WO2019154196A1 - 用于防治神经退行性疾病的新化合物及其应用 - Google Patents

用于防治神经退行性疾病的新化合物及其应用 Download PDF

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WO2019154196A1
WO2019154196A1 PCT/CN2019/073777 CN2019073777W WO2019154196A1 WO 2019154196 A1 WO2019154196 A1 WO 2019154196A1 CN 2019073777 W CN2019073777 W CN 2019073777W WO 2019154196 A1 WO2019154196 A1 WO 2019154196A1
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compound
formula
pharmaceutically acceptable
solvate
precursor
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PCT/CN2019/073777
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English (en)
French (fr)
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裴钢
俞飚
黄世超
曹鑫
石富春
周悦
安玉谦
陆婧
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上海东西智荟生物医药有限公司
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Priority to US16/967,092 priority Critical patent/US11578092B2/en
Priority to EP19751719.6A priority patent/EP3751002A4/en
Priority to KR1020207024600A priority patent/KR20200118075A/ko
Priority to AU2019217292A priority patent/AU2019217292B2/en
Priority to JP2020543031A priority patent/JP7382944B2/ja
Priority to RU2020128412A priority patent/RU2791317C2/ru
Publication of WO2019154196A1 publication Critical patent/WO2019154196A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/18—Acyclic radicals, substituted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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

Definitions

  • the present invention is in the field of pharmacy, and more particularly, the present invention relates to novel compounds for the prevention and treatment of neurodegenerative diseases and uses thereof.
  • a neurodegenerative disease is a general term for a group of diseases caused by degenerative degeneration of chronic progressive central nervous tissue.
  • the main diseases include Parkinson's Disease (PD), Alzheimer's Disease (AD), Huntington Disease (HD), Amyotrophic Lateral Sclerosis (ALS) and the like.
  • AD Alzheimer's disease
  • AD Alzheimer's disease
  • a ⁇ amyloid- ⁇
  • a ⁇ oligomerized A ⁇
  • cascade reactions including free radical reactions, mitochondrial oxidative damage and inflammatory responses acting directly or indirectly on neurons and glial cells), leading to synaptic dysfunction and neuronal damage, and causing activation of microglia and astrocytes , accelerate the formation of nerve fiber tangles, leading to cognitive impairment after long-term effects.
  • a large number of recent studies have provided a variety of evidence to support the "A ⁇ hypothesis", showing the central role of A ⁇ in the pathogenesis of Alzheimer's disease.
  • Parkinson’s disease is a common neurodegenerative disease. It is clinically characterized by slow response, tremors, stiff body, and further loss of balance. Brain tissue studies in PD patients have found that the substantia nigra dopaminergic neurons in the disease patients are lost. Lewy inclusions are one of the hallmarks of degenerative neurons in Parkinson's disease. Studies have shown that many neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and DLB (Dementia with Lewy Body) Lewy inclusion bodies are formed in the brain tissue of patients.
  • neural progenitor cells In the mammalian brain, the proliferation and self-renewal of neural progenitor cells (NPCs) lasts throughout the life process and is an important part of nerve regeneration.
  • NPCs neural progenitor cells
  • AD Alzheimer's Disease
  • Promoting nerve regeneration is considered a potential treatment for anti-aging and aging-related neurodegenerative diseases. Therefore, one possible approach is to transplant embryonic neural stem cells or neural stem cells induced in vitro for cell replacement therapy. However, this new and complex technology is still controversial, especially their safety issues and cell sources.
  • Another approach is to use pharmacological means to activate endogenous neural stem cells for the purpose of treating neurodegenerative diseases.
  • Pharmacological methods are simple to operate and can specifically target specific functions of neural stem cells. Therefore, activation of endogenous neural stem cells is not only a viable treatment, but also a preventive measure. However, those skilled in the art also need to find a suitable drug that can better cross the internal barrier to effectively activate endogenous neural stem cells, thereby achieving effective treatment.
  • R1 to R4 are independently selected from: hydrogen, hydroxy, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, halogen, or R1 to R4 Two adjacent groups are linked to each other and form a ring structure together with the parent ring; R1' to R3' are independently selected from: hydrogen, hydroxyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl And a halogen, or two adjacent groups of R1' to R3' are connected to each other and form a ring structure with the parent ring.
  • the compound of the formula (I) or an isomer, solvate or precursor thereof, or a pharmaceutically acceptable salt thereof includes a ring structure selected from the group consisting of:
  • R1 to R4 are independently selected from the group consisting of hydrogen and hydroxyl groups. a C1-C2 alkyl group, or two adjacent groups of R1 to R4 are bonded to each other, and a parent ring constitutes a five-membered ring; and R1' to R3' are independently selected from hydrogen, a hydroxyl group, a C1-C2 alkyl group, or Two adjacent groups of R1' to R3' are connected to each other and form a five-membered ring with the parent ring.
  • the compound of the formula (I) or an isomer, solvate or precursor thereof, or a pharmaceutically acceptable salt thereof wherein the five-membered ring is O-containing Ring; preferably, the five-membered ring contains two O's.
  • the compound of the formula (I) or an isomer, solvate or precursor thereof, or a pharmaceutically acceptable salt thereof comprises:
  • the use of the compound of formula (I) or an isomer, solvate or precursor thereof, or a pharmaceutically acceptable salt thereof, for the prophylaxis, amelioration or treatment A drug or kit of neurodegenerative diseases, depression, or stroke.
  • the neurodegenerative disease is:
  • a neurodegenerative disease characterized by a significant reduction in neural stem cells.
  • the intracerebral neuroinflammation is characterized by a significant increase in inflammatory factor expression; such inflammatory factors such as IL-6 and IL-1 ⁇ .
  • the neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, and Lewy body dementia (DLB).
  • DLB Lewy body dementia
  • a pharmaceutical composition comprising: the compound of the formula (I) or an isomer, solvate or precursor thereof, or a pharmaceutically thereof thereof An acceptable salt; and a pharmaceutically acceptable carrier.
  • the compound of the formula (I) or an isomer, solvate or precursor thereof, or a pharmaceutically acceptable salt thereof is an effective amount in the pharmaceutical composition; preferably Preferably, the effective amount is 0.01-50% by weight, such as, but not limited to, 0.01-5%, 0.03-3%, 0.05-1%, 20-30%, 40-50%, etc. More preferably, it is 0.03-30%; further more preferably 0.05-10%.
  • the pharmaceutical composition provides a dosage form comprising: a powder, a powder, a tablet, a pill, a capsule, a sustained release, an immediate release, an injection, an infusion, and a suspension.
  • kits comprising: the compound of the formula (I) or an isomer, solvate or precursor thereof, or a pharmaceutically thereof thereof An acceptable salt; or a pharmaceutical composition as described.
  • a method of preventing, ameliorating or treating a neurodegenerative disease, depression or stroke comprising: administering to a subject in need of treatment an effective amount of the formula (I) a compound or an isomer, solvate or precursor thereof, or a pharmaceutically acceptable salt thereof.
  • a process for the preparation of a compound of formula II which comprises the steps of reacting a pyridine rhamnoside (disaccharide) with tetrabutylammonium fluoride to give a structure such as The compound shown in (II).
