WO2022019892A1 - Agents thérapeutiques et utilisations de ceux-ci - Google Patents

Agents thérapeutiques et utilisations de ceux-ci Download PDF

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Publication number
WO2022019892A1
WO2022019892A1 PCT/US2020/042933 US2020042933W WO2022019892A1 WO 2022019892 A1 WO2022019892 A1 WO 2022019892A1 US 2020042933 W US2020042933 W US 2020042933W WO 2022019892 A1 WO2022019892 A1 WO 2022019892A1
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groups
group
compound
composition
independently selected
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PCT/US2020/042933
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English (en)
Inventor
Gene H. Zaid
Thomas W. Burgoyne
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Ankh Life Sciences Limited
CROW, Larry D.
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Application filed by Ankh Life Sciences Limited, CROW, Larry D. filed Critical Ankh Life Sciences Limited
Priority to PCT/US2020/042933 priority Critical patent/WO2022019892A1/fr
Priority to EP20946050.0A priority patent/EP4185288A4/fr
Priority to CN202080102648.3A priority patent/CN115916195A/zh
Publication of WO2022019892A1 publication Critical patent/WO2022019892A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • Cancer is a generic term for a large group of diseases that can affect any part of the body. Other terms used are malignant tumors and neoplasms.
  • One defining feature of cancer is the rapid creation of abnormal cells that grow beyond their usual boundaries, and which can then invade adjoining parts of the body and spread to other organs. This process is referred to as metastasis. Metastases are the major cause of death from cancer.
  • the transformation from a normal cell into a tumor cell is a multistage process, typically a progression from a pre-cancerous lesion to malignant tumors. These changes are the result of the interaction between a person's genetic factors and three categories of external agents, including:
  • Vimses hepatitis B and liver cancer, Human Papilloma Virus (HPV) and cervical cancer, and human immunodeficiency virus (HIV) and Kaposi sarcoma.
  • cancer treatment modalities are surgery, chemotherapy, and radiation treatments. All of these techniques have significant drawbacks in terms of side effects and patient discomfort.
  • chemotherapy may result in significant decreases in white blood cell count (neutropenia), red blood cell count (anemia), and platelet count (thrombocytopenia). This can result in pain, diarrhea, constipation, mouth sores, hair loss, nausea, and vomiting.
  • Bio therapy (sometimes called immunotherapy, biotherapy, or biological response modifier therapy) is a relatively new addition to the family of cancer treatments.
  • Biological therapies use the body's immune system, either directly or indirectly, to fight cancer or to lessen the side effects that may be caused by some cancer treatments.
  • Examples of famous negative drug interactions include the development of rhabdomyolysis, a severe muscle disease, when taking Simvastatin with Amiodarone. As a result, the FDA introduced a warning on the drug label about the interaction.
  • US Patent No. 8,039.025 describes cancer treatments in the form of extracts of Arum palaestinum Boiss, supplemented with individual amounts of b-sitosterol, isovanillin, and linoleic acid, and this patent is incorporated by reference herein in its entirety.
  • compositions which may be used as improved chemotherapeutics for treatment of humans, and especially in the treatment of human cancers, and corresponding methods for preparing such compositions and use thereof.
  • the chemotherapeutics of the invention comprise (or consist essentially of, or consist of) one or more compounds and related versions thereof.
  • a defined “therapeutic compound” or “compound” means the defined compound per se, as well as the dimers, isomers, tautomers, derivatives, solvates, metabolites, esters, metal complexes (e.g., Cu, Fe, Zn, Pt, V), prodrugs, and salts thereof.
  • the invention also provides new methods for treatment of cancers by administration of appropriate quantities of compositions comprising therapeutic compounds as described herein.
  • the compositions are particularly designed for use in the treatment of cancers, and the compositions can be used for the manufacture of medicaments for anti-cancer therapeutic applications.
  • the invention provides compositions for the treatment of cancers comprising administering therapeutically effective amounts of the new compositions, prepared by processes known per se , with a pharmaceutically acceptable carrier.
  • a “chemotherapeutic,” “chemotherapeutic agent,” or simply “therapeutic agent,” as used herein refers to one or more of the compounds described herein as useful in the treatment of human conditions, especially human cancers. Chemotherapeutics may be cytostatic, selectively toxic, or destructive of cancerous tissue and/or cells, including cancer stem cells, but also include indiscriminately cytotoxic compounds used in cancer treatments.
  • the therapeutic compounds or agents of the invention have been found to be effective in the treatment of a number of human cancer cells, and especially lymphoma, leukemia, pancreatic, endometrial, ovarian, gastric, breast, renal, cervical, head and neck, and myeloma.
  • the compounds or agents of the invention broadly comprise a plurality of fused polycyclic moieties linked or tethered by an appropriate linker; preferably, there are two tricyclic moieties.
  • the polycyclic moieties each include at least one N-containing ring b-carboline moieties are particularly useful in the invention, such as harmaline or similar moieties.
  • a pair of b -carboline moieties are bonded by means of a linker moiety, and specifically through a single atom forming at least a part of the overall linker.
  • the reaction products of b-carboline compounds and aldehyde compounds yield a number of useful anti-cancer compounds in accordance with the invention.
  • anticancer compositions of the invention do not include compounds made up of the reaction product of two harmaline moieties or two harmine moieties, with a linker moiety of benzaldehyde of p-nitro benzaldehyde
  • the anti-cancer compositions of the invention (which normally include at least one other agent, component, or compound) and treatment methods do embrace such compounds.
  • Figure 1 is a graph of cell number versus dosage amounts of an orthovanillin/harmaline compound (GZ523.001), illustrating the effect thereof in inducing the death of lymphoma cells, as described in Example 2:
  • Fig. 2 is a graph of cell number versus dosage amounts of an orthovanillin/harmaline compound (GZ523.002), illustrating the effect thereof in inducing the death of lymphoma cells, as described in Example 2:
  • Fig. 3 is a graph of cell number versus dosage amounts of an orthovanillin/harmaline compound (GZ523.003), illustrating the effect thereof in inducing the death of lymphoma cells, as described in Example 2:
  • Fig. 4 is a graph of cell number versus dosage amounts of an orthovanillin/harmaline compound (GZ523.004), illustrating the effect thereof in inducing the death of lymphoma cells, as described in Example 2:
  • Fig. 5 is a graph of cell number versus dosage amounts of an orthovanillin/harmaline compound (GZ523.005), illustrating the effect thereof in inducing the death of lymphoma cells, as described in Example 2:
  • Fig. 6 is a graph of cell number versus dosage amounts of an orthovanillin/harmaline compound (GZ523.006), illustrating the effect thereof in inducing the death of lymphoma cells, as described in Example 2:
  • Fig. 7 is a graph of cell number versus dosage amounts of an orthovanillin/harmaline compound (GZ523.007), illustrating the effect thereof in inducing the death of lymphoma cells, as described in Example 2:
  • Fig. 8 is a graph of cell number versus dosage amounts of an orthovanillin/harmaline compound (GZ523.008), illustrating the effect thereof in inducing the death of lymphoma cells, as described in Example 2:
  • Fig. 11 is a graph of cell number versus dosage amounts of an orthovanillin/harmaline compound (GZ523.003), illustrating the effect thereof in inducing the death of leukemia cells, as described in Example 2:
  • Fig. 15 is a graph of cell number versus dosage amounts of an orthovanillin/harmaline compound (GZ523.007), illustrating the effect thereof in inducing the death of leukemia cells, as described in Example 2:
  • Fig. 16 is a graph of cell number versus dosage amounts of an orthovanillin/harmaline compound (GZ523.008), illustrating the effect thereof in inducing the death of leukemia cells, as described in Example 2:
  • Fig. 18 is a graph of cell number versus dosage amounts of a composition containing high molecular weight dioligomer compound(s) derived from an orthovanillin/harmaline reaction, illustrating the effect thereof in inducing the death of leukemia cells, as described in Example 3;
  • Fig. 19 is a graph of cell number versus dosage amounts of a vanillin/harmaline compound (GZ518.000), illustrating the effect thereof in inducing the death of lymphoma cells, as described in Example 5;
  • Fig. 20 is a graph of cell number versus dosage amounts of a vanillin/harmaline compound (GZ518.001), illustrating the effect thereof in inducing the death of lymphoma cells, as described in Example 5;
  • Fig. 21 is a bar graph illustrating the IC 50 values determined by treatment of a plurality of lymphoma cell lines with GZ523.006, as explained in Example 6;
  • Fig. 22 is a bar graph depicting the results of comparative Caspase 3/7 assays using GZ523.006 against a number of lymphoma cell lines, confirming the cytotoxic properties of GZ523.006 through induction of apoptosis;
  • Fig. 23 is a graph illustrating cell growth as a function of the concentration of the 518B562 compound, in the MIA PaCa-2 cell proliferation assay described in Example 8;
