WO2020253872A1 - 具有a2a腺苷受体激动活性的2-苄叉肼基腺苷类化合物 - Google Patents

具有a2a腺苷受体激动活性的2-苄叉肼基腺苷类化合物 Download PDF

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WO2020253872A1
WO2020253872A1 PCT/CN2020/097442 CN2020097442W WO2020253872A1 WO 2020253872 A1 WO2020253872 A1 WO 2020253872A1 CN 2020097442 W CN2020097442 W CN 2020097442W WO 2020253872 A1 WO2020253872 A1 WO 2020253872A1
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pharmaceutically acceptable
compound
amino
tetrahydrofuran
hydroxymethyl
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PCT/CN2020/097442
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English (en)
French (fr)
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钟武
张珉
周辛波
樊士勇
李松
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中国人民解放军军事科学院军事医学研究院
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Priority to US17/621,019 priority Critical patent/US20220378816A1/en
Priority to CN202080044297.5A priority patent/CN114096551A/zh
Priority to JP2021576169A priority patent/JP2022545763A/ja
Priority to EP20826764.1A priority patent/EP3988559A4/en
Publication of WO2020253872A1 publication Critical patent/WO2020253872A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/167—Purine radicals with ribosyl as the saccharide radical
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals

Definitions

  • This application belongs to the technical field of medicine, and specifically relates to a 2-benzalidene hydrazino adenosine compound with A 2A adenosine receptor agonistic activity and a pharmaceutical composition containing them. These compounds and compositions can be used as medicaments.
  • BBB blood-brain barrier
  • BBBD blood-brain barrier disruption
  • BBB restricts molecules from entering the brain through two main structural features.
  • TJs tight junctions
  • the tight junctions (TJs) structure which seals endothelial cells, results in low permeability of blood molecules through the BBB.
  • TJs tight junctions
  • peripheral vascular endothelial cells there are few transport pathways between cerebral vascular endothelial cells, but the expression level of active efflux transporters is very high, such as brain capillary endothelial cells (BCECs).
  • P-glycoprotein P glycoprotein, P-gp
  • TJs Considering the key role of TJs in restricting molecules from entering the brain (HUBER J D et al., Trends Neurosci, 2001, 24(12):719-25), reversibly changing the tightness of TJs may be a feasible way to increase BBB permeability. Temporary opening of TJs is a feasible way of brain drug delivery because of its high passing efficiency and small molecular weight restriction for therapeutic drugs.
  • a 2A adenosine receptor A 2A adenosine receptor, A 2A AR
  • CARMAN AJ et, J Neurosci, 2011,31 (37) :13272-80 the specific activation of mouse brain BCECs promote drug absorption
  • a 2A adenosine receptors can up-regulate the permeability of BBB and temporarily increase the intercellular space of brain capillary endothelial cells.
  • studies have shown that the A 2A AR signaling pathway modulates intracellular actin to change cytoskeletal elements, leading to cell morphology contraction, TJs integrity destruction, and increased barrier permeability (SOHAIL MA et al., Hepatology, 2009, 49(1): 185 -94). Therefore, these studies greatly expand the A 2A AR agonists and potential application areas for development, the development of efficient A 2A AR agonist is of great significance to study the blood-brain barrier opening strategy (patent application CN200980117596.0).
  • a 2A AR agonists are recommended for the treatment of various pathological diseases.
  • Adenosine mediates A 2A AR to produce potential immunosuppressive and hypotensive effects.
  • One of the main potential therapeutic effects of A 2A AR agonists is anti-inflammatory and immunosuppressive effects by regulating the activity of neutrophils, macrophages and T lymphocytes (DE LERA RUIZ M et al., J Med Chem, 2014, 57 (9): 3623-50; VARANI K et al., FASEB J, 2010, 24(4): 1192-204).
  • a 2A adenosine receptor reduces the NF-kB pathway and reduces inflammatory cytokines such as tumor necrosis factor ⁇ (TNF- ⁇ ), interleukin 1 ⁇ (Interleukin -1 Beta, IL-1 ⁇ ), IL-8, IL-6 and inhibit the release of metalloproteinase-1 (matrix metalloproteinase-1, MMP-1) and MMP-3 (HASKO G et al., Nat Rev Drug Discov, 2008, 7( 9):759-70). Therefore, selective agonists have been developed to treat related diseases such as allergic rhinitis, asthma, and chronic obstructive pulmonary disease.
  • a 2A AR agonist system for anti-inflammatory drugs is limited, because while activating A 2A AR to produce anti-inflammatory effects, it stimulates the heart and blood vessels to cause strong anti-hypertensive activity.
  • a 2A AR agonists are potent vasodilators and have been used as diagnostic reagents for cardiac pharmacological stress tests (patent application CN200580033215.2). Although A 2A AR agonists are potent vasodilators and can produce systemic side effects, it is reported that low doses may not produce significant cardiovascular side effects.
  • a 2A AR agonist has been shown to have neuroprotective effects on neurodegenerative disease models by reducing the release of excitatory neurotransmitters, apoptosis and inflammation (MULLER CE et al., Biochim Biophys Acta, 2011, 1808(5): 1290 -308; RIVERA-OLIVER M et al., Life Sci, 2014, 101(1-2):1-9).
  • Regadenoson an adenosine analog
  • a coronary vasodilator in the United States.
  • Regadenoson is a selective A 2A adenosine receptor agonist jointly developed by CV Pharmaceutical Company and Astellas Company. The product has been marketed in the United States and Europe respectively. It is mainly used as a coronary vasodilator for myocardial perfusion. Imaging. Therefore, there is still a need in the art to have novel, effective, and optionally one or more A 2A receptor agonists with physiological and/or physicochemical advantages, and continue to synthesize and test additional A 2A receptors. It is important to develop agonists in order to develop new and improved therapeutics.
  • the purpose of this application is to find and develop a new type of small molecule agonists that act on A 2A adenosine receptors, which can agonize A 2A adenosine receptors, so as to prevent or treat human pathological conditions or symptoms on the one hand.
  • the prevention or treatment of human pathological conditions or symptoms involves the activity of A 2A adenosine receptor and the activation of this activity is required; on the other hand, the purpose of increasing the permeability of the blood-brain barrier of the subject receiving therapeutic drugs .
  • the first aspect of this application provides a compound represented by general formula (I) or its stereoisomers, its pharmaceutically acceptable salts, its pharmaceutically acceptable hydrates or solvates, and its pharmaceutically acceptable esters,
  • n 1, 2, 3, 4 or 5;
  • R represents a substituent attached to the benzene ring, each R is independently selected from hydrogen, halogen, cyano, benzyloxy, halogenated benzyloxy, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, hydroxyl, C 1-6 alkylamino, di(C 1-6 alkyl)amino, phenylamino, diphenylamino, phenylamino, -NHC( O) R 10 , aryl, heteroaryl, cycloalkyl, heterocycloalkyl, wherein R 10 is C 1-6 alkyl.
  • the second aspect of the application provides the preparation of the compound represented by the general formula (I) described in the first aspect of the application or its stereoisomers, pharmaceutically acceptable salts, pharmaceutically acceptable hydrates or solvates, and Methods of pharmaceutically acceptable esters include:
  • the compound of formula V and the substituted benzaldehyde represented by formula VI are reacted in a methanol solution under microwave heating at 70-90°C.
  • the compound of formula V is generated by the compound of formula IV through hydrazine hydrazine hydrate at 40-60°C.
  • the compound of formula IV is generated by the ammonolysis of the compound of formula III in a methanol solution of ammonia at 90-110°C.
  • the compound of formula III is produced by a substitution reaction of a compound of formula VII and a compound of formula II by adding a catalyst tin tetrachloride at 110-130°C.
  • the third aspect of the application provides a pharmaceutical composition, which comprises at least one of the compound described in the first aspect of the application or a stereoisomer, a pharmaceutically acceptable salt, or a pharmaceutically acceptable hydrate or solvate thereof. Substances, their pharmaceutically acceptable esters, and one or more pharmaceutically acceptable carriers or excipients.
  • the fourth aspect of the application provides the compound described in the first aspect of the application or its stereoisomers, pharmaceutically acceptable salts, pharmaceutically acceptable hydrates or solvates, pharmaceutically acceptable esters thereof, or the present application
  • pharmaceutical composition of the third aspect in the preparation of a medicine as an A 2A adenosine receptor agonist, or
  • the pathological state or symptom of the person described in the application is selected from: autoimmune irritation, inflammation, allergic disease, skin disease, infectious disease, wasting disease, neuropathic pain, open trauma , Adverse reactions caused by drug therapy, cardiovascular disease, ischemia-reperfusion injury, gout, chemical trauma, thermal trauma, diabetic nephropathy, cytopathic disease, laminitis, castor disease, glaucoma, high intraocular pressure, Spinal cord injury, myocardial infarction, and acute myocardial infarction.
  • the fifth aspect of the application provides the compound described in the first aspect of the application or its stereoisomers, pharmaceutically acceptable salts, pharmaceutically acceptable hydrates or solvates thereof, pharmaceutically acceptable esters thereof, or the present application
  • the use of the pharmaceutical composition of the third aspect in preparing a medicine for diagnosing abnormal myocardial perfusion in humans, or in preparing a medicine as a tubular vasodilator.
  • the sixth aspect of the application provides the compound described in the first aspect of the application or its stereoisomer, pharmaceutically acceptable salt, its pharmaceutically acceptable hydrate or solvate, its pharmaceutically acceptable ester, or the application Use of the pharmaceutical composition of the third aspect in the preparation of a medicament for increasing the permeability of the blood-brain barrier of a subject receiving a therapeutic drug, wherein the subject is beneficial for delivering the therapeutic drug across the blood-brain barrier For increased blood-brain barrier permeability.
  • the therapeutic drug is selected from: drugs for the treatment of patients or disorders of the central nervous system, antidote for nerve agents, and drugs for the treatment of glioma drug.
  • the seventh aspect of the present application provides a pharmaceutical composition, which includes:
  • Drugs that need to cross the blood-brain barrier are selected from drugs for treating patients or disorders of the central nervous system, neurotoxin antidote, drugs for treating glioma, and
  • One or more pharmaceutically acceptable carriers or excipients are provided.
  • the eighth aspect of the present application provides a method for preventing and/or treating human pathological conditions or symptoms, comprising administering to a patient in need of such treatment a preventive and/or therapeutically effective amount of the compound described in the first aspect of the present application or its Stereoisomer, pharmaceutically acceptable salt, pharmaceutically acceptable hydrate or solvate thereof, pharmaceutically acceptable ester thereof, or pharmaceutical composition according to the third aspect of the present application, wherein the pathological state or symptom of the human It is related to the activity of the A 2A adenosine receptor, and prevention or treatment of the person's pathological state or symptoms requires activation of the A 2A adenosine receptor.
  • the ninth aspect of the application provides the compound represented by the general formula (I) described in the first aspect of the application or its stereoisomers, pharmaceutically acceptable salts, pharmaceutically acceptable hydrates or solvates, and pharmaceutically acceptable hydrates or solvates thereof.
  • Acceptable esters for preventing and/or treating pathological conditions or symptoms of humans, the pathological conditions or symptoms of said people are related to the activity of A 2A adenosine receptors, and preventing or treating pathological conditions of the human Or the symptoms need to stimulate the activity of A 2A adenosine receptors.
  • the tenth aspect of the application provides the compound represented by the general formula (I) described in the first aspect of the application or its stereoisomers, pharmaceutically acceptable salts, pharmaceutically acceptable hydrates or solvates, and Acceptable esters that are used as A 2A adenosine receptor agonists or tubular vasodilators, or
  • It is used to increase the permeability of the blood-brain barrier of a subject receiving a therapeutic drug that benefits from the increased permeability of the blood-brain barrier for delivering the therapeutic drug across the blood-brain barrier,
  • the therapeutic drug is selected from: drugs for treating patients or disorders of the central nervous system, antidote for nerve poisons, and drugs for treating glioma.
  • the eleventh aspect of the present application also provides a method for diagnosing human myocardial perfusion abnormalities, which comprises administering a diagnostically effective amount of the compound described in the first aspect of the present application or its stereoisomers or pharmaceutically acceptable salts to a patient in need of such diagnosis , Its pharmaceutically acceptable hydrate or solvate, its pharmaceutically acceptable ester or the pharmaceutical composition described in the third aspect of the application.
  • the twelfth aspect of the application also provides a method for increasing the permeability of the blood-brain barrier of a subject receiving a therapeutic drug, the method comprising administering to the subject an effective amount of the compound described in the first aspect of the application or A stereoisomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable hydrate or solvate thereof, a pharmaceutically acceptable ester thereof, or the pharmaceutical composition according to the third aspect of the present application, wherein the subject is The therapeutic drugs that cross the blood-brain barrier benefit from increased blood-brain barrier permeability.
  • the therapeutic drug is selected from the group consisting of drugs for treating patients or disorders of the central nervous system, neurotoxin antidote, and treatment of glioma Drug.
  • the pathological state or symptom of the person described in the application is selected from: autoimmune irritation, inflammation, allergic disease, skin disease, infectious disease, wasting disease, neuropathic pain, open trauma , Adverse reactions caused by drug therapy, cardiovascular disease, ischemia-reperfusion injury, gout, chemical trauma, thermal trauma, diabetic nephropathy, cytopathic disease, laminitis, castor disease, glaucoma, high intraocular pressure, Spinal cord injury, myocardial infarction, and acute myocardial infarction.
  • n is 1, 2 or 3 in general formula (I).
  • n is 1 in general formula (I).
  • n is 2 in general formula (I).
  • n is 3 in general formula (I).
  • each R in the general formula (I) is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, benzyloxy, fluorobenzyloxy, C 1 -4 alkyl, halogenated C 1-4 alkyl, C 1-4 alkoxy, hydroxy, C 1-4 alkylamino, di(C 1-4 alkyl)amino, phenylamino, diphenyl Amino, -NHC(O)R 10 , phenyl, pyridyl, pyrrolidinyl, cyclopentyl, cyclohexyl, morpholinyl, imidazolyl, wherein R 10 is C 1-4 alkyl.
  • each R in the general formula (I) is independently hydrogen, di(C 1-6 alkyl)amino, C 1-6 alkylamino, benzyloxy, halogenated The benzyloxy, phenyl, halophenyl or cyano group.
  • each R in the general formula (I) is independently hydrogen, di(C 1-4 alkyl)amino, C 1-4 alkylamino, benzyloxy, halogenated The benzyloxy, phenyl, halophenyl or cyano group.
  • each R in the general formula (I) is independently hydrogen, benzyloxy, phenyl, 4-fluorobenzyl, diethylamino or cyano.
  • each R in the general formula (I) is each independently a di(C 1-6 alkyl)amino group.
