[go: up one dir, main page]

WO2025119390A1 - Antagoniste du récepteur p2x7 - Google Patents

Antagoniste du récepteur p2x7 Download PDF

Info

Publication number
WO2025119390A1
WO2025119390A1 PCT/CN2024/137672 CN2024137672W WO2025119390A1 WO 2025119390 A1 WO2025119390 A1 WO 2025119390A1 CN 2024137672 W CN2024137672 W CN 2024137672W WO 2025119390 A1 WO2025119390 A1 WO 2025119390A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
alkyl
membered
alkoxy
halogenated
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2024/137672
Other languages
English (en)
Chinese (zh)
Inventor
叶昊宇
张芮佳
苏凯月
马良
吴文爽
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sichuan University
Original Assignee
Sichuan University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sichuan University filed Critical Sichuan University
Publication of WO2025119390A1 publication Critical patent/WO2025119390A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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
    • 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
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present application belongs to the field of chemical drugs, and specifically relates to a P2X7 receptor antagonist.
  • Buenstock et al. found that ATP exerts its effects by acting on the purine receptor P2, and divided the ATP-sensitive P2 receptors into two types: ligand-gated ion channel P2X type and G protein-coupled P2Y type. According to the differences in P2X receptor components and signal transduction, 7 subtypes (P2X1-7) can be cloned in mammalian cells.
  • P2X7 is a special subtype of the purinergic receptor P2X, which is a non-selective cation channel receptor excited by high concentrations of extracellular ATP.
  • P2X receptors have the most basic structure, which consists of two transmembrane regions: the intracellular amino terminus (N-terminus) and the carboxyl terminus (C-terminus) and the extracellular cysteine residue ring. The difference is that the P2X7 receptor consists of 595 amino acid residues in its entirety, and its C-terminus is the longest among all family members (consisting of 239 amino acids).
  • P2X7 receptors are widely distributed in mammals. After activation, they can induce the maturation and release of cytokines such as IL-1 ⁇ and IL-18, plasma membrane reorganization, extracellular domain shedding and cell death, and may play the role of a "crisis response sensor" in the body.
  • the P2X7 receptor is widely distributed in tissues and organs such as the brain, kidney, liver, lung, and spleen.
  • the receptor is expressed in a variety of immune-related cells such as monocytes, macrophages, lymphocytes, mast cells, and neutrophils. Due to the wide distribution of the P2X7 receptor, it is associated with a variety of diseases such as central nervous system (CNS) diseases, inflammatory bowel disease, hepatitis, inflammatory pain, kidney injury, rheumatoid arthritis (RA), and cardiovascular disease. It is an emerging target for the treatment of inflammation and other related diseases.
  • CNS central nervous system
  • RA rheumatoid arthritis
  • JNJ47965567 is a commercially available P2X7 receptor antagonist that has good antagonistic effects on both human and rat P2X7.
  • JNJ47965567 has poor metabolic stability and pharmacokinetic properties, which reduces the therapeutic effect of the drug.
  • the purpose of the present application is to provide a new P2X7 receptor antagonist.
  • the present application provides a compound represented by Formula I, a salt thereof, an isotope compound thereof, a stereoisomer thereof or a hydrate thereof:
  • n 0, 1, 2 or 3;
  • R 1 is selected from the following groups substituted by one or more R 1a : 5-6 membered aryl, 5-6 membered heteroaryl, 3-8 membered saturated cycloalkyl, 3-8 membered saturated heterocyclic group; R 1a is independently selected from hydrogen, cyano, halogen, hydroxyl, amino, C 1-8 alkyl, nitro, carboxyl, 3-8 membered cycloalkyl, halogenated C 1-8 alkyl, C 1-8 alkoxy, halogenated C 1-8 alkoxy, SO 2 R 1b ; R 1b is selected from C 1-8 alkyl;
  • Y is CH
  • X is N, R2 is none;
  • R3 is selected from hydrogen, cyano, halogen, hydroxyl, amino, C1-8 alkyl, halogenated C1-8 alkyl, C1-8 alkoxy, halogenated C1-8 alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered aryl or 5-10 membered heteroaryl;
  • R4 is selected from the following groups substituted by one or more substituents: 5-6 membered aryl, 5-6 membered heteroaryl, fused heterocyclic group; the substituents are each independently selected from hydrogen, cyano, halogen, hydroxyl, amino, C1-8 alkyl, 3-8 membered cycloalkyl, halogenated C1-8 alkyl, C1-8 alkoxy , halogenated C1-8 alkoxy, SH, the following groups substituted by j Rh : SRk , 5-6 membered aryl, 5-6 membered heteroaryl, 5-6 membered saturated cycloalkyl, 5-6 membered saturated heterocyclic group, Rk is selected from 5- to 6-membered aryl, 5- to 6-membered heteroaryl,
  • j 0, 1, 2, or 3;
  • R h is each independently selected from hydrogen, halogen, hydroxyl, C 1-8 alkyl, halogenated C 1-8 alkyl, C 1-8 alkoxy, halogenated C 1-8 alkoxy, cyano, amino, NHR 4c , NR 4c R 4c , NHSO 2 R 4c , SO 2 R 4c , MSO 2 R 4c , MNHSO 2 R 4c ; M is selected from 5-6 membered aryl and 5-6 membered heteroaryl, and R 4c is selected from C 1-8 alkyl, 3-8 membered saturated cycloalkyl and 3-8 membered saturated heterocyclic group.
  • R 1 is selected from the following groups substituted by one or more R 1a : 5- to 6-membered aryl groups and 5- to 6-membered heteroaryl groups.
  • R 1 is selected from the following groups substituted by one or more R 1a :
  • R 1 is selected from the following groups substituted by one or more R 1a : R 1a is independently selected from halogen, halogenated C 1-8 alkyl, C 1-8 alkoxy, and 3- to 8-membered cycloalkyl.
  • R 1a is independently selected from halogen, trifluoromethyl, methoxy, and cyclopropyl.
  • the halogen is selected from chlorine and bromine.
  • R 3 is selected from hydrogen, C 1-5 alkyl, halogenated C 1-5 alkyl, C 1-5 alkoxy, and halogenated C 1-5 alkoxy.
  • R 3 is selected from hydrogen and C 1-8 alkyl.
  • R 3 is selected from C 1-8 alkyl.
  • R3 is selected from methyl.
  • R 4 is selected from a 5- to 6-membered heteroaryl group or a fused heterocyclic group substituted with one or two or more of the above substituents.
  • R4 is selected from the following groups substituted by one or two or more of the substituents:
  • R 4 is selected from a 5-membered heteroaryl group substituted with one or two or more of the substituents.
  • R4 is selected from the following groups substituted by one or two or more substituents:
