤単独に比べ、より効果的に腫瘍の成長を阻害することが示唆された。重要なことは、併用療法はマウスの体重を変化させないことであり、忍容性が高いことが示唆された。これらの結果は、T-化合物が膵臓がんにおけるゲムシタビン耐性を克服する可能性を持ち、併用療法ががん、特に膵臓がんの治療に新たな有効な方法を提供する可能性を示唆した。
　T-38は、臨床的に使用されている抗がん剤ゲムシタビンと比較して、優れたin vivo抗腫瘍活性を有することが、T-38を免疫正常C57Bl/6マウスに投与した上記実施例の試験で実証されている。また、T-38とゲムシタビンの併用は、腫瘍重量のグラフに示されるように、強力な腫瘍増殖抑制効果を示した。重要なことは、T-38および関連するT-化合物は、免疫不全マウスと免疫能力を有するコンピテントマウスの両方で、体重を変えずに腫瘍の成長を阻害することが示されたことである。したがって、T-38および関連するT-化合物は、がんの治療に使用できる可能性のある、有望な新しいクラスの抗腫瘍剤である。 <Results>
Results of the endpoint study are shown in FIG. The graph shows that administration of T-38 alone significantly reduced tumor weight compared to the control group. In combination with gemcitabine, tumor weight is further reduced. These results indicate that T-38 has potent antitumor activity in immunocompetent mice, and that the combination of T-38 and gemcitabine is more effective in inhibiting tumor growth than either agent alone. It was suggested that Importantly, the combination therapy did not change the body weight of the mice, suggesting that it was well tolerated. These results suggested that T-compounds have the potential to overcome gemcitabine resistance in pancreatic cancer, and that combination therapy may provide a new and effective way to treat cancer, especially pancreatic cancer.
T-38 has superior in vivo antitumor activity compared to the clinically used anticancer drug gemcitabine, which was demonstrated in the above examples in which T-38 was administered to immunocompetent C57Bl/6 mice. has been proven in the tests of Also, the combination of T-38 and gemcitabine showed a strong tumor growth inhibitory effect as shown in the graph of tumor weight. Importantly, T-38 and related T-compounds were shown to inhibit tumor growth without altering body weight in both immunodeficient and immunocompetent mice. . T-38 and related T-compounds are therefore a promising new class of anti-tumor agents that may be used in the treatment of cancer.
＜考察＞
　本発明は、既存の抗がん剤とは全く異なるスクリーニングで見出したものである。すなわち、栄養の豊富な状態では毒性をほとんど示さず、栄養飢餓状態においてのみがん細胞に毒性を示す極めてユニークな化合物である複数のT-化合物が見出された。これは、まさしく抗がん剤特有の深刻な副作用を回避することができることを示している。また、T-化合物は、がんの増殖や栄養飢餓耐性等の主要機構に関する複数のキナーゼを阻害する。したがって、膵臓がんのみならず、耐性を示す膵臓がんやがん全般に効果を奏すると考えられる。
　一方、がん細胞では、栄養飢餓状態であればある程、増殖能、転移能さらには悪性度が高いことが明らかになりつつある。これは、がん幹細胞に密接に関わっていると考えられ、事実栄養飢餓状態においてはがん幹細胞の発現が著しく増大している。がん幹細胞を効果的に死滅させなければ、やがてがんの再発を招くことになり極めて深刻である。本発明は、がん微小環境、すなわち栄養飢餓状態における細胞毒性に特に焦点を当てたアプローチであり、このがん幹細胞にも効果を発揮する可能性が極めて高いことに加え、複数の作用機序によって、がん細胞を効果的に死滅させることができる画期的薬剤の提案である。さらに、本発明に用いられる化合物とともに、他の抗がん剤、特に膵臓がんの場合、Gemcitabineを多剤併用すると、単独投与に比べさらに優れた腫瘍効果を示す。 <Discussion>
The present invention was discovered through screening that is completely different from existing anticancer agents. That is, multiple T-compounds were discovered, which are extremely unique compounds that exhibit little toxicity to cancer cells under nutrient-rich conditions and exhibit toxicity to cancer cells only under nutrient-starved conditions. This indicates that serious side effects peculiar to anticancer drugs can be avoided. T-compounds also inhibit multiple kinases involved in key mechanisms such as cancer growth and resistance to nutrient starvation. Therefore, it is thought to be effective not only against pancreatic cancer but also against pancreatic cancer showing resistance and cancer in general.