  • each R in the general formula (I) is each independently C 1-6 alkylamino.
  • each R in the general formula (I) is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, benzyloxy, fluorobenzyloxy, methyl , Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, tert-pentyl, neopentyl, hexyl, trifluoromethyl, difluoromethyl, fluorine Substitute methyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, hydroxyl, methylamino , Ethylamino, propylamino, butylamino, dimethylamino, diethylamino, dipropylamino
  • each R in the general formula (I) is independently selected from hydrogen, methoxy, ethoxy, acetamido, benzyloxy, trifluoromethyl, diphenylamino, 4-fluorobenzyloxy, chlorine, pyridin-2-yl, phenyl, pyrrolidin-1-yl, 1H-imidazol-1-yl, propoxy, diethylamino, hydroxyl, morpholine-4- Group, cyano.
  • the compound represented by general formula (I) of this application has a structure represented by formula (I-1),
  • R 1 , R 2 , R 3 , and R 4 are each independently selected from hydrogen, halogen, cyano, benzyloxy, halogenated benzyloxy, C 1-6 alkyl, and halogenated C 1 -6 alkyl, C 1-6 alkoxy, hydroxy, C 1-6 alkylamino, di(C 1-6 alkyl)amino, phenylamino, diphenylamino, phenylamino, -NHC(O ) R 10 , aryl, heteroaryl, cycloalkyl, heterocycloalkyl, wherein R 10 is C 1-6 alkyl.
  • R 1 , R 2 , R 3 , and R 4 in the general formula (I-1) are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, benzyloxy , Fluorobenzyloxy, C 1-4 alkyl, halogenated C 1-4 alkyl, C 1-4 alkoxy, hydroxyl, C 1-4 alkylamino, two (C 1-4 alkane Group) amino, phenylamino, diphenylamino, -NHC(O)R 10 , phenyl, pyridyl, pyrrolidinyl, cyclopentyl, cyclohexyl, morpholinyl, imidazolyl, wherein R 10 is C 1 -4 alkyl.
  • R 1 , R 2 , R 3 , and R 4 in the general formula (I-1) are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, benzyloxy , Fluorobenzyloxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, t-pentyl, neopentyl, hexyl, trifluoro Methyl, difluoromethyl, fluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy Group, n-hexyloxy, hydroxyl, methylamino, ethylamino, propylamino, butylamino, dimethylamin
  • R 1 , R 2 , R 3 , and R 4 in the general formula (I-1) are each independently selected from hydrogen, methoxy, ethoxy, acetyl, acetamido, benzyl Oxy, trifluoromethyl, diphenylamino, 4-fluorobenzyloxy, chlorine, pyridin-2-yl, phenyl, pyrrolidin-1-yl, 1H-imidazol-1-yl, propoxy , Diethylamino, hydroxyl, morpholin-4-yl, cyano.
  • R 1 in the general formula (I-1) is hydrogen or methoxy.
  • R 1 in the general formula (I-1) is hydrogen.
  • R 2 in the general formula (I-1) is di(C 1-6 alkyl)amino.
  • R 2 in the general formula (I-1) is C 1-6 alkylamino.
  • R 2 in the general formula (I-1) is di(C 1-4 alkyl)amino.
  • R 2 in the general formula (I-1) is C 1-4 alkylamino.
  • R 2 in the general formula (I-1) is benzyloxy or halogenated benzyloxy
  • R 2 in the general formula (I) is phenyl.
  • R 2 in the general formula (I) is a halophenyl group.
  • R 2 in the general formula (I-1) is hydrogen, methoxy, acetyl, benzyloxy, trifluoromethyl, diphenylamino, 4-fluorobenzyloxy , Chloro, pyridin-2-yl, phenyl, pyrrolidin-1-yl, 1H-imidazol-1-yl, propoxy, diethylamino, hydroxyl, morpholin-4-yl, or cyano.
  • R 3 in the general formula (I-1) is hydrogen, benzyloxy, trifluoromethyl, ethoxy, or methoxy.
  • R 3 in the general formula (I-1) is hydrogen or benzyloxy.
  • R 3 in the general formula (I-1) is benzyloxy.
  • R 4 in the general formula (I-1) is hydrogen, trifluoromethyl or cyano.
  • R 4 in the general formula (I-1) is hydrogen.
  • R 1 , R 3 , and R 4 are each independently hydrogen;
  • R 2 is di(C 1-6 alkyl)amino, C 1-6 alkane Alkylamino, benzyloxy, halogenated benzyloxy, phenyl, halophenyl or cyano.
  • R 1 and R 4 in the general formula (I-1) are each independently hydrogen;
  • R 2 is di(C 1-6 alkyl)amino, C 1-6 alkylamino, Benzyloxy, halogenated benzyloxy, phenyl, halogenated phenyl or cyano;
  • R 3 is hydrogen or benzyloxy.
  • R 1 and R 4 are each independently hydrogen;
  • R 2 is benzyloxy, phenyl, 4-fluorobenzyl, diethylamino, Cyano;
  • R 3 is hydrogen or benzyloxy.
  • the compound represented by the general formula (I) described in the first aspect of the application is selected from:
  • the preparation method described in the second aspect of the present application has the following synthesis reaction process:
  • alkyl refers to a saturated linear or branched monovalent hydrocarbon group, preferably having 1 to 6, 1 to 4 or 1 to 3 carbon atoms.
  • C 1-6 alkyl refers to a saturated linear or branched monovalent hydrocarbon group having 1 to 6 carbon atoms.
  • Typical examples of “alkyl” include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, t-pentyl, neopentyl, hexyl Wait.
  • hydroxyl as used herein means -OH.
  • halogen as used herein means fluorine, chlorine, bromine or iodine. Preferred halogen groups are fluorine, chlorine or bromine.
  • halo C 1-6 alkyl as used herein means a C 1-6 alkyl mono- or poly-substituted by halogen such as fluorine, chlorine, bromine or iodine.
  • Preferred haloalkyl groups are chloromethyl, chloroethyl, dichloroethyl, trifluoromethyl, difluoromethyl, monofluoromethyl and the like.
  • C 1-6 alkylamino as used herein means an amino group substituted with one C 1-6 alkyl group.
  • Typical examples of “C 1-6 alkylamino” include but are not limited to methylamino, ethylamino, Propylamino, butylamino, etc.
  • di(C 1-6 alkyl)amino as used herein means an amino group substituted with two C 1-6 alkyl groups.
  • Typical examples of "di(C 1-6 alkyl)amino” include, but are not limited to, dimethylamino, diethylamino, dipropylamino, dibutylamino and the like.
  • cycloalkyl as used herein means a saturated cyclic hydrocarbon group having 3-12 carbon atoms and having a monocyclic or bicyclic or multiple fused rings (including fused and bridged ring systems), preferably having 3 -10, 3-8, 5-8, 3-6 or 5-6 carbon atoms.
  • cycloalkyl include, but are not limited to, monocyclic structures, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.; bicyclic structures, such as bicyclic [2.2 .1] Heptyl, and polycyclic structures such as adamantyl and the like.
  • heterocycloalkyl as used herein means a cycloalkyl group as defined herein that contains one, two or more heteroatoms independently selected from N, O, and S.
  • heterocycloalkyl include, but are not limited to, tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, piperazinyl, thiazinyl, piperidinyl, morpholinyl and the like.
  • aryl as used herein means an unsaturated aromatic carbocyclic group of 5-14 carbon atoms having a single ring or two or more fused rings.
  • the aryl group preferably has 5-10, 5-8 or 5-6 carbon atoms.
  • Typical examples of “aryl” include, but are not limited to, phenyl, naphthyl, anthryl and the like.
  • heteroaryl means a heteroaromatic ring group with 5-14 ring members, including monocyclic heteroaromatic rings and polycyclic aromatic rings, in which a monocyclic aromatic ring and one or Multiple other aromatic rings are fused.
  • the heteroaryl group has one or two or more heteroatoms selected from O, S or N.
  • heteroaryl as used herein also includes groups in which an aromatic ring is fused with one or more non-aromatic rings (carbocyclic or heterocyclic), where the linking group or point is located in the aromatic Ring or non-aromatic ring.
  • the heteroaryl group preferably has 5-10 ring members, more preferably 5-6 ring members.
  • heteroaryl include, but are not limited to, furyl, imidazolyl, triazolyl, indolyl, tetrazolyl, pyridyl, pterridinyl, pyrimidinyl, triazolyl, quinolinyl, Isoquinolinyl, quinazolinyl, quinoxalinyl and the like.
  • C 1-6 alkoxy refers to the group -OR 11 , where R 11 is a C 1-6 alkyl group as defined herein.
  • Typical examples of "C 1-6 alkoxy” include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n Pentyloxy, n-hexyloxy, 1,2-dimethylbutoxy, etc.
  • the pharmaceutically acceptable salts of the compounds of general formula (I) described in the present application include their inorganic or organic acid salts, and inorganic or organic base salts.
  • the present application relates to all forms of the foregoing salts.
  • the compound of general formula (I) described in the present application can form pharmaceutically acceptable esters with organic or inorganic acids.
  • the pharmaceutically acceptable esters include phosphate, sulfate, Hydrolyzable esters such as nitric acid, formate, acetate, propionate, butyrate, valerate, caproate, and the like in vivo
  • the carrier described in this application includes, but is not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human albumin, buffer substances such as phosphate, glycerin, sorbic acid, potassium sorbate, saturated Partial glyceride mixture of plant fatty acids, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, Cellulosic substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, beeswax, lanolin.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human albumin
  • buffer substances such as phosphate, glycerin, sorbic acid, potassium sorbate, saturated Partial glyceride mixture of plant fatty acids, water,
  • excipient refers to an additive in a pharmaceutical preparation other than the main drug. It is stable in nature, has no compatibility with the main drug, does not produce side effects, does not affect the curative effect, is not easy to deform, dry, crack, mold, moth, is harmless to the human body, has no physiological effect, and does not produce chemical or physical effects with the main drug It does not affect the content determination of the main drug.
  • binders, fillers, disintegrants, lubricants in tablets; preservatives, antioxidants, flavors, fragrances, cosolvents, emulsifiers, solubilizers, and osmotic pressure regulators in oral liquid preparations , Coloring agents, etc. can all be called excipients, and so on.
  • compositions described in this application can be administered through various routes, such as oral tablets, capsules, powders, oral liquids, injections and transdermal preparations.
  • various dosage forms of drugs can be prepared according to conventional methods in the pharmaceutical field.
  • pharmaceutically acceptable carriers include diluents, fillers, disintegrants, wetting agents, lubricants, coloring agents, flavoring agents or other conventional additives.
  • Typical pharmaceutically acceptable carriers include, for example, microcrystalline cellulose, starch, crospovidone, povidone, polyvinylpyrrolidone, maltitol, citric acid, sodium lauryl sulfonate or magnesium stearate, etc. .
  • the pharmaceutical composition can be administered in any of the following ways: oral administration, spray inhalation, rectal administration, nasal administration, buccal administration, vaginal administration, topical administration, parenteral administration such as subcutaneous, intravenous, intramuscular, Intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion, or medication with an explanted reservoir.
  • an "effective amount” refers to an amount that is sufficient to treat or prevent or diagnose a patient's disease but is low enough to avoid serious side effects (at a reasonable benefit/risk ratio) within the scope of reasonable medical judgment.
  • the therapeutic or preventive or diagnostic effective amount of the compound will be based on the specific compound selected (for example, considering the potency, effectiveness and half-life of the compound), the route of administration selected, the disease to be treated or prevented or diagnosed, the treatment or prevention or The severity of the diagnosed disease, the age, size, weight, and physical illness of the patient being treated, the medical history of the patient being treated, the duration of treatment or prevention or diagnosis, the nature of concurrent therapy, the treatment or prevention or diagnosis required The effects and other factors have changed, but they can still be routinely determined by those skilled in the art.
  • the specific dosage and method of use of the compound of general formula (I) described in this application for different patients are determined by many factors, including the patient’s age, weight, gender, natural health status, nutritional status, and the activity intensity of the compound. Taking time, metabolic rate, severity of the disease and the subjective judgment of the physician.
  • the preferred dosage here is between 0.001-1000 mg/kg body weight/day.
  • the compound represented by formula (I) or its stereoisomers, pharmaceutically acceptable salts or hydrates provided in this application can agonize A 2A adenosine receptors, and thus can be used to prevent or treat human pathological states or symptoms. Human pathological conditions or symptoms can be improved by stimulating the activity of A 2A adenosine receptors.
  • Compound 2-20 can be prepared by referring to the method of Example 1, using different reactants (various substituted benzaldehydes shown in formula VI) instead of 4-acetaminobenzaldehyde in step 1.4.
  • step 1.4 4-(N,N-diphenylamino)benzaldehyde was substituted for 4-acetaminobenzaldehyde to obtain the title compound, and 390 mg of yellow solid (Compound 4) was obtained.
  • step 1.4 in Example 1 replacing 4-acetamidobenzaldehyde with 4-(1H-imidazol-1-yl)benzaldehyde to obtain the title compound, and obtain 615 mg of white solid (compound 12).
  • step 1.4 in Example 1 replacing 4-acetaminobenzaldehyde with 4-(N,N-diethyl)aminobenzaldehyde to obtain the title compound, and obtain 299 mg of white solid (compound 15).
  • Cell membranes stably transfected with (human) A 2A adenosine receptors were prepared in HEK-293 cells.
  • the cell membrane was obtained from PerkinElmer Research Products (Boston, MA).
  • CGS21680 (2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosine) was purchased from Selleck (Shanghai, CN).
  • the A 2A adenosine receptors used are all expressed in the cell membrane.
  • the compound was diluted 3 times serially with DMSO (Solarbio, D8371-250ml) to generate 10 different concentrations (10 ⁇ M, 3.3 ⁇ M, 1.1 ⁇ M, 0.37 ⁇ M, 0.12 ⁇ M, 0.0412 ⁇ M, 0.0137 ⁇ M, 0.0046 ⁇ M, 0.0015 ⁇ M, 0.0005 ⁇ M )
  • Compound source plate add 250nL compound to 384-well Opti-plate, seal with parafilm; 1mL assay buffer (50mM Tris-HCl pH 7.4, 10mM MgCl 2 , 1mM EDTA, 1 ⁇ g/mL adenosine deaminase)
  • Example 22 Adenosine receptor A 2A cAMP test
  • DMEM/F12 G418, Penicillin-Streptomycin, Versene Solution, HEPES, Hank's Buffered Saline Solution, PBS (pH 7.4, 1 ⁇ , sterile), FBS, BSA Stabilizer 7.5%, Rolipram (Rolipram) ), NECA, purchased from Gibico, Hyclone and Sigma.
