WO2020040591A1 - Nouvelle utilisation d'un dérivé de pyrimidine comprenant un inhibiteur de kinase lrrk en tant que principe actif - Google Patents

Nouvelle utilisation d'un dérivé de pyrimidine comprenant un inhibiteur de kinase lrrk en tant que principe actif Download PDF

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WO2020040591A1
WO2020040591A1 PCT/KR2019/010759 KR2019010759W WO2020040591A1 WO 2020040591 A1 WO2020040591 A1 WO 2020040591A1 KR 2019010759 W KR2019010759 W KR 2019010759W WO 2020040591 A1 WO2020040591 A1 WO 2020040591A1
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cancer
group
lrrk2
pancreatic cancer
pyrimidin
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Korean (ko)
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최환근
박종배
고은화
손정범
김남두
이승훈
남도현
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재단법인 대구경북첨단의료산업진흥재단
국립암센터
사회복지법인 삼성생명공익재단
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    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/08—Preparation by ring-closure
    • C07D213/09—Preparation by ring-closure involving the use of ammonia, amines, amine salts, or nitriles
    • C07D213/12—Preparation by ring-closure involving the use of ammonia, amines, amine salts, or nitriles from unsaturated compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/30—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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

Definitions

  • Protein kinases are enzymes that catalyze the transfer of the terminal phosphate group of adenosine triphosphate (ATP) to specific residues of the protein, tyrosine, serine, or threonine, and regulate the activity, growth and differentiation of cells against changes in cell mediators and the environment. Involved in the signal. Inappropriately high protein kinase activity is directly or indirectly associated with a number of diseases resulting from abnormal cell action. For example, the disease may be caused by failure of appropriate regulatory mechanisms of kinases related to mutations, over-expression, or inappropriate enzyme activity, or overproduction or lack of factors involved in signal transduction upstream or downstream of cytokines, kinases. Can be.
  • ATP adenosine triphosphate
  • the leucin-rich repeat kinase-2 (LRRK2) protein belongs to the leucin-rich repeat kinase family and consists of 2527 amino acid sequences with high similarity between species. LRRK2 protein is characterized by having both GTPase and Serine-threonine kinase activity in one protein. The expressed LRRK2 protein has been observed in various organs and tissues, including the pancreas. At the cellular level, it is present in the cytoplasm or cell membrane and mitochondrial outer membrane.
  • the LRRK2 protein has five functionally important domains, and is expected to regulate cell function through self-activation regulation by protein autophosphorylation, protein interaction and enzymatic action.
  • chaperone machinery, cytoskelecton arrangement, protein translational machinery, synaptic vesicle endocytosis, mitogen-activated protein kinase signal transduction Activated protein kinases signaling cascades and ubiquitin / autophage protein degradation pathways are known to be regulated by LRRK2 proteins.
  • LRRK2 protein has been reported to be associated with the imputation of mild cognitive impairment associated with Alzheimer's disease, L-Dopa induced dyskinesia, and CNS disorders associated with neuronal precursor differentiation.
  • the G2019S mutation of the LRRK2 protein has been reported to increase the incidence of acute myeloid leukemia (AML) as well as non-skin cancers such as kidney cancer, breast cancer, lung cancer, prostate cancer and the like. Specifically, the G2019S mutation of the LRRK2 protein increases the catalytic activity of the LRRK2 kinase domain. Furthermore, LRRK2 protein has also been reported to be associated with amyotrophic lateral sclerosis, rheumatoid arthritis and ankylosing spondylitis (WO 2011/038572).
  • An object in one aspect of the present invention is to provide a pharmaceutical composition for the prophylaxis or treatment of at least one cancer selected from the group consisting of pancreatic cancer, breast cancer and lung cancer containing an LRRK2 protein inhibitor as an active ingredient.
  • An object in another aspect of the present invention is to provide a use of an LRRK2 protein inhibitor for use in the manufacture of a medicament for the treatment of one or more cancers selected from the group consisting of pancreatic cancer, breast cancer and lung cancer. It is.
  • One aspect of the present invention provides a pharmaceutical composition for the prophylaxis or treatment of at least one cancer selected from the group consisting of pancreatic cancer, breast cancer and lung cancer containing an LRRK2 protein inhibitor as an active ingredient.
  • another aspect of the present invention provides a method for treating one or more cancers selected from the group consisting of pancreatic cancer, breast cancer and lung cancer, comprising administering an LRRK2 protein inhibitor to a subject in need thereof.
  • another aspect of the present invention provides an LRRK2 protein inhibitor for use in the prevention or treatment of one or more cancers selected from the group consisting of pancreatic cancer, breast cancer and lung cancer.
  • Another aspect of the invention also provides the use of an LRRK2 protein inhibitor for use in the manufacture of a medicament for the treatment of one or more cancers selected from the group consisting of pancreatic cancer, breast cancer and lung cancer. .
