WO2020027083A1 - Composition pharmaceutique comprenant un composé quinazoline en tant que principe actif - Google Patents

Composition pharmaceutique comprenant un composé quinazoline en tant que principe actif Download PDF

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WO2020027083A1
WO2020027083A1 PCT/JP2019/029735 JP2019029735W WO2020027083A1 WO 2020027083 A1 WO2020027083 A1 WO 2020027083A1 JP 2019029735 W JP2019029735 W JP 2019029735W WO 2020027083 A1 WO2020027083 A1 WO 2020027083A1
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compound
diazaspiro
oxy
methyl
prop
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PCT/JP2019/029735
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English (en)
Japanese (ja)
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建之 長島
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アステラス製薬株式会社
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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
    • A61K31/495—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a pharmaceutical composition for treating colon cancer, comprising a quinazoline compound or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Colorectal cancer is a cancer with a high morbidity and mortality worldwide, with approximately 1 million new cases reported annually worldwide (World Cancer Report 2014). Surgical operation is the most effective means for treating colorectal cancer, but recent advances in chemotherapy and radiation therapy have been remarkable. Large-scale clinical trials conducted mainly in Europe and the United States have revealed that chemotherapy combined with various anticancer drugs is effective for colorectal cancer and contributes to tumor regression and prolonged prognosis (J. Clin. Oncol., 22, 229, 2004). In addition to chemotherapy, molecular targeted drugs such as anti-vascular endothelial growth factor (VEGF) antibodies and anti-epidermal growth factor (receptor) antibodies have also been used as first-line drugs in combination with chemotherapy. With regard to anti-EGFR antibody drugs, it has been revealed that RAS mutation is a predictor of negative effects (Cancer Res. 66, 3992, 2006). Currently, anti-EGFR antibody drugs are only available for colorectal cancer patients with Adaptable.
  • VEGF vascular endothelial
  • the RAS protein is a small guanosine triphosphate (GTP) binding protein of about 21 kDa consisting of 188-189 amino acids, and four major proteins (KRAS, KRAS, NRAS, and HRAS) are generated from three genes. (KRAS4A and KRAS4B), NRAS, HRAS).
  • GTP small guanosine triphosphate
  • KRAS4A and KRAS4B NRAS
  • HRAS guanosine diphosphate
  • the RAS protein is activated by exchanging GDP and GTP by stimulating a ligand to a cell membrane receptor such as EGFR.
  • RAS Activated RAS binds to as many as 20 effector proteins, including RAF, PI3K, and RALGDS, and activates downstream signal cascades.
  • activated RAS becomes inactive when GTP is converted to GDP by endogenous GTPase activity.
  • GAP GTPase activating protein
  • RAS plays an important role as a “molecular switch” in intracellular signaling pathways such as EGFR, and plays an important role in processes such as cell growth, proliferation, and angiogenesis (Nature rev. cancer, 11, 761, 2011, Nature rev. drug discov., 13, v828, 2014, Nature rev. drug discov., 15, 771, 2016).
  • Patent Document 4 published after the earliest priority date of the present application discloses that a compound represented by the following formula (C) or a salt thereof has a G12C-mutant KRAS inhibitory activity, and exhibits lung cancer, particularly KRAS G12C. It is disclosed that it is useful as a therapeutic agent for mutation-positive lung cancer.
  • the document specifically discloses a compound that is an active ingredient of the pharmaceutical composition of the present invention as an example compound, but does not disclose an effect on colorectal cancer, particularly on KRAS G12C mutation-positive colorectal cancer. .
  • Non-Patent Document 1 reports that the compound of Example 353 (also referred to as ARS-1620) disclosed in Patent Document 1 has a cell growth inhibitory effect on human KRAS G12C mutation-positive colorectal cancer strain SW1463. Have been.
  • a pharmaceutical composition for treating colorectal cancer and in one embodiment, a pharmaceutical composition for treating KRAS G12C mutation-positive colorectal cancer.
