WO2017079864A1 - Traitement de cancers associés à un gène ras chroniquement actif - Google Patents

Traitement de cancers associés à un gène ras chroniquement actif Download PDF

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WO2017079864A1
WO2017079864A1 PCT/CN2015/000788 CN2015000788W WO2017079864A1 WO 2017079864 A1 WO2017079864 A1 WO 2017079864A1 CN 2015000788 W CN2015000788 W CN 2015000788W WO 2017079864 A1 WO2017079864 A1 WO 2017079864A1
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ras
membered
compound
cancer
aliphatic
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PCT/CN2015/000788
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English (en)
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Zhiwei Jiang
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Hangzhou Yier Biotech Co., Ltd.
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Priority to PCT/CN2015/000788 priority Critical patent/WO2017079864A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates that naphthofuranquinones and dihydroxynaphthofurans, and derivatives thereof, such as a compound of formula I or II, are effective in deactivating chronically active Ras.
  • the present invention also relates a method of treating or preventing cancer comprising steps of: 1) identifying a patient suffering from or susceptible to a cancer related to chronically active Ras; and 2) administering a therapeutically effective amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof.
  • the present invention further relates a method of treating or preventing cancer comprising steps of: 1) identifying a patient suffering from or susceptible to a cancer related to a K-Ras mutation; and 2) administering a therapeutically effective amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof.
  • the present invention provides improved methods for effective treatment of cancers related to chronically active Ras, which are often malignant and refractory to currently available therapies, such as those based on EGFR inhibitors.
  • the present invention is, in part, based on the discovery that naphthofuranquinones and dihydroxynaphthofurans, and derivatives thereof, such as a compound of formula I or II, are effective in deactivating chronically active Ras.
  • the present invention provides effective methods of treating cancers related to chronically active Ras based on a compound of formula I or II, or a pharmaceutically acceptable salt thereof.
  • the present invention is particularly effective in treating refractory cancers, including cancers refractory to treatments based on EGFR inhibitors. In some embodiments, the present invention provides methods of treating cancers for which there were no effective treatments prior to the present invention.
  • the present invention provides a method of treating or preventing cancer comprising a step of administering to a subject suffering from or susceptible to a cancer related to chronically active Ras a therapeutically effective amount of a compound of formula I or II:
  • n 0-4;
  • each R 1 is independently halogen; -NO 2 ; -CN; -OR; -SR; -N + (R) 3 ; -N (R) 2 ; -C (O) R; -CO 2 R; -S (O) R; -S (O) 2 R; -C (O) N (R) 2 ; -SO 2 N (R) 2 ; -OC (O) R; or an optionally substituted group selected from C 1-12 aliphatic; 3-to 14-membered carbocyclyl; 3-to 14-membered heterocyclyl; 6-to 14-membered aryl; or 5-to 14-membered heteroaryl;
  • each R a and R b is independently hydrogen, sodium, potassium, amine cation, or an optionally substituted group selected from C 1-12 aliphatic; 3-to 14-membered carbocyclyl; 3-to 14-membered heterocyclyl; 6-to 14-membered aryl; or 5-to 14-membered heteroaryl;
  • R c is an optionally substituted group selected from C 1-12 aliphatic; 3-to 14-membered carbocyclyl; 3-to 14-membered heterocyclyl; 6-to 14-membered aryl; or 5-to 14-membered heteroaryl;
  • R 4 is hydrogen; halogen; -NO 2 ; -OR; -SR; -N + (R) 3 ; -N (R) 2 ; -C (O) R; -CO 2 R; or an optionally substituted group selected from C 1-12 aliphatic; 3-to 14-membered carbocyclyl; 3-to 14-membered heterocyclyl; 6-to 14-membered aryl; or 5-to 14-membered heteroaryl;
  • each R is independently hydrogen or an optionally substituted group selected from C 1-12 aliphatic; 3-to 14-membered carbocyclyl; 3-to 14-membered heterocyclyl; a 6-to 14-membered aryl; or 5-to 14-membered heteroaryl.
  • the present invention provides a method of treating or preventing cancer comprising steps of: 1) identifying a patient suffering from or susceptible to a cancer related to chronically active Ras; and 2) administering a therapeutically effective amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof.
  • the chronically active Ras is caused by a Ras mutation.
  • the chronically active Ras is H-Ras, K-Ras or N-Ras.
  • the chronically active Ras is K-Ras.
  • the present invention provides a method of treating or preventing cancer comprising a step of administering to a subject suffering from or susceptible to a refractory cancer a therapeutically effective amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof.
  • the cancer is refractory to treatment with an EGFR inhibitor.
  • the present invention provides a method of treating or preventing cancer, comprising administering to a subject suffering from or susceptible to cancer a compound of formula I or II, or a pharmaceutically acceptable salt thereof, in conjunction with an EGFR inhibitor.
  • the EGFR inhibitor is administered prior to, concurrently with, or subsequently to the compound of formula I or II, or a pharmaceutically acceptable salt thereof.
  • the cancer is related to chronically active Ras.
  • the EGFR inhibitor is a small molecule inhibitor.
  • the EGFR inhibitor is gefitinib or erlotinib.
  • the EGFR inhibitor is a monoclonal antibody.
  • the EGFR inhibitor is cetuximab or panitumumab.
  • the EGFR inhibitor inhibits a target other than EGFR.
  • the EGFR inhibitor is lapatinib.
  • the cancer is a cancer selected from Table 1.
  • the cancer is lung cancer.
  • the cancer is colon cancer.
  • the cancer is pancreatic cancer.
  • R 2 is–C (O) R c .
  • R 3 is–C (O) R c .
  • n is 0.
  • R 1 is halogen or –CF 3 .
  • R 4 is hydrogen.
  • R 5 is–C (O) R.
  • the compound is selected from Tables 2 and 3, or a pharmaceutically acceptable salt thereof.
  • the compound is compound I or VII, or a pharmaceutically acceptable salt thereof.
  • the compound is compound XII, XIII, XV or XVI, or a pharmaceutically acceptable salt thereof.
  • FIG. 1 Western blot analysis of K-Ras protein in A549 lung cancer cell lines with treatment of 2 ⁇ M compound XIII for different times as indicated or without treatment of the compound as control.
  • A Active K-Ras associated with GTP was pulled out from the freshly prepared cell lysate by Ras Assay Reagent (Raf-1 RBD, agarose, Ras Activation Assay Kit, Millipore, Cat#17-218) ;
  • Ras Assay Reagent Ras Assay Reagent
  • K-Ras associated with GTP ⁇ S was pulled out from the GTP ⁇ S incubated cell lysate by Ras Assay Reagent (same as A) ;
  • C Total K-Ras in cell lysate, ⁇ -actin as reference.
  • FIG. 1 Western blot analysis of K-Ras protein in SW480 colon cancer cell lines with treatment of 2 ⁇ M 2-acetyl-naphtho [2, 3-b] furan-4, 9-dione (compound XIII) for different times as indicated or without treatment of the compound as control.
  • A Active K-Ras associated with GTP was pulled out from the freshly prepared cell lysate by Ras Assay Reagent (Raf-1 RBD, agarose, Ras Activation Assay Kit, Millipore, Cat#17-218) ;
  • B K-Ras associated with GTP ⁇ S was pulled out from the GTP ⁇ S incubated cell lysate by Ras Assay Reagent (same as A) ;
  • C Total K-Ras in cell lysate, ⁇ -actin as reference.