  • the substituent is selected from the following groups substituted by j R h : 5- to 6-membered aryl group, 5- to 6-membered heteroaryl group, 5- to 6-membered saturated cycloalkyl group, and 5- to 6-membered saturated heterocyclic group.
  • the substituent is selected from a 6-membered aryl group substituted with j R h .
  • j is 1, R h is selected from NHR 4c , NR 4c R 4c , NHSO 2 R 4c , SO 2 R 4c , MSO 2 R 4c , MNHSO 2 R 4c ; M is selected from 5- to 6-membered aryl and 5- to 6-membered heteroaryl; and R 4c is selected from C 1-8 alkyl, 3- to 8-membered saturated cycloalkyl and 3- to 8-membered saturated heterocyclic group.
  • R h is selected from MSO 2 R 4c
  • M is selected from 5- to 6-membered aryl and 5- to 6-membered heteroaryl
  • R 4c is selected from C 1-8 alkyl, 3- to 8-membered saturated cycloalkyl, and 3- to 8-membered saturated heterocyclic group.
  • the structure of the compound is as shown in Formula II:
  • n 0, 1 or 2;
  • R s6 , R s7 , R s8 , R s9 , and R s10 are each independently selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, carboxyl, C 1-5 alkyl, halogenated C 1-5 alkyl, C 1-5 alkoxy, halogenated C 1-5 alkoxy , and 3-8 membered cycloalkyl;
  • R3 is selected from hydrogen, cyano, halogen, hydroxyl, amino, C1-8 alkyl, halogenated C1-8 alkyl, C1-8 alkoxy, halogenated C1-8 alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered aryl or 5-10 membered heteroaryl;
  • R4 is selected from the following groups substituted by one or more substituents: 5-6 membered aryl, 5-6 membered heteroaryl, fused heterocyclic group; the substituents are each independently selected from hydrogen, cyano, halogen, hydroxyl, amino, C1-8 alkyl, 3-8 membered cycloalkyl, halogenated C1-8 alkyl, C1-8 alkoxy , halogenated C1-8 alkoxy, SH, the following groups substituted by j Rh : SRk , 5-6 membered aryl, 5-6 membered heteroaryl, 5-6 membered saturated cycloalkyl, 5-6 membered saturated heterocyclic group, Rk is selected from 5- to 6-membered aryl, 5- to 6-membered heteroaryl,
  • j 0, 1, 2, or 3;
  • R h is each independently selected from hydrogen, halogen, hydroxyl, C 1-8 alkyl, halogenated C 1-8 alkyl, C 1-8 alkoxy, halogenated C 1-8 alkoxy, cyano, amino, NHR 4c , NR 4c R 4c , NHSO 2 R 4c , SO 2 R 4c , MSO 2 R 4c , MNHSO 2 R 4c ; M is selected from 5-6 membered aryl and 5-6 membered heteroaryl, and R 4c is selected from C 1-8 alkyl, 3-8 membered saturated cycloalkyl and 3-8 membered saturated heterocyclic group.
  • Y6 is N; Y7 is CRs7 ; Y8 is CRs8 ; Y9 is CRs9 ; Y10 is CRs10 ; Rs6 , Rs7 , Rs8 , and Rs10 are each independently selected from hydrogen; Rs9 is selected from halogen, hydroxyl, amino, cyano, nitro, carboxyl, C1-5 alkyl, halogenated C1-5 alkyl, C1-5 alkoxy, halogenated C1-5 alkoxy, and 3-8 membered cycloalkyl; Rs9 is preferably selected from halogen, trifluoromethyl, methoxy, and cyclopropyl.
  • the structure of the compound is as shown in Formula II-1, Formula II-2 or Formula II-3:
  • n 0 or 1
  • R s6 , R s7 , R s8 , R s9 , and R s10 are each independently selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, carboxyl, C 1-5 alkyl, halogenated C 1-5 alkyl, C 1-5 alkoxy, halogenated C 1-5 alkoxy , and 3-8 membered cycloalkyl;
  • R 3 is selected from hydrogen, C 1-5 alkyl, 3-5 membered cycloalkyl
  • R 4a and R 4b are each independently selected from hydrogen, cyano, halogen, hydroxyl, amino, C 1-8 alkyl, 3-8 membered cycloalkyl, halogenated C 1-8 alkyl, C 1-8 alkoxy, halogenated C 1-8 alkoxy, the following groups substituted by j R h : 5-6 membered aryl, 5-6 membered heteroaryl, 5-6 membered saturated cycloalkyl, 5-6 membered saturated heterocyclic group,
  • j 0, 1, 2, or 3;
  • R h is each independently selected from hydrogen, halogen, hydroxyl, C 1-8 alkyl, halogenated C 1-8 alkyl, C 1-8 alkoxy, halogenated C 1-8 alkoxy, cyano, amino, NHR 4c , NR 4c R 4c , NHSO 2 R 4c , SO 2 R 4c , MSO 2 R 4c , MNHSO 2 R 4c ; M is selected from 5-6 membered aryl and 5-6 membered heteroaryl; R 4c is selected from C 1-8 alkyl, 3-8 membered saturated cycloalkyl and 3-8 membered saturated heterocyclic group.
  • the substituent is selected from the following groups substituted by j R h : 5- to 6-membered aryl group, 5- to 6-membered heteroaryl group, 5- to 6-membered saturated cycloalkyl group, and 5- to 6-membered saturated heterocyclic group.
  • R 4a and R 4b are each independently selected from a 6-membered aryl group substituted with j R h .
  • j is 1, and R h is selected from NHR 4c , NR 4c R 4c , NHSO 2 R 4c , SO 2 R 4c , MSO 2 R 4c , and MNHSO 2 R 4c ;
  • M is selected from 5- to 6-membered aryl and 5- to 6-membered heteroaryl;
  • R 4c is selected from C 1-8 alkyl, 3- to 8-membered saturated cycloalkyl, and 3- to 8-membered saturated heterocyclic group;
  • R h is selected from MSO 2 R 4c , M is selected from 5- to 6-membered aryl and 5- to 6-membered heteroaryl, and R 4c is selected from C 1-8 alkyl, 3- to 8-membered saturated cycloalkyl, and 3- to 8-membered saturated heterocyclic group.
  • R 4a is selected from hydrogen
  • R 4b is selected from hydrogen
  • the structure of the compound is as shown in Formula II-4 or Formula II-5:
  • R3 is selected from hydrogen, C1-3 alkyl
  • RS is selected from hydrogen, halogen, C1-3 alkyl, halogenated C1-3 alkyl , C1-3 alkoxy, halogenated C1-3 alkoxy, 3-5 membered saturated cycloalkyl
  • R s is selected from hydrogen, cyano, halogen, hydroxyl, amino, C 1-8 alkyl, nitro, carboxyl, 3-8 membered cycloalkyl, halogenated C 1-8 alkyl, C 1-8 alkoxy, halogenated C 1-8 alkoxy, SO 2 R 1b ; R 1b is selected from C 1-8 alkyl.
  • the structure of the compound is as shown in Formula II-6, Formula II-7, Formula II-8 or Formula II-9:
  • Rs is selected from hydrogen, halogen, C1-3 alkyl, halogenated C1-3 alkyl, C1-3 alkoxy, halogenated C1-3 alkoxy, 3-5 membered saturated cycloalkyl.
  • R s is selected from halogen, trifluoromethyl, methoxy, and cyclopropyl.
  • R s is selected from halogen and trifluoromethyl.
  • the structure of the compound is as shown in Formula II-6-1, Formula II-7-1, Formula II-8-1 or Formula II-9-1:
  • R s is selected from halogen, trifluoromethyl, methoxy, and cyclopropyl; in one embodiment, R s is selected from halogen and trifluoromethyl.
  • the compound is one of the following compounds:
  • the present application also provides a pharmaceutical composition, which is a preparation prepared by using the above-mentioned compound, its salt, its isotope compound, its stereoisomer or its hydrate as an active ingredient and adding pharmaceutically acceptable excipients.
  • the present application also provides the use of the above-mentioned compound, its salt, its isotope compound, its stereoisomer or its hydrate in the preparation of P2X7 receptor antagonist.
  • the P2X7 receptor antagonist is a drug that antagonizes the activity of the P2X7 receptor.
