WO2022231377A1 - Nouveau composé et composition pharmaceutique le comprenant pour la prévention ou le traitement du cancer, et utilisation associée - Google Patents

Nouveau composé et composition pharmaceutique le comprenant pour la prévention ou le traitement du cancer, et utilisation associée Download PDF

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WO2022231377A1
WO2022231377A1 PCT/KR2022/006181 KR2022006181W WO2022231377A1 WO 2022231377 A1 WO2022231377 A1 WO 2022231377A1 KR 2022006181 W KR2022006181 W KR 2022006181W WO 2022231377 A1 WO2022231377 A1 WO 2022231377A1
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substituted
cancer
alkyl
unsubstituted
aryl
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PCT/KR2022/006181
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Korean (ko)
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윤여진
김형남
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홀로스메딕 주식회사
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present application relates to a novel compound and a pharmaceutical composition for preventing or treating cancer comprising the compound or a pharmaceutically acceptable salt thereof, a method for preventing or treating cancer, and a use for preventing or treating cancer.
  • Cancer is one of the most common causes of death worldwide, accounting for about 12% of deaths.
  • Chemotherapy which is a representative anticancer therapy, is currently used as the most effective treatment for cancer, either alone or in combination with other therapies such as radiotherapy.
  • the efficacy of a cancer treatment drug in chemotherapy depends on its ability to kill cancer cells, but there is a problem that it can act not only on cancer cells but also normal cells when the drug is used.
  • One aspect of the present application is to provide a novel compound.
  • Another aspect of the present application is to provide a pharmaceutical composition for preventing or treating cancer comprising a novel compound.
  • Another aspect of the present application is to provide a pharmaceutical composition for preventing or treating resistant cancer comprising a novel compound.
  • Another aspect of the present application is to provide a use for preventing or treating cancer of the novel compound.
  • Another aspect of the present application is to provide a use for preventing or treating resistant cancer of the novel compound.
  • Another aspect of the present application is to provide a method for preventing or treating cancer of a novel compound.
  • Another aspect of the present application is to provide a method for preventing or treating resistant cancer of a novel compound.
  • One embodiment of the present application provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
  • R 1 is hydrogen, straight or branched chain alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, heteroaryl, alkylaryl or alkylheteroaryl, each of which is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, oxo, cyano, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl may be substituted with at least one of;
  • R 3 is hydrogen, straight or branched chain alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl, each of which is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy may be substituted with at least one of , C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, oxo, cyano, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl;
  • L 1 is C 1 -C 10 alkylene, wherein the alkylene may be substituted with at least one of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, hydroxyl, oxo or halogen. and wherein the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy may be unsubstituted or substituted with substituted aryl;
  • Q is S, Se, NR, P, P(O), P(O) 2 or P(O)OR , wherein R is hydrogen, straight or branched chain alkyl, cycloalkyl, bi or tricyclo alkyl, alkoxy , haloalkyl, haloalkoxy, aryl, heteroaryl, alkylaryl or alkylheteroaryl, each of which is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 halo may be substituted with at least one of alkyl, C 1 -C 6 haloalkoxy, oxo, cyano, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl;
  • R 2 is hydrogen, straight chain alkyl, cycloalkyl, alkoxy, haloalkoxy, haloalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl, each of which is independently hydroxyl, halogen, C 1 -C 6 alkyl, C of 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, oxo, nitro, cyano or trifluoromethyl at least one may be substituted;
  • R 4 and R 4 ′ are each independently hydrogen, straight or branched chain alkyl, cycloalkyl, alkenyl, alkynyl, alkylthio, aryl, heteroaryl, alkylaryl or alkylheteroaryl, each of which is independently hydrogen hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, oxo , may be substituted with at least one of nitro, cyano or trifluoromethyl;
  • n is an integer from 1 to 4.
  • X, Y, Z are each independently hydrogen, straight or branched chain alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl, each of which is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, oxo, nitro, cyano, or trifluoro It may be substituted with at least one of methyl.
  • One embodiment of the present application provides a pharmaceutical composition for treating or preventing cancer comprising at least one of the compound represented by Formula 1, or a pharmaceutically acceptable salt thereof.
  • One embodiment of the present application provides a pharmaceutical composition for treating or preventing resistant cancer comprising at least one of the compound represented by Formula 1, or a pharmaceutically acceptable salt thereof.
  • One embodiment of the present application provides a therapeutically effective amount of the compound represented by Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, structural isomer, optical isomer, stereoisomer/isomer, or a combination thereof. It provides a method of treating cancer, resistant cancer, or stem cell cancer comprising administering.
  • the administration may include simultaneous, separate, or sequential administration of an anticancer agent useful for the treatment of cancer or proliferative disease.
  • One embodiment of the present application provides a compound represented by Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, and structure thereof for preparing a medicament for the treatment of cancer, resistant cancer, or stem cell cancer isomers, optical isomers, stereoisomers, or combinations thereof.
  • a pharmaceutical composition comprising a compound according to an embodiment of the present application or a pharmaceutically acceptable salt thereof may exhibit excellent anticancer effect.
  • a composition comprising a compound according to an embodiment of the present application or a pharmaceutically acceptable salt thereof can enhance the anticancer activity of an anticancer agent or radiation, and can effectively treat cancer by inducing proliferation inhibition and apoptosis of cancer cells.
  • a composition comprising a compound or a pharmaceutically acceptable salt thereof according to an embodiment of the present application can effectively treat resistant cancer by overcoming the resistance of cancer with resistance to anticancer drugs or radiation, and side effects of anticancer treatment can reduce
  • a composition comprising the compound according to an embodiment of the present application or a pharmaceutically acceptable salt thereof can effectively treat stem cell cancer.
  • FIG. 1 shows the IC 50 values of paclitaxel and docetaxel anticancer drugs of SKOV3
  • FIG. 2 shows the IC 50 values of paclitaxel and docetaxel anticancer drugs of SKOV3-TR.
  • 5 to 8 show the results of WST-1 analysis of SKOV3-TR and SKOV3 for paclitaxel and 47 compounds.
  • 9 to 12 show the results of WST-1 analysis of SKOV3-TR and SKOV3 for docetaxel and 47 kinds of compounds.
  • 17 to 20 show the results of WST-1 analysis of MCF7-BC19 and MCF7 for paclitaxel and 47 compounds.
  • the term "independently” means that an independently applied variable independently changes from application to application.
  • R a XYR a if R a is "independently carbon or nitrogen,” then both R a can be carbon, both R a can be nitrogen, or one R a is carbon and , other R a may be nitrogen.
  • alkyl typically means a C 1 -C 10 saturated straight chain or branched hydrocarbon chain, and more specifically, a C 1 -C 6 alkyl saturated straight chain or C 3 .
  • ⁇ C 6 means a branched hydrocarbon chain.
  • C 1 -C 10 alkyl means straight chain or branched alkyl having 1 to 10 carbon atoms, specifically methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl , neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethyl butyl, and 2,3-dimethylbutyl, and the like.
  • the term includes both substituted and unsubstituted alkyl groups.
  • the alkyl group may be optionally substituted with one or more moieties selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphoric acid, phosphate, or phosphonate.
  • One or more hydrogen atoms attached to the carbon atoms of the alkyl may be substituted with one or more halogen atoms such as, for example, fluorine or chlorine or both, such as trifluoromethyl, difluoromethyl, fluorochloromethyl and the like.