  • FIG. 3 Western blot analysis of K-Ras protein in SW620 colon cancer cell lines with treatment of 2 ⁇ M 2-acetyl-naphtho [2, 3-b] furan-4, 9-dione (compound XIII) for different times as indicated or without treatment of the compound as control.
  • A Active K-Ras associated with GTP was pulled out from the freshly prepared cell lysate by Ras Assay Reagent (Raf-1 RBD, agarose, Ras Activation Assay Kit, Millipore, Cat#17-218) ;
  • C Total K-Ras in cell lysate, ⁇ -actin as reference.
  • FIG. 4 Western blot analysis of K-Ras protein in H1299 lung cancer cell lines with treatment of 2 ⁇ M 2-acetyl-naphtho [2, 3-b] furan-4, 9-dione (compound XIII) for different times as indicated or without treatment of the compound as control.
  • A Active K-Ras associated with GTP was pulled out from the freshly prepared cell lysate by Ras Assay Reagent (Raf-1 RBD, agarose, Ras Activation Assay Kit, Millipore, Cat#17-218) ;
  • C Total K-Ras in cell lysate, ⁇ -actin as reference.
  • FIG. 1 Western blot analysis of K-Ras protein in HT29 colon cancer cell lines with treatment of 2 ⁇ M 2-acetyl-naphtho [2, 3-b] furan-4, 9-dione (compound XIII) for different times as indicated or without treatment of the compound as control.
  • A Active K-Ras associated with GTP was pulled out from the freshly prepared cell lysate by Ras Assay Reagent (Raf-1 RBD, agarose, Ras Activation Assay Kit, Millipore, Cat#17-218) ;
  • C Total K-Ras in cell lysate, ⁇ -actin as reference.
  • FIG. 1 Western blot analysis of K-Ras protein in SW480 colon cancer cell lines with treatment of 3 ⁇ M 2-acetyl-4, 9-bis (acetoxy) -naphtho [2, 3-b] furan (compound III, 118) or 4 ⁇ M 2- (1-hydroxy-ethyl) -naphtho [2, 3-b] furan-4, 9-dione (compound XII, 1005) for different times as indicated or without treatment of the compound as control.
  • FIG. 7 Western blot analysis of activated Akt in A549 lung cancer cell lines with treatment of 2 ⁇ M 2-acetyl-naphtho [2, 3-b] furan-4, 9-dione (compound XIII) for different times as indicated or without treatment of the compound as control.
  • aliphatic or “aliphatic group, ” as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle, ” “cycloaliphatic” or “cycloalkyl” ) , that has a single point of attachment to the rest of the molecule.
  • aliphatic groups contain 1-20 aliphatic carbon atoms.
  • aliphatic groups contain 1-12 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms.
  • cycloaliphatic refers to a monocyclic C 3 -C 6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl) alkyl, (cycloalkenyl) alkyl or (cycloalkyl) alkenyl.
  • the term “3-to 14-membered carbocycle” and refers to a 3-to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 7-to 14-membered saturated or partially unsaturated polycyclic carbocyclic ring.
  • alkyl refers to saturated, straight–or branched–chain hydrocarbon derived from an aliphatic moiety containing between one and twelve carbon atoms by removal of a single hydrogen atom. Unless otherwise specified, alkyl groups contain 1–12 carbon atoms. In certain embodiments, alkyl groups contain 1–8 carbon atoms. In certain embodiments, alkyl groups contain 1–6 carbon atoms. In some embodiments, alkyl groups contain 1–5 carbon atoms. In some embodiments, alkyl groups contain 1–4 carbon atoms. In certain embodiments, alkyl groups contain 1–3 carbon atoms. In some embodiments, alkyl groups contain 1–2 carbon atoms.
  • alkyl group examples include, but are not limited to, methyl, ethyl, n–propyl, isopropyl, n–butyl, iso–butyl, sec–butyl, sec–pentyl, iso–pentyl, tert–butyl, n–pentyl, neopentyl, n–hexyl, sec–hexyl, n–heptyl, n–octyl, n–decyl, n–undecyl, dodecyl, and the like.
  • alkenyl denotes a monovalent group derived from a straight–or branched–chain aliphatic moiety having at least one carbon–carbon double bond by the removal of a single hydrogen atom.
  • alkenyl groups contain 2–12 carbon atoms. In certain embodiments, alkenyl groups contain 2–8 carbon atoms. In certain embodiments, alkenyl groups contain 2–6 carbon atoms. In some embodiments, alkenyl groups contain 2–5 carbon atoms. In some embodiments, alkenyl groups contain 2–4 carbon atoms. In some embodiments, alkenyl groups contain 2–3 carbon atoms. In some embodiments, alkenyl groups contain 2 carbon atoms. Alkenyl groups include, for example, ethenyl, propenyl, butenyl, 1–methyl–2–buten–1–yl, and the like.
  • alkynyl refers to a monovalent group derived from a straight–or branched–chain aliphatic moiety having at least one carbon–carbon triple bond by the removal of a single hydrogen atom. Unless otherwise specified, alkynyl groups contain 2–12 carbon atoms. In certain embodiments, alkynyl groups contain 2–8 carbon atoms. In certain embodiments, alkynyl groups contain 2–6 carbon atoms.
  • alkynyl groups contain 2–5 carbon atoms, in some embodiments, alkynyl groups contain 2–4 carbon atoms, in yet other embodiments alkynyl groups contain 2–3 carbon atoms, and in yet other embodiments alkynyl groups contain 2 carbon atoms.
  • Representative alkynyl groups include, but are not limited to, ethynyl, 2–propynyl (propargyl) , 1–propynyl, and the like.
  • acyl used alone or a part of a larger moiety, refers to groups formed by removing a hydroxy group from a carboxylic acid.
  • aryl used alone or as part of a larger moiety as in or “aryloxyalkyl, ” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • aryl may be used interchangeably with the term “aryl ring. ”
  • aryl refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
  • aryl is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
  • the term “6-to 14-membered aryl” refers to a phenyl or an 8-to 14-membered polycyclic aryl ring.
  • halogen means F, Cl, Br, or I.
  • heteroaryl and “heteroar–, ” used alone or as part of a larger moiety e.g., “heteroaralkyl, ” or “heteroaralkoxy, ” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3, 4-dihydro-2H-pyrrolyl) , NH (as in pyrrolidinyl) or NR+ (as in N-substituted pyrrolidinyl) ) .
  • unsaturated, " as used herein, means that a moiety has one or more units of unsaturation.
  • heterocycle As used herein, the terms “heterocycle, ” “heterocyclyl, ” “heterocyclic radical, ” and “heterocyclic ring” are used interchangeably and refer to a stable 5–to 7–membered monocyclic or 7–10–membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen in a saturated or partially unsaturated ring having 1–3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3, 4–dihydro–2H–pyrrolyl) , NH (as in pyrrolidinyl) , or +NR (as in N–substituted pyrrolidinyl) .
  • the term “3-to 14-membered heterocycle” refers to a 3-to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-to 14-membered saturated or partially unsaturated polycyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.
  • heterocycle ” “heterocyclyl, ” “heterocyclyl ring, ” “heterocyclic group, ” “heterocyclic moiety, ” and “heterocyclic radical, ” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring.
  • a heterocyclyl group may be mono–or bicyclic.