  • Fig. 24 is a graph illustrating cell growth as a function of the concentration of the 518B562 compound, in the ASPC-1 cell proliferation assay described in Example 8;
  • Fig. 25 is a graph illustrating cell growth as a function of the concentration of the 518B562 compound, in the BxPC-3 cell proliferation assay described in Example 8;
  • Fig. 26 is a graph illustrating cell growth as a function of the concentration of the 518B562 compound, in the AN3CA cell proliferation assay described in Example 8;
  • Fig. 27 is a graph illustrating cell growth as a function of the concentration of the 518B562 compound, in the HEC-la cell proliferation assay described in Example 8;
  • Fig. 28 is a graph illustrating cell growth as a function of the concentration of the 518B562 compound, in the MDA-MB-231 cell proliferation assay described in Example 8;
  • Fig. 30 is a graph illustrating cell growth as a function of the concentration of the 518B562 compound, in the HCC70 cell proliferation assay described in Example 8;
  • Fig. 32 is a graph illustrating cell growth as a function of the concentration of the 518B562 compound, in the HI 650 cell proliferation assay described in Example 8;
  • Fig. 33 is a graph illustrating cell growth as a function of the concentration of the 518B562 compound, in the A2780 cell proliferation assay described in Example 8;
  • Fig. 34 is a graph illustrating cell growth as a function of the concentration of the 518B562 compound, in the A2780CP cell proliferation assay described in Example 8;
  • Fig. 37 is a graph illustrating cell growth as a function of the concentration of the 518B562 compound, in the N87 cell proliferation assay described in Example 8;
  • Fig. 38 is a graph illustrating cell growth as a function of the concentration of the 518B562 compound, in the SiHA cell proliferation assay described in Example 8;
  • Fig. 40 is a graph illustrating cell growth as a function of the concentration of the 518B562 compound, in the DOHH-2 cell proliferation assay described in Example 8;
  • Fig. 41 is a graph illustrating cell growth as a function of the concentration of the 518B562 compound, in the SU-DHL-4 cell proliferation assay described in Example 8;
  • Fig. 44 is a graph illustrating cell growth as a function of the concentration of the 518B562 compound, in the KMM-1 cell proliferation assay described in Example 8;
  • Fig. 45 is a graph illustrating cell growth as a function of the concentration of the 518B562 compound, in the KMS-11 cell proliferation assay described in Example 8;
  • Fig. 46 is a graph illustrating cell growth as a function of the concentration of the 518B562 compound, in the KMS-27 cell proliferation assay described in Example 8;
  • Fig. 47 is a graph illustrating cell growth as a function of the concentration of the 518B562 compound, in the KMS-34 cell proliferation assay described in Example 8;
  • Fig. 48 is a graph illustrating cell growth as a function of the concentration of the 518B562 compound, in the H929 cell proliferation assay described in Example 8;
  • Fig. 49 is a graph illustrating cell growth as a function of the concentration of the 518B562 compound, in the L363 cell proliferation assay described in Example 8;
  • Fig. 50 is a graph illustrating cell growth as a function of the concentration of the 518B562 compound, in the MM. Is cell proliferation assay described in Example 8;
  • Fig. 51 is a graph illustrating cell growth as a function of the concentration of the 518B562 compound, in the MOLP-8 cell proliferation assay described in Example 8;
  • Fig. 55 is a graph illustrating cell growth as a function of the concentration of the 560 compound, in the MIA PaCa-2 cell proliferation assay described in Example 8;
  • Fig. 56 is a graph illustrating cell growth as a function of the concentration of the 560 compound, in the ASPC-1 cell proliferation assay described in Example 8;
  • Fig. 58 is a graph illustrating cell growth as a function of the concentration of the 560 compound, in the AN3CA cell proliferation assay described in Example 8;
  • Fig. 59 is a graph illustrating cell growth as a function of the concentration of the 560 compound, in the HEC-la cell proliferation assay described in Example 8;
  • Fig. 63 is a graph illustrating cell growth as a function of the concentration of the 560 compound, in the H1975 cell proliferation assay described in Example 8;
  • Fig. 65 is a graph illustrating cell growth as a function of the concentration of the 560 compound, in the A2780 cell proliferation assay described in Example 8;
  • Fig. 67 is a graph illustrating cell growth as a function of the concentration of the 560 compound, in the RXF-393 cell proliferation assay described in Example 8;
  • Fig. 68 is a graph illustrating cell growth as a function of the concentration of the 560 compound, in the A498 cell proliferation assay described in Example 8;
  • Fig. 69 is a graph illustrating cell growth as a function of the concentration of the 560 compound, in the N87 cell proliferation assay described in Example 8;
  • Fig. 70 is a graph illustrating cell growth as a function of the concentration of the 560 compound, in the SiHA cell proliferation assay described in Example 8;
  • Fig. 71 is a graph illustrating cell growth as a function of the concentration of the 560 compound, in the FaDu cell proliferation assay described in Example 8;
  • Fig. 73 is a graph illustrating cell growth as a function of the concentration of the 560 compound, in the SU-DHL-4 cell proliferation assay described in Example 8;
  • Fig. 74 is a graph illustrating cell growth as a function of the concentration of the 560 compound, in the OCI-LY3 cell proliferation assay described in Example 8;
  • Fig. 75 is a graph illustrating cell growth as a function of the concentration of the 560 compound, in the JIM1 cell proliferation assay described in Example 8;
  • Fig. 76 is a graph illustrating cell growth as a function of the concentration of the 560 compound, in the KMM-1 cell proliferation assay described in Example 8;
  • Fig. 77 is a graph illustrating cell growth as a function of the concentration of the 560 compound, in the KMS-11 cell proliferation assay described in Example 8;
  • Fig. 78 is a graph illustrating cell growth as a function of the concentration of the 560 compound, in the KMS-27 cell proliferation assay described in Example 8;
  • Fig. 79 is a graph illustrating cell growth as a function of the concentration of the 560 compound, in the KMS-34 cell proliferation assay described in Example 8;
  • Fig. 81 is a graph illustrating cell growth as a function of the concentration of the 560 compound, in the L363 cell proliferation assay described in Example 8;
  • Fig. 84 is a graph illustrating cell growth as a function of the concentration of the 560 compound, in the Jeko-1 Parental cell proliferation assay described in Example 8;
  • Fig. 85 is a graph illustrating cell growth as a function of the concentration of the 560 compound, in the Jeko-1 Lenalidomine Resistant cell proliferation assay described in Example 8;
  • Fig. 86 is a graph illustrating cell growth as a function of the concentration of the 560 compound, in the Jeko-1 Bortezomib Resistant cell proliferation assay described in Example 8;
  • Fig. 87 is a graph illustrating cell growth as a function of the concentration of the 561 compound, in the MIA PaCa-2 cell proliferation assay described in Example 8;
  • Fig. 88 is a graph illustrating cell growth as a function of the concentration of the 561 compound, in the ASPC-1 cell proliferation assay described in Example 8;
  • Fig. 89 is a graph illustrating cell growth as a function of the concentration of the 561 compound, in the BxPC-3 cell proliferation assay described in Example 8;
  • Fig. 90 is a graph illustrating cell growth as a function of the concentration of the 561 compound, in the AN3CA cell proliferation assay described in Example 8;
  • Fig. 91 is a graph illustrating cell growth as a function of the concentration of the 561 compound, in the HEC-la cell proliferation assay described in Example 8;
  • Fig. 92 is a graph illustrating cell growth as a function of the concentration of the 561 compound, in the MDA-MB-231 cell proliferation assay described in Example 8;
  • Fig. 93 is a graph illustrating cell growth as a function of the concentration of the 561 compound, in the MDA-MB-468 cell proliferation assay described in Example 8;
  • Fig. 94 is a graph illustrating cell growth as a function of the concentration of the 561 compound, in the HCC70 cell proliferation assay described in Example 8;
  • Fig. 95 is a graph illustrating cell growth as a function of the concentration of the 561 compound, in the H1975 cell proliferation assay described in Example 8;
  • Fig. 96 is a graph illustrating cell growth as a function of the concentration of the 561 compound, in the HI 650 cell proliferation assay described in Example 8;
  • Fig. 97 is a graph illustrating cell growth as a function of the concentration of the 561 compound, in the A2780 cell proliferation assay described in Example 8
  • Fig. 98 is a graph illustrating cell growth as a function of the concentration of the 561 compound, in the A2780CP cell proliferation assay described in Example 8;
  • Fig. 99 is a graph illustrating cell growth as a function of the concentration of the 561 compound, in the RXF-393 cell proliferation assay described in Example 8;
  • Fig. 100 is a graph illustrating cell growth as a function of the concentration of the 561 compound, in the A498 cell proliferation assay described in Example 8;
  • Fig. 101 is a graph illustrating cell growth as a function of the concentration of the 561 compound, in the N87 cell proliferation assay described in Example 8;
  • Fig. 102 is a graph illustrating cell growth as a function of the concentration of the 561 compound, in the SiHA cell proliferation assay described in Example 8;