On the other hand, it is becoming clear that in cancer cells, the more they are in a state of nutritional starvation, the higher their proliferative ability, metastatic ability, and malignancy. This is thought to be closely related to cancer stem cells, and in fact, the expression of cancer stem cells is remarkably increased under conditions of nutritional starvation. If cancer stem cells are not effectively killed, the cancer will eventually recur, which is extremely serious. The present invention is an approach that is specifically focused on cytotoxicity in the cancer microenvironment, i.e., nutrient starvation, and is highly likely to be effective in this cancer stem cell as well. This is a proposal for an epoch-making drug that can effectively kill cancer cells by Furthermore, in the case of pancreatic cancer, in addition to the compounds used in the present invention, combined use of other anticancer agents, especially gemcitabine, exhibits superior tumor effects compared to single administration.
　本発明は、がん治療用医薬組成物として用いることができる。 The present invention can be used as a pharmaceutical composition for cancer treatment.

Claims (20)

  1. 　下記式（Ｉ）で示される化合物、またはその薬理学的に許容可能な塩を有効成分として含有する、医薬組成物：
    Figure JPOXMLDOC01-appb-C000001
    　式中、
    　Ｒ１は、置換基を有してもよい炭素数１～２０の炭化水素基を示し、
    　Ｒ２～Ｒ５は、それぞれ独立に、水素、炭素数１～４の炭化水素基、電子供与性基または電子吸引性基を示し、Ｒ２～Ｒ５は、隣り合った基と結合し環を形成していてもよく、
    　Ｒ６～Ｒ１０は、それぞれ独立に、水素、ヒドロキシ、ハロゲン、炭素数１～２０のアルコキシ、炭素数１～４のアルキルアミノで置換された炭素数１～４のアルコキシ、または炭素数１～４のアルキルスルホニル（－ＳＯ２Ｒ；Ｒはアルキルを示す）を示し、Ｒ６～Ｒ１０は、隣り合った基と結合し環を形成していてもよい。     A pharmaceutical composition containing a compound represented by the following formula (I) or a pharmacologically acceptable salt thereof as an active ingredient:
    Figure JPOXMLDOC01-appb-C000001
    During the ceremony,
    R 1 represents a hydrocarbon group having 1 to 20 carbon atoms which may have a substituent,
    R 2 to R 5 each independently represent hydrogen, a hydrocarbon group having 1 to 4 carbon atoms, an electron-donating group or an electron-withdrawing group, and R 2 to R 5 combine with adjacent groups to form a ring may form
    R 6 to R 10 are each independently hydrogen, hydroxy, halogen, alkoxy having 1 to 20 carbon atoms, alkoxy having 1 to 4 carbon atoms substituted with alkylamino having 1 to 4 carbon atoms, or 1 to 4 carbon atoms. 4 alkylsulfonyl (--SO 2 R; R represents alkyl), and R 6 to R 10 may combine with adjacent groups to form a ring.
  2. 　前記Ｒ７およびＲ９が、それぞれ独立に、ハロゲン、または炭素数１～４のアルキルスルホニルである、請求項１に記載の医薬組成物。 The pharmaceutical composition according to claim 1, wherein said R 7 and R 9 are each independently halogen or alkylsulfonyl having 1 to 4 carbon atoms.
  3. 　前記Ｒ１が、置換基を有してもよい炭素数１～１０のアルキルである、請求項１または２に記載の医薬組成物。 The pharmaceutical composition according to claim 1 or 2, wherein said R 1 is alkyl having 1 to 10 carbon atoms which may have a substituent.
  4. 　前記Ｒ８が、ヒドロキシ、水素、炭素数１～２０のアルコキシ、または炭素数１～４のアルキルアミノで置換された炭素数１～４のアルコキシである、請求項１～３のいずれか１項に記載の医薬組成物。 4. Any one of claims 1 to 3, wherein R 8 is hydroxy, hydrogen, alkoxy having 1 to 20 carbon atoms, or alkoxy having 1 to 4 carbon atoms substituted with alkylamino having 1 to 4 carbon atoms. The pharmaceutical composition according to .
