WO2022037601A1 - Dérivé de pyrazolamide servant d'antagoniste du récepteur ep4 et son utilisation dans la préparation de médicaments pour le traitement du cancer et de l'inflammation - Google Patents

Dérivé de pyrazolamide servant d'antagoniste du récepteur ep4 et son utilisation dans la préparation de médicaments pour le traitement du cancer et de l'inflammation Download PDF

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WO2022037601A1
WO2022037601A1 PCT/CN2021/113207 CN2021113207W WO2022037601A1 WO 2022037601 A1 WO2022037601 A1 WO 2022037601A1 CN 2021113207 W CN2021113207 W CN 2021113207W WO 2022037601 A1 WO2022037601 A1 WO 2022037601A1
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cancer
compound
disease
antibody therapy
acid
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PCT/CN2021/113207
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Chinese (zh)
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张学军
臧杨
李莉娥
李群
赵双
刘哲
常少华
孙红娜
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武汉人福创新药物研发中心有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • C07D231/20—One oxygen atom attached in position 3 or 5
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings

Definitions

  • the present invention relates to the fields of chemistry and medicine, in particular, the present invention relates to pyrazole amide derivatives and uses thereof.
  • Prostaglandin E 2 is an endogenous bioactive lipid, and PGE 2 induces a wide range of upstream and downstream-dependent biological responses by activating prostaglandin receptors (Legler, DF et al, hit. J Biochem .Cell Biol.2010,42,p.198-201), involved in the regulation of many physiological and pathological processes including inflammation, pain, renal function, cardiovascular system, lung function and cancer.
  • PGE 2 is reported to be highly expressed in cancerous tissues of various cancers, and it has been demonstrated that PGE 2 is associated with the occurrence, growth and progression of cancer and disease conditions in patients. It is widely believed that PGE 2 is associated with the activation of cell proliferation and cell death (apoptosis) and plays an important role in the processes of cancer cell proliferation, disease progression and cancer metastasis.
  • EP4 receptor antagonists are promising as anti-inflammatory and/or analgesic drugs to treat diseases related to the PGE 2 -EP4 pathway, such as inflammatory diseases, diseases accompanied by various pains, and the like.
  • EP4 is a major receptor involved in arthritic pain in rodent models of rheumatoid arthritis and osteoarthritis (see eg, J. Pharmacol. Exp. Ther., 325, 425 (2008)), which upon activation leads to intracellular The signaling molecule cAMP accumulates. EP4 receptor expression has been detected on peripheral nerve endings of pain receptors, macrophages, and neutrophils, and these cell types have been shown to be extremely important in endometriosis. Studies have reported that oral EP4 antagonists can alleviate proteinuria in type 2 diabetic mice and inhibit the progression of diabetic nephropathy.
  • EP4 antagonists are useful in the treatment of arthritis, including arthritic pain as well as endometriosis, diabetic nephropathy, and overactive bladder.
  • Existing treatments for arthritis are dominated by traditional NSAIDs (non-steroidal anti-inflammatory drugs) or selective COX-2 inhibitors, which can produce cardiovascular and/or gastrointestinal side effects.
  • Selective EP4 antagonists are less likely to produce cardiovascular side effects.
  • PGE 2 persistently activates EP receptors in the tumor microenvironment (produced abundantly by tumor cells) in the tumor microenvironment (Ochs et al, J Neurochem. 2016, 136, p. 1142-1154; Zelenay, S. et al, Cell 2015, 162, p. 1257-1270), promotes the accumulation and enhances the activity of a variety of immunosuppressive cells, including type 2 tumor-associated macrophages (TAMS), Treg cells, and myeloid-derived suppressor cells (MDSCs) .
  • TAMS type 2 tumor-associated macrophages
  • Treg cells Treg cells
  • MDSCs myeloid-derived suppressor cells
  • One of the main features of the immunosuppressive tumor microenvironment is the presence of abundant MDSCs and TAMs, which in turn correlate with the development of cancers in patients with gastric, ovarian, breast, bladder, hepatocellular (HCC), head and neck, and other types of cancer. was closely related to poor overall survival.
  • PGE 2 has been reported to induce immune tolerance by inhibiting the accumulation of antigen-presenting dendritic cells (DCs) in tumors and inhibiting the activation of tumor-infiltrating DCs (Wang et al, Trends in Molecular Medicine 2016, 22, p. .1-3). All of these PGE2 - mediated actions will collectively help tumor cells evade immune surveillance.
  • PGE 2 plays an important role in promoting tumorigenesis and development.
  • EP2 and EP4 have been found to be elevated in various malignant tumors, including colon cancer, lung cancer, breast cancer, and head and neck cancer, and are often closely related to poor prognosis (Bhooshan, N. et al. al. Lung Cancer 101, 88-91). Therefore, selectively blocking the EP2 and EP4 signaling pathways can inhibit the occurrence and development of tumors by changing the tumor microenvironment and regulating tumor immune cells.
  • E7046 an EP4 antagonist developed by Eisai
  • Phase Ib Phase Ib clinical trial in combination with radiotherapy or chemoradiotherapy for rectal cancer in 2017.
  • ONO-4578 developed by Ono Pharmaceutical was launched in 2017 for a phase I clinical study of advanced or metastatic solid tumors, and in 2018, a phase I/II clinical trial for the treatment of advanced solid tumors as a single agent or in combination with nivolumab was launched.
  • EP4 antagonists have made certain progress in the treatment of inflammatory diseases, pain, cancer and other fields, but there is still a need to further develop new drugs as improvements or replacements of current drugs.
