WO2022144780A1 - Dérivés de sulfonamide, compositions les comprenant et leurs utilisations dans le traitement de cancers - Google Patents

Dérivés de sulfonamide, compositions les comprenant et leurs utilisations dans le traitement de cancers Download PDF

Info

Publication number
WO2022144780A1
WO2022144780A1 PCT/IB2021/062400 IB2021062400W WO2022144780A1 WO 2022144780 A1 WO2022144780 A1 WO 2022144780A1 IB 2021062400 W IB2021062400 W IB 2021062400W WO 2022144780 A1 WO2022144780 A1 WO 2022144780A1
Authority
WO
WIPO (PCT)
Prior art keywords
inhibitor
cancer
hydrochloride
compound
receptor
Prior art date
Application number
PCT/IB2021/062400
Other languages
English (en)
Inventor
Kenkichi Masutomi
Taro Yamashita
Shuichi Kaneko
Mami YASUKAWA
Teruki Honma
Hiroo Koyama
Takehiro Fukami
Original Assignee
National Cancer Center
National University Corporation Kanazawa University
Riken
Gf Mille Inc.
Solstar Pharma Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by National Cancer Center, National University Corporation Kanazawa University, Riken, Gf Mille Inc., Solstar Pharma Inc. filed Critical National Cancer Center
Publication of WO2022144780A1 publication Critical patent/WO2022144780A1/fr

Links

Classifications

    • 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
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms

Definitions

  • the invention relates to the field of cancer treatment, and more particularly to the use of sulfonamide derivatives having inhibitory activity against hTERT-RdRP for the treatment of cancers, including intractable solid cancers and stem cells cancer.
  • telomerase reverse transcriptase [0003] Human telomerase reverse transcriptase (hTERT) is expressed at high levels in more than 90% of human cancers, whereas its expression level is extremely low in normal cells. Thus, hTERT has been considered as an extremely promising molecular target for the development of anticancer agents.
  • telomerase inhibitors As anticancer agents and to introduce them into clinical practice, these efforts have been vain since no such anti-cancer compounds have been approved yet.
  • hTERT was identified as RNA dependent DNA polymerase (reverse transcriptase or RT). After that, it was predicted that hTERT is closely related to RNA dependent RNA polymerase (RdRP) rather than RT in terms of genetic phylogenetic tree analysis and structural biology (Nakamura et al., Science, 1997, 277:955-959).
  • RdRP RNA dependent RNA polymerase
  • RdRP activity is still not inhibited by conventional telomerase inhibitors targeting hTERT- RT because the complex that guarantees RT activity and the complex that guarantees RdRP activity are different.
  • WO 2001/00579 describes compounds that modulate the PPAR gamma receptor for the treatment lipid-related diseases and diabetes.
  • WO 2001/05793 describes sulfonamide derivatives for the treatment of depression, diabetes, obesity and CNS disorders.
  • the invention relates to a pharmaceutical composition for the treatment of a cancer, the composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof: wherein
  • R 1 and R 2 are each independently a halogen atom, and m and n are each independently an integer between 0 - 3; and a pharmaceutically acceptable carrier or excipient.
  • the invention relates to a pharmaceutical composition for the treatment of a cancer, the composition comprising a compound of Formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, and at least one of gemcitabine and capecitabine.
  • the invention relates to the use of a compound of Formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, for the treatment of cancer.
  • the invention relates to a method for suppressing tumor cell proliferation, comprising contacting cancer cells with a compound of Formula (l)as defined herein, or with a pharmaceutically acceptable salt thereof.
  • the invention relates to a method for the treatment of a cancer, comprising administering to a subject in need thereof a compound of Formula (I) as defined herein, or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is represented by Formula (la) as defined herein, or it is represented by one of the following formulas (RK-X), (RK-Y) or (RK-Z) as defined herein.
  • Figure 1 is a panel with line graphs demonstrating inhibition of hTERT-RdRP activity by compounds RK-X, RK-Y, and RK-Z, in accordance with Example 1.
  • Figure 2 is a panel with line graphs demonstrating inhibition by compound RK-X of proliferation of liver cancer cells and no inhibition in normal cells, in accordance with Example 2.
  • Figure 3A is a panel showing a photomicrograph of subcutaneous tumors developed in NOD/SCID mice treated with compound RK-X or with a control vehicle, in accordance with Example 3.
  • Figure 3D is a panel with a gel image (left side) and a bar graph (right side) demonstrating inhibitory effect of compound RK-X on RdRP activity in mice, in accordance with Example 3.
  • Figure 4A is a panel with a gel image depicting RdRP activity of Panc-1 cell and Mia-Paca-2, in accordance with Example 4.
  • Figure 4B are bar graphs demonstrating that Panc-1 cells (RdRP activity- H ig h) are more sensitive to compound RK-X than Mia-Paca-2 cells (RdRP activity-Low, in accordance with Example 4.
  • CTR (DMEM) or CTR (DMSO) are control solutions without the compound RK-X. * : indicates p value ⁇ 0.05, ANOVA followed by Newman-Keul. ***: indicates p value ⁇ 0.001 , ANOVA followed by Newman-Keul.
  • the invention provides compounds, pharmaceutical compositions and uses thereof in the prophylaxis and/or treatment of cancers.
  • anticancer compounds and anticancer compositions in accordance with the invention are effective in at least one of: (i) inhibiting hTERT-RdRP [Human telomerase reverse transcriptase (hTERT)- RNA dependent RNA Polymerase (RdRP)]; (ii) targeting cancer stem cells; (iii) inhibiting cancer cells growth; (iv) suppressing tumor cell proliferation; (v) inhibiting RNA-dependent RNA polymerase(RdRPase) of cancer cells; and (vi) inhibiting cancer cells during DNA synthesis and replication.
  • hTERT-RdRP Human telomerase reverse transcriptase (hTERT)- RNA dependent RNA Polymerase (RdRP)
  • RdRP RNA dependent RNA Polymerase
  • One aspect of the invention concerns compounds, as well as pharmaceutical compositions and uses thereof, as anticancer agents.
  • the compound is a sulfonamide compound of Formula (I), or a pharmaceutically acceptable salt thereof:
  • R 1 and R 2 are each independently a halogen atom, and m and n are each independently an integer between 0-3.
  • the compound of Formula (I) is a compound represented by the Formula (la): wherein
  • R 1a , R 1b , and R 2a are each independently a halogen atom, and R 2b is a hydrogen atom or a halogen atom.
  • the compound of Formula (I) is represented by one of the following Formulas (RK-X), (RK-Y) or (RK-Z):
  • compositions in accordance with the present invention can be used in either a free form or in the form of a “pharmaceutically acceptable salt”. Accordingly, the present invention encompasses pharmaceutically acceptable salts of any of the sulfonamide derivatives defined herein, including pharmaceutically acceptable salts of compounds of Formula (I), Formula (la), Formula (RK-X), Formula (RK-Y) and Formula (RK-Z).
