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WO2024222880A1 - Composition pharmaceutique de dérivé de pyrido-pyrazole et son utilisation en médecine - Google Patents

Composition pharmaceutique de dérivé de pyrido-pyrazole et son utilisation en médecine Download PDF

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WO2024222880A1
WO2024222880A1 PCT/CN2024/090095 CN2024090095W WO2024222880A1 WO 2024222880 A1 WO2024222880 A1 WO 2024222880A1 CN 2024090095 W CN2024090095 W CN 2024090095W WO 2024222880 A1 WO2024222880 A1 WO 2024222880A1
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pharmaceutical composition
active ingredient
mmol
composition according
composition comprises
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PCT/CN2024/090095
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English (en)
Chinese (zh)
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王利
冯晶晶
陈焱
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西藏海思科制药有限公司
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Publication of WO2024222880A1 publication Critical patent/WO2024222880A1/fr

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  • the present invention belongs to the field of pharmaceutical preparations, and specifically relates to a pharmaceutical composition, wherein the pharmaceutical composition comprises a therapeutically effective amount of an active ingredient A and a pharmaceutical excipient, wherein the active ingredient A is selected from a compound of general formula (I) or a stereoisomer, a tautomer, a deuterated substance, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a cocrystal thereof, wherein the pharmaceutical composition comprises 1-1200 mg of the active ingredient A, and the content of the active ingredient A is selected from 0.5%-99.0%.
  • the present invention also relates to the use of the pharmaceutical composition in preparing drugs for treating cancer.
  • Protein ubiquitination in cells is a key protein modification that regulates multiple cellular processes. Protein ubiquitination is controlled by the synergistic action of E3 ubiquitin ligases and deubiquitinating enzymes (DUBs). DUBs can cleave the isopeptide bond between ubiquitin and modified proteins, and are responsible for removing ubiquitin from target proteins and rescuing them from degradation pathways; they are also involved in the editing, maturation, and recycling of ubiquitin molecules after degradation.
  • DUBs E3 ubiquitin ligases and deubiquitinating enzymes
  • USP is a cysteine protease that contains a highly conserved catalytic domain
  • USP1 is a member of the USP subfamily among DUBs (Cancers, 2020, 12, 1579; Molecular Cell, 2018, 72, 925-941).
  • Fanconi Anemia (FA) and DNA Translesion Synthesis (TLS) pathways are the earliest discovered DNA damage tolerance and repair pathways regulated by reversible ubiquitination.
  • USP1 can regulate the deubiquitination of specific proteins in the FA and TLS pathways to participate in the regulation of DNA damage-repair pathways (Nature Chemical Biology, 2014, 10, 298-304). USP1 plays an important role in DNA repair in tumor cells. It has been reported that the loss of USP1 leads to reduced survival and replication fork degradation in BRCA1-deficient cells (Molecular Cell, 2018, 72, 925-941).
  • UAF1 (USP1-associated factor 1) is a cofactor of USP1, USP12, and USP46, which can enhance their deubiquitinase activity by forming a stable USP/UAF1 protein complex; the USP1/UAF1 complex deubiquitinates a variety of substrates and is associated with the regulation of DNA repair processes, tumor pathogenesis, and antiviral innate immunity (Nat Commun, 2020, 11, 6042).
  • USP1-associated factor 1 is a cofactor of USP1, USP12, and USP46, which can enhance their deubiquitinase activity by forming a stable USP/UAF1 protein complex
  • the USP1/UAF1 complex deubiquitinates a variety of substrates and is associated with the regulation of DNA repair processes, tumor pathogenesis, and antiviral innate immunity (Nat Commun, 2020, 11, 6042).
  • USP1 inhibitors has broad application prospects.
  • Compound 1 is described in PCT/CN2023/076700, which has good USP1 inhibitory activity.
