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WO2021143812A1 - PROCÉDÉ DE PRÉPARATION DE N-(β-L-RHAMNOPYRANOSYL)FÉRULAMIDE ET SON UTILISATION - Google Patents

PROCÉDÉ DE PRÉPARATION DE N-(β-L-RHAMNOPYRANOSYL)FÉRULAMIDE ET SON UTILISATION Download PDF

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WO2021143812A1
WO2021143812A1 PCT/CN2021/072054 CN2021072054W WO2021143812A1 WO 2021143812 A1 WO2021143812 A1 WO 2021143812A1 CN 2021072054 W CN2021072054 W CN 2021072054W WO 2021143812 A1 WO2021143812 A1 WO 2021143812A1
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compound
reaction
cells
molar ratio
mitochondrial
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Chinese (zh)
Inventor
裴钢
夏鹏
李剑峰
李扬
郭飞
杨海利
陆婧
李义
金凯军
王雪松
夏广新
柯樱
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Shanghai Pharmaceuticals Holding Co Ltd
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Shanghai Pharmaceuticals Holding Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7024—Esters of saccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • 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 present invention relates to a preparation method of a medicine, in particular, the present invention relates to a preparation method and application of N-( ⁇ -L-rhamnanopyranosyl) ferulic acid amide.
  • Mitochondria are dynamic organelles in eukaryotic cells, which play an important role in ATP production, cellular calcium buffering and apoptosis. Mitochondrial DNA gene mutations can cause damage to the mitochondrial reactive oxygen species (ROS) scavenging function, cause ROS to accumulate in the mitochondria, cause mitochondrial oxidative damage, and may cause a series of changes in tissues and organs.
  • SIRT3 a NAD-dependent histone deacetylase that mainly exists in mitochondria, can deacetylate the subunit proteins of the mitochondrial respiratory chain complex by exerting its deacetylase activity, and promote mitochondria to provide energy for cells Function. SIRT3 is involved in mitochondrial energy metabolism and cell aging, and is a molecular target for the treatment of aging and age-related diseases.
  • amyloid- ⁇ enters the mitochondria through the translocase of the outer membrane complex, that is, mitochondria may also serve as the target of A ⁇ , leading to a decline in cognitive ability and memory.
  • N-( ⁇ -L-rhamnopyranosyl) ferulic acid amide may have antioxidant effect and treat or alleviate mitochondrial dysfunction, A ⁇ -induced mitochondrial dysfunction, and improve cognitive ability have not been reported yet.
  • Patent CN110117302A discloses the preparation method of N-( ⁇ -L-rhamnanopyranosyl) ferulic acid amide, which uses 1-amino-2,3,4-O-triacetyl rhamnose and (4 -O-TBS)-Ferulic acid chloride is used as raw material to obtain N-( ⁇ -L-rhamnanopyranosyl) ferulic acid amide.
  • 1-amino-2,3,4-O-tri Acetyl rhamnose is a raw material, has high cost, many synthesis steps, difficult product purification, unsuitable for large-scale production, and relatively low reaction yield.
  • the synthetic route is as follows:
  • the present invention provides a preparation method and application of N-( ⁇ -L-rhamnanopyranosyl) ferulic acid amide.
  • the raw materials are cheap and easy to obtain, the reaction conditions are mild, the conversion rate is high, and the reaction steps are few. , High yield, high product purity, and applied to alleviate or treat mitochondrial dysfunction, alleviate or treat A ⁇ -induced mitochondrial dysfunction, improve or improve cognitive ability, etc.
  • the purpose of the present invention is to provide a method for preparing N-( ⁇ -L-rhamnanopyranosyl) ferulic acid amide and its medical use.
  • the present invention provides a method for preparing the compound N-( ⁇ -L-rhamnanopyranosyl) ferulic acid amide of formula I, which comprises the following steps:
  • the synthetic route is as follows:
  • P is selected from All, Boc, TMS, TES, TBS, TIPS, TBDPS, THP, MOM, MTM, MEM, BOM, SEM, EE, Bn, PMB, Cbz, DMB and Tr;
  • X is selected from Cl and Br.
  • the reaction temperature in step 1) is -25°C-100°C
  • the reaction solvent is selected from methanol, ethanol, propanol, isopropanol, tert-butanol, n-butanol, pyridine, and dichloromethane.
  • the reaction temperature in step 2) is -5°C-60°C
  • the reaction solvent is methanol, ethanol, propanol, isopropanol, tert-butanol, n-butanol, acetonitrile, 1,4 -Dioxane, tetrahydrofuran, dichloromethane or any combination thereof.
  • the base is selected from one or more of inorganic bases or organic bases, the molar ratio of compound 2 to base is 1:1-7; the molar ratio of compound 2 to compound 3 is 0.8-3:1-4; the molar ratio of compound 1 to the deprotection agent is 1:0.1-4.
  • the method further includes the step of subjecting the rhamnose compound to an ammonia source to perform a substitution reaction to obtain compound 2.
  • the reaction temperature of the substitution reaction is 15°C-100°C
  • the reaction time of the substitution reaction is 0.5-60h
  • the reaction solvent is an alcohol solvent
  • the molar ratio of the rhamnose and the ammonia source The ratio is 1:1-10, preferably 1:1-7.
  • the method further comprises subjecting compound 5 to a hydroxyl protection reaction in an organic solvent to obtain compound 6, subjecting compound 6 to alkaline hydrolysis reaction to obtain compound 7, and subjecting compound 7 to halogenation reaction to obtain compound 3 steps,
  • the synthetic route is as follows:
  • the compound 5 undergoes a hydroxyl protection reaction with a hydroxyl protecting reagent under acid binding agent conditions to obtain compound 6, and the compound 6 undergoes alkaline hydrolysis under alkaline conditions to obtain compound 7, and compound 7 React with halogenated reagent to obtain compound 3.
  • the hydroxyl protection reaction is carried out in a suitable organic solvent, the reaction temperature is -5-70°C, and the reaction time of the hydroxyl protection reaction is 1-24 h; the molar ratio of the compound 5 to the acid binding agent is 1:1 -6, the molar ratio of the compound 5 to the hydroxyl protecting reagent is 1:1-5.
  • the alkaline hydrolysis reaction solvent is preferably an aqueous tetrahydrofuran solution
  • the alkaline hydrolysis reaction temperature is preferably room temperature
  • the reaction time is 1-10 h
  • the molar ratio of the compound 5 to the base is 1:0.1-1.
