WO2019120235A1 - 一类苯基羧酸衍生物、其制备方法及其用途 - Google Patents

一类苯基羧酸衍生物、其制备方法及其用途 Download PDF

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WO2019120235A1
WO2019120235A1 PCT/CN2018/122227 CN2018122227W WO2019120235A1 WO 2019120235 A1 WO2019120235 A1 WO 2019120235A1 CN 2018122227 W CN2018122227 W CN 2018122227W WO 2019120235 A1 WO2019120235 A1 WO 2019120235A1
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group
substituted
compound
halogen
alkoxy
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French (fr)
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赵维民
章海燕
秦俊俊
吴蕾
王红敏
冯红玄
张如隽
王维
邵星橙
陶泠雪
丁循
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中国科学院上海药物研究所
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    • A—HUMAN NECESSITIES
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
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    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
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    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
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    • C07C59/40—Unsaturated compounds
    • C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
    • C07C59/52—Unsaturated compounds containing hydroxy or O-metal groups a hydroxy or O-metal group being bound to a carbon atom of a six-membered aromatic ring
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    • C07C59/40—Unsaturated compounds
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/734—Ethers
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    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/738—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
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    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
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    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide

Definitions

  • the present invention relates to a phenylcarboxylic acid derivative, a preparation method and use thereof, and more particularly to a phenylcarboxylic acid derivative, a preparation method thereof, and a preparation thereof for preventing and/or treating cerebral ischemia, Use in drugs that are deficient or hypoxic-induced brain damage and/or neurological abnormalities.
  • Stroke is caused by insufficient blood supply to the brain due to vascular occlusion or bleeding, leading to brain dysfunction. Strokes were classified as ischemic stroke and hemorrhagic stroke, with ischemic stroke accounting for 87% of all strokes. Epidemiological studies of stroke have shown that stroke is threatening the health of all humans with its high morbidity, high mortality, high disability rate, and high recurrence rate.
  • the only FDA-approved anti-ischemic stroke drug is alteplase (recombinant human tissue plasminogen activator), but due to its narrow therapeutic window, limited scope, and adverse reactions to intracranial hemorrhage, The efficacy is still controversial. At present, the search for a class of neuroprotective agents that can inhibit the cascade-induced disease response induced by ischemia and thereby protect neurons and improve nerve function has become the main research strategy for the development of therapeutic drugs for acute ischemic stroke.
  • Y is O or NH
  • R 5 is selected from H; C 1 -C 10 alkyl, C 2 -C 10 unsubstituted or substituted by one or more substituents selected from hydroxy, amino, cyano or C 1 -C 10 alkoxy Alkenyl or C 2 -C 10 alkynyl; unsubstituted or substituted with one or more substituents selected from hydroxy, amino, cyano, halogen, C 1 -C 10 alkyl or C 1 -C 10 alkoxy a substituted 3 to 8 membered cycloalkyl group; unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxy, amino, cyano, halogen, C 1 -C 10 alkyl or C 1 -C 10 alkoxy a 6- to 8-membered aryl group; unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxyl, amino, halogen, cyano, halogen,
  • R 15 is selected from H, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, halogen, hydroxy or amino; when n is greater than 1, each R 15 is the same or different; preferably, R 15 is H ;
  • R 16 is selected from H or C 1 -C 10 alkyl; preferably selected from H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl or hexyl;
  • R 17 is selected from a substituted or unsubstituted 6 to 8 membered aryl group or a 5 to 8 membered heteroaryl group, and the substituent in the substituted 6 to 8 membered aryl group or substituted 5 to 8 membered heteroaryl group is selected from the group consisting of a hydroxyl group, an amino group, a halogen, a C 1 -C 10 alkyl group or a C 1 -C 10 alkoxy group; preferably, R 17 is selected from Wherein R 18 to R 22 are selected from H, hydroxy, amino, halogen, C 1 -C 10 alkyl or C 1 -C 10 alkoxy; preferably, R 18 , R 19 and R 22 are H, and R 20 and R 21 are a hydroxyl group;
  • R 5 is selected from hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl or Wherein, n, R 15 to R 17 are as defined above;
  • R 5 is selected from the group consisting of hydrogen, methyl, butyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, pentyl, hexyl, octyl, decyl, 1-propenyl, 1-butenyl, 2-butenyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl,
  • X is selected from among them, Representing a site linked to the benzene ring in Formula I, a site representing a linkage to a carbonyl group of formula I, Represents a single or double bond;
  • A is selected from C 1 -C 10 alkylene or C 2 -C 10 alkenylene; preferably C 1 -C 6 alkylene or C 2 -C 6 alkenylene; more preferably methylene, ethylene Base, propylene, butylene, pentylene, hexylene, vinylidene, propylene or butenylene;
  • R 23 is selected from a substituted or unsubstituted aryl or heteroaryl group, and the substituent in the substituted aryl or substituted heteroaryl group is selected from a hydroxyl group, an amino group, a halogen, a C 1 -C 10 alkyl group or a C 1 group.
  • R 23 is
  • R 24 to R 28 are each independently selected from H, a hydroxyl group, an amino group, a halogen, a C 1 -C 10 alkyl group or a C 1 -C 10 alkoxy group, or a benzene adjacent thereto to which two of them are attached
  • R 24 , R 27 and R 28 are hydrogen;
  • R 0 to R 4 are each independently selected from H; hydroxy; amino; halogen; unsubstituted or substituted with one or more substituents selected from hydroxy, amino, halo, cyano or C 1 -C 10 alkoxy the C 1 ⁇ C 10 alkyl group; unsubstituted or substituted group selected from hydroxy, amino, halo, cyano or C 1 ⁇ C 10 alkoxy group substituted with one or more substituents of C 1 ⁇ C 10 alkoxy group a 3 to 8 membered cycloalkyl group which is unsubstituted or substituted with one or more substituents selected from the group consisting of a hydroxyl group, an amino group, a halogen, a cyano group, a C 1 -C 10 alkyl group or a C 1 -C 10 alkoxy group; a 6- to 8-membered aryl group which is unsubstituted or substituted with one or more substituents selected from the group
  • R 0 to R 4 are each independently selected from: H; hydroxy; amino; halogen; unsubstituted or selected from one or more selected from the group consisting of hydroxyl, amino, halogen, cyano or C 1 -C 6 alkoxy substituents of C 1 ⁇ C 6 alkyl group; unsubstituted or substituted group selected from hydroxy, one or more amino, halo, cyano or C 1 ⁇ C 6 alkoxy substituted with C 1 ⁇ C 6 alkoxy; 5 to 8 member unsubstituted or substituted with one or more substituents selected from hydroxy, amino, halogen, cyano, C 1 -C 6 alkyl or C 1 -C 6 alkoxy a cycloalkyl group; a 6 to 8 membered aromatic group which is unsubstituted or substituted with one or more substituents selected from the group consisting of a hydroxyl group, an amino group, a halogen, a cyano
  • a 5- to 8-membered heterocyclic group which is unsubstituted or substituted with one or more substituents selected from the group consisting of a hydroxyl group, an amino group, a halogen, a cyano group, a C 1 -C 6 alkyl group or a C 1 -C 6 alkoxy group;
  • a 5 to 8 membered heteroaryl group which is unsubstituted or substituted with one or more substituents selected from the group consisting of a hydroxyl group, an amino group, a halogen, a cyano group, a C 1 -C 6 alkyl group or a C 1 -C 6 alkoxy group;
  • R 0 to R 4 are each independently selected from: H, hydroxy, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
  • R 0 , R 1 and R 4 are H, and R 2 and R 3 are H, a hydroxyl group or a C 1 -C 6 alkoxy group.
  • the C 1 -C 10 alkyl group means a straight or branched alkyl group having 1 to 10 carbon atoms, and examples thereof include, but are not limited to, methyl group, ethyl group, propyl group, isopropyl group, butyl group, and isobutyl group. a base, tert-butyl or pentyl; preferably a C 1 -C 6 alkyl group;
  • the C 1 -C 10 alkoxy group means a straight or branched alkoxy group having 1 to 10 carbon atoms, and examples thereof include, but are not limited to, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group. a butoxy, isobutoxy, tert-butoxy or pentyloxy group; preferably a C 1 -C 6 alkoxy group;
  • the 3- to 8-membered cycloalkyl group represents a 3- to 8-membered saturated cycloalkyl group; examples thereof include a cyclopropyl group, a cyclobutane group, a cyclopentyl group, a cyclohexane group or a cycloheptyl group;
  • the 6 to 8 membered aryl group represents a 6 to 8 membered aryl group, and examples thereof include, but are not limited to, a phenyl group;
  • the 3- to 8-membered heterocyclic group means a 3- to 8-membered saturated or unsaturated non-aromatic cyclic hydrocarbon group containing one or more hetero atoms selected from N, O or S, and examples thereof include, but are not limited to, propylene oxide.
  • Base butylene oxide, dihydrofuranyl, tetrahydrofuranyl;
  • a 5- to 8-membered heteroaryl group means a 5- to 8-membered heteroaryl group containing one or more heteroatoms selected from N, O or S, examples of which include, but are not limited to, pyrrolyl, pyridyl, pyrimidinyl or Pyrazinyl;
  • the compound of formula I is selected from the group consisting of:
  • the compound of the present invention has excellent neuroprotective activity, and thus the compound of the present invention, its enantiomer, diastereomer, racemate or a mixture thereof, or a pharmaceutically acceptable salt thereof, and the present invention
  • the pharmaceutical composition in which the compound is the main active ingredient can be used for the treatment, prevention, and alleviation of brain damage and/or neurological abnormalities induced by cerebral ischemia, hypoglycemia or hypoxia.
  • Another object according to the invention is to provide a process for the preparation of a compound of formula I which comprises the steps of:
  • R 1 to R 4 , and X and Y are the same as defined above, and R 5 is the same as defined above except that it is not H.
  • the catalyst for the esterification reaction is concentrated sulfuric acid, the reaction temperature is 30 to 90 ° C; the amidation reaction requires the addition of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide salt.
  • Acid salt (EDCI) and 1-hydroxybenzotriazole (HOBt) the reaction temperature is normal temperature.
  • a pharmaceutical composition comprising a safe and effective amount of a compound of the formula I, an enantiomer, a diastereomer thereof, a racemate or a pharmaceutically thereof thereof.
  • the pharmaceutical composition contains from 0.1 to 95% by weight of a compound of formula I, an enantiomer, a diastereomer, a racemate or a pharmaceutically thereof thereof, based on 100% by weight of the pharmaceutical composition. Acceptable salt.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By “compatibility” it is meant herein that the components of the composition are capable of blending with the compounds of the invention and with each other without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as microcrystalline cellulose, carboxypropylmethylcellulose, sodium carboxymethylcellulose, sodium ethylcellulose, etc.), gelatin, talc, solid lubricants.
  • stearic acid such as stearic acid, magnesium stearate, etc.
  • calcium sulfate such as vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as Tween, etc.), wetting agent (such as sodium lauryl sulfate, etc.), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, other fillers (such as starch, pre-emulsified starch, carboxymethyl Based on sodium starch, starch syrup, silica, lactose, sucrose, glucose, mannitol and silicic acid, etc.).
  • vegetable oil such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyol such as propylene glycol, glycerin, mannitol, sorb
  • the compound of the formula I according to the present invention when used for the preparation of a medicament for treating, preventing and relieving cerebral ischemia, hypoglycemia, hypoxia-induced brain injury and/or neurological abnormality, it may be used alone or in combination with Pharmaceutical excipients (such as excipients, diluents, etc.) are mixed.
  • the compound of the formula I according to the invention, its enantiomer, diastereomer, racemate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same may be in unit dosage form
  • the route of administration may be intestinal or parenteral, such as oral, muscle, subcutaneous, nasal, oral mucosa, skin, peritoneum or rectum.
  • the administration method of the compound of the formula I according to the invention, its enantiomer, diastereomer, racemate or pharmaceutically acceptable salt thereof or pharmaceutical composition containing the same can be used.
  • the injection includes intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, and acupoint injection.
  • the compound of the formula I according to the invention, its enantiomer, diastereomer, racemate or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same can be formulated into a liquid preparation ,solid preparations.
  • the liquid preparation may be a true solution, a colloid, a microparticle, an emulsion, or a suspension.
  • Other dosage forms such as tablets, capsules, pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, lyophilized powders, and the like.
  • the compound of the formula I according to the present invention can be prepared into a common preparation. It can also be a cyclic preparation, a controlled release preparation, a targeted preparation, and various microparticle delivery systems.
  • the compound of the formula I according to the present invention is formulated into an injectable preparation such as a solution, a suspension solution emulsion, or a lyophilized powder injection.