  • Pharmaceutically acceptable salts of the compounds of the present invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases.
  • examples of pharmaceutically acceptable salt include salts with inorganic acids include, but are not limited to, besylic acid salt (besylate), tosylic acid salt (tosylate) and mesylic acid salt (mesylate), hydrochloric acid salt, hydrobromic acid salt, sulfuric acid salt, phosphoric acid salt, and the like, salts with organic acids such as acetic acid salt, fumaric acid salt, oxalic acid salt, citric acid salt, methanesulfonic acid salt, benzenesulfonic acid salt, tosylic acid salt, maleic acid salt, and the like; salts with amino acids such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamic acid salt, aspartic acid salt and the like; and the like. Examples of suitable salts are described in international PCT publication WO 2001/
  • prodrugs are within the ordinary skill in the art and has been described in the literature (e.g. “Development of Pharmaceuticals”, Vol. 7, Design of Molecules, p.163-198, Published by Hirokawa Shoten (1990)).
  • Anticancer compounds and compositions in accordance with the present invention may provide substantial therapeutic benefits to subjects, particularly human subjects suffering, or susceptible to suffer, from a cancer or tumour. Therefore, delivering an anticancer compound in accordance with the present invention may have useful pharmaceutical applications in the prophylaxis and the treatment of cancers and related diseases in mammalian subjects, particularly human patients.
  • an anticancer compound as defined herein for the treatment of a mammalian subject in need thereof.
  • the anticancer compound of the invention may be useful in: (i) inhibiting hTERT- RdRP [Human telomerase reverse transcriptase (hTERT)- RNA dependent RNA Polymerase (RdRP)]; (ii) targeting cancer stem cells; (iii) inhibiting cancer cells growth; (iv) suppressing tumor cell proliferation; (v) inhibiting RNA-dependent RNA polymerase (RdRPase) of cancer cells; and (vi) inhibiting cancer cells during DNA synthesis and replication.
  • hTERT- RdRP Human telomerase reverse transcriptase (hTERT)- RNA dependent RNA Polymerase (RdRP)
  • RdRPase RNA-dependent RNA polymerase
  • the anticancer compounds and compositions of the present invention may potentially be used against various types of cancers, including intractable solid cancers and stem cells cancers.
  • the cancer is liver cancer, pancreatic cancer.
  • the cancer is ovarian cancer, breast cancer, colon cancer, stomach cancer, renal cancer, glioblastoma and sarcoma.
  • the cancer is other than blood cancer.
  • the compound of the present invention and related composition is not for use as a PPAR gamma (PPARy) inhibitor, nor for the treatment of diseases associated with inhibition of PPAR gamma activity.
  • the anticancer compounds and compositions do not treat the cancer by inhibiting the peroxisome proliferator-activated receptor gamma (PPAR-y or PPARG).
  • the compound of the present invention and the related pharmaceutical composition are not for the treatment of depression, diabetes, obesity or CNS disorders.
  • the compound of the present invention and the related pharmaceutical composition are not for treating non-alcoholic fatty liver diseases (NAFLD).
  • NAFLD non-alcoholic fatty liver diseases
  • the compound of the present invention and the related pharmaceutical composition are not for treating cancers, e.g. blood cancers.
  • compositions of the invention may be formulated in accordance to desired parameters such as dosage, the patient population, route of administration, etc.
  • the pharmaceutical composition include, but are not limited to, tablet (including sugar-coated tablet, film-coated tablet, sublingual tablet, orally disintegrating tablet, buccal tablet and the like), pill, powder, granule, capsule (including soft capsule, microcapsule), troche, syrup, liquid, emulsion, suspension, controlled- release preparation (e.g., immediate-release preparation, sustained-release preparation, sustained-release microcapsule), aerosol, film (e.g., orally disintegrable film, oral mucosa- adhesive film), injection (e.g., subcutaneous injection, intravenous injection (e.g., bolus), intramuscular injection, intraperitoneal injection), intravenous drip infusion, transdermal absorption type preparation, ointment, lotion, patch, suppository (e.g., rectal suppository, vaginal suppository), pellet, nasal
  • “Pharmaceutically acceptable carrier, vehicle or excipient” refers to a diluent, adjuvant, excipient, carrier or drug delivery substance(s) with which a compound is administered.
  • pharmaceutically acceptable refers to drugs, medicaments, inert ingredients, etc., which are suitable for use in treatment of a cancer in subjects (preferably mammals such as humans) without undue toxicity, incompatibility, instability, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio. It preferably refers to a compound or composition that is approved or approvable by a regulatory agency of the Federal or state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals and more particularly in humans.
  • compositions include excipients (e.g., lactose, sucrose, D-mannitol, starch, cornstarch, crystalline cellulose, light anhydrous silicic acid etc.), lubricants (e.g., magnesium stearate, talc, colloid silica etc.), binders (e.g., crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, carboxymethylcellulose sodium etc.), disintegrant (e.g., starch, carboxymethylcellulose, carboxymethylcellulose calcium, sodium carboxymethyl starch, L-hydroxypropylcellulose etc.), and the like which be used for solid preparations.
