WO2019113345A1 - Association d'agents thérapeutiques anticancéreux pour le traitement du cancer et de maladies hyperprolifératives - Google Patents

Association d'agents thérapeutiques anticancéreux pour le traitement du cancer et de maladies hyperprolifératives Download PDF

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WO2019113345A1
WO2019113345A1 PCT/US2018/064294 US2018064294W WO2019113345A1 WO 2019113345 A1 WO2019113345 A1 WO 2019113345A1 US 2018064294 W US2018064294 W US 2018064294W WO 2019113345 A1 WO2019113345 A1 WO 2019113345A1
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cancer
alkyl
composition
group
nqol
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PCT/US2018/064294
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Spyro Mousses
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Spyro Mousses
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • This invention relates to pharmaceutical compositions, methods, and approaches
  • This invention also relates to methods of treating mammalian cancer or hyperproliferative disorders, said method comprising contacting cancer cells or any other hyperproliferative cells with said compositions.
  • Cancer is the most common cause of death in many parts of the world and over 2.5 million cases of cancer are diagnosed globally every year.
  • the high toxicity and increasingly high specificity of such drugs means there is a continuing need for new anti-cancer agents and strategies, particularly those that have fewer toxic side-effects and are efficacious against a broad spectrum of cancers.
  • new fundamental treatment paradigms that are more cancer selective are required.
  • the present invention provides such a breakthrough strategy, compositions and methods.
  • Protein kinases are components of signal transduction pathways that play a central role in many biological processes, including control of cell growth, metabolism,
  • kinase inhibitors approved byt the FDA, including some high profile drugs such as as imatinib, exhibiting up to 80% response rates in chronic- phase CML patients. Despite this, there is a significant challenge from drug resistance with kinase inhibitors.
  • kinase inhibitors are either approved or being studied as cancer therapeutics including Afatinib, Axitinib, Bosutinib, Cetuximab, Cobimetinib, Crizotinib, Cabozantinib, Dasatinib, Entrectinib, Erlotinib, Fostamatinib, Gefitinib, Ibrutinib,
  • kinase inhibitors Resistance to kinase inhibitors can occur through a variety of processes: (a) "on-target” resistance via mutations, amplifications, or altered splicing of the target kinase; (b) "on-pathway” resistance via activation of downstream components or disruption of negative feedback loops; (c) bypass mechanisms that upregulate parallel signaling pathways; (d) epigenetic alterations and histological transformations that modify a cell's phenotypic state; and (e) modulation of cellular processes that influence drug transport, distribution, or stability (see Gross supra).
  • NQOl substrates include agents like Deoxynyboquinone (DNQ), which is a potent antineoplastic agent known as an anthraquinone, synthesized in seven linear steps through a route employing three palladium-mediated coupling reactions.
  • DNQ Deoxynyboquinone
  • Deoxynyboquinone kills a wide spectrum of cancer cell types (i.e., breast, non-small-cell lung, prostate, pancreatic) in an NQOl-dependent manner with greatly improved (20- to 100-fold) potency compared to b-lapachone.
  • DNQ lethality relies on NQOl-dependent futile redox cycling, using oxygen and generating extensive reactive oxygen species (ROS), particularly superoxide and hydrogen peroxide.
  • ROS reactive oxygen species
  • NRF2 target gene products are involved in cytoprotection, and typical examples include detoxifying enzymes and antioxidant enzymes such as NQOl. See Taguchi K and Yamamoto M (2017) The KEAP1-NRF2 System in Cancer. Front. Oncol. 7:85. doi:
  • NRF2 Aberrant high levels and activity of NRF2 in cancer cells occurs through a variety of mechanisms including somatic mutations in the KEAP1 or NRF2 genes as well as through other mechanisms that disrupt the binding of KEAP1 to NRF2.
  • Unregulated NRF2 (and increase NQOl) confers on cancer cells high-level resistance to anticancer drugs and reactive oxygen species (ROS) and directs cancer cells toward metabolic reprogramming (Taguchi).
  • ROS reactive oxygen species
  • this up-regulation of NQOl is exploited by the administration of a novel NQOl substrate that increases the amount of ROS and therefore kills the cancer cells.
  • the present invention comprises a composition
  • the NQOl substrate is a quinone analog, DNQ or a DNQ analogue.
  • the NQOl substrate is beta lapchone or an analogue thereof.