  • Fig. 103 is a graph illustrating cell growth as a function of the concentration of the 561 compound, in the FaDu cell proliferation assay described in Example 8;
  • Fig. 104 is a graph illustrating cell growth as a function of the concentration of the 561 compound, in the DOHH-2 cell proliferation assay described in Example 8;
  • Fig. 105 is a graph illustrating cell growth as a function of the concentration of the 561 compound, in the SU-DHL-4 cell proliferation assay described in Example 8;
  • Fig. 106 is a graph illustrating cell growth as a function of the concentration of the 561 compound, in the OCI-LY3 cell proliferation assay described in Example 8;
  • Fig. 107 is a graph illustrating cell growth as a function of the concentration of the 561 compound, in the JIM1 cell proliferation assay described in Example 8;
  • Fig. 108 is a graph illustrating cell growth as a function of the concentration of the 561 compound, in the KMM-1 cell proliferation assay described in Example 8;
  • Fig. 109 is a graph illustrating cell growth as a function of the concentration of the 561 compound, in the KMS-11 cell proliferation assay described in Example 8;
  • Fig. 110 is a graph illustrating cell growth as a function of the concentration of the 561 compound, in the KMS-27 cell proliferation assay described in Example 8;
  • Fig. I l l is a graph illustrating cell growth as a function of the concentration of the 561 compound, in the KMS-34 cell proliferation assay described in Example 8;
  • Fig. 112 is a graph illustrating cell growth as a function of the concentration of the 561 compound, in the H929 cell proliferation assay described in Example 8
  • Fig. 113 is a graph illustrating cell growth as a function of the concentration of the 561 compound, in the L363 cell proliferation assay described in Example 8;
  • Fig. 114 is a graph illustrating cell growth as a function of the concentration of the 561 compound, in the MM. Is cell proliferation assay described in Example 8;
  • Fig. 115 is a graph illustrating cell growth as a function of the concentration of the 561 compound, in the MOLP-8 cell proliferation assay described in Example 8;
  • Fig. 116 is a graph illustrating cell growth as a function of the concentration of the 561 compound, in the Jeko-1 Parental cell proliferation assay described in Example 8;
  • Fig. 117 is a graph illustrating cell growth as a function of the concentration of the 561 compound, in the Jeko-1 Lenalidomine Resistant cell proliferation assay described in Example 8;
  • Fig. 118 is a graph illustrating cell growth as a function of the concentration of the 561 compound, in the Jeko-1 Bortezomib Resistant cell proliferation assay described in Example 8;
  • Fig. 119 is a graph illustrating cell growth as a function of the concentration of the confirmed 560 compound, in the S2-007 pancreatic ductal adenocarcinoma cell proliferation assay described in Example 15;
  • Fig. 120 is a graph illustrating cell growth as a function of the concentration of the confirmed 560 compound, in the MiaPaCa-2 pancreatic ductal adenocarcinoma cell proliferation assay described in Example 15;
  • Fig. 121 is a graph illustrating cell growth as a function of the concentration of the confirmed 562 compound, in the S2-007 pancreatic ductal adenocarcinoma cell proliferation assay described in Example 15;
  • Fig. 122 is a graph illustrating cell growth as a function of the concentration of the confirmed 562 compound, in the MiaPaCa-2 pancreatic ductal adenocarcinoma cell proliferation assay described in Example 15;
  • Fig. 123 is a series of photographs depicting the colony formations as a function of the concentration of the confirmed 560 compound, in the S2-007 pancreatic ductal adenocarcinoma cell colony formation assay described in Example 16;
  • Fig. 124 is a series of photographs depicting the colony formations as a function of the concentration of the confirmed 560 compound, in the MiaPaCa-2 pancreatic ductal adenocarcinoma cell colony formation assay described in Example 16;
  • Fig. 125 is a series of photographs depicting the colony formations as a function of the concentration of the confirmed 562 compound, in the S2-007 pancreatic ductal adenocarcinoma cell colony formation assay described in Example 16;
  • Fig. 126 is a series of photographs depicting the colony formations as a function of the concentration of the confirmed 562 compound, in the MiaPaCa-2 pancreatic ductal adenocarcinoma cell colony formation assay described in Example 16;
  • Fig. 127 is a further series of photographs depicting the colony formations as a function of the concentration of the confirmed 562 compound, in the MiaPaCa-2 pancreatic ductal adenocarcinoma cell colony formation assay described in Example 16;
  • Fig. 128 is a set of bar graphs illustrating the results of a cell cycle assay using the confirmed 560 compound with S2-007 cells over 24 and 48 hours, as described in Example 17, with Sub GO;
  • Fig. 128A is a set of bar graphs illustrating the results of a cell cycle assay using the confirmed 560 compound with S2-007 cells over 24 and 48 hours, as described in Example 17, without Sub GO;
  • Fig. 129 is a set of bar graphs illustrating the results of a cell cycle assay using the confirmed 560 compound with MiaPaCa-2 cells over 24, 48, and 72 hours, as described in Example 17, with Sub GO;
  • Fig. 129A is a set of bar graphs illustrating the results of a cell cycle assay using the confirmed 560 compound with MiaPaCa-2 cells over 24, 48, and 72 hours, as described in Example 17, without Sub GO;
  • Fig. 130 is a set of bar graphs illustrating the results of a cell cycle assay using the confirmed 562 compound with S2-007 cells over 24, 48, and 72 hours, as described in Example 17 a with Sub GO;
  • Fig. 130A is a set of bar graphs illustrating the results of a cell cycle assay using the confirmed 562 compound with S2-007 cells over 24, 48, and 72 hours, as described in Example 17, without Sub GO;
  • Fig. 131 is a set of bar graphs illustrating the results of a cell cycle assay using the confirmed 562 compound with MiaPaCa-2 cells over 24, 48, and 72 hours, as described in Example 17, with Sub GO; and Fig. 131A is a set of bar graphs illustrating the results of a cell cycle assay using the confirmed 562 compound with MiaPaCa-2 cells over 24, 48, and 72 hours, as described in Example 17, without Sub GO.
  • the therapeutic agents of the invention are used in therapeutically effective amounts, i.e., amounts that will elicit the biological or medical response of a tissue, system, or subject that is being sought, and in particular to elicit some desired therapeutic effect against a variety of human diseases, and especially cancers; in the case of cancers, the agents operate by preventing and/or inhibiting proliferation and/or survival of cancerous cells, including cancer stem cells, and/or by slowing the progression of cancers.
  • an amount may be considered therapeutically effective even if the condition is not totally eradicated or prevented, but it or its symptoms and/or effects are improved or alleviated partially in the subject.
  • the appropriate makeup of the agents hereof and dosing regimens using such agents will depend on the particular cancer being treated, the extent of the disease, and other factors related to the patient as determined by those skilled in the art.
  • the terms “therapeutic” or “treat,” as used herein refer to products or processes in accordance with the invention that are intended to produce a beneficial change in an existing condition (e.g., cancerous tissue, tumor size, metastases, etc.) of a subject, such as by reducing the severity of the clinical symptoms and/or effects of the condition, and/or reducing the duration of the symptom s/effects of a subject.
  • Additional ingredients may be included with the chemotherapeutic agents of the invention for administration to the subject.
  • additional ingredients include, other active agents, preservatives, buffering agents, salts, carriers, excipients, diluents, or other pharmaceutically acceptable ingredients.
  • the active agents that could be included in the compositions include antiviral, antibiotic, or other anticancer compounds; the latter could include the compounds described inPCT application serial number PCT/US2015/055968, such as curcumin, harmine, and isovanillin, and metabolites, dimers, derivatives, isomers, enantiomers (both D and L), tautomers, esters, complexes and salts of any of the foregoing.
  • the therapeutic agents of the invention give significant and unexpected therapeutic results, particularly in the context of anti-cancer results.
  • a therapeutically effective amount of an agent or composition in accordance with the invention is administered to a subject in need thereof.
  • Such may comprise a single unit dosage or, more usually, periodic (e.g., daily) administration of lower dosages over time.
  • the dosages may be administered in any convenient manner, such as by oral, rectal, nasal, ophthalmic, parenteral (including intraperitoneal, gastrointestinal, intrathecal, intravenous, cutaneous (e.g., dermal patch), subcutaneous (e.g., injection or implant), or intramuscular) administrations.
  • the dosage forms of the invention may be in the form of liquids, gels, suspensions, solutions, or solids (e.g., tablets, pills, or capsules).
  • therapeutically effective amounts of the agents of the invention may be co-administered with other chemotherapeutic agent(s), where the two products are administered substantially simultaneously or in any sequential manner.
  • compositions of the invention are quite variable owing to factors such as the patient’ s age, patient’ s physical condition, weight, the type of condition(s) being treated (e.g., specific cancer(s)), and the severity of the conditions.
