WO2021149786A1 - Méthodes de traitement du cancer à l'aide de composés de dihydropyrimidin-2-one - Google Patents

Méthodes de traitement du cancer à l'aide de composés de dihydropyrimidin-2-one Download PDF

Info

Publication number
WO2021149786A1
WO2021149786A1 PCT/JP2021/002137 JP2021002137W WO2021149786A1 WO 2021149786 A1 WO2021149786 A1 WO 2021149786A1 JP 2021002137 W JP2021002137 W JP 2021002137W WO 2021149786 A1 WO2021149786 A1 WO 2021149786A1
Authority
WO
WIPO (PCT)
Prior art keywords
cancer
pharmaceutically acceptable
compound
acceptable salt
acid
Prior art date
Application number
PCT/JP2021/002137
Other languages
English (en)
Inventor
Takayuki Yamaguchi
Yuichi Naka
Original Assignee
Japan Tobacco 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 Japan Tobacco Inc. filed Critical Japan Tobacco Inc.
Publication of WO2021149786A1 publication Critical patent/WO2021149786A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the present invention pertains to medicinal use of 3- ⁇ (S)-4-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl ⁇ -propionic acid or a pharmaceutically acceptable salt thereof and 3- ⁇ (S)-4-[4-((1R,2R)-2-tert-butyl-cyclopropyl)-3-chloro-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl ⁇ bicyclo[1.1.1]pentane-1-carboxylic acid or a pharmaceutically acceptable salt thereof as therapeutic agents or prophylactic agents for cancer.
  • BACKGROUND Cancer occurs when cells in the body grow out of control.
  • pancreas is a gland located in the abdomen, between the stomach and the spine.
  • Pancreatic cancer arises from cells within the pancreas.
  • Pancreatic cancers are either exocrine or neuroendocrine cancers, depending on the type of cell from which they are derived.
  • Pancreatic adenocarcinoma accounts for about 85% of all pancreatic cancers.
  • Pancreatic adenocarcinoma has a poor prognosis, with 25% of patients surviving one year after diagnosis and 5% of patients living for five years after diagnosis.
  • Breast cancer is cancer that forms in the cells of the breasts. Breast cancers that start in the cells that line the ducts are called ductal cancers. Breast cancers that start in the lobules are called lobular cancers. Some breast cancers start in the stroma.
  • liver cancer also known as hepatic cancer and primary hepatic cancer, is a cancer that starts in the liver.
  • the leading causes of liver cancer are cirrhosis due to Hepatitis B, Hepatitis C, or alcohol.
  • the prostate is located below the bladder and in front of the rectum. Prostate cancer begins when cells in the prostate gland grow out of control.
  • the invention features a method of treating or preventing a pancreatic cancer in a human subject in need thereof by administering to the human subject a therapeutically effective amount of a compound represented by the following formula: or a pharmaceutically acceptable salt thereof.
  • the invention also features a method of treating or preventing a pancreatic cancer in a human subject in need thereof by administering to the human subject a therapeutically effective amount of a compound represented by the following formula: or a pharmaceutically acceptable salt thereof.
  • the pancreatic cancer is an exocrine pancreatic cancer.
  • the exocrine pancreatic cancer is an adenocarcinoma (e.g., a ductal adenocarcinoma or an acinar adenocarcinoma).
  • the exocrine pancreatic cancer is an acinar cell carcinoma, an adenosquamous carcinoma, a colloid carcinoma, a hepatoid carcinoma, an intraductal papillary mucinous neoplasm, a mucinous cystic neoplasm, a pancreatic intraepithelial neoplasia, a pancreatoblastoma, a serous cystadenoma, a signet ring cell carcinoma, a solid-pseudopapillary neoplasm, an undifferentiated carcinoma, or an undifferentiated carcinoma with osteoclast-like giant cells.
  • the pancreatic cancer is a pancreatic neuroendocrine tumor.
  • the pancreatic neuroendocrine tumor is an insulinoma or a glucagonoma.
  • the compound or pharmaceutically acceptable salt thereof is administered orally.
  • the compound or pharmaceutically acceptable salt thereof is administered in combination with a second agent.
  • the second agent is gemcitabine.
  • gemcitabine is administered intravenously.
  • the compound or pharmaceutically acceptable salt thereof is administered orally and gemcitabine is administered intravenously.
  • gemcitabine is administered orally.
  • the compound or pharmaceutically acceptable salt thereof is administered orally and gemcitabine is administered orally.
  • the second agent is erlotinib, nab-paclitaxel, FOLFIRINOX, or TS-1.
  • the invention also features a method of treating or preventing a cancer in a human subject in need thereof by administering to the human subject a therapeutically effective amount of a compound represented by the following formula: or a pharmaceutically acceptable salt thereof, wherein the cancer is a breast cancer, a liver cancer, a prostate cancer, a lung cancer, or a leukemia.
  • the invention also features a method of treating or preventing a cancer in a human subject in need thereof by administering to the human subject a therapeutically effective amount of a compound represented by the following formula: or a pharmaceutically acceptable salt thereof, wherein the cancer is a breast cancer, a liver cancer, a prostate cancer, a lung cancer, or a leukemia.
