WO2022271540A1 - Inhibiteurs de dot1l - Google Patents

Inhibiteurs de dot1l Download PDF

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Publication number
WO2022271540A1
WO2022271540A1 PCT/US2022/033949 US2022033949W WO2022271540A1 WO 2022271540 A1 WO2022271540 A1 WO 2022271540A1 US 2022033949 W US2022033949 W US 2022033949W WO 2022271540 A1 WO2022271540 A1 WO 2022271540A1
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Prior art keywords
cancer
compound
pharmaceutically acceptable
ethyl
acceptable salt
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PCT/US2022/033949
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English (en)
Inventor
Tushar C. Patel
Thomas R. Caulfield
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Mayo Foundation For Medical Education And Research
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Publication of WO2022271540A1 publication Critical patent/WO2022271540A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • This document relates to heterocyclic compounds useful in treating cancer.
  • this document provides ((benzoimidazolyl)ethyl)cyclobutyl compounds that can be used to treat cancer (e.g., cholangiocarcinoma).
  • cancer e.g., cholangiocarcinoma
  • cancer is one of the leading causes of death in contemporary society.
  • the numbers of new cancer cases and deaths is increasing each year.
  • cancer incidence is over 450 cases of cancer per 100,000 men and women per year, while cancer mortality is over 70 cancer deaths per 100,000 men and women per year.
  • the compounds provided herein can be therapeutically efficient against cholangiocarcinoma, which is a cancer of the biliary tract.
  • the compounds provided herein are primarily excreted from the patient’s body through the biliary tract, thereby enhancing their anticancer effects on biliary tract cancers by increasing the compounds’ local concentration at the tumor site.
  • this document provides a compounds selected from any one of the following compounds: or a pharmaceutically acceptable salt thereof.
  • this document provides a pharmaceutical composition comprising a compound as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • this document provides a method of treating a cancer in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same.
  • the compound is administered to the subject in combination with at least one medication or therapy useful in treating the cancer.
  • FIG. 1 contains chemical structures of EPZ5676 and its analogs.
  • FIG. 2 contains a line plot showing IC50 for exemplary compounds in a DOT1L methyl transferase activity essay.
  • FIG. 3 contains bar graphs showing biliary excretion rate for an exemplary compound MC-21 and compound EPZ5676.
  • FIG. 4 contains bar graphs showing tumor reduction in mice treated with an exemplary compound MC-21 and a control.
  • FIG. 5 contains a plot showing tumor doubling time in mice treated with gemcitabine and cisplatin, or MC-21, gemcitabine and cisplatin.
  • FIG. 6 contains bar graphs showing that MC-21 reduces cholangiocarcinoma cell growth in vivo.
  • FIG. 7A contains a table showing a study design and mice group division for determining in vivo toxicity of MC-21 administered at 10 mg/kg and 20 mg/kg. (Bt - terminal bleeding of survived mice for hematology, plasma HPLC-MS/MS analysis and plasma clinical chemistry; Gc - general condition observation; Fs - fasting for 6 hours; Tk - sampling of tissues (brain, kidney, liver, lung, spleen, and pancreas) for HPLC-MS/MS analysis; W - weighing; X - compound or vehicle administration)
  • FIG. 7B contains a table showing a study design and mice group division for determining in vivo toxicity of MC-21 administered at 10 mg/kg and also vehicle administration.
  • Bt terminal bleeding of survived mice for hematology, plasma HPLC-MS/MS analysis and plasma clinical chemistry; Gc - general condition observation; Fs - fasting for 6 hours; Tk - sampling of tissues (brain, kidney, liver, lung, spleen, and pancreas) for HPLC-MS/MS analysis; W - weighing; X - compound or vehicle administration).
  • FIG. 9A contains a table showing individual signs of toxicity in male C57BL/6N mice during experimental period for MC21 dosed at 10 mg/kg and 20 mg/kg. (0 - good appearance, D - hypokinesia (decreased activity), P - piloerection).
  • FIG. 9B contains a table showing individual signs of toxicity in male C57BL/6N mice during experimental period (MC21 dosed at 40 mg/kg and after administration of vehicle) (0 - good appearance, D - hypokinesia (decreased activity), P piloerection).
  • FIG. 9C contains a table showing individual signs of toxicity in female C57BL/6N mice during experimental period for MC21 dosed at 10 mg/kg and 20 mg/kg. (0 - good appearance, D - hypokinesia (decreased activity), P - piloerection).
  • FIG. 9D contains a table showing individual signs of toxicity in female C57BL/6N mice during experimental period for MC21 dosed at 40 mg/kg and after administration of vehicle. (0 - good appearance, D - hypokinesia (decreased activity), P - piloerection).
  • FIG. 10 contains concentration-time curves for MC21 in male and female C57BL/6N mice following IV dosing.
