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WO2020027084A1 - 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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Publication number
WO2020027084A1
WO2020027084A1 PCT/JP2019/029736 JP2019029736W WO2020027084A1 WO 2020027084 A1 WO2020027084 A1 WO 2020027084A1 JP 2019029736 W JP2019029736 W JP 2019029736W WO 2020027084 A1 WO2020027084 A1 WO 2020027084A1
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Prior art keywords
compound
diazaspiro
oxy
pancreatic cancer
methyl
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Japanese (ja)
Inventor
建之 長島
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Astellas Pharma Inc
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Astellas Pharma Inc
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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
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • 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 pancreatic cancer, comprising a quinazoline compound or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Pancreatic cancer mainly consisting of pancreatic ductal adenocarcinoma, has a very poor prognosis with a 5-year survival rate of 10% or less (CA Cancer J. Clin., 66, 7, 2016), and 340,000 people worldwide Is newly reported as a case (GLOBOCAN 2012). In the United States, deaths are expected to rank second in 2030 (Cancer Res., 74, 2913, 2014). Surgical surgery is the most effective means of treating pancreatic cancer, but it is often difficult to detect it early and metastases often occur, so that surgical surgery is often not applicable. If surgery is not indicated, chemotherapy or radiation therapy is used, but the survival rate is poor.
  • VEGF vascular endothelial growth factor
  • the RAS protein is a small guanosine triphosphate (GTP) binding protein of about 21 kDa, consisting of 188-189 amino acids, and is composed of four major proteins [KRAS, NRAS, and HRAS genes]. (KRAS4A and KRAS4B), NRAS, HRAS]. There are two types of RAS proteins: an active GTP-binding form and an inactive guanosine diphosphate (GDP) -binding form.
  • 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 signal transduction 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, 828, 2014, Nature rev. drug discov., 15, 771, 2016).
  • Pancreatic ductal adenocarcinoma is thought to occur in pancreatic intraepithelial neoplastic lesions / pancreatic neointraepithelial neoplasiaIN (PanIN) through weak to strong stages of malformation, and KRAS mutations have already been detected in early stages of PanIN.
  • KRAS plays an important role in the carcinogenesis and development of pancreatic cancer.
  • 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 any effect on pancreatic cancer, particularly on KRAS G12C mutation-positive pancreatic cancer. .
  • Non-Patent Document 1 discloses 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 pancreatic cancer strain MIA ⁇ PaCa-2. However, it has been reported that MIA PaCa-2 exhibits an antitumor effect in a nude mouse model bearing cancer.
  • a pharmaceutical composition for treating pancreatic cancer and in one embodiment, a pharmaceutical composition for treating KRAS G12C mutation-positive pancreatic cancer.
  • the present inventors for the purpose of creating a pharmaceutical composition for the treatment of pancreatic cancer, in particular, a pharmaceutical composition for the treatment of KRAS G12C mutation-positive pancreatic cancer, as a result of intensive studies on compounds having a G12C mutation 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 pancreatic cancer.
  • the present invention has been completed based on the findings.
  • the present invention also provides a therapeutic agent for pancreatic 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, as another embodiment,
  • An agent for treating KRAS G12C mutation-positive pancreatic cancer comprising a compound selected from the group consisting of compound A, compound B, compound C and compound D, or a pharmaceutically acceptable salt thereof.
  • 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 pancreatic 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 pancreatic 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 pancreatic cancer For therapeutic use 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 pancreatic 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 pancreatic cancer which comprises administering to a subject an effective amount of a compound or a pharmaceutically acceptable salt thereof, in one embodiment, a compound A, a compound B, a compound C, and a compound D.
  • the present invention relates to a method for treating KRAS G12C mutation-positive pancreatic cancer, which comprises administering to a subject an effective amount of a selected compound 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 pancreatic cancer, and in one embodiment, a pharmaceutical composition for treating KRAS G12C mutation-positive pancreatic 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 pancreatic cancer comprising Compound A or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition for treating KRAS G12C mutation-positive pancreatic cancer comprising Compound A or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • 1-2 A therapeutic agent for pancreatic cancer, comprising Compound A or a pharmaceutically acceptable salt thereof.