  • the NQOl substrate is a DNQ analogue of the formula:
  • Ri is alkyl
  • R 3 is H
  • R 2 and R 4 are each independently— X— R
  • each X is
  • each W is independently— N(R')C(-0)— ,— C(-0)N(R)-,— OC(-O)— ,— C( _ 0)0— , -0-,— S— ,— S(O)— ,— S(0) 2 — ,— N(R')— , - C(— O)— ,— (CH 2 ) n — where n is 1-10, or a direct bond, wherein each R' is independently H, (Cl-C6)alkyl, or a nitrogen protecting group; and further wherein each A is independently (Ci
  • each R is independently alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl,
  • heterocycloalkyl alkyl, (cycloalkyl)heteroalkyl, (heterocycloalkyl)heteroalkyl, aryl, heteroaryl, (aryl)alkyl, (heteroaryl)alkyl, hydrogen, hydroxy, hydroxyalkyl, alkoxy, (alkoxy)alkyl, alkenyloxy, alkynyloxy, (cycloalkyl)alkoxy, heterocycloalkyloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino,— COR x ,— COOR x ,— CONHR x ,— NHCOR x , -NHCOOR x ,— NHCONHR x ,— N 3 ,— CN,— NC, -NCO, - N0 2 ,— SH, -halo, alkoxy
  • Z is an inorganic cation, or saccharide; where each R x is independently H, OH, alkyl or aryl, and each R Y is independently a group W; wherein any alkyl or aryl can be optionally substituted with one or more hydroxy, amino, cyano, nitro, or halo groups; or a salt or solvate thereof.
  • each of R 4 is a (Ci_ 20 ) alkyl group; Ri is a
  • Ri is a straight chain (Ci_ 20 ) alkyl group.
  • Ri , R 2 ⁇ and R 4 is methyl.
  • the present invention comprises a composition comprising a kinase inhibitor plus a compound having the formula:
  • kinase inhibitors may comprise a compound selected from an inhibitor of EGFR, ALK, BRAF, and MEK.
  • the pharmaceutical composition of the present invention may thus comprise a synergistically effective amount of an NQOl substrate, together with a synergistic effective amount of a kinase inhibitor, and a pharmaceutically acceptable carrier or diluent.
  • the kinase inhibitor is selected from Afatinib, Axitinib,
  • Bosutinib Cabozantinib, Dasatinib, Fostamatinib, , Ibrutinib, Imatinib, , Lenvatinib, Mubritinib, Nilotinib, Pazopanib, Pegaptanib, Ruxolitinib, Sorafenib, Sunitinib, SU6656, ABT-414, AC-480, AC0010MA, AEE-788, AP32788, ASP8273, AV-412, AZD3759, BMS- 690514, BPI-15086, Cetuximab, CK-101, Dacomitinib, EGF816, Erlotinib, Futuximab, Gefitinib, Hemay022, HM61713, HS-10296, lcotinib, Lapatinib, Necitumumab, Neratinib, Imotuzumab, Osimertin
  • the present invention provides methods of treating cancer
  • the method includes the use of a
  • kinase inhibitor which is an inhibitor of EGFR, ALK, BRAF, or MEK.
  • the method of the present invention includes the use of an inhibitor that is selected from ABT-414, AC-480, AC0010MA, AEE-788, AP32788, ASP8273, AV-412, AZD3759, BMS-690514, BPI-15086, Cetuximab, CK-101, Dacomitinib, EGF816, Erlotinib, Futuximab, Gefitinib, Hemay022, HM61713, HS-10296, lcotinib, Lapatinib, Necitumumab, Neratinib, Imotuzumab, Osimertinib, Panitumumab, Peltinib, PF-06747775, Rociletinib, Sapitinib, SKLB1028, Tesavatinib, Tivozanib, Vandetanib, Alectinib, ASP3026, RO5424802, CT-707,
  • the present invention comprises a method of treating lung cancer.
  • the methods of the present invention comprise a method of treating a subject suffering with a cancer is selected from the group consisting of leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer and breast cancer.
  • the present invention comprises method of treatment wherein the subject is a human.
  • the present invention comprises methods of reducing the proliferation of a cancer cell, comprising contacting the above compositions of the invention with cancer cell selected from the group consisting of leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer and breast cancer.
  • the present invention provides methods using the
  • compositions of the present invention in a method of treating cancer characterized by tumor cells with elevated NQOl levels, comprising administering to a patient affected by such cancer a therapeutically effective amount of a composition of the present invention, as described above.
  • the method of the present invention comprises a
  • the method of the present invention comprises treating a patient with the above composition, wherein the patient previously received a kinase inhibitor selected from Afatinib, Axitinib, Bosutinib, Cabozantinib, Dasatinib, Fostamatinib, , Ibrutinib, Imatinib, , Lenvatinib, Mubritinib, Nilotinib, Pazopanib, Pegaptanib, Ruxolitinib, Sorafenib, Sunitinib, SU6656, ABT-414, AC-480, AC0010MA, AEE-788, AP32788, ASP8273, AV-412, AZD3759, BMS-690514, BPI-15086, Cetuxima
  • a kinase inhibitor selected from Afatinib, Axitinib, Bosutinib, Cabozantinib, Dasatinib,
  • This invention relates to a pharmaceutical composition comprising a NQOl substrate as a method of enhancing the effectiveness of kinase targeting anticancer agents and for overcoming resistance to such drugs and subsequent relapse.
  • NRF2 target gene products are involved in cytoprotection, and typical examples include detoxifying enzymes and antioxidant enzymes such as NQOl. Taguchi and others have suggested the use of NRF2 inhibitors as anti-cancer drugs. In certain embodiments of the present invention, exactly the opposite is approach is taken: the up-regulation of NRF2 leads to an increase in NQOl and thus increased effectiveness of NQOl-substrate drugs according to the present invention.
