WO2025008526A1 - Composés contenant une fraction dialkylaryle et leur utilisation - Google Patents

Composés contenant une fraction dialkylaryle et leur utilisation Download PDF

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WO2025008526A1
WO2025008526A1 PCT/EP2024/069050 EP2024069050W WO2025008526A1 WO 2025008526 A1 WO2025008526 A1 WO 2025008526A1 EP 2024069050 W EP2024069050 W EP 2024069050W WO 2025008526 A1 WO2025008526 A1 WO 2025008526A1
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Prior art keywords
cancer
urea
dimethylphenyl
compounds
pharmaceutically acceptable
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Inventor
Eric Chevet
François-Hugues PORÉE
Leif Axel ERIKSSON
Sébastien SUERON
Timothy LANGLAIS
Xavier GUILLORY
Diana PELIZZARI-RAYMUNDO
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Centre National de la Recherche Scientifique CNRS
Universite de Rennes 1
Institut National de la Sante et de la Recherche Medicale INSERM
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Centre National de la Recherche Scientifique CNRS
Universite de Rennes 1
Institut National de la Sante et de la Recherche Medicale INSERM
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/12—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
    • C07C311/13—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C07D215/06—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to urea, amide or sulfonamide compounds, in particular urea compounds, bearing two side groups, one of which carries a dialkylaryl moiety, in particular a dialkylphenyl or dialkylpyridinyl moiety, including their pharmaceutically acceptable salts and solvates which are useful as sensitizers for chemotherapy of cancer cells, particularly in glioblastoma, and are useful as therapeutic compounds, particularly in the treatment of cancers that may be treated by alkylating agents, such as temozolomide.
  • Glioblastoma is the most common primary central nervous system (CNS) tumour, displaying high levels of aggressiveness, recurrence and heterogeneity; traits that contribute to a dismal prognosis of an average of 1.5 year survival post diagnosis.
  • the standard of care comprises maximal safe resection of the tumour followed by a combination of irradiation and chemotherapy with the alkylating agent temozolomide; however, all patients succumb to the disease (R. Stupp et al., N. Engl. J. Med., 2005, 352, 987-996).
  • GB cells as with most solid tumours, survives in a hostile environment which includes hypoxia, nutrient shortage, necrosis and immune infiltration, as well as having to cope with a high metabolic turnover and protein synthesis demand (D. Doultsinos et al., SLAS Discov. Adv. Life Sci. R&D, 2017, 22, 787-800).
  • URR Unfolded Protein Response
  • J. Obacz et al., Sci. Signal., 2017, 10, eaal2323 J. Obacz et al., Sci. Signal., 2017, 10, eaal2323
  • Inositol Requiring Enzyme 1 a major Unfolded Protein Response (UPR) transducer
  • URR Unfolded Protein Response
  • TNBC Triple Negative Breast Cancer
  • IRE1 activity inhibition can be mediated by compounds targeting either the ATP -binding kinase domain or the RNase domain.
  • Direct RNase pharmacological inhibitors include 4p8c, STF-083010, toyocamycin and a series of MKC compounds, all relying on a hydroxy-aryl aldehyde (HAA) motif, whilst kinase pharmacological inhibitors that in turn inhibit the RNase include amongst others l-(4-(8-amino-3-isopropylimidazo[l,5-a]pyrazin-l- yl)naphthalen-l-yl)-3-(3-(trifhioro-methyl)phenyl)urea (CAS# 1414938-21-8), l-(4-(8- amino-3-(tert-butyl)imidazo[l,5-a]pyrazin-l-yl)naphthalen-l-yl)-3-(3- (tri
  • urea, amide or sulfonamide compounds in particular urea compounds, bearing two side groups, one of which carries a dialkylaryl moiety, in particular a dialkylphenyl or dialkylpyridinyl moiety, more particularly a dimethylphenyl or dimethylpyridinyl moiety.
  • These compounds have the advantage of inhibiting IRE1 RNase activity and sensitizing cancer cells, in particular GB cells, to chemotherapy.
  • the invention therefore relates to compounds of general Formula I, their pharmaceutically acceptable salts and solvates as well as methods of use of such compounds or compositions comprising such compounds as sensitizers for chemotherapy of malignant tumors.
  • the invention provides compounds of general Formula I:
  • Y is -NH- or -CH 2 -;
  • R 1 and R 2 are independently H or Cl-C4-alkyl, with the proviso that R 1 and R 2 are not both H;
  • Z is N or C-H; is — C(O) ⁇ and Z is C-H.
  • Ar is selected from Meooc-
  • Y is -NH- or -CH2-; in particular Y is -NH-;
  • N atom may be located at any free position of the 6-member aromatic ring.
  • the compounds of Formula I are those wherein
  • the compounds of Formula I are those wherein
  • the compounds of Formula I are those wherein In one embodiment, the compounds of Formula I are those wherein Ar is In one embodiment, the compounds of Formula I are those wherein
  • the compounds of Formula I are those wherein Ar is
  • the compounds of Formula I are those wherein
  • the compounds of Formula I are those wherein L is selected from
  • the compounds of Formula I are those wherein L is
  • the compounds of Formula I are those wherein L is In one embodiment, the compounds of Formula I are those wherein L is
  • the compounds of Formula I are those wherein
  • the compounds of Formula I are those wherein
  • the compounds of Formula I are those wherein In one embodiment, the compounds of Formula I are those wherein
  • the compounds of Formula I are those wherein
  • the compounds of Formula I are those wherein
  • the compounds of Formula I are those wherein Y is -NH-.
  • the compounds of Formula I are those wherein Y is -CH2-.
  • the compounds of Formula I are those wherein Z is C-H.
  • the compounds of Formula I are those wherein Z is N.
  • the compounds of Formula I are those of Formula II: or pharmaceutically acceptable salts or solvates thereof, wherein Ar, B, Y, R 1 , R 2 and Z are as defined above with respect to Formula I and any of its embodiments.
  • Particular compounds of Formula II or pharmaceutically acceptable salts or solvates thereof are those wherein one or more of Ar, B, Y, R 1 , R 2 and Z are defined as follows:
  • B is -C(0)-
  • Y is -NH-; R 1 and R 2 are independently H or Cl-C4-alkyl, with the proviso that R 1 and R 2 are not both H; in particular R 1 and R 2 are independently Cl-C4-alkyl; more particularly R 1 and R 2 are independently Cl-C3-alkyl; still more particularly R 1 and R 2 are independently C1-C2- alkyl; even more particularly R 1 and R 2 are methyl; Z is N or C-H; in particular Z is C-H.
  • the compounds of Formula I are those of Formula Ila:
  • Ar, Y, R 1 , R 2 and Z are as defined above with respect to Formula I and any of its embodiments.
  • Particular compounds of Formula Ila or pharmaceutically acceptable salts or solvates thereof are those wherein one or more of Ar, Y, R 1 , R 2 and Z are defined as follows:
  • Y is -NH-;
  • R 1 and R 2 are independently H or Cl-C4-alkyl, with the proviso that R 1 and R 2 are not both H; in particular R 1 and R 2 are independently Cl-C4-alkyl; more particularly R 1 and R 2 are independently Cl-C3-alkyl; still more particularly R 1 and R 2 are independently C1-C2- alkyl; even more particularly R 1 and R 2 are methyl;
  • the compounds of Formula I are those of Formula lib : or pharmaceutically acceptable salts or solvates thereof, wherein
  • R 1 , R 2 and Z are as defined above with respect to Formula I and any of its embodiments.