  • the reaction temperature of the halogenation reaction is 10-60°C, the reaction time of the halogenation reaction is 1-10h, and the halogenation reaction solvent is selected from dichloromethane, acetonitrile or a combination thereof; the compound 7 and the halogenation reagent
  • the molar ratio is 1:1-5.
  • the compound of formula 1 is a new compound, so the present invention also relates to the compound of formula 1 in another aspect:
  • this document provides N-( ⁇ -L-rhamnopyranosyl) ferulic acid amide and pharmaceutically acceptable salts thereof in preparation for alleviating or treating mitochondrial dysfunction in the cells of a subject Use in medicine.
  • the mitochondrial dysfunction is A ⁇ protein, such as mitochondrial dysfunction induced by oligomers of A ⁇ 42 polypeptide.
  • the mitochondrial dysfunction includes, but is not limited to, increased levels of protein acetylation in mitochondria, increased levels of reactive oxygen species, decreased membrane potential, and/or decreased oxygen consumption; the drug is used to reduce mitochondria The level of protein acetylation, inhibits the reduction of membrane potential in mitochondria and/or inhibits the reduction of oxygen consumption in mitochondria.
  • N-( ⁇ -L-rhamnopyranosyl) ferulic acid amide and pharmaceutically acceptable salts thereof in the preparation of a medicament for increasing the activity or level of SIRT3 in a subject use.
  • the drug also enhances AMPK phosphorylation and/or enhances the activity or level of PGC-1.
  • the drug reduces the acetylation level of manganese superoxide dismutase (SOD2) and oligomycin sensitivity conferring protein (OSCP).
  • this article provides N-( ⁇ -L-rhamnanopyranosyl) ferulic acid amide and its pharmaceutically acceptable salt in preparation for reducing the acetylation and oxidation of mitochondrial protein in the cells of a subject.
  • the cells are nerve cells, such as SK-N-SH cells.
  • N-( ⁇ -L-rhamnanopyranosyl) ferulic acid amide and its pharmaceutically acceptable salt in the preparation of a medicament for the prevention, alleviation or treatment of depression.
  • the drug can quickly and continuously exert a preventive, alleviating or therapeutic effect in a short-term or a long-term period, for example, within 1 hour of administration, and for a longer time, such as 8 hours, 16 hours, The effect can be maintained for 24 hours or more than 24 hours, for example, 2 days, 3 days, 7 days, 10 days, 15 days or even longer.
  • a single administration or preferably multiple repeated administrations can effectively maintain the prevention, alleviation or treatment of depression and its symptoms.
  • the drug exerts a preventive, alleviating or therapeutic effect within a short period of time after a single administration, and the short-term is no longer than 1 hour, no longer than 8 hours, no longer than 16 hours, no longer than 24 hours, or 24 hours to 72 hours.
  • the drug exerts a preventive, alleviating or therapeutic effect in a long-term period through multiple administrations, and the long-term period is no less than 3 days, no less than 4 days, no less than 5 days, no Less than 6 days, no less than 1 week, no less than 1 month, no less than 3 months, no less than 6 months, no less than 1 year, no less than 3 years, no less than 5 years or Longer.
  • the dosing frequency can be once a day, once every 2 days, once a week, once every two weeks or a longer time interval. The dosing frequency can be determined by the physician according to the specific conditions of the patient or subject. The dosage is easily determined.
  • this article provides N-( ⁇ -L-rhamnanopyranosyl) ferulic acid amide and its pharmaceutically acceptable salts in preparation for preventing cognitive impairment in subjects, improving or enhancing The use of the subject's cognitive ability in drugs.
  • the decline in cognitive ability is response inhibition ability and/or memory ability.
  • N-( ⁇ -L-rhamnanopyranosyl) ferulic acid amide and pharmaceutically acceptable salts thereof in the preparation of a medicament for preventing, inhibiting or delaying senescence in a subject use.
  • the senescence is related to SIRT3.
  • a method for preventing, alleviating or treating abnormal mitochondrial function in cells of a subject which comprises administering to the subject N-( ⁇ -L-rhamnopyranosyl) ferulic acid amide Or a pharmaceutically acceptable salt thereof.
  • a method for reducing mitochondrial protein acetylation, oxidative stress levels, or reactive oxygen species in cells of a subject which comprises administering N-( ⁇ -L-pyran Rhamnosyl) ferulic acid amide or a pharmaceutically acceptable salt thereof.
  • a method for preventing, improving or enhancing the cognitive ability of a subject which comprises administering to the subject N-( ⁇ -L-Rhamnus pyran Glycosyl) ferulic acid amide or a pharmaceutically acceptable salt thereof.
  • a method for inhibiting or delaying senescence in a subject which comprises administering to the subject N-( ⁇ -L-rhamnopyranosyl) ferulic acid amide or its pharmaceutically Acceptable salt.
  • the senescence is related to SIRT3.
  • N-( ⁇ -L-rhamnopyranosyl) ferulic acid amide or a pharmaceutically acceptable salt thereof to prevent cognitive impairment, improve or improve cognitive ability of subjects the use of.
  • Figure 1 shows the compound I 1 HNMR spectrum.
  • FIG. 1 shows the HPLC profile of Compound I.
  • Figure 3 shows that treatment of SK-N-SH cells with PL171 for 24 hours has no effect on cell viability.
  • Figure 4 shows the effect of PL171 on the basic level of ROS.
  • Figures 5A-I show that PL171 promotes mitochondrial SIRT3 levels and their activity.
  • Figure 6A-L shows that PL171 promotes the expression of SIRT3 by enhancing AMPK/PGC-1.
  • Figures 7A-C show that PL171 inhibits A ⁇ 42O-induced ROS production in SK-N-SH cells.
  • Figures 8A-E show that PL171 inhibits A ⁇ 42O-induced reduction of MMP in SK-N-SH cells.
  • Figures 9A-D show that PL171 inhibits A ⁇ 42O-induced decrease in oxygen consumption in SK-N-SH cells.
  • Figures 10A-B show the acetylation level of MnSOD in the mitochondrial lysate of SK-N-SH cells after SK-N-SH cells were pretreated with 30 ⁇ M PL171 for 4 hours and then stimulated with 10 ⁇ MA ⁇ 42O for 24 hours.
  • Figures 11A-C show that PL171 inhibits the reduction of SIRT3 and PGC-1 ⁇ induced by A ⁇ 42O.