  • KEAP1 functions as a negative regulator of the transcription factor NRF2.
  • NRF2 functions to control the gene expression of detoxifying enzymes, and in particular, the enzyme NQOl.
  • DNQ and its analogues are compounds that are reduced by NQOl to generate reactive oxygen species, within cells having high expression of NQOl, leading to DNA damage and cell death.
  • Cells with loss of KEAP1 function have upregulated NRF2 and so have high NQOl expression.
  • EGFR a transmembrane glycoprotein is a member of the ERBB receptor tyrosine kinase superfamily. EGFR binds to its cognate ligand EGF, which further induces tyrosine phosphorylation and receptor dimerization with other family members leading to enhanced uncontrolled proliferation.
  • EGF ERBB receptor tyrosine kinase superfamily.
  • Several anti-EGFR therapies such as monoclonal antibodies and tyrosine kinase inhibitors have been developed, which has enabled clinicians to identify and treat specific patient cohorts. See Expert Opin Ther Targets. 2012 Jan; 16(1): 15-31. Targeting the EGFR signaling pathway in cancer therapy. Parthasarathy S. et al.
  • EGFR is targeted by the following molecules: ABT-414, AC-480, AC0010MA, AEE-788,
  • the compounds and methods of the present invention may be used to overcome or take advantage of the natural or acquired resistance to these molecules.
  • ALK Anaplastic lymphoma kinase
  • CD246 CD246
  • cluster of differentiation 246 is an enzyme that in humans is encoded by the ALK gene which becomes an oncogene when mutated.
  • ALK is a novel receptor tyrosine kinase having a transmembrane domain and an extracellular domain. See https://en. wikipedia.org/wiki/Anaplastic_lymphoma_kinase accessed November 23, 2017.
  • ALK is targeted by the following molecules: Alectinib, ASP3026, RO5424802, CT-707,
  • the compounds and methods of the present invention may be used to overcome, lessen, or take advantage of the natural or acquired resistance to these molecules.
  • BRAF is a human gene that encodes a protein called B-Raf.
  • the gene is also known as proto-oncogene B-Raf, v-Raf murine sarcoma viral oncogene homolog B, and serine/ threonine-protein kinase B-Raf.
  • the B-Raf protein is a signaling protein involved in cell growth. Mutated BRAF may lead to cancer. See https://en.wikipedia.org/wiki/ BRAF_(gene) accessed on November 23, 2017.
  • BRAF is targeted by the following molecules: Vemurafenib, ARQ 736, ARRY-300,
  • the compounds and methods of the present invention may be used to overcome, lessen or take advantage of the natural or acquired resistance to these molecules.
  • a MEK inhibitor is a chemical or drug that inhibits the mitogen-activated protein kinase kinase enzymes MEK1 and/or MEK2. They can be used to affect the MAPK/ERK pathway which is often overactive in some cancers. MEK inhibitors have potential for treatment of some cancers, especially BRAF-mutated melanoma and KRAS/BRAF mutated colorectal cancer. https://en.wikipedia.org/wiki/MEK_inhibitor accessed November 23, 2017.
  • MEK is targeted by the following molecules: ARRY-300, AS703988, AZD-8330,
  • the compounds and methods of the present invention may be used to overcome, lessen or take advantage of the natural or acquired resistance to these molecules.
  • Additional kinase inhibitors that may be used according to the present invention include Afatinib, Axitinib, Bosutinib, Cabozantinib, Dasatinib, Fostamatinib, , Ibrutinib, Imatinib, , Lenvatinib, Mubritinib, Nilotinib, Pazopanib, Pegaptanib, Ruxolitinib, Sorafenib, Sunitinib,and SU6656.
  • NQOl substrates according to the present invention can lead to effective synergy in the KEAP1 loss of function intrinsic resistance setting. Additionally, tumors that show resistance to kinase targeted therapy, can be made sensitive with addition of DNQ analogue administration.
  • each intervening number with the same degree of precision is explicitly contemplated.
  • the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 and 7.0 are explicitly contemplated.
  • abnormal cell growth and "hyperproliferative disorder” are used
  • abnormal cell growth refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition), including the abnormal growth of normal cells and the growth of abnormal cells.
  • acyl includes alkyl, aryl, or heteroaryl substituents attached to a compound via a carbonyl functionality (e.g.,— C(0)-alkyl,— C(0)-aryl, etc.). Examples are an alkylcarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl or
  • heteroarylcarbonyl substituent any of which may be further substituted (e.g., with one or more substituents).
  • acylamino refers to an acyl radical appended to an amino or alkylamino
  • acyloxy refers to the ester group— OC(O)— R, where R is H, alkyl, alkenyl, alkynyl, or aryl.
  • administering refers to providing, contacting, and/or delivery of a compound or compounds by any appropriate route to achieve the desired effect.
  • Administration may include, but is not limited to, oral, sublingual, parenteral (e.g., intravenous, subcutaneous, intracutaneous, intramuscular, intra- articular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional or intracranial injection), transdermal, topical, buccal, rectal, vaginal, nasal, ophthalmic, via inhalation, and implants.