  • the pharmaceutical composition for preventing or treating at least one cancer selected from the group consisting of pancreatic cancer, breast cancer and lung cancer provided in one aspect of the present invention exhibits excellent anticancer effect in vitro, in vivo, and therefore, pancreatic cancer, breast cancer and lung cancer. It can be usefully used as a therapeutic agent.
  • FIG. 1 is a result of confirming the P-LRRK2 inhibitory activity of Example 1, compound 2, which is an LRRK2 protein inhibitor.
  • Figure 2 is a graph showing the enzyme-substrate kinetics results of the compound of Example 1 calculated using Michaelis-Menten formula.
  • 3 is a graph showing the results of evaluating the LRRK2 inhibitory activity of the compound of Example 1.
  • Figure 4 is a result confirming the anti-cancer treatment effect of the pancreatic cancer animal model of Example 1, 2 compound which is an LRRK2 protein inhibitor.
  • 5 is a graph showing the results of evaluating the organoid target gemcitabine reactivity derived from the pancreatic cancer xenograft model (PDX).
  • Figure 6 is a graph showing the results of evaluating the anticancer activity of the test drugs against GUN # 13 organoids.
  • Figure 7 is a graph showing the results of evaluating the anticancer activity of test drugs for HPT # 19 organoids.
  • 8 is a graph showing the results of evaluating the anticancer activity of test drugs against HPT # 22 organoid.
  • FIG. 9 shows the organoid morphology identified when GUN # 13 organoids were treated with a test drug at 100 nM concentration.
  • FIG. 10 shows the organoid morphology confirmed when treated with 1000 nM concentration of test drug for GUN # 13 organoid.
  • FIG. 11 shows the organoid morphology confirmed when the test drug was treated at a concentration of 100 nM for HPT # 19 organoids.
  • FIG. 9 shows the organoid morphology identified when GUN # 13 organoids were treated with a test drug at 100 nM concentration.
  • FIG. 10 shows the organoid morphology confirmed when treated with
  • FIG. 12 shows the organoid morphology confirmed when the test drug was treated at a concentration of 1000 nM for HPT # 19 organoids.
  • FIG. 13 is a graph showing the results of evaluation of anticancer activity of each compound of Example 1 on breast cancer cell line MDA-MB231.
  • 14 is a graph showing the results of evaluation of anticancer activity of each compound of Example 1 on lung cancer cell line A549.
  • One aspect of the present invention provides a method for the prevention of at least one cancer selected from the group consisting of pancreatic cancer, breast cancer and lung cancer, containing as an active ingredient at least one Leucine Rich Repeat Kinase 2 (LRRK2) protein inhibitor selected from the following compound group:
  • LRRK2 Leucine Rich Repeat Kinase 2
  • therapeutic pharmaceutical compositions (1) (3-methoxy-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) phenyl) (morpholino ) Methanone; And (2) 3- (4-morpholino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) benzonitrile.
  • the LRRK2 protein inhibitor according to the present invention can be used in the form of a pharmaceutically acceptable salt, in which acid addition salts formed by pharmaceutically acceptable free acid are useful.
  • Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanediodes.
  • Non-toxic organic acids such as acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like, and organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid and the like.
  • These types of pharmaceutically harmless salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide and iodide.
  • the acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving a derivative of the LRRK2 protein inhibitor in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile and adding an organic acid or an inorganic acid.
  • the precipitate may be prepared by filtration and drying, or the solvent and excess acid may be distilled under reduced pressure, dried, and crystallized in an organic solvent.
  • the LRRK2 protein inhibitors of the present invention may be made as pharmaceutically acceptable metal salts using bases.
  • alkali metal or alkaline earth metal salts can be obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt.
  • Corresponding salts may also be obtained by reacting alkali or alkaline earth metal salts with a suitable negative salt (eg, silver nitrate).
  • a suitable negative salt eg, silver nitrate
  • the LRRK2 protein inhibitor, the optical isomer thereof, or the pharmaceutically acceptable salt thereof may be administered in various dosage forms, orally or parenterally, in the case of clinical administration.
  • Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, troches, and the like. , Dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), glidants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols.
  • Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidine and the like, and optionally disintegrants such as starch, agar, alginic acid or its sodium salt or the like, or Boiling mixtures, absorbents, colorants, flavoring agents, and sweetening agents.
  • Pharmaceutical compositions comprising an LRRK2 protein inhibitor, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient according to the present invention may be administered parenterally, and parenteral administration may be administered by subcutaneous injection, intravenous injection, intramuscular injection or It can be administered via intrathoracic injection.