  • Figures 12A-B show that PL171 improves A ⁇ 42O-induced oxidative stress and mitochondrial dysfunction through SIRT3.
  • Figures 13A-B show that PL171 inhibits A ⁇ 42O-induced cellular senescence through SIRT3 regulation.
  • Figures 14A-C show the antidepressant effects in mice evaluated by forced swimming immobility time (panel A, acute; panel B, medium and long period) and tail suspension experiment (panel C).
  • Figures 15A-B show a schematic diagram of the Stop-signal task model and its flow
  • Figure 15C shows the administration schedule.
  • Figure 16A-B shows the effect of PL171 administration on Stop trial operation in the rat cognitive ability test model.
  • Figure 17A-B shows the effect of PL171 administration on Go trial operation in the rat cognitive ability test model.
  • Figure 18 shows the effect of intragastric administration of low, medium and high doses of PL171 on the time of forced swimming immobility 24h after a single dose of mice.
  • the temperature usually refers to room temperature.
  • compound represented by structural formula n “intermediate represented by structural formula n”, and “compound n” have the same meaning, and all refer to the compound numbered n, where n refers to number I, 1, 2, 3, 4, 5, 6, 7.
  • compound I is sometimes referred to herein as PL171 or N-( ⁇ -L-rhamnopyranosyl) ferulic acid amide, and they have the same meaning.
  • the invention provides a method for preparing N-( ⁇ -L-rhamnopyranosyl) ferulic acid amide, which comprises the following steps:
  • the synthetic route is as follows:
  • P is selected from All (allyl), Boc (tert-butoxycarbonyl), TMS (trimethylsilyl), TES (triethylsilyl), TBS (tert-butyldimethylsilyl), TIPS (triisopropylsilyl), TBDPS (tert-butyldiphenylsilyl), THP (2-tetrahydropyranyl), MOM (methoxymethyl), MTM (methylthiomethyl) , MEM (methoxyethoxymethyl), BOM (benzyloxymethyl), SEM (trimethylsilylethoxymethyl), EE (ethoxyethyl), Bn (benzyl) , PMB (p-methoxybenzyl), Cbz (benzyloxycarbonyl), DMB (3,4-dimethoxybenzyl) and Tr (trityl);
  • X is selected from Cl and Br; preferably, P is selected from TBS, Boc, Cbz and THP; X is selected from Cl;
  • the reaction temperature in step 1) is -25°C-100°C
  • the reaction solvent is selected from methanol, ethanol, propanol, isopropanol, tert-butanol, n-butanol, pyridine, and dichloromethane.
  • reaction temperature of the step 2) is -5°C-60°C
  • reaction solvent is methanol, ethanol, propanol, and isopropanol , Tert-butanol, n-butanol, acetonitrile, 1,4-dioxane, tetrahydrofuran, dichloromethane or a combination thereof.
  • the reaction temperature in the step 1) is -5°C-70°C, and the reaction solvent is methanol, dichloromethane, tetrahydrofuran or 2-methyltetrahydrofuran or a combination thereof;
  • the reaction temperature in the step 2) is 0°C -30°C, the reaction solvent is methanol;
  • reaction temperature in step 1) is -5°C to 30°C; the reaction temperature in step 2) is 20°C to 30°C.
  • the progress of the reaction in the step 1) and the progress of the reaction in the step 2) can be monitored by conventional monitoring methods in the art (for example, TLC, HPLC, or NMR).
  • the reaction time in step 1) is 1-24 h; the reaction time in step 2) is 0.5-3 h; preferably, the reaction time in step 1) is 1-12 h; The reaction time of the step 2) is 0.5-2h.
  • the base is selected from one or more of inorganic bases or organic bases; the molar ratio of compound 2 to base is 1:1-7; the molar ratio of compound 2 to compound 3 is 0.8- 3:1-4;
  • the compound 1 undergoes a deprotection reaction under the conditions of the deprotection agent to obtain compound I; the molar ratio of the compound 1 to the deprotection agent is 1:0.1-4.
  • the molar ratio of the compound 2 to the base is 1:1-4; the molar ratio of the compound 2 to the compound 3 is 1:1-4; the molar ratio of the compound 1 to the deprotecting agent is 1:0.2-3.
  • the molar ratio of the compound 2 to the base is 1:1.5-3; the molar ratio of the compound 2 to the compound 3 is 1:1-3; the molar ratio of the compound 1 to the deprotecting agent is 1:0.3-2.2 .
  • the inorganic base is selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, lithium carbonate, lithium hydroxide, cesium hydroxide, magnesium hydroxide, calcium hydroxide, hydrogen
  • the organic base is selected from sodium methoxide, sodium ethoxide, N,N-diisopropylethylamine (DIEA), triethylamine , Diethylamine, tripropylamine, tri-n-butylamine, pyridine, N,N-lutidine, triethylenediamine, 1,5-diazabicyclo[5.4.0]undecene-5,1
  • DIEA sodium methoxide
  • DIEA N,N-diisopropylethylamine
  • pyridine N,N-lutidine
  • triethylenediamine 1,5-diazabicyclo[5.4.0]undecene-5,1
  • the base is selected from one of N,N-diisopropylethylamine (DIEA), pyridine, and sodium carbonate.
  • DIEA N,N-diisopropylethylamine
  • pyridine pyridine
  • sodium carbonate sodium carbonate
  • the deprotection agent is selected from the group consisting of tetrabutylammonium fluoride (TBAF), trifluoroacetic acid (TFA), palladium on carbon (Pd/C), palladium hydroxide on carbon (Pd(OH) 2 / C), piperidine (Piperidine), hydrochloric acid methanol solution (HCl-MeOH), acetic acid (AcOH), formic acid (HCOOH), cesium fluoride (CsF), ammonium fluoride (NH 4 F), potassium fluoride (KF) , Hydrofluoric acid-pyridine solution (HF ⁇ Py), hydrofluoric acid-triethylamine solution (3HF ⁇ TEA); preferably, the deprotecting agent is tetrabutylammonium fluoride ( TBAF), cesium fluoride (CsF), ammonium fluoride (NH 4 F), potassium fluoride (KF), hydrofluoric acid-pyridine (HF ⁇ Py
  • the preparation method of the compound 1 includes the following post-processing steps: after the reaction, filtration, spin-drying, dissolution, and purification by column chromatography.