  • alkenyl includes alkyl moieties having at least one carbon-carbon double bond, including E and Z isomers of said alkenyl moiety.
  • the term also includes cycloalkyl moieties having at least one carbon-carbon double bond, i.e., cycloalkenyl.
  • alkenyl radicals include ethenyl, propenyl, butenyl, 1,4-butadienyl, cyclopentenyl, cyclohexenyl, prop-2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl, hex-2-enyl, and the like.
  • An alkenyl group may be optionally substituted.
  • alkenyl groups include, but are not limited to, allyl, propenyl, 2-butenyl, 3-hexenyl and 3-octenyl groups.
  • One of the double bond carbons may optionally be the point of attachment of the alkenyl substituent.
  • alkenylene refers to a divalent alkenyl, e.g.,— CH-CH— ,— CH-CH 2 CH 2 — or — CH-C-CH— .
  • An alkenylene may be optionally substituted.
  • alkenylene refers to a divalent straight chain, branched chain or cyclic
  • alkoxy means an O-alkyl group. Examples of alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.
  • alkyl refers to a straight or branched hydrocarbon chain, containing the indicated number of carbon atoms. It further means, saturated monovalent
  • alkyl group may include an optional carbon-carbon double or triple bond where the alkyl group comprises at least two carbon atoms. Cycloalkyl moieties require at least three carbon atoms. Examples of straight or branched alkyl radicals include methyl (Me), ethyl (Et), n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, tert-amyl, pentyl, isopentyl, hexyl, heptyl, octyl and the like. An alkyl group may be optionally substituted.
  • alkylamino refers to the— NRR' group, where R and R' are independently selected from hydrogen (however, R and R' cannot both be hydrogen), alkyl, and aryl groups; or R and R', taken together, can form a cyclic ring system.
  • alkylene refers to a divalent straight chain, branched chain or cyclic
  • alkylene refers to a divalent alkyl, e.g.,— CH 2 — ,— CH CH— ,— CH CH CH— or— CH CH(CH 3 )CI-l— .
  • An alkylene group may be optionally substituted.
  • alkylthio alone or in combination, refers to an optionally substituted alkyl thio radical, alkyl-S— .
  • alkynyl refers to straight- and branched-chain alkynyl groups having from two to twelve carbon atoms, preferably from 2 to 6 carbons, and more preferably from 2 to 4 carbons.
  • alkynyl groups include, but are not limited to, ethynyl, propargyl, and 3-hexynyl.
  • One of the triple bond carbons may optionally be the point of attachment of the alkynyl substituent.
  • alkynylene refers to a divalent alkynyl, e.g.,— CoC— or— CoC— CH 2 — .
  • An alkynyl or alkynylene may be optionally substituted.
  • amide refers to the radical— C(0)N(R')(R") where R' and R" are each
  • R' and R" cyclize together with the nitrogen to form a heterocycloalkyl or heteroaryl.
  • amino refers to a group of the formula— NR 1 R 2 , wherein R 1 and R 2 are each independently selected from, for example, hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or R 1 and R 2 , together with the nitrogen to which they are attached, may form a ring structure.
  • amino groups include, but are not limited to,— NH 2 , alkylamino groups such as— NHCH 3 ,— NHCH2CH 3 and— NHCH(CH 3 ) 2 , dialkylamino groups such as— N(CH 3 ) 2 and— N(CH 2 CH 3 ) 2 , and arylamino groups such as— NHPh.
  • cyclic amino groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidino, piperazinyl, perhydrodiazepinyl, morpholino, and
  • the groups R 1 and R 2 may be optionally substituted.
  • amino acid refers to any of the naturally occurring amino acids, as well as synthetic analogs and derivatives thereof.
  • a-Amino acids comprise a carbon atom to which is bonded an amino group, a carboxyl group, a hydrogen atom, and a distinctive group referred to as a "side chain”.
  • side chains of naturally occurring amino acids include, for example, hydrogen (e.g., as in glycine), alkyl (e.g., as in alanine, valine, leucine, isoleucine, proline), substituted alkyl (e.g., as in threonine, serine, methionine, cysteine, aspartic acid, asparagine, glutamic acid, glutamine, arginine, and lysine), arylalkyl (e.g., as in phenylalanine and tryptophan), substituted arylalkyl (e.g., as in tyrosine), and heteroarylalkyl (e.g., as in histidine).
  • hydrogen e.g., as in glycine
  • alkyl e.g., as in alanine, valine, leucine, isoleucine, proline
  • substituted alkyl e.g., as in threonine,
  • amino acid also includes b-, g-, d-, and w-amino acids, and the like. Unnatural amino acids are also known in the art, as set forth in, for example, Williams (ed.), Synthesis of Optically Active a-Amino Acids, Pergamon Press (1989); Evans et al., J. Amer. Chem. Soc., 112:4011-4030 (1990); Pu et al., J. Amer. Chem. Soc., 56:1280-1283 (1991); Williams et al., J. Amer. Chem. Soc., 113:9276-9286 (1991); and all references cited therein.