  • the preparation may be aqueous or non-aqueous, and may contain one type. And/or a plurality of pharmaceutically acceptable carriers, diluents, binders, lubricants, preservatives, surfactants or dispersing agents.
  • the diluent may be selected from the group consisting of water, ethanol, polyethylene glycol, 1,3-propanediol, ethoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid ester, and the like.
  • an appropriate amount of sodium chloride, glucose or glycerin may be added to the preparation for injection, and a conventional solubilizer, a buffer, a pH adjuster or the like may be added.
  • the pharmaceutical or pharmaceutical composition of the present invention can be administered by any known administration method for the purpose of administration and enhancing the therapeutic effect.
  • the dosage of a pharmaceutical composition comprising a compound of formula I as described herein will depend on a number of factors, such as the nature and severity of the disease to be prevented or treated, the sex, age, weight, personality and individual of the patient or animal.
  • the reaction, the route of administration, the number of administrations, and the purpose of treatment, therefore, the therapeutic dose of the present invention can vary widely.
  • the dosages of the pharmaceutical ingredients employed in the present invention are well known to those skilled in the art.
  • the daily dose range of the compound of the present invention is preferably from 0.1 to 100 mg/kg body weight, more preferably from 10 to 200 mg/day/person.
  • the above dosages may be administered in a single dosage form or divided into several, for example two, three or four dosage forms, which are limited by the clinical experience of the administering physician and the dosing regimen including the use of other therapeutic means.
  • a compound, an enantiomer, a diastereomer, a racemate or a pharmaceutically acceptable salt thereof of the formula I in the preparation of a prophylactic and/or therapeutic brain Use in drugs for ischemic, hypoglycemic or hypoxic-induced brain damage and/or neurological abnormalities.
  • a compound of the formula I of the present invention for use in the treatment of cerebral ischemia, hypoglycemia or hypoxia-induced brain injury and/or neurological abnormalities Use in.
  • a method of treating a brain injury and/or a neurological dysfunction induced by cerebral ischemia, hypoglycemia or hypoxia comprising the steps of: applying to a subject A therapeutically effective amount of a compound of the formula I, an enantiomer, a diastereomer thereof, a racemate or a pharmaceutically acceptable salt thereof or the pharmaceutical composition.
  • Figure 1A is a graph showing that Compound 010 of the present invention improves OGD-induced SH-SY5Y cell damage.
  • Figure 1B shows a graph of the viability of cells in different treatment groups using the MTT assay.
  • 2A is a graph showing that Compound 010 of the present invention improves H 2 O 2 induced SH-SY5Y cell damage.
  • Figure 2B is a graph showing the detection of cell viability in different treatment groups using the MTT method.
  • 3A and 3B are graphs showing that the compound 010 of the present invention inhibits the production of TNF- ⁇ and IL-1 ⁇ in LPS-induced primary microglial supernatants.
  • Figure 4 is a graph showing that Compound 010 of the present invention improves the damage of LPS-stimulated primary microglial supernatants to primary cortical neurons.
  • Figure 5 is a graph showing that Compound 010 of the present invention improves cerebral infarction volume and cerebral edema in MCAO rats, wherein Figure 5A is a representative TTC staining diagram showing the degree of cerebral infarction volume and cerebral edema by TTC staining; Figure 5B is a brain Infarct volume statistics; Figure 5C is a graph of brain edema degree; Figure 5D is a graph showing mNSS score.
  • Figure 6 is a graph showing the inflammatory response of glial cells after inhibition of LPS treatment by Compound 079.
  • the Griess reagent detects the level of NO in the supernatant.
  • Data are the percentage of the LPS group and are expressed as the mean ⁇ standard error of 3 independent test results. ### p ⁇ 0.001 compared with the normal control group, **p ⁇ 0.01, ***p ⁇ 0.001 compared with the lipopolysaccharide (LPS) group.
  • LPS lipopolysaccharide
  • the rosmarinic acid (720 mg, 2.0 mmol) was dissolved in 25 mL of n-butanol, 1 mL of concentrated sulfuric acid was added dropwise, and the reaction was completed after stirring at 60 ° C for 3 h.
  • the mixture was combined with water and ethyl acetate.
  • Step (1) Dissolve L-dopa (400 mg, 2.0 mmol) in 25 mL of n-butanol, slowly add SOCl 2 (1 mL) under ice bath, react at room temperature for 24 h, and detect no starting point by TLC. . After the organic phase in the reaction mixture was removed under reduced pressure, the residue was purified by silica gel column chromatography.
  • Step (2) L-Dobubutyl ester (253 mg, 1.0 mmol) and caffeic acid (180 mg, 1.0 mmol) were dissolved in 20 mL of dichloromethane, and PyBOP (520 mg, 1.0 mmol) and 415 ⁇ L were added under ice bath. After ethylamine (3.0 mmol) was reacted for 12 hours under a nitrogen atmosphere, the reaction was completed. After distilling off the dichloromethane, the mixture was combined with water and ethyl acetate. The ethyl acetate layer was washed three times with saturated brine and dried over anhydrous sodium sulfate. , 112 mg of white gum was obtained in a yield of 27%.
  • Step (1) Weigh 13.8 g of 3,4-dihydroxybenzaldehyde (10 mmol), 55.0 g of anhydrous potassium carbonate (40 mmol) dissolved in 50 mL of N,N-dimethylformamide, and add dropwise at room temperature with stirring. 38.0 g of benzyl chloride (30 mmol) was added and heated at 120 ° C for 2 h. After cooling to room temperature, the mixture was combined with water and ethyl acetate. The ethyl acetate layer was washed three times with saturated brine and dried over anhydrous sodium sulfate. , 30.3 g of a white solid A was obtained in a yield of 95.3%.
  • Step (2) Weigh 50.0 g of n-butanol in a round bottom flask, slowly add 60 mL of chloroacetyl chloride (1.2 eq.), stir at room temperature for 1 h, add sodium bicarbonate solids in portions until no more bubbling, add water / Ethyl acetate extraction layered, the ethyl acetate layer was washed twice with saturated brine, dried over anhydrous sodium sulfate, and evaporated to ethyl acetate to give a colorless transparent oily liquid, which was distilled under reduced pressure to collect 100 ° C fractions to give 89.0 g Colorless and transparent liquid B, yield 87.6%.
  • Step (3) Weigh 2.08 g of sodium silk (9.0 mmol) into 30 mL of n-butanol until the sodium silk is completely dissolved, and the solution is cooled to room temperature to obtain a solution 1.
  • the solution 2 of 3,4-dibenzyloxybenzaldehyde 19.1 g (6.0 mmol) and 10.8 g of butyl chloroacetate (7.2 mmol) were dissolved in 30 mL of dry dioxane. Two drops of the solution were slowly added to the solution 1, and a white solid was precipitated and stirred at room temperature. 2,4-Dinitrophenylhydrazine color reaction was used to monitor the reaction process. After 1.5h, the reaction was complete.
  • Step (6) Chiral resolution of compound E [chiral column: Kromasil-5-CellCoat (250 ⁇ 4.6 mm); mobile phase: 90% n-hexane / isopropanol; flow rate: 1.0 mL / min] , a pair of enantiomers (R)-2-hydroxy-3-(3,4-dibenzyloxyphenyl)-n-propionic acid butyl ester F ⁇ [ ⁇ ] D -62 (c 0.05, MeOH) And (S)-2-hydroxy-3-(3,4-dibenzyloxyphenyl)-n-propionic acid butyl ester G ⁇ [ ⁇ ] D +70(c 0.06, MeOH) ⁇ .
  • 1 H NMR was the same as compound 010.
  • Step (1) Weigh 6.17 g of 3,4-dihydroxyacetophenone (40 mmol), dissolve it in 30 mL of THF, add 1.9 ml of acetic anhydride (200 mmol) in excess, and add 308 mg of dimethylaminopyridine at room temperature with stirring. DMAP), then warmed to 60 ° C to stir, TLC plate was detected to 3,4-dihydroxyacetophenone reaction was completed, the solvent was evaporated under reduced pressure to give a white solid, white solid was washed with water, then dried in a lyophilizer 9.28 g of a white powder was obtained in a yield of 97%.
  • Step (2) 2.38 g of Compound H (10 mmol) was weighed and dissolved in 15 mL of thionyl chloride. After stirring at 70 ° C for 1 h, the solvent was evaporated under reduced pressure.
  • Step (3, 4) Cut 345 mg (1.5 eq) of sodium metal into 5 mL of anhydrous THF, add 3.9 ml (3 eq) of ethyl acetoacetate dropwise, and slowly stir until no more gas is produced. Then the step ( 2) The obtained compound K was dissolved in 3 ml of anhydrous THF, and slowly added dropwise thereto. After stirring at room temperature for 0.5 h, 30 mL of ethyl acetate was added dropwise to the system, and 1 N HCl was added dropwise thereto, and the pH was adjusted until the solution was present. Sex. The ethyl acetate layer was washed three times with saturated brine, dried over anhydrous sodium sulfate and evaporated.
  • Examples 53 and 54 in Table 3 below were prepared using a method similar to that described in Example 11.
  • Step (1) 6.90 g of 1,2-dimethoxybenzene (50 mmol) and 10.0 g of succinic anhydride (2 eq) were weighed and dissolved in 50 mL of dichloroethane, and dissolved by stirring at room temperature. Weigh 10.35 g of aluminum chloride, slowly add the above mixture, stir at 80 ° C for 6 h, cool to room temperature, then slowly add 1 N HCl until the aluminum chloride complex is completely dissolved. Ethyl dichloroethane was evaporated under reduced pressure to give a pale yellow solid, which was washed with water, and then washed with water, to afford 9.75 g of compound 063.
  • Step (2) Weigh 500 mg of compound 025 (2.1 mmol) dissolved in 3 mL of absolute ethanol, stir to dissolve and transfer to ice bath, add 882 ⁇ L of oxalyl chloride (5 eq) dropwise, then stir at room temperature for 20 min, add ice The reaction was quenched with water, EtOAc (EtOAc)EtOAc. The yield was 59%.
  • Step (1) Weigh 1.19 g of compound 063 (5 mmol) dissolved in dichloromethane, stir to dissolve at room temperature, then transfer to ice salt bath, add 1.88 mL of boron tribromide (4 eq) dropwise, ice salt bath After stirring for 3 h, it was quenched with water and extracted with saturated brine / ethyl acetate.
  • Step (2) Weigh 200mg of the material obtained in the step (1), dissolved in anhydrous methanol, stirred at room temperature and dissolved to an ice bath, 243 ⁇ L of oxalyl chloride (3 eq) was added dropwise, and then stirred at room temperature for 20 min, added The reaction was quenched with ice water and extracted three times with brine brine and ethyl acetate. 89 mg of compound 073 were obtained. The yield was 42%.
  • Examples 65-79 in Table 5 below were prepared using methods analogous to those described in Example 64.
  • Step (1) Weigh 336 mg of 3,4-dihydroxyphenylacetic acid dissolved in absolute ethanol, stir at room temperature, and then transfer to ice bath, add 508 ⁇ L of oxalyl chloride (6 eq) dropwise, and then stir at room temperature for 20 min. The reaction was quenched by the addition of EtOAc (EtOAc)EtOAc. 580 mg of ethyl 3,4-dihydroxyphenylacetate were obtained. The yield was 98%.
  • Step (2) 300 mg of ethyl 3,4-dihydroxyphenylacetate and 167 ⁇ L of ethyl glyoxylate (1.1 eq) were weighed and dissolved in 5 mL of glacial acetic acid, and heated under reflux at 120 ° C for 24 h. After cooling to room temperature, it was extracted three times with a saturated brine / ethyl acetate system, and ethyl acetate layer was concentrated, and then separated on a high-performance liquid phase C-18 column, eluting conditions: 65% acetonitrile-water. 43 mg of compound 093 were obtained. The yield was 10%.
  • Step (1) 362 mg of ethyl 2-bromopropionate (2 mmol), 365 mg of triethyl phosphonate (2 mmol), 48 mg of NaH (2 mmol) dissolved in 3 mL of THF and heated to reflux for 0.5 h, then 276 mg of 3,4- Dihydroxybenzaldehyde (2 mmol), and the mixture was refluxed for 3 h until the reaction was completed.
  • the mixture was extracted with water and ethyl acetate.
  • Step (2) The above amorphous powder is subjected to alkali hydrolysis with sodium hydroxide, and acidified with hydrochloric acid to obtain 095,283 mg of an amorphous powder, and the yield is 100%.