  • the filtration, spin-drying, dissolution, and purification by column chromatography can be performed in accordance with the art This type of operation is carried out in the usual way.
  • the preparation method of the compound I preferably includes the following post-treatment steps: after the reaction is completed, spin-drying, dissolving, diluting, filtering, and drying, the spin-drying, dissolving, diluting, filtering, and drying can be performed in accordance with this type of operation in the art The conventional method is carried out.
  • the rhamnose compound undergoes a substitution reaction with an ammonia source to obtain compound 2.
  • the rhamnose compound and the ammonia source undergo the substitution reaction under acid binding agent conditions to obtain compound 2.
  • the reaction temperature of the substitution reaction is 15° C.-100° C.
  • the reaction time of the substitution reaction is 0.5-60 h
  • the reaction solvent is an alcohol solvent.
  • the alcohol solvent is selected from one or more of anhydrous methanol, anhydrous ethanol, isopropanol, and butanol.
  • the reaction temperature of the substitution reaction is 20° C.-80° C.
  • the reaction solvent is anhydrous methanol
  • the reaction time of the substitution reaction is 0.5-49 h.
  • the molar ratio of the rhamnose compound to the ammonia source is 1:1-10, and the molar ratio of the rhamnose compound to the acid binding agent is 1:1.5-4;
  • the molar ratio of the rhamnose compound to the ammonia source is 1:1-7, and the molar ratio of the rhamnose compound to the acid binding agent is 1:2-3.4.
  • the ammonia source is selected from one of ammonium bicarbonate, ammonium carbonate, ammonia water, and ammonia; preferably, the ammonia source is selected from one of ammonium bicarbonate, ammonium carbonate, and ammonia. kind.
  • the acid binding agent is an organic base or an inorganic base
  • the organic base is diisopropylethylamine, diethylamine, tripropylamine, N,N-lutidine, triethylamine, tri-n-butylamine, Triethylene diamine, 1,5-diazabicyclo[5.4.0]undecene-5,1,5-diazabicyclo[4.3.0]nonene-5,4-dimethylaminopyridine , Pyridine, N-methylmorpholine, one or more of tetramethylethylenediamine;
  • the inorganic base is sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, magnesium hydroxide, hydrogen
  • the acid binding agent is triethylamine.
  • the rhamnose compound undergoes substitution reaction in an ammonia-alcohol solution to obtain compound 2;
  • the mass fraction of ammonia in the ammonia-alcohol solution is 8-20%; preferably, the mass fraction of ammonia in the ammonia-alcohol solution is 10-17%.
  • the rhamnose compound is selected from one or more of L-rhamnose and D-rhamnose;
  • the L-rhamnose includes ⁇ -L-rhamnose, ⁇ -rhamnose, L-rhamnose;
  • the D-rhamnose includes ⁇ -D-rhamnose and ⁇ -D-rhamnose;
  • the ⁇ -L-rhamnose includes anhydrous ⁇ -L-rhamnose ( CAS: 6014-42-2), ⁇ -L-rhamnose monohydrate (CAS: 6155-35-7);
  • the ⁇ -L-rhamnose includes anhydrous ⁇ -L-rhamnose (CAS: 6155-36-8), ⁇ -L-rhamnose monohydrate;
  • the rhamnose compound is selected from L-rhamnose
  • the rhamnose compound is selected from ⁇ -L-rhamnose monohydrate (CAS:6155-35-7).
  • the more preferred synthetic route is as follows:
  • the preparation method of the compound 2 preferably includes the following post-treatment steps: after the reaction is completed, spin-drying and recrystallization; the spin-drying and recrystallization can be carried out according to conventional methods of this type of operation in the art.
  • the progress of the substitution reaction can be monitored by conventional monitoring methods in the art (for example, TLC, HPLC or NMR).
  • the compound 3 is obtained from compound 5 as a starting material, and is obtained through hydroxyl protection, alkaline hydrolysis, and halogenation.
  • the synthetic route is as follows:
  • the compound 5 undergoes a hydroxyl protection reaction with a hydroxyl protecting reagent under acid binding agent conditions to obtain compound 6, and the compound 6 undergoes alkaline hydrolysis under alkaline conditions to obtain compound 7, and compound 7 React with halogenated reagent to obtain compound 3.
  • the acid binding agent in the hydroxyl protection reaction is selected from one of pyridine, 2-picoline, quinoline, imidazole, triethylamine, morpholine, N,N-diisopropylethylamine (DIEA) Or multiple.
  • the acid binding agent in the hydroxyl protection reaction is selected from N,N-diisopropylethylamine.
  • the hydroxy protecting reagent is a hydroxy protecting reagent known in the art, preferably tert-butyldimethylchlorosilane (TBSCl).
  • the hydroxyl protection reaction is carried out in a suitable organic solvent, the reaction temperature is -5-70°C, and the reaction time of the hydroxyl protection reaction is 1-24 h; the molar ratio of the compound 5 to the acid binding agent is 1:1 -6, the molar ratio of the compound 5 to the hydroxyl protecting reagent is 1:1-5.
  • the organic solvent is preferably selected from dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), hexamethylphosphoramide (HMPA) ), one or more of dichloromethane (DCM).
  • DMF dimethylformamide
  • DMSO dimethylsulfoxide
  • DMAC dimethylacetamide
  • NMP N-methylpyrrolidone
  • HMPA hexamethylphosphoramide
  • DCM dichloromethane
  • the reaction time of the hydroxyl protection reaction is 3-12h.
  • the molar ratio of the compound 5 to the acid binding agent is 1:2-5, and the molar ratio of the compound 5 to the hydroxyl protecting agent is 1:1.5-4.
  • the reaction temperature in the hydroxyl protection reaction is 20-30° C.
  • the reaction solvent is DCM.
  • the preparation method of the compound 6 preferably includes the following post-processing steps: after the reaction, extraction, washing, drying, filtration, spin drying, beating, filtering, drying, the extraction, washing, drying, filtering, spin drying, and beating , Filtration, and drying can be carried out in accordance with the conventional methods of this type of operation in the field.
  • the alkali hydrolysis reaction solvent is selected from tetrahydrofuran, water or a combination thereof; the alkali includes one or more of potassium carbonate, sodium carbonate, potassium hydroxide, and sodium hydroxide.
  • the alkaline hydrolysis reaction solvent is tetrahydrofuran aqueous solution; the base is potassium carbonate; preferably, the alkaline hydrolysis reaction temperature is room temperature, and the reaction time is 1-10 h.