  • FIG. 11 A Solubilization of test compounds MCI 3, MC21 in different vehicles.
  • FIG. 11B Solubilization of test compounds MC34, MC55 in different vehicles.
  • FIG. llC Solubilization of test compound MC89 in different vehicles.
  • this document provides heterocyclic compounds comprising a ((benzoimidazolyl)ethyl)cyclobutyl moiety. Methods of using these compounds, e.g., for treating cancer, and pharmaceutical compositions comprising these compounds are also provided.
  • Therapeutic compounds are also provided.
  • this document provides a compound selected from any one of the following compounds: or a pharmaceutically acceptable salt thereof.
  • this document provides a compound having formula: or a pharmaceutically acceptable salt thereof.
  • the compound is (lR,2S,3R,5R)-3-(4-amino-lH- pyrazolo[3,4-d]pyrimidin-l-yl)-5-(((3-(2-(5-(tert-butyl)-lH-benzo[d]imidazol-2- yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)cyclopentane-l,2-diol.
  • this document provides a compound having formula: or a pharmaceutically acceptable salt thereof.
  • the compound is (lR,2S,3R,5R)-3-(7-amino-3H- [l,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(((3-(2-(5-(tert-butyl)-lH-benzo[d]imidazol-2- yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)cyclopentane-l,2-diol.
  • this document provides a compound having formula: or a pharmaceutically acceptable salt thereof.
  • the compound is (2S,3R,4S,5R)-2-(4-aminofuro[3,2- d]pyrimidin-7-yl)-5-(((3-(2-(5-(tertbutyl)-lH-benzo[d]imidazol-2- yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol.
  • this document provides a compound having formula: or a pharmaceutically acceptable salt thereof.
  • the compound is (2S,3R,4S,5R)-2-(4-aminothieno[3,2- d]pyrimidin-7-yl)-5-(((3-(2-(5-(tertbutyl)-lH-benzo[d]imidazol-2- yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol.
  • this document provides a compound having formula: or a pharmaceutically acceptable salt thereof.
  • the compound is (2S,3R,4S,5R)-2-(4-amino-5H- pyrrolo[3,2-d]pyrimidin-7-yl)-5-((((lr,3S)-3-(2-(5-(tert-butyl)-lH-benzo[d]imidazol-
  • a salt of a compound provided herein e.g., a heterocyclic compound comprising a ((benzoimidazolyl)ethyl)cyclobutyl moiety
  • a basic group of the compound such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group.
  • the compound is a pharmaceutically acceptable acid addition salt.
  • acids commonly employed to form pharmaceutically acceptable salts of the compounds provided herein include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para- toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well
  • Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylprop
  • pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such as maleic acid.
  • bases commonly employed to form pharmaceutically acceptable salts of the compounds provided herein include hydroxides of alkali metals, including sodium, potassium, and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, organic amines such as unsubstituted or hydroxyl-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N- ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-(
  • the compounds described herein e.g., heterocyclic compounds comprising a ((benzoimidazolyl)ethyl)cyclobutyl moiety), or pharmaceutically acceptable salts thereof, are substantially isolated.
  • this document provides a method of treating cancer in a subject (e.g., a human), the method comprising administering to the subject (e.g., the subject in need thereof) a therapeutically effective amount of any one or more of the compounds described herein (e.g., a heterocyclic compound comprising a ((benzoimidazolyl)ethyl)cyclobutyl moiety), or a pharmaceutically acceptable salt thereof.
  • a subject e.g., a human
  • a therapeutically effective amount of any one or more of the compounds described herein e.g., a heterocyclic compound comprising a ((benzoimidazolyl)ethyl)cyclobutyl moiety
  • a pharmaceutically acceptable salt thereof e.g., a pharmaceutically acceptable salt thereof.
  • Suitable examples of cancers that can be treated with one or more of the compounds provided herein include, without limitation, bladder cancer, gallbladder cancer, brain cancer, breast cancer, colorectal cancer, cervical cancer, gastrointestinal cancer, genitourinary cancer, head and neck cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, skin cancer, testicular cancer, blood cancer (e.g., leukemia), cancers of the biliary tract, liver cancer, ampullary cancer.
  • the subject in need of treatment as described herein is diagnosed with having a cancer by a treating physician.
  • the cancer can be diagnosed, for example, by detecting cancer biomarkers in a blood or a serum test (e.g., by detecting a carcinoembryonic antigen).
  • the cancer can also be diagnosed using an imaging technique (e.g., abdominal ultrasound), a laparoscopical biopsy, or any combination of the aforementioned diagnostic methods.
  • a skilled physician would be able to choose and implement a suitable diagnostic protocol.
  • Cholangiocarcinoma is a cancer affecting the biliary tract. Although these cancers are rare, they are increasing in incidence, and there is a lack of effective treatments. More specifically, current treatments are limited to surgical resection, followed by radiation therapy, conventional therapy, and stenting. In certain cases, a liver transplantation is necessary for successful treatment.