  • the breast cancer is triple-negative breast cancer.
  • the liver cancer is associated with hepatitis B virus or hepatitis C virus infection.
  • the prostate cancer is castration-resistant prostate cancer.
  • the lung cancer is small cell lung cancer.
  • the lung cancer is non-small cell lung cancer.
  • the leukemia is acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, or chronic myelogenous leukemia.
  • the compound or pharmaceutically acceptable salt thereof is administered orally.
  • the compound or pharmaceutically acceptable salt thereof is administered in combination with a second agent.
  • Compound A is 3- ⁇ (S)-4-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl ⁇ -propionic acid, and is represented by the following formula: .
  • Compound B is 3- ⁇ (S)-4-[4-((1R,2R)-2-tert-butyl-cyclopropyl)-3-chloro-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl ⁇ bicyclo[1.1.1]pentane-1-carboxylic acid, and is represented by the following formula: .
  • Compound A and pharmaceutically acceptable salts thereof can be produced using a known method, such as a method described in US Patent number 10,196,363, the content of which is incorporated herein for reference.
  • Compound B and pharmaceutically acceptable salts thereof can be produced using a known method, such as a method described in US published application number 2019/0300488, the content of which is incorporated herein for reference.
  • pharmaceutically acceptable salt may be any salts without excess toxicity known in the art. Specifically, it includes, for example, salts with inorganic acids, salts with organic acids, salts with inorganic bases, and salts with organic bases.
  • Various forms of pharmaceutically acceptable salts are well known in the art and are listed, for example, in the following references: (a) Berge et al., J. Pharm. Sci., 66, p1-19 (1977); (b) Stahl et al., "Handbook of Pharmaceutical Salts: Properties, Selection, and Use” (Wiley-VCH, Weinheim, Germany, 2002); (c) Paulekuhn et al., J. Med. Chem., 50, p6665-6672 (2007).
  • Compound A or Compound B may be reacted with an inorganic acid, organic acid, inorganic base, or organic base to give each pharmaceutically acceptable salt thereof.
  • Such salts with inorganic acids include, for example, salts with hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, and sulfuric acid.
  • Preferable salts include salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, and hydrobromic acid.
  • Such salts with organic acids include, for example, salts with acetic acid, adipic acid, alginic acid, 4-aminosalicylic acid, anhydromethylenecitric acid, benzoic acid, benzenesulfonic acid, camphor acid, camphor-10-sulfonic acid, carbonic acid, citric acid, edetic acid, ethane-1,2-disulfonic acid, dodecylsulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, glucoheptonic acid, glycollylarsanilic acid, hydroxynaphthoic acid, 2-hydroxy-1-ethanesulfonic acid, lactic acid, lactobionic acid, malic acid, maleic acid, mandelic acid, methanesulfonic acid, methylsulfuric acid, methylnitric acid, methylenebis(salicylic acid), galacta
  • Preferable salts include salts with oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, benzoic acid, glucuronic acid, oleic acid, pamoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and 2-hydroxy-1-ethanesulfonic acid.
  • Such salts with inorganic bases include, for example, salts with lithium, sodium, potassium, magnesium, calcium, barium, aluminum, zinc, bismuth, and ammonium.
  • Preferable salts include salts with sodium, potassium, calcium, magnesium, and zinc.
  • Such salts with organic bases include, for example, salts with arecoline, betaine, choline, clemizole, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, tris(hydroxymethyl)methylamine, arginine, and lysine.
  • Preferable salts include salts with tris(hydroxymethyl)methylamine, N-methylglucamine, and lysine.
  • Compound A or Compound B or a pharmaceutically acceptable salt thereof may exist in a solvate form.
  • solvate means Compound A or Compound B or a pharmaceutically acceptable salt thereof coordinate with a solvent molecule and includes a hydrate.
  • a solvate is preferably a pharmaceutically acceptable solvate and includes hydrates, ethanolates, and solvates with dimethylsufoxide of Compound A or Compound B or a pharmaceutically acceptable salt thereof.
  • such a solvate includes a hemihydrate, monohydrate, dihydrate, or monoethanolate of Compound A or Compound B, or a monohydrate of a hydrochloride salt or a 2/3 ethanolate of a dihydrochloride salt of Compound A or Compound B.
  • Compound A or Compound B or a pharmaceutically acceptable salt thereof may be labelled with an isotope atom such as 2 H, 3 H, 14 C, and 35 S.
  • any hydrogen atoms of Compound A or Compound B include protium 1 H (H), deuterium 2 H (D), and tritium 3 H (T).