  • the present inventors for the purpose of creating a pharmaceutical composition for treating colorectal cancer, in particular, a pharmaceutical composition for treating KRAS G12C mutation-positive colorectal cancer, as a result of intensive studies on compounds having a G12C mutant KRAS inhibitory action, the present invention
  • the quinazoline compound or a pharmaceutically acceptable salt thereof has an excellent G12C mutant KRAS inhibitory action, and that a pharmaceutical composition containing these compounds as an active ingredient is useful as a pharmaceutical composition for treating colon cancer.
  • the present invention has been completed based on the findings.
  • the present invention provides a therapeutic agent for colorectal cancer containing a compound selected from the group consisting of compound A, compound B, compound C and compound D, or a pharmaceutically acceptable salt thereof, and compound A in one embodiment. Or a compound selected from the group consisting of compound B, compound C and compound D, or a pharmaceutically acceptable salt thereof, for a therapeutic agent for KRAS G12C mutation-positive colorectal cancer.
  • the present invention also provides a compound selected from the group consisting of compound A, compound B, compound C and compound D, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for treating colon cancer.
  • a compound selected from the group consisting of compound A, compound B, compound C and compound D for the production of a pharmaceutical composition for treating KRAS G12C mutation-positive colorectal cancer
  • use of a compound selected from the group consisting of compound A, compound B, compound C and compound D, or a pharmaceutically acceptable salt thereof for the treatment of KRAS G12C mutation-positive colorectal cancer Use of treatment A compound selected from the group consisting of compound A, compound B, compound C and compound D, or a pharmaceutically acceptable salt thereof, in one embodiment, for use in treating KRAS G12C mutation-positive colorectal cancer.
  • a compound selected from the group consisting of compound A, compound B, compound C and compound D, or a pharmaceutically acceptable salt thereof; and a compound selected from the group consisting of compound A, compound B, compound C and compound D A method for treating colorectal cancer, which comprises administering to a subject an effective amount of a selected compound or a pharmaceutically acceptable salt thereof.
  • the method comprises compound A, compound B, compound C, and compound D.
  • the present invention relates to a method for treating KRAS G12C mutation-positive colorectal cancer, which comprises administering to a subject an effective amount of a compound selected from the group or a pharmaceutically acceptable salt thereof.
  • the “subject” is a human or other animal in need of the treatment, and in one embodiment, a human in need of the treatment.
  • the compound selected from the group consisting of compound A, compound B, compound C and compound D, which is an active ingredient of the pharmaceutical composition of the present invention, or a pharmaceutically acceptable salt thereof has a G12C mutant KRAS inhibitory action.
  • it can be used as an active ingredient of a pharmaceutical composition for treating colon cancer, and in one embodiment, a pharmaceutical composition for treating KRAS G12C mutation-positive colon cancer.
  • G12C mutation refers to a gene mutation in which the residue corresponding to the 12th position in the wild-type protein is changed from glycine to cysteine.
  • G12C mutant KRAS refers to a KRAS having the above “G12C mutation” in the gene encoding KRAS.
  • a pharmaceutical composition for treating colorectal cancer comprising Compound A or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition for treating KRAS G12C mutation-positive colorectal cancer comprising Compound A or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • 1-2 A therapeutic agent for colorectal cancer containing Compound A or a pharmaceutically acceptable salt thereof.
  • a therapeutic agent for KRAS G12C mutation-positive colorectal cancer comprising Compound A or a pharmaceutically acceptable salt thereof.
  • use of compound A or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for treating KRAS G12C mutation-positive colorectal cancer (1-4) Use of Compound A or a pharmaceutically acceptable salt thereof for treating colorectal cancer. In another embodiment, use of Compound A or a pharmaceutically acceptable salt thereof for the treatment of KRAS G12C mutation-positive colorectal cancer. (1-5) Compound A or a pharmaceutically acceptable salt thereof for use in treating colorectal cancer. In another embodiment, Compound A or a pharmaceutically acceptable salt thereof for use in the treatment of KRAS G12C mutation-positive colorectal cancer.