  • the compounds provided herein e.g., a heterocyclic compound comprising a
  • the rate of excretion of the compounds provided herein e.g., a heterocyclic compound comprising a ((benzoimidazolyl)ethyl)cyclobutyl moiety
  • any other route e.g., lungs, kidney, or skin.
  • this document provides a method of treating a biliary tract cancer in a subject, the method comprising administering to the subject (e.g., the subject in need thereof) a therapeutically effective amount of any one or more of the compounds described herein (e.g., a heterocyclic compound comprising a ((benzoimidazolyl)ethyl)cyclobutyl moiety), or a pharmaceutically acceptable salt thereof.
  • a therapeutically effective amount of any one or more of the compounds described herein e.g., a heterocyclic compound comprising a ((benzoimidazolyl)ethyl)cyclobutyl moiety
  • a pharmaceutically acceptable salt thereof e.g., a pharmaceutically acceptable salt thereof.
  • this document provides a method of treating a cholangiocarcinoma in a subject, the method comprising administering to the subject (e.g., the subject in need thereof) a therapeutically effective amount of any one or more of the compounds described herein (e.g., a heterocyclic compound comprising a ((benzoimidazolyl)ethyl)cyclobutyl moiety), or a pharmaceutically acceptable salt thereof.
  • a therapeutically effective amount of any one or more of the compounds described herein e.g., a heterocyclic compound comprising a ((benzoimidazolyl)ethyl)cyclobutyl moiety
  • a pharmaceutically acceptable salt thereof e.g., a pharmaceutically acceptable salt thereof.
  • the cholangiocarcinoma is selected from intrahepatic cholangiocarcinoma (a tumor in the bile ducts within the liver), hilar cholangiocarcinoma (a tumor in the bile ducts just outside the liver), and distal cholangiocarcinoma (a tumor in the bile ducts near the small intestine).
  • the compounds provided herein can exert their therapeutic action by selective modulation of the aberrant expression of an epigenetic enzyme, disruptor of telomeric silencing 1-like (“DotlL”).
  • This enzyme is a histone methyltransferase that selectively adds a methyl group to a specific amino acid (lysine 79) on histone 3.
  • lysine 79 a specific amino acid
  • this document provides a method of inhibiting DotlL polypeptide activity in a cell, the method comprising contacting the cell with an effective amount of a compound described herein (e.g., a heterocyclic compound comprising a ((benzoimidazolyl)ethyl)cyclobutyl moiety), or a pharmaceutically acceptable salt thereof.
  • a compound described herein e.g., a heterocyclic compound comprising a ((benzoimidazolyl)ethyl)cyclobutyl moiety
  • the contacting is carried out in vitro. In some embodiments, the contacting is carried out in vivo. In some embodiments, the contacting is carried out ex vivo.
  • this document provides a method of inhibiting DotlL polypeptide activity in a cell of a subject, the method comprising administering to the subject an effective amount of a compound described herein (e.g., a heterocyclic compound comprising a ((benzoimidazolyl)ethyl)cyclobutyl moiety), or a pharmaceutically acceptable salt thereof.
  • a compound described herein e.g., a heterocyclic compound comprising a ((benzoimidazolyl)ethyl)cyclobutyl moiety
  • the cell can be a cancer cell (e.g., any one of the cancers described herein). In some embodiments, the cell is a cholangiocarcinoma cell. Combination therapies
  • the compounds described herein can be administered to the subject in combination with at least one other medication or therapy useful in treating any one of the cancers described herein.
  • suitable examples of such therapies include, without limitation, chemotherapy, immune based therapies, tissue ablation, irradiation, surgery, or any combination thereof.
  • the compounds described herein e.g., a heterocyclic compound comprising a
  • chemotherapeutics include, without limitation, docetaxel, paclitaxel, cyclophosphamide, 5-fluorouracil, epirubicin, erdafitinib, avelumab, acalabrutinib, doxorubicin, everolimus, gemcitabine, imiquimod, alectinib, bevacizumab, avapritinib, encorafenib, zanubrutinib, carboplatin, cisplatin, dactinomycin, oinutuzumab, olaparib, enzalutamide, ipilimumab, abiraterone acetate, capecitabine, oxaliplatin, infigratinib
  • the compounds described herein e.g., a heterocyclic compound comprising a ((benzoimidazolyl)ethyl)cyclobutyl moiety
  • a heterocyclic compound comprising a ((benzoimidazolyl)ethyl)cyclobutyl moiety can be administered to the subject in combination with gemcitabine or cisplatin, or a combination thereof.