  • the P2X7 receptor antagonist is a drug for treating inflammation and inflammation-related diseases, kidney disease, gout, respiratory diseases, cancer, pain, central nervous system diseases, radiation brain damage, cerebral ischemia, myocardial damage, diabetes, depression, lupus erythematosus, atherosclerosis, and allergic asthma.
  • the inflammation and inflammation-related diseases are selected from neurological inflammation, arthritis, colitis, pancreatitis fibrosis, alcoholic fatty hepatitis, bronchitis, pneumonia, lumbar spondylitis, and vasculitis.
  • the kidney disease is selected from primary glomerular disease, secondary glomerular disease, interstitial nephritis, tubular disease, renal vascular disease, hereditary kidney disease, acute kidney injury caused by ischemia-reperfusion, acute kidney injury caused by sepsis, drug-induced acute kidney injury, contrast agent-induced acute kidney injury, and chronic renal failure; more preferably, the primary glomerular disease is selected from focal segmental glomerulosclerosis, crescentic nephritis, minimal change nephropathy, IgA nephropathy, and membranous nephropathy; more preferably, the secondary glomerular disease is selected from ANCA-associated vasculitis, hypertensive nephropathy, diabetic nephropathy, hepatitis B-related nephritis, lupus nephritis, purpura nephritis, hyperuricemia nephropathy, and lipoprotein nephropathy; more
  • the respiratory disease is selected from airway obstructive diseases, more preferably bronchial asthma, allergic asthma, intrinsic asthma, exogenous asthma, exercise-induced asthma, and drug-induced asthma.
  • airway obstructive diseases more preferably bronchial asthma, allergic asthma, intrinsic asthma, exogenous asthma, exercise-induced asthma, and drug-induced asthma.
  • the cancer is selected from prostate cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, intestinal cancer, colon cancer, gastric cancer, skin cancer, brain tumor, leukemia, lymphoma.
  • the pain is selected from headache, migraine, trigeminal neuralgia, atypical facial pain, joint and bone pain, pain caused by cancer and tumor invasion, and neuropathic pain syndrome.
  • the central nervous system disease is selected from Alzheimer's disease, Parkinson's syndrome, epilepsy, multiple sclerosis and other demyelinating syndromes, cerebral atherosclerosis, myasthenia gravis.
  • the lupus erythematosus is systemic lupus erythematosus.
  • the present application also provides the use of the compound, its salt, its isotope compound, its stereoisomer or its hydrate in treating diseases related to P2X7 receptor.
  • the diseases associated with P2X7 receptors are drugs for inflammation and inflammation-related diseases, kidney diseases, respiratory diseases, cancer, pain, central nervous system diseases, radiation brain damage, cerebral ischemia, myocardial damage, diabetes, depression, lupus erythematosus, atherosclerosis, and allergic asthma.
  • the inflammation and inflammation-related diseases are selected from neurological inflammation, arthritis, colitis, pancreatitis fibrosis, alcoholic fatty hepatitis, bronchitis, pneumonia, lumbar spondylitis, and vasculitis.
  • the gout is selected from acute gouty arthritis, intermittent gout, chronic gout, hyperuricemia, secondary gout, gouty nephropathy, and urinary tract stones.
  • the respiratory disease is selected from airway obstructive diseases, more preferably bronchial asthma, allergic asthma, intrinsic asthma, exogenous asthma, exercise-induced asthma, and drug-induced asthma.
  • airway obstructive diseases more preferably bronchial asthma, allergic asthma, intrinsic asthma, exogenous asthma, exercise-induced asthma, and drug-induced asthma.
  • the kidney disease is selected from primary glomerular disease, secondary glomerular disease, interstitial nephritis, tubular disease, renal vascular disease, hereditary kidney disease, acute kidney injury caused by ischemia-reperfusion, acute kidney injury caused by sepsis, drug-induced acute kidney injury, contrast agent-induced acute kidney injury, and chronic renal failure; more preferably, the primary glomerular disease is selected from focal segmental glomerulosclerosis, crescentic nephritis, minimal change nephropathy, IgA nephropathy, and membranous nephropathy; more preferably, the secondary glomerular disease is selected from ANCA-associated vasculitis, hypertensive nephropathy, diabetic nephropathy, hepatitis B-related nephritis, lupus nephritis, purpura nephritis, hyperuricemia nephropathy, and lipoprotein nephropathy; more
  • the cancer is selected from prostate cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, intestinal cancer, colon cancer, gastric cancer, skin cancer, brain tumor, leukemia, lymphoma.
  • the pain is selected from headache, migraine, trigeminal neuralgia, atypical facial pain, joint and bone pain, pain caused by cancer and tumor invasion, and neuropathic pain syndrome.
  • the central nervous system disease is selected from Alzheimer's disease, Parkinson's syndrome, epilepsy, multiple sclerosis and other demyelinating syndromes, cerebral atherosclerosis, myasthenia gravis.
  • the lupus erythematosus is systemic lupus erythematosus.
  • the present application also provides the use of the compound, its salt, its isotope compound, its stereoisomer or its hydrate in the method of treating diseases related to P2X7 receptor.
  • the diseases associated with P2X7 receptors are drugs for inflammation and inflammation-related diseases, kidney diseases, respiratory diseases, cancer, pain, central nervous system diseases, radiation brain damage, cerebral ischemia, myocardial damage, diabetes, depression, lupus erythematosus, atherosclerosis, and allergic asthma.
  • the inflammation and inflammation-related diseases are selected from neurological inflammation, arthritis, colitis, pancreatitis fibrosis, alcoholic fatty hepatitis, bronchitis, pneumonia, lumbar spondylitis, and vasculitis.
  • the gout is selected from acute gouty arthritis, intermittent gout, chronic gout, hyperuricemia, secondary gout, gouty nephropathy, and urinary tract stones.
  • the respiratory disease is selected from airway obstructive diseases, more preferably bronchial asthma, allergic asthma, intrinsic asthma, exogenous asthma, exercise-induced asthma, and drug-induced asthma.
  • airway obstructive diseases more preferably bronchial asthma, allergic asthma, intrinsic asthma, exogenous asthma, exercise-induced asthma, and drug-induced asthma.