  • the hydrocarbon chain may also contain heteroatoms such as N, O or S in the middle.
  • alkaryl or “alkylaryl” refers to an alkyl group having an aryl substituent.
  • aralkyl or arylalkyl refers to an aryl group having an alkyl substituent such as benzyl.
  • halo or “halogen” includes chloro, bromo, iodo and fluoro.
  • alkoxy means “C 1 -C 6 alkoxy” unless otherwise specified, and "C 1 -C 6 alkoxy” is a straight or branched chain having 1 to 6 carbon atoms. It means alkoxy, and includes, but is not limited to, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, and a butoxy group.
  • alkenyl means “C 2 -C 6 alkenyl” unless otherwise specified, and "C 2 -C 6 alkenyl” is one having 2 to 6 carbon atoms. refers to a straight or branched chain alkenyl containing a double bond of, vinyl, propenyl, butenyl, isobutenyl, pentenyl and hexenyl and the like, but are not limited thereto.
  • alkynyl means “C 2 -C 6 alkynyl” unless otherwise specified, and "C 2 -C 6 alkynyl” is one having 2 to 6 carbon atoms. It refers to a straight-chain or branched alkynyl containing a triple bond of, including, but not limited to, ethynyl, propynyl, butynyl, isobutynyl, pentynyl and hexynyl.
  • cycloalkyl means “C 3 -C 10 cycloalkyl” unless otherwise specified, and "C 3 -C 10 cycloalkyl” has 3 to 10 carbon atoms in the ring. means cyclic alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, etc. includes The terms “C 3 -C 8 cycloalkyl”, “C 3 -C 7 cycloalkyl” and "C 3 -C 6 cycloalkyl” have similar connotations.
  • the cycloalkyl group may have a ring substituted with an alkyl group such as cyclopropylmethyl.
  • aryl means a “C 6 to C 12 aryl group” unless otherwise specified, and "C 6 to C 12 aryl group” refers to 6 to C 12 aryl groups that do not contain a hetero atom in the ring. phenyl, biphenyl (biphenyl), or naphthyl having 12 carbon atoms, preferably phenyl. The term includes both substituted and unsubstituted moieties.
  • substituted aryl is optionally unprotected or protected hydroxyl, halogen, amino, alkylamino, arylamino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, may be substituted with one or more substituents including C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, oxo, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphoric acid, phosphate, or phosphonate,
  • C 6 -C 10 aryl group has a similar connotation.
  • heteroaryl or “heterocyclic” means “3 to 12 membered heterocyclic", and “3 to 12 membered heterocyclic” is selected from among oxygen, sulfur and nitrogen in the ring. It means a saturated or unsaturated 3-12 membered ring group containing 1 to 3 hetero atoms, for example, dioxol (dioxol).
  • dioxol dioxol
  • 3-7 membered heterocyclic has a similar connotation.
  • substituted heteroaryl refers to unprotected or protected hydroxyl, halogen, amino, alkylamino, arylamino, C 1 to C 6 alkyl, C 1 to C 6 alkoxy, C 3 to C 6 as needed. substituted with one or more substituents including cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 halo alkoxy, oxo, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphoric acid, phosphate, or phosphonate can, but is not limited thereto.
  • alkylene refers to a divalent hydrocarbyl group, since it is divalent and thus can be linked with two other groups. In general, it is -(CH 2 )n-, where n is 1 to 8 and preferably n is 1 to 4, but in certain instances the alkylene may be substituted by other groups and may be of different lengths, The open atoms do not necessarily have to be on opposite sides of the chain.
  • any alkyl, alkenyl, alkynyl, or aryl, alkylaryl or arylalkyl contained within a substituent may itself be optionally substituted by other additional substituents.
  • the nature of these substituents is similar to that recited for the primary substituents themselves, unless the substituents are otherwise stated.
  • heteroatom refers to an atom other than carbon or hydrogen, such as nitrogen, oxygen, or sulfur. If it is part of the backbone or backbone of a chain or ring, the heteroatom must be at least divalent and will generally be selected from N, O, P, and S.
  • the term "which may be substituted” or "substituted” means that the particular group or groups referred to as being optionally substituted does not have non-hydrogen substituents, or that the group or groups does not contain the chemistry of the resulting molecule. and one or more non-hydrogen substituents consistent with pharmacological activity. Unless otherwise specified, the total number of such substituents that may be present is equal to the total number of hydrogen atoms present in the unsubstituted form of the group being described; There may be fewer than the maximum number of such substituents.
  • the group takes on the two valencies available on the carbon atom to which the optional substituent is attached, so that the total number of substituents that can be included is equal to the available valence. decreases with the number of
  • substituted whether used as part of the term "which may be substituted," or otherwise, when used to modify a particular group, moiety, or radical, means that one or more hydrogen atoms are each independently to each other, means to be replaced by the same or different substituents or substituents.
  • the compounds described herein may contain one or more chiral centers and/or double bonds, they may be treated as stereoisomers, such as double-bond isomers (i.e. geometric isomers such as E and Z), enantiomers, or diastereomers. may exist.
  • stereoisomers such as double-bond isomers (i.e. geometric isomers such as E and Z), enantiomers, or diastereomers.
  • the present application also encompasses mixtures of stereoisomers that differ in chiral purity and percentages of E and Z, respectively, as isolated stereoisomeric forms (such as enantiomerically pure isomers, E and Z isomers, and other replacements of stereoisomers). unless limited to a specific stereoisomer).
  • stereoisomerically pure forms eg, geometrically pure, enantiomerically pure, or diastereomerically pure
  • enantiomer mixtures and stereoisomeric mixtures It encompasses all possible enantiomers and stereoisomers of the specified compounds.
  • Mixtures of enantiomers and mixtures of stereoisomers can be resolved into their corresponding enantiomeric or stereoisomeric components using separation techniques or chiral synthesis techniques well known in the art.
  • the present application includes mixtures of stereoisomers of varying chiral purity, including racemic mixtures as well as individual isolated stereoisomeric forms. This application also encompasses the various diastereomers.
  • One embodiment of the present application provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
  • One embodiment of the present application provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
  • Formula 1 may be represented by Formula 2 or Formula 3 below.
  • R 1 is hydrogen, straight or branched chain alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, heteroaryl, alkylaryl or alkyl heteroaryl, each of which is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, oxo, cyano, unsubstituted or substituted aryl, or It may be substituted with at least one of unsubstituted or substituted heteroaryl.
  • R 1 is hydrogen, C 1 ⁇ C 10 straight or branched chain alkyl, C 1 ⁇ C 10 alkoxy, C 1 ⁇ C 10 haloalkyl, C 1 ⁇ C 10 haloalkoxy, C 6 ⁇ C 12 aryl, C 5 ⁇ C 12 heteroaryl, alkyl(C 1 ⁇ C 10 )aryl(C 6 ⁇ C 12 ) or alkyl(C 1 ⁇ C 10 )heteroaryl(C 5 ⁇ C 12 ), each of which is independently hydroxyl, halogen , C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 3 -C 10 cycloalkyl, C 1 -C 10 haloalkyl, C 1 -C 10 haloalkoxy, oxo, cyano, unsubstituted or substituted C It may be substituted with at least one of 6 -C 12 aryl, or unsubstituted or substituted C 5 -C
  • the R 1 is specifically hydrogen, C 1 -C 6 straight or branched chain alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 6 -C 12 aryl, C 5 ⁇ C 12 heteroaryl, alkyl(C 1 ⁇ C 6 )aryl(C 6 ⁇ C 12 ) or alkyl(C 1 ⁇ C 6 )heteroaryl(C 5 ⁇ C 12 ), each of which is independently hydroxyl , halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, oxo, cyano, unsubstituted or substituted It may be substituted with at least one of C 6 -C 12 aryl, or unsubstituted or substituted C 5 -
  • R 1 is hydrogen, unsubstituted or substituted C 1 -C 6 straight chain alkyl, unsubstituted or substituted benzyl, or unsubstituted or substituted 2-phenylethyl, wherein the substituted C 1 -C 6
  • the straight chain alkyl is substituted with C 3 -C 6 cycloalkyl
  • the substituted benzyl or substituted 2-phenylethyl may be one in which at least one of ortho, meta and para positions is substituted with halogen or phenyl.
