[go: up one dir, main page]

WO2025183481A1 - Nouveaux composés de faible poids moléculaire inhibant irp2 - Google Patents

Nouveaux composés de faible poids moléculaire inhibant irp2

Info

Publication number
WO2025183481A1
WO2025183481A1 PCT/KR2025/002760 KR2025002760W WO2025183481A1 WO 2025183481 A1 WO2025183481 A1 WO 2025183481A1 KR 2025002760 W KR2025002760 W KR 2025002760W WO 2025183481 A1 WO2025183481 A1 WO 2025183481A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
substituted
pyridin
alkyl
pyrazolo
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/KR2025/002760
Other languages
English (en)
Korean (ko)
Inventor
이혁
김미현
곽재성
박아름
이준호
신상준
양재문
장성연
김태일
황지언
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Korea Research Institute of Chemical Technology KRICT
University Industry Foundation UIF of Yonsei University
Original Assignee
Korea Research Institute of Chemical Technology KRICT
University Industry Foundation UIF of Yonsei University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Korea Research Institute of Chemical Technology KRICT, University Industry Foundation UIF of Yonsei University filed Critical Korea Research Institute of Chemical Technology KRICT
Publication of WO2025183481A1 publication Critical patent/WO2025183481A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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 invention relates to a benzenesulfonamide substituted heterobicyclic derivative which is an IRP2 disruptor, a method for preparing the same, and a pharmaceutical use thereof.
  • the present invention relates to a pharmaceutical composition for preventing or treating cancer of a benzenesulfonamide-substituted heterobicyclic derivative, which is an IRP2 disruptor.
  • the present invention relates to a pharmaceutical composition for preventing or treating colon cancer of a benzenesulfonamide-substituted heterobicyclic derivative, which is an IRP2 disruptor.
  • Iron is a biologically essential component for DNA synthesis, mitochondrial respiration, and cell proliferation. Iron homeostasis is involved in redox activity, mitochondrial function, cell growth, and apoptosis (Miyazawa et al., 2019; Zhang et al., 2020). Iron metabolism dysregulation is common in cancer cells, particularly because cancer cells require a relatively higher iron requirement to sustain cell growth compared to normal cells.
  • iron regulatory proteins 1 and 2 control cellular iron homeostasis through binding to iron-responsive elements (IREs) in the 5' or 3' untranslated regions (UTRs) of selected mRNAs (Jiao et al., 2019; Wang et al., 2020).
  • IRP binding to IREs in the 5' UTR of mRNAs represses the translation of proteins including ferritin H (FTH) and ferroportin (FPN) (Li et al., 2019; Martelli et al., 2015), whereas IREs in the 3' UTR of mRNAs activate protein stability, including transferrin receptor 1 (TfR1) and divalent metal ion transporter 1 (DMT1) (Bellelli et al., 2016; Wallander et al., 2008).
  • FTH ferritin H
  • FPN ferroportin
  • IREs in the 3' UTR of mRNAs activate protein stability, including transferrin receptor 1 (TfR1) and divalent metal ion transporter 1 (DMT1) (Bellelli et al., 2016; Wallander et al., 2008).
  • TfR1 transferrin receptor 1
  • DMT1 divalent metal ion transporter 1
  • IRP1 and IRP2 share a high degree of nucleotide sequence homology, are differentially expressed depending on cellular iron availability, and are crucial for iron metabolism reprogramming (Miyazawa et al., 2019).
  • IRP1 is a ubiquitously expressed protein with a 4Fe-4S cluster that disallows IRP1 binding to IREs
  • IRP2 is a selectively expressed protein lacking the iron-sulfur cluster and reported to be the dominant IRE-binding protein (Moroishi et al., 2011).
  • IRP1 activates 4Fe-4S binding
  • IRP2 is degraded by F-box and Leucine Rich Repeat Protein 5 (FBXL5), an E3 ubiquitin ligase (Muto et al., 2017; Zumbumble-Bullough et al., 2014).
  • FBXL5 F-box and Leucine Rich Repeat Protein 5
  • Colorectal cancer is the second most lethal cancer worldwide, following lung cancer. Compared to other cancer types, colorectal cancer has a lower response rate to standard therapies and exhibits resistance to targeted therapies.
  • EGFR epidermal growth factor receptor
  • EGFR inhibitors are effective in patients with KRAS wild-type tumors (Missiaglia et al., 2014).
  • MSI-H microsatellite instability
  • the purpose of the present invention is to provide a pharmaceutical composition for preventing or treating colon cancer, which comprises as an active ingredient a benzenesulfonamide-substituted heterobicyclic derivative that kills colon cancer cells by inducing reprogramming of iron metabolism in cancer cells by interfering with IRP2 binding to IRE.
  • the present invention relates to a pharmaceutical composition for preventing or treating colon cancer, comprising a compound represented by the following chemical formula 1, a stereoisomer thereof, a solvate thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • R 1 is substituted with one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, amino, amide, cyano, halo C 1 -C 6 alkyl, NO 2 , C 1 -C 6 alkyl , C 1 -C 10 alkoxy, acetyl, acetamido, C 1 -C 6 alkylamino, di(C 1 -C 6 ) alkylamino, C 1 -C 6 alkylcarbonylamino, C 5 -C 10 aryl, C 5 -C 10 heteroaryl, C 4 -C 10 cycloalkyl and C 4 -C 10 heterocycloalkyl;
  • R 3 is independently hydrogen, halogen or C 1 -C 10 alkoxy
  • R 4 is substituted with one or more substituents selected from the group consisting of substituted or unsubstituted (C 5 -C 10 )aryl-amino, substituted or unsubstituted (C 5 -C 10 )heteroaryl-amino, substituted or unsubstituted C 5 -C 10 heteroaryl, and substituted or unsubstituted C 4 -C 10 heterocycloalkyl,