  • heterocyclylalkyl refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
  • partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
  • partially unsaturated is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational) ) forms of the structure; for example, the R and S configurations for each stereocenter, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure.
  • a particular enantiomer of a compound of the present disclosure may be prepared by asymmetric synthesis, chiral chromatography, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C-or 14C-enriched carbon are within the scope of this disclosure.
  • Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present disclosure.
  • compounds of the disclosure may contain “optionally substituted” moieties.
  • substituted, ” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable, ” as used herein refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • the term “approximately” or “about, ” as applied to one or more values of interest refers to a value that is similar to a stated reference value.
  • the term “approximately” or “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100%of a possible value) .
  • carrier and “diluent” refers to a pharmaceutically acceptable (e.g., safe and non-toxic for administration to a human) carrier or diluting substance useful for the preparation of a pharmaceutical formulation.
  • exemplary diluents include sterile water, bacteriostatic water for injection (BWFI) , a pH buffered solution (e.g. phosphate-buffered saline) , sterile saline solution, Ringer's solution or dextrose solution.
  • the terms “dosage form” and “unit dosage form” refer to a physically discrete unit of a therapeutic agent for the patient to be treated. Each unit contains a predetermined quantity of active material calculated to produce the desired therapeutic effect. It will be understood, however, that the total dosage of the composition will be decided by the attending physician within the scope of sound medical judgment.
  • a “dosing regimen” is a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time.
  • a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses.
  • a dosing regimen comprises a plurality of doses each of which are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses.
  • the therapeutic agent is administered continuously over a predetermined period. In some embodiments, the therapeutic agent is administered once a day (QD) or twice a day (BID) .
  • control individual is an individual afflicted with the same form of disease as the individual being treated, who is about the same age as the individual being treated (to ensure that the stages of the disease in the treated individual and the control individual (s) are comparable) .
  • in vitro refers to events that occur in an artificial environment, e.g., in a test tube or reaction vessel, in cell culture, etc., rather than within a multi-cellular organism.
  • in vivo refers to events that occur within a multi-cellular organism, such as a human and a non-human animal. In the context of cell-based systems, the term may be used to refer to events that occur within a living cell (as opposed to, for example, in vitro systems) .
  • administer refers to either directly administering a compound or composition to a patient.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • prodrug means an agent that is converted into the parent drug in vivo.
  • a prodrug is easier to administer than a parent drug.
  • a prodrug has improved bioavailability by oral administration compared to the parent drug.
  • Prodrugs may also have improved stability in pharmaceutical compositions over the parent drug.
  • a prodrug has reduced toxicity compared to the parent drug by avoiding unnecessary exposure to unintended target tissues.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • systemic administration means the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient’s system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
  • “palliative” refers to treatment that is focused on the relief of symptoms of a disease and/or side effects of a therapeutic regimen, but is not curative.
  • a “risk” of a disease, disorder, and/or condition comprises a likelihood that a particular individual will develop a disease, disorder, and/or condition (e.g., an inflammation-related disease, disorder, or condition) .
  • risk is expressed as a percentage.
  • risk is from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90 up to 100%.
  • risk is expressed as a risk relative to a risk associated with a reference sample or group of reference samples.
  • a reference sample or group of reference samples have a known risk of a disease, disorder, condition and/or event (e.g., an inflammation-related disease, disorder, or condition) .
  • a reference sample or group of reference samples are from individuals comparable to a particular individual.
  • relative risk is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more.
  • stable refers to the ability of the therapeutic agent to maintain its therapeutic efficacy (e.g., all or the majority of its intended biological activity and/or physiochemical integrity) over extended periods of time.
  • the stability of a therapeutic agent, and the capability of the pharmaceutical composition to maintain stability of such therapeutic agent may be assessed over extended periods of time (e.g., for at least 1, 3, 6, 12, 18, 24, 30, 36 months or more) .
  • pharmaceutical compositions described herein have been formulated such that they are capable of stabilizing, or alternatively slowing or preventing the degradation, of one or more therapeutic agents formulated therewith.
  • a stable formulation is one in which the therapeutic agent therein essentially retains its physical and/or chemical integrity and biological activity upon storage and during processes (such as freeze/thaw, mechanical mixing and lyophilization) .
  • the term “subject” refers to a human or any non-human animal (e.g., mouse, rat, rabbit, dog, cat, cattle, swine, sheep, horse or primate) .
  • a human includes pre and post natal forms.
  • a subject is a human being.
  • a subject can be a patient, which refers to a human presenting to a medical provider for diagnosis or treatment of a disease.
  • the term “subject” is used herein interchangeably with “individual” or “patient. ”
  • a subject can be afflicted with or is susceptible to a disease or disorder but may or may not display symptoms of the disease or disorder.
  • the term “substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest.
  • One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, go to completion and/or proceed to completeness or achieve or avoid an absolute result.
  • the term “substantially” is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.
  • the term “therapeutically effective amount” of a therapeutic agent means an amount that is sufficient, when administered to a subject suffering from or susceptible to a disease, disorder, and/or condition, to treat, diagnose, prevent, and/or delay the onset of the symptom (s) of the disease, disorder, and/or condition. It will be appreciated by those of ordinary skill in the art that a therapeutically effective amount is typically administered via a dosing regimen comprising at least one unit dose.
  • treat, ” “treatment, ” or “treating” refers to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of and/or reduce incidence of one or more symptoms or features of a particular disease, disorder, and/or condition. Treatment may be administered to a subject who does not exhibit signs of a disease and/or exhibits only early signs of the disease for the purpose of decreasing the risk of developing pathology associated with the disease.
  • unit dose refers to a physically discrete unit of a formulation appropriate for a subject to be treated. It will be understood, however, that the total daily usage of a formulation of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular subject or organism may depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of specific active compound employed; specific composition employed; age, body weight, general health, sex and diet of the subject; time of administration, and rate of excretion of the specific active compound employed; duration of the treatment; drugs and/or additional therapies used in combination or coincidental with specific compound (s) employed, and like factors well known in the medical arts.
  • a particular unit dose may or may not contain a therapeutically effective amount of a therapeutic agent.
  • An individual who is “suffering from” a disease, disorder, and/or condition has been diagnosed with and/or displays one or more symptoms of the disease, disorder, and/or condition.
  • An individual who is “susceptible to” a disease, disorder, and/or condition has not been diagnosed with the disease, disorder, and/or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and/or condition may not exhibit symptoms of the disease, disorder, and/or condition.
  • an individual who is susceptible to a disease, disorder, condition, or event may be characterized by one or more of the following: (1) a genetic mutation associated with development of the disease, disorder, and/or condition; (2) a genetic polymorphism associated with development of the disease, disorder, and/or condition; (3) increased and/or decreased expression and/or activity of a protein associated with the disease, disorder, and/or condition; (4) habits and/or lifestyles associated with development of the disease, disorder, condition, and/or event (5) having undergone, planning to undergo, or requiring a transplant.
  • an individual who is susceptible to a disease, disorder, and/or condition will develop the disease, disorder, and/or condition.
  • an individual who is susceptible to a disease, disorder, and/or condition will not develop the disease, disorder, and/or condition.
  • the present invention provides methods and compositions for effective treatment of cancers related to chronically active Ras based on a compound of formula I or II, or a pharmaceutically acceptable salt thereof.