  • (1-6) A method for treating colorectal cancer, comprising administering an effective amount of Compound A or a pharmaceutically acceptable salt thereof to a subject.
  • a method for treating KRAS G12C mutation-positive colorectal cancer comprising administering to a subject an effective amount of Compound A or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition for treating colorectal cancer comprising Compound B or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition for treating KRAS G12C mutation-positive colorectal cancer comprising Compound B or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a therapeutic agent for colorectal cancer comprising Compound B or a pharmaceutically acceptable salt thereof.
  • a therapeutic agent for KRAS G12C mutation-positive colorectal cancer comprising Compound B or a pharmaceutically acceptable salt thereof.
  • use of Compound B or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for treating KRAS G12C mutation-positive colorectal cancer (2-4) Use of Compound B or a pharmaceutically acceptable salt thereof for treating colon cancer.
  • use of Compound B or a pharmaceutically acceptable salt thereof for treating KRAS G12C mutation-positive colorectal cancer (2-5) Compound B or a pharmaceutically acceptable salt thereof for use in treating colorectal cancer.
  • a method for treating colorectal cancer comprising administering to a subject an effective amount of Compound B or a pharmaceutically acceptable salt thereof.
  • a method for treating KRAS G12C mutation-positive colorectal cancer comprising administering to a subject an effective amount of Compound B or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition for treating colorectal cancer comprising Compound C or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition for treating KRAS G12C mutation-positive colorectal cancer comprising Compound C or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a therapeutic agent for KRAS G12C mutation-positive colorectal cancer comprising Compound C or a pharmaceutically acceptable salt thereof.
  • use of compound C or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for treating KRAS G12C mutation-positive colorectal cancer (3-4) Use of Compound C or a pharmaceutically acceptable salt thereof for treating colorectal cancer. In another embodiment, use of Compound C or a pharmaceutically acceptable salt thereof for the treatment of KRAS G12C mutation-positive colorectal cancer. (3-5) Compound C or a pharmaceutically acceptable salt thereof for use in treating colorectal cancer. In another embodiment, Compound C or a pharmaceutically acceptable salt thereof for use in the treatment of KRAS G12C mutation-positive colorectal cancer.
  • a method for treating colorectal cancer comprising administering an effective amount of Compound C or a pharmaceutically acceptable salt thereof to a subject.
  • a method for treating KRAS G12C mutation-positive colorectal cancer comprising administering to a subject an effective amount of Compound C or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition for treating colon cancer comprising Compound D or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition for treating KRAS G12C mutation-positive colorectal cancer comprising Compound D or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • (4-2) A therapeutic agent for colorectal cancer comprising Compound D or a pharmaceutically acceptable salt thereof.
  • a therapeutic agent for KRAS G12C mutation-positive colorectal cancer comprising Compound D or a pharmaceutically acceptable salt thereof.
  • Use of Compound D or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for treating colon cancer is
  • use of compound D or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for treating KRAS G12C mutation-positive colorectal cancer (4-4) Use of Compound D or a pharmaceutically acceptable salt thereof for treating colorectal cancer. In another embodiment, use of Compound D or a pharmaceutically acceptable salt thereof for the treatment of KRAS G12C mutation-positive colorectal cancer. (4-5) Compound D or a pharmaceutically acceptable salt thereof for use in treating colorectal cancer. In another embodiment, Compound D or a pharmaceutically acceptable salt thereof for use in the treatment of KRAS G12C mutation-positive colorectal cancer.
  • a method for treating colorectal cancer comprising administering an effective amount of Compound D or a pharmaceutically acceptable salt thereof to a subject.
  • a method for treating KRAS G12C mutation-positive colorectal cancer comprising administering to a subject an effective amount of Compound D or a pharmaceutically acceptable salt thereof.
  • a pharmaceutically acceptable salt of a compound selected from the group consisting of compound A, compound B, compound C, and compound D refers to a compound A, compound B, compound C, or compound D Acid addition salts, specifically, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid Acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid, methanesulfonic acid (mesylic acid), ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid (tosyl Acid), aspartic acid, glutamic acid, and other organic acids.
