WO2022183963A1 - 一种8-(吡啶酰胺)取代香豆素类化合物及其制备方法和应用 - Google Patents

一种8-(吡啶酰胺)取代香豆素类化合物及其制备方法和应用 Download PDF

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WO2022183963A1
WO2022183963A1 PCT/CN2022/077640 CN2022077640W WO2022183963A1 WO 2022183963 A1 WO2022183963 A1 WO 2022183963A1 CN 2022077640 W CN2022077640 W CN 2022077640W WO 2022183963 A1 WO2022183963 A1 WO 2022183963A1
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group
substituted coumarin
sirt2
substituted
pyridine
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French (fr)
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李燕
陈晓光
张小曦
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朗捷睿(苏州)生物科技有限公司
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Priority to JP2023554321A priority Critical patent/JP2024508558A/ja
Priority to EP22762428.5A priority patent/EP4303219A1/en
Publication of WO2022183963A1 publication Critical patent/WO2022183963A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the application belongs to the technical field of medicine, in particular to a kind of 8-(pyridinamide) substituted coumarin compound and its preparation method and application, in particular to an 8- (Pyridinamide) substituted coumarin compounds and preparation method and application thereof.
  • Parkinson's disease is a common neurodegenerative disease, and its main clinical manifestations are slowness of movement, muscle rigidity and resting tremor.
  • the pathological changes of Parkinson's disease are mainly reflected in the degeneration and necrosis of dopaminergic neurons in the substantia nigra of the midbrain, resulting in a significant decrease in the content of dopamine in the striatum.
  • People with Parkinson's disease suffer a heavy burden both physically and psychologically.
  • the treatment drugs for Parkinson's disease (such as levodopa) on the market are mainly aimed at relieving the symptoms of the disease, and long-term use of such drugs brings serious side effects to patients. Therefore, it is of great significance to explore new treatments for Parkinson's disease and discover new drugs for Parkinson's disease.
  • Sirtuin is a class of histone acetyltransferases whose enzymatic activity is mainly manifested in the removal of acetyl groups on lysine residues in histones or other proteins. In this process, Sirtuin relies on nicotinamide adenine dinucleotide (NAD+) as one of its substrates.
  • NAD+ nicotinamide adenine dinucleotide
  • the gene sequences of the Sirtuin family are relatively conserved in different species. Crystal structure studies have shown that Sirtuin is composed of large and small domains. The large domain sequence is relatively conserved and has characteristics of NAD and NADP conjugating enzymes. In contrast, the small domain sequence changes are relatively large.
  • the active center of Sirtuin is located in the cleft portion between the large and small domains.
  • the human Sirtuin family includes seven members: SIRT1-7, which are located in different subcellular sites, bind to and act on different substrates, including p53, ⁇ -tubulin, FOXO, etc., to achieve different biological regulatory functions.
  • the biological function of Sirtuin is the current research hotspot in life medicine, and its function is mainly reflected in the fields related to metabolism, aging, longevity, stress response and genome stability.
  • SIRT2 As an important member of the Sirtuin family, SIRT2 is mainly distributed in the cytoplasm, and its substrate proteins include ⁇ -tubulin, histone H4, p53, FOXO and 14-3-3 protein. Functional studies of SIRT2 show that: SIRT2 regulates the process of cell mitosis by deacetylating H4-K16; SIRT2 maintains genome stability by activating the activity of the Anaphase Promoting Complex/Cyclosome (APC/C) system ; SIRT2 mediates the interaction of Receptor-interacting proteins 1 and 3 (RIP1 and RIP3) to regulate the process of cell necrosis.
  • APC/C Anaphase Promoting Complex/Cyclosome
  • SIRT2 inhibiting the activity of SIRT2 has potential value in the treatment of Parkinson's disease, which is embodied in: (1) SIRT2 is highly expressed in the central nervous system of the adult brain and regulates related physiological metabolism; (2) SIRT2 siRNA and the small molecule inhibitor AGK2 can rescue the neurotoxicity caused by ⁇ -synulein, and AGK2 can also protect neurons from apoptosis in a transgenic Drosophila model of Parkinson's disease in a dose-dependent manner in vivo; (3) SIRT2 is deacetylated by deacetylation FOXO3a increases the expression of Bim at the RNA and protein levels, promoting N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (N-methyl-4-phenyl-1,2,3,6 -tetrahydropyridine, MPTP)-induced apoptosis in a Parkinson's disease cell model and in the brain of a MPTP-induced mouse model.
  • SIRT2 is highly expressed in the central
  • SIRT2 small molecule inhibitors in the prior art include the following:
  • SIRT2 small molecule inhibitors Given the potential activity of SIRT2 small molecule inhibitors in the treatment of Parkinson's disease, the design and synthesis of new SIRT2 inhibitors is one of the current research hotspots.
  • the purpose of this application is to provide a kind of 8-(pyridine amide) substituted coumarin compound and its preparation method and application, especially to provide a kind of 8-(pyridine amide that can inhibit the activity or expression of SIRT2 ) substituted coumarin compounds and preparation method and application thereof.
  • This application has developed a new class of 8-(pyridinamide) substituted coumarin compounds with significant SIRT2 inhibitory activity and good selectivity for SIRT2, which can be used for Parkinson's disease and metabolic diseases , tumor prevention and treatment.
  • the present application provides an 8-(pyridine amide) substituted coumarin compound, and the structure of the 8-(pyridine amide) substituted coumarin compound is shown in formula (I):
  • a ring is independently selected from the group consisting of phenyl, naphthyl and 5-14 membered aromatic heterocyclyl (eg 5 membered aromatic heterocyclyl, 6 membered aromatic heterocyclyl, 7 membered aromatic heterocyclyl, 8-membered aromatic heterocyclic group, 9-membered aromatic heterocyclic group, 10-membered aromatic heterocyclic group, 11-membered aromatic heterocyclic group, 12-membered aromatic heterocyclic group, 13-membered aromatic heterocyclic group, 14-membered aromatic heterocyclic group);
  • aromatic heterocyclyl eg 5 membered aromatic heterocyclyl, 6 membered aromatic heterocyclyl, 7 membered aromatic heterocyclyl, 8-membered aromatic heterocyclic group, 9-membered aromatic heterocyclic group, 10-membered aromatic heterocyclic group, 11-membered aromatic heterocyclic group, 12-membered aromatic heterocyclic group, 13-membered aromatic heterocyclic group, 14-membered aromatic heterocycl
  • R a is each independently is selected from the group consisting of: deuterium, halogen, hydroxyl, sulfhydryl, amino, cyano, nitro, azido, mesyl, isopropylsulfonyl, benzenesulfonyl, aminosulfonyl, mesylate, Isopropanesulfonate, benzenesulfonate, trifluoromethyl, trifluoromethyloxy, formamido, C 1-8 alkyloxy, C 1-8 alkylcarbonyl, C 1-8 Alkyloxycarbonyl, C 1-8 alkyl, C 3-8 cycloalkyl and phenyl;
  • the C 1-8 alkyl, C 3-8 cycloalkyl and phenyl are unsubstituted or replaced by 1-5 (eg 1, 2, 3, 4, 5 ) R substituted; said R b is each independently selected from the group consisting of: deuterium, halogen, hydroxyl, mercapto, amino, cyano, nitro, azido, mesyl, isopropylsulfonyl, benzenesulfonyl Acyl, aminosulfonyl, mesylate, isopropanesulfonate, benzenesulfonate, trifluoromethyl, trifluoromethyloxy, formamido and C 1-8 alkylcarbonyl.
  • C 1-8 refers to the number of carbon atoms of the substituent group is 1, 2, 3, 4, 5, 6, 7, 8;
  • C 3-8 refers to the number of carbon atoms of the substituent group 3, 4, 5, 6, 7, 8.
  • the 8-(pyridinamide) substituted coumarin compounds involved in this application are a brand-new compound structure, and their in vitro SIRT2 inhibitory activity reaches more than 50%, of which the in vitro SIRT2 inhibitory activity IC 50 of 18 compounds reaches micromolar In particular, the IC 50 values of 11 compounds reached the level of 10 -7 mol/L, and the IC 50 values of 4 compounds reached the level of 10 -8 mol/L. Cells have a significant protective effect. Therefore, it can be widely used in the preparation of medicines for the treatment and/or prevention of diseases or conditions related to excessive SIRT2 activity or overexpression of SIRT2, or for the preparation of medicines for the treatment and/or prevention of Parkinson's disease, metabolic disease and tumor.
  • ring A is independently selected from the group consisting of phenyl, naphthyl and 5-14 membered aromatic heterocyclyl (eg 5 membered aromatic heterocyclyl, 6 membered aromatic heterocyclyl, 7-membered aromatic heterocyclic group, 8-membered aromatic heterocyclic group, 9-membered aromatic heterocyclic group, 10-membered aromatic heterocyclic group, 11-membered aromatic heterocyclic group, 12-membered aromatic heterocyclic group, 13-membered aromatic heterocyclic group, 14-membered aromatic heterocyclic group membered aromatic heterocyclic group);
  • aromatic heterocyclyl eg 5 membered aromatic heterocyclyl, 6 membered aromatic heterocyclyl, 7-membered aromatic heterocyclic group, 8-membered aromatic heterocyclic group, 9-membered aromatic heterocyclic group, 10-membered aromatic heterocyclic group, 11-membered aromatic heterocyclic group, 12-membered aromatic heterocyclic group, 13-membered aromatic heterocyclic group
  • R a is each independently is selected from the group consisting of: deuterium, halogen, hydroxyl, sulfhydryl, amino, cyano, nitro, azido, mesyl, isopropylsulfonyl, benzenesulfonyl, aminosulfonyl, mesylate, Isopropanesulfonate, benzenesulfonate, trifluoromethyl, trifluoromethyloxy, formamido, C 1-6 alkyloxy, C 1-6 alkylcarbonyl, C 1-6 Alkyloxycarbonyl, C 1-6 alkyl, C 3-6 cycloalkyl and phenyl;
  • the C 1-6 alkyl, C 3-6 cycloalkyl and phenyl are unsubstituted or replaced by 1-5 (eg 1, 2, 3, 4, 5 ) R substituted; said R b is each independently selected from the group consisting of: deuterium, halogen, hydroxyl, mercapto, amino, cyano, nitro, azido, mesyl, isopropylsulfonyl, benzenesulfonyl Acyl, aminosulfonyl, mesylate, isopropanesulfonate, benzenesulfonate, trifluoromethyl, trifluoromethyloxy, formamido and C 1-6 alkylcarbonyl.
  • C 1-6 means that the number of carbon atoms of the substituent is 1, 2, 3, 4, 5 and 6; C 3-6 means that the number of carbon atoms of the substituent is 3 or 4 , 5, 6.
  • R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, mercapto, amino, cyano, nitro, azide, methanesulfonyl, Isopropanesulfonyl, benzenesulfonyl, aminosulfonyl, mesylate, isopropanesulfonate, benzenesulfonate, trifluoromethyl, trifluoromethyloxy, formamido, C 1 -4 alkyloxy, C 1-4 alkylcarbonyl, C 1-4 alkyloxycarbonyl, C 1-4 alkyl and phenyl.
  • C 1-4 means that the number of carbon atoms of the substituent is 1, 2, 3 or 4.
  • R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, mercapto, amino, cyano, nitro, mesyl, trifluoromethyl , trifluoromethyloxy, formamido, C 1-4 alkyloxy, C 1-4 alkylcarbonyl and C 1-4 alkyl;
  • X is independently selected from N or C.
  • C 1-4 means that the number of carbon atoms of the substituent is 1, 2, 3 or 4.
  • the 8-(pyridinamide) substituted coumarin compounds are selected from the following structures (represented by structural formula or by systematic name respectively):
  • the present application provides the stereoisomer of the 8-(pyridinamide) substituted coumarin compound as described in the first aspect, a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same;
  • the pharmaceutical composition further comprises pharmaceutically acceptable pharmaceutical excipients, such as carriers, diluents, excipients, fillers, binders, wetting agents, disintegrants, emulsifiers, cosolvents, Solubilizers, osmotic pressure regulators, surfactants, coating materials, colorants, pH regulators, antioxidants, bacteriostatic agents or buffers, etc.