  • Particular compounds of Formula lib or pharmaceutically acceptable salts or solvates thereof are those wherein one or more of Ar, R 1 , R 2 and Z are defined as follows:
  • R 1 and R 2 are independently H or Cl-C4-alkyl, with the proviso that R 1 and R 2 are not both H; in particular R 1 and R 2 are independently Cl-C4-alkyl; more particularly R 1 and R 2 are independently Cl-C3-alkyl; still more particularly R 1 and R 2 are independently C1-C2- alkyl; even more particularly R 1 and R 2 are methyl;
  • the compounds of Formula I are those of Formula lie: or pharmaceutically acceptable salts or solvates thereof, wherein
  • Ar and Z are as defined above with respect to Formula I and any of its embodiments.
  • Particular compounds of Formula lie or pharmaceutically acceptable salts or solvates thereof are those wherein one or more of Ar and Z are defined as follows:
  • Z is N or C-H; in particular Z is C-H.
  • the compounds of Formula I are those of Formula lid: lid, or pharmaceutically acceptable salts or solvates thereof, wherein
  • Ar is as defined above with respect to Formula I and any of its embodiments.
  • the compounds of Formula I are those of Formula III: or pharmaceutically acceptable salts or solvates thereof, wherein
  • L, B, Y, R 1 , R 2 and Z are as defined above with respect to Formula I and any of its embodiments.
  • Particular compounds of Formula III or pharmaceutically acceptable salts or solvates thereof are those wherein one or more of L, B, Y, R 1 , R 2 and Z are defined as follows: B is — C(O) ⁇ or -S(O2)-; in particular B is -C(O)-;
  • Y is -NH- or -CH2-; in particular Y is -NH-;
  • R 1 and R 2 are independently H or Cl-C4-alkyl, with the proviso that R 1 and R 2 are not both H; in particular R 1 and R 2 are independently Cl-C4-alkyl; more particularly R 1 and R 2 are independently Cl-C3-alkyl; still more particularly R 1 and R 2 are independently C1-C2- alkyl; even more particularly R 1 and R 2 are methyl; Z is N or C-H; in particular Z is C-H; is C-H.
  • the compounds of Formula I are those of Formula Illa:
  • L, Y, R 1 , R 2 and Z are as defined above with respect to Formula I and any of its embodiments.
  • Particular compounds of Formula Illa or pharmaceutically acceptable salts or solvates thereof are those wherein one or more of L, Y, R 1 , R 2 and Z are defined as follows:
  • Y is -NH- or -CH2-; in particular Y is -NH-;
  • R 1 and R 2 are independently H or Cl-C4-alkyl, with the proviso that R 1 and R 2 are not both H; in particular R 1 and R 2 are independently Cl-C4-alkyl; more particularly R 1 and R 2 are independently Cl-C3-alkyl; still more particularly R 1 and R 2 are independently C1-C2- alkyl; even more particularly R 1 and R 2 are methyl; Z is N or C-H; in particular Z is C-H; with the proviso that L is not when Z is C-H.
  • the compounds of Formula I are those of Formula Illb : mb, or pharmaceutically acceptable salts or solvates thereof, wherein L, Y, R 1 , R 2 and Z are as defined above with respect to Formula I and any of its embodiments.
  • Particular compounds of Formula IIIc or pharmaceutically acceptable salts or solvates thereof are those wherein one or more of L, Y, R 1 , R 2 and Z are defined as follows: Y is -NH- or -CH2-; in particular Y is -CH2-;
  • R 1 and R 2 are independently H or Cl-C4-alkyl, with the proviso that R 1 and R 2 are not both H; in particular R 1 and R 2 are independently Cl-C4-alkyl; more particularly R 1 and R 2 are independently Cl-C3-alkyl; still more particularly R 1 and R 2 are independently C1-C2- alkyl; even more particularly R 1 and R 2 are methyl;
  • Z is N or C-H; in particular Z is C-H;
  • the compounds of Formula I are those of Formula IIIc:
  • R 1 , R 2 and Z are as defined above with respect to Formula I and any of its embodiments.
  • Particular compounds of Formula IIIc or pharmaceutically acceptable salts or solvates thereof are those wherein one or more of L, R 1 , R 2 and Z are defined as follows:
  • R 1 and R 2 are independently H or Cl-C4-alkyl, with the proviso that R 1 and R 2 are not both H; in particular R 1 and R 2 are independently Cl-C4-alkyl; more particularly R 1 and R 2 are independently Cl-C3-alkyl; still more particularly R 1 and R 2 are independently C1-C2- alkyl; even more particularly R 1 and R 2 are methyl;
  • Z is N or C-H; in particular Z is C-H; with the proviso that L is not when Z is C-H.
  • the compounds of Formula I are those of Formula Hid:
  • R 1 and R 2 are independently H or Cl-C4-alkyl, with the proviso that R 1 and R 2 are not both H; in particular R 1 and R 2 are independently Cl-C4-alkyl; more particularly R 1 and R 2 are independently Cl-C3-alkyl; still more particularly R 1 and R 2 are independently C1-C2- alkyl; even more particularly R 1 and R 2 are methyl.
  • the compounds of Formula I are those of Formula Ille:
  • R 1 and R 2 are independently H or Cl-C4-alkyl, with the proviso that R 1 and R 2 are not both H; in particular R 1 and R 2 are independently Cl-C4-alkyl; more particularly R 1 and R 2 are independently Cl-C3-alkyl; still more particularly R 1 and R 2 are independently C1-C2- alkyl; even more particularly R 1 and R 2 are methyl.
  • Particularly preferred compounds of the invention are those listed in Table 1 hereafter:
  • the compounds of the invention can be prepared by different ways with reactions known by the person skilled in the art. Typical routes of synthesis are described thereafter
  • the compounds of the invention are indeed capable of inhibiting IRE RNase activity and sensitizing cancer cells to anticancer drugs. They further have the advantage of sensitizing cancer cells, in particular GGM cells to anticancer drugs, in particular alkylating agents.
  • the invention thus also provides the use of the compounds of the invention, or pharmaceutically acceptable salts or solvates thereof, as sensitizers for chemotherapy of cancer cells.
  • the invention relates to the use of compounds of the invention, or pharmaceutically acceptable salts or solvates thereof, for the treatment of cancer, particularly as sensitizers for chemotherapy of cancer cells.
  • the compounds of the invention may be used as inhibitors of IRE1 RNase activity and have the potentential of increasing the sensitivity of cancer cells to an anticancer agent in a treatment of cancer.
  • the compounds of the invention i.e. the compounds of Formula I and any of its embodiments, or any of its subformulae as defined above, are able to inhibit IRE1 RNase activity and to increase the sensitivity of cancer cells to an anticancer agent in a treatment of cancer, in particular glioblastoma, triple-negative breast cancer, lung cancer, osteosarcoma, prostate cancer, ovarian cancer and pancreatic cancer.