  • Ultra cAMP kit Eu-cAMP tracer, Ulight-anti-cAMP agent, cAMP detection buffer
  • hADORA 2A- HEK293 cells were purchased from PerkinElmer Research Products (Boston, MA). All other reagents are of analytical grade and obtained from commercial sources.
  • 384-well polypropylene microplate and 384-well white solid plate were purchased from Labcyte and Corning, respectively.
  • TECAN automated pipetting workstation Echo ultrasonic pipetting system and EnVison microplate reader were purchased from TECAN, Labcyte and Envision, respectively.
  • hADORA 2A- HEK293 cells were cultured in DMEM/F12 medium containing 10% FBS, 1X Penicillin-Streptomycin and 400 ⁇ g/ml G418 at 37°C in an environment of 5% CO 2 . Before the experiment, the cells were digested with Versene solution. The cells were collected by centrifugation at 200g at room temperature for 5 minutes in a centrifuge. Finally, the assay buffer (Hank's buffered saline solution, containing 5mM HEPES, 0.1% BSA stabilizer and 10 ⁇ M rolipram) was used. pH 7.4) resuspend.
  • the TECAN automated pipetting workstation uses the TECAN automated pipetting workstation to dilute the compound in a 384-well polypropylene microtiter plate with DMSO to 11 concentration points in a 3-fold gradient to prepare the compound source plate.
  • the 11 concentration points of the compound are 10mM, 3.33mM, and 1.11mM. , 0.37mM, 0.12mM, 0.041mM, 0.013mM, 4.57 ⁇ 10 -3 mM, 1.52 ⁇ 10 -3 mM, 5 ⁇ 10 -4 mM and 1.7 ⁇ 10 -4 mM.
  • the Echo ultrasonic pipetting system (Labcyte) was used to transfer the test compound from the compound source plate to the assay plate, and the transfer volume of the compound was 10 nl/well.
  • the hADORA 2A- HEK293 cell suspension was diluted with assay buffer to 30,000 cells/ml, and the cell suspension was transferred to the assay plate at a volume of 10 ⁇ l/well (300 cells/well).
  • the assay plate was centrifuged at 150g for 1 minute and pre-incubated for 30 minutes at room temperature.
  • Eu-cAMP tracer working solution Eu-cAMP tracer 40 ⁇ l, cAMP detection buffer 1.96ml
  • Ulight-anti-cAMP working solution Ulight-anti- 13 ⁇ l of cAMP agent, cAMP detection buffer 1.95ml
  • the assay plate was rotated at 150 g for 30 seconds and incubated at room temperature for 30 minutes.
  • the compound A 2A receptor agonist titer is expressed as the EC 50 (nM) value at which the compound interacts with the A 2A adenosine receptor to stimulate the production of cyclic adenosine monophosphate.
  • Table 2 shows the EC 50 (nM) value that stimulates the level of cyclic AMP when the test compound interacts with A 2A AR.
  • the results show that the compounds 2, 5, 9, 15 and 20 prepared in this application are all shown as hA 2A AR agonists. 2,5,9,15 and 20 when compound A 2A AR effect, the inhibition constant K i and stimulation of cAMP EC 50 values are substantially the same in the nanomolar range.
  • the fluorescein-labeled dextran FITC-Dextran (CAS: 60842-46-8) has a molecular weight of 10,000 MW, and was purchased from Tixiai (Shanghai) Chemical Industry Development Co., Ltd.; PBS solution, experimental animal SD rats were obtained from commercial sources.
  • the measured fluorescence value of the microplate reader was converted into the corresponding FITC-Dextran average concentration according to the obtained FITC-Dextran concentration standard curve.
  • the results are shown in Table 3. The results show that the macromolecule FITC-Dextran itself cannot pass the blood-brain barrier, while FITC-Dextran added with compound 5 can enter the brain through the BBB, indicating that compound 5 can open the blood-brain barrier.

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Abstract

通式(I)所示的具有A 2A腺苷受体激动活性的2-苄叉肼基腺苷类化合物以及包含它们的药物组合物。该化合物和组合物可作为A 2A腺苷受体激动剂用作药剂。 (I)

Description

具有A 2A腺苷受体激动活性的2-苄叉肼基腺苷类化合物
本申请是以CN申请号为201910542124.5，申请日为2019年06月21日的申请为基础，并主张其优先权，该CN申请的公开内容在此作为整体引入本申请中。
技术领域
本申请属于医药技术领域，具体涉及一种具有A 2A腺苷受体激动活性的2-苄叉肼基腺苷类化合物以及包含它们的药物组合物。这些化合物和组合物可用作药剂。
背景技术
治疗中枢神经系统疾病的药物，其开发和相关研究失败的主要原因之一在于血脑屏障(blood-brain barrier，BBB)的阻碍，使得药物无法递送到中枢神经系统中，在脑内聚积达到药效剂量,从而产生相应的治疗作用。因此，靶向中枢的药物研发成功的一个关键因素就是需要克服血脑屏障，研究开放血脑屏障的方法成为脑内给药的热点。跨血脑屏障给药在过去的几十年中一直是一个挑战性的研究领域，研究人员付出了相当大的努力来开发各种给药系统，一系列策略的研究揭示了跨越血脑屏障运输药物和造影剂十分困难。然而中枢神经系统疾病，如脑肿瘤，中风，创伤和神经退行性疾病等，以及神经性毒剂的救治，对有效治疗药物的需求数量急剧增加，设计能够通透血脑屏障的药物显得特别重要。因此，有必要开发一种高效的血脑屏障开放(blood-brain barrier disruption，BBBD)策略，具有较小的神经损伤，能够传送较大分子量的药物，同时具有较好的药代动力学特点。
BBB通过两种主要结构特点限制分子进入大脑。首先，紧密连接(tight junctions，TJs)结构，封闭内皮细胞导致血液中的分子通过BBB的渗透率很低。另一方面，与外周血管内皮细胞相比，脑血管内皮细胞间转运途径很少，但主动外排转运蛋白表达量水平很高，如脑毛细血管内皮细胞(brain capillary endothelial cells，BCECs)上的P-糖蛋白(P glycoprotein，P-gp)。考虑到TJs在限制分子进入大脑的关键作用(HUBER J D等，Trends Neurosci,2001,24(12):719-25)，可逆地改变TJs的紧密程度可能是上调BBB渗透性的可行方法。暂时开放TJs是一种可行的脑药物输送方式，因为其对治疗药物具有高的通过效率和较小的分子量限制。Bynoe等人最近也证明了特异性激活小鼠BCECs上的A 2A腺苷受体(A 2A adenosine receptor,A 2AAR)可以促进大脑药物吸收(CARMAN A J等，J Neurosci,2011,31(37):13272-80)。进一步的研究表明，通过激活A 2A腺苷受体可以上调BBB通透性，暂时增加脑毛细血管内皮细胞的细胞间隙。研究表明A 2AAR信号通路通过调节细胞内肌动蛋白来改变细胞骨架元件，导致细胞形态收缩，TJs完整性破 坏，并增加屏障渗透性(SOHAIL M A等，Hepatology,2009,49(1):185-94)。因此这些研究大大拓展了A 2AAR激动剂的潜在应用领域和发展空间，开发高效的A 2AAR激动剂对研究开放血脑屏障的策略具有重大意义(专利申请CN200980117596.0)。
同时由于A 2AAR的广泛分布于人体，A 2AAR的激动剂被推荐用于治疗各种病理性疾病。腺苷介导A 2AAR产生潜在的免疫抑制和降血压效应。A 2AAR激动剂其中一个主要的潜在治疗作用是抗炎和免疫抑制作用,通过调节中性粒细胞，巨噬细胞和T淋巴细胞的活性(DE LERA RUIZ M等，J Med Chem,2014,57(9):3623-50；VARANI K等，FASEB J,2010,24(4):1192-204)。从细胞信号通路来看，A 2A腺苷受体的激活降低了NF-kB通路并减少了炎性细胞因子如肿瘤坏死因子α(tumor necrosis factor α，TNF-α)，白细胞介素1β(Interleukin-1 Beta,IL-1β)，IL-8，IL-6和抑制金属蛋白酶1(matrix metalloproteinase-1，MMP-1)和MMP-3释放(HASKO G等，Nat Rev Drug Discov,2008,7(9):759-70)。因此，选择性激动剂被开发用于治疗相关疾病，如过敏性鼻炎、哮喘以及慢性阻塞性肺病。然而，A 2AAR激动剂系统用于抗炎药物受到限制，原因是在激活A 2AAR产生抗炎作用的同时，其激动心脏和血管导致强效的降压活性。另一方面，A 2AAR激动剂是强效的血管扩张剂，已被应用于心脏药理应激检查的诊断试剂(专利申请CN200580033215.2)。虽然A 2AAR激动剂作为强效的血管扩张剂，能产生系统性副作用，然而据报道低剂量可以不产生显著的心血管副作用。另外，A 2AAR激动剂进一步的潜在治疗应用是治疗精神病和亨廷顿病(AKKARI R等，Curr Top Med Chem,2006,6(13):1375-99；BOSCH M P等，J Med Chem,2004,47(16):4041-53)。已显示A 2AAR激动剂对神经退行性疾病模型具有神经保护作用，通过减少兴奋性神经递质释放，细胞凋亡和炎症反应(MULLER C E等，Biochim Biophys Acta,2011,1808(5):1290-308；RIVERA-OLIVER M等，Life Sci,2014,101(1-2):1-9)。
尽管如上所述的A 2AAR激动剂得到越来越多的发展，但是仅有一种受体激动剂瑞加德松(Regadenoson，一种腺苷类似物)在美国被批准用作冠状血管扩张药。瑞加德松是由美国CV制药公司与Astellas公司联合开发的一种选择性A 2A腺苷受体激动剂，该产品已分别在美国和欧洲上市，主要作为冠状血管扩张剂，用于心肌灌注成像。因此，本领域仍然需要有结构新颖的、有效的、并且任选具有一种或多种在生理学和/或物理化学方面具有优点的A 2A受体激动剂，继续合成并测试另外的A 2A受体激动剂以便研发新的且改进的治疗剂是重要的。
申请内容
本申请的目的是寻找并开发一类新型的作用于A 2A腺苷受体的小分子激动剂，其可激动A 2A腺苷受体，从而达到一方面预防或治疗人的病理状态或症状的目的，其预防或治疗 人的病理状态或症状涉及A 2A腺苷受体的活性并且这种活性的激动是需要的；另一方面增加接受治疗药物的受治疗者血脑屏障通透性的目的。本申请经过研究现已发现，具有下面通式I的化合物可作用于A 2A腺苷受体，为A 2A腺苷受体激动剂，因此可用于以上两个目的。本申请基于上述发现而得以完成。
为此，本申请第一方面提供通式(I)所示化合物或其立体异构体、其药学可接受的盐、其药学可接受的水合物或溶剂合物、其药学可接受的酯，
Figure PCTCN2020097442-appb-000001
其中：
n为1、2、3、4或5；
R代表连接在苯环上的取代基，每个R各自独立地选自氢、卤素、氰基、苯甲氧基、卤代的苯甲氧基、C 1-6烷基、卤代的C 1-6烷基、C 1-6烷氧基、羟基、C 1-6烷基氨基、二(C 1-6烷基)氨基、苯氨基、二苯基氨基、苯基氨基、-NHC(O)R 10、芳基、杂芳基、环烷基、杂环烷基，其中R 10为C 1-6烷基。
本申请的第二方面提供制备本申请第一方面所述的通式(I)所示化合物或其立体异构体、药学可接受的盐、其药学可接受的水合物或溶剂合物、其药学可接受的酯的方法，包括：
Figure PCTCN2020097442-appb-000002
式V化合物与式VI所示取代的苯甲醛反应，得到通式(I)所示化合物，其中R和n的定义同本申请第一方面所述。
在某些实施方案中，本申请第二方面所述的制备方法中，所述式V化合物与式VI所示取代的苯甲醛在甲醇溶液中于微波加热70～90℃的条件下进行反应。
在某些实施方案中，本申请第二方面所述的制备方法中，所述式V化合物由式IV化合物在40～60℃下经过水合肼的肼解作用生成。