  • pharmaceutical excipients such as carriers, diluents, excipients, fillers, binders, wetting agents, disintegrants, emulsifiers, cosolvents, Solubilizers, osmotic pressure regulators, surfactants, coating materials, colorants, pH regulators, antioxidants, bacteriostatic agents or buffers, etc.
  • the pharmaceutically acceptable salts of 8-(pyridineamide) substituted coumarin compounds involved in the present application are salts formed by 8-(pyridineamide) substituted coumarin compounds and an acid selected from the group consisting of: hydrochloric acid, hydrogen Bromic acid, p-toluenesulfonic acid, tartaric acid, maleic acid, lactic acid, methanesulfonic acid, sulfuric acid, phosphoric acid, citric acid, acetic acid or trifluoroacetic acid.
  • Preferred are hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid or trifluoroacetic acid.
  • the present application provides a preparation method of 8-(pyridine amide) substituted coumarin compounds as described in the first aspect, the preparation method comprising:
  • the preparation method of 4-(2-oxo-2H-chromene-8-carboxamido)pyridine-2-sulfonyl chloride comprises the following steps:
  • the preparation method of the 4-(2-oxo-2H-chromene-8-carboxamido)pyridine-2-sulfonyl chloride comprises the following steps:
  • n-butyllithium (n-hexane solution) was slowly added to anhydrous tetrahydrofuran solution of 8-bromocoumarin at -78°C under nitrogen protection. After stirring at -78 °C for 3 h, the solution was frozen in a liquid nitrogen bath and then evacuated, followed by the introduction of CO gas generated by the reaction of BaCO with concentrated sulfuric acid . The mixture was stirred at -78°C for 2 hours, then quenched with saturated aqueous NH4Cl at room temperature. The pH was adjusted to about 5 with hydrochloric acid, extracted three times with ethyl acetate, washed once with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate and concentrated.
  • Coumarin-8-carboxylic acid was obtained by silica gel column purification.
  • the present application provides a stereoscopic 8-(pyridineamide) substituted coumarin compound as described in the first aspect or an 8-(pyridineamide) substituted coumarin compound as described in the second aspect
  • Use of an isomer, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the same in the manufacture of a medicament for the treatment and/or prevention of a disease or condition associated with excessive SIRT2 activity or SIRT2 overexpression.
  • the disease or condition associated with excessive SIRT2 activity or SIRT2 overexpression includes Parkinson's disease, metabolic disease or tumor.
  • the present application provides a stereoscopic 8-(pyridineamide) substituted coumarin compound as described in the first aspect or an 8-(pyridineamide) substituted coumarin compound as described in the second aspect
  • the application provides a method for treating and/or preventing a disease or condition related to excessive SIRT2 activity or overexpression of SIRT2, the method comprising: using a treatment and/or prophylaxis effective for a subject in need The amount of the 8-(pyridinamide) substituted coumarin-based compound as described in the first aspect or the stereoisomer of the 8-(pyridinamide) substituted coumarin-based compound as described in the second aspect, its pharmacy Acceptable salts, pharmaceutical compositions comprising the same.
  • the disease or condition associated with excessive SIRT2 activity or SIRT2 overexpression includes Parkinson's disease, metabolic disease or tumor.
  • halo means fluorine, chlorine, bromine or iodine, especially fluorine, chlorine or bromine.
  • alkyl refers to an alkyl group having the specified number of carbon atoms, which may be a straight-chain or branched-chain alkyl group, such as the "C 1-8 alkyl group” mentioned. , refers to alkyl groups with carbon atoms of 1, 2, 3, 4, 5, 6, 7, and 8, which may include C 1-8 alkyl, C 1-7 alkyl, C 2-8 alkyl, C 2-7 alkyl, C 2-6 alkyl, C 3-8 alkyl, C 3-7 alkyl, C 3-6 alkyl, etc.
  • C 1-6 alkyloxy refers to an alkyl group with 1, 2, 3, 4, 5, and 6 carbon atoms, which may include C 1-5 alkyl, C 1-4 alkyl, and C 2-6 alkyl , C 2-5 alkyl, C 2-4 alkyl, C 3-6 alkyl, C 3-5 alkyl, C 3-4 alkyl, etc.
  • C 1-4 alkyl group in the "C 1-4 alkylcarbonyl group” or "C 1-4 alkyloxycarbonyl group” refers to an alkane having 1, 2, 3, or 4 carbon atoms. radicals, which may include sub-range groups represented by C 1-4 alkyl, C 2-4 alkyl, etc., as well as preferred specific groups such as methyl, ethyl, n-propyl, isopropyl.
  • cycloalkyl refers to a cyclic alkyl group having the specified number of ring carbon atoms, for example, when referring to "C3-8 cycloalkyl", it refers to 3 carbon atoms , 4, 5, 6, 7, and 8 cycloalkyl groups, may include groups in the sub-ranges represented by C3-7 cycloalkyl, C3-4 cycloalkyl, C4-6 cycloalkyl, etc., and preferred specific Groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, more preferably cyclopropyl, cyclopentyl, cyclohexyl.
  • C3-6 cycloalkyl refers to a cycloalkyl group with 3, 4, 5, and 6 carbon atoms, which may include C3-6 cycloalkyl, C3-5 cycloalkyl, C4-5 Sub-range groups represented by cycloalkyl, etc., and preferred specific groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, more preferably cyclopropyl, cyclopentyl, cyclohexyl .
  • aromatic heterocyclyl refers to a heterocyclic aromatic system containing from 1 to 4 heteroatoms, including nitrogen, oxygen and sulfur heteroatoms.
  • aromatic heterocyclyl refers to a heterocyclic aromatic system containing 5-14 ring atoms.
  • aryl groups containing 1 carbon atom and 4 heteroatoms selected from nitrogen, oxygen and sulfur preferred specific groups such as tetrazolyl; containing 2 carbon atoms and 3 heteroatoms selected from nitrogen, oxygen , aryl groups of heteroatoms of sulfur, preferred specific groups such as 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl; containing 3 Aryl with carbon atoms and 2 heteroatoms selected from nitrogen, oxygen, sulfur, preferred specific groups such as imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl; containing 4 aryl groups of carbon atoms and 1-2 heteroatoms selected from nitrogen, oxygen, sulfur, preferred specific groups such as pyrrolyl, furanyl, thienyl, pyridazinyl, pyrimidinyl, pyrazinyl; containing 5 an aryl group containing 6
  • the term "effective amount" refers to a dose that will effect treatment and/or prevention of the disease or disorder described herein in a subject.
  • composition can be used to effect the treatment and/or prevention of the diseases or conditions described herein in a subject, particularly a mammal .
  • the term "subject" may refer to a patient or other animal receiving a compound, a pharmaceutically acceptable salt or a pharmaceutical composition thereof referred to in this application for the treatment and/or prevention of a disease or disorder described in this application, In particular mammals such as humans, dogs, monkeys, cows, horses and the like.
  • the term “disease and/or disorder” refers to a physical condition of the subject that is associated with the disease and/or disorder described herein.
  • the disease and/or disorder described in this application can refer to either a physical state, such as a physical state of Parkinson's disease, or a disease state, such as a disease state of Parkinson's disease. No distinction is made herein between a physical state and a disease state, or the two may refer to each other, eg, "Parkinson's disease” and “Parkinson's disease” are used interchangeably.
  • the term "pharmaceutically acceptable”, eg, when describing a “pharmaceutically acceptable salt”, means that the salt is not only physiologically acceptable to the subject, but can also refer to a pharmaceutically acceptable salt.
  • Synthetic substances of use value such as salts formed as intermediates for chiral resolution, although the salts of such intermediates cannot be administered directly to the subject, the salts can be used in order to obtain the final product of the present application. function in.
  • compositions containing the compounds of the present application as active ingredients can be prepared according to methods known in the art. Any dosage form suitable for human or animal use can be prepared by combining the compounds of the present application with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants.
  • the content of the compound of the present application in its pharmaceutical composition is usually 0.1-95% by weight.
  • the compound of the present application or the pharmaceutical composition containing it can be administered in unit dosage form, and the route of administration can be enteral or parenteral, such as oral, intravenous, intramuscular, subcutaneous, nasal cavity, oral mucosa, eye, lung and Respiratory tract, skin, vagina, rectum, etc.
  • the dosage form for administration can be a liquid dosage form, a solid dosage form or a semi-solid dosage form.
  • Liquid dosage forms can be solutions (including true solutions and colloidal solutions), emulsions (including o/w, w/o and double emulsion), suspensions, injections (including water injection, powder injection and infusion), eye drops solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric-coated capsules), granules, powders, pellets, drop pills, suppositories, films, patches, gas (powder) aerosols, sprays, etc.; semi-solid dosage forms can be ointments, Gels, pastes, etc.
  • the compounds of the present application can be prepared into ordinary preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.
  • diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; Propanol, etc.;
  • the binder can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, acacia mucilage, gelatin slurry, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose Base cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; disintegrants can be dry starch, microcrystalline cellulose, low-substi
  • the tablets can also be further prepared as coated tablets, such as sugar-coated, film-coated, enteric-coated, or bilayer and multi-layer tablets.
  • the active ingredient of the compound of the present application can be mixed with a diluent and a cosolvent, and the mixture can be directly placed in a hard capsule or a soft capsule.
  • the compound of the present application, the active ingredient can also be prepared into granules or pellets with diluents, binders and disintegrating agents, and then placed in hard capsules or soft capsules.
  • the various diluents, binders, wetting agents, disintegrants, and solubilizers used to prepare tablets of the compounds of the present application can also be used to prepare capsules of the compounds of the present application.
  • solubilizers can be poloxamer, lecithin, hydroxypropyl- ⁇ -cyclodextrin, etc.
  • the pH adjuster can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.
  • the osmotic pressure adjuster can be It is sodium chloride, mannitol, glucose, phosphate, acetate, etc.
  • mannitol, glucose, etc. can also be added as proppant.
  • colorants preservatives, fragrances, flavors, or other additives can also be added to the pharmaceutical preparations, if desired.
  • the medicine or pharmaceutical composition of the present application can be administered by any known administration method.
  • the dosage of the pharmaceutical composition of the compound of the present application can vary widely according to the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration and the dosage form.
  • the suitable daily dosage range of the compounds involved in this application is 0.001-150 mg/kg body weight, preferably 0.1-100 mg/kg body weight, more preferably 1-60 mg/kg body weight, most preferably 2-30 mg/kg body weight weight.
  • the above doses may be administered in a single dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the dosing regimen including the use of other therapeutic means.
  • the compounds or compositions of the present application may be administered alone or in combination with other therapeutic or symptomatic drugs.
  • the compound of the present application has a synergistic effect with other therapeutic drugs, its dosage should be adjusted according to the actual situation.
  • the 8-(pyridinamide) substituted coumarin compounds involved in this application are a brand-new compound structure, and their in vitro SIRT2 inhibitory activity reaches more than 50%, of which the in vitro SIRT2 inhibitory activity IC 50 of 18 compounds reaches micromolar In particular, the IC 50 values of 11 compounds reached the level of 10 -7 mol/L, and the IC 50 values of 4 compounds reached the level of 10 -8 mol/L. Cells have a significant protective effect. Therefore, it can be widely used in the preparation of medicines for the treatment and/or prevention of diseases or conditions related to excessive SIRT2 activity or overexpression of SIRT2, or for the preparation of medicines for the treatment and/or prevention of Parkinson's disease, metabolic disease and tumor.
  • FIG. 1 is a statistical graph of the protective effect of the 8-(pyridinamide) substituted coumarin compounds involved in the present application on SH-SY5Y cell damage in Test Example 3.