  • the volume ratio of tetrahydrofuran to water in the tetrahydrofuran aqueous solution is 1-50:1; preferably, the volume ratio of tetrahydrofuran to water in the tetrahydrofuran aqueous solution is 5-20:1.
  • the molar ratio of the compound 6 to the base is 1:0.1-1; preferably, the molar ratio of the compound 6 to the base is 1:0.15-0.5.
  • the preparation method of the compound 7 preferably includes the following post-processing steps: after the reaction, extraction, washing, drying, filtering, spin drying, beating, filtering, drying, the extraction, washing, drying, filtering, spin drying, and beating , Filtration, and drying can be carried out in accordance with the conventional methods of this type of operation in the field.
  • the reaction temperature in the halogenation reaction is 10-100°C, preferably 10-60°C, the reaction time of the halogenation reaction is 1-10h, and the halogenation reaction solvent is selected from methylene chloride, acetonitrile or a combination thereof; the compound 7
  • the molar ratio with the halogenated reagent is 1:1-5.
  • the reaction temperature of the halogenation reaction is 15-50° C.
  • the reaction solvent in the halogenation reaction is dichloromethane; the molar ratio of the compound 7 to the halogenation reagent is 1:1-3 .
  • the halogenating agent is selected from the group consisting of trimethylchlorosilane, trimethylbromosilane, triethylchlorosilane, tert-butyldimethylchlorosilane, phenyldimethylchlorosilane, oxalyl chloride, Acetyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus pentabromide, thionyl chloride, sulfonyl chloride or a combination thereof; preferably, the halogenated reagent is oxalyl chloride.
  • the preparation method of the compound 3 preferably includes the following post-treatment steps: after the reaction is completed, spin-drying, and the spin-drying can be carried out according to conventional methods of this type of operation in the art.
  • PL171 ie, N-( ⁇ -L-rhamnopyranosyl) ferulic acid amide
  • PL171 can increase the expression or activity of SIRT3.
  • PL171 promotes the expression of the SIRT3 gene, and/or promotes the activity of the SIRT3 protein.
  • PL171 can also increase AMPK phosphorylation and PGC-1 ⁇ expression. Since it is known that AMPK-mediated PGC-1 ⁇ is one of the transcription factors of SIRT3 gene, it is likely that PL171 can promote the expression and activity of PGC-1 ⁇ and SIRT3 by promoting AMPK activity.
  • SIRT3 as used herein, belongs to the 7 members of the "sirtuin family" in mammals. It is an NAD-dependent histone deacetylase that mainly exists in mitochondria. There are two forms of SIRT3: a long chain of 44kDa and a short chain of 28kDa, which mainly play a role in the cell through the short-chain SIRT3. SIRT3 is involved in mitochondrial energy metabolism and cell aging, and is a molecular target for the treatment of aging and age-related diseases.
  • PGC-1 ⁇ has the full name of Peroxisome Proliferator Activated Receptor- ⁇ (PPAR- ⁇ ) Coactivator-1 ⁇ . This protein and other transcription factors are involved in the regulation of oxidative phosphorylation, lipid metabolism and mitochondrial biosynthesis. It is known that SIRT3 is a transcription target of PGC-1 ⁇ .
  • PPAR- ⁇ Peroxisome Proliferator Activated Receptor- ⁇
  • PL171 can significantly increase the mRNA and protein levels of PGC-1 ⁇ , and prevent the decrease of A ⁇ -induced protein, thereby repairing the mitochondrial energy supply damage caused by A ⁇ . Therefore, PL171 may promote the expression of SIRT3 through PGC-1 ⁇ .
  • PL171 can not only prevent A ⁇ 42O-induced oxidative stress and mitochondrial damage, but also inhibit A ⁇ 42O-mediated cell senescence.
  • cognitive function in a broad sense refers to the process by which a person acquires, encodes, manipulates, extracts and uses sensory input information, including attention, memory, perception, and thinking.
  • Disorders of cognitive function generally refer to clinical syndromes of varying degrees of cognitive impairment caused by various reasons (from physiological aging to disturbance of consciousness). There are many manifestations, such as learning or memory disorders, executive function disorders, dementia, aphasia, apraxia, agnosia, and other changes in mental and neurological activities.
  • Stop-signal task model which is a commonly used response inhibition behavior model and is widely used in clinical practice. Assessment of patient cognitive function and laboratory animal research. This model is designed on the theoretical basis of the "horse racing model", which can test the animal's reaction inhibition ability, and to a certain extent also reflects the animal's learning and memory ability, decision-making reaction ability and sports reaction ability. Response inhibition ability, working memory and attention regulation together constitute the main component of executive function, which is an important cognitive function.
  • Inhibition of response refers to the suppression of the impulse of action that has been formed, which is a key component of executive control; specifically, the suppression of response is the suppression of no longer needed or inappropriate behaviors so that people can perform various flexible and active actions in the external environment. The purpose of the behavioral response.
  • the positive and progressive effects of the present invention are: the preparation method of the present invention has cheap and easily available raw materials, mild reaction conditions, high conversion rate, high yield, simple post-treatment, low production cost, and high chemical purity of the prepared product.
  • the prepared PL171 i.e. N-( ⁇ -L-rhamnanopyranosyl) ferulic acid amide
  • the prepared PL171 can play a role in treating mitochondrial dysfunction, improving the level and activity of SIRT3, treating depression, and improving cognitive ability. .
  • the system was added to ice water (0-10°C, 16mL); the system was allowed to stand for liquid separation; the organic phase was washed with 1M HCl aqueous solution (16mL), and the pH of the system was adjusted to 5-6; the system was stirred, Let stand for liquid separation; the organic phase was concentrated under vacuum and reduced pressure until no fraction was distilled out of the system, and the residue compound 6 (yellow oil, 20.16 g crude product) was collected;
  • the reagents and raw materials used in the present invention are all commercially available.
  • a ⁇ 42 polypeptide was treated with hexafluoroisopropanol (HFIP) and resuspended in dimethyl sulfoxide (DMSO), then diluted to 100 ⁇ M in DMEM/F12 phenol red-free medium, centrifuged, and then at 4°C Incubate for 24 hours under low temperature; wherein, A ⁇ 42 peptide was purchased from Genicbio (A-42-T-2).