  • a therapeutic agent for KRAS G12C mutation-positive pancreatic 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 pancreatic cancer (1-4) Use of Compound A or a pharmaceutically acceptable salt thereof for the treatment of pancreatic cancer. In another embodiment, use of Compound A or a pharmaceutically acceptable salt thereof for the treatment of KRAS G12C mutation-positive pancreatic cancer. (1-5) Compound A or a pharmaceutically acceptable salt thereof for use in treating pancreatic cancer. In another embodiment, Compound A or a pharmaceutically acceptable salt thereof for use in the treatment of KRAS G12C mutation-positive pancreatic cancer.
  • pancreatic cancer A method for treating pancreatic cancer, which comprises administering an effective amount of Compound A or a pharmaceutically acceptable salt thereof to a subject.
  • a method for treating KRAS G12C mutation-positive pancreatic cancer comprising administering to a subject an effective amount of Compound A or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition for treating pancreatic cancer comprising Compound B or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition for treating KRAS G12C mutation-positive pancreatic cancer comprising Compound B or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a therapeutic agent for pancreatic cancer comprising Compound B or a pharmaceutically acceptable salt thereof.
  • a therapeutic agent for KRAS G12C mutation-positive pancreatic 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 pancreatic cancer (2-4) Use of Compound B or a pharmaceutically acceptable salt thereof for the treatment of pancreatic cancer. In another embodiment, the use of Compound B or a pharmaceutically acceptable salt thereof for the treatment of KRAS G12C mutation-positive pancreatic cancer. (2-5) Compound B or a pharmaceutically acceptable salt thereof for use in treating pancreatic cancer. In another embodiment, Compound B or a pharmaceutically acceptable salt thereof for use in the treatment of KRAS G12C mutation-positive pancreatic cancer.
  • a method for treating pancreatic cancer which comprises administering an effective amount of Compound B or a pharmaceutically acceptable salt thereof to a subject.
  • a method for treating KRAS G12C mutation-positive pancreatic cancer comprising administering to a subject an effective amount of Compound B or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition for treating pancreatic cancer comprising Compound C or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition for treating KRAS G12C mutation-positive pancreatic cancer comprising Compound C or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a therapeutic agent for KRAS G12C mutation-positive pancreatic 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 pancreatic cancer (3-4) Use of Compound C or a pharmaceutically acceptable salt thereof for the treatment of pancreatic cancer. In another embodiment, use of Compound C or a pharmaceutically acceptable salt thereof for treating KRAS G12C mutation-positive pancreatic cancer. (3-5) Compound C or a pharmaceutically acceptable salt thereof for use in treating pancreatic cancer. In another embodiment, Compound C or a pharmaceutically acceptable salt thereof for use in the treatment of KRAS G12C mutation-positive pancreatic cancer.
  • pancreatic cancer which comprises administering an effective amount of Compound C or a pharmaceutically acceptable salt thereof to a subject.
  • a method for treating KRAS G12C mutation-positive pancreatic cancer comprising administering to a subject an effective amount of Compound C or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition for treating pancreatic cancer comprising Compound D or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition for treating KRAS G12C mutation-positive pancreatic cancer comprising Compound D or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a therapeutic agent for KRAS G12C mutation-positive pancreatic 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 KRAS G12C mutation-positive pancreatic cancer (4-4) Use of Compound D or a pharmaceutically acceptable salt thereof for the treatment of pancreatic cancer. In another embodiment, use of Compound D or a pharmaceutically acceptable salt thereof for the treatment of KRAS G12C mutation-positive pancreatic cancer. (4-5) Compound D or a pharmaceutically acceptable salt thereof for use in treating pancreatic cancer. In another embodiment, Compound D or a pharmaceutically acceptable salt thereof for use in the treatment of KRAS G12C mutation-positive pancreatic cancer.
  • pancreatic cancer which comprises administering to a subject an effective amount of Compound D or a pharmaceutically acceptable salt thereof.
  • a method for treating KRAS G12C mutation-positive pancreatic 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, hydrates. Products and ethanol solvates. “Pharmaceutically acceptable salts” also include acid addition salts of these solvates.
  • 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.