  • FIG. 1 is a statistical graph of the protective effect of the 8-(pyridinamide) substituted coumarin compounds involved in the present application on SH-SY5Y cell damage in Test Example 3.
  • the structures of the compounds were determined by hydrogen nuclear magnetic resonance spectroscopy ( 1 H NMR) or mass spectrometry (MS). H NMR spectral shifts ( ⁇ ) are given in parts per million (ppm).
  • the nuclear magnetic resonance spectrum was measured with Mercury-300 or Mercury-400 nuclear magnetic resonance apparatus, deuterated chloroform (CDCl3) or deuterated dimethyl sulfoxide (DMSO-d6) as solvent, tetramethylsilane (TMS) or 3-( Trimethylsilyl) sodium deuterated propionate (TSM) was used as the internal standard.
  • the electronic balance adopts Japanese Yanaco LY-300 electronic balance.
  • HATU is 2-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluor-ophosphat, namely 2-(7-azabenzotriazole)-N,N,N' , N'-tetramethylurea hexafluorophosphate.
  • DIPEA is N,N-diisomromylethylamine, namely N,N-diisopropylethylamine.
  • DMF is N,N-dimethylformamide, that is, N,N-dimethylformamide.
  • 8-Bromocoumarin was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd., CAS: 33491-30-4;
  • 4-Aminopyridine-2-sulfonic acid was purchased from SYNCHEM-OHG Company, CAS: 900804-14-0;
  • This preparation example prepares the intermediate 4 shown in the following formula, and the synthetic route is:
  • n-butyllithium (1.60M n-hexane solution) 14.00 mL, 22.33 mmol
  • anhydrous tetrahydrofuran of 8-bromocoumarin 5.00 g, 22.33 mmol
  • the solution was frozen in a liquid nitrogen bath, then evacuated, followed by the introduction of CO2 generated from the reaction of BaCO3 (5.29 g, 26.80 mmol) with concentrated sulfuric acid (1.43 mL, 26.80 mmol) gas.
  • the mixture was stirred at -78°C for 2 hours, then quenched with saturated aqueous NH4Cl at 20°C.
  • the pH value was adjusted to 5 with hydrochloric acid, extracted three times with ethyl acetate (15 mL ⁇ 3), washed once with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate and concentrated.
  • the product was purified by silica gel column to obtain coumarin-8-carboxylic acid (1.61 g, yield 38%).
  • the preparation was carried out with reference to the preparation method in Example 1, and 4-chloroaniline was replaced with 3-chloroaniline to obtain 0.16 g of a white solid with a yield of 26%.
  • the product was characterized as follows:
  • the preparation was carried out with reference to the preparation method in Example 1, and 4-chloroaniline was replaced with 2-chloroaniline to obtain 0.26 g of a white solid with a yield of 42%.
  • the product was characterized as follows:
  • the preparation was carried out with reference to the preparation method in Example 1, and 4-chloroaniline was replaced with 3-nitroaniline to obtain 0.23 g of a white solid with a yield of 36%.
  • the product was characterized as follows:
  • the preparation was carried out with reference to the preparation method in Example 1, and 4-chloroaniline was replaced with 2-cyanoaniline to obtain 0.153 g of a white solid with a yield of 25%.
  • the product was characterized as follows:
  • the preparation was carried out with reference to the preparation method in Example 1, and 4-chloroaniline was replaced with 4-fluoroaniline to obtain 0.17 g of a white solid with a yield of 29%.
  • the product was characterized as follows:
  • the preparation was carried out with reference to the preparation method in Example 1, and 4-chloroaniline was replaced with 4-methanesulfonylaniline to obtain 0.27 g of a white solid with a yield of 39%.
  • the product was characterized as follows:
  • the preparation was carried out with reference to the preparation method in Example 1, and 4-chloroaniline was replaced with 4-trifluoromethylaniline to obtain 0.26 g of a white solid with a yield of 39%.
  • the product was characterized as follows:
  • the preparation was carried out with reference to the preparation method in Example 1, and 4-chloroaniline was replaced with 4-phenylaniline to obtain 0.28 g of a white solid with a yield of 41%.
  • the product was characterized as follows:
  • the preparation was carried out with reference to the preparation method in Example 1, and 4-chloroaniline was replaced with 4-hydroxyaniline to obtain 0.12 g of a white solid with a yield of 21%.
  • the product was characterized as follows:
  • the preparation was carried out with reference to the preparation method in Example 1, and 4-chloroaniline was replaced with 4-methoxyaniline to obtain 0.16 g of a white solid with a yield of 26%.
  • the product was characterized as follows:
  • the preparation was carried out with reference to the preparation method in Example 1, and 4-chloroaniline was replaced with 3,4-fluoroaniline to obtain 0.22 g of a white solid with a yield of 36%.
  • the product was characterized as follows:
  • the preparation was carried out with reference to the preparation method in Example 1, and 4-chloroaniline was replaced with 7-bromo-1-naphthylamine to obtain 0.19 g of a white solid with a yield of 26%.
  • the product was characterized as follows:
  • the preparation was carried out with reference to the preparation method in Example 1, and 4-chloroaniline was replaced with 3-chloro-1-naphthylamine to obtain 0.20 g of a white solid with a yield of 29%.
  • the product was characterized as follows:
  • the preparation was carried out with reference to the preparation method in Example 1, and 4-chloroaniline was replaced with 3-bromo-5-aminoquinoline to obtain 0.24 g of a white solid with a yield of 32%.
  • the product was characterized as follows:
  • the ORF of the full-length expressed sequence of human SIRT2 gene is 1170bp (Accession No.: NM_012237), and the size of the expressed SIRT2 protein is 43KDa.
  • the expression and purification steps of the SIRT2 recombinant protein are as follows: the SIRT2 gene is cloned into the expression vector pET-15b (primers are as follows: Forward: 5'-TAATACGACTCACTATAGGG-3' (SEQ ID NO. 1); backward: 5'-TTCACTTCTGAGTTCGGCATG-3' (SEQ ID NO. 1) ID NO. 2)), the expressed SIRT2 protein contains the tag His 6 at the N-terminus for purification. Plasmids were transformed into E.
  • coli BL2 (DE3), induced with 1 mM IPTG, and expressed for 6 hours at 18°C.
  • the induced E. coli cells were collected by centrifugation and frozen at -20°C.
  • the bacterial pellet was resuspended in 15 mL of cell lysate (50 mM Tris-HCl pH 8.0, 300 mM NaCl), and the bacterial sample was sonicated for 10 min, and then centrifuged at 4°C (12000 ⁇ g, 20 min) to remove the pellet.
  • Recombinantly expressed soluble SIRT2 protein was present in the supernatant.
  • the supernatant was purified through a Ni 2+ NTA-agarose matrix column (Qiagen).
  • the unbound proteins were first washed with the loading solution (50mM Tris-HCl pH 8.0, 300mM NaCl), and then the concentration of imidazole (0-200mM) was gradually increased to wash away the non-specifically bound proteins, and finally the obtained Purified recombinant SIRT2 protein.
  • the imidazole was removed using a PD-10 column, and the concentration of purified SIRT2 protein was determined by the Bradford method.
  • Recombinant SIRT2 protein was stored in storage solution (50 mM Tris-HCl, pH 8.0, 265 mM NaCl, 0.2 mM DTT, and 10% glycerol) at -20°C.
  • SIRT2 substrate peptide Ac-Gln-Pro-Lys-[Lys-(Ac)]-AMC was synthesized as the substrate in the enzyme activity assay method.
  • the attached fluorescent tag is AMC (7-Amino-4-methylcoumarin).
  • the entire assay process consists of two steps: the catalytic reaction is carried out in 60 ⁇ L of reaction solution (25 mM Tris-HCl, pH 8.0, 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl 2 and 1 mg/ml BSA), 500 ⁇ M NAD + , 50 ⁇ M base peptides, 1.0 ⁇ g of SIRT2 and different concentrations of compounds 1-18.
  • the reaction was left at 37°C for 2 hours. In this reaction, the acetyl group of the Lysine residue on the small molecule peptide was removed to varying degrees.
  • the cytotoxicity of the compound to neuroma cell SH-SY5Y was determined, so as to determine the dosage of the next Parkinson's cell model protection test.
  • the specific experimental steps are as follows: the cultured neuroma cells SH-SY5Y were seeded in a 96-well cell culture plate, with about 6000 cells per well. After overnight incubation, change to new medium and add different concentrations of compound 1-18 (0.01, 0.05, 0.1, 0.5, 1, 5, 10, 20, 50, 100, 200 ⁇ M) to each well, and set different control samples . Cells were incubated at 37°C for an additional 48 hours.
  • the currently generally recognized nerve agent MPP + (5mM) was used to act on the neuroma cell SH-SY5Y to construct the Parkinson's disease cell model.
  • This nerve agent acts on SH-SY5Y cells to affect the abnormal accumulation of ⁇ -synuclein in the cells and causes neurotoxicity similar to Parkinson's disease.
  • the specific experimental method is as follows: about 20,000 SH-SY5Y cells were seeded in a 96-well cell plate and cultured overnight. In the control experiment, no nerve agent was added, the nerve agent MPP + (5mM) was added to each well of the other groups, and the MPP+ group was an unprotected compound. AGK is a positive control), and continued to culture for 48 hours to determine the cell viability of the Parkinson's disease cell model to evaluate their protective effect on the Parkinson's cell model.
  • GraphPad Prism was used for data analysis of experimental results. The results are shown in Figure 1.
  • the present application illustrates a kind of 8-(pyridine amide) substituted coumarin compound of the present application and its preparation method and application through the above-mentioned examples, but the present application is not limited to the above-mentioned examples, that is, it does not mean that Therefore, the present application must rely on the above-mentioned embodiments to be implemented.
  • Those skilled in the art should understand that any improvement to the application, the equivalent replacement of each raw material of the product of the application, the addition of auxiliary components, the selection of specific methods, etc., all fall within the scope of protection and disclosure of the application.