  • HFIP hexafluoroisopropanol
  • DMSO dimethyl sulfoxide
  • SK-N-SH cells were purchased from ATCC. The cell line was placed in a modified medium containing 10% fetal bovine serum (FBS), 100 U/mL penicillin and 0.1 mg/mL streptomycin, and cultured in a constant temperature incubator.
  • FBS fetal bovine serum
  • SK-N-SH cells were seeded in a 96-well plate at 1 ⁇ 10 4 cells/well. After being treated with the specified concentration of PL171 for 24 hours, the Cell Titer-Glo luminescence assay (Promega, G7573) was used to detect cell survival. Value measured by BioTek Synergy NEO (Bio-Tek, USA). As shown in Figure 3, the survival rate of SK-N-SH cells was not affected by treatment with 30uM PL171 for up to 24h.
  • Inoculate SK-N-SH cells into a 60mm culture dish wash the cells (1.5 ⁇ 10 6 cells/dish) with PBS once, decompose with trypsin-EDTA solution and centrifuge at 200g for 10 minutes, discard the supernatant, and then Resuspend the pellet in cold PBS, centrifuge at 600g for 5 minutes at 4°C, then resuspend it with 1mL mitochondrial separation solution containing 100 ⁇ M PMSF, incubate on ice for 10 minutes, and then draw the cell resuspension through a 1ml insulin needle. The homogenate was homogenized for 10 times and centrifuged at 600g for 10 minutes at 4°C. After collecting the supernatant, the supernatant was centrifuged at 11000g for 10 minutes at 4°C to obtain mitochondria, and then the mitochondrial lysate was analyzed by Western blot.
  • ROS Reactive oxygen species
  • DCFH-DA 2,7-dichloro-fluorescein diacetate
  • the cells were pre-incubated for 4 hours with or without PL171, and then treated with 10 uM A ⁇ 42O for 24 hours. At the end of the treatment, the cells were co-stained with 2.5 ⁇ M MitoSOX Red mitochondrial superoxide indicator (Invitrogen, M36008) and 3 ⁇ g/mL nuclear staining dye Hoechst (Beyotime, C1022) at 37°C for 20 min. BioTek SynergyNEO was used to record fluorescence signals at 510/580nm (MitoSOX) and 350/461nm (Hoechst). The MitoSOX fluorescence signal was normalized by Hoechst signal intensity.
  • SK-N-SH cells were seeded into 96-well plates (Costar, 3904) at a density of 10,000 cells/well.
  • Cells were treated with the indicated concentrations of A ⁇ 42-1 O A ⁇ 42O or 4 or 24h or pretreated with the indicated concentrations of PL171, and reprocessing A ⁇ 42O 24h, using the JC-1 kit (Beyotime, C2006) detect mitochondrial membrane potential of cells ( MMP) level; that is, add the mixed JC-1 staining solution to the cells at 37°C for 30 minutes, wash twice with the diluted JC-1 staining buffer, and observe the cells under the Zeiss Observer Z1 microscope.
  • MMP mitochondrial membrane potential of cells
  • BioTek SynergyNEO Bio-Tek, USA was used to detect the fluorescence intensity at 490/530nm (green) for monomers and 525/590nm aggregates (red), and the membrane potential was expressed as the ratio of red/green fluorescence intensity.
  • RNA of 2 ⁇ 10 5 cells/well was extracted with the TRI reagent provided by sigma (T9424), and then reversed with the PrimeScript RT master mix of TakaRa (RR036B) After the reverse transcription reaction was performed, SYBR Green Qpcr master mix (ExCell Bio) was selected for real-time fluorescent quantitative PCR operation, and HPRT was used as the internal control.
  • the cells (1 ⁇ 10 5 cells/well) were treated with PL171 for 24h or pretreated with PL171 for 4h and then treated with A ⁇ 42O for another 24h.
  • mitochondrial lysate preparation cells are seeded and mitochondria are isolated as previously described.
  • SDS-PAGE sodium dodecyl sulfate-polyacrylamide gel electrophoresis
  • the electrophoresis condition is 400mA constant current. , 4°C, 2h, after transfer, use 5% fat-free milk blocking solution containing 0.1% Tween-20 to block for 1 hour at room temperature. After the blocking is completed, incubate the primary antibody.
  • the primary antibodies used include:
  • SIRT1 brand Proteintech, article number 13161-1-AP
  • OSCP brand Santa Cruz Biotechnology, item number sc-365162;
  • PGC-1 ⁇ brand Proteintech, article number 66369-1-Ig;
  • Phospho-AMPK ⁇ brand Beyotime, article number AA393;
  • HRP-conjugated secondary antibody After overnight at 4°C, add HRP-conjugated secondary antibody, then incubate with ECL substrate, take pictures and analyze with imaging system.
  • Example 4 PL171 improves mitochondrial SIRT3 level and activity
  • Mitochondrial protein acetylation is closely related to mitochondrial function.
  • the effect of PL171 on the acetylation status of mitochondrial protein was tested.
  • SK-N-SH cells were treated with different concentrations of PL171 for 24 h, then mitochondria were separated, lysates were prepared, and total acetylation of mitochondrial proteins was measured by Western blotting using anti-acetylation antibody (Ac-k). The results are shown in Figure 5A, which indicates that PL171 dose-dependently reduced the effect of total acetylation of mitochondrial proteins.
  • the cells were also treated with PL171 at 30 ⁇ M for 0.5-24 h to observe the changing process of the degree of mitochondrial protein deacetylation.
  • the results are shown in Fig. 5B, which shows that the acetylation of mitochondrial proteins of the cells is the lowest after 30 ⁇ M 171 treatment for 24 hours.
  • SIRT3 In order to detect SIRT3 activity, specific antibodies were used to detect the acetylation level of SIRT3 substrates, including manganese superoxide dismutase (SOD2) and oligomycin sensitivity conferring protein (OSCP). Immunoblotting was used to detect the acetylation levels at positions 68 and 139, respectively. Acetylation. The results showed that PL171 reduced the acetylation of MnSOD and OSCP in a dose-dependent manner, and 30 ⁇ M PL171 reduced the acetylation of MnSOD (SODk68/MnSOD) and OSCP (ATP5O/OSCP) by approximately 20% and 32%, respectively (see Figure 5C, D). , E); Pretreatment with SIRT3 inhibitor (SIRT3inh., 3-TYP, 20 ⁇ M, 4h) significantly blocked the effect of PL171 (see Figure 5G, H, I).