  • the kidney disease is selected from primary glomerular disease, secondary glomerular disease, interstitial nephritis, tubular disease, renal vascular disease, hereditary kidney disease, acute kidney injury caused by ischemia-reperfusion, acute kidney injury caused by sepsis, drug-induced acute kidney injury, contrast agent-induced acute kidney injury, and chronic renal failure; more preferably, the primary glomerular disease is selected from focal segmental glomerulosclerosis, crescentic nephritis, minimal change nephropathy, IgA nephropathy, and membranous nephropathy; more preferably, the secondary glomerular disease is selected from ANCA-associated vasculitis, hypertensive nephropathy, diabetic nephropathy, hepatitis B-related nephritis, lupus nephritis, purpura nephritis, hyperuricemia nephropathy, and lipoprotein nephropathy; more
  • the cancer is selected from prostate cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, intestinal cancer, colon cancer, gastric cancer, skin cancer, brain tumor, leukemia, lymphoma.
  • the pain is selected from headache, migraine, trigeminal neuralgia, atypical facial pain, joint and bone pain, pain caused by cancer and tumor invasion, and neuropathic pain syndrome.
  • the central nervous system disease is selected from Alzheimer's disease, Parkinson's syndrome, epilepsy, multiple sclerosis and other demyelinating syndromes, cerebral atherosclerosis, myasthenia gravis.
  • the lupus erythematosus is systemic lupus erythematosus.
  • C a ⁇ b alkyl represents any alkyl group containing "a" to "b" carbon atoms.
  • C 1 ⁇ 8 alkyl refers to a straight or branched alkyl group containing 1 to 8 carbon atoms, such as methyl, ethyl, propyl, butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, heptyl, octyl, and isomers of hexyl, heptyl, and octyl.
  • aryl refers to an all-carbon monocyclic or fused polycyclic (i.e., a ring that shares adjacent pairs of carbon atoms) group with a conjugated ⁇ electron system, wherein the aryl ring may be fused to other cyclic groups (including saturated and unsaturated rings), but may not contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of connection to the parent must be on a carbon atom on the ring with a conjugated ⁇ electron system.
  • Aryl may be substituted or unsubstituted.
  • heteroaryl refers to a heteroaromatic group containing one to two or more heteroatoms.
  • the heteroatoms referred to here include nitrogen, oxygen, sulfur, phosphorus, etc.
  • the heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring.
  • the heteroaryl group can be optionally substituted or unsubstituted.
  • isotope compound refers to a compound obtained by replacing one or more atoms in a compound with their corresponding isotopes.
  • pharmaceutically acceptable excipients refer to auxiliary materials widely used in the field of drug production. These excipients should be non-toxic, not interfere with or damage the efficacy of the active ingredients of the drug, and can be flexibly selected according to the specific dosage form of the drug. These excipients are usually used to improve the physical properties, stability, solubility or absorbability of the drug.
  • the main purpose of using excipients is to provide a pharmaceutical composition that is safe to use, stable in nature and/or has specific functionality, while helping the active ingredients to dissolve at a desired rate or be effectively absorbed in the body.
  • excipients include, but are not limited to: excipients, which are used to increase the volume or weight of the drug to facilitate preparation molding and processing, such as cocoa butter, suppository wax, vegetable oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, soybean oil, etc.), alcohols (such as propylene glycol), esters (such as ethyl oleate, ethyl dodecanoate), etc.; binders, which are used to bind drug powder particles together to form tablets with a certain hardness and shape, such as microcrystalline cellulose, hydroxypropyl cellulose, povidone, starch, dextrin, etc.; disintegrants, which are used to quickly disintegrate tablets into fine particles after taking them, so as to facilitate drug dissolution and absorption.
  • excipients which are used to increase the volume or weight of the drug to facilitate preparation molding and processing
  • vegetable oils such as peanut oil, cottonseed oil, saf
  • Lubricants for example, cross-linked polyvinylpyrrolidone, pregelatinized starch, silicon dioxide, cross-linked sodium carboxymethylcellulose, etc.
  • Lubricants used to reduce the friction between drug particles, make tablets easier to compress and form, and reduce the resistance when taking the medicine, for example, magnesium stearate, sodium lauryl sulfate, etc.
  • Coating agents used to form a thin film on the surface of the drug to improve the taste, stability, moisture resistance or control the release rate of the drug, for example, polyacrylic acid resin (used as a coating material for tablets, pills, and granules), hydroxypropyl methylcellulose (used as a water-soluble film coating material for tablets and pills), sugar coating (such as coating made of sucrose, glucose, etc.), etc.
  • excipients such as colorants (used to color the drug for easy identification), flavoring agents (used to improve the taste of the drug), sweeteners (used to increase the sweetness of the drug), preservatives (used to prevent the drug from deteriorating), etc.
  • colorants used to color the drug for easy identification
  • flavoring agents used to improve the taste of the drug
  • sweeteners used to increase the sweetness of the drug
  • preservatives used to prevent the drug from deteriorating
  • benzalkonium chloride can be used as a preservative
  • fatty acid esters of sorbitol can be used as emulsifiers.
  • halogen is fluorine, chlorine, bromine or iodine.
  • alkoxy is usually represented by RO-, where R represents the alkyl part, and is a type of substituent in an organic compound molecule, consisting of an alkyl group and an oxygen atom, such as methyl (CH 3 -), ethyl (C 2 H 5 -), etc.
  • C 1-8 alkoxy refers to an alkoxy group with a carbon atom number ranging from 1 to 8, that is, C1 alkoxy (methoxy) to C8 alkoxy are all included in this range, such as methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, and octyloxy.
  • halogenated C 1-8 alkoxy refers to a compound in which one or more hydrogen atoms on the alkyl group in the alkoxy group are replaced by a halogen atom, such as monochloromethoxy, dichloroethoxy, octafluorooctoxy, and the like.
  • halogenated C 1-8 alkyl refers to a group formed by replacing one or more (such as 1, 2, 3, 4 or 5) hydrogen atoms in an alkyl group (a straight or branched saturated hydrocarbon group having 1 to 8 carbon atoms) with a halogen (fluorine, chlorine, bromine, iodine).