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Abstract

本申请公开了一种8-(吡啶酰胺)取代香豆素类化合物及其制备方法和应用，所述8-(吡啶酰胺)取代香豆素类化合物的结构如式(I)所示，其中，A环独立地选自由以下组成的组：苯基、萘基和5-14元芳杂环基。本申请所公开的8-(吡啶酰胺)取代香豆素类化合物是一种全新的化合物结构，其具有较强的SIRT2抑制活性，其中18个化合物的体外SIRT2抑制活性IC 50达到微摩尔水平，且对神经瘤细胞具有显著的保护效果。因此可以被广泛用于制备用于治疗和/或预防与SIRT2活性过高或者与SIRT2过度表达有关的疾病或病症的药物或制备用于治疗和/或预防帕金森病、代谢性疾病、肿瘤的药物。

Description

一种8-(吡啶酰胺)取代香豆素类化合物及其制备方法和应用 技术领域
本申请属于医药技术领域，具体涉及一种8-(吡啶酰胺)取代香豆素类化合物及其制备方法和应用，尤其涉及一种能够抑制Sirtuin 2(也称为SIRT2)活性或表达的8-(吡啶酰胺)取代香豆素类化合物及其制备方法和应用。
背景技术
帕金森病是一种常见的神经退行性疾病，其临床主要表现为患者行动迟缓、肌僵直以及静止性震颤。帕金森病的病理改变主要体现在中脑黑质多巴胺能神经元的变性坏死，及由此引起纹状体多巴胺含量的显著减少。帕金森病患者承受着生理和心理上的沉重负担。但是目前没有药物能够对帕金森病神经细胞的退行性病变起到保护作用。市场上对于帕金森病的治疗药物(如左旋多巴)主要是针对疾病症状进行缓解，长期服用这类药物给患者带来很严重的副反应。因此，探索新的帕金森病治疗方法，发现新的帕金森病治疗药物具有非常重要的意义。
Sirtuin是一类组蛋白乙酰基转移酶，其酶学活性主要表现为去除组蛋白或其他蛋白中赖氨酸残基上的乙酰基团。在该过程中，Sirtuin依赖烟酰胺腺嘌呤二核苷酸(NAD+)作为底物之一。Sirtuin家族的基因序列在不同物种中相对保守。晶体结构研究表明，Sirtuin由大小两个结构域组成。大的结构域序列比较保守，具有NAD和NADP结合酶的特征。相比之下小的结构域序列变化比较大。Sirtuin的活性中心位于大小结构域之间的裂隙部分。人源的Sirtuin家族包括七种成员：SIRT1-7，分别定位于不同的亚细胞部位，结合并作用于不同的底物，包括p53、α-tubulin、FOXO等，从而实现不同的生物调节功能。Sirtuin的生物学功能是目前生命医学的研究热点，其功能主要体现在与代谢、衰老、长寿、应激反应和基因组稳定等相关的领域。
作为Sirtuin家族中的重要一员，SIRT2主要分布于细胞质中，其作用的底物蛋白包括α-tubulin、histone H4、p53、FOXO和14-3-3 protein。SIRT2的功能研究表明：SIRT2通过去乙酰化H4-K16调控细胞有丝分裂的进程；SIRT2通过激活后期促进复合物/细胞周期体(Anaphase Promoting Complex/Cyclosome，APC/C)系统的活性来维持基因组的稳定；SIRT2介导Receptor-interacting protein 1和3(RIP1和RIP3)的相互结合从而调控细胞坏死的进程。最新的研究表明：抑制SIRT2的活性在治疗帕金森病方面具有潜在的价值，具体体现在：(1)SIRT2在成年大脑的中枢神经系统高丰度表达并调节相关生理代谢；(2)SIRT2的siRNA和小分子抑制剂AGK2能够挽救α-synulein造成的神经细胞毒性，AGK2也能够在体内剂量依赖性地保护转基因帕金森病果蝇模型的神经细胞减少凋亡；(3)SIRT2通过去乙酰化FOXO3a来提高Bim在RNA和蛋白水平的表达，促使N-甲基-4-苯基-1,2,3,6-四氢吡啶(N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine，MPTP)作用的帕金森病细胞模型的凋亡以及MPTP作用的小鼠模型大脑中的细胞凋亡。但是，敲除SIRT2基因的小鼠大脑中显示出很明显减少黑质纹状体损伤的现象；(4)另外，SIRT2的小分子抑制剂AK-7能够明显减少另一种神经退化性疾病-Huntington疾病转基因小鼠大脑中突变Huntingtin的聚集，并且能够明显提 高Huntington病转基因小鼠的行为表现以及延长其存活时间。现有技术中具有代表性的SIRT2小分子抑制剂包括如下几种：
Figure PCTCN2022077640-appb-000001
鉴于SIRT2小分子抑制剂在治疗帕金森病方面的潜在活性，设计合成新的SIRT2抑制剂是目前研究的热点之一。
发明内容
针对现有技术的不足，本申请的目的在于提供一种8-(吡啶酰胺)取代香豆素类化合物及其制备方法和应用，尤其提供一种能够抑制SIRT2活性或表达的8-(吡啶酰胺)取代香豆素类化合物及其制备方法和应用。本申请开发了一类结构新型的8-(吡啶酰胺)取代香豆素类化合物，且其具有显著的SIRT2抑制活性，并且对SIRT2具有较好的选择性，可用于帕金森病、代谢类疾病、肿瘤等的预防和治疗。
为达到此申请目的，本申请采用以下技术方案：
第一方面，本申请提供一种8-(吡啶酰胺)取代香豆素类化合物，所述8-(吡啶酰胺)取代香豆素类化合物的结构如式(I)所示：
Figure PCTCN2022077640-appb-000002
Figure PCTCN2022077640-appb-000003
其中，A环独立地选自由以下组成的组：苯基、萘基和5-14元芳杂环基(例如5元芳杂环基、6元芳杂环基、7元芳杂环基、8元芳杂环基、9元芳杂环基、10元芳杂环基、11元芳杂环基、12元芳杂环基、13元芳杂环基、14元芳杂环基)；
所述苯基、萘基和5-14元芳杂环基无取代或被1-5个(例如1个、2个、3个、4个、5个)R a取代；R a各自独立地选自由以下组成的组：氘、卤素、羟基、巯基、氨基、氰基、硝基、叠氮基、甲磺酰基、异丙磺酰基、苯磺酰基、氨基磺酰基、甲磺酸酯基、异丙磺酸酯基、苯磺酸酯基、三氟甲基、三氟甲基氧基、甲酰氨基、C 1-8烷基氧基、C 1-8烷基羰基、C 1-8烷基氧羰基、C 1-8烷基、C 3-8环烷基和苯基；
在所述R a中，所述C 1-8烷基、C 3-8环烷基和苯基无取代或被1-5个(例如1个、2个、3个、4个、5个)R b取代；所述R b各自独立地选自由以下组成的组：氘、卤素、羟基、巯基、氨基、氰基、硝基、叠氮基、甲磺酰基、异丙磺酰基、苯磺酰基、氨基磺酰基、甲磺酸酯基、异丙磺酸酯基、苯磺酸酯基、三氟甲基、三氟甲基氧基、甲酰氨基和C 1-8烷基羰基。
上述C 1-8是指取代基的碳原子数为1个、2个、3个、4个、5个、6个、7个、8个；C 3-8是指取代基的碳原子数为3个、4个、5个、6个、7个、8个。
本申请所涉及的8-(吡啶酰胺)取代香豆素类化合物是一种全新的化合物结构，且其体外SIRT2抑制活性达到50％以上，其中18个化合物的体外SIRT2抑制活性IC 50达到微摩尔水平，尤其是其中11个化合物的IC 50值达到10 -7mol/L水平，其中4个化合物的IC 50值达到10 -8mol/L水平，显示出良好的SIRT2抑制活性，且对神经瘤细胞具有显著的保护效果。因此可以被广泛用于制备用于治疗和/或预防与SIRT2活性过高或者与SIRT2过度表达有关的疾病或病症的药物或制备治疗和/或预防帕金森病、代谢性疾病、肿瘤的药物。
优选地，式(I)中，A环独立地选自由以下组成的组：苯基、萘基和5-14元芳杂环基(例如5元芳杂环基、6元芳杂环基、7元芳杂环基、8元芳杂环基、9元芳杂环基、10元芳杂环基、11元芳杂环基、12元芳杂环基、13元芳杂环基、14元芳杂环基)；
所述苯基、萘基和5-14元芳杂环基无取代或被1-5个(例如1个、2个、3个、4个、5个)R a取代；R a各自独立地选自由以下组成的组：氘、卤素、羟基、巯基、氨基、氰基、硝基、叠氮基、甲磺酰基、异丙磺酰基、苯磺酰基、氨基磺酰基、甲磺酸酯基、异丙磺酸酯基、苯磺酸酯基、三氟甲基、三氟甲基氧基、甲酰氨基、C 1-6烷基氧基、C 1-6烷基羰基、C 1-6烷基氧羰基、C 1-6烷基、C 3-6环烷基和苯基；
在所述R a中，所述C 1-6烷基、C 3-6环烷基和苯基无取代或被1-5个(例如1个、2个、3个、4个、5个)R b取代；所述R b各自独立地选自由以下组成的组：氘、卤素、羟基、巯基、氨基、氰基、硝基、叠氮基、甲磺酰基、异丙磺酰基、苯磺酰基、氨基磺酰基、甲磺酸酯基、异丙磺酸酯基、苯磺酸酯基、三氟甲基、三氟甲基氧基、甲酰氨基和C 1-6烷基羰基。
上述C 1-6是指取代基的碳原子数为1个、2个、3个、4个、5个、6个；C 3-6是指取代基的碳原子数为3个、4个、5个、6个。
优选地，所述8-(吡啶酰胺)取代香豆素类化合物的结构如式(IA)所示：
Figure PCTCN2022077640-appb-000004
其中，R 1、R 2、R 3、R 4和R 5独立选自由以下组成的组：氢、氘、卤素、羟基、巯基、氨基、氰基、硝基、叠氮基、甲磺酰基、异丙磺酰基、苯磺酰基、氨基磺酰基、甲磺酸酯基、异丙磺酸酯基、苯磺酸酯基、三氟甲基、三氟甲基氧基、甲酰氨基、C 1-4烷基氧基、C 1-4烷基羰基、C 1-4烷基氧羰基、C 1-4烷基和苯基。
上述C 1-4是指取代基的碳原子数为1个、2个、3个、4个。
优选地，所述8-(吡啶酰胺)取代香豆素类化合物的结构如式(IB)所示：
Figure PCTCN2022077640-appb-000005
其中，R 1、R 2、R 3、R 4和R 5独立选自由以下组成的组：氢、氘、卤素、羟基、巯基、氨基、氰基、硝基、甲磺酰基、三氟甲基、三氟甲基氧基、甲酰氨基、C 1-4烷基氧基、C 1-4烷基羰基和C 1-4烷基；X独立选自N或者C。
上述C 1-4是指取代基的碳原子数为1个、2个、3个、4个。
进一步优选地，所述8-(吡啶酰胺)取代香豆素类化合物选自如下所示的结构(分别以结构式表示或以系统命名表示)：
Figure PCTCN2022077640-appb-000006
Figure PCTCN2022077640-appb-000007
Figure PCTCN2022077640-appb-000008
Figure PCTCN2022077640-appb-000009
Figure PCTCN2022077640-appb-000010
第二方面，本申请提供如第一方面所述的8-(吡啶酰胺)取代香豆素类化合物的立体异构体、其药学上可接受的盐或包含其的药物组合物；
优选地，所述药物组合物还包含药学上可接受的药用辅料，例如载体、稀释剂、赋形剂、填充剂、粘合剂、润湿剂、崩解剂、乳化剂、助溶剂、增溶剂、渗透压调节剂、表面活性剂、包衣材料、着色剂、pH调节剂、抗氧剂、抑菌剂或缓冲剂等。
本申请所涉及的8-(吡啶酰胺)取代香豆素类化合物的药学上可接受的盐为8-(吡啶酰胺)取代香豆素类化合物与选自如下的酸形成的盐：盐酸、氢溴酸、对甲苯磺酸、酒石酸、马来酸、乳酸、甲磺酸、硫酸、磷酸、柠檬酸、乙酸或三氟乙酸。优选为盐酸、氢溴酸、对甲苯磺酸或三氟乙酸。
第三方面，本申请提供一种如第一方面所述的8-(吡啶酰胺)取代香豆素类化合物的制备方法，所述制备方法包括：
将
Figure PCTCN2022077640-appb-000011
先与DIPEA混合，再与4-(2-氧代-2H-色烯-8-羧酰胺基)吡啶-2-磺酰氯混合，反应，即得；其中，A环的限定范围与第一方面限定的范围一致；
其反应式如下所示：
Figure PCTCN2022077640-appb-000012
优选地，所述4-(2-氧代-2H-色烯-8-羧酰胺基)吡啶-2-磺酰氯的制备方法包括如下步骤：
(1)将8-溴香豆素先与正丁基锂混合，再于真空条件下与CO 2气体混合，反应，得到香豆素-8-羧酸；
(2)将香豆素-8-羧酸与HATU、DIPEA混合后，再与4-氨基吡啶-2-磺酸混合，反应，得到4-(2-氧代-2H-色烯-8-羧酰胺基)吡啶-2-磺酸；
(3)将4-(2-氧代-2H-色烯-8-羧酰胺基)吡啶-2-磺酸与二氯亚砜混合，反应，得到4-(2-氧代-2H-色烯-8-羧酰胺基)吡啶-2-磺酰氯；
其反应式如下所示：
Figure PCTCN2022077640-appb-000013