  • the administration of a therapeutically effective dose is a problem and may lead to toxic side effects or ineffective treatment. Therefore, it is very necessary to develop a pharmaceutical composition or pharmaceutical preparation with good safety, efficacy and stability.
  • the object of the present invention is to provide a pharmaceutical composition, which comprises an active ingredient A and a pharmaceutical excipient, wherein the active ingredient A is selected from the compound described in the general formula (I) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal.
  • the present invention also relates to the use of the pharmaceutical composition in the preparation of drugs for treating kidney disease.
  • the pharmaceutical composition of the invention has stable quality, good solubility, good absorption, low irritation, good safety, high bioavailability and can be absorbed orally.
  • the present invention relates to a pharmaceutical composition, which comprises a therapeutically effective amount of active ingredient A and a pharmaceutical excipient.
  • the pharmaceutical composition can be in the form of a unit preparation.
  • the present invention relates to a pharmaceutical composition, wherein the pharmaceutical composition comprises an active ingredient A and a pharmaceutical excipient, wherein the active ingredient A is selected from the compound of general formula (I) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,
  • R 1 is selected from -CH 3 , -CHF 2 , -CH 2 CH 3 ,
  • R 2 is selected from -CH 3 , -CHF 2 , -CH 2 CH 3 ,
  • the structure of the compound described by formula (I) is selected from one of the structures shown in Table S-1;
  • the compound described by general formula (I) is selected from compound 1, whose structure is:
  • the pharmaceutical composition comprises 1-1200 mg of active ingredient A;
  • the pharmaceutical composition comprises 5-1200 mg of active ingredient A;
  • the pharmaceutical composition comprises 5-1000 mg of active ingredient A;
  • the pharmaceutical composition comprises 5-900 mg of active ingredient A;
  • the pharmaceutical composition comprises 5-800 mg of active ingredient A;
  • the pharmaceutical composition comprises 10-800 mg of active ingredient A;
  • the pharmaceutical composition comprises 10-600 mg of active ingredient A;
  • the pharmaceutical composition comprises 10-400 mg of active ingredient A;
  • the pharmaceutical composition comprises 20-400 mg of active ingredient A;
  • the pharmaceutical composition comprises 30-300 mg of active ingredient A;
  • the pharmaceutical composition comprises 25-200 mg of active ingredient A;
  • the pharmaceutical composition comprises 20-200 mg of active ingredient A;
  • the pharmaceutical composition comprises 30-200 mg of active ingredient A;
  • the pharmaceutical composition comprises 30-100 mg of active ingredient A;
  • the pharmaceutical composition comprises 50-100 mg of active ingredient A;
  • the pharmaceutical composition comprises 5-100 mg of active ingredient A;
  • the pharmaceutical composition comprises 5 mg of active ingredient A;
  • the pharmaceutical composition comprises 10 mg of active ingredient A;
  • the pharmaceutical composition comprises 20 mg of active ingredient A;
  • the pharmaceutical composition comprises 25 mg of active ingredient A;
  • the pharmaceutical composition comprises 30 mg of active ingredient A;
  • the pharmaceutical composition comprises 40 mg of active ingredient A;
  • the pharmaceutical composition comprises 50 mg of active ingredient A;
  • the pharmaceutical composition comprises 75 mg of active ingredient A;
  • the pharmaceutical composition comprises 100 mg of active ingredient A;
  • the pharmaceutical composition comprises 125 mg of active ingredient A;
  • the pharmaceutical composition comprises 150 mg of active ingredient A;
  • the pharmaceutical composition comprises 200 mg of active ingredient A;
  • the pharmaceutical composition comprises 300 mg of active ingredient A;
  • the pharmaceutical composition comprises 400 mg of active ingredient A;
  • the pharmaceutical composition comprises 500 mg of active ingredient A;
  • the pharmaceutical composition comprises 600 mg of active ingredient A;
  • the pharmaceutical composition comprises 700 mg of active ingredient A;
  • the pharmaceutical composition comprises 800 mg of active ingredient A;
  • the pharmaceutical composition comprises 1000 mg of active ingredient A;
  • the pharmaceutical composition comprises 1200 mg of active ingredient A.