  • inorganic acids such as hydroch
  • the “compound selected from the group consisting of compound A, compound B, compound C and compound D” includes various solvates of compound A, compound B, compound C or compound D, specifically, Products and ethanol solvates. “Pharmaceutically acceptable salts” also include acid addition salts of these solvates. In one embodiment of the “compound A, compound B, compound C and compound D, or a pharmaceutically acceptable salt thereof”, a free base that does not form a salt, that is, , A compound A, a compound B, a compound C or a compound D. Another embodiment is a compound A, yet another embodiment is a compound B, and yet another embodiment is a compound C. In still another embodiment, it is Compound D.
  • compositions containing as an active ingredient a compound selected from the group consisting of compound A, compound B, compound C and compound D, or a pharmaceutically acceptable salt thereof, are commonly used in the art. It can be prepared by a commonly used method using a excipient, that is, a pharmaceutical excipient or a pharmaceutical carrier.
  • Oral administration by tablets, pills, capsules, granules, powders, liquids, etc., or intra-articular, intravenous, intramuscular injections, suppositories, eye drops, eye ointments, transdermal solutions Any form of parenteral administration such as an ointment, a transdermal patch, a transmucosal solution, a transmucosal patch, an inhalant and the like may be used.
  • the solid composition for oral administration tablets, powders, granules and the like are used.
  • one or more active ingredients are mixed with at least one inert excipient.
  • the composition may contain an inert additive such as a lubricant, a disintegrant, a stabilizer, and a solubilizing agent according to a conventional method.
  • the tablets or pills may be coated with sugar coating or a film of gastric or enteric substance, if necessary.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs and the like, commonly used inert diluents such as purified water Or contains ethanol.
  • the liquid composition may contain, in addition to the inert diluent, auxiliaries such as solubilizing agents, wetting agents, and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.
  • ⁇ Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • Aqueous solvents include, for example, distilled water for injection or physiological saline.
  • the non-aqueous solvent include alcohols such as ethanol.
  • Such compositions may further comprise a tonicity agent, preservative, wetting agent, emulsifier, dispersant, stabilizer, or dissolution aid. These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. In addition, these can be used by preparing a sterile solid composition, dissolving or suspending in sterile water or a sterile injection solvent before use.
  • the daily dose is about 0.001 to 100 mg / kg, preferably 0.1 to 30 mg / kg, more preferably 0.1 to 10 mg / kg per body weight.
  • the dose is divided into four to four times.
  • the daily dose is suitably about 0.0001 to 10 mg / kg per body weight, which is administered once a day or divided into several times a day.
  • the pharmaceutical composition of the present invention may comprise 0.01 to 100% by weight, and in some embodiments 0.01 to 50% by weight of compound A as active ingredient , A compound selected from the group consisting of compound B, compound C and compound D, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the present invention can be used in combination with various therapeutic agents which are considered to be effective for colorectal cancer, particularly for KRAS G12C mutation-positive colorectal cancer.
  • the combination may be administered simultaneously, or separately and continuously, or at desired time intervals. In the case of simultaneous administration, it may be a combination drug or may be separately formulated.
  • naming software such as ACD / Name (registered trademark, Advanced Chemistry Development, Inc.) may be used for compound naming.
  • concentration mol / L is expressed as M.
  • a 1 M aqueous sodium hydroxide solution means a 1 mol / L aqueous sodium hydroxide solution.
  • the reaction mixture was stirred at 150 ° C. for 2.5 hours. After allowing the reaction mixture to cool to room temperature, it was concentrated under reduced pressure, and ethyl acetate was added to the obtained residue. After the reaction mixture was poured into ice water, insolubles were filtered off, and the filtrate was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform / methanol / 28% aqueous ammonia). Acetonitrile was added to the obtained purified product, and the mixture was stirred at room temperature for 5 minutes. The precipitated solid was collected by filtration, dried at 30 ° C.
  • a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate.