  • a compound described herein e.g., a heterocyclic compound comprising a ((benzoimidazolyl)ethyl)cyclobutyl moiety
  • the subject e.g., a human
  • the one or more additional therapeutic agents e.g., in the same pharmaceutical composition or dosage form or in different compositions or dosage forms
  • the additional therapeutic agent may be administered in a separate pharmaceutical composition or dosage form before or after administration of a compound described herein.
  • kits useful useful, for example, in the treatment of cancers described herein, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound described herein (e.g., a heterocyclic compound comprising a ((benzoimidazolyl)ethyl)cyclobutyl moiety).
  • kits can further include, if desired, one or more of various pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc.
  • Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.
  • the kit may optionally include an additional therapeutic agent as described herein.
  • compositions comprising an effective amount of a compound described herein (e.g., a heterocyclic compound comprising a ((benzoimidazolyl)ethyl)cyclobutyl moiety), or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition may also comprise any one of the additional therapeutic agents described herein.
  • the application also provides pharmaceutical compositions and dosage forms comprising any one the additional therapeutic agents described herein.
  • the carrier(s) are “acceptable” in the sense of being compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, not deleterious to the recipient thereof in an amount used in the medicament.
  • Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions described herein (e.g., a pharmaceutical composition containing one or more heterocyclic compounds comprising a ((benzoimidazolyl)ethyl)cyclobutyl moiety) include, without limitation, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol, and
  • compositions or dosage forms may contain any one or more of the compounds described herein (e.g., any one or more heterocyclic compounds comprising a ((benzoimidazolyl)ethyl)cyclobutyl moiety) and therapeutic agents described herein in the range of 0.005 percent to 100 percent with the balance made up from the suitable pharmaceutically acceptable excipients.
  • compositions may contain 0.001 percent to 100 percent (e.g., 0.1 to 95 percent, 75 to 85 percent, or 20 to 80 percent) of any one of the compounds described herein (e.g., a heterocyclic compound comprising a ((benzoimidazolyl)ethyl)cyclobutyl moiety) and therapeutic agents provided herein, wherein the balance may be made up of any pharmaceutically acceptable excipient described herein, or any combination of these excipients.
  • a heterocyclic compound comprising a ((benzoimidazolyl)ethyl)cyclobutyl moiety
  • compositions described herein can be suitable for any acceptable route of administration.
  • Acceptable routes of administration include, without limitation, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intra- biliary, intrabursal, intracerebral, intracistemal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intrahepatic, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intranasal, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogas
  • compositions and formulations described herein may conveniently be presented in a unit dosage form, e.g., tablets, sustained release capsules, and in liposomes, and may be prepared using any appropriate method. See, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, Baltimore, MD (20th ed. 2000). Such preparative methods include the step of bringing into association with the molecule to be administered ingredients such as the carrier that constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • any one or more of the compounds described herein e.g., a heterocyclic compound comprising a ((benzoimidazolyl)ethyl)cyclobutyl moiety
  • any one or more of the therapeutic agents described herein can be administered orally.
  • compositions provided herein that are suitable for oral administration may be presented as discrete units such as capsules, sachets, granules or tablets each containing a predetermined amount (e.g., effective amount) of the active ingredient; a powder or granules; a solution or a suspension in an aqueous liquid or a non-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oil liquid emulsion; packed in liposomes; or as a bolus, etc.
  • Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption.
  • carriers that are commonly used include lactose, sucrose, glucose, mannitol, and silicic acid and starches.
  • Other acceptable excipients may include: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as ka
  • useful diluents include lactose and dried com starch.
  • the active ingredient is combined with emulsifying and suspending agents.
  • certain sweetening and/or flavoring and/or coloring agents may be added.
  • Compositions suitable for oral administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia.
  • compositions suitable for parenteral administration include aqueous and non- aqueous sterile injection solutions or infusion solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, saline (e.g., 0.9% saline solution) or 5% dextrose solution, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • the injection solutions may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated using any appropriate method and using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer’s solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.
  • compositions described herein may be administered in the form of suppositories for rectal administration.
  • These compositions can be prepared by mixing a compound described herein (e.g., a heterocyclic compound comprising a ((benzoimidazolyl)ethyl)cyclobutyl moiety) with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components.
  • suitable non-irritating excipient include, without limitation, cocoa butter, beeswax, and polyethylene glycols.
  • compositions described herein may be administered by nasal aerosol or inhalation.
  • Such compositions can be prepared using any appropriate method and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents. See, for example, U.S. Patent No. 6,803,031. Additional formulations and methods for intranasal administration that can be used as described herein are described elsewhere (e.g., in Ilium, L., J Pharm Pharmacol , 56:3-17, 2004 and Ilium, L., Eur J Pharm Sci 11:1-18, 2000).