  • the pyridine rhamnoside (disaccharide) is obtained by reacting pyranyl rhamnoside (disaccharide) with (4-O-tert-butyldimethylsilyl)- It is obtained by the reaction of Wei acid.
  • the pyranyl rhamnosyl glucoside (disaccharide) is obtained by reacting pyranyl rhamnoside (monosaccharide) with 1-O-trichloroacetimidate-2,3,4 -O-triacetyl rhamnose is obtained by reaction.
  • Compound A reduction reaction (more specifically, a reaction for removing the protection of the o-diol propylene) is carried out to obtain a compound represented by the formula (III) or (IV).
  • the compound By including compounds And compound The step of condensation is obtained;
  • P is H or a protecting group; preferably the protecting group comprises a group selected from the group consisting of AII, Boc, TBS, Ac, Bn, PMB, Cbz; said protecting group can be reduced to H.
  • the compound By including compounds And compound The steps of addition and o-glycol-propylidene protection are obtained.
  • Figure 5 Effect of PL404 on proliferation of human neural stem cells.
  • the inventors have intensively studied that the compound of formula (I) can significantly ameliorate the symptoms of neurodegenerative diseases.
  • the compounds of formula (I) are effective in promoting the proliferation of neural stem cells; they can not only prevent, but also serve as a treatment to promote nerve regeneration to combat cognition related to aging and neurodegenerative diseases. The function is down.
  • alkyl refers to a straight or branched saturated aliphatic hydrocarbon group containing from 1 to 4 carbon atoms, preferably from 1 to 2 carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl.
  • alkenyl as used herein, includes straight-chain and branched hydrocarbon groups containing at least one carbon-carbon double bond and 2 to 4 carbon atoms, preferably 2 to 3 carbon atoms.
  • alkynyl as used herein includes both straight-chain and branched hydrocarbon groups containing at least one carbon-carbon triple bond and from 2 to 4 carbon atoms, preferably from 2 to 3 carbon atoms.
  • halogen refers to F, Cl, Br, or I.
  • isomer as used herein includes: geometric isomers, enantiomers, diastereomers (eg, cis and trans isomers, conformational isomers).
  • P denotes H or a protecting group; preferably the protecting group comprises a group selected from the group consisting of AII, Boc, TBS, Ac, Bn, PMB, Cbz; said protecting group Can be restored to H. Also, among different compounds, the choice of protecting groups may be the same or different. Even in the same batch of reactions, different compounds or P groups at different positions of the same compound may be different.
  • solvate denotes a compound carrying a solvent molecule, for example, the solvate may be a hydrate.
  • the term "containing” means that the various ingredients can be used together in the mixture or composition of the present invention. Therefore, the terms “consisting essentially of” and “consisting of” are encompassed by the term “contains.”
  • a "pharmaceutically acceptable" ingredient is a substance which is suitable for use in humans and/or animals without excessive adverse side effects (e.g., toxicity, irritation, and allergy), i.e., has a reasonable benefit/risk ratio.
  • a "pharmaceutically acceptable carrier” is a method for delivering a compound, an isomer, a solvate, a precursor, or a pharmaceutically acceptable salt thereof of the formula (I) of the present invention to an animal or a human.
  • the carrier can be a liquid or a solid.
  • the present invention first provides a compound of formula (I):
  • the position of X is a schematic position, and is not limited to one side of R1 or R1' in the figure, and may exist between R1 and R3, between R3 and R4, and R2 and Between groups, R4 and Between groups; it can also exist between R2' and R3'R1' Between, R2' and Between, R3' and Between groups, for example, the compound can also be:
  • R1 to R4 are independently selected from: hydrogen, hydroxy, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, halogen, or R1 to R4 Two adjacent groups are linked to each other and form a ring structure together with the parent ring; R1' to R3' are independently selected from: hydrogen, hydroxyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl And a halogen, or two adjacent groups of R1' to R3' are connected to each other and form a ring structure with the parent ring.
  • R1 to R4 are independently selected from the group consisting of hydrogen, a hydroxyl group, and a C1-C2 alkyl group, or two adjacent groups of R1 to R4 are bonded to each other, and a parent ring constitutes a five-membered ring;
  • ' ⁇ R3' is independently selected from the group consisting of hydrogen, hydroxy, C1-C2 alkyl, or two adjacent groups of R1' to R3' are bonded to each other and form a five-membered ring with the parent ring.
  • the present invention also includes isomers, solvates, precursors, or pharmaceutically acceptable salts thereof of the above compounds of the formula (I), as long as they also have the same or substantially the same functions as the compounds of the formula (I).
  • pharmaceutically acceptable salt means a salt formed by reacting a compound with an inorganic acid, an organic acid, an alkali metal or an alkaline earth metal.
  • salts include, but are not limited to, (1) salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid; (2) salts with the following organic acids, such as acetic acid, oxalic acid, succinic acid, tartaric acid , methanesulfonic acid, maleic acid, or arginine.
  • Other salts include those formed with alkali or alkaline earth metals such as sodium, potassium, calcium or magnesium, in the form of esters, carbamates, or other conventional "prodrugs".
  • the compound has one or more asymmetric centers. Therefore, these compounds may exist as racemic mixtures, individual enantiomers, individual diastereomers, diastereomeric mixtures, cis or trans isomers.
  • precursor of a compound means a compound which is converted into a structural formula (I) by a metabolic or chemical reaction of a precursor of the compound in a patient after administration by an appropriate method, or a chemical structural formula (I). a salt or solution of a compound.
  • the five-membered ring is an O-containing hetero ring; preferably, the five-membered ring contains two O.
  • the compound includes the following compounds of the formulae (II) to (IV), wherein the compound of the formula (II) is particularly preferred.
  • the method of preparing a compound of formula II comprises the steps of:
  • 1-O-trichloroacetimidate-2,3,4-O-triacetyl rhamnose and glucopyranin glucoside are mixed to obtain a structure such as V-form.
  • a pyran rhamnoside (disaccharide) product is mixed to obtain a structure such as V-form.
  • a pyran rhamnoside (disaccharide) product having the structure shown in Formula V is mixed with (4-O-tert-butyldimethylsilyl)-ferulic acid to obtain a structure such as a product of a pyran rhamnoside (disaccharide) of formula VI;
  • a pyran rhamnoside (disaccharide) product having the structure shown in Formula VI is mixed with tetrabutylammonium fluoride to obtain a de-tert-butyldimethylsilyl group having a structure such as VII. TBS) product;
  • the de-tert-butyldimethylsilyl (TBS) product is hydrolyzed to give a compound of formula II;
  • the first step reaction is carried out by adding 1-O-trichloroacetimide-2,3,4- to pyranyl rhamnosylose (monosaccharide) at -78 °C. O-triacetyl rhamnose.
  • the second step of the above reaction is carried out by adding a pyridine rhamnoside (disaccharide) to (4-O-tert-butyldimethylsilyl)-ferulic acid at -78 °C. ).
  • the mixing in the third step above is the dropwise addition of tetrabutylammonium fluoride to the pyridine rhamnoside (disaccharide) product at room temperature.