  • the present invention aims to provide a compound that can effectively antagonize EP4, which can be used as an improvement or replacement of current drugs or EP4 antagonists.
  • the present invention proposes a compound, which is a compound represented by formula (I), or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable compound represented by formula (I)
  • R 1 is selected from H or halogen; halogen is selected from F, Cl, Br, I.
  • the compounds according to the embodiments of the present invention can effectively antagonize EP4 receptors, have better pharmacokinetic properties, higher in vivo exposure, lower administration doses, and better compliance, as EP4 receptor antagonists for EP4
  • the scientific research of receptors and the prevention and treatment of related diseases are of great significance and application prospects.
  • the compound represented by formula (I) may be further preferably any of the following compounds:
  • the pharmaceutically acceptable salt is selected from at least one of the following: sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrochloric acid, formic acid, acetic acid, propionic acid, benzenesulfonic acid, benzoic acid, benzene Acetic acid, salicylic acid, alginic acid, anthranilic acid, camphoric acid, citric acid, ethylene sulfonic acid, formic acid, fumaric acid, furoic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, isethionate acid, lactic acid, maleic acid, malic acid, mandelic acid, mucilic acid, pamoic acid, pantothenic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, p-toluenesulfonic acid, malonic acid, 2-hydroxypropionic acid , oxalic acid,
  • the present invention can also employ other salt types that can be used as intermediates or useful in the purification of compounds or in the preparation of other pharmaceutically acceptable salts for the identification, characterization or purification of the compounds of the present invention.
  • the present invention provides a pharmaceutical composition.
  • the pharmaceutical composition comprises: a pharmaceutically acceptable excipient and the aforementioned compound.
  • the pharmaceutical compositions according to the embodiments of the present invention can effectively antagonize EP4 receptors, have better pharmacokinetic properties, higher in vivo exposure, lower dosages, and better compliance, as EP4 receptor antagonists It has important significance and application prospects for the scientific research of EP4 receptor and the prevention and treatment of related diseases.
  • the present invention proposes the use of the aforementioned compound or the aforementioned pharmaceutical composition in the preparation of a medicament.
  • the medicament is used for treating or preventing EP4-related diseases.
  • the compounds or pharmaceutical compositions according to the embodiments of the present invention can effectively antagonize EP4 receptors, so that they can be used to prevent or treat EP4 receptor-related diseases.
  • the use may further include at least one of the following additional technical features:
  • the medicament is used to treat or prevent a disease selected from at least one of the following: inflammatory disease, pain, cancer, metabolic disease, and urinary system disease.
  • the inflammatory disease includes at least one selected from the group consisting of arthritis, rheumatoid arthritis.
  • the pain includes osteoarthritis pain, pain caused by endometriosis.
  • the medicament is administered in combination with radiotherapy and/or antibody therapy, wherein the antibody therapy is selected from one or a combination of CTLA4 antibody therapy, PDL1 antibody therapy and PD1 antibody therapy.
  • the cancer comprises solid cancer.
  • the cancer includes breast cancer, cervical cancer, colorectal cancer, endometrial cancer, glioblastoma, head and neck cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, ovarian cancer, Cancer of the pancreas, prostate, skin and/or urethra.
  • the metabolic disease includes diabetes
  • the urinary system disease includes overactive bladder.
  • the drug is suitable for inhibiting EP4 receptor calcium flux; the drug is suitable for binding to EP4 receptor.
  • the present invention proposes a series of EP4 antagonists with novel structure, better pharmacokinetic properties, better efficacy and good druggability, which can effectively treat EP4-related diseases or conditions.
  • the present invention provides a method for treating or preventing EP4 receptor-related diseases.
  • the method comprises: administering to a subject a compound or pharmaceutical composition as previously described.
  • the methods according to the embodiments of the present invention can have a better effect of preventing or treating EP4-related diseases.
  • the EP4 receptor-related disease is selected from at least one of the following diseases: inflammatory disease, pain, cancer, metabolic disease, and urinary system disease.
  • the inflammatory disease is selected from arthritis, rheumatoid arthritis; the pain is selected from osteoarthritis pain, pain caused by endometriosis; the cancer is selected from solid cancer;
  • the metabolic disease is diabetes, and the urinary system disease is selected from overactive bladder.
  • the cancer is selected from breast cancer, cervical cancer, colorectal cancer, endometrial cancer, glioblastoma, head and neck cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, ovarian cancer , pancreatic, prostate, skin and/or urethral cancer.
  • the subject is administered radiation therapy and/or antibody therapy in combination.