作为本申请的优选技术方案，所述4-(2-氧代-2H-色烯-8-羧酰胺基)吡啶-2-磺酰氯的制备方法包括如下步骤：
Figure PCTCN2022077640-appb-000014
(1)将正丁基锂(正己烷溶液)于-78℃在氮气保护下缓慢添加至8-溴香豆素的无水四氢呋喃溶液中。在-78℃下搅拌3小时后，将溶液在液氮浴中冷冻，然后抽真空，随后引入由BaCO 3与浓硫酸反应生成的CO 2气体。将混合物在-78℃下搅拌2小时，然后在室温下用饱和NH 4Cl水溶液淬灭反应。用盐酸调pH值约为5，乙酸乙酯萃取三次，饱和食盐水洗涤一次，合并的有机相用无水硫酸钠干燥并浓缩。用硅胶柱纯化即得香豆素-8-羧酸。
Figure PCTCN2022077640-appb-000015
(2)在单口瓶中加入香豆素-8-羧酸，缩合剂HATU，DIPEA，超干二氯甲烷。室温搅拌。随后逐滴滴加4-氨基吡啶-2-磺酸的二氯甲烷溶液。滴完后室温搅拌5小时。TLC检测反应完全。混合液中加入水，用乙酸乙酯萃取三次，用饱和食盐水洗涤，无水硫酸钠干燥。硅胶柱纯化即得4-(2-氧代-2H-色烯-8-羧酰胺基)吡啶-2-磺酸。
Figure PCTCN2022077640-appb-000016
(3)首先将二氯亚砜引入烧瓶中并加热至60℃。搅拌的同时，向反应液中逐滴加入4-(2- 氧代-2H-色烯-8-羧酰胺基)吡啶-2-磺酸，加热至60℃。反应产物氯化氢和二氧化硫以气态通过回流冷凝管逸出。滴完后，将混合物在60℃下再搅拌2小时，直到没有气体逸出为止。然后将过量的二氯亚砜用真空泵蒸除。用硅胶柱纯化即得4-(2-氧代-2H-色烯-8-羧酰胺基)吡啶-2-磺酰氯。
Figure PCTCN2022077640-appb-000017
(4)向各种芳香胺的无水四氢呋喃溶液中加入DIPEA。然后将混合物在室温搅拌。随后将4-(2-氧代-2H-色烯-8-羧酰胺基)吡啶-2-磺酰氯加入反应液中。将混合物在室温搅拌20分钟。TLC检测反应完全。硅胶柱纯化即得产物。
第四方面，本申请提供一种如第一方面所述的8-(吡啶酰胺)取代香豆素类化合物或如第二方面所述的8-(吡啶酰胺)取代香豆素类化合物的立体异构体、其药学上可接受的盐、包含其的药物组合物在制备用于治疗和/或预防与SIRT2活性过高或者与SIRT2过度表达有关的疾病或病症的药物中的应用。
优选地，所述与SIRT2活性过高或者与SIRT2过度表达有关的疾病或病症包括帕金森病、代谢性疾病或肿瘤。
第五方面，本申请提供一种如第一方面所述的8-(吡啶酰胺)取代香豆素类化合物或如第二方面所述的8-(吡啶酰胺)取代香豆素类化合物的立体异构体、其药学上可接受的盐、包含其的药物组合物在制备SIRT2抑制剂中的应用。
第六方面，本申请提供一种治疗和/或预防与SIRT2活性过高或者与SIRT2过度表达有关的疾病或病症的方法，该方法包括：给有需要的受试者使用治疗和/或预防有效量的如第一方面所述的8-(吡啶酰胺)取代香豆素类化合物或如第二方面所述的8-(吡啶酰胺)取代香豆素类化合物的立体异构体、其药学上可接受的盐、包含其的药物组合物。
优选地，所述与SIRT2活性过高或者与SIRT2过度表达有关的疾病或病症包括帕金森病、代谢性疾病或肿瘤。
下面对本申请的各个方面和特点作进一步的描述。
本申请使用的各种术语和短语具有本领域技术人员公知的一般含义，即便如此，本申请仍然希望在此对这些术语和短语作更详尽的说明和解释，提及的术语和短语如有与公知含义不一致的，以本申请所表述的含义为准。下面是本申请所用多种术语的定义，这些定义适用于本申请整个说明书中所用的术语，除非在具体情况中另作说明。以下提供本申请化合物各种基团的定义，除另行定义外，它们在说明书和权利要求书中统一使用。
如本申请所提及的，术语“卤”、“卤素”、“卤素原子”、“卤代”等表示氟、氯、溴或碘，特别是表示氟、氯或溴。
如本申请所提及的，术语“烷基”是指具有指定数目碳原子数的烷基，其可以为直链或支链的烷基，例如所述的“C 1-8烷基”时，是指碳原子数为1、2、3、4、5、6、7、8的烷基，可 以包括C 1-8烷基、C 1-7烷基、C 2-8烷基、C 2-7烷基、C 2-6烷基、C 3-8烷基、C 3-7烷基、C 3-6烷基等表示的子范围的基团，以及优选的具体基团例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、戊基、己基、庚基、辛基，进一步优选甲基，异丙基。例如所述的“C 1-6烷基氧基”、“C 1-6烷基甲酰基”、“C 1-6烷基氧甲酰基”或“C 1-6烷基”中的“C 1-6烷基”，是指碳原子数为1、2、3、4、5、6的烷基，可以包括C 1-5烷基、C 1-4烷基、C 2-6烷基、C 2-5烷基、C 2-4烷基、C 3-6烷基、C 3-5烷基、C 3-4烷基等表示的子范围的基团，以及优选的具体基团例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、戊基、己基，进一步优选甲基。例如所述的“C 1-4烷基羰基”或“C 1-4烷基氧羰基”中的“C 1-4烷基”，是指碳原子数为1、2、3、4的烷基，可以包括C 1-4烷基、C 2-4烷基等表示的子范围的基团，以及优选的具体基团如甲基、乙基、正丙基、异丙基。
如本申请所提及的，术语“环烷基”是指具有指定数目环碳原子数的环状烷基，例如提及的“C3-8环烷基”时，其指碳原子数为3、4、5、6、7、8的环烷基，可以包括C3-7环烷基、C3-4环烷基、C4-6环烷基等表示的子范围的基团，以及优选的具体基团例如环丙基、环丁基、环戊基、环己基、环庚基、环辛基，进一步优选环丙基，环戊基、环己基。例如所述的“C3-6环烷基”，是指碳原子数为3、4、5、6的环烷基，可以包括C3-6环烷基、C3-5环烷基、C4-5环烷基等表示的子范围的基团，以及优选的具体基团例如环丙基、环丁基、环戊基、环己基、环庚基，进一步优选环丙基，环戊基、环己基。
如本申请所提及的，术语“芳杂环基”是指包含1至4个杂原子的杂环芳香族体系，所述的杂原子包括氮、氧和硫的杂原子。如本申请所提及的，“5-14元芳杂环基”是指含有5-14个环原子的杂环芳香族体系。具体实施例包括含有1个碳原子和4个选自氮、氧、硫的杂原子的芳基，优选的具体基团例如四氮唑基；含有2个碳原子和3个选自氮、氧、硫的杂原子的芳基，优选的具体基团例如1,2,3-三氮唑基、1,2,4-三氮唑基、噁二唑基、噻二唑基；含有3个碳原子和2个选自氮、氧、硫的杂原子的芳基，优选的具体基团例如咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基、异噻唑基；含有4个碳原子和1-2个选自氮、氧、硫的杂原子的芳基，优选的具体基团例如吡咯基、呋喃基、噻吩基、哒嗪基、嘧啶基、吡嗪基；含有5个碳原子和1个选自氮、氧、硫的杂原子的芳基，优选的具体基团例如吡啶基，优选吡啶基；含有6个碳原子和3个选自氮、氧、硫的杂原子的芳基，优选的具体基团例如苯并三唑基；含有7个碳原子和2个选自氮、氧、硫的杂原子的芳基，优选的具体基团例如苯并咪唑基、苯并吡唑基；含有8个碳原子和1-2个选自氮、氧、硫的杂原子的芳基，优选的具体基团例如吲哚基、苯并呋喃基、苯并噻吩基、苯并吡嗪基、苯并嘧啶基、苯并哒嗪基；含有9个碳原子和1个选自氮、氧、硫的杂原子的芳基，优选的具体基团例如喹啉基、异喹啉基。
如本申请所提及的，术语“有效量”是指可在受试者中实现治疗和/或预防本申请所述疾病或病症的剂量。
如本申请所提及的，术语“药物组合物”，其还可以是指“组合物”，其可用于在受试者特别是哺乳动物中实现治疗和/或预防本申请所述疾病或病症。
如本申请所提及的，术语“受试者”可以指患者或者其它接受本申请所涉及化合物、药用盐或其药物组合物以治疗和/或预防本申请所述疾病或病症的动物，特别是哺乳动物，例如人、狗、猴、牛、马等。
如本申请所提及的，术语“疾病和/或病症”是指所述受试者的一种身体状态，该身体状态与本申请所述疾病和/或病症有关。例如，本申请所述疾病和/或病症既可以指一种身体状态，例如呈帕金森病症的身体状态，也可以指一种疾病状态，例如表现为帕金森病等疾病状态。在本文中对于身体状态和疾病状态不作区分，或者二者可以相互指代，例如“帕金森病”与“帕金森症”可以互换使用。
如本申请所提及的，术语“药学上可接受的”例如在描述“药学上可接受的盐”时，表示该盐不但是受试者生理学上可接受，而且还可指在药学上有使用价值的合成物质，例如在为进行手性拆分时所形成的作为中间体的盐，虽然这种中间体的盐并不能直接给予受试者，但该盐可在为获得本申请终产物中起作用。
本申请再一方面还涉及以本申请化合物作为活性成份的药物组合物。该药物组合物可根据本领域公知的方法制备。可通过将本申请化合物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合，制成适于人或动物使用的任何剂型。本申请化合物在其药物组合物中的含量通常为0.1-95重量％。
本申请化合物或含有它的药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等；固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本申请化合物可以制成普通制剂、也可制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本申请化合物制成片剂，可以广泛使用本领域公知的各种赋形剂，包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助溶剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；湿润剂可以是水、乙醇、异丙醇等；粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助溶剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。
为了将给药单元制成胶囊剂，可以将有效成分本申请化合物与稀释剂、助溶剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本申请化合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸，再置于硬胶囊或软胶囊中。用于制备本申请化合物片剂的各稀释剂、 黏合剂、润湿剂、崩解剂、助溶剂品种也可用于制备本申请化合物的胶囊剂。
为将本申请化合物制成注射剂，可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调节剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等；pH调节剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等；渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂，还可加入甘露醇、葡萄糖等作为支撑剂。
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
为达到用药目的，增强治疗效果，本申请的药物或药物组合物可用任何公知的给药方法给药。
本申请化合物药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度，患者或动物的个体情况，给药途径和剂型等可以有大范围的变化。一般来讲，本申请所涉及化合物其每天的合适剂量范围为0.001-150mg/kg体重，优选为0.1-100mg/kg体重，更优选为1-60mg/kg体重，最优选为2-30mg/kg体重。上述剂量可以一个剂量单位或分成几个剂量单位给药，这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。
本申请的化合物或组合物可单独服用，或与其他治疗药物或对症药物合并使用。当本申请的化合物与其它治疗药物存在协同作用时，应根据实际情况调整它的剂量。
相对于现有技术，本申请具有以下有益效果：