  • the method of preparing a compound of Formula III or Formula IV comprises the steps of:
  • the first step the compound And compound Performing an addition reaction to obtain an addition product
  • the second step the addition product of the first step is subjected to an o-glycol-propane protection reaction to obtain a stable reaction product at a specific position;
  • the third step the reaction product of the second step Carrying out a condensation reaction to obtain a condensation product;
  • the fourth step a reduction reaction of the condensation product, which is more specifically a reaction for removing the protection of the o-glycol-propion, thereby obtaining a compound represented by the formula (III) or (IV).
  • the compounds of the present invention can be obtained by a variety of methods well known in the art, using known starting materials, such as chemical synthesis or from organisms (such as animals or plants). The method of extraction, which is included in the present invention.
  • the synthesized compound can be further purified by column chromatography, high performance liquid chromatography or the like.
  • the present inventors have found in the study that the compound of the formula (I) of the present invention can significantly improve the symptoms of neurodegenerative diseases and is also effective for depression and stroke.
  • the compound of the present invention is capable of inhibiting neuroinflammation, reducing A ⁇ production, and promoting neural stem cell production.
  • the compounds of the present invention have a significant improvement in the learning and memory ability of animals.
  • An increase in neural stem cells will in turn promote an increase in neurons, a process known as neurogenesis.
  • the mechanism of action of the compound of the present invention it is capable of increasing neural stem cells, and thus it is also effective for Huntington's disease and amyotrophic lateral sclerosis.
  • the mechanism of action of the compound according to the present invention is also effective for depression and stroke.
  • the compound of the formula (I) of the invention is capable of increasing neural stem cells, and it is understood that it is also effective for depression and stroke.
  • the present invention provides the use of a compound of the formula (I) or an isomer, a solvate thereof, a precursor thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a prophylactic, A drug or kit that relieves or treats a neurodegenerative disease, depression, or stroke.
  • the present invention also provides the use of a compound of the formula (I) or an isomer, solvate or precursor thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a composition, a kit or a kit for inhibiting neuroinflammation Pill box.
  • the present invention also provides the use of a compound of the formula (I) or an isomer, solvate or precursor thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a composition, a kit for promoting neural stem cell production Or a pill box.
  • the present invention also provides the use of a compound of the formula (I) or an isomer, solvate or precursor thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a composition, a kit or a kit for reducing A ⁇ production. Pill box.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising: (a) an effective amount of the compound of the formula (I), or an isomer, solvate, precursor thereof, or a pharmaceutically acceptable salt thereof And (b) a pharmaceutically acceptable carrier or excipient.
  • the content of the compound of the formula (I) or an isomer, solvate or precursor thereof, or a pharmaceutically acceptable salt thereof, of the pharmaceutical composition is an effective amount.
  • the compound of the formula (I) or a pharmaceutically acceptable salt thereof may be contained in an amount of from 0.001 to 50% by weight.
  • the pharmaceutical composition contains 0.01 to 20% by weight of the compound of the formula (I) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the present invention may be in a variety of dosage forms as long as it is a dosage form capable of efficiently reaching the mammalian body.
  • it can be selected from the group consisting of powders, powders, tablets, pills, capsules, sustained release agents, controlled release agents, injections, infusion solutions, and suspensions. Based on the type of disease to which the compounds of the present invention are treated, one skilled in the art can select a dosage form that is convenient to use.
  • preferred pharmaceutical compositions are solid compositions, especially tablets and solid filled or liquid filled capsules. From the standpoint of the granule length which is easy to administer, the preferred pharmaceutical composition is an oral preparation.
  • the compounds of the invention or pharmaceutical compositions thereof may also be stored in a sterilizing device suitable for injection or drip.
  • the effective administration dose of the compound of the formula (I) as an active ingredient may vary depending on the mode of administration and the severity of the disease to be treated. However, usually, when the compound of the present invention is administered at a dose of about 0.01 to 100 mg/kg of animal body weight per day, a satisfactory effect can be obtained, preferably at a dose of 1-3 divided times per day, or in a sustained release form. Dosing. This dosage regimen can be adjusted to provide an optimal therapeutic response. For example, several separate doses may be administered per day, or the dose may be proportionally reduced, as is critical to the condition of the treatment.
  • the above product (165 mg, 0.27 mmol) was dissolved in a mixed solution of 8 mL of anhydrous CH 3 OH and anhydrous CH 2 Cl 2 (1:1), and a catalytic amount of sodium methoxide (0.2 eq.) was added to adjust the pH to 9 to 10, the reaction was stirred at 40 ° C for 5 hours, and neutralized by neutralization with an acidic cationic resin. Filtration and concentration gave the product as a white solid.
  • the compound PL402 was obtained by dissolving in 1 mL of water and chromatography on a reversed silica gel column to afford 78 mg (0.16 mmol);
  • the identification map of PL402 is shown in Fig. 8.
  • the identification map of PL404 is shown in Fig. 9.
  • the identification map of PL405 is shown in Fig. 10.
  • Example 3 PL402 improves learning and memory ability of AD mice
  • APP/PS1 transgenic male mice aged 5-6 months were selected and divided into model group and polysaccharide administration group according to the random number table method.
  • PL402 was administered by intragastric administration and administered daily (50 mg). /kg), 10 non-transgenic mice were used as a negative control group (not administered). After 90 days of continuous administration, Morris water maze behavioral experiments were used to detect the learning and cognitive function of PL402 in APP/PS1 mice. Impact.
  • This experiment uses the classic Morris water maze test procedure, which consists of two parts, the positioning navigation test and the space exploration test. A total of 7 days, 4 days and 7 days were added to the space exploration test.
  • mice in the model group were slow to respond, and there was a circle along the barrel wall after entering the water. There is no escape behavior. After artificially leading it to the platform, it jumps into the water. After many trainings, the platform is finally found, but the latency of finding the platform is obviously prolonged.
  • the ability of the mice in the drug-administered group to find the platform with the increase of the number of trainings Continuous improving.
  • the above three groups all had certain spatial memory ability.
  • the latency of the model group mice was worse than that of the control group, suggesting that the learning and memory ability of the model group mice decreased, and the model mice better simulated the learning and memory impairment of AD.
  • the latency of the mice in the drug-administered group was significantly different from that in the model group. It can be seen that the learning and memory ability of AD mice was significantly improved after PL402 administration.
  • each mouse was intragastrically administered with PL402, and 100 l was administered at a concentration of 50 mg/kg of mouse body weight; another reference group was given, and 100 l of water was administered by gavage.
  • continuous administration for 90 days, and 50 mg/kg of mouse body weight of 5-bromo-2'-deoxyuridine (BrdU) was started intraperitoneally on day 60, once daily for 7 days.
  • the mice were anesthetized with paraformaldehyde (PFA) and perfused for whole brain examination.
  • PFA paraformaldehyde
  • Example 4 PL402 inhibits neuroinflammation
  • Neuroinflammation in the AD brain is one of the causes of cognitive decline.
  • Microglia are key cells that mediate neuroinflammation.
  • the present inventors investigated whether PL402 has an inhibitory effect on neuroinflammation by detecting the expression of inflammatory factors on BV-2 cells.
  • BV-2 cells were cultured in DMEM and plated in 24-well plates for 24 hours.