  • the compositions should be dosed of from about 5 to 2000 mg per day, and more usually from about 100-800 mg per day. Such dosages may be based on a single administration per day, but more usually multiple administrations per day.
  • the phrase “and/or,” when used in a list of two or more items, means that any one of the listed items can be employed by itself or any combination of two or more of the listed items can be employed.
  • the composition can contain or exclude A alone; B alone; C alone; A and B in combination; A and C in combination; B and C in combination; or A, B, and C in combination.
  • the present description also uses numerical ranges to quantify certain parameters relating to various embodiments of the invention. It should be understood that when numerical ranges are provided, such ranges are to be construed as providing literal support for claim limitations that only recite the lower value of the range as well as claim limitations that only recite the upper value of the range. For example, a disclosed numerical range of about 10 to about 100 provides literal support for a claim reciting “greater than about 10” (with no upper bounds) and a claim reciting “less than about 100” (with no lower bounds).
  • pharmaceutically acceptable salts with reference to the therapeutic compounds of the present invention mean salts of the compounds which are pharmaceutically acceptable, i.e., salts which are useful in preparing pharmaceutical compositions that are generally safe, non-toxic, and neither biologically nor otherwise undesirable and are acceptable for human pharmaceutical use, and which possess the desired degree of pharmacological activity.
  • Such pharmaceutically acceptable salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as 1,2-ethanedi sulfonic acid, 2-hydroxyethanesulfonic acid, 2- naphthalenesulfonic acid, 3-phenylpropionic acid, 4,4'-methylenebis(3-hydroxy-2-ene-l- carboxylic acid), 4-methylbicyclo[2.2.2]oct-2-ene-l -carboxylic acid, acetic acid, aliphatic mono- and dicarboxylic acids, aliphatic sulfuric acids, aromatic sulfuric acids, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid, glucametacin
  • Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases.
  • Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide.
  • Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like. It should be recognized that the particular anion or cation forming a part of any salt of this invention is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts Properties, and Use , P.H. Stahl & C.G. Wermuth eds., ISBN 978-3-90639-058-1 (2008).
  • the preferred starting compounds or components of the invention are either synthetically derived or derived from one or more naturally occurring product(s) which have been significantly modified so as to contain at least about 90% by weight (more preferably at least about 98% by weight) of the desired component.
  • synthetically derived means that the component in question was synthesized using specific starting ingredients and one or more chemical and/or biological reactions to obtain substantially pure compounds. Modification of naturally occurring products may involve extractions, or any other physical or chemical steps to achieve the desired end product.
  • alkyl alkenyl
  • alkynyl mean and are intended to cover straight, branched chain, and cyclic groups.
  • Amines means and is intended to cover primary, secondary, and tertiary amines.
  • Sulfur groups means and is intended to cover thiols, sulfides, disulfides, and sulfoxides.
  • “Derivative” means and is intended to cover compounds, moieties, and/or groups which are substituted with atoms, groups, or side chains which do not materially degrade (e.g., no more than about 20%, preferably no more than about 10%, degradation) of the performance of the compound, moiety, or group as compared with the unsubstituted versions thereof.
  • certain preferred compounds or agents of the invention comprise a pair of fused polycyclic moieties, each including an N-containing ring, where the fused polycyclic moieties are bound or linked by a single tether or linker moiety, which are schematically illustrated as
  • PCM1 — L — PCM2 where PCM1 and PCM2 are the fused polycyclic moieties (which may be the same or different), where L is the tether or linker. As indicated by this schematic, the linker L may be attached to PCM1 and PCM2 at any position on any ring thereof, and the bonding sites need not be the same for both PCM1 and PCM2.
  • the fused polycyclic and linker moieties are described below.
  • the fused polycyclic moieties of the invention are derived or synthesized from starting ingredients which yield compounds or moieties having the following generalized structure: where one of the terminal rings is a 6-membered ring including at least one N heteroatom at any valence-permitted position(s) around the 6-membered ring (the single N-atom illustrated in Structure I is exemplary only, both in terms of the position of the N-atom, and the number of N- atoms).
  • This 6-membered ring may be aryl in character (e.g., a pyrido ring), or non-aryl (e.g., a piperidine ring), or contain multiple N-atoms (e.g., a piperazine ring).
  • RG1 is fused with the terminal 6-membered N-atom-containing ring and has from 5-8 atoms (as used herein, “fused” refers to the fact that the fused rings share 2 adjacent atoms or, in other words, 1 covalent bond).
  • Ring RG2 may be nothing (i.e., the moiety is bicyclic) and, if present, ring RG2 is fused with ring RG1 and with the terminal six-membered ring, and has from 5-8 atoms.
  • the majority of ring atoms in each case are carbon atoms.
  • these rings may also include one or more heteroatoms, such as S, 0, or N.
  • the interior dotted lines illustrated in RG1 and RG2 represent the fact that the individual rings may have one or more double bonds and may be aryl or non-aryl in character. As indicated, in the six-member N-atom-containing ring, the N-atom(s) may be at any permitted position around the ring, and the dotted lines represent that the six-membered ring may have 1, 2, or 3 double bonds.
  • the n subscript on each Y1 represents the fact that there may be single or multiple substituents at any permitted position(s) around the six-membered N-atom-containing ring, RG1, and/or RG2; preferably, each n is independently either 1 , 2, or 3.
  • Each Y 1 and Y2 is independently selected from the group consisting of nothing, OH, C1-C12 (preferably C1-C4) alkyl, alkenyl, and alkynyl groups, C1-C12 (preferably C1-C4) alkoxy and alkoxyphenyl groups, aryl and aryloxy groups, aldehyde and carbaldehyde groups, amines, nitro groups, nitrile groups, C2-C6 carboxylic acid groups, boronic groups, sulfur groups, and amino acids, where any of the aforementioned may be substituted with N, S, O, B, or halogen atoms.
  • Exemplary bicyclic compounds corresponding to the moieties in accordance with Structure I may include quinoline and derivatives thereof, purine and derivatives thereof, as well as quinolin-
  • fused tricyclic compounds corresponding to the moieties in accordance with Structure I are also useful in the invention.
  • One class of fused tricyclic compounds are b-carboline compounds and derivatives thereof, having a tricyclic ring system, e.g., a bicycle made up of a six- membered benzene ring and a fused five-membered pyrrole ring, with a terminal N-containing ring fused with the intermediate pyrrole ring.
  • Exemplary b-carbolines include tryptoline, pinoline, harmane, harmine, harmaline, tetrahydroharmaline, and 9-methyl- b-carboline. Harmaline is in some instances preferred for use in the invention.
  • Harmaline (7-methoxy-l-l-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole) is a fluorescent psychoactive alkaloid from the group of harmala alkaloids and b-carbolines, and occurs in various plants, such as Peganum harmala. Harmaline is identified as CAS #304-21-2, and exists in two tautomeric forms:
  • the bonding between the single atom and the bonding branches may be classical covalent bonding, meaning that each atom participating in the bonding contributes at least one electron as a part of a molecular orbital.
  • typical metal bonding such as coordinate or dative bonding, is generally less favored.
  • the fused tricyclic moieties are bonded to the linker through a single atom, and wherein this single atom is the carbon atom of a methine group.
  • a “methine group” is defined by th Q Illustrated Glossary of Organic Chemistry as a portion of a molecular structure equivalent to methane minus three hydrogen atoms, i.e., a CH group.
  • a methine group is to be contrasted with a “methylene group” defined as a portion of a molecular structure equivalent to methane minus two hydrogen atoms, or a CH2 group.
  • linker moieties may be derived from aldehydes, where both of the fused polycyclic moieties are bonded to the carbonyl carbon of the aldehyde functional group, thereby presenting an effective “Y” configuration.
  • appropriate aldehyde linker moieties are characterized by a six-membered ring with an attached aldehyde functional group, of the following structure. where the substituents may be located at any position around the ring.
  • aliphatic or alkenyl aldehydes may be used as linkers.
  • linkers are moieties of aldehydes, such as C1-C12 alkyl or C2-C12 alkenyl aldehydes, and include representative compounds such as (E)-hex-2-enal (C6H10O, Exact Mass: 98.07), 3- methylbutanal (isovaleraldehyde) (C5H10O, Exact Mass: 86.07), 3,7-dimethyloct-6-enal (citronellal) (C10H18O, Exact Mass: 154.14), 7-hydroxy-3,7-dimethyloctanal
  • PCM1 L — PCM2.
  • One class of compounds (Structure III below) has a central linker bonded to the N- containing B rings at respective positions at an ortho carbon atom relative to the nitrogen atom, where each of the b-carboline groups may independently be substituted or unsubstituted.