  • the LRRK2 protein inhibitor, its optical isomer, or pharmaceutically acceptable salt thereof is mixed with water together with a stabilizer or a buffer to prepare a formulation for parenteral administration into a solution or suspension, which is an ampoule or vial unit. It may be prepared in a dosage form.
  • the composition is sterile and may further contain preservatives, stabilizers, emulsifiers or emulsifiers, auxiliaries such as salts and buffers for the control of osmotic pressure, and other therapeutically useful substances, and mixing, granulating or It may be formulated according to the coating method.
  • the dosage to the human body of a pharmaceutical composition comprising the LRRK2 protein inhibitor of the present invention, its optical isomer, or a pharmaceutically acceptable salt thereof as an active ingredient is determined by the age, weight, sex, dosage form, health condition and Depending on the extent of the disease, based on an adult patient weighing 70 Kg, generally 0.1-1000 mg / day, preferably 1-500 mg / day, and also at the discretion of the physician or pharmacist It may be administered once a day to divided doses at regular time intervals.
  • another aspect of the present invention provides a method for treating one or more cancers selected from the group consisting of pancreatic cancer, breast cancer and lung cancer, comprising administering the LRRK2 protein inhibitor to a subject in need thereof. do.
  • another aspect of the present invention provides the LRRK2 protein inhibitor for use in the prevention or treatment of one or more cancers selected from the group consisting of pancreatic cancer, breast cancer and lung cancer.
  • another aspect of the present invention provides a use of the LRRK2 protein inhibitor for use in the manufacture of a medicament for the treatment of one or more cancers selected from the group consisting of pancreatic cancer, breast cancer and lung cancer. do.
  • Step 1 After dissolving 2,4-dichloro-5-iodopyrimidine (1.0 equiv) in THF, methylamine (3.5 wt% in EtOH, 1.1 equiv) was added at 0 ° C. The mixture was stirred at 0 ° C. for 2 hours, then the solvent was removed and used in the next step without further purification (yield: 100%).
  • Step 2 After filling the two-necked round-bottom flask with nitrogen, CuI (5.0 equiv) and KF (5.0 equiv) were added. The mixture was heated to 150 ° C. and then stirred for 2 hours under reduced pressure. After the reaction, the temperature was lowered to room temperature and trimethyl (trifluoromethyl) silane (5.0 equiv) dissolved in DMF / NMP (1: 1) under nitrogen was added using a syringe. After reacting for 30 minutes, 2-chloro-5-iodo-N-methylpyrimidin-4-amine (1.0 equiv) dissolved in DMF / NMP (1: 1) was added using a syringe, and 50 ° C. Reaction was carried out for 18 hours.
  • Table 1 shows the structures of the compounds prepared in Examples 1 and 2.
  • LRRK2 protein inhibitor which is an active ingredient of a pharmaceutical composition for the prevention or treatment of one or more cancers selected from the group consisting of pancreatic cancer, breast cancer and lung cancer, can effectively inhibit phosphorylated LRRK2 protein expression.
  • pancreatic cancer patient-derived cell GUN # 13 obtained from a 44-year-old pancreatic ductal adenocarcinoma patient was prepared. After 1 day of seeding, 7.5 ⁇ 10 5 to 1.0 ⁇ 10 6 cells were treated with Examples 1 and 2 at a concentration of 1 and 2 ⁇ M, respectively, and after 1 day, samples were collected and collected through Western Blot.
  • Example A group not treated with a compound was treated as a vehicle.
  • the results are shown in FIG.
  • the compounds of Examples 1 and 2 which are LRRK2 protein inhibitors, were excellent in phosphorylated LRRK2 protein expression inhibitory activity.
  • Enzyme-substrate reaction rates using the compounds according to the invention as enzymes and LRRK2 protein as substrates were calculated using the Michaelis-Menten equation.
  • the initial rate of the enzyme reaction was proportional to the concentration of the enzyme when the substrate (reactant) was small, and the enzyme approached a constant limit rate when the substrate concentration was excessive.
  • the Michaelis-Menten curve for the substrate reaction was satisfied (FIG. 2). Therefore, it was confirmed that the compound according to the present invention binds to LRRK2.
  • FIG. 3 it was confirmed whether the activity of LRRK2 was inhibited by the binding of these compounds and LRRK2.
  • the activity of LRRK2 is inhibited in proportion to the concentration of the compound.
  • the prepared oral preparations were dispensed 1 ml each and stored at -20 ° C. to be used every time they were tested. From day 25 after pancreatic cancer cells were injected, Examples 1 and 2 compounds were orally administered to a mouse model injected with pancreatic cancer cells at 60 mg / kg. After administration of the compound, MRI was used to measure the size of tumors produced in the mice. The group which was not treated with the compound of Example was set as a vehicle. The results are shown in FIG. 4 and Table 2 below. As shown in FIG. 4 and Table 2, the compounds of Examples 1 and 2, which are LRRK2 protein inhibitors, were excellent in anticancer activity against pancreatic cancer animal models.
  • Patient-derived in situ transplant mouse model (patient-derived orthotopic xenograft, PDX) obtained from patients who agreed to the study and approved directly by the pancreas of immunodeficient mice after approval from the Medical Life Research Review Board (IRB).