  • the antibody therapy is selected from one or a combination of CTLA4 antibody therapy, PDL1 antibody therapy and PD1 antibody therapy.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without more toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts derived from inorganic bases include but are not limited to metal salts formed from Al, Ca, Li, Mg, K, Na and Zn; salts derived from organic bases include but are not limited to salts of primary, secondary or tertiary amines, including Naturally occurring substituted or unsubstituted amines, cyclic amines and basic ion exchange resins such as ammonium, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, Dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, caffeine, procaine, choline, betaine, benzyl penicillin, ethylenediamine, glucos
  • salts are also contemplated by the present invention. They may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or may be used in the identification, characterization or purification of the compounds of the present invention.
  • stereoisomer refers to isomers that result from different arrangements of atoms in a molecule in space.
  • Stereochemistry definitions and conventions used herein are generally in accordance with SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds”, defined by John Wiley & Sons, Inc., New York, 1994.
  • the compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms.
  • a specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often referred to as a mixture of enantiomers.
  • a 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or method Spin body.
  • the compounds of the present invention may exist as one of the possible isomers or as a mixture thereof, for example, as pure optical isomers, or as mixtures of isomers, such as racemic and non-isomeric isomers.
  • Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques.
  • the substituent may be of E or Z configuration; if the compound contains a disubstituted cycloalkyl, the substituent of the cycloalkyl may be cis or trans (cis- or trans-) structure.
  • Compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Resolution of racemic mixtures of compounds can be carried out by any of a number of methods known in the art. Exemplary methods include fractional recrystallization using chiral resolving acids, which are optically active salt-forming organic acids. Suitable resolving agents for the fractional recrystallization process are, for example, optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acids such as ⁇ - D and L forms of camphorsulfonic acid.
  • optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acids such as ⁇ - D and L forms of camphorsulfonic
  • resolving agents suitable for fractional crystallization methods include ⁇ -methyl-benzylamine in stereoisomerically pure form (eg, S and R forms or diastereomerically pure form), 2-phenylglycinol, Norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc.
  • Resolution of the racemic mixture can also be performed by elution on a column packed with an optically active resolving agent (eg, dinitrobenzoylphenylglycine). It can be carried out by high performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC).
  • tautomer refers to an isomer of a functional group resulting from the rapid movement of an atom in two positions in a molecule.
  • the compounds of the present invention may exhibit tautomerism.
  • Tautomeric compounds can exist as two or more interconvertible species.
  • Proton tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms.
  • Tautomers generally exist in equilibrium, and attempts to separate individual tautomers usually result in a mixture whose physicochemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule.
  • the ketone form predominates; in phenols, the enol form predominates.
  • the present invention encompasses all tautomeric forms of the compounds.
  • composition means a mixture of one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as a physiologically/pharmaceutically acceptable carrier and excipients.
  • the purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.
  • solvate means that a compound of the present invention or a salt thereof includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces, and when the solvent is water, it is a hydrate.
  • prodrug refers to a compound of the invention that can be converted under physiological conditions or by solvolysis to a biologically active compound.
  • the prodrugs of the present invention are prepared by modifying functional groups in the compounds, which modifications can be removed by conventional procedures or in vivo to yield the parent compounds.
  • Prodrugs include compounds formed by connecting a hydroxyl or amino group in the compounds of the present invention to any group. When the prodrugs of the compounds of the present invention are administered to mammalian individuals, the prodrugs are cleaved to form free hydroxyl, free the amino group.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
  • excipient refers to a pharmaceutically acceptable inert ingredient.
  • classes of the term “excipient” include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of a pharmaceutical formulation, ie make the formulation more suitable for direct compression by increasing flowability and/or stickiness.
  • Examples of typical "pharmaceutically acceptable carriers" suitable for use in the above formulations are: carbohydrates such as lactose, sucrose, mannitol and sorbitol; starches such as corn starch, tapioca starch and potato starch; cellulose and derivatives thereof compounds such as sodium carboxymethylcellulose, ethylcellulose and methylcellulose; calcium phosphates such as dicalcium phosphate and tricalcium phosphate; sodium sulfate; calcium sulfate; polyvinylpyrrolidone; polyvinyl alcohol; stearic acid ; alkaline earth metal stearate salts such as magnesium stearate and calcium stearate; stearic acid; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil; nonionic, cationic and anionic surfactants Glycol polymers; fatty alcohols; and cereal hydrolyzed solids and other non-toxic compatible fillers, binders, disintegrants, buffers, pre