  • Example 89 Compound 001-012 protects SH-SY5Y cells from oxygen glucose deprivation damage
  • This assay is routinely performed using the thiazolyl blue (MTT) colorimetric assay, using human neuroblastoma cell line (SH-SY5Y cells), in MEM/F12 medium containing 10% fetal bovine serum at 37 ° C, 5 Culture in a %CO 2 incubator. One generation of cells was passed every four days and the passaged cells were observed under an inverted microscope. When the cells grow uniformly and grow to 80% to 90%, digest with 0.125% trypsin for 1-2 min, adjust the cell concentration to 2.5*10 5 cells with MEM/F12 medium containing 10% fetal bovine serum.
  • MEM/F12 medium containing 10% fetal bovine serum
  • EXPERIMENTAL RESULTS The statistical results showed that the activity of neurons was significantly decreased under oxygen-glucose deprivation conditions, and the neuronal activity was significantly restored after administration of 10 ⁇ M target compound; while the target compound did not affect the activity of neurons in the normal group. *p ⁇ 0.05, ***p ⁇ 0.001, compared to the solvent control group; ### p ⁇ 0.001, compared to the normal control group; each group of 6 wells, the experiment was repeated 3 times independently. The results are shown in Table 7.
  • Example 90 Compounds 013-022, 027-080, 083-090 protect SH-SY5Y cells from oxygen sugar deprivation damage
  • test compound was dissolved in DMSO, formulated into a 10 mM mother liquor, and stored at -20 ° C.
  • SH-SY5Y cells were trypsinized and suspended in MEM/F12 medium containing 10% fetal bovine serum.
  • SH-SY5Y cells were seeded on a 96-well culture plate at a density of 3.5 ⁇ 10 5 cells/mL, inoculated in a volume of 100 ⁇ L/well, and cultured in a 37 ° C incubator containing 5% CO 2 . After SH-SY5Y cells were cultured for 24 hours, the cells were changed once and the culture was continued for 24 hours.
  • the corresponding concentration of the test compound was added to the drug-administered group, and the mixture was pre-incubated for 2 hours, the oxygen-deficient group was added to the corresponding solvent control, and the normal group was added with the corresponding amount of the culture solution. After the compound was pre-incubated, the oxygen-deficient-damaged group and the drug-administered group were washed with the sugar-free EBSS balanced salt solution, and then replaced with DMEM (sugar-free) medium, and the corresponding concentration was added to the drug-administered group again.
  • DMEM sucgar-free
  • test compound (10 ⁇ L/well) and the oxygen sugar-deficient group were added to the compound solvent control, and cultured for 2 hours in an anaerobic apparatus (containing 85% N 2 , 10% H 2 , 5% CO 2 ).
  • the normal control group was changed to a DMEM medium containing sugar and serum, and cultured in a 37 ° C incubator containing 5% CO 2 for the same time.
  • the oxygen plate was taken out from the anaerobic apparatus, and the oxygen-deficient injury group and the administration group were supplemented with serum and glucose, and the final concentration of glucose was 1 g/L.
  • 5 mg/mL MTT (10 ⁇ L/well) was added for viable cell staining.
  • Example 91 Compounds 013-080, 083-090 protect SH-SY5Y cells from oxygen sugar deprivation damage without pre-incubation conditions
  • test compound was dissolved in DMSO, formulated into a 10 mM mother liquor, and stored at -20 ° C.
  • SH-SY5Y cells were trypsinized and suspended in MEM/F12 medium containing 10% fetal bovine serum.
  • SH-SY5Y cells were seeded on a 96-well culture plate at a density of 3.5 ⁇ 10 5 cells/mL, inoculated in a volume of 100 ⁇ L/well, and cultured in a 37 ° C incubator containing 5% CO 2 . After SH-SY5Y cells were cultured for 24 hours, the cells were changed once and the culture was continued for 24 hours.
  • the oxygen-deficient injury group and the administration group were all washed with the sugar-free EBSS balanced salt solution, and then replaced with DMEM (sugar-free) medium, and the corresponding concentration of the test compound was added to the drug-administered group.
  • the group was added with the corresponding solvent control and placed in an anaerobic apparatus (containing 85% N 2 , 10% H 2 , 5% CO 2 ) for 2 h.
  • the normal control group was changed to a DMEM medium containing sugar and serum, and cultured in a 37 ° C incubator containing 5% CO 2 for the same time.
  • the oxygen plate was taken out from the anaerobic apparatus, and the oxygen-deficient injury group and the administration group were supplemented with serum and glucose, and the final concentration of glucose was 1 g/L.
  • 5 mg/mL MTT 100 ⁇ L/well was added for viable cell staining.
  • DMSO 100 ⁇ L/well was added, and shaken on a shaker to fully dissolve.
  • the OD value of each group was measured at a wavelength of 490 nm.
  • the cell viability of the test compound group and the cell viability percentage of the normal control group, the data are the average of two independent experiments (three replicates each time). The experimental results are shown in Table 9.
  • Example 92 Compounds 025, 079, 092, 094 and 095 protected SH-SY5Y cells from oxygen sugar deprivation damage under pre-incubated conditions.
  • the experimental method used was the same as in Example 89.
  • the experimental results are shown in Table 10.
  • SH-SY5Y cells were damaged by OGD for 1 h and reoxygenated for 24 h.
  • the morphology of the cells changed significantly, the neurites broke, the cells contracted, and the number of cells decreased (Fig. 1A).
  • MTT results showed that OGD damage caused cell viability to drop to 52.95% (p ⁇ 0.001 vs. Control) (Fig. 1B).
  • Preincubation of 1 ⁇ M and 10 ⁇ M of compound 010 improved the morphological changes caused by OGD in a concentration-dependent manner (Fig.
  • Preincubation of 1 ⁇ M and 10 ⁇ M of compound 010 improved the morphological changes caused by H 2 O 2 in a concentration-dependent manner ( FIG. 2A ), the cell rupture was reduced, the cells with normal morphology were increased, and the number of cells was increased.
  • Compound 010 at 1 ⁇ M and 10 ⁇ M increased cell viability to 71.14% (p ⁇ 0.05 vs. H 2 O 2 group) and 82.31% (p ⁇ 0.01 vs. H 2 O 2 group), respectively (Fig. 2B).
  • Example 95 Anti-inflammatory effect of Compound 010 in a primary microglial LPS model
  • microglia are immune cells of the central nervous system and play a major role in immune defense.
  • the role of microglia in cerebral ischemia has received increasing attention. Under normal conditions, microglia have phagocytosis, and the surrounding microenvironment is constantly monitored to prevent cell debris from accumulating in the central nervous system.
  • the small gel cells are in a resting state or activated state depending on the surrounding environment.
  • microglia When microglia are activated, they rapidly transform into phagocytic cells, release inflammatory factors, and overexpress surface antigens with immunomodulatory effects. Within a few minutes of cerebral ischemia, microglia mediate acute inflammatory responses by releasing the pro-inflammatory factors TNF- ⁇ and IL-1 ⁇ , aggravating ischemic injury. LPS is a commonly used inducer to induce inflammatory responses in primary microglia. Therefore, in this example, the LPS model of primary microglia was used to study the anti-inflammatory effect of compound 010.
  • CM(LPS) LPS-stimulated primary microglia
  • MTT results showed primary cortex.
  • neuronal viability decreased (84.36%, p ⁇ 0.01vs.Control)
  • 010 treated primary microglial cell supernatants [CM (LPS + 3 ⁇ M 145-16A)] was added neurons, the degree of damage Alleviation (94.48%, p ⁇ 0.05 vs. [CM(LPS)] group) (Fig. 4).
  • Example 96 Protective effect of compound 010 on acute cerebral ischemia-induced nerve injury
  • SD rats were used to evaluate the degree of ischemic-induced brain damage and short-term neurobehavioral changes in patients with focal cerebral ischemia (MCAO) model induced by middle cerebral artery embolization.
  • Compound 010 was sufficiently dissolved in a vehicle (1% DMSO, 5% Cremophor EL, 94% physiological saline).
  • Rats were anesthetized with chloral hydrate (350mg/kg, ip), fixed in supine position, median incision in the neck, separation of left common neck and internal and external carotid arteries, active knot on common carotid artery, ligation of distal end of external carotid artery Ligation, activating the knot on the proximal end, and clamping the internal carotid artery with an artery clamp. Cut a small opening at the proximal bifurcation of the external carotid artery, insert the fishing line, loosen the arterial clip, push the fish line into the internal carotid artery, and stop when there is slight resistance. The insertion concentration is about 20mm. Ligation of the external carotid artery at the line and fixing the fishing line. The wound was sutured and the animals were placed back in the general cage. After 2 hours, the fish line was carefully pulled out.
  • Neurobehavioral scores were performed 24 h after surgery.
  • the improved neurobehavioral score includes a series of neurological dysfunction tests, the specific scoring criteria are as follows:
  • Auricular reflex disorder -1 point corneal reflex disorder -1 point; startle reflex disorder -1 point; myoclonus or dystonia -1 point.
  • the above evaluation indicators comprehensively reflect the movement, sensation, balance and reflex function, and the score ranges from 0 to 18. The larger the score, the more obvious the neurobehavioral injury.
  • the animals were decapitated and the brain was removed.
  • the olfactory bulb, cerebellum, brainstem and low brain stem were removed, and then 6 teeth were cut into 5 slices.
  • the brain tissue was stained with TTC (1%, w/v), the normal tissue was red, and the infarct site was white.
  • the infarct volume and ratio were calculated. The same method was used to record the infarct volume and ratio of each group, and ANOVA statistical analysis was performed.
  • the mNSS score was reduced to 6.06 points (p ⁇ 0.05 vs. model group) and 4.53 points (p ⁇ 0.001 vs. model group) (Fig. 5D).
  • Cell supernatants NO 2 - content of NO is indicative of the level of detection using Griess reagent NO 2 - content to reflect the level of NO, and thus reflects the ability of anti-inflammatory compounds.
  • the target cell for the test was the microglial cell line BV-2, and the inflammatory model used was a lipopolysaccharide (LPS)-induced microglial inflammatory response model.
  • LPS lipopolysaccharide
  • LPS final concentration was 100 ng/mL
  • the culture was continued for 24 hours, and the supernatant in the 96-well plate was directly collected.
  • 50 ⁇ L of the supernatant and an equal volume of Griess reagent were added to a 96-well plate, mixed, and allowed to react at room temperature for 15 minutes in the dark, and the absorbance was measured at a wavelength of 540 nm using a microplate reader.
  • Sodium nitrite is a standard.
  • the results of LPS-induced BV-2 microglial inflammatory response model showed that treatment with Compound 079 can effectively inhibit the excess NO content in the supernatant after LPS stimulation of BV-2, and 100 ng/ml LPS-treated BV-2 cells.
  • the content of NO in the supernatant was significantly increased to 43.9 ⁇ M (set to 100%, p ⁇ 0.001 vs. normal group), and 10 ⁇ M and 20 ⁇ M Compound 079 treatment significantly reduced the NO nitrite content in the supernatant to 37.6 ⁇ M (LPS group). 85.3%) and 33.3 ⁇ M (75.7% of the LPS group) (p ⁇ 0.01 vs. LPS group) (Fig. 6).