  • Ras is a family of related proteins called small GTPase, and are involved in transmitting signals within cells (cellular signal transduction) .
  • Exemplary Ras proteins include, but are not limited to, H-Ras, N-Ras and K-Ras. All Ras proteins function as binary signaling switches with "on” and “off” states. Typically, in the "off” state (or deactivated state) , it is bound to the nucleotide guanosine diphosphate (GDP) ; while in the "on” state (or activated state) , Ras is bound to guanosine triphosphate (GTP) . Normally, Ras is regulated by cycling between the active GTP-bound and inactive GDP-bound forms.
  • GDP nucleotide guanosine diphosphate
  • GTP guanosine triphosphate
  • chronically active Ras refers to a Ras GTPase form that is constitutively or permanently locked in an active state or has a reduced deactivation rate as compared to a wild type Ras.
  • the terms “chronically active Ras” , “chronically activated Ras, ” “constitutively active Ras” , “constitutively activated Ras” , “permanently active Ras” , “permanently activated Ras” and other grammatical equivalents thereof are used interchangeably.
  • a chronically active Ras contains a mutation that prevents or reduces the rate of GTP hydrolysis.
  • a chronically active Ras is caused by mutations found at residue G12 in the P-loop and/or the catalytic residue Q61.
  • residue 61 is responsible for stabilizing the transition state for GTP hydrolysis.
  • a chronically active Ras contains a Q61K mutation in N-Ras, which reduces the rate of intrinsic Ras GTP hydrolysis.
  • mutations in codon 12 (Gly to Ala, Arg, Asp, Cys, Ser, or Val) and codon 13 (Gly to Asp) result in chronically active K-Ras.
  • Chronically active Ras has been implicated in various cancers.
  • lung cancer K-Ras
  • pancreas K-Ras
  • K-Ras non-small cell lung adenocarcinoma
  • K-Ras K-Ras
  • colorectal K-Ras
  • thyroid K-Ras, H-Ras and N-Ras
  • seminoma K-Ras and N-Ras
  • myelodysplastic syndrome K-Ras and N-Ras
  • acute myeloid leukemia N-Ras
  • chronic myeloid leukemia N-Ras
  • melanoma N-Ras
  • bladder H-Ras
  • liver N-Ras
  • kidney H-Ras
  • Chronically active Ras has also been associated with cancers that are particularly malignant or hard to treat, including, but not limited to, metastasized cancers and refractory cancers.
  • refractory cancer refers to cancer that is unresponsive or responds poorly to standard cancer treatment such as surgery, chemo-or radiation therapy.
  • a refractory cancer can be either initially unresponsive to a standard cancer therapy, or becomes unresponsive over time.
  • chronically active Ras has been associated with cancers that are refractory to treatment with EGFR inhibitors.
  • Exemplary cancers that are related to chronically active Ras and/or refractory include but are not limited to those listed in Table 1, below.
  • Table 1 Exemplary cancer related to mutant Ras.
  • a compound in a provided method has the structure of formula I or II:
  • n 0-4;
  • each R 1 is independently halogen; -NO 2 ; -CN; -OR; -SR; -N + (R) 3 ; -N (R) 2 ; -C (O) R; -CO 2 R; -S (O) R; -S (O) 2 R; -C (O) N (R) 2 ; -SO 2 N (R) 2 ; -OC (O) R; or an optionally substituted group selected from C 1-12 aliphatic; 3-to 14-membered carbocyclyl; 3-to 14-membered heterocyclyl; 6-to 14-membered aryl; or 5-to 14-membered heteroaryl;
  • each R a and R b is independently hydrogen, sodium, potassium, amine cation, or an optionally substituted group selected from C 1-12 aliphatic; 3-to 14-membered carbocyclyl; 3-to 14-membered heterocyclyl; 6-to 14-membered aryl; or 5-to 14-membered heteroaryl;
  • R c is an optionally substituted group selected from C 1-12 aliphatic; 3-to 14-membered carbocyclyl; 3-to 14-membered heterocyclyl; 6-to 14-membered aryl; or 5-to 14-membered heteroaryl;
  • R 4 is hydrogen; halogen; -NO 2 ; -OR; -SR; -N + (R) 3 ; -N (R) 2 ; -C (O) R; -CO 2 R; or an optionally substituted group selected from C 1-12 aliphatic; 3-to 14-membered carbocyclyl; 3-to 14-membered heterocyclyl; 6-to 14-membered aryl; or 5-to 14-membered heteroaryl;
  • each R is independently hydrogen or an optionally substituted group selected from C 1-12 aliphatic; 3-to 14-membered carbocyclyl; 3-to 14-membered heterocyclyl; a 6-to 14-membered aryl; or 5-to 14-membered heteroaryl.
  • a compound in a provided method is a compound of formula I or a pharmaceutically acceptable salt thereof. In some embodiments, a compound in a provided method is a compound of formula II or a pharmaceutically acceptable salt thereof.
  • n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.
  • R 1 is halogen; -NO 2 ; -CN; -OR; -SR; -N + (R) 3 ; -N (R) 2 ; -C (O) R; -CO 2 R; or an optionally substituted group selected from C 1-12 aliphatic; 3-to 14-membered carbocyclyl; 3-to 14-membered heterocyclyl; 6-to 14-membered aryl; or 5-to 14-membered heteroaryl.
  • R 1 is halogen. In some embodiments, R 1 is–F. In some embodiments, R 1 is–Cl. In some embodiments, R 1 is–Br. In some embodiments, R 1 is–I.
  • R 1 is-NO 2 . In some embodiments, R 1 is–CN. In some embodiments, R 1 is–OR. In some embodiments, R 1 is–OH. In some embodiments, R 1 is–SR. In some embodiments, R 1 is-N + (R) 3 . In some embodiments, R 1 is-N (R) 2 . In some embodiments, R 1 is-C (O) R. In some embodiments, R 1 is-CO 2 R.
  • R 1 is an optionally substituted group selected from C 1-12 aliphatic; 3-to 14-membered carbocyclyl; 3-to 14-membered heterocyclyl; 6-to 14-membered aryl; or 5-to 14-membered heteroaryl.
  • R 1 is methyl optionally substituted with one or more halogen atoms. In some embodiments, R 1 is–CF 3 .
  • R 4 is hydrogen; halogen; -NO 2 ; -OR; -SR; -N + (R) 3 ; -N (R) 2 ; -C (O) R; -CO 2 R; or an optionally substituted group selected from C 1-12 aliphatic; 3-to 14-membered carbocyclyl; 3-to 14-membered heterocyclyl; 6-to 14-membered aryl; or 5-to 14-membered heteroaryl.
  • R 4 is hydrogen. In some embodiments, R 4 is other than hydrogen.
  • R 5 is-C (O) R. In some embodiments, R 5 is-C (O) R, wherein R is an optionally substituted group selected from C 1-12 aliphatic or an optionally substituted 6-to 14-membered aryl ring. In some embodiments, R 5 is-C (O) R, wherein R is an optionally substituted group selected from C 1-12 aliphatic. In some embodiments, R 5 is-CO 2 R. In some embodiments, R 5 is-C (O) C (O) R. In some embodiments, R 5 is-C (O) CH 2 C (O) R. In some embodiments, R 5 is-S (O) R. In some embodiments, R 5 is-S (O) 2 R. In some embodiments, R 5 is -C (O) N (R) 2 . In some embodiments, R 5 is-SO 2 N (R) 2 .