本申请所涉及的8-(吡啶酰胺)取代香豆素类化合物是一种全新的化合物结构，且其体外SIRT2抑制活性达到50％以上，其中18个化合物的体外SIRT2抑制活性IC 50达到微摩尔水平，尤其是其中11个化合物的IC 50值达到10 -7mol/L水平，其中4个化合物的IC 50值达到10 -8mol/L水平，显示出良好的SIRT2抑制活性，且对神经瘤细胞具有显著的保护效果。因此可以被广泛用于制备用于治疗和/或预防与SIRT2活性过高或者与SIRT2过度表达有关的疾病或病症的药物或制备治疗和/或预防帕金森病、代谢性疾病、肿瘤的药物。
附图说明
图1是试验例3中本申请所涉及的8-(吡啶酰胺)取代香豆素类化合物对SH-SY5Y细胞损伤的保护作用的结果统计图。
具体实施方式
下面通过具体实施方式来进一步说明本申请的技术方案。本领域技术人员应该明了，所述实施例仅仅是帮助理解本申请，不应视为对本申请的具体限制。
对于以下全部实施例或制备例，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谱(NMR)和/或质谱(MS)来确定。
对于以下全部实施例或制备例，化合物的结构是通过核磁共振氢谱( 1H NMR)或质谱(MS)来确定的。核磁共振氢谱位移(δ)以百万分之一(ppm)的单位给出。核磁共振谱用Mercury-300或Mercury-400型核磁共振仪测定，氘代氯仿(CDCl3)或氘代二甲基亚砜(DMSO-d6)作溶剂，四甲基硅烷(TMS)或3-(三甲基硅基)氘代丙酸钠(TSM)为内标。
电子天平采用日本Yanaco LY-300型电子天平。
柱层析使用200～300目或300～400目硅胶为载体。
无水溶剂均通过标准方法处理。其它试剂均为市售分析纯。
其中，
HATU为2-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluor-ophosphat，即2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯。
DIPEA为N,N-diisomromylethylamine，即N,N-二异丙基乙胺。
DMF为N,N-dimethylformamide，即N,N-二甲基甲酰胺。
下述制备例和实施例中所涉及的原料来源如下：
8-溴香豆素购于上海阿拉丁生化科技股份有限公司，CAS:33491-30-4；
4-氨基吡啶-2-磺酸购于SYNCHEM-OHG公司，CAS:900804-14-0；
4-氯苯胺、3-氯苯胺、2-氯苯胺、4-甲基苯胺、3-硝基苯胺、2-氰基苯胺、4-氟苯胺、4-甲磺酰基苯胺、4-三氟甲基苯胺、4-苯基苯胺、4-羟基苯胺、4-甲氧基苯胺、3,4-氟苯胺、3-溴-4-氯苯胺、7-溴-1-萘胺、3-氯-1-萘胺、5-氨基喹啉、3-溴-5-氨基喹啉分别购于上海麦克林生化科技有限公司、Sigma-Aldrich西格玛奥德里奇(上海)贸易有限公司、北京百灵威科技有限公司、上海迈瑞尔化学技术有限公司、阿法埃莎(中国)化学有限公司、北京偶合科技有限公司、上海阿拉丁生化科技股份有限公司、北京索莱宝科技有限公司、北京伊诺凯科技有限公司。
制备例1
本制备例制备如下式中所示的中间体4，合成路线为：
Figure PCTCN2022077640-appb-000018
(1)将正丁基锂(1.60M正己烷溶液)(14.00mL，22.33mmol)于-78℃在氮气保护下缓慢添加至8-溴香豆素(5.00g，22.33mmol)的无水四氢呋喃(30mL)溶液中。在-78℃下搅拌3小时后，将溶液在液氮浴中冷冻，然后抽真空，随后引入由BaCO 3(5.29g，26.80mmol)与浓硫酸(1.43mL，26.80mmol)反应生成的CO 2气体。将混合物在-78℃下搅拌2小时，然后在20℃下用饱和NH 4Cl水溶液淬灭反应。用盐酸调pH值为5，乙酸乙酯(15mL×3)萃取三次，饱和食盐水洗涤一次，合并的有机相用无水硫酸钠干燥并浓缩。用硅胶柱纯化即得产物香豆素-8-羧酸(1.61g，收率38％)。
(2)在单口瓶中加入香豆素-8-羧酸(1.60g，8.42mmol)，缩合剂HATU(3.20g，8.42mmol)，DIPEA(2.93mL，16.84mmol)，超干二氯甲烷(15mL)。20℃搅拌30分钟。随后逐滴滴加4-氨基吡啶-2-磺酸(1.33g，7.65mmol)的二氯甲烷(5mL)溶液。滴完后20℃搅拌5小时。TLC检测反应完全。混合液中加入水，用乙酸乙酯(15mL×3)萃取三次，用饱和食盐水洗涤，无水硫酸钠干燥。硅胶柱纯化即得产物4-(2-氧代-2H-色烯-8-羧酰胺基)吡啶-2-磺酸(1.61g，收率61％)。
(3)首先将二氯亚砜(5mL)引入烧瓶中并加热至60℃。搅拌的同时，在3小时内向反应液中逐滴加入4-(2-氧代-2H-色烯-8-羧酰胺基)吡啶-2-磺酸(1.60g，4.62mmol)，加热至60℃。反应产物氯化氢和二氧化硫以气态通过回流冷凝管逸出。滴完后，将混合物在60℃下再搅拌2小时，直到没有气体逸出为止。然后将过量的二氯亚砜用真空泵蒸除。用硅胶柱纯化即得产物4-(2-氧代-2H-色烯-8-羧酰胺基)吡啶-2-磺酰氯(0.59g，收率35％)。
实施例1
本实施例制备化合物1：N-(2-(N-(4-氯苯基)磺酰胺)-吡啶-4-基)-2-氧代-2H-色原烯-8-酰胺，其结构如下所示：
Figure PCTCN2022077640-appb-000019
向4-氯苯胺(0.17g，1.37mmol,CAS:106-47-8)的无水四氢呋喃(10mL)溶液中加入DIPEA(0.48mL，2.74mmol)。然后将混合物在20℃下搅拌10分钟。随后将4-(2-氧代-2H-色烯-8-羧酰胺基)吡啶-2-磺酰氯(0.50g，1.37mmol)加入反应液中。将混合物在20℃下搅拌20分钟。TLC检测反应完全。硅胶柱纯化即得产物(0.21g，收率33％)。对产物进行如下表征：
1H NMR(400MHz,CDCl 3):δ8.54(d,J＝4.4Hz,1H),7.52-7.79(m,4H),7.10-7.41(m,5H),6.52(m,1H),5.97(m,1H).
HR-MS(ESI):[M+H] +C21H15ClN3O5S计算值456.0421,实测值456.0454.
实施例2
本实施例制备化合物2：N-(2-(N-(3-氯苯基)磺酰胺)-吡啶-4-基)-2-氧代-2H-色原烯-8-酰胺，其结构如下所示：
Figure PCTCN2022077640-appb-000020
参照实施例1中的制备方法进行制备，将4-氯苯胺替换为3-氯苯胺，得到白色固体0.16g，收率26％。对产物进行如下表征：
1H NMR(400MHz,CDCl 3):8.53(d,J＝5.4Hz,1H),7.52-7.79(m,4H),7.10-7.38(m,5H),6.52(m,1H),5.97(m,1H).
HR-MS(ESI):[M+H] +C 21H 15ClN 3O 5S计算值456.0421,实测值456.0434.
实施例3
本实施例制备化合物3：N-(2-(N-(2-氯苯基)磺酰胺)-吡啶-4-基)-2-氧代-2H-色原烯-8-酰胺，其结构如下所示：
Figure PCTCN2022077640-appb-000021
参照实施例1中的制备方法进行制备，将4-氯苯胺替换为2-氯苯胺，得到白色固体0.26g，收率42％。对产物进行如下表征：
1H NMR(400MHz,CDCl 3):δ8.54(d,J＝4.4Hz,1H),7.52-7.79(m,4H),7.15-7.38(m,5H),6.52(m,1H),5.97(m,1H).
HR-MS(ESI):[M+H] +C 21H 15ClN 3O 5S计算值456.0421,实测值456.0414.
实施例4
本实施例制备化合物4：N-(2-(N-(4-甲基苯基)磺酰胺)-吡啶-4-基)-2-氧代-2H-色原烯-8-酰胺，其结构如下所示：
Figure PCTCN2022077640-appb-000022
参照实施例1中的制备方法进行制备，将4-氯苯胺替换为4-甲基苯胺，得到白色固体1.97g，收率33％。对产物进行如下表征：
1H NMR(400MHz,CDCl3):δ8.54(d,J＝4.4Hz,1H),7.53-7.78(m,4H),7.12-7.49(m,5H),6.52(m,1H),5.97(m,1H),2.34(s,3H).
HR-MS(ESI):[M+H] +C 22H 18N 3O 5S计算值436.0967,实测值436.0945.
实施例5
本实施例制备化合物5：N-(2-(N-(3-硝基苯基)磺酰胺)-吡啶-4-基)-2-氧代-2H-色原烯-8-酰胺，其结构如下所示：
Figure PCTCN2022077640-appb-000023
参照实施例1中的制备方法进行制备，将4-氯苯胺替换为3-硝基苯胺，得到白色固体0.23g，收率36％。对产物进行如下表征：
1H NMR(400MHz,CDCl3):δ8.53(d,J＝5.4Hz,1H),7.50-7.77(m,4H),7.10-7.36(m,5H),6.54(m,1H),5.92(m,1H).
HR-MS(ESI):[M+H] +C 21H 15N 4O 7S计算值467.0661,实测值467.0646.
实施例6
本实施例制备化合物6：N-(2-(N-(2-氰基苯基)磺酰胺)-吡啶-4-基)-2-氧代-2H-色原烯-8-酰胺，其结构如下所示：
Figure PCTCN2022077640-appb-000024
参照实施例1中的制备方法进行制备，将4-氯苯胺替换为2-氰基苯胺，得到白色固体0.153g，收率25％。对产物进行如下表征：
1H NMR(400MHz,CDCl 3):δ8.53(d,J＝5.2Hz,1H),7.52-7.75(m,4H),7.10-7.42(m,5H),6.52(m,1H),5.97(m,1H).
HR-MS(ESI):[M+H] +C 22H 15N 4O 5S计算值447.0763,实测值447.0742.
实施例7
本实施例制备化合物7：N-(2-(N-(4-氟苯基)磺酰胺)-吡啶-4-基)-2-氧代-2H-色原烯-8-酰胺，其结构如下所示：
Figure PCTCN2022077640-appb-000025
参照实施例1中的制备方法进行制备，将4-氯苯胺替换为4-氟苯胺，得到白色固体0.17g， 收率29％。对产物进行如下表征：
1H NMR(400MHz,CDCl3):δ8.62(d,J＝4.7Hz,1H),7.52-7.79(m,4H),7.15-7.42(m,5H),6.52(m,1H),5.97(m,1H).
HR-MS(ESI):[M+H] +C 21H 15FN 3O 5S计算值440.0716,实测值440.0740.
实施例8
本实施例制备化合物8：N-(2-(N-(4-甲磺酰基苯基)磺酰胺)-吡啶-4-基)-2-氧代-2H-色原烯-8-酰胺，其结构如下所示：
Figure PCTCN2022077640-appb-000026
参照实施例1中的制备方法进行制备，将4-氯苯胺替换为4-甲磺酰基苯胺，得到白色固体0.27g，收率39％。对产物进行如下表征：
1H NMR(400MHz,CDCl 3):δ8.62(d,J＝4.7Hz,1H),7.52-7.77(m,4H),7.11-7.38(m,5H),6.51(m,1H),5.93(m,1H),3.32(s,3H).
HR-MS(ESI):[M+H]+C 22H 18N 3O 7S 2计算值500.0586,实测值500.0594.
实施例9
本实施例制备化合物9：N-(2-(N-(4-三氟甲基苯基)磺酰胺)-吡啶-4-基)-2-氧代-2H-色原烯-8-酰胺，其结构如下所示：
Figure PCTCN2022077640-appb-000027
参照实施例1中的制备方法进行制备，将4-氯苯胺替换为4-三氟甲基苯胺，得到白色固体0.26g，收率39％。对产物进行如下表征：
1H NMR(400MHz,CDCl 3):δ8.62(d,J＝4.7Hz,1H),7.58-7.79(m,4H),7.11-7.49(m,5H),6.52(m,1H),5.76(m,1H).
HR-MS(ESI):[M+H]+C 22H 15F 3N 3O 5S计算值490.0685,实测值490.0683.