  • PL402 (0, 10, 30, 100, 300 ⁇ M) and LPS (300 ng) were added. /ml), after incubation for 24 hours, Trizol extracted RNA and detected the expression of related inflammatory factors by QPCR.
  • Example 5 PL402 reduces A ⁇ generation
  • a ⁇ is the major causative protein of AD.
  • the present inventors investigated whether PL402 has an effect of inhibiting the reduction of A ⁇ production by detecting the level of A ⁇ in SK-N-SH cells (which can secrete A ⁇ by itself).
  • SK-N-SH cells were cultured in DMEM, and cultured in 24-well plates for 24 hours, then PL402 was added (0, 10, 30, 100, 300 ⁇ M) After the addition, the cells were incubated for 24 hours, the supernatant was taken out, and the protein level of total A ⁇ was measured by ELISA.
  • Example 6 the effect of PL404 on animal learning and memory ability
  • the animals were selected in the same manner as in the foregoing Example 3 and the "Morris water maze test" was carried out to examine the effect of PL404 on the learning and memory ability of the animals.
  • AD mice Therefore, the learning and memory ability of AD mice was significantly improved after PL404 administration.
  • Example 7 the effect of PL404 on the proliferation of human neural stem cells
  • the present inventors investigated whether PL404 has a function of promoting proliferation by detecting the incorporation of human neural stem cells (human iPSC differentiation) EdU.
  • PL404 dosage 0, 1, 3, 10, 30, 100 ⁇ M.
  • Example 8 the effect of PL405 on the proliferation of human neural stem cells
  • Example 7 A method similar to that of Example 7 was employed, except that the compound was replaced with PL404 by PL405, and by detecting the incorporation of human neural stem cells EdU, it was examined whether PL405 has an effect of promoting proliferation.

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Abstract

本发明涉及用于防治神经退行性疾病的新化合物及其应用。提供了一种新型的式(I)化合物，在体外和体内实验中，其均能有效促进神经干细胞的增殖；其还能作为一种促进神经再生的治疗手段，对抗衰老和神经退行性疾病相关的认知功能下降。

Description

用于防治神经退行性疾病的新化合物及其应用 技术领域
本发明属于药学领域，更具体地，本发明涉及用于防治神经退行性疾病的新化合物及其应用。
背景技术
神经退行性疾病是指一组由慢性进行性的中枢神经组织退行性变性而产生的疾病的总称。主要疾病包括帕金森病(Parkinson’s Disease，PD)、阿尔茨海默病(Alzheimer’s Disease，AD)、亨廷顿病(Huntington Disease，HD)、肌萎缩侧索硬化症(Amyotrophic Lateral Sclerosis，ALS)等。
阿尔茨海默症(Alzheimer’s disease，AD)亦称为早老性痴呆，是一种慢性进行性的神经退行性疾病，主要表现为渐进性的记忆能力下降，认知功能障碍以及失去生活独立自理能力。随着人口老龄化的不断加剧，AD的发病率也逐年升高，已成为最重要的公众关注健康问题。阿尔兹海默症的主要病理学特征为病人大脑内形成的淀粉样蛋白斑和神经纤维丝缠结。淀粉样蛋白斑是阿尔兹海默症的特征性病理学变化，主要由细胞内异常大量产生的淀粉样蛋白-β(Aβ)蛋白在细胞外积聚形成的。目前，有多个理论试图解释其致病机理。Hardy和Selkoe提出的“Aβ假说”是目前被广为接受的理论。该理论认为，在复杂的遗传和环境因素长期作用下，神经细胞异常地大量产生Aβ，积累形成寡聚体和淀粉样蛋白斑，Aβ(尤其是寡聚化的Aβ)通过一系列级联反应(包括自由基反应、线粒体氧化损伤和炎症反应等直接或间接地作用于神经元和胶质细胞)，导致突触功能异常和神经元损伤，并且引起小胶质细胞和星型胶质细胞激活，加速神经纤维丝缠结的形成，长期作用后导致认知障碍。近期大量研究提供了多方面的证据支持“Aβ假说”，显示了Aβ在阿尔兹海默症致病机理中的核心作用。
帕金森症(Parkinson’s disease)是一种常见的神经退行性疾病，在临床上，它主要表现为反应迟缓，震颤，机体僵硬，进一步失去平衡等症状。对PD病人脑组织研究发现，疾病患者中脑黑质多巴胺能神经元丧失。Lewy包涵体是帕金森病中变性神经元的标志性病变之一，研究表明，许多神经退行性疾病，包括阿尔茨海默症(Alzheimer’s disease)、帕金森症和DLB症(Dementia with Lewy Body)等病人脑组织中都有Lewy包涵体形成。
在哺乳动物大脑中，神经干细胞(Neural Progenitor Cells，NPC)的增殖和自我更新持续于整个生命过程，是神经再生(Neurogenesis)的重要环节。在衰老、 长期压力以及神经系统疾病，比如阿尔兹海默症(Alzheimer’s Disease，AD)发生的情况下，神经干细胞的增殖和自我更新能力下降，导致认知功能受损。促进神经再生被认为是抵抗衰老和衰老相关神经退行性疾病的潜在治疗手段。因此，一种可能的方案是移植胚胎神经干细胞或者体外诱导的神经干细胞来进行细胞替换疗法。但是，这种新创的复杂技术目前还存在一定争议，尤其是它们的安全性问题和细胞来源等问题。另一种方案是用药理学手段来激活内源的神经干细胞，以达到治疗神经退行性疾病的目的。药理学手段操作简便，并且可以特异性靶向神经干细胞的特定功能，因此，激活内源神经干细胞不仅是一种可行的治疗手段，还能作为预防手段。然而，本领域技术人员还需要找到合适的、能给较好地穿越体内屏障以有效激活内源神经干细胞的药物，从而实现有效的治疗。