  • R 1 is halogen, –CN, or –CF 3 ; n is 0, 1, or 2; each R 2 and R 3 is independently isobutyryl, pivalyl, acetyl, octanoyl, N- (tert-butoxycarbonyl) glycinyl, N, N-dimethylglycinyl, or hydrogen; R 4 is hydrogen or an optionally substituted amine; R 5 is-C (O) R, wherein R is an optionally substituted group selected from C 1-12 aliphatic or an optionally substituted 6-to 14-membered aryl ring.
  • R 1 is halogen, –CN, or –CF 3 ; n is 0, 1, or 2; each R 2 and R 3 is independently isobutyryl, pivalyl, acetyl, octanoyl, N- (tert-butoxycarbonyl) glycinyl, N, N-dimethylglycinyl, or hydrogen; R 4 is hydrogen or –N (R) 2 or–N + (R) 3 ; R 5 is-C (O) R, wherein R is an optionally substituted group selected from C 1-12 aliphatic or an optionally substituted 6-to 14-membered aryl ring.
  • R 1 is halogen or–CF 3 ; n is 0, 1, or 2; each R 2 and R 3 is independently acetyl, N- (tert-butoxycarbonyl) glycinyl, or octanoyl; R 4 is hydrogen; R 5 is-C (O) R, wherein R is an optionally substituted group selected from C 1-12 aliphatic.
  • provided compounds are 4, 9-bis (isobutyryloxy) -naphtho [2, 3-b] furans. In some embodiments, provided compounds are 4, 9-bis (pivalyloxy) -naphtho [2, 3-b] furans. In some embodiments, provided compounds are 4, 9-diacetoxy-naphtho [2, 3-b] furans. In some embodiments, provided compounds are 4, 9-bis (dichloroacetoxy) -naphtho [2, 3-b] furans. In some embodiments, provided compounds are 4, 9-bis (octanoyloxy) -naphtho [2, 3-b] furans.
  • provided compounds are 4, 9-bis ⁇ [ (tert-butoxycarbonyl) amino] acetoxy ⁇ -naphtho [2, 3-b] furans.
  • provided compounds are 4-phosphoester-9-acetoxy-naphtho [2, 3-b] furans.
  • provided compounds are 4, 9-bis (phosphoester) -naphtho [2, 3-b] furans.
  • provided compounds are 4-sulfate-9-acetoxy-naphtho [2, 3-b] furans.
  • R 1 is halogen, –CN, or–CF 3 ; n is 0, 1, or 2; R 4 is hydrogen or an optionally substituted amine; R 5 is-C (O) R, wherien R is an optionally substituted group selected from C 1-12 aliphatic or an optionally substituted 6-to 14-membered aryl ring.
  • R 1 is halogen, –CN, or–CF 3 ; n is 0, 1, or 2; R 4 is hydrogen, –N (R) 2 or–N + (R) 3 ; R 5 is-C (O) R, wherien R is an optionally substituted group selected from C 1-12 aliphatic or an optionally substituted 6-to 14-membered aryl ring.
  • R 1 is halogen or–CF 3 ; n is 0, 1, or 2; R 4 is hydrogen; R 5 is-C (O) R, wherein R is an optionally substituted group selected from C 1-12 aliphatic.
  • provided compounds are 2-sulfonyl substituted naphtho [2, 3-b] furan-4, 9-diones. In some embodiments, provided compounds are 2-sulfinyl substituted naphtho [2, 3-b] furan-4, 9-diones. In some embodiments, provided compounds are 2- (1-hydroxy-ethyl) substituted naphtho [2, 3-b] furan-4, 9-diones. In some embodiments, provided compounds are 2-acetyl substituted naphtho [2, 3-b] furan-4, 9-diones.
  • a provided compound of formula I or II can be degraded, reduced or otherwise converted in vivo into therapeutically active 4, 9-dihydroxy-naphtho [2, 3-b] furans (WO2012119265, US9150530) .
  • conversion of compounds of formula I into the therapeutically active 4, 9-dihydroxy-naphtho [2, 3-b] furans in cell culture is slower than that of the compounds of formula II.
  • compounds of formula II may deliver better results than compounds of formula I.
  • the present invention provides various formulations of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, to be used in the provided methods.
  • the present invention provides pharmaceutical compositions comprising a compound of formula I or II, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient or carrier or diluent.
  • the pharmaceutically acceptable excipient or carrier or diluent is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.
  • the pharmaceutically acceptable excipient or carrier or diluent including, but not limited to, water, saline solution, dextrose solution, triacetin, human albumin or its derivative, glycerol mono- (or di-) fatty acid esters, lecithin, phospholipids (such as phosphatidyl choline, phosphatidyl ethanolamine, phosphatidyl inositol, sphingomyelin, and the like) , cholesterol, PEG-phospholipids, PEG-cholesterol, PEG-cholesterol derivatives, PEG-vitamin A, PEG-vitamin E, PEG-glycerol mono- (or di-) fatty acid esters, ethylene glycol mono-fatty acid esters, propylene glycol mono-fatty acid esters, 3-dialkyl (C1-8) amino-propylene glycol di-fatty acid esters, poly (ethylene glycol) mono-fatty acid esters, stearic acid, sorbitan
  • the bulking agents includes starches or its derivatives, mannitol, lactose, maltitol, maltodextrin, maltose, dextrates, dextrin, dextrose, fructose, sorbitol, glucose, sucrose, carboxymethylcellulose, hydroxypropylcellulose, microcrystalline cellulose, ethylcellulose, methylcellulose, other suitable cellulose derivatives, gelatin, alginic acid, and its salt, colloidal silicon dioxide, croscarmellose sodium, crospovidone, magnesium aluminum silicate, povidone, benzyl phenylformate, chlorobutanol, diethyl phthalate, calcium stearate, glyceryl palmitostearate, magnesium oxide, poloxamer, polyvinyl alcohol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, zinc stearate, acacia, acrylic and meth
  • Formulations of a compound of formula I or II, or a pharmaceutically acceptable salt thereof include those suitable for oral, nasal, topical (including buccal and sublingual) , rectal, vaginal and/or parenteral administration.
  • the formulation may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient, which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of 100%, this amount will range, for example, from about 1%to about 99%of active ingredient, from about 5%to about about 70%, from about 10%to about 30%.
  • a provided composition can be in any form that allows for the composition to be administered to a subject.
  • a composition can be in the form of a solid, liquid or gas (aerosol) .
  • routes of administration include, without limitation, oral, topical, parenteral, sublingual, rectal, vaginal, ocular, intra-tumor, and intranasal.
  • Parenteral administration includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • compositions can be formulated so as to allow a provided compound to be bioavailable upon administration of the composition to a patient.
  • Compositions can take the form of one or more dosage units, where for example, a tablet can be a single dosage unit, a vial may contain a single dose for intravenous administration, and a container of a provided compound in aerosol form can hold a plurality of dosage units.
  • a pharmaceutically acceptable carrier or vehicle can be particulate, so that the compositions are, for example, in tablet or powder form.
  • the carrier (s) can be liquid, with the compositions being, for example, an oral syrup or injectable liquid.
  • the carrier (s) can be gaseous or particulate, so as to provide an aerosol composition useful in, e.g., inhalatory administration.
  • a composition is preferably in solid or liquid form, where semi-solid, semi-liquid, suspension and gel forms are included within the forms considered herein as either solid or liquid.