  • Alkyl is a saturated hydrocarbon group in a hydrocarbon molecule, and its general formula is C n H 2n+1 , where n is the number of carbon atoms. In this example, n ranges from 1 to 8.
  • Halogenation refers to the process in which one or more hydrogen atoms in an alkyl group are replaced by a halogen atom.
  • Halogens include fluorine (F), chlorine (Cl), bromine (Br) and iodine (I). Specific examples include: monochloromethyl (CH 2 Cl), dichloromethyl (CHCl 2 ), trifluoromethyl (CF 3 ), 1,2-dichloroethyl (CHClCH 2 Cl), trichloroethyl, and other halogenated alkyl groups: including but not limited to monobromoethyl, difluoroethyl, trifluoroethyl, monofluorocyclopropyl, difluorocyclopropyl, etc., in which some or all of the hydrogen atoms in the alkyl group are replaced by halogen atoms.
  • 3- to 8-membered cycloalkyl includes saturated and unsaturated cyclic hydrocarbon substituents, and the ring atoms of the cyclic hydrocarbon do not have heteroatoms (including but not limited to O, S or N).
  • 3- to 8-membered cycloalkyl includes saturated cycloalkyl with 3 to 8 ring atoms and unsaturated cycloalkyl with 3 to 8 ring atoms. Examples of 3- to 8-membered cycloalkyl are:
  • saturated cycloalkyl refers to a saturated hydrocarbon group with a cyclic structure, wherein the carbon atoms are connected by single bonds, and there are no double bonds or triple bonds.
  • the cyclic hydrocarbon has no heteroatoms (including but not limited to O, S or N) in the ring atoms.
  • a 3- to 8-membered saturated cycloalkyl group refers to a saturated cycloalkyl group with 3 to 8 ring atoms, such as: cyclopropyl (C 3 H 5 -), cyclobutyl (C 4 H 7 -), cyclopentyl (C 5 H 9 -), cyclohexyl (C 6 H 11 -), and norbornyl.
  • saturated heterocyclic group refers to a saturated group with a ring structure, in which the ring atoms contain at least one heteroatom (such as nitrogen, oxygen, sulfur, etc.) in addition to carbon atoms, and all bonds in the ring are single bonds, and there are no unsaturated bonds (such as double bonds or triple bonds).
  • a 3- to 8-membered saturated heterocyclic group refers to a saturated heterocyclic group with 3 to 8 ring atoms. Specific examples include: tetrahydrofuranyl, pyrrolidinyl, piperidinyl, tetrahydrothienyl, morpholinyl, etc.
  • fused heterocyclic group refers to a polycyclic heterocyclic group of 5 to 20 members (more commonly 6 to 14 members, and more preferably 7 to 10 members), wherein each ring shares a pair of adjacent carbon atoms with other rings; these rings may contain one or more double bonds, but none of the rings has a completely conjugated electron system; some or all of the ring atoms in the fused heterocyclic group are heteroatoms (such as nitrogen, oxygen, sulfur, etc.), and the remaining ring atoms are carbon.
  • the fused heterocyclic group can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups.
  • the compound of formula I provided in the present application is a P2X7 receptor antagonist, which can not only effectively antagonize the activity of the P2X7 receptor, but also has excellent metabolic stability and pharmacokinetic properties. Compared with the positive control JNJ47965567, the metabolic stability and pharmacokinetic properties of the compound of the present application are significantly improved, and the drugability is significantly better.
  • P2X7 receptor antagonists can be used to treat inflammation and inflammation-related diseases, kidney diseases, gout, respiratory diseases, cancer, pain, central nervous system diseases, radiation brain damage, cerebral ischemia, myocardial injury, diabetes, depression, lupus erythematosus, atherosclerosis, allergic asthma and other diseases. Therefore, the compound shown in Formula I, as a P2X7 receptor antagonist, can be used to prepare drugs for treating inflammation and inflammation-related diseases, kidney diseases, respiratory diseases, cancer, pain, central nervous system diseases, radiation brain damage, cerebral ischemia, myocardial injury, diabetes, depression, lupus erythematosus, atherosclerosis, allergic asthma and other diseases, and has good application prospects.
  • FIG1 is a metabolic phenotype study of compound A28 of the present application; wherein the control group represents the metabolic rate of the compound without adding any CYP450 enzyme inhibitor; the relative inhibition rate is obtained by calculating the ratio of the metabolic rate of the CYP enzyme experimental group to that of the control group;
  • FIG2 is the effect of compound A27 of the present application on hP2X7-HEK293 current activated by Bz-ATP;
  • Figure 3 shows the effect of compound A27 of the present application on ATP-induced mitochondrial damage; wherein, (A) cells were treated with ATP (3 mM) for 1 hour and then stained with MitoTracker (red), which marks mitochondrial membrane potential; (B) cells were stained with MitoSOX (red), which marks mitochondrial reactive oxygen species; the degree of mitochondrial damage was analyzed using a fluorescence microscope (NIKON Eclipse Ts2R/FL inverted microscope), the scale bar represents 100 ⁇ m, and the ratio of MitoTracker and MitoSOX was calculated; one-way ANOVA was used to analyze statistical differences: ### indicates successful modeling, ***P ⁇ 0.001;
  • Figure 5 shows that compound A27 of the present application alleviates renal fibrosis induced by adenine in CKD mice;
  • A Schematic diagram of animal experiment;
  • B H&E staining of renal tissue of each group of mice;
  • E serum creatinine level of each group of mice;
  • F Masson staining and ⁇ -SMA immunohistochemical staining of renal tissue of each group of mice;
  • adenine A839977 treatment group data are expressed as mean ⁇ SD; abbreviations: p.o., oral; i.p., intraperitoneal injection; biw., twice a week; ****P ⁇ 0.0001, ***P ⁇ 0.001;
  • SD standard deviation
  • the raw materials and equipment used in this application are all known products, which are obtained by purchasing commercially available products.
  • compounds A2-A11 can be prepared by changing the raw materials for preparing intermediate 1.
  • compounds A13-A24 can be prepared by changing the raw materials for preparing intermediate 4.
  • compounds A26 and A28-A32 can be prepared by changing the raw materials for preparing intermediate 7 and intermediate 9 or 11.
  • Test Example 1 Antagonistic activity test of compounds on P2X7 receptors
  • P2X7 receptor is mainly regulated by ATP.
  • High concentrations of ATP of 0.5 to 1 mM and above can stimulate the activation of P2X7R, leading to the opening of the receptor pores.
  • the open “macropores” can allow the uptake of organic dyes that are originally impermeable to the intracellular environment, such as hydrophilic solutes with a molecular weight of up to 900 Da (such as ethidium bromide, YO-Pro, propidium iodide (PI) or Lucifer Yellow).