  • a topical composition containing one or more of the compounds described herein e.g., a heterocyclic compound comprising a
  • compositions described herein can be prepared and used in the form of an aerosol spray, cream, emulsion, solid, liquid, dispersion, foam, oil, gel, hydrogel, lotion, mousse, ointment, powder, patch, pomade, solution, pump spray, stick, towelette, soap, or other forms commonly employed in the art of topical administration and/or cosmetic and skin care formulation.
  • the topical compositions can be in an emulsion form. Topical administration of the pharmaceutical compositions described herein is especially useful when the desired treatment involves areas or organs readily accessible by topical application.
  • the topical composition comprises a combination of any one or more of the compounds described herein (e.g., a heterocyclic compound comprising a ((benzoimidazolyl)ethyl)cyclobutyl moiety) and one or more therapeutic agents described herein, and one or more additional ingredients, carriers, excipients, or diluents including, without limitation, absorbents, anti- irritants, anti-acne agents, preservatives, antioxidants, coloring agents/pigments, emollients (moisturizers), emulsifiers, film-forming/holding agents, fragrances, leave-on exfoliants, prescription drugs, preservatives, scrub agents, silicones, skin-identical/repairing agents, slip agents, sunscreen actives, surfactants/detergent cleansing agents, penetration enhancers, and thickeners.
  • additional ingredients, carriers, excipients, or diluents including, without limitation, absorbents, anti- irritants, anti-acne
  • any one or more of the compounds described herein e.g., a heterocyclic compound comprising a ((benzoimidazolyl)ethyl)cyclobutyl moiety
  • one or more of the therapeutic agents described herein may be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents, or catheters.
  • an implantable medical device such as prostheses, artificial valves, vascular grafts, stents, or catheters.
  • Suitable coatings and the general preparation of coated implantable devices are described elsewhere (e.g., U.S. Patent Nos. 6,099,562; 5,886,026; and 5,304,121).
  • the coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof.
  • the coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.
  • Coatings for invasive devices are to be included within the definition of pharmaceutically acceptable carrier, adjuvant or vehicle, as those terms are used herein.
  • this document provides an implantable drug release device impregnated with or containing one or more compounds described herein (e.g., a heterocyclic compound comprising a
  • the compounds may be delivered to the liver or biliary tract through the use of nanocarriers such as extracellular vesicles, micelles, liposomes, lipid polymers, dendrimers, nanogels or other nanocarriers.
  • nanocarriers such as extracellular vesicles, micelles, liposomes, lipid polymers, dendrimers, nanogels or other nanocarriers.
  • the Delivery and targeting of the compounds may be further enhanced using targeting moieties such as folic acid ligand or other targeting moieties, or with the use of surface modifications of these nanocarriers with targeting proteins such as antibodies or nanobodies, or RNA molecules, such as aptamers to EpCAM for targeting to tumor cells.
  • the compounds or their formulations with other carriers may be administered directly into the biliary tract, or to tumors within the biliary tract through percutaneous or through endoscopic approaches, or they may be administered through intravenous or intra-arterial administration to the systemic circulation, or to specific vessels such as the hepatic artery.
  • the pharmaceutical composition described herein can have preferential delivery to cells of the liver.
  • the pharmaceutical composition described herein can comprise a synthetic or biological nanoparticle.
  • the synthetic nanoparticle can be graphene oxide, nano shells, liposomes, superparamagnetic iron oxide nanoparticles, gold nanoparticles, silica, nanofibers, chitosan, carbon nanotubes, micelles, dendrimers, lipid nanocarriers, nanofibers, or polymeric nanoparticles, as described in Int J Nanomedicine. 2020; 15: 1437-1456, which is incorporated herein by reference in its entirety.
  • the biological nanoparticles can involve carriers such as extracellular vesicles, nanovesicles derived from cells, tissues or biological fluids such as milk, blood, bile or urine.
  • the pharmaceutical composition described herein can comprise an ionic liquid.
  • the ionic liquid can comprise a cation selected from the group consisting of choline, benzyl pyridinium, benzyl dimethyl dodecyl ammonium, phosphonium, tetraalkylphosphonium, benzethonium, imidazolium, pyridinium, piperidinium, quinolinium, morpholinium, quaternary phosphonium, and quaternary ammonium.
  • the ionic liquid can comprise an anion selected from the group consisting of geranate, bistriflimide, oleate, hexanoate, dodecyldimethyl ammonia propane sulfonate, N-lauryl sarcosinate, geraniolate, tetrafluoroborate, hexafluorophosphate, methyl sulfate, octyle sulfate, acesulfame, halides, bis(trifluoromethylsulfonyl)amide, bis(trifluoromethyl)amide, dicyanamide, and trifluoromethanesulfonate.