  • the above substituted (C 5 -C 10 ) aryl-amino, (C 5 -C 10 ) heteroaryl-amino, C 5 -C 10 heteroaryl or C 4 -C 10 heterocycloalkyl is substituted with one or more substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, amide, halo C 1 -C 6 alkyl, cyano, NO 2 , C 1 -C 6 alkyl, acetyl, carbamoyl, substituted or unsubstituted C 1 -C 10 alkoxy, substituted or unsubstituted C 3 -C 10 cycloalkyl, and substituted or unsubstituted C 4 -C 10 heterocycloalkyl,
  • C 1 -C 10 alkoxy, C 3 -C 10 cycloalkyl or C 4 -C 10 heterocycloalkyl is substituted with one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, amide, halo C 1 -C 6 alkyl, cyano, NO 2 , C 1 -C 6 alkyl, and C 1 -C 10 alkoxy;
  • A is independently CR 1 , CH or N;
  • n is an integer from 0 to 3;
  • the present invention relates to a pharmaceutical composition for preventing or treating colon cancer, comprising a compound represented by the above chemical formula 1, a stereoisomer thereof, a solvate thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • R 1 is hydrogen, halogen, hydroxy, amino, amide, CN, halo C 1 -C 6 alkyl, NO 2 , C 1 -C 6 alkyl, C 1 -C 10 alkoxy, acetyl, acetamido, C 1 -C 6 alkylamino, di(C 1 -C 6 ) Substituted with one or more substituents selected from the group consisting of alkylamino, C 1 -C 6 alkylcarbonylamino, phenyl, thiophenyl, and morpholinyl;
  • R 3 is independently hydrogen, halogen or C 1 -C 10 alkoxy
  • R 4 is substituted or unsubstituted , substituted or unsubstituted , substituted or unsubstituted , substituted or unsubstituted , substituted or unsubstituted and substituted or unsubstituted is substituted with one or more substituents selected from the group consisting of,
  • C 1 -C 10 alkoxy, C 3 -C 10 cycloalkyl or C 4 -C 10 heterocycloalkyl is substituted with one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, amide, halo C 1 -C 6 alkyl, CN, NO 2 , C 1 -C 6 alkyl, and C 1 -C 10 alkoxy;
  • A is each independently CR 1 , CH or N;
  • n is an integer from 0 to 3;
  • the present invention relates to a pharmaceutical composition for preventing or treating colon cancer, comprising a compound represented by the following chemical formula 2, a stereoisomer thereof, a solvate thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • R 1 is substituted with one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, amino, amide, CN, halo C 1 -C 6 alkyl, NO 2 , C 1 -C 6 alkyl, C 1 -C 10 alkoxy, acetyl, acetamido, C 1 -C 6 alkylamino, di(C 1 -C 6) alkylamino, C 1 -C 6 alkylcarbonylamino, phenyl, thiophenyl, and morpholinyl;
  • R 3 is independently hydrogen, halogen or C 1 -C 10 alkoxy
  • R 4 is substituted or unsubstituted , substituted or unsubstituted , substituted or unsubstituted , substituted or unsubstituted , substituted or unsubstituted and substituted or unsubstituted is substituted with one or more substituents selected from the group consisting of,
  • C 1 -C 10 alkoxy, C 3 -C 10 cycloalkyl or C 4 -C 10 heterocycloalkyl is substituted with one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, amide, halo C1-C6 alkyl, CN, NO 2 , C 1 -C 6 alkyl, and C 1 -C 10 alkoxy;
  • n is an integer from 0 to 3;
  • the present invention relates to a pharmaceutical composition for preventing or treating colon cancer, comprising a compound represented by the above chemical formula 2, a stereoisomer thereof, a solvate thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • R 1 is substituted with one or more substituents selected from the group consisting of hydrogen, amino, amide, halo C 1 -C 6 alkyl, C 1 -C 6 alkyl, acetyl, acetamido, phenyl, thiophenyl, and morpholinyl;
  • R 2 is substituted with one or more substituents selected from the group consisting of hydrogen, halo C 1 -C 6 alkyl, C 1 -C 6 alkyl and acetyl;
  • R 3 is independently hydrogen, halogen or C 1 -C 6 alkoxy
  • R 4 is substituted or unsubstituted and substituted or unsubstituted is substituted with one or more substituents selected from the group consisting of,
  • n is an integer from 0 to 3;
  • the present invention relates to a pharmaceutical composition for preventing or treating colon cancer, comprising a compound represented by the following chemical formula 3, a stereoisomer thereof, a solvate thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • R 1 is hydrogen, halogen, hydroxy, amino, amide, CN, halo C 1 -C 6 alkyl, NO 2 , C 1 -C 6 alkyl, C 1 -C 10 alkoxy, acetyl, acetamido, C 1 -C 6 alkylamino, di(C 1 -C 6 ) Substituted with one or more substituents selected from the group consisting of alkylamino, C 1 -C 6 alkylcarbonylamino, phenyl, thiophenyl, and morpholinyl;
  • R 3 is independently hydrogen, halogen or C 1 -C 10 alkoxy
  • R 4 is substituted or unsubstituted , substituted or unsubstituted , substituted or unsubstituted , substituted or unsubstituted , substituted or unsubstituted and substituted or unsubstituted is substituted with one or more substituents selected from the group consisting of,
  • C 1 -C 10 alkoxy, C 3 -C 10 cycloalkyl or C 4 -C 10 heterocycloalkyl is substituted with one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, amide, halo C 1 -C 6 alkyl, CN, NO 2 , C 1 -C 6 alkyl, and C 1 -C 10 alkoxy;
  • n is an integer from 0 to 3;
  • the present invention relates to a pharmaceutical composition for preventing or treating colon cancer, comprising a compound represented by the above chemical formula 3, a stereoisomer thereof, a solvate thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • R 1 is substituted with one or more substituents selected from the group consisting of hydrogen, amino, amide, halo C 1 -C 6 alkyl, C 1 -C 6 alkyl, acetyl, acetamido, phenyl, thiophenyl, and morpholinyl;