  • the compounds of the invention as defined above can thus be used for treating cancer, particularly as sensitizers for chemotherapy of cancer cells, aiming at improving the chemotherapy effect of the cancer treatment, preventing tolerance and decreasing toxicity and adverse effects.
  • the invention thus relates to a compound of Formula I, or any of its embodiments, or any of its subformulae as defined above, or a pharmaceutically acceptable salt or solvate thereof, in combination with an anticancer agent, for use in treating cancer.
  • the invention also relates to the compounds of the invention as described above, or a pharmaceutically acceptable salt or solvate thereof, for use in increasing the sensitivity of cancer cells to an anticancer agent in a treatment of cancer.
  • the invention thus relates to a compound of Formula I, or any of its embodiments or subformulae as defined above, or a pharmaceutically acceptable salt or solvate thereof, for use in treating cancer.
  • Anticancer agents within the meaning of the present invention include, but are not limited to, alkylating agents, anti -microtubule agents, anti metabolites, topoisomerase inhibitors, cytotoxic antibiotics and anti angiogenic agents.
  • the anticancer agent is an alkylating agent.
  • Preferred alkylating agent is temozolamide.
  • the compounds of the invention are therefore useful in the treatment of cancers, and particularly cancers that may be treated by anticancer agents selected from alkylating agents, anti-microtubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and antiangiogenic agents, more particularly cancers that may be treated by alkylating agents.
  • anticancer agents selected from alkylating agents, anti-microtubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and antiangiogenic agents, more particularly cancers that may be treated by alkylating agents.
  • Cancers that may be treated by anticancer agents selected from alkylating agents, antimicrotubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and antiangiogenic agents, within the meaning of the present invention include, but are not limited to, glioblastoma, triple-negative breast cancer, lung cancer, osteosarcoma, prostate cancer, ovarian cancer and pancreatic cancer.
  • a preferred cancer that may be treated by alkylating agents is glioblastoma.
  • a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof, in combination with an anticancer agent, for use in treating cancer.
  • the invention thus also relates to a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, in combination with an anticancer agent, in particular an anticancer agent selected from alkylating agents, anti -microtubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and antiangiogenic agents, more particularly an alkylating agent, even more particularity temozolamide, for use in treating cancer, preferably cancers that may be treated by anticancer agents selected from alkylating agents, anti-microtubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and antiangiogenic agents, more particularly a cancer selected from glioblastoma (GB), triplenegative breast cancer, lung cancer, osteosarcoma, prostate cancer, ovarian cancer and pancreatic cancer, even more particularly cancers that may be treated by alkylating agents, still more preferably glioblastoma.
  • an anticancer agent selected from alkylating agents, anti -micro
  • the invention also relates to a method of treating cancer, in particular cancers that may be treated by anticancer agents selected from alkylating agents, anti -microtubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and antiangiogenic agents, more particularly a cancer selected from glioblastoma, triple-negative breast cancer, lung cancer, osteosarcoma, prostate cancer, ovarian cancer and pancreatic cancer, even more particularly cancers that may be treated by alkylating agents, still more particularly glioblastoma, comprising the administration of a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, in combination with an anticancer agent, in particular an anticancer agent selected from alkylating agents, anti -microtubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and antiangiogenic agents, more particularly an alkylating agent, even more particularly temozolamide, to a patient in need
  • the invention further provides the use of a compound of the present invention, or a pharmaceutically acceptable salt or solvates thereof, in combination with an anticancer agent, in particular an anticancer agent selected from alkylating agents, anti -microtubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and anti angiogenic agents, more particularly an alkylating agent, even more particularly temozolamide, for the manufacture of a medicament for use in treating cancer, in particular cancers that may be treated by anticancer agents selected from alkylating agents, anti -microtubule agents, anti metabolites, topoisomerase inhibitors, cytotoxic antibiotics and anti angiogenic agents, more particularly a cancer selected from glioblastoma, triple-negative breast cancer, lung cancer, osteosarcoma, prostate cancer, ovarian cancer and pancreatic cancer, even more particularly cancers that may be treated by an alkylating agent, still more particularly glioblastoma.
  • an anticancer agent selected from al
  • combination it is meant a combined preparation wherein the active ingredients are physically together in the same preparation or physically separated for use in a combined therapy by simultaneous administration or sequential administration to the patient.
  • a compound of the invention or a pharmaceutically acceptable salt or solvate thereof and the anticancer agent are administered to the patient in the same preparation or in a separate form, either simultaneously or sequentially, for the treatment of cancer.
  • a compound of the present invention for use in increasing the sensitivity of cancer cells to an anticancer agent in a treatment of cancer.
  • the invention thus relates to a compound of the present invention, i.e. a compound of Formula I or any of its embodiments, or any of its subformulae as defined above, or a pharmaceutically acceptable salt or solvate thereof, for use in increasing the sensitivity of cancer cells to an anticancer agent, in particular an anticancer agent selected from alkylating agents, anti -microtubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and anti angiogenic agents, more particularly an alkylating agent, still more particularly temozolamide, in a treatment of cancer, in particular cancers that may be treated by anticancer agents selected from alkylating agents, anti -microtubule agents, anti metabolites, topoisomerase inhibitors, cytotoxic antibiotics and anti angiogenic agents, more particularly a cancer selected from glioblastoma, triple-negative breast cancer, lung cancer, osteosarcoma, prostate cancer, ovarian cancer and pancreatic cancer, even more particularly cancer that may
  • the invention also relates to a method for increasing the sensitivity of cancer cells to an anticancer agent, in particular an anticancer agent selected from alkylating agents, anti-microtubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and antiangiogenic agents, more particularly an alkylating agent, even more particularly temozolomide, in a treatment of cancer, in particular cancers that may be treated by anti cancer agents selected from alkylating agents, anti -microtubule agents, anti metabolites, topoisomerase inhibitors, cytotoxic antibiotics and antiangiogenic agents, more particularly a cancer selected from glioblastoma, triple-negative breast cancer, lung cancer, osteosarcoma, prostate cancer, ovarian cancer and pancreatic cancer, even more particularly cancers that may be treated by alkylating agents, still more particularly glioblastoma, comprising the administration of a therapeutically effective amount of a compound of the present invention, i.e.
  • an anticancer agent in particular an anticancer agent selected from alkylating agents, anti -microtubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and antiangiogenic agents, more particularly an alkylating agent, even more particularly temozolamide, to a patient in need thereof.
  • an anticancer agent selected from alkylating agents, anti -microtubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and antiangiogenic agents, more particularly an alkylating agent, even more particularly temozolamide, to a patient in need thereof.
  • the patient is a warm-blooded animal, more preferably a human.
  • the invention further provides the use of a compound of the present invention, i.e. a compound of Formula I or any of its embodiments, or any of its subformulae as defined above, or a pharmaceutically acceptable salt or solvates thereof, for the manufacture of a medicament for use in sensitizing cancer cells to an anticancer agent, in particular an anticancer agent selected from alkylating agents, anti -microtubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and anti angiogenic agents, more particularly an alkylating agent, even more particularly temozolomide, in a treatment of cancer, in particular cancers that may be treated by anticancer agents selected from alkylating agents, anti-microtubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and anti angiogenic agents, more particularly a cancer selected from glioblastoma, triple-negative breast cancer, lung cancer, osteosarcoma, prostate cancer, ovarian cancer and pancreatic cancer, even more
  • a compound of the present invention i.e. a compound of Formula I and any of its embodiments, or any of its subformulae as defined above, or a pharmaceutically acceptable salt or solvate thereof, for inhibiting IRE1 RNase activity, in a patient in need of such treatment, comprising administering to said patient an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof.