  • Compound A or Compound B, or a pharmaceutically acceptable salt thereof is preferably Compound A or Compound B, or a pharmaceutically acceptable salt thereof, substantially purified. More preferable one is Compound A or Compound B, or a pharmaceutically acceptable salt thereof, having 80% or more of purity.
  • the therapeutic agent or prophylactic agent for pancreatic cancer of the present invention is produced, for example, according to a known method in the technical field of medicinal preparations by mixing Compound A or Compound B or a pharmaceutically acceptable salt thereof with a suitable amount of at least one kind of pharmaceutically acceptable carrier or the like as appropriate.
  • the amount of Compound A or Compound B or a pharmaceutically acceptable salt thereof in said preparation differs according to the dosage form, dose, and the like, but is, for example, 0.1 to 100 wt % of the entire preparation.
  • the therapeutic agent or prophylactic agent can be administered orally or parenterally.
  • Oral administration or parenteral administration such as intravenous, intramuscular, subcutaneous, percutaneous, local, or rectal administration can be given as examples of dosage forms.
  • These can be prepared according to known methods in the technical field of medicinal preparations.
  • Examples of a “pharmaceutically acceptable carrier” include various organic or inorganic carrier substances conventionally used as formulation materials, and examples include excipients, disintegrants, binders, fluidizers, lubricants, and the like for solid preparations; solvents, solubilizing agents, suspending agents, isotonicity agents, buffering agents, soothing agents, and the like for liquid preparations; and bases, emulsifiers, humectants, stabilizers, labilizing agents, dispersants, plasticizers, pH regulators, absorption promoters, gelling agents, antiseptics, fillers, solvents, solubilizers, suspending agents, and the like for semisolid preparations. It is also acceptable to use additives such as preservatives, antioxidants, colorants, sweetening agents, and the like as necessary.
  • an "excipient” examples include lactose, sucrose, D-mannitol, D-sorbitol, cornstarch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, carmellose calcium, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, gum arabic, and the like.
  • Examples of a “disintegrant” include carmellose, carmellose calcium, carmellose sodium, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, crystalline cellulose, and the like.
  • binder examples include hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, carmellose sodium, gum arabic, and the like.
  • a "fluidizer” examples include light anhydrous silicic acid, magnesium stearate, and the like.
  • lubricant examples include magnesium stearate, calcium stearate, talc, and the like.
  • solvent examples include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, olive oil, and the like.
  • a “solubilizing agent” examples include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate, and the like.
  • a "suspending agent” examples include benzalkonium chloride, carmellose, hydroxypropylcellulose, propylene glycol, povidone, methylcellulose, glycerol monostearate, and the like.
  • an “isotonic agent” examples include glucose, D-sorbitol, sodium chloride, D-mannitol, and the like.
  • Examples of a “buffering agent” include sodium hydrogenphosphate, sodium acetate, sodium carbonate, sodium citrate, and the like.
  • a “soothing agent” examples include benzyl alcohol and the like.
  • Examples of a “base” include water, vegetable oils (olive oil, corn oil, peanut oil, sesame oil, castor oil, and the like), lower alcohols (ethanol, propanol, propylene glycol, 1,3-butylene glycol, phenol, and the like), higher fatty acids and esters thereof, waxes, higher alcohols, polyhydric alcohols, hydrocarbons (white petrolatum, liquid paraffin, paraffin, and the like), hydrophilic petrolatum, purified lanolin, absorptive ointments, hydrous lanolin, hydrophilic ointments, starches, pullulan, gum arabic, tragacanth gum, gelatins, dextran, cellulose derivatives (methyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and the like), synthetic polymers (carboxyvinyl polymer, sodium polyacrylate, polyvinyl alcohol, polyvinyl pyrrolidone, and the like), propy
  • a "preservative” examples include ethyl parahydroxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid, and the like.
  • an "antioxidant” examples include sodium sulfite, ascorbic acid, and the like.
  • Examples of a "colorant” include food colorings (such as Food Red No. 2 or No. 3, or Food Yellow No. 4 or No. 5), ⁇ -carotene, and the like.
  • sweetening agent examples include saccharine sodium, dipotassium glycyrrhizinate, aspartame, and the like.
  • Formulation examples for Compound A and Compound B include the following formulations. The present invention is not, however, limited by these formulation examples.
  • Formulation Example 1 Production of a capsule 1) Compound A or Compound B 30 mg 2) Microcrystalline cellulose 10 mg 3) Lactose 19 mg 4) Magnesium stearate 1 mg 1), 2), 3), and 4) are mixed and filled in a gelatin capsule.
  • Formulation Example 2 Production of a tablet 1) Compound A or Compound B 10 g 2) Lactose 50 g 3) Corn starch 15 g 4) Carmellose calcium 44 g 5) Magnesium stearate 1 g