  • R 2 is substituted with one or more substituents selected from the group consisting of hydrogen, halo C 1 -C 6 alkyl, C 1 -C 6 alkyl, and acetyl;
  • R 3 is independently hydrogen, halogen or C 1 -C 6 alkoxy
  • R 4 is substituted or unsubstituted and substituted or unsubstituted is substituted with one or more substituents selected from the group consisting of,
  • n is an integer from 0 to 3;
  • the present invention relates to a pharmaceutical composition for preventing or treating colon cancer, comprising a compound represented by the following chemical formula 4, a stereoisomer thereof, a solvate thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • R 1 is hydrogen, halogen, hydroxy, amino, amide, CN, halo C 1 -C 6 alkyl, NO 2 , C 1 -C 6 alkyl, C 1 -C 10 alkoxy, acetyl, acetamido, C 1 -C 6 alkylamino, di(C 1 -C 6 ) Substituted with one or more substituents selected from the group consisting of alkylamino, C 1 -C 6 alkylcarbonylamino, phenyl, thiophenyl, and morpholinyl;
  • R 3 is independently hydrogen, halogen or C 1 -C 10 alkoxy
  • R 4 is substituted or unsubstituted , substituted or unsubstituted , substituted or unsubstituted , substituted or unsubstituted , substituted or unsubstituted and substituted or unsubstituted is substituted with one or more substituents selected from the group consisting of,
  • C 1 -C 10 alkoxy, C 3 -C 10 cycloalkyl or C 4 -C 10 heterocycloalkyl is substituted with one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, amide, halo C 1 -C 6 alkyl, CN, NO 2 , C 1 -C 6 alkyl, and C 1 -C 10 alkoxy;
  • n is an integer from 0 to 3;
  • the present invention relates to a pharmaceutical composition for preventing or treating colon cancer, comprising a compound represented by the above chemical formula 4, a stereoisomer thereof, a solvate thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • R 1 is substituted with one or more substituents selected from the group consisting of hydrogen, amino, amide, halo C 1 -C 6 alkyl, C 1 -C 6 alkyl, acetyl, acetamido, phenyl, thiophenyl, and morpholinyl;
  • R 2 is substituted with one or more substituents selected from the group consisting of hydrogen, halo C 1 -C 6 alkyl, C 1 -C 6 alkyl, and acetyl;
  • R 3 is independently hydrogen, halogen or C 1 -C 6 alkoxy
  • R 4 is substituted or unsubstituted and substituted or unsubstituted is substituted with one or more substituents selected from the group consisting of,
  • n is an integer from 0 to 3;
  • the present invention relates to a pharmaceutical composition for preventing or treating colon cancer, comprising a compound represented by the following chemical formula 5, a stereoisomer thereof, a solvate thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • R 1 is substituted with one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, amino, amide, CN, halo C 1 -C 6 alkyl, NO 2 , C 1 -C 6 alkyl, C 1 -C 10 alkoxy, acetyl, acetamido, C 1 -C 6 alkylamino, di(C 1 -C 6) alkylamino, C 1 -C 6 alkylcarbonylamino, phenyl, thiophenyl, and morpholinyl;
  • R 3 is independently hydrogen, halogen or C 1 -C 6 alkoxy
  • R 4 is substituted or unsubstituted , substituted or unsubstituted , substituted or unsubstituted , substituted or unsubstituted , substituted or unsubstituted and substituted or unsubstituted is substituted with one or more substituents selected from the group consisting of,
  • C 1 -C 10 alkoxy, C 3 -C 10 cycloalkyl or C 4 -C 10 heterocycloalkyl is substituted with one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, amide, halo C 1 -C 6 alkyl, CN, NO 2 , C 1 -C 6 alkyl, and C 1 -C 10 alkoxy;
  • n is an integer from 0 to 3;
  • the present invention relates to a pharmaceutical composition for preventing or treating colon cancer, comprising a compound represented by the above chemical formula 5, a stereoisomer thereof, a solvate thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • R 1 is substituted with one or more substituents selected from the group consisting of hydrogen, amino, amide, halo C 1 -C 6 alkyl, C 1 -C 6 alkyl, acetyl, acetamido, phenyl, thiophenyl, and morpholinyl;
  • R 2 is substituted with one or more substituents selected from the group consisting of hydrogen, halo C 1 -C 6 alkyl, C 1 -C 6 alkyl, and acetyl;
  • R 3 is independently hydrogen, halogen or C 1 -C 6 alkoxy
  • R 4 is substituted or unsubstituted and substituted or unsubstituted is substituted with one or more substituents selected from the group consisting of,
  • n is an integer from 0 to 3;
  • the present invention relates to a pharmaceutical composition for preventing or treating colon cancer, comprising a compound represented by the following chemical formula 6, a stereoisomer thereof, a solvate thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • R 1 is substituted with one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, amino, amide, CN, halo C 1 -C 6 alkyl, NO 2 , C 1 -C 6 alkyl, C 1 -C 10 alkoxy, acetyl, acetamido, C 1 -C 6 alkylamino, di(C 1 -C 6) alkylamino, C 1 -C 6 alkylcarbonylamino, phenyl, thiophenyl, and morpholinyl;
  • R 3 is independently hydrogen, halogen or C 1 -C 6 alkoxy
  • R 4 is substituted or unsubstituted , substituted or unsubstituted , substituted or unsubstituted , substituted or unsubstituted , substituted or unsubstituted , and substituted or unsubstituted is substituted with one or more substituents selected from the group consisting of,