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Abstract

本发明涉及一类苯基羧酸衍生物，其制备方法及用途，更具体而言，涉及一类式I所示的苯基羧酸衍生物，其制备方法，以及其在制备预防和/或治疗脑缺血、缺糖或缺氧诱发的脑损伤和/或神经功能异常的药物中的用途。所述式I的结构如左所示：(I)。

Description

一类苯基羧酸衍生物、其制备方法及其用途 技术领域
本发明涉及一类苯基羧酸衍生物，其制备方法及用途，更具体而言，涉及一类苯基羧酸衍生物，其制备方法，以及其在制备预防和/或治疗脑缺血、缺糖或缺氧诱发的脑损伤和/或神经功能异常的药物中的用途。
背景技术
中风是由于血管阻塞或者出血造成脑供血不足，导致脑功能障碍。中风分为缺血性中风和出血性中风，其中缺血性中风患者占总中风人数的87％。中风的流行病学研究表明，中风正以其高发病率、高死亡率、高致残率、高复发率的特点威胁着全人类的健康。FDA批准的抗缺血性中风的治疗药物只有阿替普酶(重组人组织型纤溶酶原激活剂)，但由于其治疗窗窄、适用范围不广并具有颅内出血的不良反应，对其疗效尚有争议。当前，寻找一类能够抑制缺血所诱发的级联病变反应从而发挥保护神经元、改善神经功能的神经保护剂已成为研发急性缺血性脑卒中治疗药物的主要研究策略。
发明内容
本发明的目的是提供了一种式I所示的化合物、其对映异构体、非对映异构体、外消旋体或其药学上可接受的盐，
Figure PCTCN2018122227-appb-000001
其中，
Y为O或NH；
R 5选自H；未取代或被选自羟基、氨基、氰基或C 1～C 10烷氧基中的一个或多个取代基取代的C 1～C 10烷基、C 2～C 10烯基或C 2～C 10炔基；未取代或被选自羟基、氨基、氰基、卤素、C 1～C 10烷基或C 1～C 10烷氧基中的一个或多个取代基取代的3至8元环烷基；未取代或被选自羟基、氨基、氰基、卤素、C 1～C 10烷基或C 1～C 10烷氧基中的一个或多个取代基取代的6至8元芳基；未取代或被选自羟基、氨基、卤素、氰基、卤素、C 1～C 6烷基或C 1～C 6烷氧基中的一个或多个取代基取代的5至8元杂环基；未取代或被选自羟基、氨基、卤素、氰基、卤素、C 1～C 6烷基或C 1～C 6烷氧基中的一个或多个取代基取代的5至8元杂芳基；或
Figure PCTCN2018122227-appb-000002
其中，n为1至6的整数，优选为1、2、3、4、5或6；
R 15选自H、C 1～C 10烷基、C 1～C 10烷氧基、卤素、羟基或氨基；当n大于1时，各个R 15各自相同或不同；优选地，R 15为H；
R 16选自H或C 1～C 10烷基；优选选自H、甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基或己基；
R 17选自取代或未取代的6至8元芳基或5至8元杂芳基，所述取代的6至8元芳基或取代的5至8元杂芳基中的取代基选自羟基、氨基、卤素、C 1～C 10烷基或C 1～C 10烷氧基；优选地，R 17选自
Figure PCTCN2018122227-appb-000003
其中，R 18至R 22选自H、羟基、氨基、卤素、C 1～C 10烷基或C 1～C 10烷氧基；优选地，R 18、R 19和R 22为H，以及R 20和R 21为羟基；
优选地，R 5选自氢、C 1～C 10烷基、C 2～C 10烯基、C 2～C 10炔基或
Figure PCTCN2018122227-appb-000004
其中，n，R 15至R 17的定义如前所述；
更优选地，R 5选自氢、甲基、丁基、乙基、丙基、异丙基、异丁基、叔丁基、戊基、己基、辛基、癸基、1-丙烯基、1-丁烯基、2-丁烯基、1-丁炔基、2-丁炔基、1-戊炔基、2-戊炔基、3-戊炔基、
Figure PCTCN2018122227-appb-000005
X选自
Figure PCTCN2018122227-appb-000006
其中，
Figure PCTCN2018122227-appb-000007
表示与式I中的苯环连接的位点，
Figure PCTCN2018122227-appb-000008
表示与式I中的羰基连接的位点，
Figure PCTCN2018122227-appb-000009
表示单键或双键；
R 6至R 14各自独立地选自H；羟基；卤素；氨基；氧代基团(＝O)；C 1～C 10烷基；C 1～C 10烷氧基；卤素；未取代或被选自羟基、C 1～C 10烷氧基或卤素中的一个或多个取代基取代的C 1～C 10烷基；C 1～C 10烷氧基羰基；或
Figure PCTCN2018122227-appb-000010
其中，Z为O或NH；优选地，R 6至R 14各自独立地选自H；羟基；氧代基团(＝O)；C 1～C 10烷氧基羰基；或
Figure PCTCN2018122227-appb-000011
其中，Z为O或NH，并且R 6和R 7中至多一个为
Figure PCTCN2018122227-appb-000012
R 8至R 10中至多一个为
Figure PCTCN2018122227-appb-000013
以及R 11至R 14中至多一个为
Figure PCTCN2018122227-appb-000014
A选自C 1～C 10亚烷基或C 2～C 10亚烯基；优选为C 1～C 6亚烷基或C 2～C 6亚烯基；更优选为亚甲基、亚乙基、亚丙基、亚丁基、亚戊基、亚己基、亚乙烯基、亚丙烯基或亚丁烯基；
R 23选自取代或未取代的芳基或杂芳基，所述取代的芳基或取代的杂芳基中的取代基选自羟基、氨基、卤素、C 1～C 10烷基或C 1～C 10烷氧基，或者所述取代的芳基或取代的杂芳基中的两个相邻的取代基与它们连接的芳基或杂芳基上的原子一起形成环；优选地，R 23为
Figure PCTCN2018122227-appb-000015
其中，R 24至R 28各自独立地选自H、羟基、氨基、卤素、C 1～C 10烷基或C 1～C 10烷氧基，或者它们中相邻的两个与它们连接的苯环上的碳原子一起形成环；更 优选为
Figure PCTCN2018122227-appb-000016
其中，R 24至R 28各自独立地选自H、羟基、氨基、卤素、C 1～C 10烷基或C 1～C 10烷氧基，优选地，R 25和R 26为羟基或卤素，以及R 24、R 27和R 28为氢；
优选地，R 6至R 14各自独立地选H、羟基、氧代基团(＝O)、
Figure PCTCN2018122227-appb-000017
Figure PCTCN2018122227-appb-000018
乙氧基羰基或叔丁氧基羰基；当R 6至R 14中的一个为氧代基团时，与该氧代基团连接的碳原子不能参与形成碳碳双键；
R 0至R 4各自独立地选自H；羟基；氨基；卤素；未取代或被选自羟基、氨基、卤素、氰基或C 1～C 10烷氧基中的一个或多个取代基取代的C 1～C 10烷基；未取代或被选自羟基、氨基、卤素、氰基或C 1～C 10烷氧基中的一个或多个取代基取代的C 1～C 10烷氧基；未取代或被选自羟基、氨基、卤素、氰基、C 1～C 10烷基或C 1～C 10烷氧基中的一个或多个取代基取代的3至8元环烷基；未取代或被选自羟基、氨基、卤素、氰基、C 1～C 10烷基或C 1～C 10烷氧基中的一个或多个取代基取代的6至8元芳基；未取代或被选自羟基、氨基、卤素、氰基、C 1～C 10烷基或C 1～C 10烷氧基中的一个或多个取代基取代的3至8元杂环基；未取代或被选自羟基、氨基、卤素、氰基、C 1～C 10烷基或C 1～C 10烷氧基中的一个或多个取代基取代的5至8元杂芳基；
优选地，R 0至R 4各自独立地选自：H；羟基；氨基；卤素；未取代或被选自羟基、氨基、卤素、氰基或C 1～C 6烷氧基中的一个或多个取代基取代的C 1～C 6烷基；未取代或被选自羟基、氨基、卤素、氰基或C 1～C 6烷氧基中的一个或多个取代基取代的C 1～C 6烷氧基；未取代或被选自羟基、氨基、卤素、氰基、C 1～C 6烷基或C 1～C 6烷氧基中的一个或多个取代基取代的5至8元环烷基；未取代或被选自羟基、氨基、卤素、氰基、C 1～C 6烷基或C 1～C 6烷氧基中的一个或多个取代基取代的6至8元芳基；未取代或被选自羟基、氨基、卤素、氰基、C 1～C 6烷基或C 1～C 6烷氧基中的一个或多个取代基取代的5至8元杂环基；未取代或被选自羟基、氨基、卤素、氰基、C 1～C 6烷基或C 1～C 6烷氧基中的一个或多个取代基取代的5至8元杂芳基；
更优选地，R 0至R 4各自独立地选自：H、羟基、C 1～C 6烷基或C 1～C 6烷氧基；
更进一步优选地，R 0、R 1和R 4为H，以及R 2和R 3为H、羟基或C 1～C 6烷氧基。
在本发明中，除非另外指出，术语定义如下：
C 1～C 10烷基表示具有1至10个碳原子的直链或支链烷基，其实例包括，但不限于，甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基或戊基；优选为C 1～C 6烷基；
C 1～C 10烷氧基表示具有1至10个碳原子的直链或支链烷氧基，其实例包括，但不限于，甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基或戊氧基；优选为C 1～C 6烷氧基；
3至8元环烷基表示3至8元饱和环烷基；其实例包括，环丙烷基、环丁烷基、环戊烷基、环己烷基或环庚烷基；
6至8元芳基表示6至8元芳基，其实例包括，但不限于，苯基；
3至8元杂环基表示包含选自N、O或S中的一个或多个杂原子的3至8元饱和或不饱和的非芳香环烃基，其实例包括，但不限于，环氧丙烷基、环氧丁烷基、二氢呋喃基、四氢呋喃基；
5至8元杂芳基表示包含选自N、O或S中的一个或多个杂原子的5至8元杂芳基，其实例包括，但不限于，吡咯基、吡啶基、嘧啶基或吡嗪基；
优选地，式I的化合物选自如下化合物：
Figure PCTCN2018122227-appb-000019
Figure PCTCN2018122227-appb-000020
Figure PCTCN2018122227-appb-000021
Figure PCTCN2018122227-appb-000022
Figure PCTCN2018122227-appb-000023
Figure PCTCN2018122227-appb-000024
本发明化合物具有优异的神经保护活性，因此本发明化合物、其对映异构体、非对映异构体、外消旋体或其混合物，或其药学上可接受的盐，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解脑缺血、缺糖或缺氧诱发的脑损伤和/或神经功能异常。
根据本发明的另一目的是提供式I所示的化合物的制备方法，其包括如下步骤：
Figure PCTCN2018122227-appb-000025
(1)使化合物a与R 5-NH 2或R 5-OH发生酯化反应或酰胺化反应生成式I所示的化合物，
其中，R 1至R 4，以及X和Y与前面的定义相同，除了不为H之外，R 5与前述定义相同。
优选地，所述酯化反应的催化剂为浓硫酸，反应温度为30至90℃；所述酰胺化反应需加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)和1-羟基苯并三唑(HOBt)，反应温度为常温。
根据本发明的又一目，提供了一种药物组合物，其包含安全有效剂量的式I所示的化合物、其对映异构体、非对映异构体、外消旋体或其药学上可接受的盐和药学上可接受的赋形剂或载体。
其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，基于100重量％的药物组合物，药物组合物含有0.1～95重量％的式I所示的化合物、其对映异构体、非对映异构体、外消旋体或其药学上可接受的盐。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适用于人使用，并且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中个组分能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可接受的载体部分例子有纤维素及其衍生物(如微晶纤维素、羧丙甲纤维素、羧甲基纤维素钠、乙基纤维素钠等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁等)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山 梨醇等)、乳化剂(如吐温等)、润湿剂(如十二烷基硫酸钠等)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水、其他填料(如淀粉、预乳化淀粉、羧甲基淀粉钠、淀粉浆、二氧化硅、乳糖、蔗糖、葡萄糖、甘露醇和硅酸等)。