  • the total amounts of 1), 2), and 3) and 30 g of 4) are kneaded with water, vacuum dried, and sieved.
  • the sieved powder is mixed with 14 g of 4) and 1 g of 5), and the mixture is punched by means of a tableting machine. In this way, 1,000 tablets each containing 10 mg of Compound A or Compound B per tablet are obtained.
  • Compound A or a pharmaceutically acceptable salt thereof or Compound B or a pharmaceutically acceptable salt thereof can be used as an active ingredient of a therapeutic agent or prophylactic agent for cancer, such as pancreatic cancer, breast cancer, liver cancer, or prostate cancer.
  • treating also includes ameliorating symptoms, preventing from becoming severe, maintaining remission, preventing exacerbation, and preventing relapse.
  • preventing means suppressing pathogenesis of symptoms.
  • pancreatic cancer means a cancer arising from cells within the pancreas.
  • the pancreas is a gland located in the abdomen, between the stomach and the spine.
  • Pancreatic cancers are either exocrine or neuroendocrine cancers, depending on the type of cell from which they are derived.
  • exocrine pancreatic cancers include adenocarcinoma (e.g., ductal adenocarcinoma and acinar adenocarcinoma), acinar cell carcinoma, adenosquamous carcinoma, colloid carcinoma, hepatoid carcinoma, intraductal papillary mucinous neoplasm, mucinous cystic neoplasm, pancreatic intraepithelial neoplasia, pancreatoblastoma, serous cystadenoma, signet ring cell carcinoma, solid-pseudopapillary neoplasm, undifferentiated carcinoma, and undifferentiated carcinoma with osteoclast-like giant cells.
  • pancreatic neuroendocrine tumors include insulinoma and glucagonoma.
  • breast cancer means a cancer arising from cells within breast tissue.
  • Breast cancer cells have receptors on their surface, in their cytoplasm, and in their nucleus.
  • Breast cancer cells may or may not have one or more of the following three receptors: estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2).
  • HER2 human epidermal growth factor receptor 2
  • Triple-negative breast cancer is negative for each of estrogen receptor, progesterone receptor, and HER2.
  • liver cancer means a cancer arising from cells within the liver.
  • the most common risk factor for liver cancer is chronic infection with hepatitis B virus or hepatitis C virus. These infections lead to cirrhosis of the liver.
  • the most common types of liver cancer are hepatocellular carcinoma and cholangiocarcinoma.
  • prostate cancer means a cancer arising from cells within the prostate gland.
  • An example of prostate cancer includes castration-resistant prostate cancer. Most prostate cancers are adenocarcinomas. Other types of prostate cancer include small cell carcinomas, neuroendocrine tumors, transitional cell carcinomas, and sarcomas.
  • lung cancer means a cancer arising from cells within the lung.
  • Examples of lung cancer include small cell lung cancer and non-small cell lung cancer.
  • leukemia means a cancer of the blood or bone marrow.
  • leukemia include acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, and chronic myelogenous leukemia.
  • Compound A or a pharmaceutically acceptable salt thereof or Compound B or a pharmaceutically acceptable salt thereof can be used in combination (hereinafter also referred to as “concomitantly") with one or multiple other drugs (hereinafter also referred to as a “concomitant drug” or a “second agent”) using a common practice employed in the medical field.
  • Examples of a concomitant drug include Abraxane (nab-paclitaxel), Afinitor (Everolimus), Erlotinib Hydrochloride, Everolimus, 5-FU (Fluorouracil Injection), Fluorouracil Injection, Gemzar (Gemcitabine Hydrochloride), Irinotecan Hydrochloride Liposome, Mitomycin C, Onivyde (Irinotecan Hydrochloride Liposome), Paclitaxel Albumin-stabilized Nanoparticle Formulation, Sutent (Sunitinib Malate), Tarceva (Erlotinib Hydrochloride), FOLFIRINOX (Oxaliplatin, Fluorouracil, Leucovorin Calcium, and Irinotecan Hydrochloride combination), GEMCITABINE-CISPLATIN (Gemcitabine Hydrochloride and Cisplatin combination), GEMCITABINE-OXALIPLATIN (Gemcitabine Hydrochloride and Oxaliplatin combination),
  • Gemzar can be administered intravenously or orally.
  • an exemplary dosing regimen is 1000 mg/m 2 over 30 minutes once weekly for the first 7 weeks, then one week rest, then once weekly for 3 weeks of each 28-day cycle.
  • the timing of administration of a drug comprising Compound A or a pharmaceutically acceptable salt thereof or Compound B or a pharmaceutically acceptable salt thereof and a concomitant drug is not limited, it is acceptable to administer these to an administration subject as a combination drug, and it is also acceptable to administer the two formulations either simultaneously or at a fixed interval. Furthermore, it is also acceptable to use the therapeutic agent or prophylactic agent of the present invention and a concomitant drug as a medication that is characterized in that the medication is a kit comprising said agent and concomitant drug.