  • 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 dose is appropriately determined according to individual cases in consideration of symptoms, age, sex, and the like.
  • 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 pancreatic cancer, particularly for KRAS G12C mutation-positive pancreatic 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 5 to 11 Compounds shown in Tables 5 to 11 below were produced by the production methods of the above Production Examples and the same methods. In addition, Tables 5 to 11 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. Fractionation was performed by chromatography (CHIRALPAK AS-H (manufactured by Daicel), carbon dioxide / ethanol / triethylamine).
  • 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 Corporation), carbon dioxide / methanol / triethylamine, carbon dioxide / ethanol / triethylamine).
  • Reference Example 2 (Compound B) was produced in the same manner as in the above-mentioned production method of Reference Example 4.
  • Tables 12 to 13 below show the structures of the compounds of Reference Examples, and Table 14 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.
  • MIA PaCa-2 Phosphorylation of ERK 202 threonine (Thr202) and 204 th tyrosine (Tyr204) downstream of KRAS signal ERK phosphorylation inhibitory effect of the test compound was evaluated by measuring by Cell ELISA.
  • MIA PaCa-2 cells (RIKEN, RCB2094) were seeded in a 384-well plate (Greiner bio-one) at 36 ⁇ L / well at 2.0 ⁇ 10 4 cells per well. Cell culture was performed at 37 ° C.
  • test compound (six points in the final concentration range of 100 nM to 0.3 nM), trametinib (GlaxoSmithKline; MEK inhibitor) at a final concentration of 1 ⁇ M as a positive control, and DMSO, a solvent for the test compound, as a negative control were used. After diluting 100 times with fresh medium, adding 4 ⁇ L to each well, and culturing for 2 hours.
  • PBS containing 0.5% sodium dodecyl sulfate (SDS) (Invitrogen) was added to each well in an amount of 20 ⁇ L, left at room temperature for 30 minutes, and then centrifuged to remove the supernatant. Subsequently, 20 ⁇ L of a blocking solution (ODYSSEY Blocking Buffer; LI-COR Biosciences) was added to each well and allowed to stand at room temperature for 1 hour.
  • SDS sodium dodecyl sulfate
  • the supernatant was removed by centrifugation, and the phosphorylated ERK (Thr202 / Tyr204) antibody (Phospho-p44 / 42 MAPK (Erk1 / 2) (Thr202 / Tyr204) (Thr202 / Tyr204) (D13.14.4E) diluted 2,500-fold with the blocking solution as the primary antibody )
  • XP Rabbit mAb (Cell Signaling Technology) was added to each well in an amount of 10 ⁇ L, and the mixture was allowed to stand at 4 ° C overnight.
  • the plate was centrifuged to remove the reaction solution, PBS containing 0.05% Tween-20 (Thermo Scientific; 20x PBS Tween-20 diluted 20-fold with ion-exchanged water) was added to each well in an amount of 20 ⁇ L, and centrifuged. Each well was washed by removing the supernatant. Washing was performed three times in total. After washing, 10 ⁇ L of IRDye 800CW Goat anti-Rabbit IgG (LI-COR Biosciences) diluted 1,000-fold with a blocking solution as a secondary antibody was added to each well, and left at room temperature for 1 hour.
  • PBS containing 0.05% Tween-20 Thermo Scientific; 20x PBS Tween-20 diluted 20-fold with ion-exchanged water
  • Example 3 Evaluation of Intratumoral pERK Inhibitory Activity The phosphorylation level of ERK 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). Examined. 3.0 ⁇ 10 6 MIA PaCa2 cells were prepared using a solution obtained by adding an equal amount of Matrigel (Becton Dickinson) to PBS, and 4-5 week old male nude mice (CAnN.Cg-Foxn1nu / CrlCrlj (nu / nu), Charles River Japan) injected subcutaneously at a dose of 100 ⁇ L and used for testing 17 days later.
  • Matrigel Becton Dickinson
  • the test was performed in each of the solvent group and the test compound administration group, each of which was performed using three solvents, and the test compound was prepared using a solvent so as to have the dose shown in Table 3.
  • 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.