发明内容
本发明的目的在于提供用于防治神经退行性疾病的新化合物及其应用。
在本发明的第一方面，提供式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐，
Figure PCTCN2019073777-appb-000001
其中，
Figure PCTCN2019073777-appb-000002
为六元杂环，X为O；R1～R4独立地选自：氢、羟基、C1-C4烷基、C2-C4链烯基、C2-C4链炔基、卤素，或R1～R4中相邻两个基团相互连接、并与母环共同构成环结构；R1’～R3’独立地选自：氢、羟基、C1-C4烷基、C2-C4链烯基、C2-C4链炔基、卤素，或R1’～R3’中相邻两个基团相互连接、与母环构成环结构。
在一个优选例中，所述的式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐，
Figure PCTCN2019073777-appb-000003
包括选自下组的环结构：
Figure PCTCN2019073777-appb-000004
Figure PCTCN2019073777-appb-000005
在一个优选例中，所述的式(I)所示化合物或其异构体、溶剂合物或前体， 或它们的药学上可接受的盐，
Figure PCTCN2019073777-appb-000006
包括环结构：
Figure PCTCN2019073777-appb-000007
在一个优选例中，所述的式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐，R1～R4独立地选自：氢、羟基、C1-C2烷基，或R1～R4中相邻两个基团相互连接、与母环构成五元环；R1’～R3’独立地选自：氢、羟基、C1-C2烷基，或R1’～R3’中相邻两个基团相互连接、与母环构成五元环。
在另一优选例中，所述的式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐，所述的五元环为含O杂环；较佳地，所述的五元环含有两个O。
在另一优选例中，所述的式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐，所述的化合物包括：
Figure PCTCN2019073777-appb-000008
在另一优选例中，所述的式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐的用途，用于制备预防、缓解或治疗神经退行性疾病、抑郁症或中风的药物或药盒。
在另一优选例中，神经退行性疾病是：
以脑内发生神经炎症为特征的神经退行性疾病；
以Aβ生成显著性增加为特征的神经退行性疾病；
以学习记忆能力显著性下降为特征的神经退行性疾病；或
以神经干细胞显著减少为特征的神经退行性疾病。
在另一优选例中，所述的脑内发生神经炎症以炎症因子表达显著性提高为特征；所述的炎症因子如IL-6和IL-1β。
在另一优选例中，所述的神经退行性疾病包括：阿尔茨海默症，帕金森症，路易体痴呆(DLB症)。
在本发明的另一方面，提供所述的式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐的用途，用于制备抑制神经炎症的组合物、试剂盒或药盒。
在本发明的另一方面，提供所述的式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐的用途，用于制备促进神经干细胞生成的组合物、试剂盒或药盒。
在本发明的另一方面，提供所述的式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐的用途，用于制备降低Aβ生成的组合物、试剂盒或药盒。
在本发明的另一方面，提供一种药物组合物，所述的药物组合物包含：所述的式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐；和药学上可接受的载体。
在一个优选例中，所述的式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐在药物组合物中是有效量的；较佳地，较佳地，所述的有效量按照重量含量为0.01-50％，例如但不限于，0.01-5％、0.03-3％、0.05-1％、20-30％、40-50％等；更佳地为0.03-30％；进一步更佳地为0.05-10％。
在本发明的另一方面，提供所述的药物组合物的剂型包括：粉剂、散剂、片剂、丸剂、胶囊剂、缓释剂、控速释剂、注射剂、输液剂、混悬剂。
在本发明的另一方面，提供一种药盒，所述的药盒中包括：所述的式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐；或所述的药物组合物。
在本发明的另一方面，提供一种预防、缓解或治疗神经退行性疾病、抑郁症或中风的方法，所述方法包括：给予需要治疗的对象有效量的所述的式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐。
在本发明的另外一方面，提供了一种如式II所示的化合物的制备方法，所述方法包括步骤：使吡喃鼠李糖苷(二糖)与四丁基氟化铵反应得到结构如(II)所示的化合物。
Figure PCTCN2019073777-appb-000009
在另一优选例中，所述吡喃鼠李糖苷(二糖)是通过将吡喃鼠李糖硫苷(二糖)与(4-O-叔丁基二甲基甲硅烷基)-阿魏酸反应而得到。
在另一优选例中，所述吡喃鼠李糖硫苷(二糖)是通过将吡喃鼠李糖硫苷(单糖)与1-O-三氯乙酰亚胺-2,3,4-O-三乙酰基鼠李糖反应而得到。
在本发明的另一方面，提供一种如式(III)或(IV)所示的化合物的制备方法，所述方法包括步骤：
将化合物
Figure PCTCN2019073777-appb-000010
进行还原反应(更特别地为去除邻二醇丙叉保护的反应)，获得式(III)或(IV)所示的化合物。
在一个优选中，所述化合物
Figure PCTCN2019073777-appb-000011
通过包括将化合物
Figure PCTCN2019073777-appb-000012
与化合物
Figure PCTCN2019073777-appb-000013
缩合的步骤来获得；
其中P为H或保护基团；较佳地所述保护基团包括选自下组的基团：AII，Boc，TBS，Ac，Bn，PMB，Cbz；所述的保护基团可被还原为H。
在另一优选例中，所述化合物
Figure PCTCN2019073777-appb-000014
通过包括将化合物
Figure PCTCN2019073777-appb-000015
与化合物
Figure PCTCN2019073777-appb-000016
加成以及邻二醇丙叉保护反应的步骤来获得。
本发明的其它方面由于本文的公开内容，对本领域的技术人员而言是显而易见的。
附图说明
图1、PL402改善AD小鼠Morris水迷宫指标。
图2、PL402抑制神经炎症。
图3、PL402减少Aβ生成。
图4、PL404对动物学习记忆能力的影响。
图5、PL404对人源神经干细胞增殖的影响。
图6、PL405对人源神经干细胞增殖的影响。
图7、化合物5的鉴定图。
图8、PL402的鉴定图。
图9、PL404的鉴定图。
图10、PL405的鉴定图。
具体实施方式
本发明人经过深入的研究，式(I)化合物能够显著改善神经退行性疾病的症状。在体外和体内实验中，式(I)化合物均能有效促进神经干细胞的增殖；其不仅能够预防，还能作为一种促进神经再生的治疗手段，来对抗衰老和神经退行性疾病相关的认知功能下降。
术语
本文所用的术语“烷基”指直链或支链饱和的、含有1-4个碳原子(较佳地1-2个碳原子)的脂族烃类基团。例如，烷基包括但不限于甲基，乙基，正丙基，异丙基，正丁基，异丁基，叔丁基。