  • C 1 -C 10 alkoxy, C 3 -C 10 cycloalkyl or C 4 -C 10 heterocycloalkyl is substituted with one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, amide, halo C 1 -C 6 alkyl, CN, NO 2 , C 1 -C 6 alkyl, and C 1 -C 10 alkoxy;
  • n is an integer from 0 to 3;
  • the present invention relates to a pharmaceutical composition for preventing or treating colon cancer, comprising a compound represented by the above chemical formula 6, a stereoisomer thereof, a solvate thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • R 1 is substituted with one or more substituents selected from the group consisting of hydrogen, amino, amide, halo C 1 -C 6 alkyl, C 1 -C 6 alkyl, acetyl, acetamido, phenyl, thiophenyl, and morpholinyl;
  • R 2 is substituted with one or more substituents selected from the group consisting of hydrogen, halo C 1 -C 6 alkyl, C 1 -C 6 alkyl, and acetyl;
  • R 3 is independently hydrogen, halogen or C 1 -C 6 alkoxy
  • R 4 is substituted or unsubstituted and substituted or unsubstituted is substituted with one or more substituents selected from the group consisting of,
  • n is an integer from 0 to 3;
  • Compound 105 3-(4-oxo-1,4-dihydroquinolin-6-yl)-N-(m-tolyl)benzenesulfonamide (Compound 105); is selected from the group consisting of:
  • the present invention relates to a pharmaceutical composition used for treating, preventing, inhibiting, or eliminating an IRP2-dependent disease or disorder, comprising a compound represented by the above chemical formula 1, a stereoisomer thereof, a solvate thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention relates to a pharmaceutical composition for the prevention or treatment of solid cancer, which is an IKZF2-dependent disease, comprising a compound represented by the above chemical formula 1, a stereoisomer thereof, a solvate thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the solid cancer may be selected from the group consisting of non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, gastrointestinal stromal tumor (GIST), prostate cancer, breast cancer, lymphoma, leukemia, melanoma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid cancer, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, soft tissue sarcoma, rhabdomyosarcoma (RMS), synovial sarcoma, osteosar
  • the compound represented by the chemical formula 1 of the present invention, a stereoisomer thereof, a solvate thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof can enhance the cancer treatment effect by combination therapy with an anticancer agent for the treatment of solid cancer
  • the anticancer agent that can be used in the combination therapy can be selected from taxane-based anticancer agents, antitumor alkylating agents, antitumor antimetabolites, antitumor antibiotics, plant-derived antitumor agents, antitumor platinum complexes, antitumor camptothecin derivatives, antitumor kinase inhibitors, antitumor antibodies, hormonal antitumor agents, antitumor viral agents, and angiogenesis inhibitors.
  • the above taxane anticancer agent is paclitaxel, docetaxel, cabazitaxel, larotaxel, BMS-184476, BMS-188797, BMS275183, milataxel, ortaxel, TL-310, docosahexaenoic acid-paclitaxel (DHA-paclitaxel), nab-paclitaxel, EndoTAG+paclitaxel, XRP9881, polymer-micelle paclitaxel or RPR-109881A, the above antitumor alkylating agent is nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, busulan, mitobronitol, carboquone, thiotepa, ranimustine, nimustine, temozolomide or carmustine, and the above antitumor antimetabolite is methotrexate, 6-mercaptopurine riboside, Mercaptopurine
  • halogen refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).
  • alkyl refers to a straight or branched chain hydrocarbon group with a single bond. Examples include methyl, ethyl, propyl, n-butyl, isobutyl, tert-butyl, and 1-methylpropyl.
  • amino means -NH 2 .
  • alkoxy refers to an oxygen group bonded to a straight or branched chain saturated hydrocarbon group with a single bond. Examples include methoxy, ethoxy, propoxy, n-butoxy, tert-butoxy, and 1-methylpropoxy.
  • cycloalkyl refers to a saturated hydrocarbon group with a single bond in a ring shape. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • aryl as used herein means an aromatic substituent having at least one ring having a shared pi electron system, including but not limited to phenyl, benzyl, and the like.
  • heterocycloalkyl refers to a saturated hydrocarbon group with a single bond in a ring shape containing one or more heteroatoms such as N, O, or S, and includes, but is not limited to, aziridinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, etc., depending on the number and type of heteroatoms contained in the ring and the number of carbon atoms.
  • heteroaryl refers to an aromatic ring compound containing one or more heteroatoms such as N, O, or S, and includes, but is not limited to, pyrrolyl, furanyl, pyridinyl, pyrimidinyl, pyranyl, pyrazolyl, thiophenyl (or thienyl), etc., depending on the number and type of heteroatoms contained in the ring and the number of carbon atoms.
  • haloalkyl means an alkyl group substituted with a halo group, where halo and alkyl are as disclosed above.
  • alkylamino above means an amino group substituted with an alkyl group, wherein alkyl and amino are as disclosed above.
  • dialkylamino means an amino group substituted with two alkyl groups, wherein alkyl and amino are as disclosed above.
  • dialkylaminoalkyl means an alkyl group substituted with a dialkylamino group, where dialkylamino and alkyl are as disclosed above.
  • arylamino means an amino group substituted with an aryl group, wherein aryl and amino are as disclosed above.