实施例10
本实施例制备化合物10：N-(2-(N-(4-苯基苯基)磺酰胺)-吡啶-4-基)-2-氧代-2H-色原烯-8-酰胺，其结构如下所示：
Figure PCTCN2022077640-appb-000028
参照实施例1中的制备方法进行制备，将4-氯苯胺替换为4-苯基苯胺，得到白色固体0.28g，收率41％。对产物进行如下表征：
1H NMR(400MHz,CDCl 3):δ8.62(d,J＝4.7Hz,1H),8.09-8.23(m,2H),7.55-7.89(m,10H),6.52-6.78(m,2H),5.76-6.12(m,2H).
HR-MS(ESI):[M+H]+C 27H 20N 3O 5S计算值498.1124,实测值498.1145.
实施例11
本实施例制备化合物11：N-(2-(N-(4-羟基苯基)磺酰胺)-吡啶-4-基)-2-氧代-2H-色原烯-8-酰胺，其结构如下所示：
Figure PCTCN2022077640-appb-000029
参照实施例1中的制备方法进行制备，将4-氯苯胺替换为4-羟基苯胺，得到白色固体0.12g，收率21％。对产物进行如下表征：
1H NMR(400MHz,CDCl 3):δ8.72(d,J＝4.9Hz,1H),7.62-7.77(m,4H),7.12-7.56(m,5H),6.42(m,1H),5.66(m,1H),5.45(s,1H).
HR-MS(ESI):[M+H]+C 21H 16N 3O 6S计算值438.0760,实测值438.0788.
实施例12
本实施例制备化合物12：N-(2-(N-(4-甲氧基苯基)磺酰胺)-吡啶-4-基)-2-氧代-2H-色原烯-8-酰胺，其结构如下所示：
Figure PCTCN2022077640-appb-000030
参照实施例1中的制备方法进行制备，将4-氯苯胺替换为4-甲氧基苯胺，得到白色固体0.16g，收率26％。对产物进行如下表征：
1H NMR(400MHz,CDCl 3):δ8.72(d,J＝4.5Hz,1H),7.62-7.76(m,4H),7.12-7.66(m,5H),6.42(m,1H),5.66(m,1H),3.83(s,3H).
HR-MS(ESI):[M+H]+C 22H 18N 3O 6S计算值452.0916,实测值452.0933.
实施例13
本实施例制备化合物13：N-(2-(N-(3，4-二氟苯基)磺酰胺)-吡啶-4-基)-2-氧代-2H-色原烯-8-酰胺，其结构如下所示：
Figure PCTCN2022077640-appb-000031
参照实施例1中的制备方法进行制备，将4-氯苯胺替换为3,4-氟苯胺，得到白色固体0.22g，收率36％。对产物进行如下表征：
1H NMR(400MHz,CDCl 3):δ8.62(d,J＝5.7Hz,1H),7.57-7.77(m,4H),7.13-7.49(m,4H),6.62(m,1H),5.93(m,1H).
HR-MS(ESI):[M+H]+C 21H 14F 2N 3O 5S计算值458.0622,实测值458.0636.
实施例14
本实施例制备化合物14：N-(2-(N-(3-溴-4-氯苯基)磺酰胺)-吡啶-4-基)-2-氧代-2H-色原烯-8-酰胺，其结构如下所示：
Figure PCTCN2022077640-appb-000032
参照实施例1中的制备方法进行制备，将4-氯苯胺替换为3-溴-4-氯苯胺，得到白色固体0.23g，收率32％。对产物进行如下表征：
1H NMR(400MHz,CDCl3):δ8.62(d,J＝5.7Hz,1H),7.53-7.78(m,4H),7.15-7.41(m,4H),6.62(m,1H),5.93(m,1H).
HR-MS(ESI):[M+H]+C 21H 14BrClN 3O 5S计算值533.9526,实测值533.9554.
实施例15
本实施例制备化合物15：N-(2-(N-(7-溴奈-1-基)磺酰胺)-吡啶-4-基)-2-氧代-2H-色原烯-8-酰胺，其结构如下所示：
Figure PCTCN2022077640-appb-000033
参照实施例1中的制备方法进行制备，将4-氯苯胺替换为7-溴-1-萘胺，得到白色固体0.19g，收率26％。对产物进行如下表征：
1H NMR(400MHz,CDCl3):δ8.56(d,J＝54Hz,1H),8.10-8.13(m,3H),7.52-7.81(m,4H),7.02-7.45(m,4H),6.67-6.89(m,2H).
HR-MS(ESI):[M+H]+C 25H 17BrN 3O 5S计算值550.0072,实测值550.0098.
实施例16
本实施例制备化合物16：N-(2-(N-(3-氯萘-1-基)磺酰胺)-吡啶-4-基)-2-氧代-2H-色原烯-8-酰胺，其结构如下所示：
Figure PCTCN2022077640-appb-000034
参照实施例1中的制备方法进行制备，将4-氯苯胺替换为3-氯-1-萘胺，得到白色固体0.20g，收率29％。对产物进行如下表征：
1H NMR(400MHz,CDCl3):δ8.56(d,J＝54Hz,1H),8.11-8.15(m,3H),7.55-7.87(m,4H),7.02-7.45(m,4H),6.69-6.92(m,2H).
HR-MS(ESI):[M+H]+C 25H 17ClN 3O 5S计算值506.0577,实测值506.0599.
实施例17
本实施例制备化合物17：N-(2-(N-(喹啉-5-基)磺酰胺)-吡啶-4-基)-2-氧代-2H-色原烯-8-酰胺，其结构如下所示：
Figure PCTCN2022077640-appb-000035
参照实施例1中的制备方法进行制备，将4-氯苯胺替换为5-氨基喹啉，得到白色固体 0.22g，收率34％。对产物进行如下表征：
1H NMR(400MHz,CDCl 3):δ8.35-8.58(m,5H),8.19(m,1H),7.51-7.87(m,5H),7.31(m,1H),6.52(m,1H),5.57(m,1H).
HR-MS(ESI):[M+H]+C 24H 17N 4O 5S计算值473.0920,实测值473.0934.
实施例18
本实施例制备化合物18：N-(2-(N-(7-溴-喹啉-5-基)磺酰胺)-吡啶-4-基)-2-氧代-2H-色原烯-8-酰胺，其结构如下所示：
Figure PCTCN2022077640-appb-000036
参照实施例1中的制备方法进行制备，将4-氯苯胺替换为3-溴-5-氨基喹啉，得到白色固体0.24g，收率32％。对产物进行如下表征：
1H NMR(400MHz,CDCl 3):δ8.31-8.52(m,4H),8.13(m,1H),7.51-7.82(m,5H),7.31(m,1H),6.52(m,1H),5.57(m,1H).
HR-MS(ESI):[M+H]+C 24H 16BrN 4O 5S计算值551.0025,实测值551.0043.
试验例1
SIRT2抑制剂的体外活性筛选：
人SIRT2基因的全长表达序列ORF为1170bp(Accession No.:NM_012237)，所表达的SIRT2蛋白大小为43KDa。SIRT2重组蛋白的表达纯化步骤如下：SIRT2基因被克隆到表达载体pET-15b(引物如下Forward：5’-TAATACGACTCACTATAGGG-3’(SEQ ID NO.1)；backward:5’-TTCACTTCTGAGTTCGGCATG-3’(SEQ ID NO.2))，表达的SIRT2蛋白在N末端含有用于纯化的标签His 6。质粒被转化到E.coli BL2(DE3)，经过1mM IPTG诱导，在18℃表达6小时。离心收集诱导的大肠杆菌细胞，冻于-20℃。细菌沉淀重悬于15mL的细胞裂解液(50mM Tris-HCl pH 8.0,300mM NaCl)，细菌样品采用超声破碎10min，之后在4℃离心(12000×g，20min)去除沉淀。重组表达的可溶性SIRT2蛋白存在于上清中。将上清通过Ni 2+NTA-agarose matrix柱(Qiagen)进行纯化。在纯化的过程中，首先用上样液(50mM Tris-HCl pH 8.0,300mM NaCl)洗掉没有结合的蛋白，之后逐渐提高咪唑的浓度(0-200mM)洗去非特异性结合的蛋白，最后得到纯化的重组SIRT2蛋白。采用PD-10柱子去除咪唑，并用Bradford方法测定纯化的SIRT2蛋白浓度。重组SIRT2蛋白贮存于保存液中(50mM Tris-HCl,pH 8.0,265mM NaCl,0.2mM DTT,and 10％glycerol)，放置于-20℃。
根据文献的报道，建立了SIRT2酶活性测定方法。首先合成SIRT2的作用底物肽段Ac-Gln-Pro-Lys-[Lys-(Ac)]-AMC作为酶活性测定方法中的底物。所连接的荧光标签为AMC(7-Amino-4-methylcoumarin)。整个测定过程包括两个步骤：催化反应在60μL的反应液中进行(25mM Tris-HCl,pH 8.0,137mM NaCl,2.7mM KCl,1mM MgCl 2and 1mg/ml BSA)，加 入500μM NAD +、50μM底物肽段、1.0μg的SIRT2和不同浓度的化合物1-18。反应放置37℃2个小时。在这个反应中，小分子肽段上Lysine残基的乙酰基团被不同程度地去除。之后向反应溶液中加入60μL的样品处理液(50mM Tris-HCl,pH 8.0,100mM NaCl,Trypsin和4mM nicotinamide)并混合，放置于37℃20分钟。将酶标仪设置为激发光355nm，吸收光为460nm，测定吸收强度。试验中的每个化合物每个浓度都有2个平行试验，并设置合理的对照，实验结果采用处理软件GraphPad Prism计算每个抑制剂的抑制活性IC 50。结果如表1所示(其中AGK为阳性对照组)：
表1
Figure PCTCN2022077640-appb-000037
由表1数据可知：受试的18个化合物的体外SIRT2抑制活性IC 50均达到微摩尔水平，尤其是其中11个化合物的IC 50值达到了10 -7mol/L水平，其中4个化合物的IC 50值达到了10 -8mol/L水平，显示出本申请所涉及的8-(吡啶酰胺)取代香豆素类化合物具有良好的SIRT2抑制活性。
试验例2
化合物对神经瘤细胞SH-SY5Y的细胞毒性测定：
本试验例测定化合物对神经瘤细胞SH-SY5Y的细胞毒性，从而用于确定下一步的帕金森细胞模型保护试验的剂量。对于细胞毒性的测定，具体的实验步骤如下：将培养的神经瘤细 胞SH-SY5Y种植于96孔的细胞培养板，每孔大约6000细胞。经过过夜培养，换取新的培养液，并在每孔中加入不同浓度的化合物1-18(0.01,0.05,0.1,0.5,1,5,10,20,50,100,200μM)，并设置不同的对照样品。细胞在37℃下继续培养48小时。在每孔中加入10μL染料
Figure PCTCN2022077640-appb-000038
(Invitrogen)继续放置37℃培养大约2个小时，可以观察到染色液颜色变化，在酶标仪下读取吸收值的变化(Ex：530nm；Em：590nm)。试验中化合物的每个浓度都有2个平行试验。实验结果采用数据处理软件GraphPad Prism计算每个化合物的细胞毒性CC 50。结果如表2所示(其中Taxol为阳性对照组)：
表2
Figure PCTCN2022077640-appb-000039
由表2数据可知：受试的18个化合物对SH-SY5Y的细胞毒性IC50均大于20μM，即本申请所涉及的8-(吡啶酰胺)取代香豆素类化合物对SH-SY5Y细胞并无明显抑制活性。
试验例3
筛选对帕金森病细胞模型具有保护活性的化合物：
对于帕金森病细胞模型保护作用的筛选试验，采用目前普遍认可的神经毒剂MPP +(5mM)作用于神经瘤细胞SH-SY5Y来构建帕金森病细胞模型。这种神经毒剂作用于SH-SY5Y细胞从而影响α-synuclein在细胞内的不正常积聚，并造成类似帕金森病的神经毒性。具体的实验方法如下：将大约20000的SH-SY5Y细胞种植于96孔细胞板中，过夜培养。对照试验 control采用不加神经毒剂，其他各组每孔中加入神经毒剂MPP +(5mM)，MPP+组为不加保护化合物，保护试验的培养孔中同时分别加入化合物1-18(10μM)(其中AGK为阳性对照)，继续培养48小时，测定帕金森病细胞模型的细胞活性，从而评估他们对于帕金森细胞模型的保护作用。对于试验结果的数据分析采用GraphPad Prism。结果如图1所示。