  • excipients e.g., lactose, sucrose, D-mannitol, starch, cornstarch, crystalline cellulose, light anhydrous silicic acid etc.
  • the pharmaceutically acceptable vehicle, carrier or excipient can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol and the like), suitable mixtures thereof, and vegetable oils.
  • a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol and the like), suitable mixtures thereof, and vegetable oils.
  • compositions include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water- miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection
  • water- miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol,
  • carriers, vehicle or excipients may include solubilizing agents (e.g., polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate etc.), suspending agents (surfactants, for example, stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, glycerin monostearate and the like; hydrophilic polymers, for example, poly(vinyl alcohol), polyvinylpyrrolidone, carboxymethylcellulose sodium, methylcellulose, hydroxymethylcellulose, hydroxypropylcellulose and the like, etc.), isotonic agents (e.g., glucose, D-sorbitol, sodium chloride, glycerol, D-mannitol etc.), buffering agents (buffer solutions, for example, phosphate, citrate and the like, etc.), and soothing agents (e.g.,
  • Prevention of the action of microorganisms in the composition can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents are included, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition.
  • Prolonged absorption of injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.
  • preparation additives such as antiseptic (e.g., p-oxybenzoic acid esters, chlorobutanol, benzyl alcohol, sorbic acid etc.), antioxidant (e.g., sulfite, ascorbic acid, a-tocopherol etc.), colorant, sweetening agent, and the like may further be added.
  • antiseptic e.g., p-oxybenzoic acid esters, chlorobutanol, benzyl alcohol, sorbic acid etc.
  • antioxidant e.g., sulfite, ascorbic acid, a-tocopherol etc.
  • colorant e.g., ascorbic acid, a-tocopherol etc.
  • One particular aspect concerns the use of a therapeutically effective amount of one or more anticancer compound as defined herein for prophylaxis and/or treatment of cancer(s) in subjects.
  • the term "therapeutically effective amount” or “effective amount” means the amount of compound that, when administered to a subject for treating or preventing a particular disorder, disease or condition, is sufficient to effect such treatment or prevention of that disorder, disease orcondition. Dosages and therapeutically effective amounts may vary, for example, depending upon a variety of factors including the activity of the specific agent employed, the age, body weight, general health, gender, and diet of the subject, the time of administration, the route of administration, the rate of excretion, and any drug combination, if applicable, the effect which the practitioner desires the compound to have upon the subject and the properties of the compounds (e.g.
  • the therapeutically effective amount may depend on the severity of the disease state, or underlying disease or complications. Such appropriate doses may be determined using any available assays.
  • a dose of the compound according to the invention is about 0.1 to about 8000 mg in the case of oral administration (e.g., a dose of about 0.1 mg, about 0.5 mg, or about 1 mg, or about 5 mg, or about 10 mg, or about 50 mg, or about 100 mg, or about 500 mg, or about 1000 mg, or about 2500 mg, or about 5000 mg, or about 6000 mg, or about 7500 mg, or about 8000 mg).
  • the daily dose to an adult may be about 1 to 8000 mg.
  • a dose may be administered in 1 to 3 divided portions per day.
  • a dose When administered in the form of a sustained-release preparation, a dose may be administered every other day or at longer intervals (e.g., every 2, 3, 4, 5, 6 or 7 days). When the compound is administered parenterally, it is may be administered in the form of a liquid (e.g., intravenous injection).
  • a single dose may be about 0.01 mg - about 100 mg per kg of body weight, preferably about 0.01 - about 50 mg, more preferably about 0.01 - about 20 mg.
  • the active compound i.e. anticancer compound
  • Formulations of the anticancer compound may be prepared so as to provide a pharmaceutical composition in a form suitable for any route of administration such as oral administration, injections (e.g., subcutaneous, intramuscular, intrathecal, intravenous, intra-nasal), sublingual, buccal, rectal, vaginal, ocular, otic, nasal, inhalation (e.g., intratracheal, pulmonary), nebulization, cutaneous, and transdermal administration.
  • the route of administration is oral or parenteral.
  • the anticancer compounds be formulated under the form of nanoparticles, liposomes or any other suitable controlled release system for a chronology delivery, an extended release, and/or a targeted delivery.
  • compositions or formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well-known in the art of pharmaceutical formulation. All methods include the step of bringing together the active pharmaceutical ingredient(s) with liquid carriers or finely divided solid carriers or both as the need dictates. When appropriate, the above-described formulations may be adapted so as to provide sustained release of the active pharmaceutical ingredient. Sustained release formulations well-known to the art include the use of a bolus injection, continuous infusion, biocompatible polymers or liposomes. In preferred embodiments, the compositions according to the invention are formulated for oral administration.