  • PI was used as a fluorescent dye, and a PI dye uptake experiment was conducted.
  • HEK293 human embryonic kidney cells 293
  • ATP was used to induce cell P2X7R activation
  • fluorescent dyes were added for labeling.
  • the antagonistic activity of drugs on hP2X7R (human P2X7R) and mP2X7R (mouse P2X7R) was tested.
  • Test drugs Compounds A1-A32, with the known P2X7R antagonist JNJ47965567 as a positive control.
  • the compound was prepared into a 10 mmol/L stock solution using 100% DMSO;
  • PI was prepared into a 1 mg/ml stock solution using sterile PBS;
  • ATP was prepared into a 600 mM stock solution in sterile PBS.
  • the action concentrations of PI and ATP were 0.05g/mL and 3mM, respectively.
  • the raw data of each well were read and recorded, and the raw data were converted accordingly to calculate the antagonistic activity of each compound against hP2X7R and mP2X7R.
  • Test drugs Compounds A8, A9, A12, A19, A20, A21, A22, A24, A25, A26, A27, A28, A29, A30, A31, A32, with the known P2X7R antagonist JNJ47965567 as a positive control.
  • Test method The compound is incubated in vitro with human or mouse liver microsome solution at 37°C, with the concentration of the compound at the 0-min incubation time point being 100%, and the concentrations at other incubation time points being compared with the concentrations to obtain the remaining percentages. The natural logarithm of the remaining percentages at each time point is then linearly regressed against the incubation time to obtain the slope k.
  • Test drugs Compounds A12, A19, A25, A27, A29, with the known P2X7R antagonist JNJ47965567 as a positive control.
  • Test Examples 2 and 3 show that compared with the positive control JNJ47965567, the compounds of the present application have better drugability.
  • the plasma protein binding test was performed using a plasma matrix containing 10 ⁇ M of the drug.
  • the dialysis chamber of the dialysis plate was filled with phosphate buffered saline (PBS, pH 7.4), and an equal amount of drug-containing plasma matrix was added to the sample side. Analysis was performed after 6 hours of reaction at 37°C. After the reaction was completed, samples were taken from each compartment, treated with acetonitrile containing the internal standard SAHA and centrifuged, and the supernatant was filled into a sample injection bottle for LC-MS/MS analysis.
  • the control sample was prepared in the same way, but the dialysis step was omitted, and all experiments were repeated three times to ensure accuracy and reliability.
  • the test results are presented as the percentage of protein binding in plasma.
  • the plasma protein binding rate of compound A28 is 97.87%
  • the plasma protein binding rate of compound A25 is 98.62%
  • the plasma protein binding rate of compound A27 is 99.27%.
  • CYP450 enzyme inhibitors ticlopidine hydrochloride as an inhibitor of CYP2C19, ⁇ -naflavone as a specific selective inhibitor of CYP1A2, pilocarpine as a specific selective inhibitor of CYP2A6, sodium diethyldithiocarbamate as a specific selective inhibitor of CYP2E1, sulfaphenazole as a specific selective inhibitor of CYP2C9, quinidine as a specific selective inhibitor of CYP2C9, and quinidine as a specific selective inhibitor of CYP2C19.
  • specific CYP450 enzyme inhibitors ticlopidine hydrochloride as an inhibitor of CYP2C19, ⁇ -naflavone as a specific selective inhibitor of CYP1A2, pilocarpine as a specific selective inhibitor of CYP2A6, sodium diethyldithiocarbamate as a specific selective inhibitor of CYP2E1, sulfaphenazole as a specific
  • Ding is a specific selective inhibitor of CYP2D6, and ketoconazole is a specific selective inhibitor of CYP3A4) was incubated at 37°C.
  • the total volume of each incubation system was 200 ⁇ L, and the system included 0.1MPH7.4 phosphate buffer, NADPH regeneration system (1mMNADP, 5mM 6-phosphate glucose, 1U/mL 6-phosphate glucose dehydrogenase, 3.3mM magnesium chloride); each sample was paralleled 3 times, and the group without selective inhibitor was used as the control.
  • 3 volumes of pre-cooled acetonitrile were added to terminate the reaction.
  • LC-MS/MS was used to determine the residual concentration of the prototype drug in the incubation solution.
  • Compound A27 was prepared into a solution with a concentration of 1 mg/mL with 5% DMSO and 95% saline, and 10 mg/kg was administered orally to Balb/c male mice (3 mice at each time point) (200 ⁇ L injection volume per 20 g mouse body weight). Plasma samples and mouse kidneys were collected at 1h, 6h, 24h, 3d, 7d and 14d after administration.
  • the plasma sample was centrifuged at 4500rpm for 10 minutes, 5 ⁇ L of plasma was mixed with 100 ⁇ L of acetonitrile containing 20 ng/mL internal standard SAHA and centrifuged at 13000rpm for 10 minutes, and the supernatant was taken again, and the sample was analyzed by LC-MS/MS (ABSCIEX5500Qtrapmassspetrometer). Deionized water was added to the kidney sample, and small steel balls were added for precooling and grinding (60 Hz, 2 minutes).
  • HEK293 cell line stably expressing human P2X7 receptor (gene information: NM_002562.6) was used. These cells were cultured in DMEM medium containing 10% fetal bovine serum at 37°C and 5% CO 2. Before the patch clamp experiment, the cells were digested with 0.25% trypsin-EDTA and seeded on coverslips in 24-well plates (final volume: 500 ⁇ L) and incubated for 18 hours. The operation of the patch clamp experiment included making microelectrodes using an electrode puller, placing the coverslip in a recording chamber under an inverted microscope, and then moving the microelectrode into the extracellular fluid to measure the electrode resistance (Rpip).
  • the electrode was gently attached to the cell surface, negative pressure was applied to form a high resistance seal (G ⁇ ), and fast capacitance compensation was performed. Further negative pressure was then applied to rupture the cell membrane, establish a whole-cell recording configuration, and record slow capacitance compensation and series resistance as experimental parameters. All electrophysiological experiments were performed at room temperature.
  • the whole-cell patch clamp recording protocol for P2X7 receptor currents used gap current mode stimulation at -80 mV.
  • Cells were first treated with 100 ⁇ M BZ-ATP, followed by a 1-minute preincubation of the drug, and then mixed working solutions were added according to different concentrations.
  • the peak current of P2X7 receptor induced by drug + BZ-ATP (100 ⁇ M) was compared with the peak current induced by BZ-ATP (100 ⁇ M) alone (BZ-ATP 100 ⁇ M).