  • the content of the active ingredient A in the aforementioned pharmaceutical composition is selected from 0.5%-99.0%;
  • the content of active ingredient A is 0.5%-99.0%; in some embodiments, the content of active ingredient A is 1.0%-80.0%; in some embodiments, the content of active ingredient A is 1.0%-70.0%; in some embodiments, the content of active ingredient A is 1.0%-60.0%; in some embodiments, the content of active ingredient A is 1.0%-50.0%; in some embodiments, the content of active ingredient A is 1.0%-40.0%; in some embodiments, the content of active ingredient A is 1.0%-30.0%; in some embodiments, its content is 1.0%-20.0%; in some embodiments, the content of active ingredient A is 1.0%-10.0%; in some embodiments, the content of active ingredient A is 5.0%-90.0%; in some embodiments, the content of active ingredient A is 5.0%-85.0%; in some embodiments, the content of active ingredient A is 5.0%-70.0%; in some embodiments, the content of active ingredient A is 5.0%-60.0%; in some embodiments, the content of active ingredient A is 5.0%-50.0%; in some embodiments,
  • the pharmaceutical excipient in the aforementioned pharmaceutical composition is selected from one or more of a filler, a disintegrant, a binder, a glidant, a lubricant, a surfactant, and a pH adjuster;
  • the filler is selected from one or more of microcrystalline cellulose, mannitol, lactose, sucrose, sorbitol, dextran, pregelatinized starch, monocalcium phosphate, starch;
  • the disintegrant is selected from sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, One or more of cross-linked sodium carboxymethyl cellulose and calcium carboxymethyl cellulose;
  • the binder is selected from one or more of povidone, hydroxypropyl cellulose, hypromellose, and methyl cellulose;
  • the wetting agent is selected from one or both of water and ethanol.
  • the glidant is selected from one or more of talc, silicon dioxide, micronized silica gel, polyethylene glycol, and magnesium dodecyl sulfate;
  • the lubricant is selected from one or more of magnesium stearate, calcium stearate, stearic acid, and sodium stearyl fumarate;
  • the surfactant is selected from one or more of sodium lauryl sulfate, polysorbate, poloxamer, soluplus, polyoxyethylene castor oil.
  • the pH adjuster is selected from one or more of citric acid, tartaric acid, and fumaric acid.
  • the pharmaceutical excipients further comprise one or more of flavoring agents, antioxidants, preservatives, opacifiers, and film coating premixes.
  • the aforementioned pharmaceutical compositions are in solid form.
  • compositions include one or more of fillers, binders, wetting agents, disintegrants, glidants, lubricants, surfactants, and surface active agents;
  • the filler comprises one or more of microcrystalline cellulose, mannitol, lactose, sucrose, sorbitol, dextran, pregelatinized starch, calcium dihydrogen phosphate, and starch;
  • the binder comprises one or more of povidone, hydroxypropyl cellulose, hypromellose, and methyl cellulose;
  • the wetting agent comprises one or more of water and ethanol
  • the disintegrant comprises one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, and calcium carboxymethyl cellulose;
  • the glidant comprises one or more of talc, silicon dioxide, micronized silica gel, polyethylene glycol, and magnesium dodecyl sulfate;
  • the lubricant comprises one or more of magnesium stearate, calcium stearate, stearic acid, and sodium stearyl fumarate;
  • a surfactant selected from sodium lauryl sulfate, polysorbate, poloxamer, soluplus, polyoxyethylene One or more of castor oil;
  • pH adjuster selected from one or more of citric acid, tartaric acid and fumaric acid
  • composition may further contain one or more of a flavoring agent, an antioxidant, a preservative, a sunscreen agent, and a film coating premix.
  • the pharmaceutical composition described in any of the above schemes can be prepared into a preparation selected from tablets, granules, powders, oral solutions, emulsions or capsules.