  • a pharmaceutical composition in accordance with the present invention may further comprise at least one of a hormonal therapeutic agent, a chemotherapeutic agent, an immunotherapeutic agent, a pharmaceutical agent inhibiting the action of cell growth factor, a pharmaceutical agent inhibiting the action of cell growth factor receptor.
  • the hormonal therapeutic agent is one or more of: fosfestrol, diethylstylbestrol, chlorotrianisene, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, allylestrenol, gestrinone, mepartricin, raloxifene, ormeloxifene, levormeloxifene, anti-estrogens (e.g., tamoxifen citrate, toremifene citrate), pill preparations, mepitiostane, testrolactone, aminoglutethimide, LH-RH agonists (e.g., goserelin acetate, buserelin, leuprorelin acetate), droloxifene, epitiostanol, ethinylestradiol sulfonate, aromatase inhibitors (
  • the chemotherapeutic agent is one or more of an alkylating agent, a metabolic antagonist, an antitumor antibiotic, and a plant-derived antitumor drugs.
  • the alkylating agent is one or more of nitrogen mustard, nitrogen mustard-N-oxide hydrochloride, chlorambutyl, cyclophosphamide, ifosfamide, thiotepa, carboquone, improsulfan tosylate, busulfan, nimustine hydrochloride, mitobronitol, melphalan, dacarbazine, ranimustine, estramustine phosphate sodium, triethylenemelamine, carmustine, lomustine, streptozocin, pipobroman, etoglucid, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambamustine, dibrospidium hydrochloride, fotemustine, prednimustine, pumitepa, ribomustin, temozolomide, treosulphan, trophosphamide, zino
  • the antitumor antibiotic is one or more of “actinomycin-D, actinomycin-C, mitomycin-C, chromomycin-A3, bleomycin hydrochloride, bleomycin sulfate, peplomycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride, neocarzinostatin, mithramycin, sarcomycin, carzinophilin, mitotane, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride, and DDS preparations thereof (e.g., doxorubicin-encapsulating PEG ribosome) can be used.
  • actinomycin-D actinomycin-C
  • mitomycin-C mitomycin-C
  • the plant-derived antitumor drug is one or more of etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel, cabazitaxel, vinorelbine, and DDS preparations thereof can be used.
  • the metabolic antagonist is one or more of mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, pemetrexed, enocitabine, cytarabine, cytarabine ocfosfate, ancitabine hydrochloride, 5-FU drugs (e.g., fluorouracil, tegafur, UFT, doxifluridine, carmofur, 15 enzazepine 15 , 15 enzazep, capecitabine), aminopterine, nelzarabine, leucovorin calcium, tabloid, butocine, folinate calcium, levofolinate calcium, cladribine, emitefur, fludarabine, gemcitabine, hydroxycarbamide, pentostatin, piritrexim, idoxuridine, mitoguazone, thiazophrine, ambamustine, bendamustine, and DDS
  • 5-FU drugs e
  • the immunotherapeutic agent is one or more of “picibanil, krestin, sizofiran, lentinan, ubenimex, interferons, interleukins, macrophage colony- stimulating factor, granulocyte colony-stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, Corynebacterium parvum, levamisole, polysaccharide K, procodazole, anti- CTLA4 antibody (e.g., ipirimumab, tremelimumab), anti-PD-1 antibody (e.g., nivolumab, pembrolimazab), and anti-PD-L1 antibody can be used.
  • CTLA4 antibody e.g., ipirimumab, tremelimumab
  • anti-PD-1 antibody e.g., nivolumab, pembrolimazab
  • anti-PD-L1 antibody can be used.
  • the pharmaceutical agent inhibiting the action of cell growth factor or pharmaceutical agent inhibiting the action of cell growth factor receptor is one or more of EGF inhibitor, TGF ⁇ inhibitor, haregulin inhibitor, insulin inhibitor, IGF inhibitor, FGF inhibitor, KGF inhibitor, CSF inhibitor, EPO inhibitor, IL-2 inhibitor, NGF inhibitor, PDGF inhibitor, TGF ⁇ inhibitor, HGF inhibitor, VEGF inhibitor, angiopoietin inhibitor, EGF receptor inhibitor, HER2 inhibitor, HER4 inhibitor, insulin receptor inhibitor, IGF-1 receptor inhibitor, IGF-2 receptor inhibitor, FGF receptor-1 inhibitor, FGF receptor-2 inhibitor, FGF receptor-3 inhibitor, FGF receptor-4 inhibitor, VEGF receptor inhibitor, Tie-2 inhibitor, PDGF receptor inhibitor, Abl inhibitor, Raf inhibitor, FLT3 inhibitor, c-Kit inhibitor, Src inhibitor, PKC inhibitor, Smo inhibitor, ALK inhibitor, ROR1 inhibitor, Trk inhibitor, Ret inhibitor, mTOR inhibitor, Aurora inhibitor, PLK inhibitor, MEK(MEK1/2)
  • anti-VEGF antibody e.g., Bevacizumab, Ramucurumab
  • anti-HER2 antibody e.g., Trastuzumab, Pertuzumab
  • anti-EGFR antibody e.g., Cetuximab, Panitumumab, Matuzumab, Nimotuzumab
  • anti-HGF antibody e.g., Imatinib, Erlotinib, Gefitinib, Sorafenib, Sunitinib, Dasatinib, Lapatinib, Vatalanib, Ibrutinib, Bosutinib, Cabozantinib, Crizotinib, Alectinib, Vismodegib, Axitinib, Motesanib, Nilotinib), 6-[4-(4- ethylpiperazine-1-ylmethyl)phenyl]-N-[1 l-phenylethyl]-7H-pyr
  • the pharmaceutical composition further comprises one or more of asparaginase, aceglatone, procarbazine hydrochloride, protoporphyrin-cobalt complex salt, mercuric hematoporphyrin-sodium, topoisomerase I inhibitors, topoisomerase II inhibitors, differentiation-inducing factors, angiogenesis inhibitors, a- blockers, bis phosphonic acid, thalidomide, lenalidomide, pomalidomide, 5 azacytidine, decitabine, proteasome inhibitor, NEDD8 inhibitor, UAE inhibitor, PARP inhibitor, antitumor antibodies, anti-CCR4 antibody, and an antibody drug complex.
  • asparaginase aceglatone
  • procarbazine hydrochloride protoporphyrin-cobalt complex salt
  • mercuric hematoporphyrin-sodium mercuric hematoporphyrin-sodium
  • topoisomerase I inhibitors topoisomerase II