本文所用的术语“链烯基”包括含有至少一个碳碳双键和2-4个碳原子(较佳地2-3个碳原子)的直链和支链烃基。
本文所用的术语“链炔基”包括含有至少一个碳碳三键和2-4个碳原子(较佳地2-3个碳原子)的直链和支链烃基。
本文所用的术语“卤素”指F、Cl、Br、或I。
本文所用的术语“异构体”包括：几何异构体、对映异构体、非对映异构体(如顺反异构体，构象异构体)。
本文所用的
Figure PCTCN2019073777-appb-000017
的表示方法是本领域人员熟知的，其表示一个带有X原 子的杂环。在本发明的优选方式中，所述的
Figure PCTCN2019073777-appb-000018
为六元杂环。
本文所用的
Figure PCTCN2019073777-appb-000019
的表示方法是本领域人员熟知的，其表示基团可选的R1～R4取代在环上的任意一个或多个可被取代的位置。并且，在不同的取代位置上，基团的选择可以是不同的。
本文所用的
Figure PCTCN2019073777-appb-000020
的表示方法是本领域人员熟知的，其表示基团可选的R1’～R3’取代在环上的任意一个或多个可被取代的位置。并且，在不同的取代位置上，基团的选择可以是不同的。
本文所用的“P”表示H或保护基团；较佳地所述保护基团包括选自下组的基团：AII，Boc，TBS，Ac，Bn，PMB，Cbz；所述的保护基团可被还原为H。并且，不同的化合物中，保护基团的选择可以是相同的或是不同的。即使在同一批次的反应中，不同化合物或同一化合物的不同位置上的P基团也可以是不同的。
本文所用的术语“溶剂合物”表示携带有溶剂分子的化合物，例如，所述的溶剂合物可以是水合物。
本发明中，术语“含有”表示各种成分可一起应用于本发明的混合物或组合物中。因此，术语“主要由...组成”和“由...组成”包含在术语“含有”中。
本发明中，“药学上可接受的”成分是适用于人和/或动物而无过度不良副反应(如毒性、刺激和变态反应)即有合理的效益/风险比的物质。
本发明中，“药学上可接受的载体”是用于将本发明的式(I)化合物、异构体、溶剂合物、前体，或它们的药学上可接受的盐传送给动物或人的药学上或食品上可接受的溶剂、悬浮剂或赋形剂。载体可以是液体或固体。
化合物
本发明首先提供了一种如结构式(I)所示的化合物：
Figure PCTCN2019073777-appb-000021
应理解，式(I)中，X的位置为示意的位置，并不限于图中R1或R1’的一侧，其也可以存在于，R1与R3之间，R3与R4之间，R2与
Figure PCTCN2019073777-appb-000022
基团之间，R4与
Figure PCTCN2019073777-appb-000023
基团之间；其也可以存在于R2’与R3’之间R1’与
Figure PCTCN2019073777-appb-000024
之间，R2’与
Figure PCTCN2019073777-appb-000025
之间，R3’与
Figure PCTCN2019073777-appb-000026
基团之间，例如，该化合物也可以是：
Figure PCTCN2019073777-appb-000027
其中，
Figure PCTCN2019073777-appb-000028
为六元杂环，X为O；R1～R4独立地选自：氢、羟基、C1-C4烷基、C2-C4链烯基、C2-C4链炔基、卤素，或R1～R4中相邻两个基团相互连接、并与母环共同构成环结构；R1’～R3’独立地选自：氢、羟基、C1-C4烷基、C2-C4链烯基、C2-C4链炔基、卤素，或R1’～R3’中相邻两个基团相互连接、与母环构成环结构。
作为本发明的一种优选方式，R1～R4独立地选自：氢、羟基、C1-C2烷基，或R1～R4中相邻两个基团相互连接、与母环构成五元环；R1’～R3’独立地选自：氢、羟基、C1-C2烷基，或R1’～R3’中相邻两个基团相互连接、与母环构成五元环。
本发明还包括上述式(I)化合物的异构体、溶剂合物、前体，或它们的药学上可接受的盐，只要它们也具有与式(I)化合物具有相同或基本相同的功能。所述的“药学上可接受的盐”是指化合物与无机酸、有机酸、碱金属或碱土金属等反应生成的盐。这些盐包括(但不限于)：(1)与如下无机酸形成的盐：如盐酸、硫酸、硝酸、磷酸；(2)与如下有机酸形成的盐，如乙酸、草酸、丁二酸、酒 石酸、甲磺酸、马来酸、或精氨酸。其它的盐包括与碱金属或碱土金属(如钠、钾、钙或镁)形成的盐，以酯、氨基甲酸酯，或其它常规的“前体药物”的形式。化合物具有一个或多个不对称中心。所以，这些化合物可以作为外消旋的混合物、单独的对映异构体、单独的非对映异构体、非对映异构体混合物、顺式或反式异构体存在。
所述的“化合物的前体”指当用适当的方法服用后，该化合物的前体在病人体内进行代谢或化学反应而转变成结构式(I)的一种化合物，或化学结构式(I)的一个化合物所组成的盐或溶液。
作为本发明的优选方式，所述的五元环为含O杂环；较佳地，所述的五元环含有两个O。
作为本发明的优选方式，所述的化合物包括以下的式(II)～(IV)的化合物，其中式(II)化合物是特别优选的。
Figure PCTCN2019073777-appb-000029
又称PL402；
Figure PCTCN2019073777-appb-000030
又称PL404；
Figure PCTCN2019073777-appb-000031
又称PL405。
在本发明的一种实施方式中，式II化合物的制备方法包括步骤：
第一步，将1-O-三氯乙酰亚胺-2,3,4-O-三乙酰基鼠李糖和吡喃鼠李糖硫苷(单糖)混合，反应得到结构如Ⅴ式所示的吡喃鼠李糖硫苷(二糖)产物；
Figure PCTCN2019073777-appb-000032
第二步，将结构如式Ⅴ所示的吡喃鼠李糖硫苷(二糖)产物与(4-O-叔丁基二甲基甲硅烷基)-阿魏酸混合，反应得到结构如Ⅵ式所示吡喃鼠李糖苷(二糖)的 产物；
Figure PCTCN2019073777-appb-000033
第三步，将结构如式Ⅵ所示的吡喃鼠李糖苷(二糖)产物与四丁基氟化铵混合，反应得到结构如Ⅶ式所示脱叔丁基二甲基甲硅烷基(TBS)产物；
Figure PCTCN2019073777-appb-000034
第四步，将脱叔丁基二甲基甲硅烷基(TBS)产物水解得到式II化合物；
在本发明的一个实施例中，上述第一步反应在-78℃下的吡喃鼠李糖硫苷(单糖)中滴入1-O-三氯乙酰亚胺-2,3,4-O-三乙酰基鼠李糖。
在本发明的一个实施例中，上述第二步反应在-78℃下的(4-O-叔丁基二甲基甲硅烷基)-阿魏酸中滴入吡喃鼠李糖苷(二糖)。
在本发明的一个实施例中，上述第三步中的混合是在室温下将四丁基氟化铵滴入吡喃鼠李糖苷(二糖)产物中。
在本发明的一种实施方式中，式III或式IV化合物的制备方法包括步骤：
第一步：将化合物
Figure PCTCN2019073777-appb-000035
与化合物
Figure PCTCN2019073777-appb-000036
进行加成反应，获得加成产物；
第二步：对第一步的加成产物进行邻二醇丙叉保护反应，获得特定位置上稳定的反应产物；
第三步：将第二步的反应产物与
Figure PCTCN2019073777-appb-000037
进行缩合反应，获得缩合产物；
第四步：对所述缩合产物进行还原反应，该还原反应更特别地为去除邻二醇丙叉保护的反应，从而获得式(III)或(IV)所示的化合物。
本领域人员应理解，在得知了本发明化合物的结构以后，可通过多种本领域熟知的方法、利用公知的原料，来获得本发明的化合物，比如化学合成或从生物(如动物或植物)中提取的方法，这些方法均包含在本发明中。
合成的化合物可以进一步通过柱层析法、高效液相色谱法等方式进一步纯 化。
用途