  • the invention also provides a method for inhibiting IRE1 RNase activity, in a patient in need of such treatment, which comprises the step of administering to said patient an effective amount of a compound of the present invention, i.e. a compound of Formula I and any of its embodiments, or any of its subformulae as defined above, or a pharmaceutically acceptable salt or solvate thereof.
  • the patient is a warm blooded animal, and even more preferably a human.
  • the invention also relates to a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, for use in treating cancer, preferably cancers that may be treated by anticancer agents selected from alkylating agents, anti -microtubule agents, anti metabolites, topoisomerase inhibitors, cytotoxic antibiotics and anti angiogenic agents, more particularly a cancer selected from glioblastoma (GB), triple-negative breast cancer, lung cancer, osteosarcoma, prostate cancer, ovarian cancer and pancreatic cancer, even more particularly cancers that may be treated by alkylating agents, still more preferably glioblastoma.
  • anticancer agents selected from alkylating agents, anti -microtubule agents, anti metabolites, topoisomerase inhibitors, cytotoxic antibiotics and anti angiogenic agents
  • GB glioblastoma
  • lung cancer osteosarcoma
  • prostate cancer ovarian cancer
  • the invention also relates to a method of treating cancer, in particular cancers that may be treated by anticancer agents selected from alkylating agents, anti -microtubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and anti angiogenic agents, more particularly a cancer selected from glioblastoma, triple-negative breast cancer, lung cancer, osteosarcoma, prostate cancer, ovarian cancer and pancreatic cancer, even more particularly cancers that may be treated by alkylating agents, still more particularly glioblastoma, comprising the administration of a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, to a patient in need of such treatment.
  • the patient is a warm-blooded animal, more preferably a human.
  • the cancers that may be treated by an alkylating agent are preferably those defined above.
  • the invention further provides the use of a compound of the present invention, or a pharmaceutically acceptable salt or solvates thereof, for the manufacture of a medicament for use in treating cancer, in particular cancers that may be treated by anticancer agents selected from alkylating agents, anti -microtubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and antiangiogenic agents, more particularly a cancer selected from glioblastoma, triple-negative breast cancer, lung cancer, osteosarcoma, prostate cancer, ovarian cancer and pancreatic cancer, even more particularly cancers that may be treated by an alkylating agent, still more particularly glioblastoma.
  • the patient is a warm-blooded animal, more preferably a human.
  • the cancers that may be treated by an alkylating agent are preferably those defined above.
  • the compound of the invention or the compound for use according to the invention may be administered as a pharmaceutical formulation in a therapeutically effective amount by any of the accepted modes of administration, preferably by intravenous or oral route.
  • Therapeutically effective amount ranges are typically from 0.1 to 50 000 pg/kg of body weight daily, preferably from 1 000 to 40 000 pg/kg of body weight daily, depending upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound, the route and the form of administration, the indication towards which the administration is directed, and the preferences and experience of the medical practitioner involved.
  • One of ordinary skill in the art of treating such diseases will be able in reliance upon personal knowledge, to ascertain a therapeutically effective amount of the anti cancer agent of the present invention for a given cancer.
  • the compounds of the invention may be administered as part of a combination therapy.
  • a combination therapy comprising coadministration of, and compositions and medicaments which contain, in addition to a compound of the present invention, a pharmaceutically acceptable salt or solvate thereof as active ingredient, additional therapeutic agents and/or active ingredients.
  • Such multiple drug regimens often referred to as combination therapy, may be used in the treatment of cancer, particularly those defined above.
  • the methods of treatment and pharmaceutical compositions of the present invention may employ the compounds of the invention or their pharmaceutical acceptable salts or solvates thereof in the form of monotherapy, but said methods and compositions may also be used in the form of multiple therapy in which one or more compounds of the invention or their pharmaceutically acceptable salts or solvates are co-administered in combination with one or more other therapeutic agents.
  • additional therapeutic agents include, but are not limited to, alkylating agents, and preferably temozolomide.
  • the methods of treatment and pharmaceutical compositions of the present invention may employ the compounds of the present invention, or their pharmaceutical acceptable salts or solvates thereof, in combination with radiation therapy.
  • the compounds of the invention, their pharmaceutical acceptable salts or solvates may be administered in combination with radiation therapy.
  • radiation therapies include, but are not limited to, external beam radiation therapy, brachytherapy and systemic radioisotope therapy.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention, i.e. a compound of Formula I or any of its embodiments, or any of its subformulae as defined above, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant.
  • compositions which contain, in addition to a compound of the present invention, a pharmaceutically acceptable salt or solvate thereof as active ingredient, additional therapeutic agents and/or active ingredients, in particular an anticancer agent.
  • the invention also provides a compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, for use in a therapeutic treatment in humans or animals.
  • Another object of this invention is a medicament comprising at least one compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, as active ingredient.
  • the compounds of the invention may be formulated as a pharmaceutical preparation comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant, and optionally one or more further pharmaceutically active compounds.
  • such a formulation may be in a form suitable for oral administration, for parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), for topical administration (including ocular), cerebral administration, for administration by inhalation, by a skin patch, by an implant, by a suppository, etc.
  • parenteral administration such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion
  • topical administration including ocular
  • cerebral administration for administration by inhalation, by a skin patch, by an implant, by a suppository, etc.
  • suitable administration forms - which may be solid, semi-solid or liquid, depending on the manner of administration - as well as methods and carriers, diluents and excipients for use in the preparation thereof, will be clear to the skilled person; reference is made to the latest edition of Remington’s Pharmaceutical Sciences.
  • the compound of the invention or a pharmaceutical composition comprising a compound of the invention can be administered orally in the form of tablets, coated tablets, pills, capsules, soft gelatin capsules, oral powders, granules, ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications.
  • the tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, a disintegrant such as starch (preferably corn, potato or tapioca starch), sodium starch glycollate, croscarmellose sodium and certain complex silicates, a binder such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia, a lubricant such as magnesium stearate, stearic acid, glyceryl behenate.
  • solid compositions of a similar type may also be employed as fillers in hard gelatin capsules.
  • Preferred excipients in this regard include lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin.
  • Hard gelatin capsules may contain granules of the compound of the invention.
  • Soft gelatin capsules may be prepared with capsules containing the compound of the invention, vegetable oil, waxes, fat, or other suitable vehicle for soft gelatin capsules.
  • the acceptable vehicle can be an oleaginous vehicle, such as a long chain triglyceride vegetable oil (e.g. corn oil).
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water may contain the active ingredient in a mixture with dispersing agents, wetting agents, and suspending agents and one or more preservatives. Additional excipients, for example sweetening, flavouring and colouring agents, may also be present. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Liquid dosage forms for oral administration may include pharmaceutically acceptable, solutions, emulsions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water or an oleaginous vehicle.