  • anion selected from the group consisting of geranate, bistriflimide, oleate, hexanoate, dodecyldimethyl ammonia propane sulfonate, N-lauryl sarcosinate, geraniolate, tetrafluoroborate, hex
  • the ionic liquid can be as described in either W02022/036309 or Sci Transl Med. 2021 Feb 10;13(580):eabe3889. doi: 10.1126/scitranslmed.abe3889, which are incorporated herein by reference in their entireties.
  • a compound described herein e.g., a heterocyclic compound comprising a ((benzoimidazolyl)ethyl)cyclobutyl moiety
  • an effective amount e.g., a therapeutically effective amount
  • Effective doses may vary, depending on the diseases treated, the severity of the disease, the route of administration, the sex, age and general health condition of the subject, excipient usage, the possibility of co-usage with other therapeutic treatments such as use of other agents and the judgment of the treating physician.
  • an effective amount of the can range, for example, from about 0.001 mg/kg to about 500 mg/kg (e.g., from about 0.001 mg/kg to about 200 mg/kg; from about 0.01 mg/kg to about 200 mg/kg; from about 0.01 mg/kg to about 150 mg/kg; from about 0.01 mg/kg to about 100 mg/kg; from about 0.01 mg/kg to about 50 mg/kg; from about 0.01 mg/kg to about 10 mg/kg; from about 0.01 mg/kg to about 5 mg/kg; from about 0.01 mg/kg to about 1 mg/kg; from about 0.01 mg/kg to about 0.5 mg/kg; from about 0.01 mg/kg to about 0.1 mg/kg; from about 0. 0.01 mg/kg to about 500 mg/kg (e.g., from about 0.001 mg/kg to about 200 mg/kg; from about 0.01 mg/kg to about 200 mg/kg; from about 0.01 mg/kg to about 150 mg/kg; from about 0.01 mg/kg to about 100 mg/kg; from about 0.
  • an effective amount of the compound is about 0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 2 mg/kg, or about 5 mg/kg.
  • the foregoing dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses, e.g., once daily, twice daily, thrice daily) or non-daily basis (e.g., every other day, every two days, every three days, once weekly, twice weekly, once every two weeks, once a month).
  • a daily basis e.g., as a single dose or as two or more divided doses, e.g., once daily, twice daily, thrice daily
  • non-daily basis e.g., every other day, every two days, every three days, once weekly, twice weekly, once every two weeks, once a month.
  • the term “about” means “approximately” (e.g., plus or minus approximately 10% of the indicated value).
  • the compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.
  • Cis and trans geometric isomers of the compounds described herein are described and may be isolated as a mixture of isomers or as separated isomeric forms.
  • the compounds described herein can have the (3 ⁇ 4 ) -configuration.
  • the compounds described herein can have the (S) -configuration.
  • Compounds provided herein also include tautomeric forms.
  • Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton.
  • Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Examples of prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • the term “cell” is meant to refer to a cell that is in vitro, ex vivo or in vivo.
  • an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal (e.g., a human).
  • an in vitro cell can be a cell in a cell culture.
  • an in vivo cell is a cell living in an organism such as a mammal.
  • contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • a DOT1L polypeptide with a compound described herein e.g., a heterocyclic compound comprising a ((benzoimidazolyl)ethyl)cyclobutyl moiety
  • a compound described herein can include the administration of the compound to an individual or patient, such as a human, having a DOT1L polypeptide, as well as, for example, introducing the compound into a sample containing a cellular or purified preparation containing the DOT1L polypeptide.
  • the term “individual”, “patient”, or “subject” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • the phrase “effective amount” or “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • treating refers to 1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology), or 2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology).
  • Group A Captisol: 7 Male mice, and 9 female mice
  • Group B MC21 : 3 Male mice and 5 female mice
  • Example 5 Effect of gemcitabine/cisplatin alone or in combination with MC21
  • gemcitabine was administered by intraperitoneal injection at 15 mg/kg in 0.1 mL PBS, biweekly for 3 weeks, and cisplatin by intraperitoneal injection at 4 mg/kg in 0.1 mL PBS, weekly for 3 weeks. Tumor volume was assessed after 35 days of infusion pump implantation.
  • Control Captisol infusion: 4 Male mice, and 4 female mice
  • Group 2 Gemcitabine + cisplatin: 3 Male mice and 5 female mice
  • Group 3 MC21 + Gemcitabine + cisplatin: 3 Male mice and 5 female mice
  • Dose levels, group division, and sampling The design and group division presented in Figures 7A and 7B.
  • the mice were divided into four groups.
  • the Groups 1, 2, and 3 consisted of twelve male and twelve female C57BL/6N mice each and were IV dosed with the test compound at one of the selected doses: 10 mg/kg, 20 mg/kg, or 40 mg/kg, respectively.
  • the control twelve male and twelve female C57BL/6N mice of Group 4 were IV dosed with Vehicle (Captisol - water for injections (20%:80%, w/v)).