  • HPT surgically resected primary tumor specimen
  • GUN biopsy tissue
  • athymus Nude-Foxn1 nude mice were excised and sutured into the pancreas of the pancreas (PDX Generation 1, F1).
  • the size of the tumor was measured periodically through abdominal palpation and MRI imaging equipment, and when the size of the tumor reached 3000 mm 3 , the tumor was sacrificed to obtain the tumor tissue, and then a certain size (3 mm ⁇ 3 mm ⁇ 3 mm) was obtained.
  • a human cell dissociation kit (Miltenyi Biotech Inc.) containing collagenase and reacted for 1 hour in a tissue dissociation apparatus (Gentle Macs, Miltenyi Biotech Inc)
  • RPMI medium containing (FBS) Inhibiting enzymatic activity with RPMI medium containing (FBS) followed by centrifugation can yield precipitates of cells dissociated from tissues.
  • PDX-derived cancer cell line for each pancreatic cancer patient.
  • Established PDX-derived cancer cell lines and patient clinical information are shown in Table 3 below.
  • Example 1 Compounds and control drugs were dissolved in 5% DMSO, 0.2% TWEEN 80, and 1% AVICELL. Control drugs GNE7915, PF-06447475, MLi-2 and Example 1 compound were treated with 100 nM, 1000 nM. For vehicles, only excipients containing no test substance were treated.
  • Organisms formed by incubating in 96-well plates for 7 days were treated with gemcitabine by concentration (0, 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 50, 100 uM).
  • the medium containing the drug was exchanged every 3 days, and after 7 days, the survival rate of the organoids was evaluated by ATP assay. This method can be used to analyze the resistance of organoids to gemcitabine.
  • test drug was also treated with 0, 100, 1000 nM concentrations after 7 days of incubation by seeding at 2 ⁇ 10 3 cells / well in 96-well plates. After 7 days, the survival rate of organoids was evaluated by ATP assay, and the shape of organoids was observed using a microscope. In this way, the evaluation of morphological changes and evaluation of the inhibitory effect of pancreatic cancer cells on test drugs of organoids can be compared.
  • Example 1 showed a concentration-dependent anticancer activity against the pancreatic cancer-derived organoids, like the control drug.
  • the compound of Example 1 also showed anticancer activity in a concentration-dependent manner to the organoids of GUN # 13 and HPT # 19 patients resistant to gemcitabine. It is shown in Figures 9 to 12 that the form of GUN # 13 and HPT # 19 organoids form small according to the test drug treatment.
  • the breast cancer cell line MDA-MB-231 was cultured one day before the cell lines were allowed to repeat three times with 1000 cells in one well in a 96 well plate. The following day, the compound of Example 1 was dissolved in DMSO for 24 hours, and then grown for 24 hours. Growth was measured using ProTitle-GloLuminescent Cell Viability Assay. This method uses energy ATP, which is an indicator that cells are growing, so a higher value means that the cell is growing, and a lower value means that the cell is dying. Therefore, with the ATP measurement, the effect on the breast cancer cell line following the treatment of the compound of Example 1 can be measured graphically. The results are shown in FIG. As shown in FIG. 13, the compound of Example 1 was shown to exhibit concentration-dependent anticancer activity against breast cancer cell lines.
  • Example 1 of the Invention When applying a compound as a drug to a living body, an indicator of pharmacokinetics was used to evaluate the movement and effect of the drug in a living body. These pharmacokinetic indicators influence the determination of the route of administration and dosage of the drug. Specifically, when the compound of Example 1 of the present invention was quantitatively administered to mouse, rat, dog or monkey by intravenous (i.v.) or oral administration (PO), the pharmacokinetic index of the compound was evaluated. The indicators of the pharmacokinetics and the results are shown in Table 6 below.
  • T 1/2 the time it takes for the drug to decrease to half its original concentration
  • AUC integral of the concentration-time curve (area under the curve), blood concentration over time
  • MRT the average time a drug stays in the body
  • the pharmaceutical composition for preventing or treating at least one cancer selected from the group consisting of pancreatic cancer, breast cancer and lung cancer provided in one aspect of the present invention exhibits excellent anticancer effect in vitro, in vivo, and therefore, pancreatic cancer, breast cancer and lung cancer. Useful as a therapeutic.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une nouvelle utilisation d'un dérivé de pyrimidine comprenant un inhibiteur de kinase LRRK en tant que principe actif. Une composition pharmaceutique, obtenue selon un aspect de la présente invention, pour la prévention ou le traitement d'au moins l'un choisi parmi le cancer du pancréas, le cancer du sein et le cancer du poumon présente un excellent effet thérapeutique sur le cancer in vitro et in vivo et, en tant que telle, peut être avantageusement utilisée en tant qu'agent thérapeutique pour le cancer du pancréas, le cancer du sein et le cancer du poumon.
PCT/KR2019/010759 2018-08-23 2019-08-23 Nouvelle utilisation d'un dérivé de pyrimidine comprenant un inhibiteur de kinase lrrk en tant que principe actif WO2020040591A1 (fr)