  • the R 1 is more specifically hydrogen, C 1 -C 6 straight-chain alkyl, C 3 -C 6 branched chain alkyl, C 3 -C 6 cycloalkyl, , , or
  • X 1 may be hydrogen, halogen, C 1 to C 3 straight-chain alkyl, CF 3 , CN, NO 2 or phenyl.
  • R 3 is hydrogen, straight or branched chain alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl, each of which is independently hydroxyl, halogen, C 1 to C 6 be substituted with at least one of alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, oxo, cyano, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl can
  • R 3 is hydrogen, C 1 ⁇ C 10 straight or branched chain alkyl, C 3 ⁇ C 10 cycloalkyl, C 6 ⁇ C 12 aryl, C 5 ⁇ C 12 heteroaryl, alkyl (C 1 ⁇ C 10 ) aryl ( C 6 -C 12 ) or alkyl (C 1 -C 10 )heteroaryl (C 5 -C 12 ), each of which is independently hydroxyl, halogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, It may be substituted with at least one of C 1 -C 10 haloalkyl, C 1 -C 10 haloalkoxy, oxo, cyano, unsubstituted or substituted aryl, or unsubstituted or substituted C 5 -C 12 heteroaryl.
  • R 3 is hydrogen, C 1 ⁇ C 6 straight or branched chain alkyl, C 3 ⁇ C 6 cycloalkyl, C 6 ⁇ C 12 aryl, C 5 ⁇ C 12 heteroaryl, alkyl (C 1 ⁇ C 6 ) aryl ( C 6 -C 12 ) or alkyl (C 1 -C 6) heteroaryl (C 5 -C 12 ), each of which is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, It may be substituted with at least one of C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, oxo, cyano, unsubstituted or substituted aryl, or unsubstituted or substituted C 5 -C 12 heteroaryl.
  • R 3 is specifically hydrogen, unsubstituted or substituted C 1 -C 3 straight chain alkyl, unsubstituted or substituted C 1 -C 3 alkoxy, halogen, or unsubstituted or substituted 2-phenylethyl, wherein the substituted In the 2-phenylethyl group, at least one of ortho, meta, and para positions is substituted with halogen, and the substituted C 1 -C 6 alkoxy may be substituted with phenyl or benzyl.
  • R 3 may be hydrogen, unsubstituted or substituted C 1 -C 3 straight-chain alkyl, unsubstituted or substituted C 1 -C 3 alkoxy, or halogen.
  • the R 3 may be more specifically hydrogen, C 1 -C 3 alkoxy, or halogen.
  • the halogen may be bromine.
  • R 2 is hydrogen, straight chain alkyl, cycloalkyl, alkoxy, haloalkoxy, haloalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl, each of which is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, oxo, nitro, cya may be substituted with at least one of no or trifluoromethyl.
  • R 2 is hydrogen, C 1 -C 10 straight chain alkyl, C 3 -C 10 cycloalkyl, C 1 -C 10 alkoxy, C 1 -C 10 haloalkoxy, C 1 -C 10 haloalkyl, C 6 -C 12 aryl, C 5 -C 12 heteroaryl, alkyl (C 1 -C 10 )aryl (C 6 -C 12 ) or alkyl (C 1 -C 10 )heteroaryl (C 5 -C 12 ), each of which is independently with hydroxyl, halogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 1 -C 10 haloalkyl, C 1 -C 10 haloalkoxy, unsubstituted or substituted C 6 -C 12 aryl, unsubstituted or substituted C 5 -C 12 heteroaryl, oxo, nitro, cyano or at least one of trifluor
  • the R 2 is specifically hydrogen, C 1 ⁇ C 6 straight chain alkyl, C 3 ⁇ C 6 cycloalkyl, C 1 ⁇ C 6 alkoxy, C 1 ⁇ C 6 haloalkoxy, C 1 ⁇ C 6 haloalkyl, C 6 ⁇ C 12 aryl, C 5 -C 12 heteroaryl, alkyl (C 1 -C 6 )aryl (C 6 -C 12 ) or alkyl (C 1 -C 6) heteroaryl (C 5 -C 12 ), each of is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, unsubstituted or substituted C 6 -C 12 aryl, It may be substituted with at least one of unsubstituted or substituted C 5 -C 12 heteroaryl, oxo, nitro, cyano or tri
  • R 2 is more specifically hydrogen, unsubstituted or substituted C 1 -C 6 straight chain alkyl, unsubstituted or substituted cyclohexyl, unsubstituted or substituted benzyl, unsubstituted or substituted 2-phenylethyl, unsubstituted or substituted biphenyl, 2-naphthylmethyl or 1-naphthylmethyl, wherein the substituted straight chain alkyl is substituted with halogen, and the substituted benzyl is at least one of ortho, meta and para positions of halogen, C 1 -C 3 straight chain alkyl, trifluoromethyl, cyano, nitro, C 1 -C 3 alkoxy or C 6 -C 12 aryl, wherein 2-phenylethyl is at least one of ortho, meta and para positions is substituted with halogen, and the substituted biphenyl may be substituted with C 1 -C 3 straight-chain alkyl.
  • the R 2 is more specifically hydrogen, C 1 ⁇ C 6 straight chain alkyl, , , , , , , , , , , , , , or can be
  • R 4 and R 4 ' are each independently hydrogen, straight or branched chain alkyl, cycloalkyl, alkenyl, alkynyl, alkylthio, aryl, heteroaryl, alkylaryl or alkylheteroaryl; , each of which is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, unsubstituted or substituted aryl, unsubstituted or may be substituted with at least one of substituted heteroaryl, oxo, nitro, cyano or trifluoromethyl.