  • Each of the Groups was divided into four Subgroups, consisted of 3 male and 3 female mice: Subgroup A, B, C, and D for terminal blood and organs sampling at 24 hours’ time point after 1, 3, 7, and 14 daily MC21 administrations, respectively.
  • Each mouse was subjected to blood sampling for hematological, plasma clinical chemistry, and plasma HPLC-MS/MS analysis, as well as to organs sampling (brain, kidney, liver, lung, spleen, and pancreas) for subsequent HPLC-MS/MS analysis. All mice of Group 3 surviving on day 8 of the study (Subgroups 3C and 3D) were subjected to terminal blood and organs sampling after 7 MC21 administrations due to the mortality in Group 3.
  • mice of Subgroups A were single dosed, the mice of Subgroups B, C, and D of the Groups 1-4 were repeatedly dosed for 3, 7, and 14 consecutive days, respectively, with 24-hour intervals.
  • the treatment of mice of Subgroup 3D was terminated after 7 th dosing due to the high mortality in Group 3.
  • Lethality The animals were monitored for mortality at the beginning and at the end of working day during the experimental period.
  • Body weight Animals were weighed on the day of randomization and every day during the study (from 8 am to 10 am, before the dosing on the days of dosing). The body weight change was calculated for the terminal day of the study (day 15) as a percentage change of initial (day 1) weight for each animal surviving on day 15.
  • Hematological study For hematological study, 25 m ⁇ of fresh blood were quickly mixed with equal volume of 0.36% solution of K 2 EDTA in saline. Assessment of the hematological parameters was performed using the hematology analyzer MCL- 3124 and consumable reagents Cormay within two hours after blood drawing.
  • ASAT Aspartate aminotransferase
  • ALAT Aspartate aminotransferase
  • ALP Aspartate aminotransferase
  • glucose was determined in the plasma using commercial kits according to the manufacturer’s instructions.
  • ASAT Aspartate aminotransferase
  • the principle of the method is the ability of aspartate aminotransferase to catalyze the interconversion of aspartate and a- oxoglutarate to oxaloacetate and glutamate.
  • Alanine aminotransferase ALAT
  • the principle of the method is the ability of alanine aminotransferase to catalyze the interconversion of L-alanine and a- oxoglutarate to pyruvate and glutamate.
  • Alkaline phosphatase (ALP) Alkaline phosphatase (ALP). Kinetic method recommended by International Federation of Clinical Chemistry (IFCC).
  • the principle of the method is the ability of ALP to catalyze the interconversion of 2-amino-2-methyl-l -propanol and p-nitrophenylophosphate to 4- nitrophenol and 2-amino-2-methyl-l -propanol phosphate.
  • Lactate dehydrogenase (LDH) Lactate dehydrogenase (LDH).
  • DGKC fur Klinische Chemie
  • Tissues samples preparation One brain hemisphere, left lateral lobe of the liver, right kidney, whole spleen, whole pancreas, and left lung from each individual animal was placed in labeled cryo tubes, flash- frozen on dry ice, and stored at -25 °C until subsequent HPLC-MS/MS analysis. The weights of the collected samples, as well as whole organs, were recorded.
  • mice Lethality ⁇ one female mouse (#37) dosed at 40 mg/kg died on the 4 th day of the study; one female mouse (#25) and two male mice (#81 and 103) dosed at 40 mg/kg died on the 8 th day of the study.
  • One female and one male mouse (#30 and 62) dosed at 40 mg/kg were sacrificed on the 8 th day of the study due to the small remaining sample of animals for the 14 th day due to their mortality. All other mice survived up to the days of terminal sacrifice and blood and organs sampling.
  • Clinical signs no clinical signs were observed in the mice of Group 1 and Group 2 dosed with MC21 at 10 mg/kg and 20 mg/kg, except for one mouse (#93, dosed at 20 mg/kg), which exhibited piloerection starting from the 4 th day and until terminal sacrifice on the 8 th day.
  • each administration of MC21 at the dose of 40 mg/kg evoked a pronounced toxic response, which began 3-7 minutes after administration and lasted for several hours: hypokinesia, piloerection, deep and heavy respiration, and half-closed eyes.
  • Body weight the average body weight of MC21 -dosed animals did not differ significantly from the control mice during the study for all groups
  • the purpose of this study was to determine the pharmacokinetic characteristics of compound MC21 in male and female C57BL/6N mice following intravenous (IV) administration. Levels of MC21 were determined by LC-MS/MS in the blood plasma samples over time after a single dose.
  • the animals were randomly assigned to the treatment groups before the pharmacokinetic study; all animals were fasted for 4 h before dosing.
  • Six time points (5, 10, 15, 30, 60, and 120 min) and intravenous (IV) route of administration were set for this pharmacokinetic study.
  • Each of the time point treatment group included 8 animals (4 males & 4 female). There was also a control group of two animals (1 male and 1 female).