  • a composition for oral administration, a composition can be formulated into a powder, granule, compressed tablet, pill, capsule, chewing gum, wafer or the like form.
  • a solid composition typically contains one or more inert diluents.
  • binders such as carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, or gelatin
  • excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, corn starch and the like
  • lubricants such as magnesium stearate or Sterotex
  • glidants such as colloidal silicon dioxide
  • sweetening agents such as sucrose or saccharin, a flavoring agent such as peppermint, methyl salicylate or orange flavoring, and a coloring agent.
  • a composition can be in the form of a liquid, e.g., an elixir, syrup, solution, emulsion or suspension.
  • the liquid can be useful for oral administration or for delivery by injection.
  • a composition can comprise one or more of a sweetening agent, preservatives, dye/colorant and flavor enhancer.
  • a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent can also be included.
  • Liquid compositions can also include one or more of the following: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono or digylcerides which can serve as the solvent or suspending medium, polyethylene glycols, glycerin, cyclodextrin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride
  • fixed oils such as synthetic mono or digyl
  • a parenteral composition can be enclosed in ampoule, a disposable syringe or a multiple-dose vial made of glass, plastic or other material.
  • Physiological saline is an exemplary adjuvant.
  • An injectable composition is preferably sterile.
  • compositions comprise an effective amount of a provided compound such that a suitable dosage will be obtained. In some embodiments, this amount is at least about 0.01%of a provided compound by weight of the composition. When intended for oral administration, this amount can be varied to range from about 0.1%to about 80%by weight of the composition. In one aspect, oral compositions can comprise from about 4%to about 50%of a provided compound by weight of the composition. In yet another aspect, a provided composition is prepared so that a parenteral dosage unit contains from about 0.01%to about 2%by weight of a provided compound or composition.
  • a provided composition can comprise from about 0.01 to about 100 mg of a provided compound per kg of a subject's body weight. In one aspect, the composition can include from about 1 to about 100 mg of a provided compound per kg of a subject's body weight. In another aspect, the amount administered will be in the range from about 0.1 to about 25 mg/kg of body weight of a provided compound.
  • a provided compound can be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc. ) . Administration can be systemic or local.
  • Various delivery systems are known, e.g., encapsulation in liposomes, microparticles, microcapsules, capsules, etc., and can be used to administer a provided compound or composition. In certain embodiments, more than one provided compound or composition is administered to a patient.
  • administration can be by direct injection at the site (or former site) of a cancer, tumor or neoplastic or pre-neoplastic tissue. In another embodiment, administration can be by direct injection at the site (or former site) of a manifestation of an autoimmune disease.
  • Intraventricular injection can be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir.
  • Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent, or via perfusion in a fluorocarbon or synthetic pulmonary surfactant.
  • a provided compound or compositions can be delivered in a controlled release system, such as a pump or various polymeric materials can be used.
  • a controlled-release system can be placed in proximity of a target of a provided compound or compositions, e.g., the brain, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, vol. 2, pp. 115-138 (1984) ) .
  • Other controlled-release systems discussed in the review by Langer Science 249: 1527-1533 (1990) can be used.
  • a compound of formula I or II, or a pharmaceutically acceptable salt thereof is formulated as emulsion suspension suitable for oral, nasal, topical (including buccal and sublingual) , rectal, vaginal and/or parenteral administration.
  • the emulsion suspension contains water immiscible organic solvent in which a compound of formula I or II, or a pharmaceutically acceptable salt thereof, is dissolved and aqueous solution and surface surfactant.
  • the water immiscible organic solvent in the emulsion suspension is vegetable oil.
  • the surface surfactant in the emulsion suspension is lecithin.
  • the aqueous solution in the emulsion suspension is saline.
  • Formulations of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, suitable for oral administration may be in the form of capsules, pills, tablets, cachets, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous or aqueous-organic solvent emulsion liquid, each containing a predetermined amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, as an active ingredient.
  • crystalline solids of a provided compound of formula I or II, or a pharmaceutically acceptable salt thereof is used in a provided pharmaceutical formulation.
  • amorphous solids of a provided compound of formula I or II, or a pharmaceutically acceptable salt thereof is used in a provided pharmaceutical composition.
  • amorphous solids have better bioavailability than the corresponding crystalline solids.
  • provided compounds of the present invention are prodrugs which will turns into therapeutically active dihydroxynapthofuran chemical species in vivo.
  • a provided compound is more stable than the corresponding therapeutically active chemical species in vitro.
  • the effective daily dose of a provided compound may be administered as two, three, four, five, six, or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
  • Actual dosage levels of a provided compound in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required to achieve the desired therapeutic effect and then gradually increasing the dosage until the desired effect is achieved.
  • a compound or pharmaceutical composition of the invention is provided to a subject chronically.
  • Chronic treatments include any form of repeated administration for an extended period of time, such as repeated administrations for one or more months, between a month and a year, one or more years, or longer.
  • a chronic treatment involves administering a compound or pharmaceutical composition of the invention repeatedly over the life of the subject.
  • chronic treatments involve regular administrations, for example one or more times a day, one or more times a week, or one or more times a month.
  • a suitable dose such as a daily dose of a compound of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • doses of the compounds of this invention for a patient when used for the indicated effects, will range from about 0.0001 to about 100 mg per kg of body weight per day.
  • the daily dosage will range from 0.001 to 50 mg of compound per kg of body weight, and even more preferably from 0.01 to 10 mg of compound per kg of body weight.
  • the daily dosage is from 0.01 to 0.1 mg of compound per kg of body weight.
  • the daily dosage is from 0.01 to 0.5 mg of compound per kg of body weight.
  • the daily dosage is from 0.01 to 1 mg of compound per kg of body weight.
  • the daily dosage is from 0.01 to 2 mg of compound per kg of body weight.
  • the daily dosage is from 0.01 to 3 mg of compound per kg of body weight. In some embodiments, the daily dosage is from 0.01 to 4 mg of compound per kg of body weight. In some embodiments, the daily dosage is from 0.01 to 5 mg of compound per kg of body weight. In some embodiments, the daily dosage is from 0.01 to 6 mg of compound per kg of body weight. In some embodiments, the daily dosage is from 0.01 to 7 mg of compound per kg of body weight. In some embodiments, the daily dosage is from 0.01 to 8 mg of compound per kg of body weight. In some embodiments, the daily dosage is from 0.01 to 9 mg of compound per kg of body weight. In some embodiments, the daily dosage is from 0.5 to 2 mg of compound per kg of body weight.
  • the daily dosage is from 1 to 3 mg of compound per kg of body weight. In some embodiments, the daily dosage is from 2 to 4 mg of compound per kg of body weight. In some embodiments, the daily dosage is from 3 to 5 mg of compound per kg of body weight. In some embodiments, the daily dosage is from 4 to 6 mg of compound per kg of body weight. In some embodiments, the daily dosage is from 5 to 7 mg of compound per kg of body weight. In some embodiments, the daily dosage is from 6 to 8 mg of compound per kg of body weight. In some embodiments, the daily dosage is from 7 to 9 mg of compound per kg of body weight. In some embodiments, the daily dosage is from 8 to 10 mg of compound per kg of body weight. However, lower or higher doses can be used.
  • the dose administered to a subject may be modified as the physiology of the subject changes due to age, disease progression, weight, or other factors.