  • the dosage of a concomitant drug is acceptable as long as it is based on a dosage used in clinical practice, and the dosage can be appropriately selected according to the administration subject, disease, symptoms, dosage form, administration route, administration time, combination, and so on.
  • the dosage form of a concomitant drug is not particularly limited, and is acceptable as long as a drug comprising Compound A or a pharmaceutically acceptable salt thereof or Compound B or a pharmaceutically acceptable salt thereof are combined with the concomitant drug.
  • Examples of one embodiment of the present invention include a method for the treatment or prophylaxis of pancreatic cancer that comprises administering to a human a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof or Compound B or a pharmaceutically acceptable salt thereof.
  • Examples of another embodiment of the present invention include a method for the treatment or prophylaxis of breast cancer (e.g., triple-negative breast cancer) that comprises administering to a human a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof or Compound B or a pharmaceutically acceptable salt thereof.
  • a method for the treatment or prophylaxis of breast cancer e.g., triple-negative breast cancer
  • Examples of another embodiment of the present invention include a method for the treatment or prophylaxis of liver cancer (e.g., liver cancer associated with hepatitis B virus or hepatitis C virus infection) that comprises administering to a human a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof or Compound B or a pharmaceutically acceptable salt thereof.
  • liver cancer e.g., liver cancer associated with hepatitis B virus or hepatitis C virus infection
  • Examples of another embodiment of the present invention include a method for the treatment or prophylaxis of prostate cancer that comprises administering to a human a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof or Compound B or a pharmaceutically acceptable salt thereof.
  • Examples of another embodiment of the present invention include a method for the treatment or prophylaxis of lung cancer that comprises administering to a human a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof or Compound B or a pharmaceutically acceptable salt thereof.
  • Examples of another embodiment of the present invention include a method for the treatment or prophylaxis of leukemia that comprises administering to a human a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof or Compound B or a pharmaceutically acceptable salt thereof.
  • an “effective amount” signifies, for example, the amount of a medication or drug that elicits a biological or medical response in a tissue, system, or human.
  • a “therapeutically effective amount” signifies an arbitrary amount that either produces a treatment, cure, prophylaxis, or improvement where cancer or a side effect is improved in comparison with a corresponding subject that has not received such an amount.
  • Example 1 Evaluation of the Effect of Compounds on Viability of Organoid Lines The effect of three compounds on cell proliferation of three organoid lines was evaluated.
  • the three test compounds evaluated were Compound A, Compound B, and gemcitabine.
  • the organoid lines used are described in Table 1.
  • the major reagents used are described in Table 2.
  • the cells were cultured in a 37ºC incubator with 5% CO 2 and 95% air.
  • Gemcitabine was purchased from Selleck (Cat. no. S1714). Staurosporine, a positive control, was purchased from Selleck (Cat. no. S1421).
  • EnVision Multi Label Reader 2104-0010A PerkinElmer, Equip ID:TAREA0011; CO 2 Water Jacketed Incubator, SANYO, Equip ID: TAINC0020; Digital Dispenser, Tecan D300e; and Multidrop Combi reagent dispenser, Thermofisher.
  • organoids were sheared to uniform sizes.
  • the organoids were processed 1:1 using 50% Matrigel to define the size of the organoids to perform the screen.
  • organoids were seeded, as follows. a) The organoids were collected from each well by adding 20 ⁇ l 100x Dispase solution to each well from a 6-well plate, which contains 2 ml of organoid medium. b) The plates were put back in the incubator, at 37°C for 30 minutes. c) The organoids were collected from all wells and pipetted through a pre-wet 100 ⁇ m filter into a 50 ml plastic tube. d) Once all wells were filtered over 100 ⁇ m filters, the flow though was filtered over a pre-wet 20 ⁇ m filter. e) The 20 ⁇ m filter was inverted and the organoids were recovered in a new 50 ml tube.
  • the top working concentration was 100 ⁇ M, with 3.16-fold serial dilutions of each dose level, to achieve 9 dose levels, identified below as C1-C9.
  • the top working concentration was 1 ⁇ M, with 3.16-fold serial dilutions of each dose level, to achieve 9 dose levels, identified below as C1-C9. l) Screening plates were placed back into the incubator.
  • a dose-response curve was fitted using nonlinear regression model with a sigmoidal dose response.
  • the formula for calculating surviving rate is shown below.
  • the surviving rate (%) (Lum Test article -Lum Medium control )/ (Lum None treated -Lum Medium control ) x 100%.