  • “Substituted” with respect to the first moiety ring, and the b-carboline groups means that these may be substituted at any position (and independently in the case of the respective b-carboline groups) with any substituent which does not materially degrade (e.g., no more than about 20%, preferably no more than about 10%, degradation) of the performance of the compound as compared with the unsubstituted version thereof.
  • each of XI, X2, X3, and X9 is independently selected from the group consisting of nothing, OH, C1-C12 alkyl, alkenyl, and alkynyl groups, C1-C12 alkoxy and alkoxyphenyl groups, aryl and aryloxy groups, aldehyde and carbaldehyde groups, amines, nitro groups, nitrile groups, C2-C6 carboxylic acid groups, boronic groups, sulfur groups, and amino acids, where any of the aforementioned may be substituted with N, S, O, B, or halogen atoms, Z contains the single bonding atom described above and is selected from the group consisting of C1-C12 alkyl, alkenyl, and alkynyl groups, C1-C12 alkoxy and alkoxyphenyl groups, aryl and aryloxy groups, aldehyde and carbaldehyde
  • Each X3 may be attached at any position around the corresponding terminal phenyl moieties of the b-carboline groups.
  • Each Y is independently nothing (e.g., there is a direct bond between the two B rings, or Z may be directly coupled to one or both of the B rings), H, OH, C1-C12 (preferably Cl -C4) alkyl, alkenyl, and alkynyl groups, Cl- C12 (preferably C1-C4) alkoxy and alkoxyphenyl groups, aryl and aryloxy groups, aldehyde groups, amines, nitro groups, nitrile groups, C2-C6 carboxylic acid groups, boronic groups, sulfur groups, and amino acids, where any of the aforementioned may be substituted with N, S, O, B, or halogen atoms.
  • Y is a C1-C12 (preferably C1-C4) group composed of C, CH, and/or CH2 atoms or groups, and Z is C, CH, or CH2.
  • X9 is preferably selected from the group consisting of nothing (e.g., M may be bonded to Z), C1-C12 (preferably C1-C4) alkyl groups, and C2-C12 (preferably C2-C5) alkenyl groups.
  • Each X4, X5, X6, X7, and X8 of Structure IIIA is attached at any position around the A ring and is independently selected from the group consisting of nothing, OH, C1-C12 (preferably C1-C4) alkyl, alkenyl, and alkynyl groups, C1-C12 (preferably C1-C4) alkoxy and alkoxyphenyl groups, aryl and aryloxy groups, aldehyde groups, amines, nitro groups, nitrile groups, C2-C6 carboxylic acid groups, boronic groups, sulfur groups, and amino acids, where any of the aforementioned may be substituted with N, S, O, B, or halogen atoms.
  • the designation in the A ring refers to the fact that there may optionally be 0, 1, 2, or 3 double bonds (e.g., the A ring may be cyclohexane, cyclohexene, cyclohexadiene, benzene, or derivatives thereof), and wherein the designation ⁇ in connection with the two B rings refers to the fact that there may optionally be: 1) one or two non- fused double bonds at one or two valence-permitted positions around either or both of the B rings, such as illustrations a-d below; 2) a double bond between either or both of the B rings and Y or Z, with or without an additional non-fused double bond at any valence-permitted position around the corresponding N-containing ring, such as illustrations e-g below.
  • XI may be nothing, such as illustrations a-c and g.
  • the corresponding XI is as defined above, and is preferably selected from the group consisting of H, OH, and C1-C12 (preferably C1-C4) alkyl groups, such as illustrations d-f; or 3) either or both of the B rings are free of non-fused double bonds, and each XI is as set forth above, and is preferably from the group consisting of H, OH, and C1-C12 (more preferably C1-C4) alkyl groups.
  • XI 1, X12, X13, and X14 are each independently selected from the group consisting of H, -OH, methoxy, ethoxy, and phenoxy, F, and Cl, with the provisos that: 1) at least one of X12, X13, or X14 is H; 2) when one or more of XI 1, X12, X13, or X14 is/are F or Cl, the remainder of the XI 1, X12, X13, and X14 are all H; 3) a phenoxy group is present only at X12, and XI 1, X13, and X14 are all H, and 4) if a methoxy or ethoxy is present, at least one such methoxy or ethoxy must be at either the 2 or 3 position, wherein the designation in connection with the two N-containing rings refers to the fact that there may optionally be: 1) one or two non- fused double bonds at one
  • certain compounds within the ambit of Structure IV containing two harmaline moieties and a single linker moiety are provided. These compounds are selected from the group consisting of
  • the preferred starting compounds or components of the invention are either synthetically derived or derived from one or more naturally occurring product(s) which have been significantly modified so as to contain at least about 90% by weight (more preferably at least about 98% by weight) of the desired component.
  • synthetically derived means that the component in question was synthesized using specific starting ingredients and one or more chemical and/or biological reactions to obtain substantially pure compounds. Modification of naturally occurring products may involve extractions, or any other physical or chemical steps to achieve the desired end product.
  • the weight amount of the aldehyde component(s) should be present in a weight excess relative to the amount of the fused polycyclic compound(s).
  • the components are usually mixed with an organic solvent, such as a C1-C4 lower alcohol (e.g., methanol, ethanol, or propanol) and/or dimethyl sulfoxide (DMSO), and allowed to stand for a period (typically from about 12 hours - 4 weeks) at a temperature ranging from about 20-60°C at ambient pressures. Alternately, the mixture may be refluxed (e.g., 30 minutes-2 hours at 50- 85°C in ethanol or 30 minutes at 55°C in methanol).
  • the reaction products can then be recovered in either liquid or solid form. Depending upon the selected solvent, the reaction products may exhibit different colors, but this does not affect the anti-cancer properties of the reaction products.
  • the particular reaction conditions are generally not critical.
  • reaction product derivatives e.g., reduction products produced by hydrogenation, esters, or salts
  • the preferred molecular weights recited herein are for the non-derivatized versions of the reaction products.
  • a second synthesis method may be used when it is desired to produce fused tricyclic compounds such as b-carboline and its derivatives.
  • this method involves reacting an indole alkyl amine with a diacid to produce an intermediate, followed by a ring-closure reaction to produce the final compound of interest.
  • a third reaction method particularly useful for the production of compounds having fused bicyclic moieties bonded with a linker moiety, is illustrated below.
  • Benzaldehyde is a benzene ring with an aldehyde substituent, and is the primary constituent of bitter almond oil. It is identified by CAS# 100-52-7.
  • Certain compounds are formed with one moiety of harmaline and one moiety of benzaldehyde, one of which has a molecular weight of approximately 320.
  • Other products also have one moiety of harmaline and one of benzaldehyde, but have a molecular weight of approximately 302, owing to loss of water attendant to the reaction. These products are set forth below.
  • useful compounds are formed with two harmaline moieties and a single linker moiety derived from benzaldehyde, with molecular weights of approximately 516, as follows.
  • a confirmed compound is 1 , 1 '-(2-phenylpropane- 1 ,3-diyI)bis(7-methoxy-4,9-dihydro-3H -pyrido[3,4-/b]indole)
  • An analog of the above compound has a molecular weight of 520.68 and is a reduced version wherein the nitrogen atoms of the two harmaline moieties are hydrogenated, eliminating the double bond therein, as set forth below:
  • appropriate benzaldehyde/harmaline compounds include one or more of the structure: and the dimers, isomers, and tautomers thereof, where the -0-R3 groups may be independently located at any position on the terminal phenyl groups, where each R1 is independently selected from the group consisting of nothing, H, OH, C1-C12 (preferably C1-C4) alkyl groups, and halogens (such as I and Br), each R2 is independently selected form the group consisting of H, OH, and C1-C12 (preferably C1-C4) alkyl groups, and halogens (such as I and Br), each R3 group is independently selected from the group consisting of C1-C12 (preferably C1-C4) alkyl groups, and substituted or unsubstituted phenyl groups, and wherein the designation refers to the fact that there may optionally be: 1) one or two non-fused double bonds at one or two valence-permitted positions around either or both of the six-member
  • R1 is nothing, such as illustrations a-c and g. However, if there is no such nitrogen double bond, the corresponding R1 is selected from the group consisting of H, OH, and C1-C12 (preferably C1-C4) alkyl groups, such as illustrations d-f; or 3) either or both of the B rings are free of non-fused double bonds, and each R1 is independently selected from the group consisting of H, OH, and C1-C12 (preferably C1-C4) alkyl groups.
  • R7 and R8 are attached at any position around the benzene ring and are independently selected from the group consisting of H, OH, and C1-C12 (preferably C1-C4) alkoxy groups, and where, preferably, R7 is OH, R8 is a C1-C12 (preferably C1-C4) alkoxy group.