  • R 4 and R 4 ' are each independently C 1 -C 10 straight or branched chain alkyl, C 3 -C 10 cycloalkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1 -C 10 Alkylthio, C 6 ⁇ C 12 aryl, C 5 ⁇ C 12 heteroaryl, alkyl (C 1 ⁇ C 10 ) aryl (C 6 ⁇ C 12 ) or alkyl (C 1 ⁇ C 10 ) heteroaryl (C 5 ⁇ C 12 ), each of which is independently hydroxyl, halogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 1 -C 10 haloalkyl, C 1 -C 10 haloalkoxy, unsubstituted or substituted It may be substituted with at least one of C 6 -C 12 aryl, unsubstituted or substituted C 5 -C 12 heteroaryl, oxo
  • R 4 and R 4 ' are each independently C 1 ⁇ C 6 straight or branched chain alkyl, C 3 ⁇ C 6 cycloalkyl, C 2 ⁇ C 6 alkenyl, C 2 ⁇ C 6 alkynyl, C 1 ⁇ C 6 alkylthio, C 6 -C 12 aryl, C 5 -C 12 heteroaryl, alkyl (C 1 -C 6 )aryl (C 6 -C 12 ) or alkyl (C 1 -C 6) heteroaryl (C 5 -C 12 ), each of which is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, unsubstituted or substituted It may be substituted with at least one of C 6 -C 12 aryl, unsubstituted or substituted C 5 -C 12 heteroaryl, oxo,
  • the R 4 and R 4 ' are each independently specifically C 1 -C 6 straight or branched chain alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 ⁇ C 6 alkylthio, unsubstituted or substituted benzyl, 2-naphthylmethyl or 1-naphthylmethyl, wherein the substituted straight chain alkyl is substituted with methylthio, alkynyl or benzyloxycarbonylamino ,
  • the substituted benzyl may be substituted with at least one of ortho, meta and para positions with halogen, aryl, nitro, cyano, C 1 -C 3 alkoxy, trifluoromethyl or benzyloxy.
  • R 4 and R 4 ' may be each independently C 1 to C 3 straight-chain alkyl.
  • L 1 is a direct linkage or C 1 -C 10 alkylene, wherein the alkylene is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 7 alkoxy, hydroxy may be substituted with at least one of hydroxyl, oxo or halogen, wherein the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 7 alkoxy is unsubstituted or substituted C 6 -C 12 aryl or C 3 -C 6 cycloalkyl may be substituted.
  • the L 1 is specifically C 1 -C 4 alkylene, wherein the alkylene is at least one of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, hydroxyl, or oxo. may be substituted, wherein the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy is unsubstituted or substituted with C 6 -C 12 aryl or C 3 -C 6 cycloalkyl.
  • the alkylene is at least one of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, hydroxyl, or oxo.
  • the L 1 is specifically C 1 -C 3 alkylene, wherein the C 1 -C 3 alkylene is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, unsubstituted or substituted C 1 -C 6 It may be substituted with at least one of alkoxy, hydroxyl, or oxo, and the substituted C 1 -C 6 alkoxy may be substituted with cyclohexyl, phenyl, naphthyl, or biphenyl.
  • L 1 is specifically methylene, ethylene, or propylene, wherein the methylene, ethylene, or propylene is methyl, ethyl, propyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, hydroxyl, Or it may be substituted with at least one of oxo, and the methoxy may be substituted with cyclohexyl, phenyl, naphthyl, or biphenyl.
  • Q may be S, Se, NR, P, P(O), P(O) 2 or P(O)OR.
  • R is hydrogen, C 1 ⁇ C 6 straight or branched chain alkyl, C 3 ⁇ C 6 cycloalkyl, bi or tri C 3 ⁇ C 6 cycloalkyl, C 1 ⁇ C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 6 -C 12 aryl, C 5 -C 12 heteroaryl, alkyl(C 1 -C 6 )aryl(C 6 -C 12 ) or alkyl (C 1 -C 6) heteroaryl (C 5 -C 12 ), each of which is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 It may be substituted with at least one of ⁇ C 6 haloalkoxy, oxo, cyano, unsubstituted or substituted C 6 ⁇ C 12 aryl,
  • R is, specifically hydrogen, unsubstituted or substituted C 1 ⁇ C 4 straight chain alkyl, , , , , or can be
  • n is an integer of 1 to 4, and specifically, n may be 1.
  • X, Y, and Z are each independently hydrogen, C 1 ⁇ C 6 straight or branched chain alkyl, C 3 ⁇ C 6 cycloalkyl, C 6 ⁇ C 12 aryl, C 5 ⁇ C 12 heteroaryl, Alkyl (C 1 -C 6 )aryl (C 6 -C 12 ) or alkyl (C 1 -C 6) heteroaryl (C 5 -C 12 ), each of which is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, unsubstituted or substituted C 6 -C 12 aryl, unsubstituted or substituted C 5 -C 12 heteroaryl , oxo, nitro, cyano, or at least one of trifluoromethyl.
  • the compound according to the present application may be at least one compound selected from the group consisting of Chemical Formulas shown in Table 1 below, but is not limited thereto.
  • the terms “treat” or “treatment” refer to a therapeutic, prophylactic, curative, or prophylactic method.
  • prevention refers to any action of inhibiting cancer or delaying the onset of cancer by administering the pharmaceutical composition.
  • beneficial or desired clinical outcomes include, but are not limited to, detectable or undetectable, symptom relief, attenuation of disease severity, stable (i.e., not attenuated) state of disease, delayed or gradual disease progression progression, amelioration or temporary treatment of the disease state, and remission (whether partial or total).
  • Treatment can also mean sustained survival when compared to expected survival if not receiving treatment.
  • Those in need of treatment include those prone to have the condition or disorder, as well as those already having the condition or disorder or in which the condition or disorder has been prevented.
  • the expression "therapeutically effective amount” or “effective amount” refers to (i) treating or preventing a particular disease, condition, or disorder, (ii) one of the particular disease, condition, or disorder described herein. an amount of the compound of formula (I), when administered to a mammal in need thereof, sufficient to attenuate, ameliorate or alleviate the symptoms, or (iii) prevent or delay the onset of one or more symptoms of a particular disease, condition, it means.
  • the amount of compound corresponding to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, the identity (eg weight) of the mammal in need of treatment, but nevertheless is within the skill of the artisan. can be determined routinely.
  • cancer refers to or express a physiological condition in a mammal that is typically characterized by abnormal or unregulated cell growth.
  • a “tumor” includes one or more cancerous cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancy. More specific examples of such cancers include squamous cell carcinoma (eg, epithelial squamous cell carcinoma), lung cancer (small cell lung cancer, non-small cell lung cancer (“NSCLC”)), adenocarcinoma of the lung and squamous cell carcinoma of the lung.
  • NSCLC non-small cell lung cancer
  • peritoneal cancer hepatocellular cancer, gastric or gastric cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, liver tumor, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma , salivary adenocarcinoma, kidney or kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatocarcinoma, anal carcinoma, penile carcinoma, skin cancer including melanoma, as well as head and neck cancer.
  • “Pharmaceutically acceptable” as used herein refers to that the substance or composition is chemically and/or animal compatible with the mammal and/or other ingredients, including formulations, being treated thereby.
  • pharmaceutically acceptable salt refers to a pharmaceutically acceptable organic or inorganic salt of the compound of the present application.
  • salts refers to a pharmaceutically acceptable organic or inorganic salt of a compound described herein.
  • Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, Acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, phor Mate, benzoate, glutamate, methanesulfonate, ethylate, ethanesulfonate, ethanedisulfonate, benzenesulfonate, p- toluenesulfonate, and pamonate (i.e.
  • a pharmaceutically acceptable salt may contain an inclusion body of another molecule, such as an acetate ion, a succinate ion or other counter ion.
  • the counter ion can be any organic or inorganic moiety that stabilizes the charge of the parent compound.
  • a pharmaceutically acceptable salt may have more than one charged atom in its structure.
  • An example where multiple charged atoms are part of a pharmaceutically acceptable salt may have multiple counter ions.
  • a pharmaceutically acceptable salt may have one or more charged atoms and/or one or more counter ions.
  • One embodiment of the present application is a pharmaceutical for preventing or treating cancer comprising a compound represented by Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, structural isomer, optical isomer, stereoisomer, or a combination thereof A composition is provided.