Figure PCTCN2020097442-appb-000003
在某些实施方案中，本申请第二方面所述的制备方法中，所述式IV化合物由式III化合物在氨的甲醇溶液中90～110℃氨解生成。
Figure PCTCN2020097442-appb-000004
在某些实施方案中，本申请第二方面所述的制备方法中，所述式III化合物由式VII化合物与式II化合物在110～130℃下加入催化剂四氯化锡发生取代反应生成。
本申请的第三方面提供一种药物组合物，其包括至少一种本申请第一方面所述的化合物或其立体异构体、药学可接受的盐、其药学可接受的水合物或溶剂合物、其药学可接受的酯，以及一种或多种药学上可接受的载体或赋形剂。
本申请的第四方面提供本申请第一方面所述的化合物或其立体异构体、药学可接受的盐、其药学可接受的水合物或溶剂合物、其药学可接受的酯或者本申请第三方面所述药物组合物在制备作为A 2A腺苷受体激动剂的药物中的用途，或者
在制备用于预防和/或治疗人的病理状态或症状的药物中的用途，其中所述人的病理状态或症状是与A 2A腺苷受体的活性相关的，并且预防或治疗该人的病理状态或症状需要激动A 2A腺苷受体的活性。
根据本申请的某些实施方案，本申请所述人的病理状态或症状选自：自身免疫性刺激，炎症，过敏性疾病，皮肤病，感染性疾病，消耗病，神经性疼痛，开放性创伤，由药物疗法造成的不良反应，心血管病症，缺血再灌注损伤，痛风，化学外伤，热外伤，糖尿病性肾病，令廉状细胞病，蹄叶炎，铸工病，青光眼，高眼压，脊髓损伤，心肌梗塞，以及急性心肌梗塞。
本申请的第五方面提供本申请第一方面所述的化合物或其立体异构体、药学可接受的 盐、其药学可接受的水合物或溶剂合物、其药学可接受的酯或者本申请第三方面所述药物组合物在制备用于诊断人心肌灌注异常的药物中的用途，或者在制备作为管状血管扩张剂的药物中的用途。
本申请的第六方面提供本申请第一方面所述的化合物或其立体异构体、药学可接受的盐、其药学可接受的水合物或溶剂合物、其药学可接受的酯或者本申请第三方面所述药物组合物在制备用于增加接受治疗药物的受治疗者血脑屏障通透性的药物中的用途，其中所述受治疗者对于递送所述治疗药物穿过血脑屏障受益于增加的血脑屏障通透性。
根据本申请的某些实施方案，本申请第六方面所述的用途中，所述治疗药物选自：治疗中枢神经系统的病患或病症的药物，神经毒剂解毒剂，治疗脑胶质瘤的药物。
本申请的第七方面提供一种药物组合物，其包括：
至少一种本申请第一方面所述的化合物或其立体异构体、药学可接受的盐或水合物，和
需要穿过血脑屏障的药物，其选自治疗中枢神经系统的病患或病症的药物，神经毒剂解毒剂，治疗脑胶质瘤的药物，以及
一种或多种药学上可接受的载体或赋形剂。
本申请的第八方面提供一种预防和/或治疗人的病理状态或症状的方法，包括给予需要这种治疗的患者预防和/或治疗有效量的本申请第一方面所述的化合物或其立体异构体、药学可接受的盐、其药学可接受的水合物或溶剂合物、其药学可接受的酯或者本申请第三方面所述药物组合物，其中所述人的病理状态或症状是与A 2A腺苷受体的活性相关的，并且预防或治疗该人的病理状态或症状需要激动A 2A腺苷受体的活性。
本申请的第九方面提供本申请第一方面所述的通式(I)所示化合物或其立体异构体、药学可接受的盐、其药学可接受的水合物或溶剂合物、其药学可接受的酯，其用于预防和/或治疗人的病理状态或症状，所述人的病理状态或症状是与A 2A腺苷受体的活性相关的，并且预防或治疗该人的病理状态或症状需要激动A 2A腺苷受体的活性。
本申请的第十方面提供本申请第一方面所述的通式(I)所示化合物或其立体异构体、药学可接受的盐、其药学可接受的水合物或溶剂合物、其药学可接受的酯，其用作A 2A腺苷受体激动剂或管状血管扩张剂，或者
其用于诊断人心肌灌注异常，或者
其用于增加接受治疗药物的受治疗者血脑屏障通透性，所述受治疗者对于递送所述治疗药物穿过血脑屏障受益于增加的血脑屏障通透性，
优选地，所述治疗药物选自：治疗中枢神经系统的病患或病症的药物，神经毒剂解毒剂，治疗脑胶质瘤的药物。
本申请的第十一方面还提供诊断人心肌灌注异常的方法，包括给予需要这种诊断的患 者诊断有效量的本申请第一方面所述的化合物或其立体异构体、药学可接受的盐、其药学可接受的水合物或溶剂合物、其药学可接受的酯或者本申请第三方面所述药物组合物。
本申请的第十二方面还提供一种增加接受治疗药物的受治疗者血脑屏障通透性的方法，该方法包括包括给予受治疗者有效量的本申请第一方面所述的化合物或其立体异构体、药学可接受的盐、其药学可接受的水合物或溶剂合物、其药学可接受的酯或者本申请第三方面所述药物组合物，其中所述受治疗者对于递送所述治疗药物穿过血脑屏障受益于增加的血脑屏障通透性。
根据本申请的某些实施方案，本申请第十二方面所述的方法中，所述治疗药物选自：治疗中枢神经系统的病患或病症的药物，神经毒剂解毒剂，治疗脑胶质瘤的药物。
根据本申请的某些实施方案，本申请所述人的病理状态或症状选自：自身免疫性刺激，炎症，过敏性疾病，皮肤病，感染性疾病，消耗病，神经性疼痛，开放性创伤，由药物疗法造成的不良反应，心血管病症，缺血再灌注损伤，痛风，化学外伤，热外伤，糖尿病性肾病，令廉状细胞病，蹄叶炎，铸工病，青光眼，高眼压，脊髓损伤，心肌梗塞，以及急性心肌梗塞。
根据本申请的某些实施方案，通式(I)中n为1、2或3。
根据本申请的某些实施方案，通式(I)中n为1。
根据本申请的某些实施方案，通式(I)中n为2。
根据本申请的某些实施方案，通式(I)中n为3。
根据本申请的某些实施方案，通式(I)中每个R各自独立地选自氢、氟、氯、溴、碘、氰基、苯甲氧基、氟代苯甲氧基、C 1-4烷基、卤代的C 1-4烷基、C 1-4烷氧基、羟基、C 1-4烷基氨基、二(C 1-4烷基)氨基、苯氨基、二苯基氨基、-NHC(O)R 10、苯基、吡啶基、吡咯烷基、环戊基、环己基、吗啉基、咪唑基，其中R 10为C 1-4烷基。
根据本申请的某些实施方案，通式(I)中每个R各自独立地为氢、二(C 1-6烷基)氨基、C 1-6烷基氨基、苯甲氧基、卤代的苯甲氧基、苯基、卤代苯基或氰基。
根据本申请的某些实施方案，通式(I)中每个R各自独立地为氢、二(C 1-4烷基)氨基、C 1-4烷基氨基、苯甲氧基、卤代的苯甲氧基、苯基、卤代苯基或氰基。
根据本申请的某些实施方案，通式(I)中每个R各自独立地为氢、苄氧基、苯基、4-氟苄基、二乙基氨基或氰基。
根据本申请的某些实施方案，通式(I)中每个R各自独立地为二(C 1-6烷基)氨基。
根据本申请的某些实施方案，通式(I)中每个R各自独立地C 1-6烷基氨基。
根据本申请的某些实施方案，通式(I)中每个R各自独立地选自氢、氟、氯、溴、碘、氰基、苯甲氧基、氟代苯甲氧基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、叔戊基、新戊基、己基、三氟甲基、二氟代甲基、氟代甲基、甲氧基、 乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、仲丁氧基、正戊氧基、正己氧基，羟基、甲氨基、乙氨基、丙氨基、丁氨基、二甲氨基、二乙氨基、二丙氨基、二丁氨基、苯氨基、二苯基氨基、乙酰氨基、甲酰氨基、丙酰胺基、苯基、吡啶基、吡咯烷基、环戊基、环己基、吗啉基、咪唑基。
根据本申请的某些实施方案，通式(I)中每个R各自独立地选自氢、甲氧基、乙氧基、乙酰氨基、苄氧基、三氟甲基、二苯基氨基、4-氟苄基氧基、氯、吡啶-2-基、苯基、吡咯烷-1-基、1H-咪唑-1-基、丙氧基、二乙基氨基、羟基、吗啉-4-基、氰基。
根据本申请的某些实施方案，本申请通式(I)所示化合物具有式(I-1)所示的结构，
Figure PCTCN2020097442-appb-000005
其中，R 1、R 2、R 3、R 4各自独立地选自氢、卤素、氰基、苯甲氧基、卤代的苯甲氧基、C 1-6烷基、卤代的C 1-6烷基、C 1-6烷氧基、羟基、C 1-6烷基氨基、二(C 1-6烷基)氨基、苯氨基、二苯基氨基、苯基氨基、-NHC(O)R 10、芳基、杂芳基、环烷基、杂环烷基，其中R 10为C 1-6烷基。
根据本申请的某些实施方案，通式(I-1)中R 1、R 2、R 3、R 4各自独立地选自氢、氟、氯、溴、碘、氰基、苯甲氧基、氟代苯甲氧基、C 1-4烷基、卤代的C 1-4烷基、C 1-4烷氧基、羟基、C 1-4烷基氨基、二(C 1-4烷基)氨基、苯氨基、二苯基氨基、-NHC(O)R 10、苯基、吡啶基、吡咯烷基、环戊基、环己基、吗啉基、咪唑基，其中R 10为C 1-4烷基。
根据本申请的某些实施方案，通式(I-1)中R 1、R 2、R 3、R 4各自独立地选自氢、氟、氯、溴、碘、氰基、苯甲氧基、氟代苯甲氧基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、叔戊基、新戊基、己基、三氟甲基、二氟代甲基、氟代甲基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、仲丁氧基、正戊氧基、正己氧基，羟基、甲氨基、乙氨基、丙氨基、丁氨基、二甲氨基、二乙氨基、二丙氨基、二丁氨基、苯氨基、二苯基氨基、乙酰氨基、甲酰氨基、丙酰胺基、苯基、吡啶基、吡咯烷基、环戊基、环己基、吗啉基、咪唑基。
根据本申请的某些实施方案，通式(I-1)中R 1、R 2、R 3、R 4各自独立地选自氢、甲氧基、乙氧基、乙酰基、乙酰氨基、苄氧基、三氟甲基、二苯基氨基、4-氟苄基氧基、氯、吡啶-2-基、苯基、吡咯烷-1-基、1H-咪唑-1-基、丙氧基、二乙氨基、羟基、吗啉-4-基、氰基。
根据本申请的某些实施方案，通式(I-1)中R 1为氢或甲氧基。
根据本申请的某些实施方案，通式(I-1)中R 1为氢。
根据本申请的某些实施方案，通式(I-1)中R 2为二(C 1-6烷基)氨基。
根据本申请的某些实施方案，通式(I-1)中R 2为C 1-6烷基氨基。
根据本申请的某些实施方案，通式(I-1)中R 2为二(C 1-4烷基)氨基。
根据本申请的某些实施方案，通式(I-1)中R 2为C 1-4烷基氨基。
根据本申请的某些实施方案，通式(I-1)中R 2为苯甲氧基或卤代的苯甲氧基、
根据本申请的某些实施方案，通式(I)中R 2为苯基。
根据本申请的某些实施方案，通式(I)中R 2为卤代苯基。
根据本申请的某些实施方案，通式(I-1)中R 2为氢、甲氧基、乙酰基、苄氧基、三氟甲基、二苯基氨基、4-氟苄基氧基、氯、吡啶-2-基、苯基、吡咯烷-1-基、1H-咪唑-1-基、丙氧基、二乙氨基、羟基、吗啉-4-基、或氰基。
根据本申请的某些实施方案，通式(I-1)中R 3为氢、苄氧基、三氟甲基、乙氧基、甲氧基。
根据本申请的某些实施方案，通式(I-1)中R 3为氢或苄氧基。
根据本申请的某些实施方案，通式(I-1)中R 3为苄氧基。
根据本申请的某些实施方案，通式(I-1)中R 4为氢、三氟甲基或氰基。
根据本申请的某些实施方案，通式(I-1)中R 4为氢。
根据本申请的某些实施方案，通式(I-1)中R 1、R 3、R 4各自独立地为氢；R 2为二(C 1-6烷基)氨基、C 1-6烷基氨基、苯甲氧基、卤代的苯甲氧基、苯基、卤代苯基或氰基。
根据本申请的某些实施方案，通式(I-1)中R 1、R 4各自独立地为氢；R 2为二(C 1-6烷基)氨基、C 1-6烷基氨基、苯甲氧基、卤代的苯甲氧基、苯基、卤代苯基或氰基；R 3为氢或苄氧基。
根据本申请的某些实施方案，通式(I-1)中，R 1、R 4各自独立地为氢；R 2为苄氧基、苯基、4-氟苄基、二乙基氨基、氰基；R 3为氢或苄氧基。
根据本申请的某些实施方案，本申请第一方面所述的通式(I)所示化合物选自：
N-{4-{(E)-{2-{6-氨基-9-[(2R,3R,4S,5R)-3,4-二羟基-5-(羟甲基)四氢呋喃-2-基]-9H-嘌呤-2-基}亚肼基}甲基}苯基}乙酰胺；
(2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-3,4-二(苄氧基)亚苄基]肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇；
(2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-2,4-双(三氟甲基)亚苄基]肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇；
(2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-4-(二苯基氨基)苯亚甲基]肼基}-9H-嘌呤-9- 基}-5-(羟甲基)四氢呋喃-3,4-二醇；
(2R,3R,4S,5R)-2-{6-氨基-2-{2-{(E)-4-[(4-氟苄基)氧基]苯亚甲基}肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇；
(2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-3-(苄氧基)亚苄基]肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇；
(2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-4-氯-3-(三氟甲基)亚苄基]肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇；
(2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-4-(吡啶-2-基)亚苄基]肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇；
(2R,3R,4S,5R)-2-{2-{2-[(E)-[1,1'-联苯]-4-基亚甲基]肼基}-6-氨基-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇；
(2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-4-(吡咯烷-1-基)亚苄基]肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇；
(2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-4-(三氟甲基)亚苄基]肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇；
(2R,3R,4S,5R)-2-{2-{2-[(E)-4-(1H-咪唑-1-基)亚苄基]肼基}-6-氨基-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇；
(2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-4-丙氧基亚苄基]肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇；
2-{(E)-{2-{6-氨基-9-[(2R,3R,4S,5R)-3,4-二羟基-5-(羟甲基)四氢呋喃-2-基]-9H-嘌呤吡啶-2-基}亚肼基}甲基}苯甲腈；
(2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-4-(二乙基氨基)亚苄基]肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇；
(2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-3-乙氧基-4-羟基亚苄基]肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇；
(2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-4-吗啉代亚苄基]肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇；
(2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-3,4,5-三甲氧基亚苄基]肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇；