将本发明所述的式I所示的化合物用来制备治疗、预防以及缓解脑缺血、缺糖、缺氧诱发的脑损伤和/或神经功能异常药物时，可以单独使用，或者将其与可药用辅料(如赋形剂、稀释剂等)混合。
本发明所述的式I所示的化合物、其对映异构体、非对映异构体、外消旋体或其药学上可接受的盐，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、肌肉、皮下、鼻腔、口腔黏膜、皮肤、腹膜或直肠等。
本发明所述的式I所示的化合物、其对映异构体、非对映异构体、外消旋体或其药学上可接受的盐或含有它的药物组合物的给药途径可为注射给药，注射包括静脉注射、肌肉注射、皮下注射、皮内注射和穴位注射等。
本发明所述的式I所示的化合物、其对映异构体、非对映异构体、外消旋体或其药学上可接受的盐或含有它的药物组合物可以配制成液体制剂、固体制剂。如液体制剂可以是真溶液类、胶体类、微粒剂型、乳剂剂型、混悬剂型。其他剂型例如片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、栓剂、冻干粉针剂等。
本发明所述的式I所示的化合物、其对映异构体、非对映异构体、外消旋体或其药学上可接受的盐或含有它的药物组合物可以制成普通制剂、也可以是环式制剂、控释制剂、靶向制剂及各种微粒给药系统。
例如，将本发明所述的式I所示的化合物制成注射用制剂，如溶液剂、混悬剂溶液乳剂、冻干粉针剂，这种制剂可以是含水或非水的，可含一种和/或多种药效学上可接受的载体、稀释剂、粘合剂、润滑剂、防腐剂、表面活性剂或分散剂。如稀释剂可选自水、乙醇、聚乙二醇、1,3-丙二醇、乙氧基化的异硬脂醇、聚氧乙烯山梨醇脂肪酸酯等。另外，为了制备等渗注射液，可以向注射用制剂中添加适量的氯化钠、葡萄糖或甘油，此外，还可以添加常规助溶剂、缓冲剂、pH调节剂等。
为达到用药目的，增强治疗效果，本发明的药物或药物组合物可用任何公知的给药方法给药。
包含本发明所述的式I所示的化合物的药物组合物的给药剂量取决于许多因素，例如所要预防或治疗疾病的性质和严重程度，患者或动物的性别、年龄、体重、性格及个体反应，给药途径、给药次数、治疗目的，因此本发明的治疗剂量可以有大范围的变化。一般来讲，本发明中药学成分的使用剂量是本领域技术人员公知的。本发明化合物的每天的何时剂量范围优选为0.1～100mg/kg体重，更优选为10～200mg/天/人。上述剂量可以单一剂量形式或分成几个，例如二、三或四个剂量形式给药，这受限于给药医生的临床经验以及包括运用其他治疗手段的给药方案。
根据本发明的另一目的，提供了式I所示的化合物、对映异构体、非对映异构体、外消旋体或其药学上可接受的盐在制备预防和/或治疗脑缺血、缺糖或缺氧诱发的脑损伤和/或神经功能异常的药物中的用途。
根据本发明的再一目的，提供了一种本发明式I所示的化合物，或包含其的药物组合物用于治疗脑缺血、缺糖或缺氧诱发的脑损伤和/或神经功能异常中的用途。
根据本发明的又一目的，提供了一种治疗预防和/或治疗脑缺血、缺糖或缺氧诱发的脑损伤和/或神经功能异常的方法，其包括如下步骤：向受试者施加治疗有效量的所述的式I所示的化合物、其对映异构体、非对映异构体、外消旋体或其药学上可接受的盐或所述药物组合物。
附图说明
图1A为显示本发明的化合物010改善OGD诱导的SH-SY5Y细胞损伤的图。
图1B显示使用MTT法检测不同处理组细胞活力的图表。
图2A为显示本发明的化合物010改善H 2O 2诱导的SH-SY5Y细胞损伤的图。
图2B为显示使用MTT法检测不同处理组细胞活力的图表。
图3A和图3B分别为显示本发明的化合物010抑制LPS诱导的原代小胶质细胞上清中TNF-α和IL-1β的生成的图表。
图4为显示本发明的化合物010改善LPS刺激的原代小胶质细胞的上清对原代皮层神经元的损伤的图表。
图5为显示本发明的化合物010改善MCAO大鼠脑梗死体积和脑水肿的图，其中图5A为显示用TTC法染色评价脑梗死体积和脑水肿程度的代表性TTC染色图；图5B为脑梗死体积统计图；图5C为脑水肿程度统计图；图5D为显示mNSS评分的图。
图6为化合物079抑制LPS处理后胶质细胞的炎症反应的图。Griess试剂检测上清中NO水平。数据为LPS组的百分比，表示为3次独立试验结果的平均值±标准误。 ###p<0.001与正常对照组相比，**p<0.01，***p<0.001与脂多糖(LPS)组相比。
具体实施方式
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
所有实施例中， 1H-NMR用Bruker Advance III 400核磁共振记录，化学位移以δ(ppm)表示；分离纯化用硅胶，未说明均为200-300目，洗脱液的配比均为体积比。
化合物制备实施例
实施例1：化合物001的制备
Figure PCTCN2018122227-appb-000026
将迷迭香酸(720mg,2.0mmol)溶于25mL正丁醇中，滴加1mL浓硫酸，60℃下搅拌3h后反应完全。加水/乙酸乙酯萃取分层，乙酸乙酯层以饱和食盐水洗涤3次，无水硫酸钠干燥后硅胶柱层析，洗脱条件：石油醚/丙酮＝2:1，得700mg棕褐色胶状物，收率84.0％。 1H NMR(400MHz,Acetone-d 6):7.59(d,J＝16.0Hz,1H),7.20(d,J＝2.0Hz,1H),7.08(dd,J＝8.2,2.0Hz,1H),6.89(d,J＝8.2Hz,1H),6.84(d,J＝2.0Hz,1H),6.77(d,J＝8.1Hz,1H),6.66(m,1H),6.33(m,1H),5.19(m,1H),4.10(m,2H),3.05(m,2H),1.57(m,2H),1.40(m,2H),0.90(t,J＝7.4Hz,3H)。
实施例2：化合物002的制备
Figure PCTCN2018122227-appb-000027
步骤(1).将L-多巴(400mg,2.0mmol)溶于25mL正丁醇中，冰浴条件下缓慢滴加SOCl 2(1mL)，室温反应24h后，TLC检测无原料点，终止反应。减压除去反应液中的有机相后，经硅胶柱分离纯化得L-多巴丁酯。 1H NMR(400MHz,DMSO-d 6):δ6.61(d,J＝2.0Hz,1H),6.52(dd,J＝8.2,2.0Hz,1H),6.57(d,J＝8.2Hz,1H),4.14(m,1H),4.06(q,J＝7.4Hz,2H),3.54(m,1H),3.29(m,1H),1.57(m,2H),1.40(m,2H),0.90(t,J＝7.4Hz,3H)。
步骤(2).将L-多巴丁酯(253mg,1.0mmol)与咖啡酸(180mg,1.0mmol)溶于20mL二氯甲烷中，冰浴条件下加入PyBOP(520mg,1.0mmol)以及415μL三乙胺(3.0mmol)后，在氮气氛围下反应12h后结束反应。蒸除二氯甲烷后，加水/乙酸乙酯萃取分层，乙酸乙酯层以饱和食盐水洗涤3次，无水硫酸钠干燥后，制备HPLC色谱洗脱，洗脱条件：50％乙腈-水，得112mg白色胶状物，收率27％。δ7.37(d,J＝15.6Hz,1H),7.01(d,J＝2.0Hz,1H),6.89(m,1H),6.82(m,1H),6.77(d,J＝2.0Hz,1H),6.70(d,J＝8.1Hz,1H),6.65(d,J＝15.6Hz,1H),6.56(dd,J＝8.1,2.0Hz,1H),4.66(m,1H),4.06(td,J＝6.5,1.3Hz,2H),2.97(m,2H),1.58(m,2H),1.34(m,2H),0.91(m,3H)。
下表1中的实施例3-9的化合物是使用与实施例2中所述类似的方法得以制备。
表1.实施例3-9
Figure PCTCN2018122227-appb-000028
Figure PCTCN2018122227-appb-000029
实施例10：化合物010、011和012的制备
Figure PCTCN2018122227-appb-000030
步骤(1).称取13.8g 3,4-二羟基苯甲醛(10mmol)，55.0g无水碳酸钾(40mmol)溶于50mL N,N-二甲基甲酰胺中，室温边搅拌边滴加38.0g氯苄(30mmol)，滴加完全后，120℃加热2h。冷却至室温，加水/乙酸乙酯萃取分层，乙酸乙酯层以饱和食盐水洗涤3次，无水硫酸钠干燥后硅胶柱层析，洗脱条件：石油醚/乙酸乙酯＝5:1，得30.3g白色固体A，收率95.3％。 1H NMR(400MHz,Chloroform-d):δ9.80(s,1H),7.50–7.29(m,12H),7.02(d,J＝8.2Hz,1H),5.26(s,2H),5.21(s,2H)。
步骤(2).称取50.0g正丁醇于圆底烧瓶中，慢慢滴加60mL氯乙酰氯(1.2当量)，室温搅拌1h后分批加入碳酸氢钠固体至不再冒泡后，加水/乙酸乙酯萃取分层，乙酸乙酯层以饱和食盐水洗涤2次，无水硫酸钠干燥，蒸除乙酸乙酯得无色透明油状液体，减压蒸馏，收集100℃馏分，得89.0g无色透明状液体B，收率87.6％。 1H NMR(400MHz,Chloroform-d):δ4.20(t,J＝6.7Hz,2H),4.07(s,2H),1.66(m,2H),1.41(m,2H),0.95(t,J＝7.4Hz,3H)。
步骤(3).称取2.08g钠丝(9.0mmol)至30mL正丁醇中，至钠丝完全溶解，冷却至室温得溶液一。称取3,4-二苄氧基苯甲醛19.1g(6.0mmol)与10.8g氯乙酸丁酯(7.2mmol)溶于30mL干燥的二氧六环中得溶液二。慢慢将溶液二滴加入溶液一，开始析出白色固体，室温搅拌。2,4-二硝基苯肼显色监测反应过程，1.5h后反应完全，滴加1N HCl至体系pH为中性后，加水/乙酸乙酯萃取分层，乙酸乙酯层以饱和食盐水洗涤2次，无水硫酸钠干燥后硅胶柱层析，石油醚/乙酸乙酯＝10:1，得24.0g淡黄色固体C，收率93％。 1H NMR(400MHz,Chloroform-d):δ7.48–7.27(m,10H),6.90(d,J＝8.1Hz,1H),6.85(d,J＝2.0Hz,1H),6.83(brs,1H),5.16(s,2H),5.15(s,2H),4.20(m,2H),3.98(d,J＝1.8Hz,1H),3.41(d,J＝1.8Hz,1H),1.64(m,2H),1.39(m,2H),0.94(t,J＝7.4Hz,3H)。
步骤(4).称取17.2g化合物C(4.0mmol)溶于50mL二甲亚砜中，滴加12mL三氟化硼·乙醚溶液，室温搅拌2h后，加入水淬灭过量的三氟化硼后，二氯甲烷/水萃取，硅胶柱层析，洗脱条件：石油醚/乙酸乙酯＝10:1，得14.0g白色固体D，收率82.0％。产物酮式与烯醇式互变(酮式：烯醇式≈2:1)。酮式： 1H NMR(400MHz,Chloroform-d):δ7.50–7.29(m,10H),7.23(dd,J＝8.4,2.0Hz,1H),6.91(d,J＝8.2Hz,1H),6.42(brs,1H),5.19(s,4H),4.52(s,2H),4.29(t,J＝6.7Hz,2H),1.73(m,2H),1.43(m,2H),0.97(t,J＝7.4Hz,3H)；烯醇式： 1H NMR(400MHz,Chloroform-d):δ9.80(s,0.5H),7.92(s,0.5H),7.50–7.29(m,5.0H),7.04(dd,J＝8.4,2.1Hz,0.5H),7.02(d,J＝8.4Hz,0.5H),6.36(brs,0.5H),5.26(s,1H),5.22(s,1H),4.34(t,J＝6.7Hz,1H),1.73(m,1H),1.43(m,1H),0.97(t,J＝7.4Hz,1.5H)。
步骤(5).称取8.64g化合物D(2.0mmol)溶于THF 10mL，加入226.8mg硼氢化钠(0.6当量)，室温搅拌30min，滴加1N HCl至体系pH为中性后，加水/二氯甲烷萃取分层，硅胶柱层析，洗脱条件：石油醚/乙酸乙酯＝3:1，得5.8g白色固体E，收率66.7％。 1H NMR(400MHz,Chloroform-d):δ7.47–7.27(m,10H),6.85(d,J＝8.2Hz,1H),6.84(d,J＝2.0Hz,1H),6.71(dd,J＝8.2,2.0Hz,1H),5.14(s,2H),5.12(s,2H),4.37(dd,J＝6.5,4.4Hz,1H),4.11(qt,J＝10.7,6.7Hz,2H),3.01(dd,J＝14.1,4.4Hz,1H),2.86(dd,J＝14.0,6.5Hz,1H),1.61(m,2H),1.35(m,2H),0.93(t,J＝7.4Hz,3H)。