  • PL171 can protect mitochondrial function by increasing the level or activity of SIRT3 in mitochondria to promote mitochondrial protein deacetylation.
  • Example 5 PL171 promotes the expression of SIRT3 by enhancing AMPK phosphorylation-mediated PGC-1
  • SK-N-SH cells were treated with different concentrations of PL171 for 24h, and then the cells were collected to prepare lysates.
  • SIRT3 gene is controlled by the transcription factor PGC-1 ⁇ involved in mitochondrial biogenesis. Therefore, the stimulation of PGC-1mRNA and protein expression by PL171 was tested. The results show that treatment with PL171 for 24h can promote PGC-1 ⁇ mRNA and protein levels, indicating that PL171 may Promote the expression of SIRT3 by enhancing PGC-1 (see Figure 6D-F).
  • Example 6 PL171 inhibits A ⁇ 42O-induced ROS production in SK-N-SH cells
  • Example 7 PL171 inhibits the decrease of mitochondrial membrane potential (MMP) in SK-N-SH cells induced by A ⁇ 42O
  • a ⁇ 42O can induce the loss of MMP.
  • the JC-1 probe is used to evaluate the MMP in SK-N-SH cells.
  • the red fluorescence and green fluorescence represent the high and low permeability of the mitochondrial membrane, respectively, and this ratio can represent the change of MMP.
  • Example 8 PL171 inhibits the reduction of oxygen consumption in SK-N-SH cells induced by A ⁇ 42O
  • a ⁇ accumulates in mitochondria, leading to ATP depletion, decreased respiratory rate, and decreased respiratory enzyme activity.
  • OCR oxygen consumption rate
  • Example 9 PL171 inhibits the increase of A ⁇ 42O-induced acetylation level in SK-N-SH cells
  • Mitochondrial protein acetylation is closely related to mitochondrial function.
  • a ⁇ 42O (10 ⁇ M) increased the acetylation level of MnSOD, which was significantly down-regulated by pre-incubating with 30 ⁇ M PL171 for 4h ( Figure 10A, 10B).
  • Example 10 PL171 inhibits the reduction of SIRT3 and PGC-1 ⁇ induced by A ⁇ 42O
  • a ⁇ 42O (10 ⁇ M, 24h) reduced the expression of SIRT3 and PGC-1 ⁇ .
  • Pretreatment with PL171 for 4h attenuated the decrease in the expression of SIRT3 and PGC-1 induced by A ⁇ 42O.
  • Pre-incubation with 30 ⁇ M PL171 completely blocked The reduction of SIRT3 and PGC-1 ⁇ expression caused by A ⁇ 42O ( Figure 11A, 11B, 11C).
  • Example 11 PL171 improves A ⁇ 42O-induced oxidative stress and mitochondrial dysfunction through SIRT3
  • Example 12 PL171 inhibits A ⁇ 42O-induced cellular senescence through SIRT3 regulation
  • the medium is three distilled water
  • mice Divide healthy C57BL/6J mice into 5 groups randomly, 10 mice in each group, which are vehicle group (three distilled water); control group (fluoxetine hydrochloride 20.0mg/kg); PL171 high and medium , Low-dose group (50.0, 15.0, 5.0mg/kg), intragastric administration once.
  • the animals were free to eat and drink.
  • the mice were placed in a container with a diameter of about 18 cm, a water depth of 18 cm, and a water temperature of 25°C.
  • the swimming time of the mice was 6 minutes. Movement time (that is, the mouse stops struggling in the water, or the animal is floating, with only small limbs moving to keep the head floating on the water). This time is also known as the forced swimming immobility time, which is an indicator known in the art for determining the degree of depression. The shorter the time, the higher the activity of the mouse and the better the antidepressant effect.
  • the low, medium and high doses of PL171 can significantly reduce the immobility time of forced swimming in mice, and the antidepressant effect is obvious.
  • Example 14 Evaluation of the antidepressant efficacy of PL171 in mice after a single administration 24h
  • Fluoxetine hydrochloride (Fluoxetine): Tokyo Chemical Industry Co., Ltd., product number: F0750
  • mice Divide healthy C57BL/6J mice into 6 groups randomly, 15 mice in each group, which are the vehicle group (0.9% saline); the control group (fluoxetine hydrochloride 10.0mg/kg); the control group (the wormwood hydrochloride) Sketamine 10.0 mg/kg); PL171 high, medium and low dose groups (50.0, 15.0, 5.0 mg/kg). Forced swimming was measured 24 hours after intraperitoneal administration in the control group, and forced swimming was measured 24 hours after intragastric administration in the other groups. During the experiment, the animals were free to eat and drink. After a single dose of 24 hours, the mice were individually placed in a cylindrical glass cylinder with a height of 30 cm and a diameter of 20 cm.
  • the water depth in the tank was 15 cm, so that the mice could not escape.
  • the feet and tail of the glass cylinder do not touch the bottom of the cylinder, and the water temperature is 23°C-25°C.
  • a video was taken 6 minutes after the mice entered the water. Since most mice are very active in the first two minutes, the immobility time after 4 minutes is calculated (criteria of immobility: the mouse stops struggling in the water, does not move, and is in order to maintain balance or display. Small limb movements in a floating state. Mice in each group operate in parallel). This time is the time of forced swimming immobility.
  • Example 15 Evaluation of antidepressant efficacy of PL171 in mice for a long period of time
  • mice Divide healthy C57BL/6J mice into 5 groups randomly, 10 mice in each group, which are vehicle group (three distilled water); control group (fluoxetine hydrochloride 20.0mg/kg); PL171 high and medium , Low-dose group (50.0, 15.0, 5.0 mg/kg), intragastric administration, once a day, for 7 consecutive days.
  • vehicle group three distilled water
  • control group fluoxetine hydrochloride 20.0mg/kg
  • PL171 high and medium Low-dose group (50.0, 15.0, 5.0 mg/kg), intragastric administration, once a day, for 7 consecutive days.
  • the animals were free to eat and drink.
  • 24 hours after the last administration the mice were placed in a container with a diameter of about 18 cm, a water depth of 18 cm, and a water temperature of 25°C.
  • the swimming time of the mice was 6 minutes, and the mice were floating motionless within 4 minutes. (Ie, the mouse stops struggling in the water, or the animal is floating, with only small limbs moving to keep
  • PL171 The three doses of PL171 have significant antidepressant effects. Because of forced swimming after 24 hours of administration, fluoxetine takes 2-3 weeks to take effect, which also indicates that PL171 may have a rapid antidepressant effect.