(2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-4-(苄氧基)-3-甲氧基亚苄基]肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇；
4-{E-{2-{6-氨基-9-[(2R,3R,4S,5R)-3,4-二羟基-5-(羟甲基)四氢呋喃-2-基]-9H-嘌呤吡啶-2-基}亚肼基}甲基}苯甲腈。
根据本申请的某些实施方案，本申请第二方面所述的制备方法，其合成反应流程如下：
Figure PCTCN2020097442-appb-000006
呋喃核糖四乙酸酯(式VII化合物)起始原料与2,6-二氯嘌呤(式II化合物)在110～130℃下加入催化剂四氯化锡发生取代反应生成2,6-二氯-2',3',5'-三乙酰嘌呤核苷(式III化合物)；将得到的2,6-二氯-2',3',5'-三乙酰嘌呤核苷(式III化合物)在氨的甲醇中90～110℃密封氨解，得到2-氯腺苷(式IV化合物)；2-氯腺苷(式IV化合物)在40～60℃经过水合肼的肼解作用，生成2-肼腺苷(式V化合物)；最后2-肼腺苷(式V化合物)在甲醇溶液中于微波70～90℃下与取代苯甲醛(式VI化合物)反应得到2-苄叉肼基腺苷类化合物(式I化合物)，其中取代基R和n的定义同本申请第一方面化合物所述，按需选择。
取代基定义
本文中使用的术语“烷基”是指饱和的直链或支链一价烃基，优选具有1－6，1－4或1－3个碳原子。例如，“C 1-6烷基”是指具有1－6个碳原子的饱和的直链或支链一价烃基。“烷基”的典型实例包括但不限于甲基，乙基，正丙基，异丙基，正丁基，异丁基，叔丁基，正戊基，叔戊基，新戊基，己基等。
本文中使用的术语“羟基”意指-OH。
本文所用的术语“卤素”意指氟，氯，溴或碘。优选的卤素基团为氟、氯或溴。
本文所用的术语“卤代C 1-6烷基”意指被卤素例如氟，氯，溴或碘单或多取代的C 1-6烷基。优选的卤代烷基为氯甲基、氯乙基、二氯乙基、三氟甲基、二氟甲基、单氟甲基等。
本文中使用的术语“C 1-6烷基氨基”意指被一个C 1-6烷基取代的氨基，“C 1-6烷基氨基”的典型实例包括但不限于甲氨基，乙氨基，丙氨基，丁氨基等。
本文中使用的术语“二(C 1-6烷基)氨基”意指被两个C 1-6烷基取代的氨基。“二(C 1-6烷基)氨基”的典型实例包括但不限于二甲氨基，二乙氨基，二丙氨基，二丁氨基等。
本文中使用的术语“环烷基”意指具有3－12个碳原子并且具有单环或二环或多 个稠合环(包括稠合和桥连环系)的饱和环状烃基，优选具有3－10，3－8，5－8，3－6或5－6个碳原子。“环烷基”的典型实例包括但不限于单环结构，诸如环丙基，环丁基，环戊基，环己基、环庚基、环辛基等；二环结构，诸如二环[2.2.1]庚基，和多环结构，例如金刚烷基等。
本文所用的术语“杂环烷基”意指包含一个、两个或多个独立地选自N，O和S的杂原子的如本文所定义的环烷基。“杂环烷基”的典型实例包括但不限于四氢呋喃基，四氢噻吩基，吡咯烷基，哌嗪基，噻嗪基，哌啶基和吗啉基等。
本文所用的术语“芳基”意指具有一个单环或两个或多个稠合环的5－14个碳原子的不饱和芳族碳环基。所述芳基优选具有5－10、5－8或5－6个碳原子。“芳基”的典型实例包括但不限于苯基，萘基和蒽基等。
本文所用的术语“杂芳基”表示意指具有5－14个环成员的杂芳族环基团，包括单环杂芳族环和多环芳族环，其中单环芳族环与一个或多个其他芳族环稠合。杂芳基中具有一个或两个或多个选自O，S或N的杂原子。本文所用的术语“杂芳基”范围内还包括的是其中芳族环与一个或多个非芳族环(碳环或杂环)稠合的基团，其中连接基团或点位于芳族环或非芳族环上。所述杂芳基优选具有5－10个环成员，更优选5－6个环成员。“杂芳基”的典型实例包括但不限于呋喃基，咪唑基，三氮唑基、吲哚基，四氮唑基、吡啶基，蝶啶基，嘧啶基，三唑基，喹啉基，异喹啉基，喹唑啉基，喹喔啉基等。
本文所用的术语“C 1-6烷氧基”意指基团-OR 11，其中R 11为如本文所定义的C 1-6烷基。“C 1-6烷氧基”的典型实例包括但不限于甲氧基，乙氧基，正丙氧基，异丙氧基，正丁氧基，叔丁氧基，仲丁氧基，正戊氧基，正己氧基，1,2-二甲基丁氧基等。
本文中使用的化合物名称与化学结构式不一致时，以化学结构式为准。
根据本申请的某些实施方案，本申请所述通式(I)化合物的药学上可接受的盐包括其无机或有机酸盐，以及无机或有机碱盐，本申请涉及上述盐的所有形式。其中包括但不限于:钠盐、钾盐、钙盐、锂盐、葡甲胺盐、盐酸盐，氢澳酸盐，氢腆酸盐，硝酸盐，硫酸盐，硫酸氢盐，磷酸盐，磷酸氢盐，乙酸盐，丙酸盐，丁酸盐，草酸盐，三甲基乙酸盐，己二酸盐，藻酸盐，乳酸盐，柠檬酸盐，酒石酸盐，琥珀酸盐，马来酸盐，富马酸盐，苦味酸盐，天冬氨酸盐，葡糖酸盐，苯甲酸盐，甲磺酸盐，乙磺酸盐，苯磺酸盐，对甲苯磺酸盐和双羟萘酸盐等。
根据本申请的某些实施方案，本申请所述通式(I)化合物可以与有机酸或无机酸形成药学上可接受的酯，所述的药学上可接受的酯包括磷酸酯、硫酸酯、硝酸、甲酸酯、乙酸酯、丙酸酯、丁酸酯、戊酸酯、己酸酯等在生物体内可水解的酯类。
本申请所述的载体包括但不限于：离子交换剂，氧化铝，硬脂酸铝，卵磷脂，血清 蛋白如人血白蛋白，缓冲物质如磷酸盐，甘油，山梨酸，山梨酸钾，饱和植物脂肪酸的部分甘油酯混合物，水，盐或电解质，如硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，氯化钠，锌盐，胶态氧化硅，三硅酸镁，聚乙烯吡咯烷酮，纤维素物质，聚乙二醇，羧甲基纤维素钠，聚丙烯酸酯，蜂蜡，羊毛脂。
本申请中使用的术语“赋形剂”是指在药物制剂中除主药以外的附加物。其性质稳定，与主药无配伍禁忌，不产生副作用，不影响疗效，在常温下不易变形、干裂、霉变、虫蛀、对人体无害、无生理作用，不与主药产生化学或物理作用，不影响主药的含量测定等。如片剂中的黏合剂、填充剂、崩解剂、润滑剂；口服液体制剂中的防腐剂、抗氧剂、矫味剂、芳香剂、助溶剂、乳化剂、增溶剂、渗透压调节剂、着色剂等均可称为赋形剂，等等。
本申请所述的药物组合物可以经多种途径施用，例如口服片剂，胶囊，粉剂，口服液，注射剂和透皮制剂。上述各种剂型的药物均可以按照药学领域的常规方法制备。根据常规的药物上的惯例，药学上可接受的载体包括稀释剂、填充剂、崩解剂、润湿剂、润滑剂、着色剂、调味剂或其它常规添加剂。典型的药学上可接受的载体包括例如微晶纤维素、淀粉、交连聚维酮、聚维酮、聚乙烯吡咯烷酮、麦芽糖醇，柠檬酸，十二烷基磺酸钠或硬脂酸镁等。
根据申请，所述的药物组合物可以以下面的任意方式施用：口服、喷雾吸入、直肠用药、鼻腔用药、颊部用药、阴道用药、局部用药、非肠道用药如皮下、静脉、肌内、腹膜内、鞘内、心室内、胸骨内和颅内注射或输入、或借助一种外植储器用药。
如本文所述的，“有效量”是指在合理的医学判断范围内，足以治疗或预防或诊断患者疾病但足够低地避免严重副作用(在合理的利益/风险比)的量。化合物的治疗或预防或诊断有效量将根据所选择的具体化合物(例如考虑化合物的效力、有效性和半衰期)、所选择的给药途径、所治疗或预防或诊断的疾病、所治疗或预防或诊断的疾病的严重性、所治疗的患者的年龄、大小、体重和身体疾病、所治疗的患者的医疗史、治疗或预防或诊断持续时间、并行疗法的性质、所需的治疗或预防或诊断效果等因素发生变化，但仍可以由本领域技术人员常规确定。
另外需要指出，本申请所述通式(I)化合物针对不同患者的特定使用剂量和使用方法决定于诸多因素，包括患者的年龄，体重，性别，自然健康状况，营养状况，化合物的活性强度，服用时间，代谢速率，病症的严重程度以及诊治医师的主观判断。这里优选使用剂量介于0.001-1000mg/kg体重/天。
本申请的有益技术效果
本申请提供的式(I)所示化合物或其立体异构体、药学可接受的盐或水合物可激动 A 2A腺苷受体，从而可以用于预防或治疗人的病理状态或症状，该人的病理状态或症状可以通过激动A 2A腺苷受体的活性而得到改善。
具体实施方式
通过下面的实施例和试验例可以对本申请进行进一步的描述。然而，本申请的范围并不限于下述实施例或试验例。本领域的专业人员能够理解，在不背离本申请的精神和范围的前提下，可以对本申请进行各种变化和修饰。本申请对试验中所使用到的材料以及试验方法进行一般性和/或具体的描述。虽然为实现本申请目的所使用的许多材料和操作方法是本领域公知的，但是本申请仍然在此作尽可能详细描述。
对于以下全部实施例，可以使用本领域技术人员已知的标准操作和纯化方法。除非另有说明，所有温度以℃(摄氏度)表示。化合物的结构是通过核磁共振(NMR)或质谱(MS)来确定的。化合物熔点m.p.由RY-1型熔点仪测定，温度计未经较正，m.p.是以℃给出。1H NMR由日本电子JNM-ECA-400型核磁共振仪测定。质谱由API3000(ESI)仪测定。所有反应用溶剂未注明都经标准化预处理。
实施例1：N-{4-{(E)-{2-{6-氨基-9-[(2R,3R,4S,5R)-3,4-二羟基-5-(羟甲基)四氢呋喃-2-基]-9H-嘌呤-2-基}亚肼基}甲基}苯基}乙酰胺(化合物1)的合成
Figure PCTCN2020097442-appb-000007
1.1(2R,3R,4R,5R)-2-(乙酰氧基甲基)-5-(2,6-二氯-9H-嘌呤-9-基)四氢呋喃-3,4-二基二乙酸酯(式III化合物)的合成
将21g(0.066mol)(2S,3R,4R,5R)-5-(乙酰氧基甲基)四氢呋喃-2,3,4-三基三乙酸酯(式VII化合物)加热至90℃直到它变清，这时加入12g(0.063mol)2,6-二氯嘌呤(式II化合物)和0.3g四氯化锡搅拌。将反应进一步加热至120℃下搅拌15分钟。真空蒸发溶剂，冷却残余物。向残余物中加入甲醇(50ml)，过滤分离固体粗产品。将粗产物在乙醇中重结晶，得到淡黄色粉末产物(2R,3R,4R,5R)-2-(乙酰氧基甲基)-5-(2,6-二氯-9H-嘌呤-9-基)四氢呋喃-3,4-二基二乙酸酯(式III化合物)12g，直接投入下一步反应。
1.2(2R,3R,4S,5R)-2-(6-氨基-2-氯-9H-嘌呤-9-基)-5-(羟甲基)四氢呋喃-3,4-二醇(式IV化合物)的合成
10g(0.022mol)(2R,3R,4R,5R)-2-(乙酰氧基甲基)-5-(2,6-二氯-9H-嘌呤-9-基)四氢呋喃-3,4-二基二乙酸酯(式III化合物)在200ml氨的甲醇溶液中加热至100℃，在高压灭菌 器中保持24小时。将溶液进一步搅拌24小时至室温，然后将溶液在减压下蒸发至干去除氨。使用快速色谱法纯化残余物，CH 2Cl 2和MeOH的混合溶剂(CH 2Cl 2:MeOH＝10:1(v/v))作为洗脱液，产物在50℃以下干燥得到4.5g淡黄色粉末(2R,3R,4S,5R)-2-(6-氨基-2-氯-9H-嘌呤-9-基)-5-(羟甲基)四氢呋喃-3,4-二醇(式IV化合物)，直接投入下一步反应。
1.3(2R,3R,4S,5R)-2-(6-氨基-2-肼基-9H-嘌呤-9-基)-5-(羟甲基)四氢呋喃-3,4-二醇(式V化合物)的合成
在25ml水合肼(65wt％水溶液)中加入5g(0.017mol)(2R,3R,4S,5R)-2-(6-氨基-2-氯-9H-嘌呤-9-基)-5-(羟甲基)四氢呋喃-3,4-二醇(式IV化合物),搅拌的同时加热到50℃，持续加热4小时直至反应物(式IV化合物)消失，通过TLC(CH 2Cl 2:MeOH＝3:1(v/v))监测反应进度。然后将反应混合物升至25℃，并加入2-丙醇(50ml)稀释搅拌过夜。分离得到的沉淀物过滤，得到4.4g(2R,3R,4S,5R)-2-(6-氨基-2-肼基-9H-嘌呤-9-基)-5-(羟甲基)四氢呋喃-3,4-二醇(式V化合物)，为黄色固体，直接投入下一步反应。
1.4N-{4-{(E)-{2-{6-氨基-9-[(2R,3R,4S,5R)-3,4-二羟基-5-(羟甲基)四氢呋喃-2-基]-9H-嘌呤-2-基}亚肼基}甲基}苯基}乙酰胺(化合物1)的合成
0.5g(0.0017mol)(2R,3R,4S,5R)-2-(6-氨基-2-肼基-9H-嘌呤-9-基)-5-(羟甲基)四氢呋喃-3,4-二醇(式V化合物)和0.31g(0.0019mol)4-乙酰氨基苯甲醛(1.1当量)在甲醇(30ml)中混合并通过微波80℃加热30分钟。粗产物从甲醇中沉淀出来，过滤后粗产物进一步纯化，使用中压制备色谱采用C18反相柱上纯化得到171mg白色固体(化合物1)。m.p.126℃； 1H NMR(DMSO-d 6):δ(ppm)10.54(s,1H),10.03(s,1H),8.02(s,2H),7.66-7.59(m,4H),7.03(br,2H),5.79(d,1H,J＝6.4Hz),5.44(d,1H,J＝6.0Hz),5.24-5.21(m,1H),5.11(d,1H,J＝4.4),4.67(dd,1H,J＝5.6Hz,5.6Hz),4.24-4.21(m,1H),3.98-3.96(m,1H),3.75-3.57(m,2H),2.06(s,3H)；HRMS(ESI+)m/z[M+H] +calculated for C 19H 22N 8O 5:443.1786；found:443.1786。
化合物2-20可参考实施例1的方法制备，用不同的反应物(式VI所示的各种取代的苯甲醛)代替步骤1.4中的4-乙酰氨基苯甲醛进行制备。
实施例2：(2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-3,4-二(苄氧基)亚苄基]肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇(化合物2)的合成
Figure PCTCN2020097442-appb-000008
参考实施例1步骤1.4的方法，以3,4-二苄氧基苯甲醛替代4-乙酰氨基苯甲醛得标题 化合物，得到553mg白色固体(化合物2)。m.p.220℃； 1H NMR(DMSO-d 6):δ(ppm)10.55(s,1H),8.00(s,1H),7.98(s,1H),7.96(s,1H),7.52-7.30(m,10H),7.09-7.05(m,4H),5.76(d,1H,J＝7.2Hz),5.49-5.47(m,2H),5.19-5.14(m,5H),4.89-4.84(m,1H),4.20-4.18(m,1H),4.00(s,1H),3.76-3.54(m,2H)；HRMS(ESI+)m/z[M+H] +calculated for C 31H 31N 7O 6:598.2409；found:598.2408。
实施例3：(2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-2,4-双(三氟甲基)亚苄基]肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇(化合物3)的合成
Figure PCTCN2020097442-appb-000009
参考实施例1步骤1.4的方法，以2,4-双(三氟甲基)苯甲醛替代4-乙酰氨基苯甲醛得标题化合物，得到474mg白色固体(化合物3)。m.p.239℃； 1H NMR(DMSO-d 6):δ(ppm)11.44(s,1H),8.70(d,1H,J＝8.4Hz),8.47(s,1H),8.12-8.01(m,3H),7.31(br,2H),5.81(d,1H,J＝6.4Hz),5.47(br,1H),5.30(br,1H),5.19(br,1H),4.73-4.71(m,1H),4.25-4.24(m,1H),4.00-3.98(m,1H),3.77-3.62(m,2H)；HRMS(ESI+)m/z[M+H] +calculated for C 19H 17F 6N 7O 4:522.1319；found:522.1319。
实施例4：(2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-4-(二苯基氨基)苯亚甲基]肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇(化合物4)的合成
Figure PCTCN2020097442-appb-000010
参考实施例1步骤1.4的方法，以4-(N,N-二苯氨基)苯甲醛替代4-乙酰氨基苯甲醛得标题化合物，得到390mg黄色固体(化合物4)。m.p.184℃； 1H NMR(DMSO-d 6):δ(ppm)10.56(s,1H),8.01(s,2H),7.63(d,2H,J＝8.4Hz),7.35-6.94(m,14H),5.77(d,1H,J＝6.4Hz),5.45(d,1H,J＝6.0Hz),5.27-5.24(m,1H),5.11(d,1H,J＝4.4Hz),4.70-4.66(m,1H),4.21-4.18(m,1H),3.93(d,1H,J＝2.4Hz),3.73-3.53(m,2H)；HRMS(ESI+)m/z[M+H] +calculated for C 29H 28N 8O 4:553.2306；found:553.2306。