  • the dose administered to a subject may be modified in combinatorial therapy. For example, when used combinatorially with an EGFR inhibitor, a compound of formula I or II, or a pharmaceutically acceptable salt thereof, is administered at a lower dosage than when it is administered without an EGFR inhibitor.
  • the present invention provides a method of treating or preventing cancer comprising steps of:
  • the step of identifying a patient suffering from or susceptible to a cancer related to chronically active Ras comprises:
  • Detection kits are commercially available, for example, K-Ras kit to detect K-Ras mutations (TheraScreen: K-Ras mutation kit from Qiagen Manchester Ltd., UK) .
  • the present invention provides a method of treating or preventing cancer comprising a step of administering to a subject suffering from or susceptible to a refractory cancer a therapeutically effective amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof.
  • a refractory cancer is unresponsive or responds poorly to standard cancer treatment such as surgery, chemo-or radiation therapy.
  • a refractory cancer is unresponsive or responds poorly to surgery.
  • a refractory cancer is unresponsive or responds poorly to chemotherapy.
  • a refractory cancer is unresponsive or responds poorly to radiation therapy.
  • a refractory cancer can be either initially unresponsive to a standard cancer therapy, or becomes unresponsive over time. In some embodiments, a refractory cancer is initially unresponsive or responds poorly to a standard cancer therapy. In some embodiments, a refractory cancer becomes unresponsive to, or becomes to respond poorly to, a standard cancer therapy over time.
  • a refractory cancer is a cancer refractory to treatment with an EGFR inhibitor. In some embodiments, a refractory cancer is a cancer related to chronically active Ras. In some embodiments, a cancer refractory to treatment with an EGFR inhibitor is related to chronically active Ras.
  • the present invention provides a method of treating or preventing cancer, comprising administering to a subject suffering from or susceptible to cancer a compound of formula I or II, or a pharmaceutically acceptable salt thereof, in conjunction with an EGFR inhibitor.
  • an EGFR inhibitor is administered prior to, concurrently with, or subsequently to the compound of formula I or II, or a pharmaceutically acceptable salt thereof.
  • an EGFR inhibitor is administered prior to the compound of formula I or II, or a pharmaceutically acceptable salt thereof.
  • an EGFR inhibitor is administered concurrently with the compound of formula I or II, or a pharmaceutically acceptable salt thereof.
  • an EGFR inhibitor is administered subsequently to the compound of formula I or II, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of deactivating chronically active Ras comprising contacting the chronically active Ras and/or GTPase activating protein ( “GAP” ) with a compound of formula I or II, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a method of reducing GTP-bound mutant Ras with an effective amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a method of selectively deactivating chronically active Ras comprising contacting the chronically active Ras and/or GTPase activating protein ( “GAP” ) with a compound of formula I or II, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a method of selectively reducing GTP-bound mutant Ras with an effective amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof.
  • a provided compound of formula I or II, or a pharmaceutically acceptable salt thereof can perform its function in a provided method through various modes.
  • a provided compound performs its function through direct physical interaction with the Ras protein, for example, through binding to the Ras protein.
  • a provided compound performs its function without direct physical interaction with the Ras protein.
  • a provided compound performs its function through, for example, deactivating its activators and/or promoting its deactivators.
  • a provided compound performs its function through modulating the functions of more than one proteins.
  • a provided compound performs its function through binding to one or more proteins, one of which is a Ras protein.
  • a provided compound performs its function through binding to one or more proteins, one of which is a chronically active Ras protein.
  • the present invention provides methods for determining whether a subject is suitable for treatment with a compound of formula I or II, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides methods for predicting responsiveness of a subject with cancer to treatment with a compound of formula I or II, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method for determining whether a subject is suitable for a provided treatment with a compound of formula I or II, or a pharmaceutically acceptable salt thereof, comprising:
  • the present invention provides a method for determining whether a cancer patient is suitable for treatment with a compound of formula I or II, or a pharmaceutically acceptable salt thereof, comprising steps of:
  • chronically active Ras is identified through detection of one or more mutations that cause chronically active Ras.
  • the step of identifying chronically active Ras comprises identifying a Ras mutation, wherein a Ras mutation is identified.
  • the step of identifying chronically active Ras comprises identifying a Ras mutation, wherein a Ras mutation causing chronically active Ras is identified.
  • the present invention provides a method of treating or preventing cancer in a subject comprising steps of:
  • a provided compound of formula I or II, or a pharmaceutically acceptable salt thereof, in a provided method deactivates chronically active Ras.
  • the activity of chronically active Ras is decreased by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%or 99%.
  • a provided compound of formula I or II, or a pharmaceutically acceptable salt thereof, in a provided method deactivates chronically active Ras by reducing the amount or percentage of GTP-bound mutant Ras.
  • the present invention provides a method of reducing the amount or percentage of GTP-bound mutant Ras, comprising administering an effective amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof.
  • a compound of formula I or II, or a pharmaceutically acceptable salt thereof, in a provided method reduce the amount of GTP-bound mutant Ras by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%or 99%.
  • a compound of formula I or II, or a pharmaceutically acceptable salt thereof, in a provided method reduce the percentage of GTP-bound mutant Ras by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%or 99%.
  • Decrease of GTP-bound mutant Ras can be readily measured by multiple methods known in the art, including those described in the Examples, infra.
  • the present invention provides a method of inhibiting cell proliferation, comprising contacting the cell with an effective amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, wherein the cell is identified to have chronically active Ras.
  • Cancer cell lines A549, SW480, and SW620 have K-Ras codon 12 or 13 mutated. Treatment with compound XIII led to significant reduction of the GTP bound K-Ras (panels A of figures 1, 2, and 3) , but not the total K-Ras (panels B and C of figures 1, 2, and 3) .
  • panels B of Figures 1 and 2 cell lysates were incubated with GTP ⁇ S which restored all K-Ras to GTP ⁇ S bound.
  • panels C of Figures 1, 2, and 3 cell lysates were directly used without Raf-1 RBD-agarose treatment.
  • Cancer cell lines H1299 and HT29 have wild type K-Ras.
  • Figure 8 showed in vivo test results of 2-acetyl-4, 9-bis (octanoyloxy) -naphtho [2, 3-b] furan, compound VII, HZZ112, in the treatment of subcutaneous H1299 (panel A) and A549 (panel B) lung cancer xenograft model.
  • Compound VII was not active against wild type K-Ras lung cancer cell line H1299, but was extremely active against codon 12 mutated K-Ras lung cancer cell line A549.
  • DBU 1, 8-Diazabicyclo [5.4.0] undec-7-ene
  • DMEM Modified Eagle Medium
  • FBS fetal bovine serum
  • penicillin/streptomycin/amphotercin B Invitrogen, Carlsbad, CA, USA
  • Cell Lysate Preparation Culture cells to approximately 85-90%confluence, add a compound of formula I or II or DMSO as negative control, then incubate the cells for desired time at 37°C in CO 2 incubator. Remove culture media, rinse twice with ice-cold PBS. Add 0.7ml of ice-cold MLB (25 mM HEPES, pH7.5, 150 mM NaCl, 1%Igepal, 10 mM MgCl 2 , 1 mM EDTA and 2%glycerol) to rinse cells. Detach (and lyse) the cells from plates by scraping with a cell scraper.