  • a pharmaceutically acceptable salt a pharmaceutically acceptable salt thereof
  • hydrate solvate
  • structural isomer a pharmaceutically acceptable salt thereof
  • optical isomer a pharmaceutically acceptable salt thereof
  • One embodiment of the present application is a compound represented by Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, structural isomer, optical isomer, stereoisomer, or a combination thereof for preventing or treating resistant cancer
  • a pharmaceutical composition is provided.
  • the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is administered in combination with an anticancer drug or radiation therapy to resistant cancer, there is an effect of inhibiting the activity of resistant cancer.
  • One embodiment of the present application is a compound represented by Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, structural isomer, optical isomer, stereoisomer, or stem cell cancer prevention or A therapeutic pharmaceutical composition is provided.
  • the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof acts as an inhibitor targeting the SERCA protein, thereby inhibiting stem cell cancer activity.
  • the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof When the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is administered in combination with an anticancer drug or radiation therapy to cancer or resistant cancer, it may be administered simultaneously, individually, or sequentially.
  • the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered before or after an anticancer drug or radiation therapy.
  • the cancer or resistant cancer is ovarian cancer, colorectal cancer, pancreatic cancer, stomach cancer, liver cancer, breast cancer, cervical cancer, thyroid cancer, parathyroid cancer, lung cancer, non-small cell lung cancer, prostate cancer, gallbladder cancer, Biliary tract cancer, blood cancer, bladder cancer, kidney cancer, melanoma, colon cancer, bone cancer, skin cancer, head and neck cancer, uterine cancer, rectal cancer, brain cancer, perianal cancer, fallopian tube carcinoma, endometrial carcinoma, vaginal cancer, vulvar carcinoma, esophageal cancer, small intestine cancer, Endocrine adenocarcinoma, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, ureter cancer, renal cell carcinoma, renal pelvic carcinoma, leukemia, central nervous system (CNS) tumor, spinal cord tumor, brainstem glioma and pituitary adenoma It may be at least one selected from the group.
  • CNS central nervous system
  • the anticancer drug or anticancer agent is nitrogen mustard, imatinib, oxaliplatin, rituximab, erlotinib, neratinib, lapatinib, gefitinib, vandetanib, nirotinib, semasa Nib, bosutinib, axitinib, masitinib, cediranib, restaurtinib, trastuzumab, gefitinib, bortezomib, sunitinib, pazopanib, toceranib, nintedanib, regorafenib, Semaxanib, tivozanib, ponatinib, caboxantinib, carboplatin, sorafenib, lenvatinib, bevacizumab, cisplatin, cetuximab, viscumalbum, asparaginase, tretin, aminox
  • the pharmaceutical composition according to an embodiment of the present application contains a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof and an anticancer agent from 1:0.001 to 1:1000, 1:0.01 to 1:100, 1:0.1 to 1 It may be included in a molar concentration ratio of :50 or 1:0.1 to 1:20.
  • the pharmaceutical composition according to one embodiment of the present application may be in the form of a capsule, tablet, granule, injection, ointment, powder or beverage.
  • compositions according to an embodiment of the present application may be formulated and used in the form of oral dosage forms such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories, and injections.
  • the pharmaceutical composition according to one embodiment of the present application may include a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers may be binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, coloring agents, flavoring agents, etc., in the case of oral administration, and in the case of injections, buffers, preservatives, analgesics, Solubilizers, isotonic agents, stabilizers, etc. can be mixed and used, and for topical administration, bases, excipients, lubricants, preservatives, etc. can be used.
  • the dosage form of the pharmaceutical composition according to one embodiment of the present application may be prepared in various ways by mixing with a pharmaceutically acceptable carrier, for example, tablets, troches, capsules, elixirs, It may be prepared in the form of a suspension, syrup, wafer, etc., and in the case of an injection, it may be prepared in the form of unit dose ampoules or multiple doses.
  • a pharmaceutically acceptable carrier for example, tablets, troches, capsules, elixirs
  • It may be prepared in the form of a suspension, syrup, wafer, etc., and in the case of an injection, it may be prepared in the form of unit dose ampoules or multiple doses.
  • the formulation of the pharmaceutical composition of the present application may be prepared as a solution, suspension, tablet, capsule, sustained-release formulation, and the like.
  • Carriers, excipients and diluents for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, filler, anticoagulant, lubricant, wetting agent, flavoring, emulsifying agent or preservative and the like.
  • One embodiment of the present application relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention together with a pharmaceutically applicable adjuvant and/or excipient as an active ingredient. will be.
  • adjuvant refers to any substance capable of producing, exacerbating or modifying a particular reaction to the active ingredient of the present invention if administered simultaneously, at the same time or sequentially.
  • adjuvants for injectable solutions are, for example, aluminum compositions such as aluminum hydroxide or aluminum phosphate, saponins such as QS21, muramyldipeptide or muramyltripeptide, proteins such as gamma-interferon or TNF, M59, squalene or polyol.
  • the route of administration of the pharmaceutical composition according to one embodiment of the present application is not limited thereto, but oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal , enteral, topical, sublingual or rectal.
  • the pharmaceutical composition according to an embodiment of the present application may be administered orally or parenterally, and when administered parenterally, external application to the skin or intraperitoneal injection, intrarectal injection, subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection A method may be selected.
  • the dosage of the pharmaceutical composition according to one embodiment of the present application varies depending on the patient's condition and weight, the degree of disease, drug form, administration route and period, but may be appropriately selected by those skilled in the art.
  • the pharmaceutical composition according to one embodiment of the present application may be administered at 0.0001 to 1000 mg/kg or 0.001 to 500 mg/kg per day.
  • Administration of the pharmaceutical composition according to an embodiment of the present application may be administered once a day, may be administered in divided several times.
  • the above dosage does not limit the scope of the present application in any way.
  • the present application provides the use of a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer.
  • the present application provides the use of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for use in the treatment of resistant cancer.
  • the present application provides the use of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for use in the treatment of stem cell cancer.
  • Resistant cancer and the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof are the same as those described above, and detailed descriptions thereof will be omitted.
  • the present application relates to a compound represented by Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, structural isomer, optical isomer, stereoisomer, or Provided is a method of treating cancer, resistant cancer, or stem cell cancer comprising administering a therapeutically effective amount of a combination thereof.
  • the administration may include simultaneous, separate, or sequential administration of a chemotherapeutic agent or anticancer drug useful for the treatment of cancer or proliferative disease.
  • administration means introducing a given substance into a subject by an appropriate method.
  • Subject with resistant cancer refers to an individual who has developed or has a high probability of developing resistant cancer and requires appropriate treatment. It may be an individual who has received radiation therapy or immunotherapy, but has developed resistance to it and has relapsed.
  • Subjects with resistant cancer may include humans, cattle, dogs, guinea pigs, rabbits, chickens, or insects. Specifically, it may be a mammal such as a human, a cow, a horse, a pig, a dog, a sheep, a goat, or a cat. The subject may be an individual who has or is likely to have cancer.
  • the present application relates to a compound represented by Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, structural isomer, optical isomer, stereoisomer, or administering a therapeutically effective amount of a combination thereof; And irradiating radiation; provides a radiation treatment method comprising a.
  • Resistant cancer a subject with resistant cancer, the compound represented by Formula 1, or a pharmaceutically acceptable salt thereof is the same as described above, and detailed descriptions thereof will be omitted.