  • Liquid dosage form may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, complexing agents such as 2-hydroxypropyl-beta-cyclodextrin, sulfobutylether-beta-cylodextrin, and sweetening, flavouring, perfuming agents, colouring matter or dyes with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
  • adjuvants such as wetting agents, emulsifying and suspending agents, complexing agents such as 2-hydroxypropyl-beta-cyclodextrin, sulfobutylether-beta-cylodextrin, and sweetening, flavouring, perfuming agents, colouring matter or dyes with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
  • These compositions may be preserved by the addition of an antioxidant such as
  • examples of such administration include one or more of: intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly or subcutaneously administering the agent; and/or by using infusion techniques.
  • the compound of the invention can be administered via the parenteral route with a readily available or a depot-type formulation.
  • compositions for the parenteral administration of a readily available formulation may be in the form of a sterile injectable aqueous or oleagenous solution or suspension in a non-toxic parenterally-acceptable diluent or solvent and may contain formulatory agents such as suspending, stabilising dispersing, wetting and/or complexing agents such as cyclodextrin e.g. 2-hydroxypropyl-beta-cyclodextrin, sulfobutylether-beta- cylodextrin.
  • formulatory agents such as suspending, stabilising dispersing, wetting and/or complexing agents such as cyclodextrin e.g. 2-hydroxypropyl-beta-cyclodextrin, sulfobutylether-beta- cylodextrin.
  • the depot-type formulation for the parenteral administration may be prepared by conventional techniques with pharmaceutically acceptable excipient including without being limited to, biocompatible and biodegradable polymers (e.g. poly(P-caprolactone), polyethylene oxide), poly(gly colic acid), poly [(lactic acid)-co-(gly colic acid)...)], poly(lactic acid)...), non-biodegradable polymers (e.g. ethylene vinylacetate copolymer, polyurethane, polyester(amide), polyvinyl chloride%) aqueous and non-aqueous vehicles (e.g.
  • biocompatible and biodegradable polymers e.g. poly(P-caprolactone), polyethylene oxide), poly(gly colic acid), poly [(lactic acid)-co-(gly colic acid)...)], poly(lactic acid)
  • non-biodegradable polymers e.g. ethylene vinylacetate copolymer, polyurethane, polyester(amide), polyvinyl chloride
  • the active ingredient may be in dry form such as a powder, crystalline or freeze-dried solid for constitution with a suitable vehicle.
  • suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
  • the compound of the present invention can be administered intranasally or by inhalation and is conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray or nebuliser with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, di chlorotetrafluoroethane, (for example from Ineos Fluor), carbon dioxide or other suitable gas.
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, di chlorotetrafluoroethane, (for example from Ineos Fluor), carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurised container, pump, spray or nebuliser may contain a solution or suspension of the active compound.
  • Capsules and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound and a suitable powder base such as lactose or starch.
  • a suitable powder base such as lactose or starch.
  • the compound or salt of the invention is in a particle-size-reduced form, and more preferably the size-reduced form is obtained or obtainable by micronisation.
  • the preferable particle size of the size-reduced (e.g. micronised) compound or salt or solvate is defined by a D50 value of about 0.5 to about 50 microns (for example as measured using laser diffraction).
  • the compound of the present invention can be administered in the form of a suppository or pessary, or it may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder.
  • the compound of the present invention may also be dermally or transdermally administered, for example, by the use of a skin patch. They may also be administered by the pulmonary or rectal routes. It may also be administered by the ocular route.
  • the compound can be formulated as micronised suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzylalkonium chloride. Alternatively, it may be formulated in an ointment such as petrolatum.
  • the agent of the present invention can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • it can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • any reference to compounds of the invention herein means the compounds as such as well as their pharmaceutically acceptable salts and solvates.
  • unsubstituted means that a radical, a group or a residue carries no substituents.
  • substituted means that a radical, a group or a residue carries one or more substituents.
  • halo refers to the atoms of the group 17 of the periodic table (halogens) and includes in particular fluorine, chlorine, bromine and iodine atom. Preferred halo groups in the context of the invention are fluoro and iodo, fluoro being particularly preferred.
  • alkyl by itself or as part of another substituent refers to a hydrocarbyl group of Formula CnEhn+i wherein n is a number greater than or equal to 1.
  • Alkyl groups may thus comprise 1 or more carbon atoms and generally, according to this invention comprise from 1 to 12, more preferably from 1 to 8 carbon atoms, and still more preferably from 1 to 6 carbon atoms.
  • Alkyl groups within the meaning of the invention may be linear or branched.
  • alkyl groups include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopenyl, isopentyl, sec-pentyl, tert-pentyl, n-hexyl, neohexyl, isohexyl, sec-hexyl and tert-hexyl.
  • Particular examples of alkyl groups in the context of the invention include methyl, ethyl, isopropyl and tert-butyl.
  • haloalkyl alone or in combination, refers to an alkyl group having the meaning as defined above wherein one or more hydrogens are replaced with a halogen as defined above.
  • Non -limiting examples of such haloalkyl groups include chloromethyl, 1- bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1 -trifluoroethyl and the like.
  • cycloalkyl as used herein is a monovalent, saturated, or unsaturated monocyclic or bicyclic hydrocarbyl group.
  • Cycloalkyl groups may comprise 3 or more carbon atoms in the ring and generally, according to this invention comprise from 3 to 10, more preferably from 3 to 8 carbon atoms, and still more preferably from 3 to 6 carbon atoms.
  • Examples of cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • heteroatom refers to any atom that is not carbon or hydrogen.
  • Non-limiting examples of such heteroatoms include nitrogen, oxygen, sulfur, and phosphorus.
  • Preferred heteroatoms according to the invention are nitrogen, oxygen and sulfur.
  • heterocyclyl refers to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3- to 7-membered monocyclic, 7- to 11-membered bicyclic, or containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom-containing ring.
  • Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized.
  • heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows.
  • heterocyclyl groups include but are not limited to aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, piperazinyl, morpholinyl.
  • aryl refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (e.g. phenyl) or multiple aromatic rings fused together (e.g. naphthyl), typically containing 5 to 12 atoms; preferably 6 to 10, wherein at least one ring is aromatic.
  • aryl groups include but are not limited to phenyl, biphenyl, 1 -naphthyl (or naphthal ene-l-yl), 2-naphthyl (or naphthalene-2-yl), anthracenyl, indanyl, indenyl, 1, 2,3,4- tetrahydronaphthyl .
  • heteroaryl refers but is not limited to 5 to 12 carbon-atom aromatic rings or ring systems containing 1 to 2 rings which are fused together, each ring typically containing 5 to 6 atoms; at least one of which is aromatic, in which one or more carbon atoms in one or more of these rings is replaced by oxygen, nitrogen and/or sulfur atoms where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quatemized.
  • heteroaryl groups include but are not limited to pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, furanyl, benzofuranyl, pyrrolyl, indolyl, thiophenyl, benzothiophenyl, imidazolyl, benzimidazolyl, pyrazolyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzisoxazolyl, thiazolyl, and benzothiazolyl, triazolyl, oxadi azolyl, thiadi azolyl, di oxazolyl, di thiazolyl and tetrazolyl.
  • the compounds of the invention containing a basic functional group may be in the form of pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts of the compounds of the invention containing one or more basic functional groups include in particular the acid addition salts thereof. Suitable acid addition salts are formed from acids which form nontoxic salts.
  • Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/ carbonate, bi sulphate/ sulphate, borate, camsylate, cinnamate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tanna
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionization in the salt may vary from completely ionized to almost non-ionized.
  • solvate is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • solvent molecules for example, ethanol.
  • hydrate is employed when said solvent is water.
  • the compounds of the invention include compounds of the invention as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) and isotopically-labeled compounds of the invention.
  • salts of the compounds of the invention are preferred, it should be noted that the invention in its broadest sense also includes non-pharmaceutically acceptable salts, which may for example be used in the isolation and/or purification of the compounds of the invention.
  • non-pharmaceutically acceptable salts which may for example be used in the isolation and/or purification of the compounds of the invention.
  • salts formed with optically active acids or bases may be used to form diastereoisomeric salts that can facilitate the separation of optically active isomers of the compounds of the invention.
  • patient refers to a warm-blooded animal, more preferably a human, who/which is awaiting or receiving medical care or is or will be the object of a medical procedure.
  • human refers to subjects of both genders and at any stage of development (i.e. neonate, infant, juvenile, adolescent, adult). In one embodiment, the human is an adolescent or adult, preferably an adult.
  • treat are meant to include alleviating or abrogating a condition or disease and/or its attendant symptoms.
  • therapeutically effective amount means the amount of active agent or active ingredient which is sufficient to achieve the desired therapeutic or prophylactic effect in the individual to which it is administered.
  • administration means providing the active agent or active ingredient, alone or as part of a pharmaceutically acceptable composition, to the patient in whom/which the condition, symptom, or disease is to be treated.
  • pharmaceutically acceptable is meant that the ingredients of a pharmaceutical composition are compatible with each other and not deleterious to the patient thereof.
  • excipient means a substance formulated alongside the active agent or active ingredient in a pharmaceutical composition or medicament. Acceptable excipients for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington’s Pharmaceutical Sciences, 21 st Edition 2011. The choice of excipient can be selected with regard to the intended route of administration and standard pharmaceutical practice. The excipient must be acceptable in the sense of being not deleterious to the recipient thereof.
  • the at least one pharmaceutically acceptable excipient may be for example, a binder, a diluent, a carrier, a lubricant, a disintegrator, a wetting agent, a dispersing agent, a suspending agent, and the like.
  • pharmaceutical vehicle means a carrier or inert medium used as solvent or diluent in which the pharmaceutically active agent is formulated and/or administered.
  • pharmaceutical vehicles include creams, gels, lotions, solutions, and liposomes.
  • cancer refers to the physiological condition in subjects that is characterized by unregulated or dysregulated cell growth with the potential to invade or spread to other parts of the body.
  • cancer includes solid tumors and blood born tumors, whether malignant or benign.
  • cancer examples include, but are not limited to: Acinar adenocarcinoma, acinar carcinoma, acral-lentiginous melanoma, actinic keratosis, adenocarcinoma, adenocystic carcinoma, adenosquamous carcinoma, adnexal carcinoma, adrenal rest tumor, adrenocortical carcinoma, aldosterone secreting carcinoma, alveolar soft part sarcoma, amelanotic melanoma, ameloblastic thyroid carcinoma, angiosarcoma, apocrine carcinoma, Askin’s tumor, astrocytoma, basal cell carcinoma, basaloid carcinoma, basosquamous cell carcinoma, biliary cancer, bone cancer, bone marrow cancer, botryoid sarcoma, brain cancer, breast cancer, bronchioalveolar carcinoma, bronchogenic adenocarcinoma, bronchogenic carcinoma, carcinoma ex pleomorphic adenom
  • anticancer agent refers to a chemical agent used to treat cancer, administered in regimens of one or more cycles, alone or combined with one or more agents over a period of days to weeks. Such agents are toxic to cells with high proliferative rates, such as cancer cells.
  • anticancer agents include, but are not limited to: alkylating agents, such as for example cyclophosphamide, mechlorethamine, chlorambucil, melphalan, dacarbazine, dacarbazine, nitrosoureas or temozolomide; anti metabolites, including antifolates, such as for example methotrexate, pemetrexed, pralatrexate or trimetrexate; pyrimidine analogues, such as for example azacitidine, capecitabine, cytarabine, decitabine, floxurinine, fluorouracil, gemcitabine or trifluridine; and purine analogues such as for example azathioprine, cladribine, fludarabine, mercaptopurine or tioguanine (formerly thioguanine); anti -microtubule agents, including taxanes, such as for example paclitaxel, docetaxel,
  • topoisomerase inhibitors including inhibitors of topoisomerase I, such as for example irinotecan or topotecan; and inhibitors of topoisomerase II, such as for example etoposide, teniposide or tafluposide; epothilones; histone deacetylase inhibitors, such as for example vorinostat, romidepsin, panobinostat or quisinostat; kinase inhibitors, such as for example afatinib, avitinib, bortezomib, carfilzomib, dabrafenib, erlotinib, gefitinib, imatinib, osimertinib, vemurafenib or vismodegib; platinum-based agents, such as for example carboplatin, cisplatin or oxaliplatin; proteasome inhibitors, such as for example bortezomib
  • Preferred anticancer agents according to the invention are alkylating agents.
  • Preferred anti cancer agent according to the invention is temozolomide.
  • DiPE diisopropylethylether
  • DIPEA diisopropylethylamine
  • DPPA diphenylphosphoryl azide
  • EGTA ethylene glycol-bis(P-aminoethyl ether)-A, N, N', N' -tetraacetic acid eq. or equiv. : equivalent;
  • PE petroleum ether
  • ppm parts per million
  • r.t. or rt room temperature
  • TFA trifluoroacetic acid
  • Silica-gel column chromatography was carried out using silica gel (particle size 40-63 pm) with isocratic or step gradient elution as indicated. Automated flash column chromatography was carried out on an Interchim PuriFlash 450 using FlashPure Ecoflex silica cartridges (irregular particle size 50 pm). NMR spectra were acquired on 300/400/500 MHz spectrometers and were referenced to the residual solvent. All chemical shifts are reported in parts per million (ppm).
  • the carboxylic acid (1.0 eq.) was added in a round-bottom dry flask equipped with a magnetic stirring bar under argon. Toluene was then added (6 mL / mmol) followed by EtsN (1.05 eq.). The mixture was stirred under argon at room temperature during 10 min and DPPA (1.05 eq.) was added. The mixture was stirred at room temperature overnight. Then, 2,5-dimethylaniline (1.1 eq.) was added and the mixture was stirred under argon at reflux during few hours. After completion, the mixture is concentrated under vacuo to obtain the crude product. The product obtained was then purified via silica column chromatography to afford the desired product.
  • Triethylamine (21.40 mmol, 1.5 equiv., 2.98 mL) was added in a solution of but-3-yn-2-ol (14.27 mmol, 1.0 equiv., 1.129 mL, 1.0 g) in DCM (10 mL). The resulting solution was cooled to 0°C and mesyl chloride (17.12 mmol, 1.2 equiv., 1.33 mL, 1.96 g) was added dropwise. The mixture was allowed to reach ambient temperature and stirred for 4h.