实施例5：(2R,3R,4S,5R)-2-{6-氨基-2-{2-{(E)-4-[(4-氟苄基)氧基]苯亚甲基}肼基}-9H- 嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇(化合物5)的合成
Figure PCTCN2020097442-appb-000011
参考实施例1步骤1.4的方法，以4-(4-氟苄氧基)苯甲醛替代4-乙酰氨基苯甲醛得标题化合物，得到291mg白色固体(化合物5)。m.p.144℃； 1H NMR(DMSO-d 6):δ(ppm)10.51(s,1H),8.02(s,2H),7.68(d,2H,J＝8.8Hz),7.54-7.50(m,2H),7.26-7.22(m,2H),7.04(d,4H,J＝8.8Hz),5.80(d,1H,J＝6.8Hz),5.47(d,1H,J＝6.4Hz),5.31-5.28(m,1H),5.16(d,1H,J＝4.0Hz),5.12(s,2H),4.70-4.66(m,1H),4.22-4.19(m,1H),3.98-3.96(m,1H),3.74-3.57(m,2H)；HRMS(ESI+)m/z[M+H] +calculated for C 24H 24FN 7O 5:510.1896；found:510.1895。
实施例6：(2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-3-(苄氧基)亚苄基]肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇(化合物6)的合成
Figure PCTCN2020097442-appb-000012
参考实施例1步骤1.4的方法，以3-苄氧基苯甲醛替代4-乙酰氨基苯甲醛得标题化合物，得到355mg白色固体(化合物6)。m.p.148℃； 1H NMR(DMSO-d 6):δ(ppm)10.73(s,1H),8.05(s,2H),7.62-6.95(m,11H),5.79(d,1H,J＝6.8Hz),5.48(d,1H,J＝6.0Hz),5.38(s,1H),5.16(s,3H),4.79-4.75(m,1H),4.19(s,1H),3.98(s,1H),3.74-3.55(m,2H)；HRMS(ESI+)m/z[M+H] +calculated for C 24H 25N 7O 5:492.1990；found:492.1990。
实施例7：(2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-4-氯-3-(三氟甲基)亚苄基]肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇(化合物7)的合成
Figure PCTCN2020097442-appb-000013
参考实施例1步骤1.4的方法，以4-氯-3-(三氟甲基)苯甲醛替代4-乙酰氨基苯甲醛得标题化合物，得到443mg白色固体(化合物7)。m.p.242℃； 1H NMR(DMSO-d 6):δ(ppm) 10.94(s,1H),8.46(s,1H),8.07(s,1H),8.01(s,1H),7.89(d,1H,J＝8.0Hz),7.68(d,1H,J＝8.4Hz),7.13(br,2H),5.73(d,1H,J＝7.2Hz),5.46(d,1H,J＝5.2Hz),5.39(d,1H,J＝6.4Hz),5.14(s,1H),4.79-4.77(m,1H),4.12(s,1H),3.96(s,1H),3.68-3.51(m,2H)；HRMS(ESI+)m/z[M+H] +calculated for C 18H 17ClF 3N 7O 4:488.1055；found:488.1055。
实施例8：(2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-4-(吡啶-2-基)亚苄基]肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇(化合物8)的合成
Figure PCTCN2020097442-appb-000014
参考实施例1步骤1.4的方法，以4-(2-吡啶基)苯甲醛替代4-乙酰氨基苯甲醛得标题化合物，得到537mg白色固体(化合物8)。m.p.164℃； 1H NMR(DMSO-d 6):δ(ppm)10.83(s,1H),8.69(s,1H),8.15-7.85(m,8H),7.36-7.35(m,1H),7.18(br,2H),5.83(d,1H,J＝6.4Hz),5.50(s,1H),5.28(s,1H),5.20(s,1H),4.71(s,1H),4.25(s,1H),4.00(s,1H),3.77-3.62(m,2H)；HRMS(ESI+)m/z[M+H] +calculated for C 22H 22N 8O 4:463.1837；found:463.1838。
实施例9：(2R,3R,4S,5R)-2-{2-{2-[(E)-[1,1'-联苯]-4-基亚甲基]肼基}-6-氨基-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇(化合物9)的合成
Figure PCTCN2020097442-appb-000015
参考实施例1步骤1.4的方法，以4-联苯甲醛替代4-乙酰氨基苯甲醛得标题化合物，得到467mg白色固体(化合物9)。m.p.234℃； 1H NMR(DMSO-d 6):δ(ppm)10.78(s,1H),8.12(s,1H),8.07(s,1H),7.83(d,2H,J＝8.4Hz),7.31-7.71(m,4H),7.48(t,2H,J＝7.2Hz),7.38(t,J＝7.2Hz,1H),7.16(br,2H),5.82(d,1H,J＝6.8Hz),5.49(d,1H,J＝6.0Hz),5.28(s,1H),5.19(d,1H,J＝4.4Hz),4.69-4.67(m,1H),4.22(d,1H,J＝2.4Hz),3.98(d,1H,J＝2.4Hz),3.75-3.60(m,2H)；HRMS(ESI+)m/z[M+H] +calculated for C 23H 23N 7O 4:462.1884；found:462.1884。
实施例10：(2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-4-(吡咯烷-1-基)亚苄基]肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇(化合物10)的合成
Figure PCTCN2020097442-appb-000016
参考实施例1步骤1.4的方法，以4-(1-吡咯烷基)苯甲醛替代4-乙酰氨基苯甲醛得标题化合物，得到352mg白色固体(化合物10)。m.p.174℃； 1H NMR(DMSO-d 6):δ(ppm)10.23(s,1H),7.98(s,1H),7.94(s,1H),7.54(d,2H,J＝8.8Hz),6.95(br,2H),6.54(d,2H,J＝8.8Hz),5.78(d,1H,J＝6.8Hz),5.44(d,1H,J＝6.4Hz),5.27-5.24(m,1H),5.11(d,1H,J＝4.0Hz),4.69-4.65(m,1H),4.20(s,1H),3.97(s,1H),3.73-3.57(m,2H),3.26(s,4H),1.96(s,4H)；HRMS(ESI+)m/z[M+H] +calculated for C 21H 26N 8O 4:455.2150；found:455.2150。
实施例11：(2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-4-(三氟甲基)亚苄基]肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇(化合物11)的合成
Figure PCTCN2020097442-appb-000017
参考实施例1步骤1.4的方法，以4-(三氟甲基)苯甲醛替代4-乙酰氨基苯甲醛得标题化合物，得到404mg白色固体(化合物11)。m.p.260℃； 1H NMR(DMSO-d 6):δ(ppm)10.97(s,1H),8.14(s,1H),8.08(s,1H),7.96(d,2H,J＝8.4Hz),7.74(d,2H,J＝8.4Hz),7.18(br,2H),5.82(d,1H,J＝6.4Hz),5.47(d,1H,J＝5.6Hz),5.29(s,1H),5.18(d,1H,J＝3.2Hz),4.71-4.69(m,1H),4.23(s,1H),3.98(d,1H,J＝2Hz),3.76-3.60(m,2H)；HRMS(ESI+)m/z[M+H] +calculated for C 18H 18F 3N 7O 4:454.1445；found:454.1446。
实施例12：(2R,3R,4S,5R)-2-{2-{2-[(E)-4-(1H-咪唑-1-基)亚苄基]肼基}-6-氨基-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇(化合物12)的合成
Figure PCTCN2020097442-appb-000018
参考实施例1步骤1.4的方法，以4-(1H-咪唑-1-基)苯甲醛替代4-乙酰氨基苯甲醛得标题化合物，得到615mg白色固体(化合物12)。m.p.276℃； 1H NMR(DMSO-d 6):δ(ppm) 10.77(s,1H),8.33(s,1H),8.11(s,1H),8.05(s,1H),7.89(d,2H,J＝8.4Hz),7.81(s,1H),7.70(d,2H,J＝8.8Hz),7.13(s,1H),7.11(br,2H),5.81(d,1H,J＝6.8Hz),5.48(d,1H,J＝6.4Hz),5.35-5.32(m,1H),5.19(d,1H,J＝4.0Hz),4.74-4.70(m,1H),4.22-4.20(m,1H),3.99(s,1H),3.76-3.59(m,1H)；HRMS(ESI+)m/z[M+H] +calculated for C 20H 21N 9O 4:452.1789；found:452.1789。
实施例13：(2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-4-丙氧基亚苄基]肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇(化合物13)的合成
Figure PCTCN2020097442-appb-000019
参考实施例1步骤1.4的方法，以4-丙氧基苯甲醛替代4-乙酰氨基苯甲醛得标题化合物，得到306mg白色固体(化合物13)。m.p.218℃； 1H NMR(DMSO-d 6):δ(ppm)10.55(s,1H),8.04(s,1H),8.02(s,1H),7.67(d,2H,J＝8.4Hz),7.11(br,2H),6.95(d,1H,J＝8.8Hz),5.80(d,1H,J＝6.4Hz),5.47(d,1H,J＝5.2Hz),5.28(s,1H),5.17(s,1H),4.68(s,1H),4.20(s,1H),3.97-3.94(m,3H),3.73-3.61(m,2H),1.76-1.71(m,2H),0.98(t,3H,J＝7.6Hz)；HRMS(ESI+)m/z[M+H] +calculated for C 20H 25N 7O 5:444.1990；found:444.1990。
实施例14：2-{(E)-{2-{6-氨基-9-[(2R,3R,4S,5R)-3,4-二羟基-5-(羟甲基)四氢呋喃-2-基]-9H-嘌呤吡啶-2-基}亚肼基}甲基}苯甲腈(化合物14)的合成
Figure PCTCN2020097442-appb-000020
参考实施例1步骤1.4的方法，以2-氰基苯甲醛替代4-乙酰氨基苯甲醛得标题化合物，得到359mg白色固体(化合物14)。m.p.260℃； 1H NMR(DMSO-d 6):δ(ppm)11.21(s,1H),8.45(s,1H),8.35(d,1H,J＝8.0Hz),8.08(s,1H),7.83(d,1H,J＝7.6Hz),7.72(t,1H,J＝7.6Hz),7.48(t,1H,J＝7.6Hz),7.18(br,2H),5.81(d,1H,J＝6.4),5.47(d,1H,J＝5.6Hz),5.29-5.27(m,1H),5.17(d,1H,J＝3.6Hz),4.73-4.71(m,1H),4.23(s,1H),3.98(s,1H),3.75-3.58(m,2H)；HRMS(ESI+)m/z[M+H] +calculated for C 18H 18N 8O 4:411.1524；found:411.1523。
实施例15：(2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-4-(二乙基氨基)亚苄基]肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇(化合物15)的合成
Figure PCTCN2020097442-appb-000021
参考实施例1步骤1.4的方法，以4-(N,N-二乙基)氨基苯甲醛替代4-乙酰氨基苯甲醛得标题化合物，得到299mg白色固体(化合物15)。m.p.164℃； 1H NMR(DMSO-d 6):δ(ppm)10.27(s,1H),7.99(s,1H),7.92(s,1H),7.51(d,2H,J＝8.8Hz),6.99(br,2H),6.66(d,2H,J＝8.8Hz),5.78(d,1H,J＝6.8Hz),5.47(d,1H,J＝6Hz),5.30-5.26(m,1H),5.15(d,1H,J＝4.4Hz),4.69-4.65(m,1H),4.21-4.18(m,1H),3.97-3.95(m,1H),3.73-3.56(m,2H),3.39-3.34(m,4H),1.10(t,6H,J＝6.8Hz)；HRMS(ESI+)m/z[M+H] +calculated for C 21H 28N 8O 4:457.2306；found:457.2305。
实施例16：(2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-3-乙氧基-4-羟基亚苄基]肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇(化合物16)的合成
Figure PCTCN2020097442-appb-000022
参考实施例1步骤1.4的方法，以乙基香兰素替代4-乙酰氨基苯甲醛得标题化合物，得到322mg白色固体(化合物16)。m.p.198℃； 1H NMR(DMSO-d 6):δ(ppm)10.43(s,1H),9.19(s,1H),7.99(s,1H),7.94(s,1H),7.66(s,1H),7.04(br,2H),6.92(d,1H,J＝8.0Hz),6.77(d,1H,J＝8.4Hz),5.75(d,1H,J＝7.2Hz),5.48(d,1H,J＝6.4Hz),5.44-5.43(m,1H),5.14(d,1H,J＝4.0Hz),4.86-4.84(m,1H),4.17(s,1H),4.09(q,2H,J＝6.8Hz),4.00(s,1H),3.72-3.52(m,2H),1.37(t,3H,J＝6.8Hz)；HRMS(ESI+)m/z[M+H] +calculated for C 19H 23N 7O 6:446.1783；found:446.1782。
实施例17：(2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-4-吗啉代亚苄基]肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇(化合物17)的合成