  • Dosing was done according to the treatment schedules outlined in Table 1. Mice were injected IP with 2,2,2-tribromoethanol at the dose of 150 mg/kg prior to drawing the blood. Blood collection was performed from the orbital sinus in microtainers containing K2EDTA. All blood samples were immediately centrifuged for 10 min at 3000 rpm, flash- frozen and stored at -70 °C until subsequent analysis.
  • Plasma samples 40 pi
  • 200 m ⁇ of IS solution After mixing by pipetting and centrifuging for 4 min at 6000 rpm, 4 m ⁇ of each supernatant was injected into LC-MS/MS system.
  • Solution of compound thiamethoxam 1000 ng/ml in water-methanol mixture 1 :9, v/v was used as internal standard IS for quantification of MC21 in plasma samples.
  • HPLC system consisted of 2 isocratic pumps LC-lOADvp, an autosampler SIL-20AC, a sub-controller FCV-14AH and a degasser DGU- 14A.
  • Mass spectrometric analysis was performed using API 3000 (triple-quadrupole) instrument from AB Sciex (Canada) with an electro-spray (ESI) interface. The data acquisition and system control was performed using Analyst 1.5.2 software (AB Sciex, Canada).
  • Example 8 Formulation analysis for MC21
  • the solubilizing excipient (Cremophor EL, Kolliphor HS, or Vitamin E TGPS) was first melted at 50°C. Dry compound was added to the melted phase, mixed and sonicated at 50 °C to apparent homogeneity. Organic solvents (vehicles 6, 9 and 10) prewarmed to 50 °C were then added under vigorous mixing. Aqueous phase preheated to 50 °C was added last under vigorous mixing.
  • the compound was first dissolved in the calculated volume of DMSO and then mixed with 9 volumes of previously prepared solution Cremophor-EL: 5% Mannitol (1:8, v/v) prewarmed to 50 °C. The final mixture was sonicated for 30 minutes at 50 °C.*
  • test compounds MC13, MC21, MC34, and MC89 were fully solubilized in all tested vehicles at the concentration 5 mg/ml, except for Com Oil (100%), where the compounds remained insoluble at both 5 mg/ml and 2 mg/ml concentrations. These formulations were stable for 24 hours at ambient temperature.
  • the test compound MC55 was fully solubilized in all tested vehicles, except for Ethanol- Glycerol - physiological saline (10%:20%:70%), and Com Oil (100%) at both 5 mg/ml and 2mg/ml concentrations. These formulations were stable for 24 hours at ambient temperature. Details on the solubility of the compounds in the tested vehicles are listed in the Tables provided in Figures 11 A, 1 IB, and 11C. OTHER EMBODIMENTS

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Abstract

Ce document concerne des composés contenant du ((benzoimidazolyl) éthyl) cyclobutyle utiles dans le traitement du cancer tel que le cholangiocarcinome.
PCT/US2022/033949 2021-06-21 2022-06-17 Inhibiteurs de dot1l WO2022271540A1 (fr)

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Citations (4)

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Publication number Priority date Publication date Assignee Title
US20150284422A1 (en) * 2012-08-10 2015-10-08 Epizyme, Inc. Inhibitors of protein methyltransferase dot1l and methods of use thereof
US20160060269A1 (en) * 2014-08-27 2016-03-03 Dana-Farber Cancer Institute, Inc. DOT1L Inhibitors
US20180280422A1 (en) * 2010-12-03 2018-10-04 Epizyme, Inc. Substituted purine and 7-deazapurine compounds
WO2020250123A1 (fr) * 2019-06-10 2020-12-17 Lupin Limited Inhibiteurs de prmt5

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Publication number Priority date Publication date Assignee Title
US20180280422A1 (en) * 2010-12-03 2018-10-04 Epizyme, Inc. Substituted purine and 7-deazapurine compounds
US20150284422A1 (en) * 2012-08-10 2015-10-08 Epizyme, Inc. Inhibitors of protein methyltransferase dot1l and methods of use thereof
US20160060269A1 (en) * 2014-08-27 2016-03-03 Dana-Farber Cancer Institute, Inc. DOT1L Inhibitors
WO2020250123A1 (fr) * 2019-06-10 2020-12-17 Lupin Limited Inhibiteurs de prmt5

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Title
SPURR SOPHIE S.; BAYLE ELLIOTT D.; YU WENYU; LI FENGLING; TEMPEL WOLFRAM; VEDADI MASOUD; SCHAPIRA MATTHIEU; FISH PAUL V.: "New small molecule inhibitors of histone methyl transferase DOT1L with a nitrile as a non-traditional replacement for heavy halogen atoms", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 26, no. 18, 21 July 2016 (2016-07-21), Amsterdam NL , pages 4518 - 4522, XP029695102, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2016.07.041 *

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