  • But-3-yn-2-yl methanesulfonate Al (14.62 mmol, 1.0 equiv., 2.16 g) was stirred for 18h with aqueous NH3 (5.3 ml) at 25/30°C.
  • the resulting mixture was diluted with DCM (10 mL) and H2O (10 mL), the organic layer was separated and dried over MgSCh. The organic layer was set up to reflux for 2h30, until the vapour above the double condenser no longer gave a positive alkali test.
  • EXAMPLE 1 methyl 4-(3-(3-(2,5-dimethylphenyl)ureido)but-1-yn-1-yl)benzoate 1 According to TP2 Bis with 1-(but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea A3 (0.231 mmol, 1.0 equiv., 50 mg) and methyl 4-iodobenzoate (0.277 mmol, 1.2 equiv., 73 mg), THF (2 mL) as solvent and the resulting solution was heated at 50°C overnight.
  • EXAMPLE 2 1-(4-(3-acetylphenyl)but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea 2 According to TP2 Bis with 1-(but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea A3 (0.231 mmol, 1.0 equiv., 50 mg) and 1-(3-iodophenyl)ethanone (0.277 mmol, 1.2 equiv., 68 mg), THF (2 mL) as solvent and the resulting solution was heated at 50°C overnight.
  • EXAMPLE 3 1-(2,5-dimethylphenyl)-3-(4-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6- yl)but-3-yn-2-yl)urea 3 According to TP2 Bis with 1-(but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea A3 (0.231 mmol, 1.0 equiv., 50 mg) and 6-bromo-3,4-dihydroisoquinolin-1(2H)-one (0.277 mmol, 1.2 equiv., 52 mg), DMF (2 mL) as solvent and the resulting solution was heated at 90°C for 2 hours.
  • EXAMPLE 5 1-(2,5-dimethylphenyl)-3-(4-(2-oxo-1,2,3,4-tetrahydroquinolin-5-yl)but- 3-yn-2-yl)urea 5 According to TP2 Bis with 1-(but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea A3 (0.231 mmol, 1.0 equiv., 50 mg) and 5-Bromo-3,4-dihydroquinolin-2(1H)-one (0.277 mmol, 1.2 equiv., 52 mg), DMF (2 mL) as solvent and the resulting solution was heated at 90°C for 2 hours.
  • EXAMPLE 6 1-(2,5-dimethylphenyl)-3-(4-(1-oxo-1,2-dihydroisoquinolin-6-yl)but-3- yn-2-yl) urea 6 According to TP2 Bis with 1-(but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea A3 (0.231 mmol, 1.0 equiv., 50 mg) and 6-Bromoisoquinolin-1(2H)-one (0.277 mmol, 1.2 equiv., 52 mg), DMF (2 mL) as solvent and the resulting solution was heated at 90°C for 2 hours.
  • EXAMPLE 7 1-(4-(1H-indazol-5-yl)but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea 7 According to TP2 Bis with 1-(but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea A3 (0.231 mmol, 1.0 equiv., 50 mg) and 5-bromo-1H-indazole (0.277 mmol, 1.2 equiv., 45 mg), DMF (2 mL) as solvent and the resulting solution was heated at 90°C for 2 hours.
  • EXAMPLE 8 1-(2,5-dimethylphenyl)-3-(4-(3-methyl-1H-indazol-5-yl)but-3-yn-2- yl)urea 8 According to TP2 Bis with 1-(but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea A3 (0.231 mmol, 1.0 equiv., 50 mg) and 5-bromo-3-methyl-1H-indazole (0.277 mmol, 1.2 equiv., 49 mg), DMF (2 mL) as solvent and the resulting solution was heated at 90°C for 2 hours.
  • EXAMPLE 9 1-(4-(1H-pyrazolo[4,3-c]pyridin-4-yl)but-3-yn-2-yl)-3-(2,5- dimethylphenyl)urea 9 According to TP2 Bis with 1-(but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea A3 (0.231 mmol, 1.0 equiv., 50 mg) and 4-bromo-1H-pyrazolo[4,3-c]pyridine (0.277 mmol, 1.2 equiv., 46 mg), DMF (2 mL) as solvent and the resulting solution was heated at 90°C for 2 hours.
  • EXAMPLE 10 1-(4-(2H-indazol-5-yl)but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea 10 According to TP2 Bis with 1-(but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea A3 (0.231 mmol, 1.0 equiv., 50 mg) and 5-bromo-2H-indazole (0.277 mmol, 1.2 equiv., 46 mg), DMF (2 mL) as solvent and the resulting solution was heated at 90°C for 2 hours.
  • EXAMPLE 12 1-(4-(1H-indazol-6-yl)but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea 12 According to TP2 Bis with 1-(but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea A3 (0.231 mmol, 1.0 equiv., 50 mg) and 6-bromo-1H-indazole (0.277 mmol, 1.2 equiv., 45 mg), DMF (2 mL) as solvent and the resulting solution was heated at 90°C for 2 hours.
  • EXAMPLE 13 1-(2,5-dimethylphenyl)-3-(1-(4-hydroxyphenyl)-1H-indazol-3-yl)urea 13 STEP 1: Synthesis of compound B1 According to TP2, methyl 1H-indazole-3-carboxylate (400 mg, 2.27 mmol, 1.0 eq.), 4- methoxyphenylboronic acid (690 mg, 4.54 mmol, 2 eq.) and CuOAc2.H2O (681 mg, 3.41 mmol, 1.5 eq.) were dissolved in DCM (40 mL). Et3N (0.61 mL, 4.54 mmol, 2.0 eq.) was added and the mixture was stirred at room temperature during 2h.
  • EXAMPLE 14 1-(2,5-dimethylpyridin-3-yl)-3-(1-(4-hydroxyphenyl)-1H-indol-3- yl)urea 14 STEP 1: Synthesis of compound C1 In a round-bottom dry flask, under argon, were successively added methyl 1H-indole-3- carboxylate (300 mg, 1.71 mmol, 1.0 eq.), 4-iodoanisole (521 mg, 2.23 mmol, 1.3 eq.), CuI (33 mg, 10 mol%) K 3 PO 4 (693 mg, 3.423 mmol, 2.0 eq.) and trans-1,2-diaminocyclohexane (20 ⁇ L, 10 mol%) in 1,4-dioxane (4 mL).
  • STEP 2 Synthesis of compound C2 To a solution of compound C1 (100 mg, 0.35 mmol, 1.0 eq.) in THF (1 mL) and MeOH (0.5 mL) at room temperature was added 1N aqueous NaOH solution (0.9 mL, 0.9 mmol, 2.5 eq.). The solution was stirred to 50°C overnight. After completion (monitored by TLC), the mixture was allowed to return at room temperature and was acidified using 1N aqueous HCl.
  • the crude product was purified via silica column chromatography with a mixture of DCM/MeOH (100/0 to 95/5) to obtain the desired urea C4 as a light-yellow solid (54 mg, 41%).
  • Rf (DCM/MeOH, 95/5) 0.3.