  • Amino acid residues are abbreviated as follows: Phenylalanine is Phe or F; Leucine is Leu or L; Isoleucine is lie or I; Methionine is Met or M; Norleucine is Nle;
  • Valine is Val or V; Serine is Ser or S; Proline is Pro or P; Threonine is Thr or T; Alanine is Ala or A; Tyrosine is Tyr or Y; Histidine is His or H; Glutamine is Gin or Q; Asparagine is Asn or N; Lysine is Lys or K; Aspartic Acid is Asp or D; Glutamic Acid is Glu or E; Cysteine is Cys or C; Tryptophan is Trp or W; Arginine is Arg or R; Glycine is Gly or G, and X is any amino acid.
  • Stereoisomers e.g., D-amino acids of the twenty conventional amino acids, unnatural amino acids such as a,a-disubstituted amino acids, N-alkyl amino acids, and other unconventional amino acids may also be suitable components for compounds of the present invention.
  • unconventional amino acids include: 4-hydroxy- proline, O-phosphoserine, N-acetylserine, N-formylmethionine, 3-methylhistidine, 5- hydroxy lysine, and other similar amino acids and imino acids (e.g., 4-hydroxyproline).
  • the left-hand direction is the amino terminal direction and the right-hand direction is the carboxy-terminal direction, in accordance with standard usage and convention.
  • anti-neoplastic agent refers to agents capable of inhibiting or preventing the growth of neoplasms, or checking the maturation and proliferation of malignant (cancer) cells.
  • aromatic refers to compounds or moieties comprising multiple conjugated double bonds.
  • aromatic moieties include, without limitation, aryl or heteroaryl ring systems.
  • Aryl or “Ar” refers to an unsaturated aromatic carbocyclic group of from 6 to 14
  • aryls having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) carbon atoms, which can optionally be unsubstituted or substituted with from 1 to 3 substituents selected from hydroxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amido, amino, aryloxy, carboxyl, halo, mercapto, cyano, nitro, --S0 3 , --S0 2 NH 2 and other non-interfering substituents.
  • Preferred aryls include phenyl and alkyl substituted phenyl.
  • Preferred aryl groups have from 4 to 20 ring atoms, and more preferably from 6 to 14 ring atoms. An aryl group may be optionally substituted.
  • aryl moieties include, but are not limited to, phenyl, naphthyl, and anthracenyl.
  • arylalkyl refers to an alkyl moiety in which an alkyl hydrogen atom is
  • Arylalkyl includes groups in which more than one hydrogen atom has been replaced with an aryl group.
  • Examples of arylalkyl groups include benzyl, 2-phenylethyl, 3-phenylpropyl, 9-fluorenyl, benzhydryl, and trityl groups.
  • aryloxy means aryl-O—.
  • arylthio means an aryl thio radical, aryl-S— .
  • carbamoyl or “carbamate” refers to the group— O— C(O)— NRR" where R and R" are independently selected from hydrogen, alkyl, and aryl groups; and R and R" taken together can form a cyclic ring system.
  • Carbocyclyl includes optionally substituted cycloalkyl and aryl moieties.
  • the term “carbocyclyl” also includes cycloalkenyl moieties having at least one carbon-carbon double bond.
  • carboxy esters refers to— C(0)0R where R is alkyl or aryl.
  • cancermas refers to lesions that are cancerous. Examples include malignant melanomas, breast cancer, prostate cancer and colon cancer.
  • Contacting refers to contacting a cell directly or indirectly in vitro, ex vivo, or in vivo (i.e. within a subject, such as a mammal, including humans, mice, rats, rabbits, cats, and dogs). Contacting a cell, which also includes “reacting" a cell, can occur as a result of administration to a subject. Contacting encompasses administration to a cell, tissue, mammal, subject, patient, or human. Further, contacting a cell includes adding an agent to a cell culture. Other suitable methods may include introducing or administering an agent to a cell, tissue, mammal, subject, or patient using appropriate procedures and routes of administration as defined herein.
  • cycloalkyl refers to a monocyclic or polycyclic radical which contains only carbon and hydrogen, and may be saturated, partially unsaturated, or fully unsaturated.
  • a cycloalkyl group may be optionally substituted.
  • Preferred cycloalkyl groups include groups having from three to twelve ring atoms, more preferably from 5 to 10 ring atoms. Any ring atom can be substituted (e.g., with one or more substituents).
  • Cycloalkyl groups can contain fused rings. Fused rings are rings that share one or more common carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, methylcyclohexyl, adamantyl, norbornyl and norbornenyl.
  • Effective amount refers to a dosage of the compounds or
  • compositions effective for eliciting a desired effect may also refer to an amount effective at bringing about a desired in vivo effect in an animal, mammal, or human, such as reducing proliferation of a cancer cell.
  • the terms “enhance” or “enhancing” means to increase or prolong either in potency or duration a desired effect.
  • the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system (e.g., a tumor cell).
  • An “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system (including, by way of example only, a tumor cell in a patient).
  • amounts effective for this use will depend on the severity and course of the proliferative disorder (including, but not limited to, cancer), previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician. It is considered well within the skill of the art for one to determine such enhancing-effective amounts by routine experimentation.