Abstract

L'invention concerne un agent thérapeutique ou prophylactique pour le cancer à base d'acide 3-{(S)-4-[3-chloro-4-(3,3-diméthyl-butyl)-phényl]-5-isopropyl-4-méthyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionique ou un sel pharmaceutiquement acceptable de celui-ci ou d'acide 3-{(S)-4-[4-((1R,2R)-2-tert-butyl-cyclopropyl)-3-chloro-phényl]-5-isopropyl-4-méthyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}bicyclo[1.1.1]pentane-1-carboxylique ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/JP2021/002137 2020-01-24 2021-01-22 Méthodes de traitement du cancer à l'aide de composés de dihydropyrimidin-2-one WO2021149786A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202062965254P 2020-01-24 2020-01-24
US62/965,254 2020-01-24

Publications (1)

Publication Number Publication Date
WO2021149786A1 true WO2021149786A1 (fr) 2021-07-29

Family

ID=74561971

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2021/002137 WO2021149786A1 (fr) 2020-01-24 2021-01-22 Méthodes de traitement du cancer à l'aide de composés de dihydropyrimidin-2-one

Country Status (1)

Country Link
WO (1) WO2021149786A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023232870A1 (fr) 2022-05-31 2023-12-07 Immunic Ag Modulateurs de rorg/rorgt pour le traitement d'infections virales de type covid-19

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10196363B2 (en) 2014-12-12 2019-02-05 Japan Tobacco Inc. Dihydropyrimidin-2-one compounds and medical use thereof
US20190300488A1 (en) 2018-02-28 2019-10-03 Japan Tobacco Inc. 4-methyldihydropyrimidinone compounds and pharmaceutical use thereof
WO2020172467A1 (fr) * 2019-02-20 2020-08-27 The Regents Of The University Of California Traitement de cancers dépendant du récepteur orphelin lié au récepteur de l'acide rétinoïque (rorɣ)