  • EXAMPLE 15 1-(2,5-dimethylphenyl)-N-(4-(4-hydroxyphenyl)butan-2- yl)methanesulfonamide
  • STEP 1 Synthesis of (2,5-dimethylphenyl)methanesulfonyl chloride D1 In an oven dry round bottom flask, under argon, were added 2-(chloromethyl)-1,4- dimethylbenzene (3.23 mmol, 1.0 equiv., 0.48 mL) and thiourea (3.23 mmol, 1.0 equiv., 0.25 g) in absolute EtOH (5 mL) and refluxed at 80°C.
  • STEP 2 Synthesis of 1-(4-((tert-butyldimethylsilyl)oxy)phenyl)-1H-indol-4-amine 1-(4-((tert-butyldimethylsilyl)oxy)phenyl)-4-nitro-1H-indole (0.768 g, 2,08 mmol, 1.0 eq.) and Pd/C (80 mg, 10 mol%) were dissolved in EtOH (20 mL) in a two-necked round-bottom flask. The mixture was purged with argon (5 min) and stirred at 0°C.
  • STEP 3 Synthesis of 1-(1-(4-((tert-butyldimethylsilyl)oxy)phenyl)-1H-indol-4-yl)-3-(2,5- dimethylphenyl)urea 1-(4-((tert-butyldimethylsilyl)oxy)phenyl)-1H-indol-4-amine (50 mg, 0.148 mmol, 1.0 eq.) was dissolved in DCM (2 mL) under argon and 2-isocyanato-1,4-dimethylbenzene (21 ⁇ L, 0.148 mmol, 1.0 eq.) was added dropwise.
  • STEP 4 Synthesis of 1-(2,5-dimethylphenyl)-3-(1-(4-hydroxyphenyl)-1H-indol-4-yl)urea
  • 1-(2,5-dimethylphenyl)-3-(1-(4-hydroxyphenyl)-1H-indol-4-yl)urea (30 mg, 0.062 mmol, 1.0 eq.) was dissolved in dry THF (0.63 mL) at 0°C under argon. Then, a solution of TBAF in THF (1M, 0.37 mL, 6 eq.) was added dropwise and the mixture was stirred at room temperature during 1h.
  • EXAMPLE 17 1-(2,5-dimethylphenyl)-N-(1-(4-hydroxyphenyl)-1H-indol-4- yl)methanesulfonamide
  • STEP 1 Synthesis of N-(1-(4-((tert-butyldimethylsilyl)oxy)phenyl)-1H-indol-4-yl)-1-(2,5- dimethylphenyl)methanesulfonamide
  • 1-(4-((tert-butyldimethylsilyl)oxy)phenyl)-1H-indol-4-amine 200 mg, 0.59 mmol, 1.0 eq.
  • pyridine 3 mL
  • (2,5-dimethylphenyl)methanesulfonyl chloride (128 ⁇ L, 0.59 mmol, 1.0 eq.
  • N-(1-(4-((tert-butyldimethylsilyl)oxy)phenyl)-1H-indol-4-yl)-1-(2,5- dimethylphenyl)methanesulfonamide (223 mg, 0.43 mmol, 1.0 eq.) was dissolved in dry THF (10 mL) at 0°C under argon. Then, a solution of TBAF in THF (1M, 0.47 mL, 1.1 eq.) was added dropwise and the mixture was stirred at room temperature during 2h. Then, the mixture was diluted with EtOAc (30 mL) and washed with water (20 mL) and brine (20 mL).
  • BIOLOGICAL EVALUATION Materials and methods Materials – IRE1 wild-type recombinant protein encoding the cytoplasmic domain (amino acids 465–977) with N-terminal polyhistidine-tag and GST tag was from Sinobiological (Sino Biological Europe GmbH, Eschborn, Germany, #11905-H20B). The fluorescent probe used for the in vitro IRE1 RNase assay was from Eurogentec. Tunicamycin was purchased from Calbiochem (Merck KGaA, Darmstadt, Germany).
  • IRE1-mediated in vitro RNase assay – Inhibitors were diluted in minimal volume of DMSO and subsequently re-diluted in reaction buffer (20 mM HEPES pH 7.5; 1 mM MgOAc; 50 mM KOAc). Maximum volume of DMSO per reaction never exceeded 1%. Reaction volume was 25 ⁇ L. Recombinant IRE1 (0.6 ⁇ g/ reaction) was incubated at room temperature for 10 minutes with varying concentrations (0-100 ⁇ M) of inhibitor and reaction buffer.
  • FRET fluorescence resonance energy transfer
  • Luciferase assays were seeded in 96-well plate. Cells were treated with increasing concentration of inhibitors. Medium was discarded and the plate was tapped to remove residual medium. 100 ⁇ L of lysis buffer (25 mM Tricine pH 7.8; 15 mM Potassium Phosphate pH 7.8; 15 mM MgSO4; 4 mM EGTA; 1% Triton X-100; 1 mM DTT) were added per well and incubated for 20 minutes at RT.50 ⁇ L were transferred to a white 96-well plate and 50 ⁇ L of substrate buffer (25 mM Tricine pH 7.8; 15 mM Potassium Phosphate pH 7.8; 15 mM MgSO4; 4 mM EGTA; 1% Triton X-100; 1 mM DTT; 1 mM ATP; 0.2 mM luciferin) were added in each well and the luminescence was read. Results IRE1-mediated in vitr

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Abstract

Les inventeurs ont réussi à développer des composés d'urée, d'amide ou de sulfonamide, en particulier des composés d'urée, portant deux groupes latéraux, dont l'un porte une fraction dialkylaryle, en particulier une fraction dialkylphényle ou dialkylpyridinyle. Ces composés présentent l'avantage d'inhiber l'activité de la ribonucléase IRE1 et de sensibiliser des cellules cancéreuses, en particulier des cellules GB, en chimiothérapie. La présente invention concerne des composés d'urée, d'amide ou de sulfonamide, en particulier des composés d'urée, portant deux groupes latéraux, dont l'un porte une fraction dialkylaryle, en particulier une fraction dialkylphényle ou dialkylpyridinyle, y compris leurs sels et solvates pharmaceutiquement acceptables qui sont utiles en tant que sensibilisateurs pour la chimiothérapie de cellules cancéreuses, en particulier dans le glioblastome, et sont utiles en tant que composés thérapeutiques, en particulier dans le traitement de cancers qui peuvent être traités par des agents alkylants, tels que le témozolomide.
PCT/EP2024/069050 2023-07-05 2024-07-05 Composés contenant une fraction dialkylaryle et leur utilisation Ceased WO2025008526A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2023131677A1 (fr) * 2022-01-07 2023-07-13 INSERM (Institut National de la Santé et de la Recherche Médicale) Composés contenant une fraction hydroxyphényle et leur utilisation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023131677A1 (fr) * 2022-01-07 2023-07-13 INSERM (Institut National de la Santé et de la Recherche Médicale) Composés contenant une fraction hydroxyphényle et leur utilisation

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PELIZZARI-RAYMUNDO DIANA ET AL: "A novel blood brain barrier-permeable IRE1 kinase inhibitor sensitizes glioblastoma to chemotherapy in mice.", CHEMRXIV, 11 January 2022 (2022-01-11), pages 1 - 30, XP055935455, Retrieved from the Internet <URL:https://chemrxiv.org/engage/chemrxiv/article-details/61d97d56db142ef572b84e87> [retrieved on 20220625], DOI: 10.26434/chemrxiv-2022-2ld35 *
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