  • An additional related aspect relates to therapeutic methods (e.g. for treating a cancer) comprising administering a therapeutically effective amount of one or more anticancer compound or composition as described herein to a subject.
  • the invention also encompasses methods, compounds, and pharmaceutical compositions for the treatment of a cancer in mammals including, but not limited to intractable solid cancers and stem cells cancer.
  • the cancer is any one of liver cancer, pancreatic cancer, ovarian cancer, breast cancer, colon cancer, stomach cancer, renal cancer, glioblastoma and sarcoma.
  • the term “mammal”, “mammalian subject” or “mammalian cell” includes mammals and cells in which cancer treatment and/or tumor suppression is desirable.
  • the term “subject” includes domestic animals (e.g. cats, dogs, horses, pigs, cows, goats, sheep), rodents (e.g. mice or rats), rabbits, squirrels, bears, primates (e.g., chimpanzees, monkeys, gorillas, and humans), wild animals such as those living in zoos (e.g. lion, tiger, elephant, and the like), and transgenic species thereof.
  • the mammalian subject is a human, more preferably a human patient in need of treatment. Even more preferably the mammalian subject is a human patient diagnosed or susceptible to suffer from a cancer or tumor.
  • treatment or “treating” of a subject include one or more of administration of an anticancer compound or composition to a subject with the purpose of stabilizing, curing, healing, alleviating, relieving, altering, remedying, less worsening, ameliorating, improving, or affecting the disease or condition, the symptom of the disease or condition, or the risk of (or susceptibility to) the disease or condition.
  • the term “treating” refers to any indication of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission; lessening of the rate of worsening; lessening severity of the disease; stabilization, diminishing of symptoms or making the injury, pathology or condition more tolerable to the subject; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; or improving a subject’s physical or mental well-being.
  • the treatment method comprises administering to the subject a therapeutically effective amount of an anticancer agent or composition as defined herein.
  • the term treatment encompasses “prophylaxis”, i.e.
  • the compound or composition is administered for prevention of the onset of the disease (the whole pathology, or one or more pathologies), and delay of the onset of the disease.
  • a “prophylactically effective amount” refers to a dose of the compound of the present invention which is sufficient to achieve such object.
  • a physician may for example, prescribe a relatively low dose at first, subsequently increasing the dose until an appropriate response is obtained.
  • the effective amount for a human subject may be a single administration of a high concentration of the anticancer compound.
  • the anticancer compound may be administered more frequently (e.g., daily, weekly, monthly) and/or until the patient is tested negative for cancer cells and even afterwards.
  • the methods of treatments, anticancer compounds and compositions of the present invention may also be used in combination with other medicament(s), preferably to provide superior prophylactic and/or treatment effect associated to the combined use with other medicament(s).
  • combination therapy may also reduce the dose of other medicaments and reduce the side effects thereof.
  • the anticancer compounds and compositions of the present invention are used in combination with one or more well-known anticancer drugs including, but not limited to, gemcitabine and capecitabine.
  • the methods of treatments, anticancer compounds and compositions of the present invention are used in combination with anticancer therapies and/or anticancer vaccines (especially already approved anticancer therapies) including those particular compounds mentioned hereinbefore.
  • methods of treatments in accordance with the present invention comprises concomitant administration of one or more existing therapies (e.g., anticancer agents, vaccines, etc.) as mentioned hereinbefore.
  • therapies e.g., anticancer agents, vaccines, etc.
  • the term “concomitant” or “concomitantly” as in the phrases “administering concomitantly” or “concomitantly with” or “concomitant administration” includes administering a first compound in the presence of a second compound.
  • a concomitant administration includes methods in which the first or second compounds are co-administered.
  • a concomitant administration treatment method may be executed step-wise by different actors.
  • one actor may administer to a subject a first compound and as a second actor may administer to the subject a second compound.
  • the administering steps may be executed at the same time, or nearly the same time (e.g. within 1 , 2, 5, 10, 20 or 30 minutes), or at distant times (e.g. more than 1 hour, more than 2 hours, more than 3 hours, more than 6 hours, more than 12 hours, more than 24 hours, etc.).
  • the actor and the subject may be the same entity (e.g., a human).
  • the dose of the concomitant drug can be appropriately selected based on the dose used clinically.
  • the mixing ratio of the compound of the present invention and the concomitant drug can be appropriately selected according to factors such as the disease and symptom of the subject, the administration route, the kind of the concomitant drug to be used, and the like.
  • the concomitant drug is a well-known anticancer drug such as gemcitabine and/or capecitabine.
  • Example 1 Inhibition of hTERT-RdRP activity