Figure PCTCN2020097442-appb-000023
参考实施例1步骤1.4的方法，以4-(吗啉-4-基)苯甲醛替代4-乙酰氨基苯甲醛得标题化合物，得到348mg白色固体(化合物17)。m.p.186℃； 1H NMR(DMSO-d 6):δ(ppm)10.42(s,1H),8.01(s,1H),7.97(s,1H),7.59(d,2H,J＝8.4Hz),7.02(br,2H),6.95(d,2H,J＝8.8Hz),5.79(d,1H,J＝6.4Hz),5.46(d,1H,J＝6.0Hz),5.29-5.26(m,1H),5.15(d,1H,J＝4.0Hz),4.69-4.65(m,1H),4.21-4.18(m,1H),3.97-3.95(m,1H),3.74(t,4H,J＝8.4Hz),3.71-3.56(m,2H),3.17(t,4H,J＝8.8Hz)；HRMS(ESI+)m/z[M+H] +calculated for C 21H 26N 8O 5:471.2099；found:471.2100。
实施例18：(2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-3,4,5-三甲氧基亚苄基]肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇(化合物18)的合成
Figure PCTCN2020097442-appb-000024
参考实施例1步骤1.4的方法，以3,4,5-三甲氧基苯甲醛替代4-乙酰氨基苯甲醛得标题化合物，得到352mg白色固体(化合物18)。m.p.246℃； 1H NMR(DMSO-d 6):δ(ppm)10.68(s,1H),8.01(s,1H),7.98(s,1H),7.16(s,2H),7.09(br,2H),5.75(d,1H,J＝7.2Hz),5.49-5.45(m,2H),5.12(s,1H),4.92-4.88(m,1H),4.15(s,1H),3.99(s,1H),3.84(s,6H),3.68(s,3H),3.72-3.52(m,2H)；HRMS(ESI+)m/z[M+H] +calculated for C 20H 25N 7O 7:476.1888；found:476.1887。
实施例19：(2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-4-(苄氧基)-3-甲氧基亚苄基]肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇(化合物19)的合成
Figure PCTCN2020097442-appb-000025
参考实施例1步骤1.4的方法，以4-(苄氧基)-3-甲氧基苯甲醛替代4-乙酰氨基苯甲醛得标题化合物，得到281mg白色固体(化合物19)。m.p.146℃； 1H NMR(DMSO-d 6):δ(ppm)10.54(s,1H),8.00(s,1H),7.99(s,1H),7.77(s,1H),7.47-4.33(m,5H),7.06(br,2H),7.03(s,2H),5.75(d,1H,J＝7.2H),5.48(d,1H,J＝6.4Hz),5.46(d,1H,J＝4.0Hz),5.13(d,1H,J＝4.0Hz),5.11(s,2H),4.90-4.85(m,1H),4.17-4.15(m,1H),3.99(s,1H),3.85(s,3H), 3.74-3.53(m,2H)；HRMS(ESI+)m/z[M+H] +calculated for C 25H 27N 7O 6:522.2096；found:522.2096。
实施例20：4-{E-{2-{6-氨基-9-[(2R,3R,4S,5R)-3,4-二羟基-5-(羟甲基)四氢呋喃-2-基]-9H-嘌呤吡啶-2-基}亚肼基}甲基}苯甲腈(化合物20)的合成
Figure PCTCN2020097442-appb-000026
参考实施例1步骤1.4的方法，以4-氰基苯甲醛替代4-乙酰氨基苯甲醛得标题化合物，得到373mg白色固体(化合物20)。m.p.276℃； 1H NMR(DMSO-d 6):δ(ppm)10.99(s,1H),8.11(s,1H),8.07(s,1H),7.91(d,2H,J＝8.4Hz),7.83(d,2H,J＝8.0Hz),7.13(br,2H),5.81(d,1H,J＝6.4Hz),5.44(d,1H,J＝6.4Hz),5.28-5.26(m,1H),5.15(d,1H,J＝4.8Hz),4.72-4.67(m,1H),4.23-4.20(m,1H),3.98(d,1H,J＝2.4Hz),3.75-3.57(m,2H)；HRMS(ESI+)m/z[M+H] +calculated for C 18H 18N 8O 4:411.1524；found:411.1525。
实施例21：放射性配体结合试验
1)实验材料
[3H]CGS21680(2-[对-(2-羧乙基)苯乙基氨基]-5’-N-乙基甲酰氨基腺苷，[羧基-1-乙基-3H(N)]-；250μCi)购自PerkinElmer Research Products公司(Boston，MA)。
稳定转染(人)A 2A腺苷受体的细胞膜在HEK-293细胞中制备。该细胞膜获自PerkinElmer Research Products公司(Boston，MA)。
CGS21680(2-[对-(2-羧乙基)苯乙氨基]-5’-N-乙基甲酰氨基腺苷)购自Selleck公司(上海，CN)。
所有其他试剂均为分析纯，并从商业来源获得。
2)实验方法
所用的A 2A腺苷受体都在细胞膜中表达。对化合物用DMSO(Solarbio,D8371-250ml)进行3倍连续稀释生成10种不同浓度(10μM、3.3μM、1.1μM、0.37μM、0.12μM、0.0412μM、0.0137μM、0.0046μM、0.0015μM、0.0005μM)的化合物源板，加入250nL化合物到384孔Opti-plate中，封口膜封口；1mL测定缓冲液(50mM Tris-HCl pH 7.4,10mM MgCl  2,1mM EDTA，1μg/mL腺苷脱氨酶)中加入20U hA 2A HEK-293细胞膜稀释,在稀释的细胞膜中加入0.75μCi[3H]CGS 21680(final 25nM),混匀；将配制好的细胞膜稀释液50μL转移到含有新化合物的384孔Opti-plate上，在25℃孵育90分钟；向UNIFILTER-96 GF/B滤板中加入100μL 0.5％聚乙烯亚胺溶液(PEI)，4℃浸泡90 min；然后用Cell Harvester转移500μL洗涤缓冲液/孔(50mM Tris-HCl pH 7.4,154mMNaCl)，清洗UNIFILTER-96 GF/B滤板2次；将Opti-plate中混合体系转移至清洗后的UNIFILTER-96 GF/B滤板中；500μL洗涤缓冲液/孔(50mM Tris-HCl pH 7.4,154mMNaCl)清洗UNIFILTER-96 GF/B滤板9次；37℃温箱孵育3min；每孔加入40μL ULTIMA GOLD闪烁液(Perkin Elmer,Cat#77-16061)，MicroBeta液体闪烁计数器(liquid scintillation counter，PerkinElmer)读取CPM(count per minute)值。根据CPM值计算出[3H]CGS21680特异性结合百分比，％specific binding of[3H]CGS21680＝(CPM sample-CPM Low  Control)/(CPM High  Control-CPM Low  Control)*100,High Control为0.5％DMSO，Low Control为100μM CGS21680。根据化合物浓度与[3H]CGS21680特异性结合百分比进行曲线似合计算IC 50值。
3)实验结果
抑制常数(K i)值由IC 50值根据Cheng和Prusoff等式K i＝IC 50/(1+[S]/K m)计算得到，其中[S]是放射性配体的浓度(25nM)，K m为[3H]CGS21680的人类A 2AAR解离常数(22nM)。本申请的化合物1-20与A 2A腺苷受体结合的抑制常数K i见表1。
表1化合物与A 2A腺苷受体的结合测试结果
化合物 IC 50(nM) K i(nM)
化合物1 2840 1329
化合物2 3.9 1.8
化合物3 >10,000 6276
化合物4 142.5 66.7
化合物5 11.7 5.5
化合物6 369.2 172.8
化合物7 1712 801.4
化合物8 444.9 208.3
化合物9 43.6 20.4
化合物10 >10,000 6624.8
化合物11 130.9 61.3
化合物12 461.8 216.2
化合物13 479.3 224.4
化合物14 2790 1306
化合物15 13.7 6.4
化合物16 3465 1622
化合物17 1708 799.5
化合物18 >10,000 5495
化合物19 216.4 101.3
化合物20 18.07 8.5
实施例22：腺苷受体A 2A cAMP试验
1)实验材料
实验所需试剂及耗材：DMEM/F12、G418、Penicillin-Streptomycin、Versene Solution、HEPES、Hank’s Buffered Saline Solution、PBS(pH 7.4,1×,sterile)、FBS、BSA Stabilizer 7.5％，Rolipram(咯利普兰)，NECA，分别购自Gibico、Hyclone和Sigma公司。
Figure PCTCN2020097442-appb-000027
Ultra cAMP kit试剂盒(Eu-cAMP示踪剂、Ulight-anti-cAMP剂、cAMP检测缓冲液)和hADORA 2A-HEK293细胞购自PerkinElmer Research Products公司(Boston，MA)。所有其他试剂均为分析纯，并从商业来源获得。384孔聚丙烯微孔板和384孔白色固体板分别购自Labcyte和Corning。
实验所需仪器：TECAN自动化移液工作站，Echo超声波移液系统和EnVison酶标仪分别购自TECAN，Labcyte及Envision。
2)实验方法
稳定表达人腺苷受体A 2A的细胞(hADORA 2A-HEK293细胞)使用含有10％FBS,1X Penicillin-Streptomycin和400μg/ml G418的DMEM/F12培养基培养在37℃ 5％CO 2的环境中。于实验前将细胞用Versene溶液消化，使用离心机在200g，室温下离心5分钟收集细胞，最后用测定缓冲液(Hank’s缓冲盐水溶液，含有5mM HEPES，0.1％BSA稳定剂和10μM咯利普兰，pH 7.4)重悬。使用TECAN自动化移液工作站将化合物在384孔聚丙烯微孔板中用DMSO进行3倍梯度稀释到11个浓度点以制备化合物源板，化合物的11个浓度点分别为10mM,3.33mM,1.11mM,0.37mM,0.12mM,0.041mM,0.013mM,4.57×10 -3mM,1.52×10 -3mM,5×10 -4mM和1.7×10 -4mM。使用Echo超声波移液系统(Labcyte)将测试化合物从化合物源板转移到测定板，化合物的转移体积为10nl/孔。将hADORA 2A-HEK293细胞悬液用测定缓冲液稀释到30000个细胞/ml,将细胞悬液以10μl/孔(300个细胞/孔)的体积转移到测定板中。将测定板以150g离心1分钟，并在室温下预孵育30分钟。将Eu-cAMP示踪剂工作溶液(Eu-cAMP示踪剂40μl,cAMP检测缓冲液1.96ml)(5μl/孔)加入到测定板中，然后将Ulight-anti-cAMP工作溶液(Ulight-anti-cAMP剂13μl,cAMP检测缓冲液1.95ml)(5μl/孔)加入测定板中。将测定板在150g下旋转30秒，并在室温下温育，持续30分钟。使用EnVison酶标仪(EnVision multimode plate reader，PerkinElmer)测试最终溶液中的环磷酸腺苷水平 (λ ex＝320nm,λ em＝665nm&615nm)。计算待测化合物与A 2A腺苷受体作用时，刺激产生环磷酸腺苷水平的EC 50(nM)值。化合物A 2A受体激动剂效价表示为化合物与A 2A腺苷受体作用，刺激环磷酸腺苷产生水平的EC 50(nM)值。
3)实验结果
待测化合物与A 2AAR作用时，刺激环AMP水平的EC 50(nM)值见表2。结果显示，本申请制备的化合物2、5、9、15和20都显示为hA 2AAR激动剂。化合物2、5、9、15和20与A 2AAR作用时，其抑制常数K i和刺激cAMP的EC 50值基本都在相同纳摩尔范围。
表2化合物A 2A激动剂功能测定的EC 50值测试结果
化合物 cAMP EC 50(nM)
化合物2 0.64
化合物5 4.1
化合物9 5.7
化合物15 17.9
化合物20 15.3
实施例23：血脑屏障开放方法动物实验
1)实验材料
荧光素标记葡聚糖FITC-Dextran(CAS:60842-46-8)分子量为10000MW，购自梯希爱(上海)化成工业发展有限公司；PBS溶液，实验动物SD大鼠从商业来源获得。
2)实验方法
用PBS配制FITC-Dextran溶液六个浓度梯度(0.001、0.01、0.1、1、0.5、10μg/ml)使用酶标仪(λex＝490nm,λem＝520nm)制做FITC-Dextran浓度标准曲线；另配制10mg/ml FITC-Dextran溶液，化合物5加入PBS溶液配制成1mg/ml溶液，取1ml 10mg/ml FITC-Dextran溶液和1ml 1mg/ml化合物5的PBS溶液配制成给药溶剂；取1ml 10mg/ml FITC-Dextran溶液和1ml PBS溶液配制成空白对照溶液；取6只SD大鼠尾静脉分别注射2ml给药溶剂，同时另取6只SD大鼠尾静脉注射2ml空白对照溶液；30分钟后取出所有SD大鼠脑组织，进行匀浆后10000rpm离心15min，取上清液待测；将待测液使用酶标仪(λex＝490nm,λem＝520nm)进行荧光检测。
3)实验结果
将测得的酶标仪荧光数值，根据得到的FITC-Dextran浓度标准曲线换算出相应的FITC-Dextran平均浓度，结果见表3。结果表明大分子FITC-Dextran本身无法通过血脑屏障，而添加有化合物5的FITC-Dextran能够通过BBB进入脑内，说明化合物5能够开放血脑屏障。
表3 SD大鼠脑内FITC-Dextran浓度检测结果
Figure PCTCN2020097442-appb-000028
尽管本申请的具体实施方式已经得到详细的描述，本领域技术人员将会理解，根据已经公开的所有教导，可以对那些细节进行各种修改和替换，这些改变均在本申请的保护范围之内。本申请的全部范围由所附权利要求及其任何等同物给出。本申请所引用的出版物和专利文献通过参考引入本文。

Claims (21)

  1. 通式(I)所示化合物或其立体异构体、药学可接受的盐、其药学可接受的水合物或溶剂合物、其药学可接受的酯，
    Figure PCTCN2020097442-appb-100001
    其中：
    n为1、2、3、4或5；
    R代表连接在苯环上的取代基，每个R各自独立地选自氢、卤素、氰基、苯甲氧基、卤代的苯甲氧基、C 1-6烷基、卤代的C 1-6烷基、C 1-6烷氧基、羟基、C 1-6烷基氨基、二(C 1-6烷基)氨基、苯氨基、二苯基氨基、苯基氨基、-NHC(O)R 10、芳基、杂芳基、环烷基、杂环烷基，其中R 10为C 1-6烷基。
  2. 权利要求1所述的化合物或其立体异构体、药学可接受的盐、其药学可接受的水合物或溶剂合物、其药学可接受的酯，其中n为1、2或3。
  3. 权利要求1所述的化合物或其立体异构体、药学可接受的盐、其药学可接受的水合物或溶剂合物、其药学可接受的酯，其中，每个R各自独立地选自氢、氟、氯、溴、碘、氰基、苯甲氧基、氟代苯甲氧基、C 1-4烷基、卤代的C 1-4烷基、C 1-4烷氧基、羟基、C 1-4烷基氨基、二(C 1-4烷基)氨基、苯氨基、二苯基氨基、-NHC(O)R 10、苯基、吡啶基、吡咯烷基、环戊基、环己基、吗啉基、咪唑基，其中R 10为C 1-4烷基。