  • Ester or “carboxyl ester” refers to the group --C(0)0R where R is alkyl, aryl, arylalkyl, or heteroaryl (including substituted alkyl, substituted aryl, substituted heteroaryl, or substituted arylalkyl).
  • An "excipient” generally refers to substance, often an inert substance, added to a
  • halo or halogen means fluoro, fluorine, chloro, chlorine, bromo, bromine, iodo, or iodine.
  • haloalkyl, haloalkenyl, haloalkynyl and haloalkoxy include alkyl, alkenyl,
  • alkynyl and alkoxy structures that are substituted with one or more halo groups or with combinations thereof.
  • heteroalkyl “heteroalkenyl” and “heteroalkynyl” include optionally
  • heteroaryl refers to an aromatic 5-8 membered monocyclic
  • heteroaryl groups include, but are not limited to, radicals of pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, imidazole, pyrazole, oxazole, isoxazole, furan, thiazole, isothiazole, thiophene, quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline, indole, isoindole, indolizine, indazole, benzimidazole, phthalazine, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, phenazine, naphthyridines and purines.
  • heterocyclyl refers to aromatic and non-aromatic heterocyclic groups
  • Non-aromatic heterocyclic groups include groups having only 4 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system.
  • the heterocyclic groups include benzo-fused ring systems.
  • An example of a 4 membered heterocyclic group is azetidinyl (derived from azetidine).
  • An example of a 5 membered heterocyclic group is thiazolyl.
  • An example of a 6 membered heterocyclic group is pyridyl, and an example of a 10 membered heterocyclic group is quinolinyl.
  • Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolin
  • aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinox
  • furopyridinyl may be C- attached or N-attached where such is possible.
  • a group derived from pyrrole may be pyrrol-l-yl (N-attached) or pyrrol-3-yl (C-attached).
  • a group derived from imidazole may be imidazol-l-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached).
  • the heterocyclic groups include benzo-fused ring systems and ring systems substituted with one or two oxo ( O) moieties such as pyrrolidin-2-one.
  • a heterocyclyl group may be optionally substituted.
  • Heterocycle or “heterocyclic” refers to a monovalent saturated, unsaturated or
  • aromatic (heteroaryl) carbocyclic group having a single ring or multiple condensed rings having at least one hetero atom, such as nitrogen, sulfur or oxygen within the ring, which can optionally be unsubstituted or substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, halo, mercapto, and other non-interfering substituents.
  • heterocycloalkyl refers to a cycloalkyl group that includes at least one
  • heteroatom selected from nitrogen, oxygen and sulfur.
  • the radicals may be fused with an aryl or heteroaryl.
  • hydroxy refers to an—OH radical.
  • alkoxy refers to an—O-alkyl radical.
  • tumor cells By the term “inhibiting the growth of tumor cells” as used herein is meant the inhibition of the growth of tumor cells which are sensitive to the method of the subject invention, e.g., therapy involving the administration of an effective amount of the combination of a compound of the camptothecin class, such as topotecan, and a platinum coordination compound, such as cisplatin to a human afflicted therewith.
  • a compound of the camptothecin class such as topotecan
  • a platinum coordination compound such as cisplatin
  • lower alkoxy refers to alkoxy groups having from 1 to 8 carbons, including straight, branched or cyclic arrangements.
  • lower alkylmercapto refers to a sulfide group that is substituted with a lower alkyl group
  • lower alkyl sulfonyl refers to a sulfone group that is substituted with a lower alkyl group.
  • membered ring can embrace any cyclic structure.
  • membered is meant to denote the number of skeletal atoms that constitute the ring.
  • cyclohexyl, pyridine, pyran and thiopyran are 6-membered rings and cyclopentyl, pyrrole, furan, and thiophene are 5-membered rings.
  • Neoplasm is defined as in Stedman's Medical Dictionary 25th Edition (1990) and refers to an abnormal tissue that grows by cellular proliferation more rapidly than normal and continues to grow after the stimuli that initiated the new growth ceases. Neoplasms show partial or complete lack of structural organization and functional coordination compared with normal tissue, and usually form a distinct mass of tissue that may be either benign (benign tumor) or malignant (cancer).
  • Optionally substituted groups may be substituted or unsubstituted.
  • the substituents of an “optionally substituted” group may include, without limitation, one or more substituents independently selected from the following groups or designated subsets thereof: (Cl-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cl-C6)heteroalkyl, (Cl- C6)haloalkyl, (C2-C6)haloalkenyl, (C2-C6)haloalkynyl, (C3-C6)cycloalkyl, phenyl, (Cl- C6)alkoxy, phenoxy, (Cl-C6)haloalkoxy, amino, (Cl-C6)alkylamino, (Cl-C6)alkylthio, phenyl-S— , oxo, (Cl-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl,
  • An optionally substituted group may be unsubstituted (e.g.,— CH2CH3), fully substituted (e.g.,— CF2CF3), monosubstituted (e.g.,— CH2CH2F) or substituted at a level anywhere in-between fully substituted and monosubstituted (e.g.,— CH2CF3).