  • the colon cancer may collectively refer to rectal cancer, colon cancer, and anal cancer, but is not particularly limited thereto.
  • the pharmaceutically acceptable salt refers to a salt or complex of chemical formula 1 having desirable biological activity.
  • examples of such salts include, but are not limited to, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), and acid addition salts formed with acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, naphthalene disulfonic acid, and poly-galacturonic acid.
  • inorganic acids e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.
  • Salts formed with the same organic acid are included.
  • the compound may also be administered as a pharmaceutically acceptable quaternary salt known to those skilled in the art, particularly chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (e.g., benzoate, succinate, acetate, glycolate, maleate, malate, fumarate, citrate, tartrate, ascorbate, cinnamoate, mandeloate, and diphenylacetate).
  • the compound of formula 1 of the present invention may include not only pharmaceutically acceptable salts, but also all salts, hydrates, solvates, and prodrugs that can be prepared by conventional methods.
  • the acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the derivative of chemical formula 1 in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile, etc., adding an organic acid or inorganic acid, filtering and drying the resulting precipitate, or by distilling the solvent and an excess acid under reduced pressure, drying, and crystallizing in the presence of an organic solvent.
  • an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile, etc.
  • metal salts can be prepared using bases.
  • Alkali metal or alkaline earth metal salts can be obtained, for example, by dissolving a compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering out the undissolved compound salt, and evaporating and drying the filtrate.
  • the metal salts sodium, potassium, or calcium salts are pharmaceutically suitable.
  • the corresponding salts can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).
  • the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All such compounds and diastereomers are included within the scope of the present invention.
  • compositions according to the present invention can be formulated into a suitable form together with a pharmaceutically acceptable carrier commonly used.
  • “Pharmaceutically acceptable” refers to a composition that is physiologically tolerable and does not typically cause allergic reactions or similar reactions such as gastrointestinal disorders or dizziness when administered to humans.
  • the composition can be formulated and used in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, and sterile injectable solutions, each according to a conventional method.
  • Carriers, excipients and diluents that may be included in the above composition include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl parahydroxybenzoate, propyl parahydroxybenzoate, talc, magnesium stearate and mineral oil.
  • the composition is prepared using diluents or excipients such as commonly used fillers, stabilizers, binders, disintegrants and surfactants.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations are prepared by mixing the compound of the present invention with at least one excipient, such as starch, microcrystalline cellulose, sucrose or lactose, low-substituted hydroxypropyl cellulose, hypromellose, etc.
  • excipients such as starch, microcrystalline cellulose, sucrose or lactose, low-substituted hydroxypropyl cellulose, hypromellose, etc.
  • lubricants such as magnesium stearate and talc are also used.
  • Liquid preparations for oral administration include suspensions, oral solutions, emulsions, syrups, etc., and in addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, flavoring agents, preservatives, etc.
  • Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories.
  • Non-aqueous solvents and suspending agents may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
  • Suppository bases may include witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol, gelatin, etc.
  • the benzenesulfonamide-substituted heterobicyclic derivative compound of the above chemical formula 1 or a pharmaceutically acceptable salt thereof is sterilized and/or mixed in water with auxiliary agents such as preservatives, stabilizers, wetting agents or emulsifying promoters, salts for osmotic pressure control and/or buffers, and other therapeutically useful substances to prepare a solution or suspension, which may be prepared in an ampoule or vial unit dosage form.
  • the above pharmaceutical composition provides a pharmaceutical composition comprising a benzenesulfonamide substituted heterobicyclic derivative compound of the above chemical formula 1 and an excipient.
  • the compound may be added in an amount of preferably 0.001 wt% to 50 wt%, more preferably 0.001 wt% to 40 wt%, and most preferably 0.001 wt% to 30 wt% based on the total weight of the entire composition.
  • the pharmaceutical composition comprising the compound of chemical formula 1 disclosed in the present invention as an active ingredient can be administered to mammals such as mice, livestock, and humans by various routes. All modes of administration are conceivable, and for example, it can be administered orally, rectally, or by intravenous, intramuscular, subcutaneous, intrauterine, or intracerebrovascular injection.