  4. 权利要求1所述的化合物或其立体异构体、药学可接受的盐、其药学可接受的水合物或溶剂合物、其药学可接受的酯，其中，每个R各自独立地选自氢、氟、氯、溴、碘、氰基、苯甲氧基、氟代苯甲氧基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、叔戊基、新戊基、己基、三氟甲基、二氟代甲基、氟代甲基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、仲丁氧基、正戊氧基、正己氧基，羟基、甲氨基、乙氨基、丙氨基、丁氨基、二甲氨基、二乙 氨基、二丙氨基、二丁氨基、苯氨基、二苯基氨基、乙酰氨基、甲酰氨基、丙酰胺基、苯基、吡啶基、吡咯烷基、环戊基、环己基、吗啉基、咪唑基。
  5. 权利要求1所述的化合物或其立体异构体、药学可接受的盐或水合物，其中，每个R各自独立地选自氢、甲氧基、乙氧基、乙酰基、乙酰氨基、苄氧基、三氟甲基、二苯基氨基、4-氟苄基氧基、氯、吡啶-2-基、苯基、吡咯烷-1-基、1H-咪唑-1-基、丙氧基、二乙氨基、羟基、吗啉-4-基、氰基。
  6. 权利要求1所述的化合物或其立体异构体、药学可接受的盐、其药学可接受的水合物或溶剂合物、其药学可接受的酯，其中所述化合物具有式I-1所示的结构，
    Figure PCTCN2020097442-appb-100002
    其中，R 1、R 2、R 3、R 4各自独立地选自氢、卤素、氰基、苯甲氧基、卤代的苯甲氧基、C 1-6烷基、卤代的C 1-6烷基、C 1-6烷氧基、羟基、C 1-6烷基氨基、二(C 1-6烷基)氨基、苯氨基、二苯基氨基、苯基氨基、-NHC(O)R 10、芳基、杂芳基、环烷基、杂环烷基，其中R 10为C 1-6烷基；
    例如，R 1、R 2、R 3、R 4各自独立地选自氢、氟、氯、溴、碘、氰基、苯甲氧基、氟代苯甲氧基、C 1-4烷基、卤代的C 1-4烷基、C 1-4烷氧基、羟基、C 1-4烷基氨基、二(C 1-4烷基)氨基、苯氨基、二苯基氨基、-NHC(O)R 10、苯基、吡啶基、吡咯烷基、环戊基、环己基、吗啉基、咪唑基，其中R 10为C 1-4烷基；
    例如，R 1、R 2、R 3、R 4各自独立地选自氢、氟、氯、溴、碘、氰基、苯甲氧基、氟代苯甲氧基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、叔戊基、新戊基、己基、三氟甲基、二氟代甲基、氟代甲基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、仲丁氧基、正戊氧基、正己氧基，羟基、甲氨基、乙氨基、丙氨基、丁氨基、二甲氨基、二乙氨基、二丙氨基、二丁氨基、苯氨基、二苯基氨基、乙酰氨基、甲酰氨基、丙酰胺基、苯基、吡啶基、吡咯烷基、环戊基、环己基、吗啉基、咪唑基；
    例如，R 1、R 2、R 3、R 4各自独立地选自氢、甲氧基、乙氧基、乙酰氨基、苄氧 基、三氟甲基、二苯基氨基、4-氟苄基氧基、氯、吡啶-2-基、苯基、吡咯烷-1-基、1H-咪唑-1-基、丙氧基、二乙氨基、羟基、吗啉-4-基、氰基；
    例如，R 1为氢或甲氧基；
    例如，R 2为氢、甲氧基、乙酰氨基、苄氧基、三氟甲基、二苯基氨基、4-氟苄基氧基、氯、吡啶-2-基、苯基、吡咯烷-1-基、1H-咪唑-1-基、丙氧基、二乙氨基、羟基、吗啉-4-基、或氰基；
    例如，R 3为氢、苄氧基、三氟甲基、乙氧基、甲氧基；
    例如，R 4为氢、三氟甲基或氰基。
    例如，R 1、R 4各自独立地为氢；R 2为二(C 1-6烷基)氨基、C 1-6烷基氨基、苯甲氧基、卤代的苯甲氧基、苯基、卤代苯基或氰基；R 3为氢或苄氧基。
    例如，R 1、R 3、R 4各自独立地为氢；R 2为二(C 1-6烷基)氨基、C 1-6烷基氨基、苯甲氧基、卤代的苯甲氧基、苯基、卤代苯基或氰基。
  7. 权利要求1所述的化合物或其立体异构体、药学可接受的盐、其药学可接受的水合物或溶剂合物、其药学可接受的酯，其中所述化合物选自：
    N-{4-{(E)-{2-{6-氨基-9-[(2R,3R,4S,5R)-3,4-二羟基-5-(羟甲基)四氢呋喃-2-基]-9H-嘌呤-2-基}亚肼基}甲基}苯基}乙酰胺；
    (2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-3,4-二(苄氧基)亚苄基]肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇；
    (2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-2,4-双(三氟甲基)亚苄基]肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇；
    (2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-4-(二苯基氨基)苯亚甲基]肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇；
    (2R,3R,4S,5R)-2-{6-氨基-2-{2-{(E)-4-[(4-氟苄基)氧基]苯亚甲基}肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇；
    (2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-3-(苄氧基)亚苄基]肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇；
    (2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-4-氯-3-(三氟甲基)亚苄基]肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇；
    (2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-4-(吡啶-2-基)亚苄基]肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇；
    (2R,3R,4S,5R)-2-{2-{2-[(E)-[1,1'-联苯]-4-基亚甲基]肼基}-6-氨基-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇；
    (2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-4-(吡咯烷-1-基)亚苄基]肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇；
    (2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-4-(三氟甲基)亚苄基]肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇；
    (2R,3R,4S,5R)-2-{2-{2-[(E)-4-(1H-咪唑-1-基)亚苄基]肼基}-6-氨基-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇；
    (2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-4-丙氧基亚苄基]肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇；
    2-{(E)-{2-{6-氨基-9-[(2R,3R,4S,5R)-3,4-二羟基-5-(羟甲基)四氢呋喃-2-基]-9H-嘌呤吡啶-2-基}亚肼基}甲基}苯甲腈；
    (2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-4-(二乙基氨基)亚苄基]肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇；
    (2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-3-乙氧基-4-羟基亚苄基]肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇；
    (2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-4-吗啉代亚苄基]肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇；
    (2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-3,4,5-三甲氧基亚苄基]肼基}-9H-嘌呤-9-基}-5-(羟甲基)四氢呋喃-3,4-二醇；
    (2R,3R,4S,5R)-2-{6-氨基-2-{2-[(E)-4-(苄氧基)-3-甲氧基亚苄基]肼基}-9H-嘌呤-9- 基}-5-(羟甲基)四氢呋喃-3,4-二醇；
    4-{E-{2-{6-氨基-9-[(2R,3R,4S,5R)-3,4-二羟基-5-(羟甲基)四氢呋喃-2-基]-9H-嘌呤吡啶-2-基}亚肼基}甲基}苯甲腈。
  8. 制备权利要求1～5任一项所述的通式(I)所示化合物或其立体异构体、药学可接受的盐、其药学可接受的水合物或溶剂合物、其药学可接受的酯的方法，包括：
    Figure PCTCN2020097442-appb-100003
    式V化合物与式VI所示取代的苯甲醛反应，得到通式(I)所示化合物，其中R和n的定义同权利要求1～4所述，
    优选地，式V化合物与式VI所示取代的苯甲醛在甲醇溶液中于微波加热70～90℃的条件下进行反应；
    优选地，式V化合物由式IV化合物在40～60℃下经过水合肼的肼解作用生成；
    Figure PCTCN2020097442-appb-100004
    优选地，式IV化合物由式III化合物在氨的甲醇溶液中90～110℃氨解生成；
    Figure PCTCN2020097442-appb-100005
    优选地，式III化合物由式VII化合物与式II化合物在110～130℃下加入催化剂四氯化锡发生取代反应生成。
  9. 一种药物组合物，其包括至少一种权利要求1～7任一项所述的化合物或其立体异构体、药学可接受的盐、其药学可接受的水合物或溶剂合物、其药学可接受的酯，以及一种或多种药学上可接受的载体或赋形剂。
  10. 权利要求1～7任一项所述的化合物或其立体异构体、药学可接受的盐、其药学可接受的水合物或溶剂合物、其药学可接受的酯或者权利要求9所述药物组合物在制备作为A 2A腺苷受体激动剂的药物中的用途，或者
    在制备用于预防和/或治疗人的病理状态或症状的药物中的用途，其中所述人的病理状态或症状是与A 2A腺苷受体的活性相关的，并且预防或治疗该人的病理状态或症状需要激动A 2A腺苷受体的活性。
  11. 根据权利要求10所述的用途，其中人的病理状态或症状选自：自身免疫性刺激，炎症，过敏性疾病，皮肤病，感染性疾病，消耗病，神经性疼痛，开放性创伤，由药物疗法造成的不良反应，心血管病症，缺血再灌注损伤，痛风，化学外伤，热外伤，糖尿病性肾病，令廉状细胞病，蹄叶炎，铸工病，青光眼，高眼压，脊髓损伤，心肌梗塞，以及急性心肌梗塞。
  12. 权利要求1～7任一项所述的化合物或其立体异构体、药学可接受的盐、其药学可接受的水合物或溶剂合物、其药学可接受的酯或者权利要求9所述药物组合物在制备用于诊断人心肌灌注异常的药物中的用途，或者在制备作为管状血管扩张剂的药物中的用途。
  13. 权利要求1～7任一项所述的化合物或其立体异构体、药学可接受的盐、其药学可接受的水合物或溶剂合物、其药学可接受的酯或者权利要求9所述药物组合物 在制备用于增加接受治疗药物的受治疗者血脑屏障通透性的药物中的用途，其中所述受治疗者对于递送所述治疗药物穿过血脑屏障受益于增加的血脑屏障通透性。
  14. 根据权利要求13所述的用途，其中所述治疗药物选自：治疗中枢神经系统的病患或病症的药物，神经毒剂解毒剂，治疗脑胶质瘤的药物。
  15. 一种药物组合物，其包括：
    至少一种权利要求1～7任一项所述的化合物或其立体异构体、药学可接受的盐、其药学可接受的水合物或溶剂合物、其药学可接受的酯，和
    需要穿过血脑屏障的药物，其选自治疗中枢神经系统的病患或病症的药物，神经毒剂解毒剂，治疗脑胶质瘤的药物，以及
    一种或多种药学上可接受的载体或赋形剂。
  16. 一种预防和/或治疗人的病理状态或症状的方法，包括给予需要这种治疗的患者治疗有效量的至少一种权利要求1～7任一项所述的化合物或其立体异构体、药学可接受的盐、其药学可接受的水合物或溶剂合物、其药学可接受的酯或者或者权利要求9所述药物组合物，其中所述人的病理状态或症状是与A 2A腺苷受体的活性相关的，并且预防或治疗该人的病理状态或症状需要激动A 2A腺苷受体的活性；
    优选地，所述人的病理状态或症状选自：自身免疫性刺激，炎症，过敏性疾病，皮肤病，感染性疾病，消耗病，神经性疼痛，开放性创伤，由药物疗法造成的不良反应，心血管病症，缺血再灌注损伤，痛风，化学外伤，热外伤，糖尿病性肾病，令廉状细胞病，蹄叶炎，铸工病，青光眼，高眼压，脊髓损伤，心肌梗塞，以及急性心肌梗塞。
  17. 权利要求1～7任一项所述的通式(I)所示化合物或其立体异构体、药学可接受的盐、其药学可接受的水合物或溶剂合物、其药学可接受的酯，其用于预防和/或治疗人的病理状态或症状，所述人的病理状态或症状是与A 2A腺苷受体的活性相关的，并且预防或治疗该人的病理状态或症状需要激动A 2A腺苷受体的活性，
    优选地，所述人的病理状态或症状选自：自身免疫性刺激，炎症，过敏性疾病，皮肤病，感染性疾病，消耗病，神经性疼痛，开放性创伤，由药物疗法造成的不良反应，心血管病症，缺血再灌注损伤，痛风，化学外伤，热外伤，糖尿病性肾病，令廉状细胞病，蹄叶炎，铸工病，青光眼，高眼压，脊髓损伤，心肌梗塞，以及急性心肌梗塞。
  18. 权利要求1～7任一项所述的通式(I)所示化合物或其立体异构体、药学可接受的盐、其药学可接受的水合物或溶剂合物、其药学可接受的酯，其用作A 2A腺苷受体激动剂或管状血管扩张剂，或者
    其用于诊断人心肌灌注异常，或者
    其用于增加接受治疗药物的受治疗者的血脑屏障通透性，所述受治疗者对于递送所述治疗药物穿过血脑屏障受益于增加的血脑屏障通透性，
    优选地，所述治疗药物选自：治疗中枢神经系统的病患或病症的药物，神经毒剂解毒剂，治疗脑胶质瘤的药物。
  19. 诊断人心肌灌注异常的方法，包括给予需要这种诊断的患者诊断有效量的权利要求1～7任一项所述的化合物或其立体异构体、药学可接受的盐、其药学可接受的水合物或溶剂合物、其药学可接受的酯或者权利要求9所述药物组合物。
  20. 一种增加接受治疗药物的受治疗者的血脑屏障通透性的方法，该方法包括包括给予受治疗者有效量的权利要求1～7任一项所述的化合物或其立体异构体、药学可接受的盐、其药学可接受的水合物或溶剂合物、其药学可接受的酯或者权利要求9所述药物组合物，其中所述受治疗者对于递送所述治疗药物穿过血脑屏障受益于增加的血脑屏障通透性。
  21. 优选地，所述治疗药物选自：治疗中枢神经系统的病患或病症的药物，神经毒剂解毒剂，治疗脑胶质瘤的药物。
PCT/CN2020/097442 2019-06-21 2020-06-22 具有a2a腺苷受体激动活性的2-苄叉肼基腺苷类化合物 WO2020253872A1 (zh)

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JP2021576169A JP2022545763A (ja) 2019-06-21 2020-06-22 Ａ２ａアデノシン受容体アゴニスト活性を有する２－ベンジリデンヒドラジノアデノシン化合物
EP20826764.1A EP3988559A4 (en) 2019-06-21 2020-06-22 2-BENZYLIDENE HYDRAZINOADENOSINE COMPOUNDS WITH A2A ADENOSINE RECEPTOR AGNOSTIC ACTIVITY

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