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10196363B2 (en) 2014-12-12 2019-02-05 Japan Tobacco Inc. Dihydropyrimidin-2-one compounds and medical use thereof
US20190300488A1 (en) 2018-02-28 2019-10-03 Japan Tobacco Inc. 4-methyldihydropyrimidinone compounds and pharmaceutical use thereof
WO2020172467A1 (fr) * 2019-02-20 2020-08-27 The Regents Of The University Of California Traitement de cancers dépendant du récepteur orphelin lié au récepteur de l'acide rétinoïque (rorɣ)

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
BERGE ET AL., J. PHARM. SCI., vol. 66, 1977, pages l-19
LYTLE NIKKI K ET AL: "A Multiscale Map of the Stem Cell State in Pancreatic Adenocarcinoma", CELL, vol. 177, no. 3, 10 March 2019 (2019-03-10), pages 572, XP085663710, ISSN: 0092-8674, DOI: 10.1016/J.CELL.2019.03.010 *
PAULEKUHN ET AL., J. MED. CHEM., vol. 50, 2007, pages 6665 - 6672
STAHL ET AL.: "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", 2002, WILEY-VCH
WANG JUNJIAN ET AL: "ROR-[gamma] drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer", NATURE MEDICINE, NATURE PUB. CO, NEW YORK, vol. 22, no. 5, 28 March 2016 (2016-03-28), pages 488 - 496, XP037202995, ISSN: 1078-8956, [retrieved on 20160328], DOI: 10.1038/NM.4070 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023232870A1 (fr) 2022-05-31 2023-12-07 Immunic Ag Modulateurs de rorg/rorgt pour le traitement d'infections virales de type covid-19

Similar Documents

Publication Publication Date Title
WO2016023422A1 (fr) Dérivé 2-(aniline 2,4,5-substituée)pyrimidine, composition pharmaceutique et leur utilisation
ES2573515T3 (es) Agente antitumoral que emplea compuestos con efecto inhibitorio de cinasas combinados
CN104797581B (zh) 杂芳基炔烃化合物及其应用
EP4186895A1 (fr) Composé utile en tant qu'inhibiteur de kinase cdk7 et son utilisation
KR101668931B1 (ko) 항종양제의 효과 증강제
US20210085630A1 (en) Pharmaceutical composition and use thereof in preparing drug for treating tumor multi-drug resistance
JP4110347B2 (ja) 抗ｈｉｖ剤
US20220387384A1 (en) Methods of treating lsd1-related diseases and disorders with lsd1 inhibitors
US20230310394A1 (en) Sorafenib, regorafenib and novel use of analogue or derivative thereof
CN105985323A (zh) 新型表皮生长因子受体抑制剂及其应用
TR201815685T4 (tr) Kanser tedavisi için akt ve mek inhibe edici bileşiklerin kombinasyonları.
CN111558044B (zh) 一种包含舒尼替尼的药物组合物及其制剂和应用
JP2024050645A (ja) ヘテロアリールで置換されたピラゾール化合物及びその医薬用途
WO2021149786A1 (fr) Méthodes de traitement du cancer à l'aide de composés de dihydropyrimidin-2-one
US11219619B2 (en) Therapeutic agent for hepatocellular carcinoma
CN102010420B (zh) [(10s)-9，10-二氢青蒿素-10-氧基]苯甲醛缩氨基(硫)脲系列物及其制备方法和用途
CN104603133B (zh) 用于治疗癌症和免疫抑制的组合疗法
CN110698491B (zh) 2-(喜树碱-10-氧基)乙酰胺类化合物和应用
US20150238488A1 (en) Drug composition for treating tumors and application thereof
JP2020023447A (ja) フェニルテトラヒドロピリドインドール誘導体及び医薬組成物
CN111362924A (zh) 氘代的嘧啶衍生物及其用途
AU2020386903A1 (en) Dosing regimens for a protein kinase C inhibitor
CN105001167A (zh) 1-取代苯基-3-（4-取代苯基氨基-6-喹唑啉基）脲类化合物及制备方法和用途
CN115286574B (zh) Blvrb酶功能抑制剂及其制备方法和用途
JPH02304058A (ja) キサントシリンｘモノメチルエーテル誘導体及びそれを含有する抗腫瘍剤

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: 21704030

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21704030

Country of ref document: EP

Kind code of ref document: A1