  • the dosage will vary depending on the age, sex, and body weight of the subject to be treated, the specific disease or pathological condition to be treated, the severity of the disease or pathological condition, the time of administration, the route of administration, the absorption, distribution, and excretion rates of the drug, the types of other drugs used, and the judgment of the prescriber.
  • the dosage based on these factors is within the level of those skilled in the art, and the dosage generally ranges from 0.01 mg/kg/day to approximately 2000 mg/kg/day. A more preferred dosage is 1 mg/kg/day to 500 mg/kg/day.
  • the dosage can be administered once a day or divided into several doses. The above dosage does not limit the scope of the present invention in any way.
  • the present invention relates to a pharmaceutical composition for preventing or treating colon cancer, comprising a benzenesulfonamide-substituted heterobicyclic derivative, which is an IRP2 disruptor, as an active ingredient, and can provide a benzenesulfonamide-substituted heterobicyclic derivative compound that kills colon cancer cells by inducing reprogramming of iron metabolism in cancer cells by interfering with IRP2 binding to IRE.
  • Figure 1 shows the results showing that IRP2 is an important factor regulating cell growth and has therapeutic relevance in colon cancer.
  • Figure 2 shows the results of identifying small molecule inhibitors with strong selectivity for IRP2.
  • Figure 3 shows the results showing changes in iron metabolism-related factors through cancer cell toxicity and IRP2 inhibition induced by compounds 1 and 44.
  • Figure 4 shows the results of IRP2 ubiquitination and sequential LIP, ROS reduction, and mitochondrial OCR reduction by IRP2 inhibitor.
  • Figure 5 shows the results of gene profiling and GSEA analysis showing a decrease in mitochondrial OCR genes and an increase in autophagy genes by compound 1.
  • Figure 6 shows the results of inducing autophagic cancer cell death through activation of the AMPK-ULK1-Beclin1-LC3B pathway by compound 1 and compound 44.
  • Figure 7 shows the results of inhibiting tumor growth in organoid and in vivo animal models of compound 1 and compound 44.
  • Figure 8 shows the results of examining iron metabolism-related factors by changing the amount of intracellular iron using FAC and DFO.
  • Figure 9 shows the results of confirming the mRNA and protein expression levels of IRP1 and IRP2 in normal and cancerous tissues of a patient.
  • Figure 10 shows the results of compound hits from the pharmacophore-based screening of the Database (DB).
  • Figure 11 is a synthetic route scheme for compound 1 (A) and compound 44 (B).
  • Figure 12 shows the effects on transcriptional activity and cell cycle after treatment with compound 1 and compound 44.
  • Figure 13 shows the results showing mitochondrial dysfunction and autophagy-dependent cancer cell death induced by compound 1.
  • compound 1-2 (3-bromo-4-methoxy-N-(m-tolyl)benzenesulfonamide; 1.78 g, 5 mmol)(1.0 eq.) and sodium carbonate aqueous solution (2 M, 5 mL)(2.0 eq.) were added and reacted at 120 °C for 1 hour.
  • the solvent was removed by celite filtration, extracted with water and EtOAc, and the organic layer was dried over MgSO 4 and concentrated under reduced pressure. After that, compound 1 was obtained in a yield of 25% (495 mg) by separation by silica gel column chromatography.
  • the mixture was filtered using a celite pad, extracted with water and EtOAc, and the organic layer was dried over MgSO 4 and concentrated under reduced pressure. Afterwards, the compound 62-3 was separated by silica gel column chromatography, and a yield of 60% (728 mg) was obtained.
  • compound 90-3 (4-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)morpholine; 39 mg, 0.14 mmol) and sodium carbonate aqueous solution (2 M, 0.15 mL) were added and reacted at 120 °C for 1 h. After the reaction was completed, the solvent was removed by celite filtration, extracted with water and EtOAc, and the organic layer was dried over MgSO 4 and concentrated under reduced pressure. After separation by silica gel column chromatography, compound 90 was obtained with a yield of 11% (8 mg).
  • 6-Bromo-1H-imidazo[4,5-b]pyridine (693 mg, 3.5 mmol) and DMF (35 mL) were stirred at 0 °C, then NaH (235 mg, 7.0 mmol) was added and stirred for 10 minutes.
  • 2-(trimethylsilyl)ethoxymethyl chloride (990 ⁇ L, 5.95 mmol) was added and stirred at room temperature for 6 hours. After completion of the reaction, the mixture was quenched with water, extracted with DCM, and the organic layer was dried over MgSO 4 and concentrated under reduced pressure. The compound was then separated by silica gel column chromatography in a yield of 52% (597 mg).
  • Step B Synthesis of 4-methoxy-N-(m-tolyl)-3-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)benzenesulfonamide (Compound 99)
  • IRP2 is crucial for determining cell proliferation through the regulation of iron homeostasis.
  • TCGA Cancer Genome Atlas
  • Fig. 1F Gene ontology analysis confirmed a positive correlation between IRP2 expression and genes related to ubiquitination-related signaling pathways and cell differentiation (Fig. 1G). Additionally, using a Kaplan-Meier curve to compare survival outcomes according to IRP2 expression, we confirmed that patients with IRP2 overexpression had a poor survival prognosis (Fig. 1H), emphasizing the importance of IRP2 as a therapeutic target for colon cancer.
  • the present inventors also compared IRP1/2 mRNA and protein expression in paired normal and tumor tissues derived from colorectal cancer patients. Interestingly, IRP2 mRNA and protein expression was overexpressed by more than 1.5-fold in 5 out of 10 colon patient tissues, whereas IRP1 expression did not differ significantly between normal and tumor tissues ( Figures 9A and 9B). Therefore, we confirmed that IRP2, rather than IRP1, is a more important factor in colorectal cancer cell growth.