本发明人在研究中发现，本发明的式(I)化合物能够显著改善神经退行性疾病的症状，并对于抑郁症和中风也是有效的。本发明的化合物能够抑制神经炎症、降低Aβ生成、促进神经干细胞生成。经过实验论证，本发明的化合物对于动物的学习记忆能力有显著的改善。神经干细胞增加会进而会促进神经元的增加，该整个过程都称为神经发生。根据本发明的化合物的作用机制，其能够增加神经干细胞，因此其对于亨廷顿病、肌萎缩侧索硬化症也是有效的。根据本发明的化合物的作用机制，其对于抑郁症和中风也是有效的，抑郁症或中风发病过程中，也涉及脑内发生神经炎症的发生，进而引起神经干细胞的减少和神经功能的改变；本发明的式(I)化合物能够增加神经干细胞，籍此可以理解，其对于抑郁症和中风也是有效的。
基于本发明人的新发现，本发明提供了式(I)所示的化合物或其异构体、溶剂合物、前体，或它们的药学上可接受的盐的用途，用于制备预防、缓解或治疗神经退行性疾病、抑郁症或中风的药物或药盒。
本发明还提供了式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐的用途，用于制备抑制神经炎症的组合物、试剂盒或药盒。
本发明还提供了式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐的用途，用于制备促进神经干细胞生成的组合物、试剂盒或药盒。
本发明还提供了式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐的用途，用于制备降低Aβ生成的组合物、试剂盒或药盒。
药物组合物
本发明还提供了一种药物组合物，含有：(a)有效量的式(I)所述的化合物、或其异构体、溶剂合物、前体，或它们的药学上可接受的盐；和(b)药学上可接受的载体或赋形剂。
在本发明的中，所述的药物组合物中，式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐的含量是有效量。例如，可以含有按照重量比例为0.001-50％的式(I)所示的化合物或其药学上可接受的盐。较佳的，所述的药物组合物含有按照重量比例为0.01-20％的式(I)所示的化合物或其药学 上可接受的盐。
本发明所述的药物组合物的剂型可以是多种多样的，只要是能够使活性成分有效地到达哺乳动物机体的剂型都是可以的。比如可选自：粉剂、散剂、片剂、丸剂、胶囊剂、缓释剂、控速释剂、注射剂、输液剂、混悬剂。根据本发明的化合物所治疗的疾病类型，本领域人员可以选择方便应用的剂型。
从易于制备和储存的立场看，优选的药物组合物是固态组合物，尤其是片剂和固体填充或液体填充的胶囊。从易于给药的粒长看，优选的药物组合物是口服制剂。本发明的化合物或其药物组合物也可储存在适宜于注射或滴注的消毒器具中。
式(I)化合物作为活性成分的有效施用剂量可随给药的模式和待治疗的疾病的严重程度而变化。然而，通常当本发明的化合物每天以约0.01-100mg/kg动物体重的剂量给予时，能得到令人满意的效果，较佳地每天以1-3次分开的剂量给予，或以缓释形式给药。可调节此剂量方案以提供最佳治疗应答。例如，由治疗状况的迫切要求，可每天给予若干次分开的剂量，或将剂量按比例地减少。
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，通常按照常规条件如J.萨姆布鲁克等编著，分子克隆实验指南，第三版，科学出版社，2002中所述的条件，或按照制造厂商所建议的条件。
数据统计分析
下面的实施例中，所有实验数据表示为平均值±标准误差。不同处理组之间采用t检验进行比较。多组结果之间采用one-way ANOVA进行分析，并用Fisher’s protected least significant difference test或Bonferroni t test进行事后检验，或者采用two-way ANOVA进行分析，并用Tukey post hoc test进行事后检验。P<0.05时认为组间有显著性差异。
实施例1、化合物PL402的合成
Figure PCTCN2019073777-appb-000038
1、化合物3的制备
依文献J.Chem.Soc.，Perkin Trans.1，2000，1445-1453的方法，将化合物2(248mg，1.0mmol)(Organic and Biomolecular Chemistry,2014,vol.12,#7,p.1114-1123)、干燥的
Figure PCTCN2019073777-appb-000039
分子筛(250mg)与CH 2Cl 2(12mL)加入干燥反应瓶中，室温下搅拌10min，冷却至-78℃加入三氟甲磺酸三甲基硅酯(TMSOTf)(0.036mL，0.2mmol)的CH 2Cl 2溶液和化合物1(521mg，1.2mmol)(Journal of the American Chemical Society,2000,vol.122,#41,p.9939-9953)CH 2Cl 2溶液(2mL)。30分钟后加入Et 3N 0.1mL停止反应。过滤浓缩，柱层析(石油醚:乙酸乙酯＝3:1)得化合物3，获得468mg(0.9mmol)，收率90％。
1H NMR(300MHz；CDCl 3)5.51(s，1H)，5.33(d，1H，J＝1.7Hz)，5.30(dd，1H，J＝1.9Hz，3.3)，5.22(dd，1H，J 1＝3.3Hz，J 2＝10.1Hz)，5.08(t，1H，J＝10.0Hz)，4.21-4.13(m，2H)，4.06(m，1H)，3.89(m，1H)，3.56(dd，1H，J 1＝7.1Hz，J 2＝9.9Hz)，2.61(m，2H)，2.15(s，1H)，2.05(s，1H)，1.98(s，1H)，1.53(s，1H)，1.32(s，1H)，1.34-1.21(m，9H)；ESI-MS m/z 521(M+1) +。
2、化合物5的制备
将化合物4(
Figure PCTCN2019073777-appb-000040
308mg，1.0mmol)和
Figure PCTCN2019073777-appb-000041
分子筛混溶于干燥的CH 2Cl 2(20mL)中，室温下搅拌30min，冷却至-78℃，再搅拌30min，依 次加入N-碘代丁二酰亚胺(NIS)(225mg，1.0mmol)和TMSOTf(0.018mL，0.1mmol)，最后将溶于干燥CH 2Cl 2(DCM，20mL)中的化合物3(312mg，0.6mmol)缓慢滴入体系中，于-78℃搅拌反应20min后慢慢恢复室温搅拌。2小时后加入Na 2S 2O 3和NaHCO 3饱和溶液淬灭反应，过滤，乙酸乙酯萃取，饱和食盐水洗，无水Na 2SO 4干燥，过滤，浓缩，柱层析(石油醚:乙酸乙酯＝3:1)，得白色固体化合物5，获得368mg(0.48mmol)，得率80％。
1H NMR(400MHz；CDCl 3)7.52(d，1H，J＝12Hz),6.09-6.88(m,2H),6.69(d，1H，J＝8Hz),6.24(s，1H),6.14(d，1H，J＝8Hz),5.20-5.15(m,2H),5.03(d，1H，J＝8Hz),4.93-4.90(m,1H),4.14(dd，1H，J 1＝4Hz，J 2＝8Hz),3.99(d，1H，J＝4Hz),3.37-3.69(m,2H),3.68(s，3H),3.43(dd，1H，J 1＝4Hz，J 2＝8Hz),1.98(s，3H),1.89(s，3H),1.81(s，3H),1.38(s，3H),1.15(s，3H),1.11-1.05(m,6H),0.82(s，9H),0(s,6H)；ESI-MS m/z 767(M+1) +。
化合物5的鉴定图如图7。
3、化合物PL402的制备
称取化合物5(306mg，0.4mmol)溶于四氢呋喃(8mL)和醋酸(16μL，1.12mmol)，室温磁力搅拌下加入1M的四丁基氟化铵(TBAF)的四氢呋喃(THF)溶液(0.54mL，0.54mmol)。室温反应3.5h，加入30mL乙酸乙酯稀释，蒸馏水洗，饱和NaHCO 3溶液洗，食盐水洗，无水Na 2SO 4干燥。过滤，旋干得235mg粗品，直接下一步反应。