  • Cinnamaldehyde/Hcirmaline 561 Compounds
  • appropriate cinnamaldehyde/harmaline compounds include one or more compounds of the structure:
  • appropriate vanillin/harmaline compounds include one or more compounds of the structure: and the dimers, isomers, and tautomers thereof, where each R4 is independently selected from the group consisting of nothing, H, OH, and C1-C12 (preferably C1-C4) alkyl groups, each R5 is independently selected from the group consisting of H, OH, and C1-C12 (preferably C1-C4) alkyl groups, each R6 group is independently located at any position around the corresponding terminal phenyl group, or at either of the two open positions of the two N-containing rings, and is selected from the group consisting of C1-C12 (preferably C1-C4) alkoxy groups, H, OH, and substituted or unsubstituted phenyl groups, R7 and R8 are attached at any position around the benzene ring and are independently selected from the group consisting of H, OH
  • R4 is nothing, such as illustrations a'-c' and g' below. However, if there is no such nitrogen double bond, the corresponding R4 is selected from the group consisting of H, OH, and C1-C12 (preferably C1-C4) alkyl groups, such as illustrations d'-f; or 3) either or both of the N-containing rings are free of non-fused double bonds and each R4 is independently selected from the group consisting of H, OH, and C1-C12 (preferably C1-C4) alkyl groups.
  • An exemplary compound consistent with 3) above is a hydrogenated form of the preferred 562 compound having the structure
  • scheme 4 compounds involve coupling between harmaline and orthovanillin via a pyrrole nitrogen linkage, i.e., the orthovanillin moieties bond to the nitrogen atom of the pyrrole ring forming a part of harmaline.
  • the initial aldehyde reaction between orthovanillin and harmaline of scheme 1 may also produce the following compound having the chemical formula C21H20N2O3 and a molecular weight of 348.15. It will be observed that in this instance the initial reaction between orthovanillin and harmaline occurs at the cyclohexyl diene nitrogen atom.
  • the structure of a preferred orthovanillin/diharmaline compound is set forth below:
  • preferred orthovanillin/diharmaline compounds are defined by Structure VIII below: and the dimers, isomers, and tautomers thereof, where the -O-R3 groups may be independently located at any position on the terminal phenyl groups, where each R1 is independently selected from the group consisting of nothing, H, OH, and C1-C12 (preferably C1-C4) alkyl groups, each R2 is independently selected form the group consisting of H, OH, and C1-C12 (preferably C1-C4) alkyl groups, each R3 group is independently selected from the group consisting of C1-C12 (preferably C1-C4) alkyl groups, and substituted or unsubstituted phenyl groups, and wherein the designation refers to the fact that there may optionally be: 1) one or two non-fused double bonds at one or two valence-permitted positions around either or both of the six-membered, N- containing rings, such as illustrations a-d below; 2) a double bond between
  • R1 is nothing, such as illustrations a-c and g. However, if there is no such nitrogen double bond, the corresponding R1 is selected from the group consisting of H, OH, and C1-C12 (preferably C1-C4) alkyl groups, such as illustrations d-f; or 3) either or both of the N-containing rings are free of non-fused double bonds and eachRl is independently selected from the group consisting ofH, OH, and C1-C12 (preferably C1-C4) alkyl groups.
  • One particular aldehyde reaction for preparing orthovanillin-harmaline compounds is to mix together solid particulate orthovanillin and harmaline at a weight ratio of orthovanillin :harmaline of about 2:1, followed by adding ethanol, DMSO, or a 90% ethanol/10% DMSO mixture to the particulates. Thereupon, the dispersion is agitated and allowed to stand for 24 hours at room temperature.
  • the specific steps are: (1) mix together 500 mg of orthovanillin and 250 mg of harmaline in a 15 mL jar; (2) gently shake the jar until a uniform powder mixture is present; (3) add 10 mL of ethanol and/or DMSO to the dry mixture; (4) agitate with a vortex mixer at 1000 rpm for 10 minutes; and (5) let the dispersion set and the reaction proceed for 24 hours at room temperature.
  • a similar technique involving reactions between harmaline and vanillin comprises mixing particulate harmaline and vanillin together at a weight ratio of about 2:1 (vanillin: harmaline), followed by adding ethanol to a final concentration of the reactions of from about 10-100 mg/mL. This mixture is then allowed to sit for approximately 3 days at 50°C. A bluish solid forms, which is filtered and washed with methanol, and recovered.
  • Phenoxy Benzaldehyde/Harmaline 594 Compounds The aldehyde reactions between phenoxy benzaldehyde and harmaline components, carried out in the same fashion as the benzaldehyde/harmaline reaction, yield products as set forth below.
  • the -0-R3 groups may be independently located at any position on the terminal phenyl groups, where each R1 is independently selected from the group consisting of nothing, H, OH, and C1-C12 (preferably C1-C4) alkyl groups, each R2 is independently selected form the group consisting of H, OH, and C1-C12 (preferably C1-C4) alkyl groups, each R3 group is independently selected from the group consisting of C1-C12 (preferably C1-C4) alkyl groups, and substituted or unsubstituted phenyl groups, and the phenoxy group may be substituted at any position on the benzyl ring, and wherein the designation — refers to the fact that there may optionally be: 1) one or two non-fused double bonds at one or two valence-permitted positions around either or both of the six-membered, N-containing rings, such as illustrations a-d below; or 2) a double bond between either
  • R1 is nothing, such as illustrations a-c and g. However, if there is no such nitrogen double bond, the corresponding R1 is selected from the group consisting of H, OH, and C1-C12 (preferably C1-C4) alkyl groups, such as illustrations d-f; or 3) either or both of the N-containing rings are free of non-fused double bonds and eachRl is independently selected from the group consisting ofH, OH, and C1-C12 (preferably C1-C4) alkyl groups.
  • the makeup of the respective compounds is identified by reactant moieties therein less any dehydration and/or reduction by virtue of the reaction, along with the approximate molecular weights thereof.
  • a given compound recited as ⁇ + A - H20 refers to a product containing one moiety of harmaline and one moiety of Aldehyde, minus one water molecule
  • 2H+A-H20-2H refers to a product containing two moieties of harmaline, one moiety of aldehyde, less one water molecule and less two hydrogen atoms.
  • reaction was carried out by mixing together 500 mg of a selected aldehyde and 250 mg of a harmaline-like compound in a 15 mL jar, followed by gentle shaking the jar until a uniform powder mixture is present. Thereupon, 10 mL of ethanol was added to the dry mixture, the jar was capped, and was placed in a warm water bath of about 40°C for approximately 24 hours.
  • Example 1 The 523 compounds of Example 1 were subjected to a series of identical in vitro assays against lymphoma (MO205) and leukemia (jurkat E6-1) cell lines, in order to determine the anti cancer properties of the compositions, as determined by cell death.
  • the protocol for the assays is given below.
  • the individual cells were grown in suspension in media (RPMI supplemented with 10% FBS), maintained at approximately 500,000 cells/mL.
  • the cells were directly plated in 96-well plates, and each well was exposed to increasing doses of the GZ523.001-.008 compositions for 24 hours (a minimum of 4 replicates for each dosage).
  • PrestoBlue Life Technologies, Inc
  • fluorescence readings were taken 4-6 hours later with an excitation wavelength of 485 nm and an emission wavelength of 560nm, using a microplate reader (Enspire Multimode, PerkinElmer). Results were averaged following background subtraction and normalized to untreated cell controls.
  • Figs. 1-16 The results of these tests are set forth in Figs. 1-16, where Figs. 1-8 are the lymphoma test results and Figs. 9-16 are the leukemia test results and, in each case, the compositions exhibited excellent anti-cancer activity at relatively low dosages. In general, dosages exceeding 10 ⁇ g/mL gave very good results, with extraordinary results above about 40 ⁇ g/mL.
  • a 523 compound was prepared containing orthovanillin and harmaline at a weight ratio of 2: 1, using solid synthetic orthovanillin (99% pure) and solid synthetic harmaline (92% pure).
  • the reactants were dispersed in ethanol to achieve a concentration 75 mg/mL, and allowed to react for a period of 24 hours.
  • the compound designated as GZ523F001
  • the compound was treated by HPLC to recover a high molecular weight fraction predominantly (about 70% by weight) made up of dioligomer(s) having a molecular weight of approximately 696, and unreacted harmaline.
  • These dioligomer(s) included one or more compounds exemplified by the Scheme 1 dimers.
  • non-Hodgkin lymphomas were tested for their susceptibility to a preferred compound in accordance with the invention, namely GZ523.006 described in Example 1.
  • the cell lines were grown in suspension according to the vendors’ instructions and tested by the methods described in Example 2, except that there were no replications.
  • the following Table sets forth each subtype of non-Hodgkin lymphoma tested, the cell line ID number, and the median effective dose (IC 50 ).
  • the IC 50 represents the potency of the GZ523.006 composition against the cell lines, and ranged from 8-38 ⁇ g/mL, which is considered a therapeutically appropriate dosage range.
  • the effect size of the highest concentration of GZ523.006 determines how well the composition worked to directly kill the respective cells. For all of the cell lines tested, 100% of the cancer cells were dead at a dosage of 25 ⁇ g/mL or greater.