  • HeLa cells cultured from the previous day in a DMEM medium (Wako) supplemented with 10% inactivated bovine fetal serum (IFS), Penicillin (100 U/mL) and Streptomycin (100 ⁇ g/mL) as a general medium were seeded at 1x10 6 cells in a 10 cm dish. After culturing for 2 days, the general medium was exchanged with a general medium further supplemented with thymidine (Nacalai Tesque, final 2.5 mM), and the cells were cultured.
  • IFS inactivated bovine fetal serum
  • Penicillin 100 U/mL
  • Streptomycin 100 ⁇ g/mL
  • the cells were washed 3 times with 10 mL of PBS (phosphate buffered saline), the medium was exchanged with the general medium, and the cells were cultured. After culturing for 6 h, the general medium was exchanged with a general medium further supplemented with Nocodazole (Sigma, final 0.1 ⁇ g/mL), and the cells were cultured. After culturing for 14 h, the cells were recovered.
  • PBS phosphate buffered saline
  • the recovered cells were washed with cooled PBS, 1x10 7 cells were suspended in 1 mL of Lysis buffer A (20 mM Tris-HCI (pH 7.4), 150 mM NaCI, 0.5% NonidetTM P-40 (NP-40)). After sonication for 10 seconds, the supernatant was collected by centrifugation. To the supernatant was added 40 uL of Protein A agarose (Thermo Fisher Scientific, bed volume 20 ⁇ L), and the mixture was rotated and pre-cleared at 4°C for 30 min.
  • Lysis buffer A 20 mM Tris-HCI (pH 7.4), 150 mM NaCI, 0.5% NonidetTM P-40 (NP-40)
  • the immunoprecipitated beads were washed by the following method. Briefly, the beads were washed 4 times with 1 ml of Wash buffer I (1x acetate buffer (10 mM Hepes-KOH (pH 7.8), 100 mM potassium acetate, 4 mM MgCI 2 ) containing 10% glycerol, 0.1% Triton-XTM and 0.06x protease inhibitors (Roche, complete EDTA-free)) (rotated for 5 min at 4°C).
  • Wash buffer I (1x acetate buffer (10 mM Hepes-KOH (pH 7.8), 100 mM potassium acetate, 4 mM MgCI 2 ) containing 10% glycerol, 0.1% Triton-XTM and 0.06x protease inhibitors (Roche, complete EDTA-free)
  • composition of the RdRP reaction reagent is as shown in Table 1. [00084] Table 1 : Composition of the RdRP reaction reagent
  • RNA sample was dissolved in 20 ⁇ l of H 2 O, RNase OneTM (10 U/pl, Promega) (0.2 ⁇ l), 10 x reaction buffer (20 ⁇ l), H 2 O (159.8 ⁇ l) were added and RNase treatment was performed at 37°C for 2 h.
  • the purified sample was dissolved in 20 ⁇ l of H 2 O, 20 ⁇ l of 2x loading buffer (95% formamide, 20 mM EDTA and 1 % Orange G) was added, and the mixture was treated at 95°C for 10 min, rapidly cooled, electrophoresed on a 7M Urea 15% acrylamide gel. The gel was dried, developed on an X-ray film, and the intensity of the obtained signal was measured to verify the effect of the inhibitor.
  • 2x loading buffer 95% formamide, 20 mM EDTA and 1 % Orange G
  • Various types of cells (c.f., Table 2) were seeded on a 96-well plate (2000 cells/well), cultured overnight, the medium was replaced with a medium containing compound RK-X (0 - 50 ⁇ M), and MTT assay was performed 120 h later.
  • the MTT assay reagent was Cell Proliferation Kit I of Roche and the test was performed according to the protocol.
  • compound RK-X did dot inhibit proliferation of normal cells not expressing hTERT as compared with tumor cells, the compound only inhibiting proliferation of liver cancer cells. As reported in Table 2, compound RK-X the IC 50 of cell proliferation inhibition was about 3-18 ⁇ M, depending of the type of cell. [00095] Table 2: Suppression of tumor cell proliferation by compound RK-X
  • Example 3 In vivo animal study
  • NOD/SCID mice Six-week-old male NOD/SCID mice (NOD/NCrCRI-Prkdc scid ) were purchased from Charles River Laboratories, Inc.
  • Patient-derived cancer cells (MT) were established from a surgically resected hepatocellular carcinoma specimen.
  • mice were intraperitoneally injected with vehicle or compound RK-X b.i.d. 5 days per week (from Monday to Friday) for 14 days.
  • the experimental protocol was approved by the Kanazawa University Animal Care and Use Committee and conformed to the Guide for the Care and Use of Laboratory Animals prepared by the National Academy of Sciences.
  • the tumors removed from the mice were sonicated and then immunoprecipitated with anti-hTERT antibody, and the activity was measured according to the RdRP activity measurement protocol.
  • the method for preparing the tumor applying for the RdRP assay was as follows.
  • the tumor was placed in a MagNA Lyser Green BeadsTM (Roche Diagnostics) tube, 500 ⁇ l of Lysis buffer A was added, and the mixture was crushed used MagNA LyserTM instrument (Roche Diagnostics). After centrifugation, the protein concentration was measured. Each 5 mg was subjected to immunoprecipitation to activity measurement.
  • RdRP activity of the tumor taken out from the mouse under respective test conditions is shown in Figure 3D.
  • the solidified cell layer was covered with 50 ⁇ l of DMEM ⁇ treatment that was replaced two times a week over a 21 -day period.
  • Phase contrast images (six fields per well) were captured using a digital video camera (OlympusTM U- CMT) and analyzed with Northern EclipseTM v.5.0 software.
  • 50 ⁇ l of alamar BlueTM (Invitrogen, Burlington, Ontario) were added to each well and fluorescence readings (Ex: 530/25-nm and Em: 590/35-nm) were performed every 10 minutes for 3h. The experiment was done in triplicates.
  • Panc-1 cells exhibited high-level and robust RdRP activity.
  • Mia-Paca-2 cells demonstrated less RdRP activity.
  • sensitivity to compound RK-X is associated with RdRP activity. More specifically, 5 ⁇ M (P ⁇ 0.05) or 50 ⁇ M (P ⁇ 0.001) of RK-X successfully reduced the growth of Panc-1 cells (RdRP activity-High) in anchorage-independent cell growth assay while Mia-Paca-2 cells (RdRP activity-Low) failed to demonstrate sensitivity to RK-X in 5 ⁇ M of RK-X in anchorage-independent cell growth assay.

