WO2023149549A1 - Nouvelle composition pharmaceutique - Google Patents

Nouvelle composition pharmaceutique 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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carbon atoms
pharmaceutical composition
cancer
compound
hydroxy
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PCT/JP2023/003581
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English (en)
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/fr

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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.

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Abstract

Un but de la présente invention est de fournir une nouvelle composition pharmaceutique, en particulier une nouvelle composition pharmaceutique anticancéreuse, et un nouveau composé utilisé pour l'agent anticancéreux.　La présente invention concerne une composition pharmaceutique comprenant, en tant que principe actif, un composé représenté par la formule (I) ci-dessous ou un sel pharmacologiquement acceptable de celui-ci.
PCT/JP2023/003581 2022-02-03 2023-02-03 Nouvelle composition pharmaceutique WO2023149549A1 (fr)

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JP2002514636A (ja) * 1998-05-12 2002-05-21 アメリカン・ホーム・プロダクツ・コーポレイション インスリン抵抗性または高血糖症の治療に有用なフェニルオキソ−酢酸類
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JP2013539757A (ja) * 2010-10-06 2013-10-28 ジェイファーマ株式会社 強力な尿酸トランスポーター阻害剤の開発：それらの尿酸排泄効果のために設計された化合物
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