  • the binder can be added in a solution state or in a powder state; the disintegrant can be added internally, externally, or both internally and externally.
  • the present invention also provides the use of the pharmaceutical composition in preparing drugs related to treating cancer.
  • Preparation specifications refers to the weight of the main drug (active ingredient A) contained in each vial, tablet or other unit preparation.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds described in the present invention all include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds described in the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein carbon isotopes include 12 C, 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
  • carbon isotopes include 12 C, 13 C and 14 C
  • hydrogen isotopes include pro
  • alkyl optionally substituted with F means that alkyl may but need not be substituted with F, and the description includes situations where alkyl is substituted with F and situations where alkyl is not substituted with F.
  • “Pharmaceutically acceptable salt” or “pharmaceutically acceptable salt thereof” refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, and the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.
  • “Pharmaceutical composition” refers to a mixture of one or more compounds of the present invention, or stereoisomers, tautomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals thereof and other chemical components, wherein “other chemical components” refers to pharmaceutically acceptable carriers, excipients and/or one or more other therapeutic agents.
  • a “carrier” is a substance that does not cause significant irritation to an organism and does not abrogate the biological activity and Characteristics of materials.
  • Excipient refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound.
  • Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrants.
  • Prodrug refers to a compound of the present invention that can be converted into a biologically active compound through in vivo metabolism.
  • the prodrug of the present invention is prepared by modifying the amino or carboxyl group in the compound of the present invention, and the modification can be removed by conventional operations or in vivo to obtain the parent compound.
  • the prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.
  • Co-crystal refers to a crystal formed by the active pharmaceutical ingredient (API) and the co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, in which the pure state of API and CCF are solid at room temperature and there is a fixed stoichiometric ratio between the components.
  • Co-crystal is a multi-component crystal, including binary eutectics formed between two neutral solids and multi-component eutectics formed between neutral solids and salts or solvates.
  • Animal is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.
  • Stepoisomers refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers, and conformational isomers.
  • Tautomers refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions, such as keto-enol isomerism and amide-imino alcohol isomerism.
  • IC50 is the concentration of a drug or inhibitor required to inhibit a specified biological process (or a component of such a process, such as an enzyme, receptor, cell, etc.) by half.
  • the “content %" of a substance in a pharmaceutical composition in this application refers to the percentage of the weight of the substance in the total weight of the pharmaceutical composition.
  • the “content %" in the content determination of a preparation refers to the percentage of the weight of the main drug of the preparation obtained by testing according to the determination method to the weight of the main drug in the preparation.
  • the compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art.
  • the starting point is commercially available chemicals and/or compounds described in the chemical literature. “Commercially available chemicals” are obtained from regular commercial sources, and suppliers include: Titan Technology, Anage Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and Bailingwei Technology.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100 ⁇ 4.6mm, 3.5 ⁇ M);
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF 254 or Qingdao GF 254 silica gel plate.
  • the silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm;
  • Boc tert-butoxycarbonyl
  • Ts p-toluenesulfonyl
  • 1,1-Dibromo-3,3,3-trifluoroacetone (4.98 g, 18.49 mmol, CAS: 431-67-4) was placed in a 250 mL single-mouth bottle, 30 mL of water and sodium acetate (1.89 g, 23.09 mmol) were added, and the mixture was reacted at 90 °C for 1 h. After cooling to room temperature, 60 mL of methanol, 2B (3.02 g, 15.39 mmol) and concentrated aqueous ammonia (15 mL) were added in sequence, and the mixture was reacted at 90 °C for 2 h.
  • reaction solution was poured into 200 mL of water, filtered, and the filter cake was washed with water (2 x 10 mL), and the filter cake was dried under reduced pressure to obtain 2C (2.9 g, yield: 62%).