  • the present inventors found that S446 of IRP2 interacts with N7 of adenine (A15) in IRE through a hydrogen bond, R454 interacts with N7 of guanine (G16) in IRE through a hydrogen bond, and hydrophobic interactions are formed between A15 and G16 of IRE and I333, S444, V445, S446, P451, R454, and N610 of IRP2 (Fig. 2B).
  • the final structure-based pharmacophore model consists of seven pharmacophore functions: one hydrogen bond donor (HBD), three hydrogen bond acceptors (HBAs), one hydrophobic (Hy), and two cyclic aromatic (RA) functions.
  • HBA hydrogen bond donor
  • HBAs hydrogen bond acceptors
  • Hy hydrophobic
  • RA cyclic aromatic
  • the three HBA functions were derived from the hydroxyl group of S446, the quinidine group of Arg454, and the backbone of N610, respectively.
  • Two RA functions were added considering the purine base characteristics of A15 and G16 of IRE (Figs. 2B and 2C).
  • One hydrophobic function reflected the hydrophobic terminal loop binding pocket generated by D334 and one HBD function (Fig. 2C).
  • the present inventors assessed the antitumor effects of compounds 1 and 44 by measuring cell viability in colon cancer cells. These compounds exhibited significant cytotoxicity in an IRP2-dependent manner and did not affect proliferation in cells lacking IRP2 (Fig. 3A). In contrast, they exhibited slight cytotoxicity at high doses in various normal cell lines, including CCD-18Co, VERO, HFL-1, L929, NIH 3T3, and CHO-K1 (Fig. 3A).
  • Iron is utilized in various mitochondrial functions such as ATP production, iron-sulfur cluster biogenesis, and respiration (Bauckman et al., 2015), and intracellular iron deficiency has been reported to impair mitochondrial activity due to the deficiency of iron-sulfur complexes (Cloonan et al., 2016; Li et al., 2019). Therefore, we predicted that IRP2 inhibitors would induce iron deficiency through changes in iron metabolism and thus affect mitochondrial function.
  • Compound 1 inhibited mitochondrial oxidative phosphorylation (OXPHOS), reducing oxygen consumption rate (OCR), basal respiration, and ATP production ( Figures 4D and 13A), whereas it activated glycolysis, showing an increase in basal and compensatory glycolysis ( Figures 4D and 13B).
  • GSEA gene set enrichment analysis
  • Mitochondrial dysfunction leads to mitophagy, which is the selective degradation of mitochondria by autophagy (Youn DH et al., 2021), and stimulates AMP-activated protein kinase (AMPK), which activates Unc-51-like autophagy-activating kinase-1 (ULK1) and Beclin-1, which acts as an autophagy promoter (You L et al., 2015). This suggests that disruption of iron metabolism targeting IRP2 leads to activation of autophagy via mitochondrial dysfunction.
  • AMPK AMP-activated protein kinase
  • ULK1 Unc-51-like autophagy-activating kinase-1
  • Beclin-1 acts as an autophagy promoter
  • Organoids treated with compound 1 exhibited complete destruction of organoid structure as well as cell death, with differential sensitivity ranging from 0.5 to 40 ⁇ M IC ( Figure 7A ).
  • organoids were divided into the most and least sensitive to compound 1, and IRP2 protein expression was significantly reduced in the most sensitive organoid ( Figures 7B and 7C), confirming a decrease in IRP2 protein expression after compound 1 treatment in colorectal cancer organoids.
  • the expression level of IRP2 correlated with organoid sensitivity to compound 1, while no correlation was observed for IRP1 ( Figure 7D).
  • the anticancer activity of the compound of the present invention was confirmed by measuring the % or IC 50 value using CCK.
  • Human colon cancer cell lines were purchased from the Korea Cell Line Bank. Cell lines were maintained in appropriate complete growth media, primarily Dulbecco's Modified Eagle Medium (DMEM) and Roswell Park Memorial Institute-1640 (RPMI-1640) supplemented with 10% fetal bovine serum (FBS), 100 U/ml penicillin, and 100 ⁇ g/ml streptomycin. Cell lines were cultured at 37°C in a 5% CO2 incubator.
  • DMEM Dulbecco's Modified Eagle Medium
  • RPMI-1640 Roswell Park Memorial Institute-1640
  • FBS fetal bovine serum
  • streptomycin 100 fetal bovine serum
  • Cell lines were cultured at 37°C in a 5% CO2 incubator.
  • Cell viability was measured using the Cell Counting Kit-8 (CCK-8). An appropriate number of cells (2 ⁇ 10 4 ) were seeded in 96-well plates and cultured for 24 h. The cells were then treated with various concentrations of compounds 1 and 44 for 48 h. After adding CCK-8 solution and incubating for 3 h at 37°C, the absorbance was measured at 450 nm using a microplate reader, and the experiment was performed in triplicate.
  • CCK-8 Cell Counting Kit-8
  • 100 mg of the compound of the present invention 100 mg of the compound of the present invention 1, 100 mg of microcrystalline cellulose, 60 mg of lactose monohydrate, 20 mg of low-substituted hydroxypropyl cellulose, and 2 mg of magnesium stearate were mixed and then compressed into tablets according to a conventional tablet manufacturing method.
  • 100 mg of the compound of the present invention 100 mg of the compound of the present invention 1, 100 mg of microcrystalline cellulose, 60 mg of lactose monohydrate, 20 mg of low-substituted hydroxypropyl cellulose, and 2 mg of magnesium stearate were mixed, and then the above ingredients were mixed according to a conventional capsule manufacturing method and filled into a gelatin capsule to manufacture a capsule.