  • the reaction mixture was filtered through celite, and the filtrate was extracted with chloroform. After the organic layer was dried over anhydrous magnesium sulfate, the solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol / 28% aqueous ammonia). Acetonitrile was added to the obtained purified product, and the precipitated solid was collected by filtration.
  • Tables 4 to 10 Compounds shown in Tables 4 to 10 below were produced by the production methods described in the above Production Examples and in the same manner. In addition, Tables 4 to 10 show the production methods, structures, and physicochemical data of each production example compound.
  • Reference example 1 1- ⁇ 7- [6-Cyclopropyl-2- ⁇ [1- (3-methoxypropyl) piperidin-4-yl] oxy ⁇ -7- (5-methyl-1H-indazol-4-yl) -8- (2,2,2-trifluoroethoxy) quinazolin-4-yl] -2,7-diazaspiro [3.5] non-2-yl ⁇ prop-2-en-1-one (2.2 g) was subjected to supercritical fluid chromatography. Separation was performed by chromatography (CHIRALPAK AS-H (manufactured by Daicel), carbon dioxide / ethanol / triethylamine).
  • CHIRALPAK AS-H manufactured by Daicel
  • Reference example 3 1- ⁇ 7- [2- ⁇ [1- (2-methoxyethyl) piperidin-4-yl] oxy ⁇ -7- (5-methyl-1H-indazol-4-yl) -8- (2,2, Supercritical fluid chromatography of 2-trifluoroethoxy) -6-vinylquinazolin-4-yl] -2,7-diazaspiro [3.5] non-2-yl ⁇ prop-2-en-1-one (2.0 g) (CHIRALPAK AS-H (manufactured by Daicel), carbon dioxide / methanol / triethylamine, carbon dioxide / ethanol / triethylamine).
  • Reference example 4 1- (7- ⁇ 8-ethoxy-7- (5-methyl-1H-indazol-4-yl) -2-[(1-methylpiperidin-4-yl) oxy] -6-vinylquinazolin-4-yl ⁇ -2,7-diazaspiro [3.5] non-2-yl) prop-2-en-1-one (1.5 g) was subjected to supercritical fluid chromatography (CHIRALPAK AS-H (manufactured by Daicel), carbon dioxide / ethanol) / Triethylamine). Hexane and ethyl acetate were added to the obtained fraction to perform trituration.
  • CHIRALPAK AS-H manufactured by Daicel
  • Hexane and ethyl acetate were added to the obtained fraction to perform trituration.
  • Reference Example 2 (Compound B) was produced in the same manner as in the above-mentioned production method of Reference Example 4.
  • Tables 11 and 12 below show the structures of the compounds of Reference Examples, and Table 13 shows the production methods and physicochemical data of the compounds of Reference Examples.
  • Example 1 Evaluation of KRAS G12C / SOS / c-Raf Complex Formation Inhibitory Effect Using human recombinant KRAS G12C, SOS and c-Raf proteins, the inhibitory effect of a test compound on complex formation of these proteins was time-resolved fluorescence-fluorescence. It was examined by the resonance energy transfer (TR-FRET) method.
  • TR-FRET resonance energy transfer
  • Biotinylated AviTag-KRAS G12C (amino acid region 1-185, GDP) dissolved in assay buffer (50 mM HEPES, 150 mM NaCl, 5 mM MgCl 2 , 0.05% Tween 20, pH 7.4) in a 384-well plate (Corning) 2.5 ⁇ L; 400 nM) and a test compound were added in a volume of 2.5 ⁇ L from 4,000 nM to 4 nM.
  • the fluorescence intensity at 620 nm and 665 nm was measured under the condition of 337 nm. After standardizing the values with the fluorescence intensity at the reference wavelength of 620 nm, the signal value in the solvent treatment is 0% inhibited, the signal value without GTP is 100% inhibition, and the 50% inhibition concentration (IC 50 ) is the Sigmoid-Emax model. It was calculated by nonlinear regression analysis. Table 1 shows the test results using Compound A, Compound B, Compound C and Compound D as test compounds.