  • Radiation irradiation can be applied to any radiation method conventionally used for radiation treatment of cancer or radiation method for cancer to be developed later.
  • the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof according to the present application When the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof according to the present application is administered in combination with irradiation, it gives a synergistic effect on growth inhibition and/or death induction of cancer cells, resistant cancer cells or cancer stem cells. Thus, it is possible not only to effectively prevent or treat cancer, but also to prevent resistance to radiation, metastasis of cancer, or recurrence of cancer.
  • Piperazine-2-carboxylic acid (1.0 eq.) was cooled to 5° C. or less in a dioxane/distilled water solvent, and sodium carbonate (3.0 eq.) was added.
  • Di-tertiary -butyl dicarbonate (2.2 equivalents) was added dropwise while maintaining 5° C. or less, followed by stirring at room temperature overnight. After confirming the completion of the reaction, it was concentrated under reduced pressure, dissolved in methylene chloride, and neutralized with hydrochloric acid. The organic layer was washed with sodium chloride, dehydrated over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified with n -hexane to obtain 1,4-bis( tertiary -butoxycarbonyl)piperazine-2-carboxylic acid.
  • Step 4 d - turkey Preparation of -butyl 2-((1-methoxy-2-methyl-1-oxopropan-2-yl)carbamoyl)piperazine-1,4-dicarboxylate
  • Step 5 Preparation of methyl 2-methyl-2-(piperazine-2-carboxamido)propanoate-2-trifluoroacetic acid
  • Step 6 7,7-dimethylhexahydro-2 H -Pyrazino[1,2- a ]Preparation of pyrazine-6,9-dione/2 trifluoroacetic acid
  • Step 7 2-((2-ethyl-1-benzo[ b ]Thiophen-3-yl)methyl)-7,7-dimethylhexahydro-2 H -Pyrazino[1,2- a ] Preparation of pyrazine-6,9-dione (S801)
  • step 7 of Preparation Example 1 benzo[ b ]thiophene-3-carbaaldehyde was used instead of 2-ethyl-1-benzo[ b ]thiophen-3-carbaaldehyde, and after concentration in the purification process after the reaction The residue was purified by silica gel column chromatography without solidifying with n -hexane.
  • the rest of the preparation method is 2-(benzo[ b ]thiophen-3-ylmethyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ] in the same manner as in step 7 of Preparation Example 1.
  • Pyrazine-6,9-dione (S822) was prepared.
  • step 7 of Preparation Example 1 2-methylbenzo[ b ]thiophene-3-carbaaldehyde was used instead of 2-ethyl-1-benzo[ b ]thiophen-3-carbaaldehyde, and the purification process after the reaction After concentration in , the residue was solidified with ethyl acetate instead of n -hexane.
  • the rest of the preparation method is 7,7-dimethyl-2-((2-methylbenzo[ b ]thiophen-3-yl)methyl)hexahydro- 2H -pyrazino[1] in the same manner as in step 7 of Preparation Example 1.
  • 2- a ]pyrazine-6,9-dione was prepared.
  • step 7 of Preparation Example 1 2-butylbenzo[ b ]thiophene-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophene-3-carbaaldehyde, and after concentration in the purification process after the reaction The residue was solidified with ethyl acetate instead of n -hexane.
  • the rest of the preparation method is 2-((2-butylbenzo[ b ]thiophen-3-yl)methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1] in the same manner as in step 7 of Preparation Example 1.
  • 2-butylbenzo[ b ]thiophen-3-yl)methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1] in the same manner as in step 7 of Preparation Example 1.
  • 2-butylbenzo[ b ]thiophen-3-yl)methyl -7,
  • Step 7 of Preparation Example 1 2-hexylbenzo[ b ]thiophene-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophene-3-carbaaldehyde, and the same as in Step 7 of Preparation Example 1 Method 2-((2-hexylbenzo[ b ]thiophen-3-yl)methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S825) was prepared.
  • step 7 of Preparation Example 1 2-benzylbenzo[ b ]thiophene-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophene-3-carbaaldehyde, and the same as in Step 7 of Preparation Example 1 Method 2-((2-benzylbenzo[ b ]thiophen-3-yl)methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S827) was prepared.
  • step 7 of Preparation Example 1 2-(4-methylbenzylbenzo[ b ]thiophene-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophene-3-carbaaldehyde, and In the same manner as in step 7, 7,7-dimethyl-2-((2-(4-methylbenzyl)benzo[ b ]thiophen-3-yl)methyl)hexahydro- 2H -pyrazino[1,2- a ] Pyrazine-6,9-dione (S828) was prepared.
  • step 7 of Preparation Example 1 2-(4-chlorobenzyl)benzo[ b ]thiophene-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophen-3-carbaaldehyde, and after the reaction After concentration in the purification process, the residue was purified by silica gel column chromatography without solidifying with n -hexane.
  • the rest of the preparation method is 2-((2-(4-chlorobenzyl)benzo[ b ]thiophen-3-yl)methyl)-7,7-dimethylhexahydro- 2H in the same manner as in step 7 of Preparation Example 1.
  • -Pyrazino[1,2- a ]pyrazine-6,9-dione (S829) was prepared.
  • step 7 of Preparation Example 1 2-(4-bromobenzyl)benzo[ b ]thiophene-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophen-3-carbaaldehyde, and the reaction After concentration in the subsequent purification process, the residue was solidified with ethyl acetate instead of n -hexane.
  • the rest of the preparation method is 2-((2-(4-bromobenzyl)benzo[ b ]thiophen-3-yl)methyl)-7,7-dimethylhexahydro-2 in the same manner as in step 7 of Preparation Example 1.
  • H -pyrazino[1,2- a ]pyrazine-6,9-dione (S830) was prepared.
  • step 7 of Preparation Example 1 2-(4-fluorobenzyl)benzo[ b ]thiophene-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophen-3-carbaaldehyde, and after the reaction After concentration in the purification process, the residue was purified by silica gel column chromatography without solidifying with n -hexane.
  • the rest of the preparation method is 2-((2-(4-fluorobenzyl)benzo[ b ]thiophen-3-yl)methyl)-7,7-dimethylhexahydro- 2H in the same manner as in step 7 of Preparation Example 1.
  • -Pyrazino[1,2- a ]pyrazine-6,9-dione (S831) was prepared.
  • Step 7 of Preparation Example 1 1-methyl- 1H -indole-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophen-3-carbaaldehyde, and the same method as in Step 7 of Preparation Example 1 to 7,7-dimethyl-2-((1-methyl- 1H -indol-3-yl)methyl)hexahydro- 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S833 ) was prepared.
  • step 7 of Preparation Example 1 1-(cyclohexylmethyl)-1H-indole-3- carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophen-3-carbaaldehyde, and the step of Preparation Example 1 In the same manner as 7, 2-((1-cyclohexylmethyl)-1H-indol-3-yl)methyl) -7,7 -dimethylhexahydro- 2H -pyrazino[1,2- a ]pyrazine- 6,9-dione (S834) was prepared.
  • step 7 of Preparation Example 1 1-benzyl- 1H -indole-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophen-3-carbaaldehyde, and the same method as in Step 7 of Preparation Example 1 as 2-((1-benzyl- 1H -indol-3-yl)methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S835 ) was prepared.