  • lysis buffer 1 Phospho lysis buffer [Cisbio], Complete EDTA free [Roche], Phosphatase inhibitor cocktail2 [Sigma-Aldrich]
  • YTZ ball 5 mm [Nikkato] YTZ ball 5 mm [Nikkato]
  • the cells were crushed (frequency 25 / s, 3 minutes) using Tissue Lyser II (QIAGEN).
  • the whole amount was transferred to a new tube, and centrifuged (20,400 ⁇ g, 10 minutes, 4 ° C.) using a micro high-speed cooling centrifuge to obtain a tumor lysate as a supernatant.
  • Tumor lysate was quantified using a protein quantification kit (Pierce 660 nm Protein Assay Kit [Thermo Fisher]) and lysis buffer 2 (Phospho lysis buffer [Cisbio Company], Blocking Agent [supplied with pERK measurement kit]).
  • the p-ERK1 / 2 Cryptate antibody and the p-ERK1 / 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.
  • tumor lysate diluted to 0.5 ⁇ 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.
  • the count of the solvent group was set to 0% inhibition and the count without the addition of lysate was set to 100% inhibition, and the inhibition value of the test compound administration sample was calculated as a% inhibition rate.
  • Table 3 shows the test results using Compound A, Compound B, Compound C and Compound D as test compounds.
  • 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 4 shows the test results obtained 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 pancreatic cancer, particularly KRAS G12C mutation-positive pancreatic 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 of a pharmaceutical composition for treating pancreatic cancer, and in one embodiment, a pharmaceutical composition for treating KRAS G12C mutation-positive pancreatic cancer.

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  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention vise à fournir une composition pharmaceutique pour le traitement du cancer du pancréas, en particulier, le cancer du pancréas positif à la mutation G12C de KRAS. Les inventeurs ont examiné des composés ayant un effet inhibiteur de la mutation G12C de KRAS. L'invention concerne par conséquent des composés de quinazoline spécifiques dont les inventeurs ont confirmé qu'ils avaient un 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 pancréas, en particulier, le cancer du pancréas positif à la mutation G12C de KRAS.
PCT/JP2019/029736 2018-07-31 2019-07-30 Composition pharmaceutique comprenant un composé quinazoline en tant que principe actif Ceased WO2020027084A1 (fr)

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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
WO2022266206A1 (fr) 2021-06-16 2022-12-22 Erasca, Inc. Conjugués d'inhibiteurs de kras
WO2023119677A1 (fr) * 2021-12-24 2023-06-29 Astellas Pharma Inc. Composition pharmaceutique comprenant un composé quinazoline
WO2023205701A1 (fr) 2022-04-20 2023-10-26 Kumquat Biosciences Inc. Hétérocycles macrocycliques et leurs utilisations
US11845761B2 (en) 2020-12-18 2023-12-19 Erasca, Inc. Tricyclic pyridones and pyrimidones
EP4389751A1 (fr) 2021-09-03 2024-06-26 Kumquat Biosciences Inc. Composés hétérocycliques et leurs utilisations
US12122787B2 (en) 2019-09-20 2024-10-22 Shanghai Jemincare Pharmaceuticals Co., Ltd Fused pyridone compound, and preparation method therefor and use thereof
WO2024243441A1 (fr) 2023-05-24 2024-11-28 Kumquat Biosciences Inc. Composés hétérocycliques et leurs utilisations