  • Example 2 Evaluation of Intratumoral pERK Inhibitory Effect
  • the amount of ERK phosphorylation in a tumor sample after administration of a test compound was determined by TR-FRET method using a pERK measurement kit (Advanced ERK phospho-T202 / Y204 kit, Cisbio).
  • SW1463 cells ATCC, CCL-2314
  • SW1463 cells were cultured at 37 ° C. in Leibovitz's L-15 medium (Life technologies) containing 10% fetal bovine serum (GE Life Sciences), and 2.0 ⁇ 10 6 cells were equilibrated to PBS. It was prepared using a solution to which Matrigel (Becton Dickinson) was added.
  • the cell suspension was subcutaneously injected into a 4-week-old male SCID mouse (CB17 / Icr-Prkdcscid / CrlCrlj, Charles River Japan) at a dose of 100 ⁇ L, and used for testing 25 days later.
  • the test was performed in each of the solvent group and the test compound administration group, and the test compound was prepared using a solvent so as to have the dose shown in Table 2.
  • the test compound was orally administered, and a 6% 2-hydroxypropyl- ⁇ -cyclodextrin (Sigma-Aldrich) aqueous solution was used as a solvent.
  • the tumor was excised from the mouse that underwent cervical dislocation under anesthesia with isoflurane, a part of which was placed in a 2 mL Eppendorf tube, and frozen using liquid nitrogen. Tumor samples were stored in a deep freezer at -80 ° C until subjected to the pERK measurement test.
  • 500 ⁇ L of lysis buffer 1 Phospho lysis buffer [Cisbio], Complete EDTA free [Roche], Phosphatase inhibitor cocktail2 [Sigma-Aldrich]
  • YTZ ball 5 mm [Nikkato] were added.
  • the cells were crushed (frequency 25 / s, 3 minutes) using Tissue Lyser II (QIAGEN).
  • Tumor lysate was quantified using a protein quantification kit (Pierce 660 nm Protein Assay Kit [Thermo Fisher]), and each sample was lysed in lysis buffer 2 (Phospho lysis buffer [Cisbio lysis buffer] to a final concentration of 1.0 ⁇ g / ⁇ L). Company], Blocking Agent [supplied with pERK measurement kit]).
  • the pERK1 / 2 Cryptate antibody and pERK1 / 2 d2 antibody were diluted 40-fold with a detection buffer (supplied with the pERK measurement kit) to prepare a mixed solution of these two antibodies.
  • the antibody mixed solution was added to a 384-well plate at a volume of 4 ⁇ L / well. Further, tumor lysate diluted to 1.0 ⁇ g / ⁇ L was added at a volume of 16 ⁇ L / well.
  • the fluorescence intensity at 620 nm and 665 nm was measured using an EnVision 2103 Multilabel Reader (PerkinElmer) at an excitation wavelength of 337 nm. After normalizing the values by the fluorescence intensity at the reference wavelength of 620 nm, the count of the vehicle administration group was set to 0% inhibition and the count without addition of lysate was set to 100% inhibition, and the inhibition value of the test compound administration sample was calculated by% inhibition rate.
  • Table 2 shows the test results using Compound A, Compound B, Compound C and Compound D as test compounds.
  • SW1463 tumor-bearing mouse 2.0 ⁇ 10 6 SW1463 cells were prepared using a solution obtained by adding an equal amount of Matrigel (Becton Dickinson) to PBS, Four-week-old male SCID mice (CB17 / Icr-Prkdcscid / CrlCrlj, Charles River Japan) were subcutaneously injected and injected at a dose of 100 ⁇ L. Approximately three weeks after planting, the animals were divided into groups so that the tumor volumes and body weights between the groups were almost equal, and administration of the test compound was started the next day.
  • Matrigel Becton Dickinson
  • the test was performed in each of the solvent group and the test compound administration group, each of which had 5 animals.
  • a 6% 2-hydroxypropyl- ⁇ -cyclodextrin (Sigma-Aldrich) aqueous solution was used in the solvent group, and a 6% 2-hydroxyl solution was used in the test compound administration group.