  • the compounds or pharmaceutical compositions of the present invention can effectively antagonize EP4 receptor activity, have better pharmacokinetic properties, higher in vivo exposure, lower dosage and better compliance . It has broad application prospects in the scientific research of EP4 receptor and the preparation of drugs for preventing or treating EP4-related diseases.
  • the compounds of the present invention are identified by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the units of NMR shifts are 10-6 (ppm).
  • the solvents for NMR measurement are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS).
  • Liquid-mass spectrometry was determined by Waters Acquity H-class UPLC-SQD2 mass spectrometer and monitored using Ultimate UHPLC XB C18 1.8um 2.1mm*50mm chromatographic column.
  • Gradient elution condition 1 run at a flow rate of 0.6 mL/min for 3.0 min, start with 5% solvent B1 for 0.2 min, increase from 5% solvent B1 to 95% solvent B1 within 1.3 min, and then keep 95% solvent B1 for 1.0 min, 0.1 It is reduced to 5% solvent B1 within min, and then 5% solvent B1 is maintained for 0.4min, and the percentage is the volume percentage of a certain solvent in the total solvent volume.
  • solvent A1 an aqueous solution of 0.05% formic acid
  • solvent B1 an acetonitrile solution of 0.05% formic acid.
  • the percentage is the volume percent of the solute in the solution.
  • Injection volume determined by the concentration of the reaction solution, generally 1.0mg/mL concentration sample, injection 1 ⁇ L; detection wavelength: 254/214/280nm; chromatographic column temperature: 40°C; sample tray temperature 25°C; Source: ESI source; molecular weight scan range: 150-1000; capillary voltage: 3.5kV; desolvation temperature: 650°C; ion source temperature: 150°C; cone voltage: 30V.
  • DIPEA can also be written as DIEA, diisopropylethylamine, that is, N,N-diisopropylethylamine
  • HATU 2-(7-Azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • IC 50 the half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved.
  • the reference compound was synthesized with reference to patent application WO2012039972A1.
  • control compounds in the following test examples all refer to the compounds described in Control Example 1.
  • the first step the preparation of 5-(3-bromophenol)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde (I-2B)
  • the third step (3-(difluoromethyl)-1-methyl-5-(3-(propane-1-yn-1-yl)phenoxy)-1H-pyrazole-4-carboxylic acid (I -2D) preparation
  • Preparation conditions Welch, Ultimate C18 column, 10 nm, 21.2 nm x 250 mm.
  • Mobile phase A is 1 ⁇ trifluoroacetic acid pure aqueous solution
  • mobile phase B is 1 ⁇ trifluoroacetic acid acetonitrile solution.
  • Gradient conditions 0 to 3 minutes, mobile phase A maintained at 90%, 3 to 18 minutes for gradient elution, from 90% to 5%, and 18 to 22 minutes to maintain 5%.
  • Test Example 1 Determination of Inhibitory Effect on EP4 Receptor Calcium Flux
  • Inhibition rate (%) 100-(test group-EP4 complete antagonist group)/(DMSO group-EP4 complete antagonist group)*100
  • the IC50 values of the compounds for the inhibition of EP4 calcium flux ie, the drug concentration when the intracellular Ca 2+ flux is inhibited by half after the overexpression of human EP4 receptors
  • Test Example 2 Radioligand EP4 Receptor Binding Assay
  • Radioligand EP4 binding assays were performed using recombinant human EP4 receptor membrane protein (prepared from 293 cells overexpressing human EP4 receptor). Compounds to be tested and PGE 2 were prepared as 10 mM stock solutions in DMSO solvent, and then 8 concentration point 4x working solutions were serially diluted in buffer (50 mM HBSS, 0.1% BSA, 500 mM NaCl).
  • the reaction mixture was filtered through a GF/C plate using a Perkin Elmer Filtermate Harvester, then the filter plate was washed and dried at 50°C for 1 hour. After drying, the bottom of the filter plate wells were sealed using Perkin Elmer Unifilter-96 sealing tape, and 50 ⁇ L of MicroScint TM -20 cocktail (Perkin Elmer) was added to seal the top of the filter plate. 3H counts captured on the filters were read using a Perkin Elmer MicroBeta2 Reader.
  • Inhibition rate (%) 100-(test group-PGE 2 group)/(DMSO group-PGE 2 group)*100
  • the IC50 and Ki values of the compounds determined by the binding of the radioligand EP4 were calculated.
  • test compound IC50 (nM) Ki(nM) control compound 30 16 Compound I-1 9.1 5.0
  • the experimental results show that, compared with the control compound, the compound of the present invention has better affinity with the EP4 receptor, and is better than the control compound, and the compound of the present invention shows a better affinity for the EP4 receptor.
  • mice Pharmacokinetic test in mice, using male ICR mice, 20-25 g, fasted overnight. Three mice were taken and administered orally orally at 5 mg/kg. Blood was collected before administration and at 15, 30 minutes and 1, 2, 4, 8, and 24 hours after administration; another 3 mice were taken and administered 1 mg/kg intravenously, before and after administration Blood was collected at 15, 30 minutes and 1, 2, 4, 8, and 24 hours. Blood samples were centrifuged at 6800g at 2-8°C for 6 minutes, and plasma was collected and stored at -80°C.
  • the experimental results show that, compared with the control compound, the compound of the present invention has a lower or equivalent clearance rate by intravenous administration, and a higher or equivalent exposure by oral administration, and the exposure in mice after oral administration is about 4 times that of the control compound, After oral administration to dogs, the exposure is about twice that of the control compound, and the compound of the present invention exhibits better pharmacokinetic properties and good druggability.