由图1可知：受试的18个化合物均能够在一定程度上保护MPP +神经毒剂对于SH-SY5Y细胞的损伤，表明本申请所涉及的8-(吡啶酰胺)取代香豆素类化合物具有对神经瘤细胞的保护效果；并且其中化合物1，13，14，15对于神经瘤细胞的保护效果更为明显。
申请人声明，本申请通过上述实施例来说明本申请的一种8-(吡啶酰胺)取代香豆素类化合物及其制备方法和应用，但本申请并不局限于上述实施例，即不意味着本申请必须依赖上述实施例才能实施。所属技术领域的技术人员应该明了，对本申请的任何改进，对本申请产品各原料的等效替换及辅助成分的添加、具体方式的选择等，均落在本申请的保护范围和公开范围之内。
以上详细描述了本申请的优选实施方式，但是，本申请并不限于上述实施方式中的具体细节，在本申请的技术构思范围内，可以对本申请的技术方案进行多种简单变型，这些简单变型均属于本申请的保护范围。
另外需要说明的是，在上述具体实施方式中所描述的各个具体技术特征，在不矛盾的情况下，可以通过任何合适的方式进行组合，为了避免不必要的重复，本申请对各种可能的组合方式不再另行说明。

Claims (10)

  1. 一种8-(吡啶酰胺)取代香豆素类化合物，其结构如式(I)所示：
    Figure PCTCN2022077640-appb-100001
    其中，A环独立地选自由以下组成的组：苯基、萘基和5-14元芳杂环基；
    所述苯基、萘基和5-14元芳杂环基无取代或被1-5个R a取代；R a各自独立地选自由以下组成的组：氘、卤素、羟基、巯基、氨基、氰基、硝基、叠氮基、甲磺酰基、异丙磺酰基、苯磺酰基、氨基磺酰基、甲磺酸酯基、异丙磺酸酯基、苯磺酸酯基、三氟甲基、三氟甲基氧基、甲酰氨基、C 1-8烷基氧基、C 1-8烷基羰基、C 1-8烷基氧羰基、C 1-8烷基、C 3-8环烷基和苯基；
    在所述R a中，所述C 1-8烷基、C 3-8环烷基和苯基无取代或被1-5个R b取代；所述R b各自独立地选自由以下组成的组：氘、卤素、羟基、巯基、氨基、氰基、硝基、叠氮基、甲磺酰基、异丙磺酰基、苯磺酰基、氨基磺酰基、甲磺酸酯基、异丙磺酸酯基、苯磺酸酯基、三氟甲基、三氟甲基氧基、甲酰氨基和C 1-8烷基羰基。
  2. 如权利要求1所述的8-(吡啶酰胺)取代香豆素类化合物，其中，式(I)中，A环独立地选自由以下组成的组：苯基、萘基和5-14元芳杂环基；
    所述苯基、萘基和5-14元芳杂环基无取代或被1-5个R a取代；R a各自独立地选自由以下组成的组：氘、卤素、羟基、巯基、氨基、氰基、硝基、叠氮基、甲磺酰基、异丙磺酰基、苯磺酰基、氨基磺酰基、甲磺酸酯基、异丙磺酸酯基、苯磺酸酯基、三氟甲基、三氟甲基氧基、甲酰氨基、C 1-6烷基氧基、C 1-6烷基羰基、C 1-6烷基氧羰基、C 1-6烷基、C 3-6环烷基和苯基；
    在所述R a中，所述C 1-6烷基、C 3-6环烷基和苯基无取代或被1-5个R b取代；所述R b各自独立地选自由以下组成的组：氘、卤素、羟基、巯基、氨基、氰基、硝基、叠氮基、甲磺酰基、异丙磺酰基、苯磺酰基、氨基磺酰基、甲磺酸酯基、异丙磺酸酯基、苯磺酸酯基、三氟甲基、三氟甲基氧基、甲酰氨基和C 1-6烷基羰基。
  3. 如权利要求1或2所述的8-(吡啶酰胺)取代香豆素类化合物，其中，所述8-(吡啶酰胺)取代香豆素类化合物的结构如式(IA)所示：
    Figure PCTCN2022077640-appb-100002
    其中，R 1、R 2、R 3、R 4和R 5独立选自由以下组成的组：氢、氘、卤素、羟基、巯基、氨基、氰基、硝基、叠氮基、甲磺酰基、异丙磺酰基、苯磺酰基、氨基磺酰基、甲磺酸酯基、异丙磺酸酯基、苯磺酸酯基、三氟甲基、三氟甲基氧基、甲酰氨基、C 1-4烷基氧基、C 1-4烷基羰基、C 1-4烷基氧羰基、C 1-4烷基和苯基。
  4. 如权利要求1或2所述的8-(吡啶酰胺)取代香豆素类化合物，其中，所述8-(吡啶酰胺)取代香豆素类化合物的结构如式(IB)所示：
    Figure PCTCN2022077640-appb-100003
    其中，R 1、R 2、R 3、R 4和R 5独立选自由以下组成的组：氢、氘、卤素、羟基、巯基、氨基、氰基、硝基、甲磺酰基、三氟甲基、三氟甲基氧基、甲酰氨基、C 1-4烷基氧基、C 1-4烷基羰基和C 1-4烷基；X独立选自N或者C。
  5. 如权利要求1或2所述的8-(吡啶酰胺)取代香豆素类化合物，其中，所述8-(吡啶酰胺)取代香豆素类化合物选自如下所示的结构：
    Figure PCTCN2022077640-appb-100004
    Figure PCTCN2022077640-appb-100005
  6. 如权利要求1-5中任一项所述的8-(吡啶酰胺)取代香豆素类化合物的立体异构体、其药学上可接受的盐或包含其的药物组合物；
    优选地，所述药物组合物还包含药学上可接受的药用辅料。
  7. 如权利要求1-5中任一项所述的8-(吡啶酰胺)取代香豆素类化合物的制备方法，其包括：
    将
    Figure PCTCN2022077640-appb-100006
    先与DIPEA混合，再与4-(2-氧代-2H-色烯-8-羧酰胺基)吡啶-2-磺酰氯混合，反应，即得；其中，A环的限定范围与权利要求1-5中任一项限定的范围一致；
    其反应式如下所示：
    Figure PCTCN2022077640-appb-100007
  8. 如权利要求7所述的8-(吡啶酰胺)取代香豆素类化合物的制备方法，其中，所述4-(2-氧代-2H-色烯-8-羧酰胺基)吡啶-2-磺酰氯的制备方法包括如下步骤：
    (1)将8-溴香豆素先与正丁基锂混合，再于真空条件下与CO 2气体混合，反应，得到香豆素-8-羧酸；
    (2)将香豆素-8-羧酸与HATU、DIPEA混合后，再与4-氨基吡啶-2-磺酸混合，反应，得到4-(2-氧代-2H-色烯-8-羧酰胺基)吡啶-2-磺酸；
    (3)将4-(2-氧代-2H-色烯-8-羧酰胺基)吡啶-2-磺酸与二氯亚砜混合，反应，得到4-(2-氧代-2H-色烯-8-羧酰胺基)吡啶-2-磺酰氯；
    其反应式如下所示：
    Figure PCTCN2022077640-appb-100008
  9. 如权利要求1-5中任一项所述的8-(吡啶酰胺)取代香豆素类化合物或如权利要求6所述的8-(吡啶酰胺)取代香豆素类化合物的立体异构体、其药学上可接受的盐、包含其的药物组合物在制备用于治疗和/或预防与SIRT2活性过高或者与SIRT2过度表达有关的疾病或病症的药物中的应用。
  10. 如权利要求9所述的应用，其中，所述与SIRT2活性过高或者与SIRT2过度表达有关的疾病或病症包括帕金森病、代谢性疾病或肿瘤。
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017156181A1 (en) * 2016-03-09 2017-09-14 Raze Therapeutics, Inc. 3-phosphoglycerate dehydrogenase inhibitors and uses thereof
WO2018085348A1 (en) * 2016-11-03 2018-05-11 Actavalon, Inc. Substituted quinolines and methods for treating cancer
CN109293606A (zh) * 2018-11-20 2019-02-01 西华大学 2,5-双取代呋喃衍生物及其作为sirt蛋白抑制剂在药物制备中的用途
CN110551048A (zh) * 2018-06-04 2019-12-10 中国科学院上海药物研究所 一类sirt2抑制剂、其制备方法及用途
CN112939955A (zh) * 2021-03-05 2021-06-11 朗捷睿(苏州)生物科技有限公司 一种8-(吡啶酰胺)取代香豆素类化合物及其制备方法和应用

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120165330A1 (en) * 2010-12-22 2012-06-28 Sirtris Pharmaceuticals, Inc. Quinazolinone and related analogs as sirtuin modulators
GB201419102D0 (en) * 2014-10-27 2014-12-10 Imp Innovations Ltd Novel compounds
CN106496132B (zh) * 2016-10-13 2019-03-08 西华大学 N-(4-取代苯基)-2-取代乙酰胺类化合物及其作为sirt2蛋白抑制剂的用途
WO2018068357A1 (zh) * 2016-10-13 2018-04-19 西华大学 一类新型sirt2蛋白抑制剂及其在制药中的用途
CN108309982B (zh) * 2017-01-17 2020-10-09 四川大学 3位取代的5H-[1,2,4]三嗪[5,6-b]吲哚衍生物的用途

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017156181A1 (en) * 2016-03-09 2017-09-14 Raze Therapeutics, Inc. 3-phosphoglycerate dehydrogenase inhibitors and uses thereof
WO2018085348A1 (en) * 2016-11-03 2018-05-11 Actavalon, Inc. Substituted quinolines and methods for treating cancer
CN110551048A (zh) * 2018-06-04 2019-12-10 中国科学院上海药物研究所 一类sirt2抑制剂、其制备方法及用途
CN109293606A (zh) * 2018-11-20 2019-02-01 西华大学 2,5-双取代呋喃衍生物及其作为sirt蛋白抑制剂在药物制备中的用途
CN112939955A (zh) * 2021-03-05 2021-06-11 朗捷睿(苏州)生物科技有限公司 一种8-(吡啶酰胺)取代香豆素类化合物及其制备方法和应用

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CAS, no. 33491-30-4
DANTE ROTILI; VINCENZO CARAFA; DOMENICO TARANTINO; GIORGIA BOTTA; ANGELA NEBBIOSO; LUCIA ALTUCCI; ANTONELLO MAI;: "Simplification of the tetracyclic SIRT1-selective inhibitor MC2141: Coumarin- and pyrimidine-based SIRT1/2 inhibitors with different selectivity profile", BIOORGANIC & MEDICINAL CHEMISTRY, ELSEVIER, AMSTERDAM, NL, vol. 19, no. 12, 13 January 2011 (2011-01-13), AMSTERDAM, NL, pages 3659 - 3668, XP028378031, ISSN: 0968-0896, DOI: 10.1016/j.bmc.2011.01.025 *
MATTHIAS SCHIEDEL, MARTIN MAREK , JULIEN LANCELOT , BERIN KARAMAN , INGRID ALMLÖF, JOHAN SCHULTZ , WOLFGANG SIPPL , RAYMOND J. PI: "Fluorescence-based screening assays for the NAD+-dependent histone deacetylase smSirt2 from Schistosoma mansoni", JOURNAL OF BIOMOLECULAR SCREENING SOCIETY FOR LABORATORY AUTOMATION AND SCREENING, vol. 20, no. 1, 1 January 2015 (2015-01-01), pages 112 - 121, XP055962999, DOI: 10.1177/1087057114555307 *

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