  • the test compound (10 or 40 mg / kg) was mixed with an aqueous solution of propyl- ⁇ -cyclodextrin and orally administered.
  • the administration was performed once a day for 14 days, and the tumor diameter and body weight were measured twice a week.
  • the following formula was used to calculate the tumor volume.
  • [Tumor volume (mm 3 )] [Tumor major axis (mm)] x [Tumor minor axis (mm)] 2 x 0.5
  • the tumor growth inhibition rate (%) by the test compound was calculated as 100% inhibition of the tumor volume in the test compound administration group on the day before the start of administration, and 0% inhibition of the tumor volume in the solvent group on the end day of the administration.
  • the tumor volume of the test compound administration group was lower than the tumor volume on the day before the administration start, the tumor volume on the day before the administration start was reduced by 0%, and the tumor volume was set to 100% regression, and the tumor regression rate of the test compound (%) was calculated.
  • Table 3 shows the test results using Compound A, Compound B, Compound C and Compound D as test compounds.
  • a compound selected from the group consisting of compound A, compound B, compound C and compound D or a pharmaceutically acceptable salt thereof can be used for the treatment of colorectal cancer, particularly KRAS G12C mutation-positive colorectal cancer.
  • the active ingredient of the pharmaceutical composition of the present invention a compound selected from the group consisting of compound A, compound B, compound C and compound D, or a pharmaceutically acceptable salt thereof has a G12C mutant KRAS inhibitory action. It can be used as an active ingredient in a pharmaceutical composition for treating colorectal cancer, and in one embodiment, a pharmaceutical composition for treating KRAS G12C mutation-positive colorectal cancer.

Abstract

La présente invention vise à fournir une composition pharmaceutique pour le traitement du cancer du côlon, en particulier, le cancer du côlon positif à la mutation G12C de KRAS. Les inventeurs ont examiné des composés ayant un effet inhibiteur sur la mutation G12C de KRAS. L'invention concerne par conséquent des composés de quinazoline spécifiques dont les inventeurs ont confirmé qu'ils avaient effet inhibiteur de la mutation G12C de KRAS et une composition pharmaceutique comprenant un tel composé en tant que principe actif, qui a un effet thérapeutique sur le cancer du côlon, en particulier, le cancer du côlon positif à la mutation G12C de KRAS et ont ainsi réalisé la présente invention.
PCT/JP2019/029735 2018-07-31 2019-07-30 Composition pharmaceutique comprenant un composé quinazoline en tant que principe actif WO2020027083A1 (fr)

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JP2018144066A JP2021176819A (ja) 2018-07-31 2018-07-31 キナゾリン化合物を有効成分とする医薬組成物
JP2018-144066 2018-07-31

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WO2020177629A1 (fr) * 2019-03-01 2020-09-10 劲方医药科技(上海)有限公司 Composé cyclique fusionné à une pyrimidine spiro-substitué, son procédé de préparation et son utilisation médicale
WO2021129820A1 (fr) * 2019-12-27 2021-07-01 微境生物医药科技(上海)有限公司 Composé de quinazoline contenant un cycle spiro
WO2022063297A1 (fr) * 2020-09-27 2022-03-31 微境生物医药科技(上海)有限公司 Dérivé de quinazoline, son procédé de préparation et son utilisation
CN116390728A (zh) * 2020-09-27 2023-07-04 微境生物医药科技(上海)有限公司 喹唑啉衍生物及其制备方法和用途
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US11845761B2 (en) 2020-12-18 2023-12-19 Erasca, Inc. Tricyclic pyridones and pyrimidones
US20220331324A1 (en) * 2021-04-08 2022-10-20 Mirati Therapeutics, Inc. Combination Therapies Using PRMT5 Inhibitors for the Treatment of Cancer
WO2022266206A1 (fr) 2021-06-16 2022-12-22 Erasca, Inc. Conjugués d'inhibiteurs de kras
WO2023205701A1 (fr) 2022-04-20 2023-10-26 Kumquat Biosciences Inc. Hétérocycles macrocycliques et leurs utilisations

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