步骤(6).对化合物E进行手性拆分[手性色谱柱：Kromasil-5-CellCoat(250×4.6mm)；流动相：90％正己烷/异丙醇；流速：1.0mL/min]，得到一对对映异构体(R)-2-羟基-3-(3,4-二苄氧基苯基)-正丙酸丁酯F{[α] D–62(c 0.05,MeOH)}和(S)-2-羟基-3-(3,4-二苄氧基苯基)-正丙酸丁酯G{[α] D+70(c 0.06,MeOH)}。
步骤(7).称取2g化合物F溶于30mL甲醇与四氢呋喃的混合溶液中，加入100mg钯炭(5)，室温通氢气还原8h，滤过，减压蒸除溶剂，硅胶柱层析，洗脱条件：石油醚/乙酸乙酯＝3:1，得1.05g棕褐色胶状物010，收率90％。 1H NMR(400MHz,DMSO-d 6):δ6.61(d,J＝8.2Hz,1H),6.57(brs,1H),6.52(d,J＝8.2,1H),4.81(m,1H),4.06(q,J＝7.4Hz,2H),3.21(m,1H),2.96(m,1H),1.54(m,2H),1.40(m,2H),0.90(t,J＝7.4Hz,3H)。
步骤(8).称取2g化合物G溶于30mL甲醇与四氢呋喃的混合溶液中，加入100mg钯炭(5)，室温通氢气还原8h，滤过，减压蒸除溶剂，硅胶柱层析，洗脱条件：石油醚/乙酸乙酯＝3:1，得1.05g棕褐色胶状物011，收率90％。 1H NMR同化合物010。
步骤(9).称取2g化合物C溶于30mL甲醇与四氢呋喃的混合溶液中，加入100mg钯炭(5)，室温通氢气还原3h，滤过，减压蒸除溶剂，硅胶柱层析，洗脱条件：石油醚/乙酸乙酯＝3:1，得758mg棕褐色胶状物012，收率65％。产物酮式与烯醇式互变(酮式：烯醇式≈2:1)。酮式： 1H NMR(400MHz,Chloroform-d):δ7.23(dd,J＝8.4,2.0Hz,1H),6.91(d,J＝8.2Hz,1H),6.42(brs,1H),4.29(t,J＝6.7Hz,2H),1.73(m,2H),1.43(m,2H),0.97(t,J＝7.4Hz,3H)；烯醇式： 1H NMR(400MHz,Chloroform-d):δ9.80(s,0.5H),7.93(s,0.5H),7.04(dd,J＝8.4,2.2Hz,0.5H),7.02(d,J＝8.4Hz,0.5H),6.36(brs,0.5H),4.34(t,J＝6.7Hz,1H),1.73(m,1H),1.43(m,1H),0.97(t,J＝7.4Hz,1.5H)。
实施例11：化合物014的制备
Figure PCTCN2018122227-appb-000031
称取200mg化合物16(1.1mmol)溶于3mL无水甲醇中，搅拌溶解转至冰浴条件下，逐滴加入470μL草酰氯(5eq)，然后室温条件下搅拌20min，加入冰水淬灭反应，用饱和食盐水/乙酸乙酯体系萃取3次，乙酸乙酯层浓缩，用高效液相C-18柱分离，洗脱条件：45％乙腈-水，得到192mg化合物014，收率89％。 1H NMR(400MHz,Methanol-d 4):δ7.55(d,J＝15.9Hz,1H),7.03(d,J＝2.1Hz,1H),6.94(dd,J＝8.2,2.1Hz,1H),6.77(d,J＝8.1Hz,1H),6.26(d,J＝15.9Hz,1H),3.76(s,3H)。
实施例22：化合物025和026的制备
Figure PCTCN2018122227-appb-000032
称取138mg 3,4-二羟基苯甲醛(1.0mmol)溶于3mL甲苯中，然后加入160mg丙二酸二乙酯(1eq)，9.8μL哌啶(0.1eq)和5.7μL冰醋酸(0.1eq)。该反应置于油浴中130℃加热回流20h,然后冷却至室温，加水/乙酸乙酯萃取分层，乙酸乙酯层以饱和食盐水洗涤3次，无水硫酸钠干燥后硅胶柱层析，洗脱条件：石油醚/乙酸乙酯＝5:1，得到120mg化合物025。收率43％。 1H NMR(400MHz,Methanol-d 4):δ7.55(s,1H),6.94(d,J＝2.2Hz,1H),6.88(dd,J＝8.2,2.2Hz),6.78(d,J＝8.2Hz,1H),4.35(q,J＝7.1Hz,2H),4.25(q,J＝7.1Hz,2H),1.31(t,J＝7.1Hz,3H),1.30(t,J＝7.1Hz,3H)。
以3,4-二羟基苯甲醛，丙二酸二叔丁酯为原料，按照实施例22中所述类似的方法，制备得到化合物026。 1H NMR(400MHz,Methanol-d 4):δ7.36(s,1H),7.00(d,J＝2.2Hz,1H),6.91(dd,J＝8.3,2.2Hz,1H),6.77(d,J＝8.2Hz,1H),1.55(s,9H),1.52(s,9H)。
下表2中的实施例12-21，23-51的化合物是分别以化合物013,027,036,045,051为原料，按照实施例11中所述类似的方法得以制备。
表2.实施例12-21、23-51
Figure PCTCN2018122227-appb-000033
Figure PCTCN2018122227-appb-000034
Figure PCTCN2018122227-appb-000035
Figure PCTCN2018122227-appb-000036
Figure PCTCN2018122227-appb-000037
Figure PCTCN2018122227-appb-000038
Figure PCTCN2018122227-appb-000039
Figure PCTCN2018122227-appb-000040
实施例52：化合物060的制备
Figure PCTCN2018122227-appb-000041
步骤(1).称取6.17g 3,4-二羟基苯乙酮(40mmol)，溶于30mL THF中，加入过量1.9ml乙酸酐(200mmol)，室温搅拌下再加入308mg二甲胺基吡啶(DMAP)，然后升温到60℃搅拌，TLC板检测至3,4-二羟基苯乙酮反应完全，减压蒸除溶剂得到白色固体，白色固体经过多次水洗，然后放入冻干机抽干得9.28g白色粉末，收率97％。
步骤(2).称取2.38g化合物H(10mmol)溶于15mL氯化亚砜中，70℃条件下搅拌1h之后，减压蒸去溶剂，用油泵抽30min之后得淡黄色油状物I。
步骤(3、4).切取345mg(1.5eq)金属钠至5mL无水THF中,逐滴加入乙酰乙酸乙酯3.9ml(3eq)，慢慢搅拌，至不再产生气体为止.然后将步骤(2)得到的化合物K溶于3ml无水THF中，慢慢滴加进来，室温搅拌0.5h后，向体系中滴加30mL乙酸乙酯，分层后滴加1N HCl，调节PH至溶液呈中性。乙酸乙酯层以饱和食盐水洗涤3次，无水硫酸钠干燥后减压蒸干，得淡黄色油状液体。
步骤(5).步骤(4)得到的油状物溶于10mL无水乙醇中，加入2.72g无水醋酸钠90摄氏度回流过夜，减压蒸除乙醇后，用饱和氯化钠/乙酸乙酯体系萃取3次，乙酸乙酯层浓缩，硅胶柱层析，洗脱条件：石油醚/丙酮＝3:1得到784mg淡黄色油状物060，收率35％。 1H NMR(400MHz,Methanol-d 4)：δ7.40(m,2H),6.84(d,J＝8.7Hz,1H),4.16(m,2H),3.51(s,2H),1.24(t,J＝7.1Hz,3H)。
下表3中的实施例53和54是使用与实施例11中所述类似的方法得以制备。
表3.实施例53和54
Figure PCTCN2018122227-appb-000042
Figure PCTCN2018122227-appb-000043
实施例55：化合物063和064的制备
Figure PCTCN2018122227-appb-000044
步骤(1).称取6.90g 1,2-二甲氧基苯(50mmol)、10.0g丁二酸酐(2eq)溶于50mL二氯乙烷中，室温搅拌溶解。称取10.35g氯化铝，慢慢加入上述混合液中，80℃搅拌6h，冷却至室温，然后慢慢加入1N HCl至氯化铝络合物完全溶解。减压蒸除二氯乙烷，得到淡黄色固体，淡黄色固体用水洗涤多次，得到9.75g化合物063. 1H NMR(400MHz,DMSO-d 6)δ7.66(dd,J＝8.4,2.0Hz,1H),7.46(d,J＝2.0Hz,1H),7.07(d,J＝8.4Hz,1H),3.84(s,3H),3.82(s,3H),3.21(t,J＝6.5Hz,2H),2.56(t,J＝6.5Hz,2H)。收率82％。
步骤(2).称取500mg化合物025(2.1mmol)溶于3mL无水乙醇中，搅拌溶解转至冰浴条件下，逐滴加入882μL草酰氯(5eq)，然后室温条件下搅拌20min，加入冰水淬灭反应，用饱和食盐水/乙酸乙酯体系萃取3次，乙酸乙酯层浓缩，硅胶柱层析，洗脱条件：石油醚/丙酮＝8:1，得到332mg化合物064。收率59％。 1H NMR(400MHz,DMSO-d 6):δ7.69(d,J＝8.4Hz,1H),7.53(s,1H),7.04(dd,J＝8.4,1.5Hz,1H),4.13(q,J＝7.1Hz,2H),3.91(s,3H),3.88(s,3H),3.27(m,2H),2.69(t,J＝6.5Hz,2H),1.24(t,J＝7.1Hz,3H)
下表4中的实施例56-63是使用与实施例11中所述类似的方法得以制备。
表4.实施例56-63
Figure PCTCN2018122227-appb-000045
Figure PCTCN2018122227-appb-000046
实施例64：化合物073的制备
Figure PCTCN2018122227-appb-000047
步骤(1).称取1.19g化合物063(5mmol)溶于二氯甲烷中，室温下搅拌溶解，然后转至冰盐浴中，逐滴加入1.88mL三溴化硼(4eq)，冰盐浴中搅拌3h，然后加水淬灭，用饱和食盐水/乙酸乙酯体系萃取，乙酸乙酯层减压浓缩备用。
步骤(2).称取200mg步骤(1)所得物质，溶于无水甲醇中，室温搅拌溶解转至冰浴条件下，逐滴加入243μL草酰氯(3eq)，然后室温条件下搅拌20min，加入冰水淬灭反应，用饱和食盐水/乙酸乙酯体系萃取3次，乙酸乙酯层浓缩，用高效液相C-18柱分离，洗脱条件：45％乙腈-水。得到89mg化合物073。产率42％。 1H NMR(400MHz,Methanol-d 4)δ7.45(dd,J＝8.2,2.1Hz,1H),7.42(d,J＝2.1Hz,1H),6.83(d,J＝8.3Hz,1H),3.67(s,3H),3.25(t,J＝6.4Hz,2H),2.67(t,J＝6.4Hz,2H)
下表5中的实施例65-79是使用与实施例64中所述类似的方法得以制备。
表5.实施例65-79
Figure PCTCN2018122227-appb-000048
Figure PCTCN2018122227-appb-000049
Figure PCTCN2018122227-appb-000050
实施例82：化合物091的制备
Figure PCTCN2018122227-appb-000051
称取1.15mL胡椒环(10mmol)、1.96g马来酸酐(2eq)溶于15mL二氯乙烷中，室温搅拌溶解。称取6g氯化铝，慢慢加入上述混合液中，室温搅拌12h，然后慢慢加入1N HCl至氯化铝络合物完全溶解，室温下继续搅拌6h。减压蒸除二氯乙烷，得到淡黄色固体，淡黄色固体用水洗涤多次后，用硅胶柱层析，洗脱条件：二氯甲烷/甲醇＝6:1，得到340mg化合物091。收率16％。 1H NMR(400MHz,Methanol-d 4)δ7.92(d,J＝15.5Hz,1H),7.51(dd,J＝8.3,2.2Hz,1H),7.47(d,J＝2.1Hz,1H),6.88(d,J＝8.3Hz,1H),6.74(d,J＝15.5Hz,1H)。
实施例83：化合物092的制备
Figure PCTCN2018122227-appb-000052
称取152mg 3,4-二羟基苯乙酮(1mmol)、198μL乙醛酸乙酯(2eq)溶于5mL冰醋酸中，120℃加热回流24h。冷却至室温后，用饱和食盐水/乙酸乙酯体系萃取3次，乙酸乙酯层浓缩，用高效液相C-18柱分离，洗脱条件：60％乙腈-水。得到52mg化合物092。收率22％。 1H NMR(400MHz,Methanol-d 4)δ7.94(d,J＝15.5Hz,1H),7.51(dd,J＝8.3,2.2Hz,1H),7.47(d,J＝2.1Hz,1H),6.88(d,J＝8.3Hz,1H),6.75(d,J＝15.5Hz,1H),4.29(q,J＝7.2Hz,2H),1.34(t,J＝7.1Hz,3H).