Landscapes

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

Abstract

L'invention concerne des dérivés de sulfonamide de formule (I) pouvant inhiber l'activité de l'ARN polymérase ARN-dépendante (RdRp) de cellules cancéreuses. L'invention concerne également des compositions pharmaceutiques comprenant ces composés et leurs utilisations dans la prophylaxie et/ou le traitement de cancers, y compris les cancers solides réfractaires et le cancer à cellules souches. La composition pharmaceutique peut en outre comprendre au moins l'un d'un agent thérapeutique hormonal, un agent chimiothérapeutique, un agent immunothérapeutique, un agent pharmaceutique inhibant l'action du facteur de croissance cellulaire et un agent pharmaceutique inhibant l'action du récepteur du facteur de croissance cellulaire.
PCT/IB2021/062400 2020-12-29 2021-12-28 Dérivés de sulfonamide, compositions les comprenant et leurs utilisations dans le traitement de cancers WO2022144780A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2020-219884 2020-12-29
JP2020219884A JP2022104746A (ja) 2020-12-29 2020-12-29 抗がん剤

Publications (1)

Publication Number Publication Date
WO2022144780A1 true WO2022144780A1 (fr) 2022-07-07

Family

ID=82259875

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2021/062400 WO2022144780A1 (fr) 2020-12-29 2021-12-28 Dérivés de sulfonamide, compositions les comprenant et leurs utilisations dans le traitement de cancers

Country Status (2)

Country Link
JP (1) JP2022104746A (fr)
WO (1) WO2022144780A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009127417A1 (fr) * 2008-04-16 2009-10-22 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Dérivés de quinolines utilisés comme inhibiteurs des kinases axl
WO2018035446A1 (fr) * 2016-08-18 2018-02-22 Intekrin Therapeutics, Inc. Agoniste de ppary pour le traitement de cancers du sang
WO2020243058A1 (fr) * 2019-05-30 2020-12-03 Coherus Biosciences, Inc. Compositions et procédés de traitement du cancer

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009127417A1 (fr) * 2008-04-16 2009-10-22 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Dérivés de quinolines utilisés comme inhibiteurs des kinases axl
WO2018035446A1 (fr) * 2016-08-18 2018-02-22 Intekrin Therapeutics, Inc. Agoniste de ppary pour le traitement de cancers du sang
WO2020243058A1 (fr) * 2019-05-30 2020-12-03 Coherus Biosciences, Inc. Compositions et procédés de traitement du cancer

Also Published As

Publication number Publication date
JP2022104746A (ja) 2022-07-11

Similar Documents

Publication Publication Date Title
JP7234283B2 (ja) 翼状片を治療するための組成物及び方法
CN112839649A (zh) Cxcr4抑制剂组合物以及制备和使用的方法
CN105407889A (zh) 针对Rb阳性异常细胞增殖的HSPC节制性治疗
MX2008008723A (es) Tratamiento de la hepatitis viral.
JP6570512B2 (ja) 新規なＳｔａｔ３阻害剤
JP2013533257A (ja) 血液癌の治療法
US10703747B2 (en) Benzothiophene-based selective mixed estrogen receptor downregulators
JP2017537129A (ja) 選択的ｓ１ｐ１レセプターアゴニストを含む薬学的合剤
WO2017023739A1 (fr) Dérivés de rufinamide et leur utilisation dans l'inhibition de l'activation des canaux sodiques humains à déclenchement par la tension
CA3173658A1 (fr) Therapies avantageuses pour des troubles medies par ikaros ou aiolos
US20100008912A1 (en) Combination drug
WO2022144780A1 (fr) Dérivés de sulfonamide, compositions les comprenant et leurs utilisations dans le traitement de cancers
AU2018249154A1 (en) Novel cyclin-dependent kinase 8 and/or 19 inhibitor
EP3914257B1 (fr) Combinaison d'un inhibiteur de bcl-2/bcl-xl avec l'osimertinib
US20110003805A1 (en) Concomitant drug
EP3250291B1 (fr) Malonate cristallin c21h22c12n4o2
US8741893B2 (en) 6,7-dihydro-[1,3,4]thiadiazolo-[3,2-a][1,3]diazepin derivatives and pharmaceutical compositions containing the same as hypnotic or anesthetic agent and method for their preparation
WO2022223543A1 (fr) Association comprenant un inhibiteur spécifique de hdac6 et au moins un inhibiteur de point de contrôle ctla4
KR20240016298A (ko) 재발성 원발성 cns 신생물에 대한 용도 및 방법
CA3152424A1 (fr) Inhibiteurs de la quinoleine de rad52 et methodes d'utilisation
WO2023048878A1 (fr) Déplétion de fndc5 réduisant la perte de muscle/la cachexie induite par le cancer
WO2021170811A1 (fr) Méthode de traitement d'une maladie oculaire à l'aide d'antagonistes de trpv4
CN117982636A (zh) 一种预防和/或治疗脑胶质瘤的联合用药组合产品以及联合制药用途
WO2009110416A1 (fr) Médicament concomitant
CN114206329A (zh) 组合疗法方法、组合物和试剂盒

Legal Events

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

Ref document number: 21914837

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

NENP Non-entry into the national phase

Ref country code: JP

122 Ep: pct application non-entry in european phase

Ref document number: 21914837

Country of ref document: EP

Kind code of ref document: A1