  • step 7 of Preparation Example 1 1-(naphthalen-2-yl)methyl- 1H -indole-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophen-3-carbaaldehyde, and Preparation Example 7,7-dimethyl-2-((1-naphthalen-2-ylmethyl)-1H-indol-3-yl)methyl)hexahydro- 2H - pyrazino [1, 2- a ]pyrazine-6,9-dione (S836) was prepared.
  • step 7 of Preparation Example 1 1-benzyl-2-methyl- 1H -indole-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophen-3-carbaaldehyde, and the step of Preparation Example 1 In the same manner as in 7, 2-((1-benzyl-2-methyl- 1H -indol-3-yl)methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ]pyrazine -6,9-dione (S839) was prepared.
  • step 7 of Preparation Example 1 1-benzyl-5-bromo- 1H -indole-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophen-3-carbaaldehyde and In the same manner as in step 7, 2-((1-benzyl-5-bromo- 1H -indol-3-yl)methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ]Pyrazine-6,9-dione (S840) was prepared.
  • step 7 of Preparation Example 1 1-benzyl-5-methoxy- 1H -indole-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophen-3-carbaaldehyde and In the same manner as in step 7, 2-((1-benzyl-5-methoxy-1 H -indol-3-yl)methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ]Pyrazine-6,9-dione (S841) was prepared.
  • step 7 of Preparation Example 1 1 H -indole-3-carbaaldehyde was used instead of 2-ethylbenzo[ b ]thiophen-3-carbaaldehyde and 2-( ( 1H -indol-3-yl)methyl)-7,7-dimethylhexahydro- 2H -pyrazino[1,2- a ]pyrazine-6,9-dione (S842) was prepared.
  • Hela a cervical cancer epithelial cell line
  • Hela-PTX-R which was derived therefrom and produced as a resistant cancer cell line having resistance to the anticancer drug Paclitaxel, were prepared.
  • MCF7 a breast cancer epithelial cell line
  • MCF7-BC19 prepared as a resistant cancer cell line having resistance to the anticancer drug Paclitaxel by overexpressing P-gp therefrom were prepared.
  • FIGS. 1 to 4 Cell experiments were performed with these cell lines, and are shown in FIGS. 1 to 4 .
  • 1 shows the IC 50 values of paclitaxel and docetaxel anticancer drugs of SKOV3
  • FIG. 2 shows the IC 50 values of paclitaxel and docetaxel anticancer drugs of SKOV3-TR.
  • Figure 3 shows the IC 50 value of the anticancer agent Paclitaxel of Hela and Hela-PTX-R
  • Figure 4 shows the IC 50 value of the anticancer agent Paclitaxel of MCF7 and MCF7-BC19.
  • paclitaxel treatment induced a decrease in metabolism in SKOV3, SKOV3-TR, Hela, Hela-PTX-R, MCF7, and MCF7-BC19.
  • DMSO paclitaxel, S-form solvent
  • paclitaxel Paclitaxel
  • 47 kinds of S-forms were co-treated with WST-1 analysis 3 days later, and are shown in FIGS. 5 to 8 .
  • 5 and 7 show DMSO, paclitaxel, S801 (10 ⁇ M), S802 (10 ⁇ M), S803 (10 ⁇ M), S804 (10 ⁇ M), S806 (10 ⁇ M), S807 (10 ⁇ M), S808 (10 ⁇ M), S809 (10 ⁇ M), S810 (10 ⁇ M), S811 (10 ⁇ M), S812 (10 ⁇ M), S813 (10 ⁇ M), S815 (10 ⁇ M), S816 (10 ⁇ M), S819 (10 ⁇ M), S820 (10 ⁇ M), S821 (10 ⁇ M), S845 (10 ⁇ M), S855 (10 ⁇ M), S805 (10 ⁇ M), S822 (10 ⁇ M), S833 (10 ⁇ M), S834 (10 ⁇ M), S835 (10 ⁇ M) are shown in the order.
  • 6 and 8 show DMSO, paclitaxel, S836 (10 ⁇ M), S838 (10 ⁇ M), S840 (10 ⁇ M), S841 (10 ⁇ M), S842 (10 ⁇ M), S857 (10 ⁇ M), S858 (10 ⁇ M), S860 (10 ⁇ M), S823 (10 ⁇ M), S824 (10 ⁇ M), S825 (10 ⁇ M), S826 (10 ⁇ M), S856 (10 ⁇ M), S859 (10 ⁇ M), S839 (10 ⁇ M), S827 (10 ⁇ M), S828 (10 ⁇ M), S814 (10 ⁇ M), S830 (10 ⁇ M), S832 (10 ⁇ M), S829 (10 ⁇ M), S831 (10 ⁇ M), and S847 (10 ⁇ M) are shown in this order.
  • the absorbance at 450 nm was decreased compared to the DMSO-treated group due to phenomena such as apoptosis induction and cell growth inhibition in SKOV3-TR and SKOV3.
  • S-forms were treated in combination with paclitaxel, SKOV3-TR, a resistant cancer cell line, enhanced the anticancer effect of paclitaxel and showed lower absorbance compared to the paclitaxel-treated group.
  • a baseline was included in the absorbance of the paclitaxel-treated group, which is a comparative example.
  • the absorbance (OD Value at 450nm) was significantly decreased in the WST-1 analysis when paclitaxel + S-forms was treated compared to the paclitaxel-treated group.
  • docetaxel treatment induced a decrease in metabolism in SKOV3-TR and SKOV3.
  • SKOV3-TR and SKOV3 cancer cell lines were treated with 47 types of S-forms, then treated with docetaxel, and WST-1 analysis was performed.
  • 10 and 12 show DMSO, docetaxel, S836 (2 ⁇ M), S838 (2 ⁇ M), S840 (2 ⁇ M), S841 (2 ⁇ M), S842 (2 ⁇ M), S857 (2 ⁇ M), S858 (2 ⁇ M), S860 (2 ⁇ M), S823 (2 ⁇ M), S824 (2 ⁇ M), S825 (2 ⁇ M), S826 (2 ⁇ M), S856 (2 ⁇ M), S859 (2 ⁇ M), S839 (2 ⁇ M), S827 (2 ⁇ M), S828 (2 ⁇ M), S814 (2 ⁇ M), S830 (2 ⁇ M), S832 (2 ⁇ M), S829 (2 ⁇ M), S831 (2 ⁇ M), and S847 (2 ⁇ M) are shown in this order.
  • the docetaxel (Doxetaxel) treatment group had a decrease in absorbance at 450 nm compared to the DMSO treatment group due to phenomena such as apoptosis induction and cell growth inhibition in SKOV3-TR and SKOV3.
  • the resistant cancer cell line, SKOV3-TR enhanced the anticancer effect of docetaxel and showed lower absorbance compared to the docetaxel-treated group.
  • a reference line was put in the absorbance of the comparative example docetaxel (Doxetaxel) treatment group.
  • the anticancer enhancing efficacy of docetaxel was significantly reduced in the WST-1 analysis when docetaxel+S-forms were treated compared to docetaxel (Doxetaxel) in absorbance (OD Value at 450nm).
  • Hela-PTX-R and Hela cancer cell lines were treated with 47 types of compounds, then treated with paclitaxel, and WST-1 analysis was performed.
  • paclitaxel paclitaxel, S-form solvent
  • paclitaxel Paclitaxel
  • 47 kinds of S-forms were co-treated 3 days after WST-1 analysis was performed and shown in FIGS. 13 to 16 .