实施例84：化合物093的制备
Figure PCTCN2018122227-appb-000053
步骤(1)：称取336mg 3,4-二羟基苯乙酸溶于无水乙醇中，室温搅拌溶解转至冰浴条件下，逐滴加入508μL草酰氯(6eq)，然后室温条件下搅拌20min，加入冰水淬灭反应，用饱和食盐水/乙酸乙酯体系萃取3次，乙酸乙酯层浓缩，硅胶柱层析，洗脱条件：石油醚/丙酮＝5:1。得到580mg的3,4-二羟基苯乙酸乙酯。收率98％。 1H NMR(400MHz,Chloroform-d)δ6.74(d,J＝2.1Hz,1H),6.71(dd,J＝8.1,2.1Hz,1H),6.59(d,J＝8.1Hz,1H),4.13(q,J＝7.0Hz,2H),3.45(s,2H),1.23(t,J＝7.0Hz,3H)。
步骤(2)：称取300mg 3,4-二羟基苯乙酸乙酯、167μL乙醛酸乙酯(1.1eq)溶于5mL冰醋酸中，120℃加热回流24h。冷却至室温后，用饱和食盐水/乙酸乙酯体系萃取3次，乙酸乙酯层浓缩，用高效液相C-18柱分离，洗脱条件：65％乙腈-水。得到43mg化合物093。收率10％。 1H NMR(400MHz,Chloroform-d)δ6.90(dd,J＝8.1,2.1Hz,1H),6.73(d,J＝2.1Hz,1H),6.65(d,J＝8.0Hz,1H),6.58(s,1H),4.22(q,J＝7.1Hz,2H),4.15(q,J＝7.1Hz,2H),1.28(t,J＝7.4Hz,3H),1.26(t,J＝7.3Hz,3H)。
实施例85：化合物094和095的制备
Figure PCTCN2018122227-appb-000054
步骤(1)：将362mg 2-溴丙酸乙酯(2mmol)，365mg膦酸三乙酯(2mmol)，48mg NaH(2mmol)溶于3mL THF中加热回流0.5h后，加入276mg 3,4-二羟基苯甲醛(2mmol)，继续回流3h至反应完全，加水/乙酸乙酯进行分配萃取，乙酸乙酯层以饱和食盐水洗涤3次，无水硫酸钠干燥后利用硅胶柱层析，洗脱条件：石油醚/丙酮＝3:1，得324mg无定形粉末094，收率73.0％。
1H NMR(400MHz,Chloroform-d)δ7.60(q,J＝1.4Hz,1H),7.02(d,J＝1.3Hz,1H),6.92(dd,J＝8.3,1.3Hz,1H),6.91(d,J＝8.3Hz,1H),4.28(q,J＝7.1Hz,2H),2.14(d,J＝1.4Hz,3H),1.36(t,J＝7.1Hz,3H)。
步骤(2)：将上述无定形粉末利用氢氧化钠进行碱解，盐酸酸化后得无定形粉末095，283mg，收率100％。
1H NMR(400MHz,Methanol-d 4)δ12.27(s,1H),9.37(s,1H),9.14(s,1H),7.47(s,1H),6.83(d,J＝1.3Hz,1H),6.82(d,J＝8.3Hz,1H),6.99(dd,J＝8.3,1.3Hz,1H),2.06(s,3H)。
下表6中的实施例86-88是使用与实施例85中所述类似的方法得以制备。
Figure PCTCN2018122227-appb-000055
Figure PCTCN2018122227-appb-000056
实施例89：化合物001-012保护SH-SY5Y细胞免受氧糖剥夺损伤
本测定按常规采用噻唑蓝(MTT)比色试验法，即用人神经母细胞瘤细胞株(SH-SY5Y细胞)，以含10％的胎牛血清的MEM/F12培养基，在37℃、5％CO 2培养箱中培养。每四天传一代细胞，在倒置显微镜下观察传代细胞。当细胞均匀贴壁生长，生长至80％至90％时，用0.125％胰蛋白酶消化1～2min后，用含10％的胎牛血清的MEM/F12培养基调整细胞浓度为2.5*10 5cells/mL，接种在96孔培养板中，每孔100μL，于37℃、5％CO 2培养箱中继续培养24h。给药组的处理如下：24h后往细胞培养基中分别加入化合物001-021(终浓度为10μM)，于37℃、5％CO 2培养箱孵育2h，结束后用EBSS溶液(单位为mM:116NaCl，5.4KCl，1.8CaCl 2，0.8MgSO 4，1.25NaH 2PO 4·2H 2O，26.2NaHCO 3，pH 7.2～7.4，0～4℃，使用前通入95％O 2/5％CO 2，平衡15min)润洗细胞一遍，并将培养基换为不含葡萄糖的DMEM培养基(Life Technologies公司，货号为1227494)，同时加入相应化合物001-012，并放进厌氧箱，在5％CO 2/10％H 2/85％N 2、37℃的条件下培养4h，结束后加入葡萄糖及胎牛血清使培养基的条件恢复到原来水平，并放回原来的培养环境继续培养；模型组的处理与给药组相似，但加入的是空白溶剂；而正常对照组则进行EBSS平衡溶液润洗一遍后换为新的含葡萄糖及胎牛血清的DMEM培养基，继续培养。24h后，每孔加入10μL MTT(5mg/mL)，37℃孵育3h，终止培养，小心吸出培养板中的液体，每孔加入100μL DMSO，37℃振荡5min，使紫蓝色甲瓒(formazan)结晶充分溶解，在酶标仪上以490nm波长测定各孔OD值，根据下式计算给药后对氧糖剥夺诱发的神经元存活率：
存活率＝(OD 给药组-OD 空白组)/(OD 正常组-OD 空白组)×100％。
实验结果：统计结果显示，氧糖剥夺条件下神经元的活性显著下降，而给予10μM目标化合物后，神经元活性得到明显恢复；而目标化合物不影响正常组神经元的活性。*p<0.05，***p<0.001，相比于溶剂对照组； ###p<0.001，相比于正常对照组；每组6孔，独立重复实验3次。结果如表7所示。
表7.化合物001-012对OGD诱导的SH-SY5Y细胞损伤的保护作用
Figure PCTCN2018122227-appb-000057
Figure PCTCN2018122227-appb-000058
实施例90：化合物013-022、027-080、083-090保护SH-SY5Y细胞免受氧糖剥夺损伤
待测化合物溶于DMSO，配成10mM母液，-20℃保存，使用时现用现稀释。SH-SY5Y细胞经胰蛋白酶消化后，悬于含10％胎牛血清的MEM/F12培养液中。以3.5×10 5cells/mL的密度将SH-SY5Y细胞接种于96孔培养板上，接种体积为100μL/孔，置于含5％CO 2的37℃恒温培养箱内培养。SH-SY5Y细胞培养24h后，半换液一次，继续培养24h后进行实验。在给药组中加入相应浓度的待测化合物，预孵育2h，氧糖缺乏组加入相应的溶剂对照，正常组加入相应量的培养液。化合物预孵育结束后，将氧糖缺乏损伤组及给药组均用无糖EBSS平衡盐溶液润洗一遍细胞，随后换成DMEM(无糖)培养液，并再次在给药组中加入相应浓度的待测化合物(10μL/well)，氧糖缺乏组加入化合物溶剂对照，置于厌氧仪(含85％N 2，10％H 2，5％CO 2)中培养2h。正常对照组换成含糖及血清的DMEM培养液，放入含5％CO 2的37℃恒温培养箱中培养相同时间。2h后将培氧板从厌氧仪中取出，氧糖缺乏损伤组及给药组补回血清及葡萄糖，葡萄糖的终浓度为1g/L。继续培养24h后，加入5mg/mL MTT(10μL/well)，进行活细胞染色。孵育3h后，弃去培养液，加入DMSO(100μL/well)，并在摇板机上振摇使之充分溶解。490nm的波长下测定各组的OD值。待测化合物组细胞活力与正常对照组细胞活力百分比，数据为单次试验三复孔平均值。结果如表8所示。
表8.化合物013-022、027-080和083-090对OGD诱导的SH-SY5Y细胞损伤的保护作用(预孵2h)
Figure PCTCN2018122227-appb-000059
Figure PCTCN2018122227-appb-000060
Figure PCTCN2018122227-appb-000061
实施例91：未预孵条件下，化合物013-080、083-090保护SH-SY5Y细胞免受氧糖剥夺损伤
待测化合物溶于DMSO，配成10mM母液，-20℃保存，使用时现用现稀释。SH-SY5Y细胞经胰蛋白酶消化后，悬于含10％胎牛血清的MEM/F12培养液中。以3.5×10 5cells/mL的密度将SH-SY5Y细胞接种于96孔培养板上，接种体积为100μL/孔，置于含5％CO 2的37℃恒温培养箱内培养。SH-SY5Y细胞培养24h后，半换液一次，继续培养24h后进行实验。将氧糖缺乏损伤组及给药组均用无糖EBSS平衡盐溶液润洗一遍细胞，随后换成DMEM(无糖)培养液，在给药组中加入相应浓度的待测化合物，氧糖缺乏组加入相应的溶剂对照，置于厌氧仪(含85％N 2，10％H 2，5％CO 2)中培养2h。正常对照组换成含糖及血清的DMEM培养液，放入含5％CO 2的37℃恒温培养箱中培养相同时间。2h后将培氧板从厌氧仪中取出，氧糖缺乏损伤组及给药组补回血清及葡萄糖，葡萄糖的终浓度为1g/L。继续培养24h后，加入5mg/mL MTT(100μL/well)，进行活细胞染色。孵育3h后，弃去培养液，加入DMSO(100μL/well)，并在摇板机上振摇使之充分溶解。490nm的波长下测定各组的OD值。待测化合物组细胞活力与正常对照组细胞活力百分比，数据为两次独立实验(每次三复孔)平均值。实验结果如表9所示。
表9.化合物013-080、083-092对OGD诱导的SH-SY5Y细胞损伤的保护作用(未预孵)
Figure PCTCN2018122227-appb-000062
Figure PCTCN2018122227-appb-000063
Figure PCTCN2018122227-appb-000064
实施例92：未预孵条件下，化合物025、079、092、094和095保护SH-SY5Y细胞免受氧糖剥夺损伤。所用实验方法同实施例89。实验结果见表10。
表10.化合物025、026、079、094和095对OGD诱导的SH-SY5Y细胞损伤的保护作用(未预孵)
Figure PCTCN2018122227-appb-000065
实施例93：化合物010在SH-SY5Y细胞OGD模型中的神经保护作用
OGD损伤造成SH-SY5Y细胞的活力显著下降，用形态学和MTT对其损伤程度进行评价。SH-SY5Y细胞经过OGD损伤1h，复糖复氧24h，细胞形态发生明显变化，突起断裂，细胞收缩，细胞数目减少(图1A)。与细胞形态学变化相一致，MTT的结果显示，OGD损伤造成细胞活力下降至52.95％(p<0.001vs.Control)(图1B)。预孵育1μM和10μM的化合物010能浓度依赖性改善OGD导致的形态学变化(图1A)，细胞突起断裂减少，形态正常的细胞增多，细胞数目增加。1μM和10μM的化合物010浓度依赖性的将细胞活力分别提高至86.19％(p<0.05vs.OGD组)和87.03％(p<0.01vs.OGD组)(图1B)。
实施例94：化合物010在SH-SY5Y细胞H 2O 2模型中的神经保护作用
为了进一步评价化合物010的作用，建立H 2O 2致SH-SY5Y细胞损伤的模型以模拟氧化应激的病理状态。H 2O 2损伤造成SH-SY5Y细胞的活力显著下降，用形态学和MTT对其损伤程度进行评价。SH-SY5Y细胞经过H 2O 2刺激24h，细胞形态发生明显变化，突起断裂，细胞收缩，细胞数目减少(图2A)。与细胞形态学变化相一致，MTT的结果显示，H 2O 2损伤造成细胞活力下降至35.32％(p<0.001vs.Control)(图2B)。预孵育1μM和10μM的化合物010能浓度依赖性改善H 2O 2导致的形态学变化(图2A)，细胞突起断裂减少，形态正常的细胞增多，细胞数目增加。1μM和10μM的化合物010将细胞活力分别提高至71.14％(p<0.05vs.H 2O 2组)和82.31％(p<0.01vs.H 2O 2组)(图2B)
实施例95：化合物010在原代小胶质细胞LPS模型中的抗炎作用
缺血性中风的病理进程除了早期缺血再灌、兴奋性毒性和氧化应激，还有后期的炎症反应。外周的白细胞浸润及大脑的小胶质细胞和星形胶质细胞的激活开启了缺血性中风引起的炎症反应。小胶质细胞是中枢神经系统的免疫细胞，在免疫防御起主要作用。小胶质细胞在脑缺血中的作用受到越来越多的关注。正常状态下，小胶质细胞有吞噬作用，时刻监测着周围的微环境防止细胞碎片在中枢神经系统中堆积。小胶细胞处于静息状态或激活状态取决周围的环境。当小胶质细胞被激活，从形态上迅速转换成吞噬细胞，释放炎症因子，过表达具有免疫调节作用的表面抗原。在脑缺血发生的几分钟内，小胶质细胞通过释放促炎因子TNF-α和IL-1β介导急性炎症反应，加剧缺血损伤。LPS是引发原代小胶质细胞产生炎症反应的常用诱导剂，因此，本实施例选用原代小胶质细胞的LPS模型来研究化合物010的抗炎作用。ELISA的结果显示，终浓度为100ng/mL的LPS刺激原代小胶质细胞24h，能引起原代小胶质细胞产生大量的TNF-α(570.58pg/mL，p<0.001vs.Control)(图3A)和IL-1β(658.62pg/mL，p<0.01vs.Control)(图3B)。3μM的化合物001与原代小胶质细胞预孵育后能显著降低上清中TNF-α(285.74pg/mL，p<0.05vs.LPS组)和IL-1β(365.61pg/mL，p<0.05vs.LPS组)的水平。