  5. 　電子吸引性基が、ハロゲン、炭素数１～４のハロゲン化アルキル、炭素数１～１０のカルボン酸エステル、炭素数１～４のアシル、シアノ（－ＣＮ）、ニトロ（－ＮＯ2）、炭素数１～４のアルキルチオ（－ＳＲ；Ｒはアルキルを示す）、炭素数１～４のアルキルスルフィニル（－ＳＯＲ；Ｒはアルキルを示す）、もしくは炭素数１～４のアルキルスルホニル（－ＳＯ２Ｒ；Ｒはアルキルを示す）；またはこれらの電子吸引性基を置換基として有するアリールもしくはヘテロアリールである、請求項１～４のいずれか１項に記載の医薬組成物。 The electron withdrawing group is halogen, halogenated alkyl having 1 to 4 carbon atoms, carboxylic acid ester having 1 to 10 carbon atoms, acyl having 1 to 4 carbon atoms, cyano (-CN), nitro (-NO 2 ), carbon Alkylthio having 1 to 4 numbers (-SR; R represents alkyl), alkylsulfinyl having 1 to 4 carbon atoms (-SOR; R represents alkyl), or alkylsulfonyl having 1 to 4 carbon atoms (-SO 2 R ; R represents alkyl); or aryl or heteroaryl having these electron-withdrawing groups as substituents.
  6. 　電子供与性基がヒドロキシ、炭素数１～４のアルコキシ、またはアミノである、請求項１～５のいずれか１項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 5, wherein the electron-donating group is hydroxy, alkoxy having 1 to 4 carbon atoms, or amino.
  7. 　栄養飢餓状態の腫瘍細胞を選択的に死滅させるための、請求項１～６のいずれか１項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 6, for selectively killing nutrient-starved tumor cells.
  8. 　抗がん用である、請求項１～７のいずれか１項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 7, which is for anticancer use.
  9. 　前記がんが、膵臓がんである、請求項８に記載の医薬組成物。 The pharmaceutical composition according to claim 8, wherein the cancer is pancreatic cancer.
  10. 　前記膵臓がんが、式（Ｉ）で示される化合物、またはその薬理学的に許容可能な塩以外の抗がん化合物に対して耐性を示す膵臓がんである、請求項９に記載の医薬組成物。 The pharmaceutical composition according to claim 9, wherein the pancreatic cancer is resistant to an anticancer compound other than the compound represented by formula (I) or a pharmacologically acceptable salt thereof. thing.
  11. 　がん幹細胞の発生抑制用、または、がん幹細胞の殺傷用である、請求項１～１０のいずれか１項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 10, which is for suppressing the development of cancer stem cells or for killing cancer stem cells.
  12. 　さらに、式（Ｉ）で示される化合物、またはその薬理学的に許容可能な塩以外の抗がん化合物を含有する、請求項１～１１のいずれか１項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 11, further comprising an anticancer compound other than the compound represented by formula (I) or a pharmacologically acceptable salt thereof.
  13. 　式（Ｉ）で示される化合物、またはその薬理学的に許容可能な塩以外の抗がん化合物と併用投与されるように用いられるための、請求項１～１２のいずれか１項に記載の医薬組成物。 13. The compound according to any one of claims 1 to 12, for use in combination administration with an anticancer compound other than the compound represented by formula (I) or a pharmacologically acceptable salt thereof. pharmaceutical composition.
  14. 　前記式（Ｉ）で示される化合物、またはその薬理学的に許容可能な塩以外の抗がん化合物が、代謝拮抗薬である、請求項１０、１２または１３のいずれか１項に記載の医薬組成物。 14. The medicament according to any one of claims 10, 12 or 13, wherein the anticancer compound other than the compound represented by formula (I) or a pharmacologically acceptable salt thereof is an antimetabolite. Composition.
  15. 　前記代謝拮抗薬が、ゲムシタビンである、請求項１４に記載の医薬組成物。 The pharmaceutical composition according to claim 14, wherein the antimetabolite is gemcitabine.