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Abstract

L'invention concerne un composé capable d'antagoniser de manière efficace un récepteur EP4, ledit composé étant un composé représenté par la formule (I), et un tautomère, un stéréoisomère, un hydrate, un solvate, un sel pharmaceutiquement acceptable ou un promédicament de celui-ci, R1 étant choisi parmi H ou un halogène, et l'halogène étant choisi parmi F, Cl, Br et I.
PCT/CN2021/113207 2020-08-18 2021-08-18 Dérivé de pyrazolamide servant d'antagoniste du récepteur ep4 et son utilisation dans la préparation de médicaments pour le traitement du cancer et de l'inflammation WO2022037601A1 (fr)

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PCT/CN2021/113207 WO2022037601A1 (fr) 2020-08-18 2021-08-18 Dérivé de pyrazolamide servant d'antagoniste du récepteur ep4 et son utilisation dans la préparation de médicaments pour le traitement du cancer et de l'inflammation

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1950333A (zh) * 2004-05-04 2007-04-18 辉瑞大药厂 取代的甲基芳基或杂芳基酰胺化合物
CN103097358A (zh) * 2010-09-21 2013-05-08 卫材R&D管理有限公司 药物组合物
CN106572993A (zh) * 2014-05-23 2017-04-19 卫材R&D管理有限公司 用于治疗癌症的组合疗法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1950333A (zh) * 2004-05-04 2007-04-18 辉瑞大药厂 取代的甲基芳基或杂芳基酰胺化合物
CN103097358A (zh) * 2010-09-21 2013-05-08 卫材R&D管理有限公司 药物组合物
CN106572993A (zh) * 2014-05-23 2017-04-19 卫材R&D管理有限公司 用于治疗癌症的组合疗法

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