  • P2X7 receptor plays a key role in mitochondrial damage, especially under ATP stimulation.
  • ATP as an agonist of P2X7, induces intracellular calcium influx, thereby triggering mitochondrial damage and promoting the production of reactive oxygen species (ROS).
  • ROS reactive oxygen species
  • Mitochondrial damage can be identified by changes in red oxygen status and membrane potential.
  • MitoTracker staining the fluorescence of active mitochondria is stronger than that of apoptotic mitochondria. As superoxide levels increase, the fluorescence intensity of MitoSOX also increases accordingly.
  • mP2X7R-HEK293 and hP2X7R-HEK293 cells were pretreated with compound A27 for 30 minutes before 3mM ATP stimulation, and MitoTracker and MitoSOX staining were added 30 minutes before ATP stimulation. ATP stimulation lasted for 1 hour, and then the cells were washed with pre-cooled PBS and observed under a fluorescence microscope. Image analysis was completed by ImageJ software.
  • CKD adenine-induced chronic kidney disease
  • Compound A27 was administered orally at a dose of 0.3 mg/kg, 1 mg/kg or 10 mg/kg, 1 or 2 times a week, and A839977 (30 ⁇ mol/kg, intraperitoneal injection, twice a week) and pirfenidone (PFD) (250 mg/kg, oral, once a day) were selected as positive controls.
  • PFD pirfenidone
  • euthanasia was performed by cervical dislocation, and blood and kidney tissue samples were collected. Serum was separated by centrifugation at 3000 rpm for 30 minutes.
  • kidney tissue sample was quickly frozen in liquid nitrogen and stored in a -80 ° C refrigerator for Western blot and RT-qPCR analysis, and the other part was fixed in 10% formaldehyde, dehydrated and embedded in paraffin for H&E, Masson and IHC staining.
  • kidney sections were scanned at 20 times magnification using an Olympus VS200 slice scanner (Tokyo, Japan). Tubular injury was scored as follows: 0, normal; 1, percentage of injury area ⁇ 25%; 2, percentage of injury area 25%-50%; 3, percentage of injury area 51%-75%; 4, injury area >75%.
  • the positive area of Masson staining was evaluated using collagen volume fraction (CVF).
  • the positive area of immunohistochemical staining was calculated by ImageJ software (version 1.51, Wayne Rasband, National Institutes of Health, USA).
  • A27 significantly alleviated renal injury in adenine-induced CKD mice, reduced serum creatinine and BUN levels, improved renal fibrosis, and downregulated the mRNA and protein levels of pro-fibrotic markers (Figure 5A-J).
  • A27 also inhibited the activation of NLRP3 inflammasome, as shown by decreased mRNA levels of Il1b, Nlrp3, Gsdmd and Casp1, and decreased protein levels of NLRP3, activated Caspase-1, GSDMD-N and activated IL-1 ⁇ ( Figure 5K and L).
  • mice were randomly assigned to three different experimental groups and received the following treatments: (1) The control group mice were injected with 20 ⁇ L of sterile saline into the right ankle joint cavity; (2) The model group mice were first injected with 100 ⁇ L of ATP solution (10 mM) intraperitoneally, and 30 minutes later, 20 ⁇ L of MSU crystal suspension (25 mg/ml) was injected into the right ankle joint cavity; (3) The drug group mice were orally administered with A27 (10 mg/kg) 1 hour before the injection of ATP and MSU.
  • ATP solution 10 mM
  • A27 10 mg/kg
  • the inflammatory response of the mice was evaluated by measuring the ankle circumference and calculating the joint swelling index.
  • the calculation formula of the joint swelling index was: (post-treatment circumference-initial circumference)/initial circumference.
  • the present application provides a P2X7 receptor antagonist shown in formula I.
  • the compound provided in the present application not only has excellent antagonistic activity on the P2X7 receptor, but also has excellent metabolic stability and pharmacokinetic properties. Compared with the positive control JNJ47965567, the metabolic stability and pharmacokinetic properties of the compound of the present application are significantly improved, and the drugability is significantly better.
  • the compound provided in the present application can be used to prepare P2X7 receptor antagonists, as well as to prepare drugs for treating inflammation and inflammation-related diseases, kidney diseases, gout, respiratory diseases, cancer, pain, central nervous system diseases, radiation brain damage, cerebral ischemia, myocardial damage, diabetes, depression, lupus erythematosus, atherosclerosis, allergic asthma and other diseases, and has broad application prospects.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Immunology (AREA)
  • Pain & Pain Management (AREA)
  • Pulmonology (AREA)
  • Diabetes (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Hematology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Cardiology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Psychiatry (AREA)
  • Rheumatology (AREA)
  • Hospice & Palliative Care (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Psychology (AREA)
  • Oncology (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Obesity (AREA)
  • Vascular Medicine (AREA)
  • Transplantation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne le domaine des médicaments chimiques et divulgue un antagoniste du récepteur P2X7. La structure de l'antagoniste du récepteur P2X7 est telle que représentée par la formule I. Le composé représenté par la formule I selon la présente invention s'est avéré présenter non seulement une excellente activité antagoniste pour le récepteur P2X7, mais également d'excellentes stabilité métabolique et propriétés pharmacocinétiques. Par comparaison avec le témoin positif JNJ47965567, la stabilité métabolique et les propriétés pharmacocinétiques du composé selon la présente invention sont considérablement améliorées et la pharmacopotentialité est considérablement meilleure. Le composé représenté par la formule I est utilisé en tant qu'antagoniste du récepteur P2X7 et peut être utilisé pour préparer un médicament pour le traitement de maladies telles qu'une inflammation et des maladies liées à une inflammation, des maladies rénales, des maladies respiratoires, un cancer, la douleur, des maladies du système nerveux central, des lésions cérébrales induites par l'exposition à un rayonnement, une ischémie cérébrale, une lésion myocardique, le diabète, la dépression, le lupus érythémateux, l'athérosclérose et l'asthme allergique et présente de vastes perspectives d'application.
PCT/CN2024/137672 2022-12-13 2024-12-09 Antagoniste du récepteur p2x7 Pending WO2025119390A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CN202211595660 2022-12-13
CN202311673729.0 2023-12-07
CN202311673729.0A CN118184647A (zh) 2022-12-13 2023-12-07 一种p2x7受体拮抗剂