  • perhaloalkyl groups include— CF3 and— CFCI2.
  • a "pharmacological composition” refers to a mixture of one or more of the compounds described herein, or physiologically acceptable salts thereof, with other chemical components, such as physiologically acceptable carriers and/or excipients.
  • the purpose of a pharmacological composition is to facilitate administration of a compound to an organism.
  • a “physiologically acceptable carrier” refers to a carrier or diluent that does not cause significant or otherwise unacceptable irritation to an organism and does not unacceptably abrogate the biological activity and properties of the administered compound.
  • pharmaceutically acceptable salts and prodrugs refer to derivatives of the disclosed compounds that are modified by making acid or base salts, or by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo in relation to the parent compounds.
  • examples include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; acetyl formyl and benzoyl derivatives of amines; and the like.
  • compositions of the compounds of the invention are prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference in its entirety.
  • the salts can be prepared in situ during the final isolation and purification of such
  • Representative acid addition salts include the hydrochloride, hydrobromide, sulfate, bisulfate, acetate, valerate, oleate, palmatate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate, maleate, fumarate, succinate, tartrate, glucoheptonate, lactobionate, lauryl sulfate salts and the like.
  • Representative alkali and alkaline earth metal salts include the sodium, calcium, potassium and magnesium salts.
  • a pharmaceutically acceptable salt is intended to mean a salt that retains the
  • a compound of the invention may possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • exemplary pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or an inorganic base, such as salts including sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyn
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid, 2-
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • an inorganic or organic base such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, carbonates, bicarbonates, primary, secondary, and tertiary amines, and cyclic amines, such as benzylamines, pyrrolidines, piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • amino acids such as glycine and arginine
  • ammonia carbonates, bicarbonates, primary, secondary, and tertiary amines
  • cyclic amines such as benzylamines, pyrrolidines, piperidine, morpholine and piperazine
  • inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • subject is intended to include human and non-human
  • non-human animals includes all vertebrates, e.g., non-mammals (such as chickens, amphibians, reptiles) and mammals, such as non human primates, domesticated and/or agriculturally useful animals (such as sheep, dogs, cats, cows, pigs, etc.), and rodents (such as mice, rats, hamsters, guinea pigs, etc.).
  • non-mammals such as chickens, amphibians, reptiles
  • mammals such as non human primates, domesticated and/or agriculturally useful animals (such as sheep, dogs, cats, cows, pigs, etc.), and rodents (such as mice, rats, hamsters, guinea pigs, etc.).
  • substituted means that the group in question, e.g., alkyl group, etc., may bear one or more substituents.
  • groups and substituents thereof may be selected in accordance with permitted valence of the atoms and the substituents, such that the selections and substitutions result in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • [130] is used in structural formulas herein to depict the bond that is the point of attachment of the moiety or substituent to the core or backbone structure.
  • the substituted aryl and heteroaryl groups of the invention have one or more hydrogen atoms replaced with a halo, hydroxy, alkyl, alkoxy, amino, cyano, carboxy, carbalkoxy, nitro or trifluoromethyl group.
  • a halo group is a halogen, and includes fluoro, chloro, bromo and iodo groups.
  • alkoxy refers to an alkyl group having at least one oxygen substitutent.
  • carbalkoxy refers to groups of the formula -R-C(0)0- where R is an alkyl group.
  • Substituted alkoxy refers to -O-substituted alkyl and includes, by way of example, -- OCF 3 , --OCH 2 -f and the like.
  • compositions containing the compound(s) of the described herein can be
  • compositions are administered for prophylactic and/or therapeutic treatments.
  • the compositions are administered to a patient already suffering from a proliferative disorder or condition (including, but not limited to, cancer), as described above, in an amount sufficient to cure or at least partially arrest the symptoms of the proliferative disorder or condition.
  • An amount adequate to accomplish this is defined as "therapeutically effective amount or dose.” Amounts effective for this use will depend on the severity and course of the proliferative disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.
  • compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular proliferative disorder or condition.
  • Such an amount is defined to be a "prophylactically effective amount or dose.”
  • the precise amounts also depend on the patient's state of health, weight, and the like. It is considered well within the skill of the art for one to determine such therapeutically effective or prophylactically effective amounts by routine
  • experimentation e.g., a dose escalation clinical trial.
  • thioalkoxy or "thioether” refers to an— S-alkyl radical.
  • thioaryloxy refers to an— S-aryl radical.
  • administering a regimen to the subject e.g., the administration of a compound or a composition comprising a compound, such that at least one symptom of the disorder is cured, healed, alleviated, relieved, altered, remedied, ameliorated, or improved.
  • Treating includes administering an amount effective to alleviate, relieve, alter, remedy, ameliorate, improve or affect the disorder or the symptoms of the disorder.
  • the treatment may inhibit deterioration or worsening of a symptom of a disorder.
  • ureyl refers to the group— N(R)— C(O)— NR'R" where R, R', and R" are independently selected from hydrogen, alkyl, aryl; and where each of R— R', R'— R", or R— R" taken together can form a cyclic ring system.