  • FIG. 13 and 15 show DMSO, paclitaxel, S801 (10 ⁇ M), S802 (10 ⁇ M), S803 (10 ⁇ M), S804 (10 ⁇ M), S806 (10 ⁇ M), S807 (10 ⁇ M), S808 (10 ⁇ M), S809 (10 ⁇ M), S810 (10 ⁇ M), S811 (10 ⁇ M), S812 (10 ⁇ M), S813 (10 ⁇ M), S815 (10 ⁇ M), S816 (10 ⁇ M), S819 (10 ⁇ M), S820 (10 ⁇ M), S821 (10 ⁇ M), S845 (10 ⁇ M), S855 (10 ⁇ M), S805 (10 ⁇ M), S822 (10 ⁇ M), S833 (10 ⁇ M), S834 (10 ⁇ M), S835 (10 ⁇ M) are shown in the order.
  • 14 and 16 show DMSO, paclitaxel, S836 (10 ⁇ M), S838 (10 ⁇ M), S840 (10 ⁇ M), S841 (10 ⁇ M), S842 (10 ⁇ M), S857 (10 ⁇ M), S858 (10 ⁇ M), S860 (10 ⁇ M), S823 (10 ⁇ M), S824 (10 ⁇ M), S825 (10 ⁇ M), S826 (10 ⁇ M), S856 (10 ⁇ M), S859 (10 ⁇ M), S839 (10 ⁇ M), S827 (10 ⁇ M), S828 (10 ⁇ M), S814 (10 ⁇ M), S830 (10 ⁇ M), S832 (10 ⁇ M), S829 (10 ⁇ M), S831 (10 ⁇ M), and S847 (10 ⁇ M) are shown in this order.
  • the paclitaxel-treated group had a decrease in absorbance at 450 nm compared to the DMSO-treated group due to phenomena such as apoptosis induction and cell growth inhibition in Hela-PTX-R and Hela.
  • S-forms were treated in combination with paclitaxel, Hela-PTX-R, a resistant cancer cell line, enhanced the anticancer effect of paclitaxel and showed lower absorbance compared to the paclitaxel-treated group.
  • a baseline was included in the absorbance of the paclitaxel-treated group, which is a comparative example.
  • the absorbance (OD Value at 450nm) was significantly decreased in the WST-1 analysis when paclitaxel + S-forms was treated compared to the paclitaxel-treated group.
  • MCF7-BC19 and MCF7 cancer cell lines were treated with 47 types of compounds and then treated with paclitaxel, and WST-1 analysis was performed.
  • paclitaxel paclitaxel, S-form solvent
  • paclitaxel Paclitaxel
  • WST-1 analysis was performed 3 days later and shown in FIGS. 17 to 20 .
  • FIG. 17 Figure 17, Figure 19 DMSO, paclitaxel, S801 (10 ⁇ M), S802 (10 ⁇ M), S803 (10 ⁇ M), S804 (10 ⁇ M), S806 (10 ⁇ M), S807 (10 ⁇ M), S808 (10 ⁇ M), S809 (10 ⁇ M), S810 (10 ⁇ M), S811 (10 ⁇ M), S812 (10 ⁇ M), S813 (10 ⁇ M), S815 (10 ⁇ M), S816 (10 ⁇ M), S819 (10 ⁇ M), S820 (10 ⁇ M), S821 (10 ⁇ M), S845 (10 ⁇ M), S855 (10 ⁇ M), S805 (10 ⁇ M), S822 (10 ⁇ M), S833 (10 ⁇ M), S834 (10 ⁇ M), S835 (10 ⁇ M) are shown in the order.
  • 18 and 20 show DMSO, paclitaxel, S836 (10 ⁇ M), S838 (10 ⁇ M), S840 (10 ⁇ M), S841 (10 ⁇ M), S842 (10 ⁇ M), S857 (10 ⁇ M), S858 (10 ⁇ M), S860 (10 ⁇ M), S823 (10 ⁇ M), S824 (10 ⁇ M), S825 (10 ⁇ M), S826 (10 ⁇ M), S856 (10 ⁇ M), S859 (10 ⁇ M), S839 (10 ⁇ M), S827 (10 ⁇ M), S828 (10 ⁇ M), S814 (10 ⁇ M), S830 (10 ⁇ M), S832 (10 ⁇ M), S829 (10 ⁇ M), S831 (10 ⁇ M), and S847 (10 ⁇ M) are shown in this order.
  • the absorbance at 450 nm was decreased compared to the DMSO-treated group due to phenomena such as apoptosis induction and cell growth inhibition in MCF7-BC19 and MCF7.
  • the resistant cancer cell line MCF7-BC19 enhanced the anticancer effect of paclitaxel and showed lower absorbance compared to the paclitaxel-treated group.
  • a baseline was included in the absorbance of the paclitaxel-treated group, which is a comparative example.
  • the absorbance (OD Value at 450nm) was significantly decreased in the WST-1 analysis when paclitaxel + S-forms was treated compared to the paclitaxel-treated group.

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Abstract

La présente invention concerne une composition pharmaceutique comprenant un nouveau composé ou un sel pharmaceutiquement acceptable de celui-ci pour la prévention ou le traitement du cancer réfractaire. La composition selon la présente invention peut être administrée conjointement avec un agent anticancéreux ce qui permet d'obtenir un excellent effet anticancéreux.
PCT/KR2022/006181 2021-04-29 2022-04-29 Nouveau composé et composition pharmaceutique le comprenant pour la prévention ou le traitement du cancer, et utilisation associée WO2022231377A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008157500A1 (fr) * 2007-06-17 2008-12-24 Kalypsys, Inc. Modulateurs du récepteur cannabinoïde à base d'aminoquinazoline pour le traitement de maladies
KR20140020224A (ko) * 2010-10-14 2014-02-18 제이더블유중외제약 주식회사 리버스-턴 유사체의 신규한 화합물 및 그 제조방법과 용도
WO2020037079A1 (fr) * 2018-08-14 2020-02-20 Epizyme, Inc. Indoles substitués et procédés d'utilisation associés
KR20200081320A (ko) * 2018-12-27 2020-07-07 홀로스메딕 주식회사 신규한 화합물 및 이를 포함하는 항암 활성 증진용 약학 조성물
WO2021086038A1 (fr) * 2019-10-31 2021-05-06 홀로스메딕 주식회사 Nouveau composé et composition pharmaceutique le comprenant pour prévenir ou traiter un cancer

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1886384A (zh) 2003-11-25 2006-12-27 希龙公司 喹唑酮化合物作为抗癌药剂

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008157500A1 (fr) * 2007-06-17 2008-12-24 Kalypsys, Inc. Modulateurs du récepteur cannabinoïde à base d'aminoquinazoline pour le traitement de maladies
KR20140020224A (ko) * 2010-10-14 2014-02-18 제이더블유중외제약 주식회사 리버스-턴 유사체의 신규한 화합물 및 그 제조방법과 용도
WO2020037079A1 (fr) * 2018-08-14 2020-02-20 Epizyme, Inc. Indoles substitués et procédés d'utilisation associés
KR20200081320A (ko) * 2018-12-27 2020-07-07 홀로스메딕 주식회사 신규한 화합물 및 이를 포함하는 항암 활성 증진용 약학 조성물
WO2021086038A1 (fr) * 2019-10-31 2021-05-06 홀로스메딕 주식회사 Nouveau composé et composition pharmaceutique le comprenant pour prévenir ou traiter un cancer

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