  • Example 5 In this Example, a 562 compound was prepared by mixing 500 mg of vanillin powder and
  • Example 6 the IC 50 values of GZ523.006 was determined for 25 different lymphoma cell lines. The experiments were performed using two-fold serial dilutions of GZ523.006 between 0.4 ⁇ g/mL and 100 ⁇ g/mL. Test wells were prepared using media and GZ523.006 controls for background subtraction. Each cell line was seeded with 10,000 cells/well, with triplicate technical replicates. After a 96-hour exposure, Alamar Blue Reagent (Life Technologies) was added to each well and incubated one hour at 37°C. Fluorescence values were recorded using a 560 nm excitation/590 nm emission filter set, and IC 50 concentrations were calculated using GraphPad Prism software.
  • GCB- DLBCL Germinal Center B-Cell-Diffuse Large B-Cell Lymphoma cell lines
  • ABC-DLBCL are Activated B-Cell-Diffuse Large B-Cell Lymphoma cell lines
  • MCL Mantle Cell Lymphoma cell lines
  • FL Follicular Lymphoma cell lines.
  • the error bars represent standard error of the mean values.
  • Fig. 21 Each of the cell lines of Fig. 21 were incubated with 5, 10, or 20 ⁇ g/mL for 72 hours, then incubated Hoechst 33342 dye (BD Pharmigen) for 60 minutes at 37°C. The cells were washed twice and fluorescence data was acquired using a LSRII 4-laser flow cytometer (BD Biosciences). Data was analyzed using Flojo vlO and Modfit v4.05 software to quantify the percentage of dead cells (sub-Gl), senescent cells (G1 peak), and cycling cells (S-phase and G2) in each condition. The data from this series of tests is summarized in Table 2.
  • GZ523.0006 cell death was interrogated using Annexin V and 7-AAD staining, with the BD Apoptosis Detection Kit (BD Pharmigen).
  • BD Pharmigen the BD Apoptosis Detection Kit
  • Four cell lines were selected that showed high sensitivity to GZ523.006. The cell lines were incubated with 5, 10, or 20 ⁇ g/mL of GZ523.006 for 72 hours, washed, re-suspended in IX Annexin V Binding Buffer, and stained with
  • a Caspace 3/7 assay was performed by induction of apoptosis using a luminescence-based Caspace cleavage assay. Cells were plated at 10,000 cells per well and exposed to 20 ⁇ g/mL of GZ523.006 for 48 hours. Caspace activation was measured using the Caspace-Glo 3/7 assay (Promega), and compared with vehicle control exposures. Caspace activation was measured with triplicate technical replicates and duplicate experimental replicates using a luminescence plate reader. These test results are summarized in Fig. 22, where Bar 1 is the control and Bar 2 is treated cells. The error bars represent standard error of the mean values.
  • GZ523.006 exhibits cytotoxic properties against lymphoma cell lines to the induction of apoptosis.
  • Mantle cell lymphoma cell lines exhibited the highest resistance, while Diffuse Large B-Cell Lymphomas of the Germinal Center B-Cell-like subtype exhibited the greatest sensitivity.
  • GZ523.010 was prepared by mixing 2433 mg orthovanillin, 1217 mg harmaline, and 5 mL of ethanol. This mixture was then sonicated at 35°C for one hour to assure complete mixing, and was then allowed to stand for 24 hours at room temperature.
  • mice/sex/group There were four dose groups consisting of a vehicle control group and 3 dose groups for 7 days of repeated oral gavage dosing with 10 mice/sex/group. Animals were dosed once daily with GZ523.010 and euthanized on study Day 8. All animals were observed daily for any clinical signs after dose administration. Gross necropsy was conducted for each animal and clinical pathology was performed for all available samples at termination. The first day of dosing was defined as study Day 1. The study design and variables evaluated are presented in Table 4 and Table 5.
  • Clinical pathology was performed at termination. The clinical pathology analysis was performed on all designated animals that were euthanized on schedule. Animals were food fast overnight.
  • Serum Chemistry Blood samples when available ( ⁇ 0.5 mL) were collected from three study animals per gender from each group, and allowed to clot for 15 minutes in room temperature. No anticoagulant was used. Serum samples were prepared by centrifuging at 3000 RPM for - 15 minutes. The serum chemistry includes with priority (V) When a sample was insufficient for analysis, several samples from same group were pooled together:
  • Plasma samples (-0.4 mL/animal) when available were collected from three study animals per gender from each group. Sodium citrate (3.2%) was used as the anticoagulant. Plasma was prepared by centrifuging for approximately 15 minutes at 3000 rpm at 4°C. The blood coagulation analysis included, but was not limited to:
  • Hematology Analysis Blood samples when available ( ⁇ 0.4 mL) were collected from three study animals per gender from each group. K3-EDTA was used as anticoagulant. The hematology analysis includes (with priority (V)):
  • Hematology and coagulation data are summarized in Table 11. When compared to the control group (Group 1), none of the hematology or coagulation parameters appeared to be affected in the mice that were treated with test article at different dose levels.
  • Necropsy included examination of the external surface, all orifices, and cranial, thoracic, abdominal, and pelvic cavities including contents. Macroscopic findings are summarized in Table 13. All findings were considered to be incidental, and unrelated to the test article administration. All tissues were collected, including the entire remaining carcasses, and fixed for future potential evaluation.
  • in vitro cell proliferation assays were performed using: (1) Human Myeloma tumor cell lines; (2) Human Lymphoma tumor cell lines; (3) Solid Human tumor cell lines; and (4) Parental, Lenalidomide resistant and Bortezomib resistant Ieko-1 Mantle cell Lymphoma tumor cell lines.
  • the compounds tested were three diharmaline compounds, namely the 518B562 (or simply 562), 560, and 561 compounds.
  • a monoharmaline product designated as 518F014 was also tested. This monoharmaline product had the following structure:
  • the 518B562 compound was prepared by mixing together particulate harmaline and vanillin at a weight ratio of about 2:1 (vanillin: harmaline), followed by adding ethanol to a final concentration of the reactions of from about 10-100 mg/mL. This mixture is then allowed to sit for approximately 3 days at 50°C. A bluish solid forms, which is filtered and washed with methanol, and recovered. It was found that addition of an acid such as hydrochloric acid to reduce the pH of the product, increased the solubility thereof.
  • the 560 compound was prepared by mixing together 500 mg of benzaldehyde and 250 mg of harmaline in a 15 mL jar followed by shaking. 10 mL of DSMO was then added to the mixture, followed by agitation using a vortex mixer at 1000 rpm for 10 minutes. The vortexed mixture was then allowed to set for 24 hours at room temperature. The resultant product was an orange liquid containing 10.6 mM compound, and was stored at 4°C until use.
  • the 561 compound was prepared by mixing together 500 mg of cinnamaldehyde and 250 mg of harmaline in a 15 mL jar followed by shaking. 10 mL of DSMO was then added to the mixture, followed by agitation using a vortex mixer at 1000 rpm for 10 minutes. The vortexed mixture was then allowed to set for 24 hours at room temperature. The resultant product was an orange solid dispersed in liquid containing 10 mM compound, and was stored at 4°C until use.
  • Each proliferation assay was carried out as follows.
  • the test cells were plated in growth media using a 384-well microtiter plate at 50 ⁇ g volume.
  • the cells were incubated for 24 hours at 37°C in a humidified incubator.
  • the test compounds were added to the test wells in DSMO solvent, at concentrations ranging from 0.0075-100 mM.
  • Control wells received equal volumes of DSMO, without compound.
  • the cells were incubated for 72 hours at 37°C in a humidified incubator. After this exposure, 100 ⁇ g of a 1:1 mixture of sterile water and CellTiter-Glo® reagent (Promega) was added to each well.
  • the plates were then incubated for 60 minutes at room temperature, followed by recording the luminescence value of each well using a luminometer as a measure of cell proliferation.
  • IOOmM or 0.005M was used to average the values and obtain an IC 50 .
  • a compound mixture was prepared by reacting 2:1 by weight harmaline and 3-phenoxybenzaldehyde (3-phenoxybenzaldehyde:harmaline).
  • the reaction mixture had three components, namely fractions having molecular weights of 608 (47% by weight), 788 (32% by weight), and 394 (21% by weight).
  • the MW 608 product contained two moieties of harmaline and one of 3-phenoxybenzaldehyde, with one removed water molecule
  • the MW 788 product contained two moieties of harmaline and two moieties of 3-phenoxybenzaldehyde, with two removed molecules of water
  • the MW 394 product contained one mole each of harmaline and 3-phenoxybenzaldehyde with one water molecule removed.
  • pancreatic cancer cells S2-007 and Mia-PaCa2
  • pancreatic cancer cells S2-007 and Mia-PaCa2
  • This product significantly inhibited the proliferation of the cells in doses of 1-25 ⁇ g/mL and in a time-dependent manner of 24-72 hours.