Landscapes

  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition pharmaceutique contenant un dérivé hétérobicyclique substitué par benzènesulfonamide, qui est une substance perturbatrice de IRP2, utilisé en tant que principe actif pour prévenir ou traiter le cancer. La présente invention peut fournir un composé dérivé hétérobicyclique substitué par benzènesulfonamide qui interfère avec la liaison de IRP2 à l'IRE pour induire la reprogrammation du métabolisme du fer dans des cellules cancéreuses, ce qui permet de tuer les tumeurs solides, en particulier les cellules cancéreuses colorectales.
PCT/KR2025/002760 2024-02-29 2025-02-27 Nouveaux composés de faible poids moléculaire inhibant irp2 Pending WO2025183481A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020240030059A KR20250132936A (ko) 2024-02-29 2024-02-29 Irp2를 저해하는 신규 저분자 화합물
KR10-2024-0030059 2024-02-29

Publications (1)

Publication Number Publication Date
WO2025183481A1 true WO2025183481A1 (fr) 2025-09-04

Family

ID=96921760

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2025/002760 Pending WO2025183481A1 (fr) 2024-02-29 2025-02-27 Nouveaux composés de faible poids moléculaire inhibant irp2

Country Status (2)

Country Link
KR (1) KR20250132936A (fr)
WO (1) WO2025183481A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007076320A2 (fr) * 2005-12-22 2007-07-05 Smithkline Beecham Corporation Composes
WO2022217239A1 (fr) * 2021-04-09 2022-10-13 Board Of Regents, The University Of Texas System Inhibiteurs de pu.1 pour le traitement d'une maladie
CN116162087A (zh) * 2023-02-20 2023-05-26 杭州医学院 一种hpk 1和/或lck激酶调节剂、制备方法及其应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007076320A2 (fr) * 2005-12-22 2007-07-05 Smithkline Beecham Corporation Composes
WO2022217239A1 (fr) * 2021-04-09 2022-10-13 Board Of Regents, The University Of Texas System Inhibiteurs de pu.1 pour le traitement d'une maladie
CN116162087A (zh) * 2023-02-20 2023-05-26 杭州医学院 一种hpk 1和/或lck激酶调节剂、制备方法及其应用

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GORECKI, L ET AL.: "7-Azaindole, 2,7-diazaindole, and 1H-pyrazole as core structures for novel anticancer agents with potential chemosensitizing properties", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 240, no. 114580, 2022, pages 1 - 20, XP087144955, DOI: 10.1016/j.ejmech.2022.114580 *
HONG, S. ET AL.: "Discovery of new azaindole-based PI3Kalpha inhibitors: Apoptotic and antiangiogenic effect on cancer cells.", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 20, 2010, pages 7212 - 7215, XP027501408, DOI: 10.1016/j.bmcl.2010.10.108 *

Also Published As

Publication number Publication date
KR20250132936A (ko) 2025-09-05

Similar Documents

Publication Publication Date Title
WO2021145521A1 (fr) Dérivé de pyrido[3,4-d]pyrimidine et composition pharmaceutique thérapeutique le comprenant
AU2023363515A1 (en) Novel triheterocyclic compounds
WO2020171499A1 (fr) Nouveau dérivé de pyrido[3,4-d]pyrimidin-8-one ayant une activité inhibitrice de protéine kinase, et composition pharmaceutique pour prévenir, soulager ou traiter le cancer, comprenant celui-ci
WO2020190119A1 (fr) Dérivé hétéroaryle, son procédé de production et composition pharmaceutique le comprenant en tant que constituant efficace
WO2010044543A2 (fr) Composé hétérocyclique utilisé comme inhibiteur de la protéine kinase
WO2020149723A1 (fr) Dérivé de pyrrolopyrimidine et composition pharmaceutique pour la prévention ou le traitement d'une maladie liée à la protéine kinase le comprenant en tant que principe actif
WO2015160192A1 (fr) Composition pharmaceutique permettant de traiter et de prévenir la leucémie, contenant un dérivé de thiénopyrimidine ou un sel pharmaceutiquement acceptable de celui-ci
WO2017039331A1 (fr) Composés hétéroaryle et leur utilisation comme médicaments thérapeutiques
WO2020149553A1 (fr) Dérivé d'aryle ou d'hétéroaryle, et composition pharmaceutique le comprenant en tant que principe actif pour le traitement d'une maladie associée à une kinase
WO2018004213A1 (fr) Nouveau composé ayant une activité inhibitrice de smo et composition comprenant celui-ci en tant qu'ingrédient actif pour prévenir ou traiter le cancer
WO2019212256A1 (fr) Nouveau dérivé hétérocyclique
WO2022177302A1 (fr) Composé cyclique fusionné à la pyrimidine avec une activité d'inhibition de l'adn-pk et son utilisation
WO2022060196A1 (fr) Dérivé hétéroaryle, son procédé de préparation et composition pharmaceutique le comprenant en tant que principe actif
WO2022035303A1 (fr) Nouveaux dérivés de dioxoloisoquinolinone et leur utilisation
WO2021086077A1 (fr) Dérivé d'isoquinolinone, son procédé de préparation et composition pharmaceutique le comprenant en tant que principe actif pour la prévention ou le traitement d'une maladie associée à la poly(adp-ribose) polymérase-1 (parp-1)
EP4110781A1 (fr) Composés dérivés de 1,3,4-oxadiazole utilisés comme inhibiteurs d'histone désacétylase 6, et composition pharmaceutique les comprenant
WO2017135589A1 (fr) Raf kinase inhibant un dérivé pyridine et récepteur de facteur de croissance endothélial vasculaire, procédé pour le préparer, composition pharmaceutique le contenant, et son utilisation
WO2022245085A1 (fr) Composé dérivé d'hétéroaryle et son utilisation
WO2022240213A1 (fr) Nouveau dérivé de benzothiazole, son procédé de préparation et son utilisation pour la prévention ou le traitement d'une maladie hépatique
WO2020185044A1 (fr) Dérivés d'hétéroaryle et composition pharmaceutique les comprenant en tant que principe actif
WO2021261970A1 (fr) Nouveau composé et composition pharmaceutique le comprenant pour prévenir ou traiter un cancer résistant
WO2025183481A1 (fr) Nouveaux composés de faible poids moléculaire inhibant irp2
WO2020096416A1 (fr) Composé inhibant la liaison yap-tead et composition pharmaceutique pour prévenir ou traiter le cancer contenant ledit composé en tant que principe actif
WO2022114812A1 (fr) Composé hétérocyclique en tant qu'inhibiteur de la diacylglycérol kinase et son utilisation
WO2023113457A1 (fr) Nouveau composé pour dégrader une protéine ou un polypeptide cible par polyubiquitination

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 25762398

Country of ref document: EP

Kind code of ref document: A1