  16. 　下記式（Ｉ）’で示される化合物、またはその薬理学的に許容可能な塩：
    Figure JPOXMLDOC01-appb-C000002
    　式中、
    　Ｒ１’は、置換基を有してもよい炭素数１～２０の炭化水素基を示し、
    　Ｒ２’～Ｒ５’は、それぞれ独立に、水素、炭素数１～４の炭化水素基、電子供与性基または電子吸引性基を示し、Ｒ２’～Ｒ５’は、隣り合った基と結合し環を形成していてもよく、
    　Ｒ６’およびＲ１０’は、それぞれ独立に、水素、ヒドロキシ、ハロゲン、炭素数１～２０のアルコキシ、炭素数１～４のアルキルアミノで置換された炭素数１～４のアルコキシ、または炭素数１～４のアルキルスルホニル（－ＳＯ２Ｒ；Ｒはアルキルを示す）を示し、
    　Ｒ７’およびＲ９’は、それぞれ独立に、ハロゲン、または炭素数１～４のアルキルスルホニルを示し、
    　Ｒ８’は、ヒドロキシ、水素、炭素数１～２０のアルコキシ、または炭素数１～４のアルキルアミノで置換された炭素数１～４のアルコキシを示し、
    　Ｒ１’が炭素数４のアルキルである場合、Ｒ２’～Ｒ５’の少なくとも１つは水素以外である。     A compound represented by the following formula (I)', or a pharmacologically acceptable salt thereof:
    Figure JPOXMLDOC01-appb-C000002
    During the ceremony,
    R 1 ' represents an optionally substituted hydrocarbon group having 1 to 20 carbon atoms,
    R 2 ' to R 5 ' each independently represents hydrogen, a hydrocarbon group having 1 to 4 carbon atoms, an electron donating group or an electron withdrawing group, and R 2 ' to R 5 ' are adjacent groups may be combined to form a ring,
    R 6 ' and R 10 ' are each independently hydrogen, hydroxy, halogen, alkoxy having 1 to 20 carbon atoms, alkoxy having 1 to 4 carbon atoms substituted with alkylamino having 1 to 4 carbon atoms, or alkoxy having 1 to 4 carbon atoms. 1 to 4 alkylsulfonyl (--SO 2 R; R represents alkyl);
    R 7 ' and R 9 ' each independently represent halogen or alkylsulfonyl having 1 to 4 carbon atoms,
    R 8 ' represents hydroxy, hydrogen, alkoxy having 1 to 20 carbon atoms, or alkoxy having 1 to 4 carbon atoms substituted with alkylamino having 1 to 4 carbon atoms,
    When R 1 ' is C4 alkyl, at least one of R 2 '-R 5 ' is other than hydrogen.
  17. 　電子吸引性基が、ハロゲン、炭素数１～４のハロゲン化アルキル、炭素数１～１０のカルボン酸エステル、炭素数１～４のアシル、シアノ（－ＣＮ）、ニトロ（－ＮＯ2）、炭素数１～４のアルキルチオ（－ＳＲ；Ｒはアルキルを示す）、炭素数１～４のアルキルスルフィニル（－ＳＯＲ；Ｒはアルキルを示す）、もしくは炭素数１～４のアルキルスルホニル（－ＳＯ２Ｒ；Ｒはアルキルを示す）；またはこれらの電子吸引性基を置換基として有するアリールもしくはヘテロアリールである、請求項１６に記載の化合物。 The electron withdrawing group is halogen, halogenated alkyl having 1 to 4 carbon atoms, carboxylic acid ester having 1 to 10 carbon atoms, acyl having 1 to 4 carbon atoms, cyano (-CN), nitro (-NO 2 ), carbon Alkylthio having 1 to 4 numbers (-SR; R represents alkyl), alkylsulfinyl having 1 to 4 carbon atoms (-SOR; R represents alkyl), or alkylsulfonyl having 1 to 4 carbon atoms (-SO 2 R R represents alkyl); or aryl or heteroaryl having these electron-withdrawing groups as substituents.
  18. 　電子供与性基がヒドロキシ、炭素数１～４のアルコキシ、またはアミノである、請求項１６または１７に記載の化合物。 The compound according to claim 16 or 17, wherein the electron-donating group is hydroxy, alkoxy having 1 to 4 carbon atoms, or amino.
  19. 　請求項１６～１８のいずれか１項に記載の化合物、またはその薬理学的に許容可能な塩の、栄養飢餓状態の腫瘍細胞を選択的に死滅させる抗がん剤としての使用。 Use of the compound according to any one of claims 16 to 18, or a pharmacologically acceptable salt thereof, as an anticancer agent that selectively kills nutrient-starved tumor cells.
  20. 　請求項１６～１８のいずれか１項に記載の化合物、またはその薬理学的に許容可能な塩の、がん幹細胞の発生を抑制させる、または、がん幹細胞を殺傷させる抗がん剤としての使用。 The compound according to any one of claims 16 to 18, or a pharmacologically acceptable salt thereof, as an anticancer agent that suppresses the development of cancer stem cells or kills cancer stem cells use.
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