Publications (1)

Publication Number Publication Date
WO2025119390A1 true WO2025119390A1 (fr) 2025-06-12

Family

ID=91400638

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2024/137672 Pending WO2025119390A1 (fr) 2022-12-13 2024-12-09 Antagoniste du récepteur p2x7

Country Status (2)

Country Link
CN (1) CN118184647A (fr)
WO (1) WO2025119390A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN118184647A (zh) * 2022-12-13 2024-06-14 四川大学 一种p2x7受体拮抗剂

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115894452A (zh) * 2021-08-18 2023-04-04 四川大学 一种p2x7受体抑制剂
CN118184647A (zh) * 2022-12-13 2024-06-14 四川大学 一种p2x7受体拮抗剂

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115894452A (zh) * 2021-08-18 2023-04-04 四川大学 一种p2x7受体抑制剂
CN118184647A (zh) * 2022-12-13 2024-06-14 四川大学 一种p2x7受体拮抗剂

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ZHANG RUIJIA, SU KAIYUE, YANG LETIAN, DUAN HUAICHUAN, TANG LEI, TANG MINGHAI, ZHAO MIN, YE NENG, CAI XIAOYING, JIANG XUEQIN, LI NA: "Discovery of a Potent, Orally Active, and Long-Lasting P2X7 Receptor Antagonist as a Preclinical Candidate for Delaying the Progression of Chronic Kidney Disease", JOURNAL OF MEDICINAL CHEMISTRY, vol. 67, no. 19, 10 October 2024 (2024-10-10), US , pages 17472 - 17496, XP093322082, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.4c01395 *
ZHANG RUIJIA, SU KAIYUE, YANG LETIAN, TANG MINGHAI, ZHAO MIN, YE NENG, CAI XIAOYING, JIANG XUEQIN, LI NA, PENG JING, ZHANG XINLU, : "Design, Synthesis, and Biological Evaluation of Novel P2X7 Receptor Antagonists for the Treatment of Septic Acute Kidney Injury", JOURNAL OF MEDICINAL CHEMISTRY, vol. 66, no. 16, 24 August 2023 (2023-08-24), US , pages 11365 - 11389, XP093322081, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.3c00837 *

Also Published As

Publication number Publication date
CN118184647A (zh) 2024-06-14

Similar Documents

Publication Publication Date Title
EP4155313B1 (fr) Composé imidazole hétéroaromatique à cinq chaînons et son utilisation
KR101991327B1 (ko) 오피오이드 수용체 리간드와 그 용도 및 제조방법
CN101827593B (zh) 用于治疗(特别是)囊性纤维化的异噻唑并吡啶酮
EP3353156B1 (fr) Inhibiteurs de l'autopalmitoylation du facteur de transcription tead
CN101687883B (zh) 囊性纤维化跨膜传导调节因子的调节剂
CN109563047A (zh) 含有硅原子的依伐卡托类似物
EP3319444B1 (fr) Modulateurs du récepteur opioïde de type mu
CN100398533C (zh) 作为胰高血糖素受体拮抗剂的取代的3-氰基噻吩乙酰胺
CN107531633A (zh) 5‑芳香炔基取代的苯甲酰胺类化合物及其制备方法、药物组合物和用途
US20170333385A1 (en) Methods of Treating Hyperalgesia
TW201026676A (en) A method of inhibiting hepatitis C virus by combination of a 5,6-dihydro-1H-pyridin-2-one and one or more additional antiviral compounds
JP2022511555A (ja) 非ＡＴＰ／触媒部位ｐ３８マイトジェン活性化プロテインキナーゼ阻害剤
JP4933607B2 (ja) 創薬標的タンパク質及び標的遺伝子、並びにスクリーニング方法
CN108699107B (zh) Cftr调节剂及其使用方法
CN108601775A (zh) 阿片受体配体和细胞色素p450抑制剂的组合
CN117069698A (zh) 靶向shp2降解的双功能分子及其制备和应用
CN110092745A (zh) 一种含芳环的化合物及其应用
TWI688565B (zh) 萘啶二酮（ｎａｐｈｔｈｙｒｉｄｉｎｅｄｉｏｎｅ）衍生物
TWI415613B (zh) Anti-cancer agent resistance to overcome the agent
WO2025119390A1 (fr) Antagoniste du récepteur p2x7
CN112239459A (zh) 稠环嘧啶氨基化合物、其制备方法、药物组合物及应用
WO2020001166A1 (fr) Composé glycoside et son procédé de préparation, composition, application et intermédiaire
KR102743295B1 (ko) Cftr 조절제 및 이의 이용 방법
TW201512201A (zh) 化合物的多晶型及鹽類
JP2022527980A (ja) 新規化合物およびこれを有効成分として含む呼吸器疾患の予防または治療用組成物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24900023

Country of ref document: EP

Kind code of ref document: A1