  • 2D (1.2 g, 3.48 mmol) was dissolved in 20 mL THF, lithium borohydride (0.38 g, 17.40 mmol) was added, and the mixture was stirred at 60 °C for 2 h. After cooling to room temperature, a saturated aqueous solution of ammonium chloride was added to quench the reaction, and water and ethyl acetate were added to extract the mixture. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2E (0.9 g, yield: 81%).
  • Embodiment 2 is a diagrammatic representation of Embodiment 1:
  • Embodiment 3 is a diagrammatic representation of Embodiment 3
  • 5B (4.81 g, 11.89 mmol) was dissolved in DCM (30 mL), pyridine (1.41 g, 17.84 mmol) was added, trifluoromethanesulfonic anhydride (4.03 g, 14.29 mmol) was slowly added dropwise under ice bath, and the mixture was naturally heated to room temperature and stirred for 1 h. 30 mL of dichloromethane and 50 mL of water were added for extraction, and the organic layer was washed once with 30 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 5C.
  • Embodiment 4 is a diagrammatic representation of Embodiment 4:
  • Embodiment 5 is a diagrammatic representation of Embodiment 5:
  • Embodiment 6 is a diagrammatic representation of Embodiment 6
  • Embodiment 7 is a diagrammatic representation of Embodiment 7:
  • Embodiment 8 is a diagrammatic representation of Embodiment 8
  • Embodiment 9 is a diagrammatic representation of Embodiment 9:
  • 11A (0.13 g, 0.18 mmol) was dissolved in DCM (4 mL), trifluoroacetic acid (4 mL) was added at room temperature, and the mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure, 20 mL of dichloromethane was added to the residue, and 10 mL of saturated sodium bicarbonate aqueous solution was added, and the mixture was stirred for 10 min. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 11B.
  • Embodiment 10 is a diagrammatic representation of Embodiment 10:
  • the ratio (%) refers to the percentage of the weight of a component to the total weight of the formulation.
  • the above prescription preparations 1-5 adopt the following process:
  • Micro powder weigh and mix the API and surfactant (if any)/pH adjuster (if any) according to the prescription ratio, and then micronize after mixing evenly.
  • Mixing Mix the API, excipient micronized material, filler, binder, glidant, and disintegrant for 5 minutes, and add lubricant and mix for 2 minutes.
  • Tableting Use a suitable die to press the powder in 3) into tablets with controlled tablet weight and appropriate hardness.
  • Test Example 1 USP1/UAF1 Enzyme Inhibition Activity
  • the activity of deubiquitinase USP1/UAF1 after drug treatment was detected using ubiquitin rhodamine 110 as substrate.
  • the total test system was 20 ⁇ l, and the test buffer was 50 mM Tris-HCl, pH 7.8, 0.5 mM EDTA, 0.01% Bovine Serum Albumin, 1 mM DTT, 0.01% Tween-20.
  • the compounds of the present invention have a good inhibitory effect on the enzymatic activity of USP1/UAF1.
  • Test purpose To administer the test substance to beagle dogs by single-dose intravenous and oral gavage, determine the concentration of the test substance in beagle dog plasma, and evaluate the pharmacokinetic characteristics of the test substance in beagle dogs.
  • mice Male beagle dogs, about 8-11 kg, purchased from Beijing Mas Biotechnology Co., Ltd.
  • test method On the day of the test, beagles were randomly divided into groups according to body weight. They were fasted but not watered for 14-18 hours one day before administration, and were fed 4 hours after administration. Administration was performed according to the information in the table below.
  • Intravenous administration solvent 5% DMA + 5% Solutol + 90% Saline; intragastric administration solvent: 0.5% MC
  • the compound synthesized by the technology of the present invention has good oral absorption performance in beagle dogs, and its oral performance is better than that of the control compound A, wherein the control compound A is Its preparation method can be found in WO2020132269.
  • Test Example 3 MDA-MB-436 cell clone formation test
  • MDA-MB-436 cells After adding the test compound, the ability of cell clone formation is detected.