  • MLB 0.7ml of ice-cold MLB (25 mM HEPES, pH7.5, 150 mM NaCl, 1%Igepal, 10 mM MgCl 2 , 1 mM EDTA and 2%glycerol)
  • GTP ⁇ S Loading as Positive Control To 0.5 ml of the cell lysate, add 10 ⁇ l of 0.5M EDTA and 5 ⁇ l of 100X GTP ⁇ S (10 mM in sterile water) . Incubate the mixture for 30 minutes at 30 °C with agitation, then stop the incubation by placing the mixture on ice and adding 32.5 ⁇ l of 1M MgCl 2 .
  • Ras Pull-Down Assay (Ras Activation Assay Kit , Millipore, Cat#17-218) : To 0.5 ml of the cell lysate with or without GTP ⁇ S treatment, add 5 ⁇ l of the Ras Assay Reagent (Raf-1 RBD, agarose) . Incubate the reaction mixures for 45 minutes at 4 °C with gentle agitation. Pellet the agarose beads by brief centrifuge (10 seconds, 14, 000xg, 4 °C) , then remove and discard the supernatant. Wash the beads (add 0.5ml of MLB, mix gently, pellet beads, remove MLB) 3 times. Resuspend the agarose beads in 40 ⁇ l of 2X Laemmli reducing sample buffer and boil for 5 minutes. Pellet the beads by brief centrifugation.
  • the H1299 or A549 tumor cells were maintained in vitro as a monolayer culture in DMEM medium supplemented with 10%heat inactivated fetal bovine serum, 100 U/ml penicillin and 100 ⁇ g/ml streptomycin, and L-glutamine (2 mM) at 37 °C in an atmosphere of 5%CO 2 in air.
  • the tumor cells were routinely subcultured twice weekly by trypsin-EDTA treatment.
  • the cells growing in an exponential growth phase were harvested and counted for tumor inoculation.
  • Tumor Inoculation Each mouse was inoculated subcutaneously at the right flank with H1299 or A549 tumor cells (5 x 10 6 ) in 0.1 ml of PBS for tumor development. The treatments were started when the mean tumor size reaches approximately 100 mm 3 .
  • Compound Formulation Compound VII was dissolved in PEG400/poloxamer 188 and diluted with water to desired concentration before administration.

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Abstract

Selon la présente invention, des naphtofuranquinones et des dihydroxynaphtofuranes et leurs dérivés, par exemple un composé de formule I ou II, se révèlent efficaces pour désactiver un gène Ras chroniquement actif. L'invention concerne également une méthode de traitement ou de prévention du cancer comprenant les étapes consistant : 1) à identifier un patient souffrant ou susceptible de souffrir d'un cancer associé à un gène Ras chroniquement actif; et 2) à lui administrer une quantité thérapeutiquement efficace d'un composé de formule I ou II, ou d'un sel de qualité pharmaceutique de celui-ci. L'invention concerne encore une méthode de traitement ou de prévention du cancer comprenant les étapes consistant : 1) à identifier un patient souffrant ou susceptible de souffrir d'un cancer associé à une mutation d'un gène K-Ras; et 2) à lui administrer une quantité thérapeutiquement efficace d'un composé de formule I ou II, ou d'un sel de qualité pharmaceutique de celui-ci.
PCT/CN2015/000788 2015-11-12 2015-11-12 Traitement de cancers associés à un gène ras chroniquement actif WO2017079864A1 (fr)

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CN107973788A (zh) * 2018-01-09 2018-05-01 沈阳药科大学 Bbi608衍生物及其制备与用途
US10125134B2 (en) 2016-05-18 2018-11-13 Mirati Therapeutics, Inc. KRas G12C inhibitors
US10647715B2 (en) 2017-11-15 2020-05-12 Mirati Therapeutics, Inc. KRas G12C inhibitors
US10689377B2 (en) 2017-11-15 2020-06-23 Mirati Therapeutics, Inc. KRas G12C inhibitors
CN113214201A (zh) * 2021-03-22 2021-08-06 毕庶壮 一类Napabucasin的衍生物及其药物用途
WO2021257736A1 (fr) 2020-06-18 2021-12-23 Revolution Medicines, Inc. Méthodes de retardement, de prévention et de traitement de la résistance acquise aux inhibiteurs de ras
WO2022060583A1 (fr) 2020-09-03 2022-03-24 Revolution Medicines, Inc. Utilisation d'inhibiteurs de sos1 pour traiter des malignités à mutations de shp2
US11453683B1 (en) 2019-08-29 2022-09-27 Mirati Therapeutics, Inc. KRas G12D inhibitors
US11548888B2 (en) 2019-01-10 2023-01-10 Mirati Therapeutics, Inc. KRas G12C inhibitors
US11702418B2 (en) 2019-12-20 2023-07-18 Mirati Therapeutics, Inc. SOS1 inhibitors
US11890285B2 (en) 2019-09-24 2024-02-06 Mirati Therapeutics, Inc. Combination therapies
US11932633B2 (en) 2018-05-07 2024-03-19 Mirati Therapeutics, Inc. KRas G12C inhibitors

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Cited By (17)

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Publication number Priority date Publication date Assignee Title
US11267812B2 (en) 2016-05-18 2022-03-08 Mirati Therapeutics, Inc. KRAS G12C inhibitors
US10125134B2 (en) 2016-05-18 2018-11-13 Mirati Therapeutics, Inc. KRas G12C inhibitors
US10633381B2 (en) 2016-05-18 2020-04-28 Mirati Therapeutics, Inc. KRas G12C inhibitors
US10689377B2 (en) 2017-11-15 2020-06-23 Mirati Therapeutics, Inc. KRas G12C inhibitors
US10647715B2 (en) 2017-11-15 2020-05-12 Mirati Therapeutics, Inc. KRas G12C inhibitors
CN107973788B (zh) * 2018-01-09 2021-07-09 沈阳药科大学 Bbi608衍生物及其制备与用途
CN107973788A (zh) * 2018-01-09 2018-05-01 沈阳药科大学 Bbi608衍生物及其制备与用途
US11932633B2 (en) 2018-05-07 2024-03-19 Mirati Therapeutics, Inc. KRas G12C inhibitors
US11548888B2 (en) 2019-01-10 2023-01-10 Mirati Therapeutics, Inc. KRas G12C inhibitors
US11964989B2 (en) 2019-08-29 2024-04-23 Mirati Therapeutics, Inc. KRas G12D inhibitors
US11453683B1 (en) 2019-08-29 2022-09-27 Mirati Therapeutics, Inc. KRas G12D inhibitors
US11890285B2 (en) 2019-09-24 2024-02-06 Mirati Therapeutics, Inc. Combination therapies
US11702418B2 (en) 2019-12-20 2023-07-18 Mirati Therapeutics, Inc. SOS1 inhibitors
WO2021257736A1 (fr) 2020-06-18 2021-12-23 Revolution Medicines, Inc. Méthodes de retardement, de prévention et de traitement de la résistance acquise aux inhibiteurs de ras
WO2022060583A1 (fr) 2020-09-03 2022-03-24 Revolution Medicines, Inc. Utilisation d'inhibiteurs de sos1 pour traiter des malignités à mutations de shp2
CN113214201B (zh) * 2021-03-22 2023-08-15 毕庶壮 一类Napabucasin的衍生物及其药物用途
CN113214201A (zh) * 2021-03-22 2021-08-06 毕庶壮 一类Napabucasin的衍生物及其药物用途

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