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WO2022084210A1 (fr) * 2020-10-20 2022-04-28 F. Hoffmann-La Roche Ag Polythérapie à base d'antagonistes de liaison à l'axe pd-1 et d'inhibiteurs de lrrk2

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WO2008075007A1 (fr) * 2006-12-21 2008-06-26 Cancer Research Technology Limited Composé bicyclohétéroarylés substitué par morpholino et leur utilisation en tant qu'agents anti-cancer
KR20150027267A (ko) * 2012-06-29 2015-03-11 화이자 인코포레이티드 LRRK2 억제제로서의 4-(치환된-아미노)-7H-피롤로[2,3-d]피리미딘
US20170209460A1 (en) * 2014-07-10 2017-07-27 The J. David Gladstone Institutes Compositions and methods for treating dengue virus infection

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WO2008075007A1 (fr) * 2006-12-21 2008-06-26 Cancer Research Technology Limited Composé bicyclohétéroarylés substitué par morpholino et leur utilisation en tant qu'agents anti-cancer
KR20150027267A (ko) * 2012-06-29 2015-03-11 화이자 인코포레이티드 LRRK2 억제제로서의 4-(치환된-아미노)-7H-피롤로[2,3-d]피리미딘
US20170209460A1 (en) * 2014-07-10 2017-07-27 The J. David Gladstone Institutes Compositions and methods for treating dengue virus infection

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HENDERSON, J. L.: "Discovery and Preclinical Profiling of 3-[4-(Morpholin -4-yl)-7H-pyrrolo[2,3-d]pyrirnidin-5-yl]benzonitrile (PF-06447475), a Highly Potent, Selective, Brain Penetrant, and in Vivo Active LRRK2 Kinase Inhibitor", J. MED. CHEM., 2015, XP055687675 *
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022084210A1 (fr) * 2020-10-20 2022-04-28 F. Hoffmann-La Roche Ag Polythérapie à base d'antagonistes de liaison à l'axe pd-1 et d'inhibiteurs de lrrk2

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