  • the three doses of compound PL171 can significantly reduce the immobility time of mice, suggesting that the antidepressant effect is significant, showing an obvious dose-effect relationship.
  • the mice After 14 days of continuous administration of the positive drug fluoxetine, the mice also showed significant antidepressant effects. Because fluoxetine has no obvious effect after 7 days of administration, while PL171 has an antidepressant effect after 7 days, it indicates that PL171 has a significant antidepressant effect, and the antidepressant has a faster onset time, and the effective dose is also lower than fluoxetine. .
  • SIRT3 as a key molecule for PL171
  • Examples 13-14 show that PL-171 can quickly and continuously exert anti-depressant effects in a single dose and multiple repeated doses at a smaller dose than the positive control. Prevention, relief and treatment of symptoms and symptoms.
  • Example 16 Test results of the effect of PL171 on the ability of reaction inhibition
  • the behavior test includes a session, a session has 320 trials, and the 21st-320th trial is used for parameter calculation. Divided into 3 blocks, each block contains 100 trials, of which 80 go trials and 20 stop trials.
  • Stop-signal reaction time indicates the ability of reaction inhibition and internal decision-making power. The smaller the SSRT value, the better the reaction inhibition ability, and vice versa.
  • Each correct go trial can calculate a Go response time (Go RT), arrange the Go RT of each block from small to large, take the value of the nth Go RT, and then subtract the stop signal of 20 stop trials The average value of the stop-signal delay (SSD) that appears.
  • the final SSRT is the average of 3 SSRTs calculated by 3 blocks.
  • Stop accuracy indicates the ability to inhibit reaction and disciplinary reaction.
  • the change of the correct rate of stopping operation can reflect the change of the reaction inhibition ability. If it becomes larger, it indicates that the reaction inhibition ability is enhanced.
  • Go trial reaction time the time when the animal probes the nose into the behavioral port (ms)-the time when the nose is withdrawn from the initial port (ms).
  • Go accuracy indicates memory ability.
  • the Go operation accuracy rate can reflect the application of the animal's operation rules for behavioral tasks. If the accuracy of the Go operation becomes smaller, it indicates that it affects the use of familiar operating rules by animals, and involves changes in memory ability.
  • Go correct rate number of Go trials with correct operations/240 (the number of Go trials with 3 blocks is 240).
  • Stop accuracy rate the number of stop trials with correct operations/60 (the number of stop trials for 3 blocks is 60).
  • mice Male Sprague-Dawley rats (160-180g) were purchased from SLACC (Shanghai, China). All rats were grouped and housed in a light/dark cycle of 12:12 (lights on at 8:00 in the morning). Food and water are freely available. The rats are weighed daily to ensure that about 95% of their original body weight is maintained. All experimental procedures were carried out in accordance with the "Guidelines for the Care and Use of Laboratory Animals of the National Institutes of Health" (NIH Publication No. 80-23, 1996), and were approved and monitored by the animal experiment ethics committees of the institutes. College (Shanghai, China).
  • Test1 Test after 2 consecutive administrations (each dose is 10 mg/kg), and conduct a behavioral test 3 hours after the second administration.
  • Test2 Test after 5 consecutive administrations (the first 2 doses are 10 mg/kg, the last 3 doses are 5 mg/kg), and the behavioral test is performed 3 hours after the 5th administration.
  • Test3 A test 48 hours after the 5th dose to compare whether the results of Test1 and Test2 are caused by drug effects or repeated behavioral tests.
  • Fig. 16 show that the reaction inhibition ability of the rats was significantly improved after taking the medicine.
  • the signal stop reaction time (SSRT) of the rats was significantly shortened after taking the medicine, and there was no change in the drinking water control group. 48 hours after stopping the medication, the rat's SSRT no longer decreased, indicating that the changes in SSRT in Test1 and Test2 were the effect of the drug.
  • FIG. 17 show that the rats' exercise response ability and the use of behavioral task rules are not affected after taking the drug.
  • the Go reaction time (GoRT) of the rats did not change after taking the drug, indicating that the drug had no effect on the exercise response ability of the rats.
  • the Go trial accuracy of rats after taking the drug is not affected, indicating that the drug does not affect the rat's use of behavioral rules.

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Abstract

La présente invention concerne un procédé de préparation du composé I, N-(β-L-rhamnopyranosyl)férulamide, et l'utilisation du composé I dans la préparation d'un médicament pour soulager ou traiter une dysfonction mitochondriale et une dysfonction mitochondriale induite par Aβ chez un sujet, traiter la dépression, et améliorer ou stimuler la fonction cognitive.
PCT/CN2021/072054 2020-01-17 2021-01-15 PROCÉDÉ DE PRÉPARATION DE N-(β-L-RHAMNOPYRANOSYL)FÉRULAMIDE ET SON UTILISATION Ceased WO2021143812A1 (fr)

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Citations (4)

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Publication number Priority date Publication date Assignee Title
US4337249A (en) * 1981-08-03 1982-06-29 American Cyanamid Company Modulators of the complement system
CN101591364A (zh) * 2008-05-30 2009-12-02 中国药科大学 氨基糖衍生物、其制法及其医药用途
CN107141236A (zh) * 2017-04-24 2017-09-08 台州职业技术学院 替卡格雷中间体(1r,2r)‑2‑(3,4‑二氟代苯基)环丙烷腈的新合成方法
CN110117302A (zh) * 2018-02-06 2019-08-13 上海东西智荟生物医药有限公司 神经退行性疾病的治疗药物及其应用

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* Cited by examiner, † Cited by third party
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CN104958287B (zh) * 2015-05-28 2019-01-22 四川大学 一种阿魏酸衍生物作为神经保护药物的用途

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4337249A (en) * 1981-08-03 1982-06-29 American Cyanamid Company Modulators of the complement system
CN101591364A (zh) * 2008-05-30 2009-12-02 中国药科大学 氨基糖衍生物、其制法及其医药用途
CN107141236A (zh) * 2017-04-24 2017-09-08 台州职业技术学院 替卡格雷中间体(1r,2r)‑2‑(3,4‑二氟代苯基)环丙烷腈的新合成方法
CN110117302A (zh) * 2018-02-06 2019-08-13 上海东西智荟生物医药有限公司 神经退行性疾病的治疗药物及其应用

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