  • the IC 50 values of the compound against S2-007 and Mia-PaCa2 cells was determined as 3 ⁇ g/mL and 5 ⁇ g/mL, respectively.
  • RNA sequences for cancer stem cell (CSC) markers was performed before and after treatment of S2-007 human pancreatic cancer cells with 518B562. This experiment was conducted using a Whole Transcriptome Shotgun Sequence (WTSS), followed by bioinformatics data analysis of CSC markers. An RNA-Seq/heat map was generated to obtain a genome-wide gene expression profile of the pancreatic cancer cells.
  • WTSS Whole Transcriptome Shotgun Sequence
  • RNA-Seq generated around 48.6 and 60.1 reads, of which between 97.2% and 98.3% of the reads mapped to the reference genome.
  • 518B562 significantly inhibited clusters of genes on proliferative, anti-apoptotic, and angiogenic markers, while up-regulating anti proliferative and apoptotic markers.
  • 518B562 up-regulated apoptotic markers [ICAM5, WNK4, ALPP, LTRC26, SHBG, MT1X] and anti-proliferative markers [NRP1, ATF2A, CYPlbl, ALPP, DEPTOR, MTIF]
  • 518B562 down-regulated angiogenesis markers [OXTR, SYCP2, CRHR1, SPEG], anti-apoptotic markers [TUG1, FABPl, PI3, DOK5] and proliferation signaling markers [FOXj l, SPP1, C3]
  • a three-dimensional representation of the above 560 compound is shown below, with the large circles representing carbon atoms, and the small circles representing hydrogen atoms; the double bonds are not shown in this representation.
  • a hydrogen bond is illustrated in dotted lines between the nitrogens N1 and N4. It is believed that this hydrogen bond may be important to the functionality of the compound.
  • the other numbered atoms are provided for reference.
  • the above compound may be subject to isomerization, particularly during NMR analysis, to give the following two-dimensional isomeric structure: A reduced form of either of the above isomers may be less prone to additional isomerization.
  • the two-dimensional structure of this reduced compound (produced by hydrogenation of the above compounds) is set forth below.
  • Example 15 the 560 and 562 compounds of Examples 12 and 14, respectively, were tested in cell proliferation assays using two pancreatic cancer cells, S2-007 and MiaCaPa-2.
  • 5x 1 cells were seeded in 96-well culture plates. After incubation for 24 hours, the cells were treated at various concentrations of the 560 or 562 compounds, and allowed to incubate for further periods of 72 hours.
  • Cell proliferation values were determined by enzymatic hexoseaminidase assay. The results of these tests are set forth in Figs. 119 and 120 (560 compound), and Figs. 121 and 122 (562 compound). These Figures also provide the IC 50 values for each assay.
  • the 560 and 562 compounds of Examples 12 and 14, respectively, were tested using cell colony formation assays.
  • 500 viable S2-007 and MiaCaPa-2 cells were plated in six-well dishes and allowed to grow for 24 hours. The cells were then incubated in the presence or absence of the 560 and 562 compounds for 72 hours. The compound-containing media were then removed, and the cells were washed in PBS and incubated for an additional 10 days in complete media. The resultant colonies were then washed in PBS and fixed using 10% formalin for 10 minutes at room temperature, followed by washing with PBS and staining with Crystal Violet. The colonies of the control and compound-supplemented assays were then counted and compared.
  • Figure 123 (560 compound, S2-007 cells) illustrates the colony formation with control (no 560 compound), and 4 ⁇ g and 6 ⁇ g 560 compound at 24, 48, and 72 hours.
  • the 560 compound significantly disrupted colony formation, particularly at the 6 ⁇ g level of use.
  • Figure 124 (560 compound, MiaPaCa-2 cells) illustrates the colony formation with control (no 560 compound), and 3 ⁇ g and 5 ⁇ g 560 compound at 24, 48, and 72 hours.
  • the 560 compound significantly disrupted colony formation at both levels of use.
  • Figure 125 (562 compound, S2-007 cells) illustrates the colony formation with control (no 562 compound), and 14 ⁇ g and 16 ⁇ g 562 compound at 24, 48, and 72 hours.
  • Figure 126 (562 compound, S2-007 cells) illustrates the colony formation with control (no 562 compound), and 20 ⁇ g and 24 ⁇ g 562 compound at 24, 48, and 72 hours.
  • Figure 127 (562 compound, MiaPaCa-2 cells) illustrates the colony formation with control (no 562 compound), and 3 ⁇ g, 7 ⁇ g, 10 ⁇ g, and 12 ⁇ g 562 compound at 24, 48, and 72 hours.
  • the 562 compound significantly disrupted colony formation, particularly at the higher levels of use.
  • the 560 and 562 compounds of Examples 12 and 14, respectively were used in cell cycle assays against S2-07 and MiaPaCa02 cells.
  • cells treated with the 560 and 562 compounds for 72 hours were trypsinized and suspended in PBS.
  • the single-cell suspensions were fixed using pre-chilled 70% ethanol for 3 hours, and were subsequently permeabilized with PBS containing 0.1% Triton X-100, 1 mg/mL propidium iodide, and 2 mg DNase-free RNase at room temperature.
  • Flow cytometry assays were then performed using a FASCalibur analyzer (Becton Dickinson), capturing 10,000 events for each sample.
  • Figures 128 and 128 A illustrates the cell cycle results at 24 and 48 hours with and without Sub GO.
  • Figures 129 and 129 A illustrates the cell cycle results at 24, 48, and 72 hours with and without Sub GO.
  • Figures 130 and 130A illustrates the cell cycle results at 24,
  • Figures 131 and 131 A illustrates the cell cycle results at 24, 48, and 72 hours with and without Sub GO.
  • the principal compound referred to herein as the 561 product, has the following structure:
  • Example 24 In this test, a related diharmaline compound 594, diharmaline 3-phenoxybenzaldehyde was tested using the same cell lines and procedures as described in Example 8. The structure of the 594 compound is set forth below, and the collected cell proliferation assay data is given in the following table.
  • the 594 compound is effective against a wide variety of cancer cells.
  • Example 25 different cell lines were subjected to in vitro cell proliferation assays as described in Example 8.
  • the cell lines are identified in the following Table 17, and the tissue types were: Pancreatic; Endometrial; Triple-Negative Breast Cancer (TNBC); Non- Small-Cell Lung Carcinoma (NSCLC); Ovarian; Renal Cell Carcinoma (RCC); Cervical- Squamous Cell; Hemagglutinin and Neuraminidase (H&N-Squamous Cell); Germinal Center B Cell-Like Novo Diffuse Large B-Cell Lymphoma (GCB-DLBCL); Activated B-Cell — Diffuse Large B Cell Lymphoma (ABC-DLBCL); Human Myeloma; Human Myeloma Cell Line Lymphocyte-Like; Human Myeloma Cell Line Lymphocyte-Like Myeloma Pleural Effusion Infiltration; Human Multiple Myeloma; Plasma Cell Le
  • HMCL-B Human myeloma cell line lymphocyte-like myeloma pleural effusion infiltration (IgAk)
  • Example 25 a compound was produced via the reaction between a fused bicyclic compound, namely l-methyl-3,4-dihydroisoquinoline and vanillin, as described in Example 25. This compound was tested against the same cell lines of Example 25, giving the following results.
  • compositions of the invention may be applicable to virtually all cancers, such as the following: Acute Lymphoblastic Leukemia, Adult; Acute Lymphoblastic Leukemia, Childhood; Acute Myeloid Leukemia, Adult; Acute Myeloid Leukemia, Childhood; Adrenocortical Carcinoma; Adrenocortical Carcinoma, Childhood; Adolescents, Cancer in; AIDS-Related Cancers; AIDS-Related Lymphoma; Anal Cancer; Appendix Cancer; Astrocytomas, Childhood; Atypical Teratoid/Rhabdoid Tumor, Childhood, Central Nervous System; Basal Cell Carcinoma; Bile Duct Cancer, Extrahepatic; Bladder Cancer; Bladder Cancer, Childhood; Bone Cancer, Osteosarcoma and Malignant Fibrous Histiocytoma; Brain Stem Glioma, Childhood; Brain Tumor, Adult;

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Abstract

L'invention concerne des compositions thérapeutiques pour l'être humain, comprenant des composés contenant une pluralité de fractions polycycliques fusionnées et une fraction de liaison. Dans certains modes de réalisation, les composés sont les produits de la réaction de composants aldéhyde et harmaline. Les compositions présentent des propriétés anticancéreuses, en particulier contre le lymphome, la leucémie, ainsi que les lignées cellulaires du cancer du pancréas, de l'endomètre, de l'ovaire, de l'estomac, du sein, du rein, du col de l'utérus, de la tête et du cou et du myélome.
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