为了进一步检验化合物010对炎症反应抑制产生的保护效应，将LPS刺激的原代小胶质细胞的上清[CM(LPS)]加入到原代皮层神经元中培养24h，MTT结果显示原代皮层神经元的活力降低(84.36％，p<0.01vs.Control)，而010处理过的原代小胶质细胞上清[CM(LPS+3 μM 145-16A)]加入神经元中，损伤程度减轻(94.48％，p<0.05vs.[CM(LPS)]组)(图4)。
实施例96：化合物010对急性脑缺血诱发神经损伤的保护作用
试验采用SD大鼠，应用中脑动脉栓塞所致局灶性脑缺血(MCAO)模型评价化合物010对缺血诱发的大脑损伤程度以及短期的神经行为学变化。化合物010充分溶解于溶媒(1％DMSO，5％Cremophor EL，94％生理盐水)中。大鼠用水合氯醛(350mg/kg，i.p.)麻醉，仰卧位固定，颈部正中切口，分离左侧颈总及颈内、外动脉，颈总动脉上打活结，结扎颈外动脉远心端结扎，近心端上打活结，用动脉夹夹闭颈内动脉。在颈外动脉近分叉处剪一小口，将鱼线插入，松开动脉夹，将鱼线推进颈内动脉，遇轻微阻力时即停止，插入浓度约20mm。结扎颈外动脉插线处，固定鱼线。缝合伤口，动物放回笼统中饲养，2h后将鱼线小心拔出。
术后24h进行神经行为评分。改进的神经行为评分包括一系列的神经功能障碍测试，具体的评分标准如下：
A.运动功能测试：
1)提尾测试——提尾后通过比较对侧肢体瘫痪程度评价：前肢不能伸展-1分；后肢不能伸展-1分；30秒内头部侧弯与垂直轴角度超过10度-1分。
2)动物置于地上，不能直线行走-1分；朝对侧旋转运动-2分；对侧偏瘫-3分。
B.感觉功能测试：
1)视觉和触觉测试障碍-1分；
2)肢体本体感受功能测试障碍-1分。
C.平衡木评分测试：
抓住平衡木时间超过60秒-1分；单肢脱离抱住平衡木-2分；两肢脱离抱住平衡木-3分；40秒后从平衡木上掉下-4分；20秒后从平衡木上掉下-5分；20秒内从平衡木上掉下-6分。
D.反射和异常运动测试：
耳廓反射障碍-1分；角膜反射障碍-1分；惊吓反射障碍-1分；肌阵挛或肌张力障碍-1分。
上述的评价指标综合反映了运动、感觉、平衡以及反射功能，分数范围为0～18，分数越大表明神经行为损伤越明显。
神经行为评分结束后，将动物断头取脑，去掉嗅球、小脑、脑干和低位脑干，然后冠状切5刀共6片。脑片组织用TTC(1％，w/v)染色，正常组织为红色，梗死部位为白色，求算梗死体积及比值。同法操作，记录各组梗死体积及比值，进行ANOVA统计分析。
实验结果：
大鼠MCAO缺血2h，再灌24h后，TTC染色(图5A)结果显示，模型组左侧大脑梗死面积占半脑的比例为33.31％(图5B)，脑水肿程度为14.92％(图5C)，假手术组未发生脑梗死和脑水肿，未在图中表示。再灌后立即静脉给予化合物010或阳性对照依达拉奉，化合物010的给药剂量为10mg/kg或30mg/kg，依达拉奉的给药剂量为10mg/kg。结果显示，化合物010在给药剂量为10mg/kg或30mg/kg时，脑梗死面积分别减少至17.50％(p<0.05vs.模型组)和14.56％(p<0.01vs.模型组)(图5B)，脑水肿程度分别减轻至10.83％和8.75％±1.51(p<0.05vs.模型组)(图5C)。阳性对照依达拉奉减少脑梗面积至9.80％(p<0.01vs.模型组)，减轻脑水肿程度至7.90％(p<0.05vs.模型组)。化合物010在给药剂量为10mg/kg或30mg/kg时，mNSS分数降低至6.06分(p<0.05vs.模型组)和4.53分(p<0.001vs.模型组)(图5D)。
实施例97：化合物079的体外抗炎作用
实验方法：
化合物079抗小胶质细胞炎症反应作用测定
细胞上清中NO 2 －的含量是NO水平的指示，利用Griess试剂检测NO 2 －含量从而反映NO的水平，进而反映化合物抗炎症能力。试验目标细胞是小胶质细胞系BV-2，采用的炎症模型是脂多糖(LPS)诱导小胶质细胞炎症反应模型。BV-2细胞接种于96孔板，每孔接种2×10 4个细胞。细胞贴壁处理24小时后，更换新鲜培养基并孵育相应浓度的BV-2化合物，2小时后加入LPS(终浓度为100ng/mL)，继续培养24小时，直接收集96孔板中的上清。将50μL的上清与等体积的Griess试剂加入96孔板中，混匀，避光、室温反应15分钟，用酶标仪在540nm波长处检测吸光度值。亚硝酸钠为标准品。
NO绝对含量计算公式：NO浓度(μM)＝181.82×OD 540-0.4318
校正公式：NO相对含量(percentage of LPS group)＝测试组上清NO绝对含量/LPS组上清NO绝对浓度绝对值×100％
实验结果：
应用LPS诱发BV-2小胶质细胞炎症反应模型研究结果表明，用化合物079处理可有效抑制LPS刺激BV-2后上清中过量产生的NO含量，100ng/ml的LPS处理后BV-2细胞上清中NO的含量明显增加至43.9μM(设置成100％，p<0.001相比于正常组)，10μM和20μM化合物079处理显著降低上清中NO亚硝酸盐含量分别至37.6μM(LPS组的85.3％)和33.3μM(LPS组的75.7％)(p<0.01相比于LPS组)(图6)。

Claims (9)

  1. 一种式I所示的化合物、其对映异构体、非对映异构体、外消旋体或其药学上可接受的盐，
    Figure PCTCN2018122227-appb-100001
    其中，
    Y为O或NH；
    R 0至R 4各自独立地选自H；羟基；氨基；卤素；未取代或被选自羟基、氨基、卤素、氰基或C 1～C 10烷氧基中的一个或多个取代基取代的C 1～C 10烷基；未取代或被选自羟基、氨基、卤素、氰基或C 1～C 10烷氧基中的一个或多个取代基取代的C 1～C 10烷氧基；未取代或被选自羟基、氨基、卤素、氰基、C 1～C 10烷基或C 1～C 10烷氧基中的一个或多个取代基取代的3至8元环烷基；未取代或被选自羟基、氨基、卤素、氰基、C 1～C 10烷基或C 1～C 10烷氧基中的一个或多个取代基取代的6至8元芳基；未取代或被选自羟基、氨基、卤素、氰基、C 1～C 10烷基或C 1～C 10烷氧基中的一个或多个取代基取代的3至8元杂环基；未取代或被选自羟基、氨基、卤素、氰基、C 1～C 10烷基或C 1～C 10烷氧基中的一个或多个取代基取代的5至8元杂芳基；
    R 5选自H；未取代或被选自羟基、氨基、氰基或C 1～C 10烷氧基中的一个或多个取代基取代的C 1～C 10烷基、C 2～C 10烯基或C 2～C 10炔基；未取代或被选自羟基、氨基、氰基、卤素、C 1～C 10烷基或C 1～C 10烷氧基中的一个或多个取代基取代的3至8元环烷基；未取代或被选自羟基、氨基、氰基、卤素、C 1～C 10烷基或C 1～C 10烷氧基中的一个或多个取代基取代的6至8元芳基；未取代或被选自羟基、氨基、卤素、氰基、卤素、C 1～C 6烷基或C 1～C 6烷氧基中的一个或多个取代基取代的5至8元杂环基；未取代或被选自羟基、氨基、卤素、氰基、卤素、C 1～C 6烷基或C 1～C 6烷氧基中的一个或多个取代基取代的5至8元杂芳基；或
    Figure PCTCN2018122227-appb-100002
    其中，n为1至6的整数；
    R 15选自H、C 1～C 10烷基、C 1～C 10烷氧基、卤素、羟基或氨基；当n大于1时，各个R 15各自相同或不同；
    R 16选自H或C 1～C 10烷基；
    R 17选自取代或未取代的6至8元芳基或5至8元杂芳基，所述取代的6至8元芳基或取代的5至8元杂芳基中的取代基选自羟基、氨基、卤素、C 1～C 10烷基或C 1～C 10烷氧基；
    X选自
    Figure PCTCN2018122227-appb-100003
    其中，
    Figure PCTCN2018122227-appb-100004
    表示与式I中的苯环连接的位点，
    Figure PCTCN2018122227-appb-100005
    表示与式I中的羰基连接的位点，
    Figure PCTCN2018122227-appb-100006
    表示单键或双键；
    R 6至R 14各自独立地选自H；羟基；卤素；氨基；氧代基团(＝O)；C 1～C 10烷基；C 1～C 10烷氧基；卤素；未取代或被选自羟基、C 1～C 10烷氧基或卤素中的一个或多个取代基取代的C 1～C 10烷基；C 1～C 10烷氧基羰基；或
    Figure PCTCN2018122227-appb-100007
    其中，Z为O或NH；
    A为C 1～C 10亚烷基或C 2～C 10亚烯基；
    R 23选自取代或未取代的6至8元芳基或5至8元杂芳基，所述取代的6至8元芳基或取代的5至8元杂芳基中的取代基选自羟基、氨基、卤素、C 1～C 10烷基或C 1～C 10烷氧基，或者所述取代的6至8元芳基或取代的5至8元杂芳基中的两个相邻的取代基与它们连接的6至8元芳基或5至8元杂芳基上的原子一起形成环；
    当R 6至R 14中的一个为氧代基团时，与该氧代基团连接的碳原子不能参与形成碳碳双键。
  2. 根据权利要求1所述的式I所示的化合物、其对映异构体、非对映异构体、外消旋体或其药学上可接受的盐，其中，R 17选自
    Figure PCTCN2018122227-appb-100008
    其中，R 18至R 22选自H、羟基、氨基、卤素、C 1～C 10烷基或C 1～C 10烷氧基。
  3. 根据权利要求1所述的式I所示的化合物、其对映异构体、非对映异构体、外消旋体或其药学上可接受的盐，其中，R 23选自
    Figure PCTCN2018122227-appb-100009
    其中，R 24至R 28各自独立地选自H、羟基、氨基、卤素、C 1～C 10烷基或C 1～C 10烷氧基，或者它们中相邻的两个与它们连接的苯环上的碳原子一起形成环。
  4. 根据权利要求1所述的式I所示的化合物、其对映异构体、非对映异构体、外消旋体或其药学上可接受的盐，其中，R 6至R 14各自独立地选H、羟基、氧代基团(＝O)、
    Figure PCTCN2018122227-appb-100010
    乙氧基羰基或叔丁氧基羰基。
  5. 根据权利要求1所述的式I所示的化合物、其对映异构体、非对映异构体、外消旋体或其药学上可接受的盐，其中，所述式I所示的化合物具有如下结构：
    Figure PCTCN2018122227-appb-100011
    Figure PCTCN2018122227-appb-100012
    Figure PCTCN2018122227-appb-100013
    Figure PCTCN2018122227-appb-100014
    Figure PCTCN2018122227-appb-100015
    Figure PCTCN2018122227-appb-100016
    Figure PCTCN2018122227-appb-100017
  6. 一种制备权利要求1至5中任一项所述的式I所示的化合物的制备方法，其包括如下步骤：
    Figure PCTCN2018122227-appb-100018
    (1)使化合物a与R 5-NH 2或R 5-OH发生酯化反应或酰胺化反应生成式I所示的化合物，
    其中，R 1至R 4，以及X和Y与前面的定义相同，除了不为H之外，R 5与前述定义相同。
  7. 一种药物组合物，其包含权利要求1至5中任一项所述的式I所示的化合物、其对映异构体、非对映异构体、外消旋体或其药学上可接受的盐和药学上可接受的赋形剂或载体。
  8. 根据权利要求1至5中任一项所述的式I所示的化合物、其对映异构体、非对映异构体、外消旋体或其药学上可接受的盐或根据权利要求7所述的药物组合物在制备预防和/或治疗脑缺血、缺糖或缺氧诱发的脑损伤和/或神经功能异常的药物中的用途。
  9. 一种治疗预防和/或治疗脑缺血、缺糖或缺氧诱发的脑损伤和/或神经功能异常的方法，其包括如下步骤：向受试者施加治疗有效量的根据权利要求1至5中任一项所述的式I所示的化合物、其对映异构体、非对映异构体、外消旋体或其药学上可接受的盐或根据权利要求7所述的药物组合物。
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