  • MDA-MB-436 cells ATCC, HTB-130
  • 96-well plate Cornning, 3599
  • 500 cells per well 500 cells per well, and adhered overnight
  • the compound was added with gradient dilutions, and the cells were placed in a 37°C, CO2 -free incubator for continued culture.
  • the old culture medium was discarded, and the test compound was added with gradient dilutions again.
  • the 96-well plate was removed, the culture medium was discarded, and the cell clones were detected using the Crystal violet Assay kit.
  • the PHERAstar FSX microplate reader BMG LABTECH
  • the IC 50 value was calculated using GraphPad Prism software.
  • the compounds of the present invention have a good inhibitory effect on the clone formation of MDA-MB-436 cells.
  • mice Male ICR mice, 25-30 g, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • mice On the day of the experiment, ICR mice were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours one day before administration and fed 4 hours after administration.
  • Blood was collected from the eye sockets at designated time points before and after administration, placed in EDTAK2 centrifuge tubes, and centrifuged at 5000rpm, 4°C for 10min to collect plasma.
  • the blood collection time points for the intravenous group and the gavage group were: 0, 5min, 15min, 30min, 1h, 2h, 4h, 7h, 24h.
  • All samples were stored below -60°C, and the samples were quantitatively analyzed by LC-MS/MS.
  • the compound synthesized by the technology of the present invention has good oral absorption performance in mice.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition pharmaceutique d'un dérivé de pyridine-pyrazole et son utilisation en médecine. La composition pharmaceutique comprend un principe actif A et un excipient pharmaceutique, le principe actif A étant choisi parmi un composé représenté par la formule générale (I) ou un stéréo-isomère, un tautomère, un produit deutéré, un solvate, un promédicament, un métabolite, un sel pharmaceutiquement acceptable ou un cristal eutectique de celui-ci. La composition pharmaceutique contient 1 à 1200 mg du principe actif A, et la teneur en principe actif A est choisie entre 0,5 et 99,0 %. La présente invention concerne également une utilisation de la composition pharmaceutique dans la préparation de médicaments associés au traitement de cancers.
PCT/CN2024/090095 2023-04-27 2024-04-26 Composition pharmaceutique de dérivé de pyrido-pyrazole et son utilisation en médecine WO2024222880A1 (fr)

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WO2015051713A1 (fr) * 2013-10-11 2015-04-16 四川海思科制药有限公司 Dérivé de spiro-4,5-dihydro-pyrazolo[3,4-c]pyridin-2-one, son procédé de préparation et son utilisation
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CN109311843A (zh) * 2016-06-16 2019-02-05 詹森药业有限公司 作为PI3Kβ抑制剂的氮杂苯并咪唑衍生物
CN113164485A (zh) * 2018-12-20 2021-07-23 Ksq治疗公司 被取代的吡唑并嘧啶和被取代的嘌呤以及其作为泛素特异性加工蛋白酶1(usp1)抑制剂的用途
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CN102014631A (zh) * 2008-03-03 2011-04-13 泰格尔医药科技公司 酪氨酸激酶抑制剂
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WO2015051713A1 (fr) * 2013-10-11 2015-04-16 四川海思科制药有限公司 Dérivé de spiro-4,5-dihydro-pyrazolo[3,4-c]pyridin-2-one, son procédé de préparation et son utilisation
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CN108948002A (zh) * 2017-05-19 2018-12-07 厦门大学 五元并六元氮杂芳环类化合物、其制备方法、药用组合物及其应用
CN113164485A (zh) * 2018-12-20 2021-07-23 Ksq治疗公司 被取代的吡唑并嘧啶和被取代的嘌呤以及其作为泛素特异性加工蛋白酶1(usp1)抑制剂的用途
WO2023155866A1 (fr) * 2022-02-18 2023-08-24 四川海思科制药有限公司 Dérivé de pyrazolopyridine et son application en médecine

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