WO2024246220A1 (fr) * 2023-05-31 2024-12-05 Institut National de la Santé et de la Recherche Médicale Méthodes et compositions pour le traitement du cancer du poumon
US12162893B2 (en) 2020-09-23 2024-12-10 Erasca, Inc. Tricyclic pyridones and pyrimidones
WO2025007000A1 (fr) 2023-06-30 2025-01-02 Kumquat Biosciences Inc. Composés aminés tricycliques condensés substitués et leurs utilisations en tant qu'inhibiteurs de ras
WO2025171055A1 (fr) 2024-02-06 2025-08-14 Kumquat Biosciences Inc. Conjugués hétérocycliques et leurs utilisations
JP2025528008A (ja) * 2022-08-12 2025-08-26 アステラス製薬株式会社 Ｇ１２ｄ変異ｋｒａｓ阻害活性を有する二官能性化合物を含む抗がん剤の組合せ
JP7733274B1 (ja) 2022-08-12 2025-09-02 アステラス製薬株式会社 Ｇ１２ｄ変異ｋｒａｓ阻害活性を有する二官能性化合物を含む抗がん剤の組合せ
WO2025230971A1 (fr) 2024-04-30 2025-11-06 Kumquat Biosciences Inc. Hétérocycles macrocycliques en tant qu'agents anticancéreux

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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
US12122787B2 (en) 2019-09-20 2024-10-22 Shanghai Jemincare Pharmaceuticals Co., Ltd Fused pyridone compound, and preparation method therefor and use thereof
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
JP2023508482A (ja) * 2019-12-27 2023-03-02 ウィゲン・バイオメディシン・テクノロジー・（シャンハイ）・カンパニー・リミテッド スピロ環含有キナゾリン化合物
US12479843B2 (en) 2019-12-27 2025-11-25 Soochow University Spiro ring-containing quinazoline compounds
US12162893B2 (en) 2020-09-23 2024-12-10 Erasca, Inc. Tricyclic pyridones and pyrimidones
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
CN116390728B (zh) * 2020-09-27 2024-03-29 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
US11845761B2 (en) 2020-12-18 2023-12-19 Erasca, Inc. Tricyclic pyridones and pyrimidones
WO2022266206A1 (fr) 2021-06-16 2022-12-22 Erasca, Inc. Conjugués d'inhibiteurs de kras
EP4389751A1 (fr) 2021-09-03 2024-06-26 Kumquat Biosciences Inc. Composés hétérocycliques et leurs utilisations
WO2023120742A1 (fr) * 2021-12-24 2023-06-29 Astellas Pharma Inc. Composition pharmaceutique comprenant un composé de quinazoline
JP7640945B2 (ja) 2021-12-24 2025-03-06 アステラス製薬株式会社 キナゾリン化合物を含有する医薬組成物
WO2023119677A1 (fr) * 2021-12-24 2023-06-29 Astellas Pharma Inc. Composition pharmaceutique comprenant un composé quinazoline
JP2024545933A (ja) * 2021-12-24 2024-12-13 アステラス製薬株式会社 キナゾリン化合物を含有する医薬組成物
WO2023205701A1 (fr) 2022-04-20 2023-10-26 Kumquat Biosciences Inc. Hétérocycles macrocycliques et leurs utilisations
JP7733273B2 (ja) 2022-08-12 2025-09-02 アステラス製薬株式会社 Ｇ１２ｄ変異ｋｒａｓ阻害活性を有する二官能性化合物を含む抗がん剤の組合せ
JP2025528008A (ja) * 2022-08-12 2025-08-26 アステラス製薬株式会社 Ｇ１２ｄ変異ｋｒａｓ阻害活性を有する二官能性化合物を含む抗がん剤の組合せ
JP7733274B1 (ja) 2022-08-12 2025-09-02 アステラス製薬株式会社 Ｇ１２ｄ変異ｋｒａｓ阻害活性を有する二官能性化合物を含む抗がん剤の組合せ
JP2025530624A (ja) * 2022-08-12 2025-09-17 アステラス製薬株式会社 Ｇ１２ｄ変異ｋｒａｓ阻害活性を有する二官能性化合物を含む抗がん剤の組合せ
WO2024243441A1 (fr) 2023-05-24 2024-11-28 Kumquat Biosciences Inc. Composés hétérocycliques et leurs utilisations
WO2024246220A1 (fr) * 2023-05-31 2024-12-05 Institut National de la Santé et de la Recherche Médicale Méthodes et compositions pour le traitement du cancer du poumon
WO2025007000A1 (fr) 2023-06-30 2025-01-02 Kumquat Biosciences Inc. Composés aminés tricycliques condensés substitués et leurs utilisations en tant qu'inhibiteurs de ras
WO2025171055A1 (fr) 2024-02-06 2025-08-14 Kumquat Biosciences Inc. Conjugués hétérocycliques et leurs utilisations
WO2025230971A1 (fr) 2024-04-30 2025-11-06 Kumquat Biosciences Inc. Hétérocycles macrocycliques en tant qu'agents anticancéreux

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