  • compositions according the present inventions comprise compounds that are substrates for detoxifying enzymes such as NAD(P)H quinone oxidoreductase (NQOl).
  • NQOl is an FAD-dependent 2-electron reductase whose primary function is to protect the cell from cytotoxins, especially quinones. It is a Phase II detoxifying enzyme, the expression of which is regulated by NRF-2 and the antioxidant response element (ARE) in response to electrophilic or oxidative stress.
  • ARE antioxidant response element
  • quinone-containing molecules are frequently cytotoxic and harm cells through two mechanisms.
  • Many quinones are conjugate addition acceptors and readily alkylate nucleophilic species such as DNA and cysteine residues.
  • Quinones are also substrates for 1-electron reductases, such as cytochrome P450s, cytochrome b5, xanthine oxidase, and glutathione reductase. Reduction of quinones by these enzymes generates a highly reactive semiquinone that can damage biomolecules directly, or can be oxidized by dissolved oxygen resulting in the formation of an equivalent of superoxide anion radical and the parent quinone.
  • 1-electron reduction of quinones can catalytically create reactive oxygen species (ROS) that damage the cell.
  • ROS reactive oxygen species
  • DNQ analogues are potent chemotherapeutic agents exhibiting a wide therapeutic
  • compositions of the present invention also comprise additional, often synergistic molecules that modify the reactive oxygen species created or enhanced through the addition of the NQOl substrate molecules.
  • These molecules include but are not limited to ROS-inducible DNA cross-linking agents.
  • ROS are increased preferentially in cancer cells.
  • a compound of the quinone class is meant any tumor cell growth
  • quinone which is structurally related to quinone.
  • compounds of the quinone class include, but are not limited to, DNQ and its derivatives. Such compounds also include, but are not limited to, any tumor cell growth-inhibiting quinone analog.
  • the present invention is subject to many variations, modifications and extensions, without varying from the essential invention, as disclosed herein.
  • the content of the active ingredients in the pharmaceutical compositions of this invention may vary quite widely depending upon numerous factors, such as, the desired dosage and the pharmaceutically acceptable carrier being employed.
  • Physiological pH of injectables or infusion drugs and combinations may be established by inclusion of buffering agents as is known in the pharmaceutical formulation art.
  • Such pharmaceutically acceptable excipients preferably include saline (e.g., 0.9% saline), Cremophor EL (which is a derivative of castor oil and ethylene oxide available from Sigma Chemical Co., St. Louis, Mo.) (e.g., 5% Cremophor EL/5% ethanol/90% saline, 10% Cremophor EL/90% saline, or 50% Cremophor EL/50% ethanol), propylene glycol (e.g., 40% propylene glycol/10% ethanol/50% water), polyethylene glycol (e.g., 40% PEG 400/60% saline), and alcohol (e.g., 40% t-butanol/60% water).
  • the most preferred pharmaceutical excipient for use in conjunction with the present invention is polyethylene glycol, such as PEG 400, and particularly a composition comprising 40% PEG 400 and 60% water or saline.

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Abstract

La présente invention concerne des compositions pharmaceutiques et des méthodes comprenant un agent thérapeutique qui génère ou produit des espèces réactives de l'oxygène (« ERO ») dans un microenvironnement de maladie, et au moins un inhibiteur de kinase pour le traitement d'un cancer, de troubles dysplasiques, de troubles néoplasiques ou hyperprolifératifs chez le mammifère et leurs méthodes d'utilisation pour le traitement d'un cancer, de troubles dysplasiques, de troubles néoplasiques ou hyperprolifératifs chez le mammifère.
PCT/US2018/064294 2017-12-06 2018-12-06 Association d'agents thérapeutiques anticancéreux pour le traitement du cancer et de maladies hyperprolifératives WO2019113345A1 (fr)

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WO2021089038A1 (fr) * 2019-11-09 2021-05-14 石药集团中奇制药技术（石家庄）有限公司 Utilisation d'un inhibiteur de protéines kinases multi-cible
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WO2021089038A1 (fr) * 2019-11-09 2021-05-14 石药集团中奇制药技术（石家庄）有限公司 Utilisation d'un inhibiteur de protéines kinases multi-cible
CN114650826A (zh) * 2019-11-09 2022-06-21 石药集团中奇制药技术（石家庄）有限公司 一种多靶点蛋白激酶抑制剂的用途
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CN114650826B (zh) * 2019-11-09 2024-03-22 石药集团中奇制药技术（石家庄）有限公司 一种多靶点蛋白激酶抑制剂的用途
CN116194095A (zh) * 2020-04-03 2023-05-30 百济神州有限公司 用于治疗癌症的米达替尼与利非芬尼的共同施用
CN112451523A (zh) * 2020-12-11 2021-03-09 澳门大学 Deoxynyboquinone在制备抗炎药物或抗氧化药物中的应用
WO2022143933A1 (fr) * 2020-12-31 2022-07-07 石药集团中奇制药技术（石家庄）有限公司 Composition pharmaceutique d'inhibiteurs de protéine kinase à cibles multiples, et son utilisation

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