向盛有上步产物(235mg，0.36mmol)反应瓶中加入溶有三氟乙酸(TFA)的CH 2Cl 2溶液(2:25，5mL)，室温搅拌反应1小时，停止反应。冰浴下加入NaOH水溶液(5mL，1M)淬灭反应，CH 2Cl 2萃取，无水Na 2SO 4干燥。过滤，旋干得165mg粗品，直接投入下一步反应。
将上步产物(165mg，0.27mmol)溶于8mL无水CH 3OH和无水CH 2Cl 2(1:1)的混合溶液中，加入催化量的甲醇钠(0.2eq.)，调节pH为9～10，在40℃下搅拌反应5小时，加入酸性阳离子树脂中和至中性。过滤，浓缩，得白色固体产物。溶于1mL水，反相硅胶柱层析得化合物PL402，获得78mg(0.16mmol)；三步收率40％。
1H NMR(400MHz；MeOD)7.683(d，1H，J＝15.6Hz),7.229(d，1H，J＝1.6Hz),7.114(dd，1H，J 1＝1.6Hz，J 2＝8Hz),6.829(d，1H，J＝8.8Hz),6.407(d，1H，J＝15.6Hz),6.403(d，1H，J＝1.6Hz),5.231(d，1H，J＝1.6Hz),3.994(q， 1H，J＝2Hz),3.896(s,3H),3.880(s,1H),3.845-3.831(m,1H),3.777-3.700(m,2H),3.650-3.621(m,2H),3.431-3.408(m,1H),1.319(d，3H，J＝6Hz),1268(d，3H，J＝6.4Hz)；ESI-MS m/z 487(M+1) +。
PL402的鉴定图如图8。
实施例2、化合物PL404和PL405的合成
Figure PCTCN2019073777-appb-000042
1、化合物7的制备
化合物6(12.2g，5mmol)(Chemistry-A European Journal,21(29),10416-10430；2015)、干燥的
Figure PCTCN2019073777-appb-000043
分子筛(20g)与CH2Cl2(1.5L)加入干燥反应瓶中，室温下搅拌20min，冷却至-78℃加入三氟甲磺酸三甲基硅酯(TMSOTf)(0.18mL，1mmol)的CH2Cl2溶液和化合物1(25.6g，60mmol)(Journal of the American Chemical Society,2000,vol.122,#41,p.9939-9953)CH2Cl2溶液(2.5L)。30分钟后加入Et3N 0.5mL停止反应。过滤浓缩，柱层析(石油醚:乙酸乙酯＝10:1至3:1)得化合物7，获得21.9g(42.4mmol)，收率85％。ESI-MS m/z 517(M+1) +。
2、化合物8的制备
化合物7(21.9g，42.4mmol)溶于2L无水CH3OH和无水CH2Cl2(1:1)的混合溶液中，加入催化量的甲醇钠(0.2eq.)，调节pH为9～10，在40℃下 搅拌反应4小时，加入酸性阳离子树脂中和至中性。过滤，浓缩，柱层析(石油醚:乙酸乙酯＝10:1至1:1)得化合物8，获得11.6g(29.7mmol)，收率70％。ESI-MS m/z 391(M+1) +。
3、化合物9的制备
向1L三口瓶中加入化合物8(11.6g,29.7mmol)，加入丙酮(120ml)，加入对甲苯磺酸(116mg,1％w/w)，再加入2,2-二甲氧基丙烷(9.3g,89.4mmol)，反应液于15-20℃，反应1h，TLC显示反应完全，向反应液中加入三乙胺(24ml)，反应液浓缩干，柱层析(石油醚:乙酸乙酯＝20:1至5:1)得化合物9，获得8.9g(20.7mmol)，收率70％。
ESI-MS m/z 431(M+1) +。
4、化合物10的制备
向1L三口瓶中加化合物9(8.9g,20.7mmol)，加入二氯甲烷(500ml)，加入化合物4(9.6g,30.2mmol)，依次加入DIEA(10.7g，82.9mmol)，EDCI.HCl(7.9g，，41.1mmol)，DMAP(0.3g，2.5mmol)，DIEA(6.7g，51.9mmol),反应液于15-20℃，搅拌18h,有机相用饱和食盐水(50ml)洗涤,有机相减压浓缩，柱层析(石油醚:乙酸乙酯＝10:1至2:1)得化合物10，获得10g(13.9mmol)，收率70％。
ESI-MS m/z 721(M+1) +。
5、化合物11的制备
向500ml三口瓶中加入THF(100ml)，加入化合物10(10g，13.9mmol)，加入化合物TABF(25ml，1mol/L的THF溶液)，反应与于10～20℃下反应，TLC显示反应完全，将反应液加入水中(200ml)，用乙酸乙酯萃取(200ml*3)，合并有机相，用饱和食盐水洗涤(200ml*6)，有机相用无水硫酸钠干燥，过滤浓缩，柱层析(石油醚:乙酸乙酯＝10:1至3:1)得化合物11，获得4.2g(6.9mmol)，收率50％。
ESI-MS m/z 607(M+1) +。
6、化合物12的制备
向1L三口瓶中加入化合物11(4.2g,6.9mmol)，加入100ml醋酸，5ml水，NaOAc(37.5g,276mmol)，PdCl2(2.0g,11.3mmol)，反应液于15-20℃，搅拌40h，反应液过滤，浓缩，柱层析(石油醚:乙酸乙酯＝10:1至1:1)得化合物12，获得2.35g(4.2mmol)，收率60％。
ESI-MS m/z 567(M+1) +。
7、PL404和PL405的制备
向500ml三口瓶中加入化合物12(2.35g,4.2mmol)，加入28ml二氯甲烷，TFA(2.4g,21mmol)，反应液于15-20℃，搅拌20分钟，将反应液降温至0℃-5℃，用饱和碳酸氢钠调节pH8～9，分液，有机相浓缩，柱层析(石油醚:乙酸乙酯＝20:1至1:1)得化合物PL404(273mg,0.52mmol)和PL405(200mg,0.41mmol)。
PL404：
1H NMR(400MHz；CDCl3)7.689(d,1H,J＝15.6Hz),7.081(dd,1H,J1＝1.6Hz,J2＝8Hz),7.034(s,1H),6.936(d,1H,J＝13.6Hz),6.339(d,1H,J＝16Hz),5.372(d,0.7H,J＝6Hz),5.086(s,1H),4.99(d,0.3H,J＝6Hz),4.86-4.80(m,1H),4.768(d,0.7H,J＝6Hz),4.695(d,0.3H,J＝6Hz),4.609(d,0.7H,J＝6Hz),4.524(d,0.3H,J＝6Hz),4.028-4.008(m,2H),3.981-3.896(m,6H),1.446-1.223(m,12H)；ESI-MS m/z 527(M+1) +。
PL404的鉴定图如图9。
PL405：
1H NMR(400MHz；MeOD)7.67(dd，1H，J1＝4Hz，J2＝8Hz),7.21(s，1H，J＝1.6Hz),7.09(dd，1H，J1＝1.6Hz，J2＝8Hz),6.81(d，1H，J＝8Hz),6.43(dd，1H，J1＝4Hz，J2＝12Hz),5.26(d，1H，J＝4Hz),5.05(t，1H，J＝8Hz),5.00(s,0.5H),4.72(s,0.5H),4.04-4.00(m,1H),3.95-3.93(m,1H),3.89(s,3H),3.88-3.85(m,2H),3.77-3.75(m,1H),3.55-3.50(m,0.5H),3.48-3.45(m,1H),3.34-3.31(m,0.5H),1.33(d，1H，J＝4Hz),1.30(d，2H，J＝4Hz),1.27(d，3H，J＝4Hz)；ESI-MS m/z487(M+1) +。
PL405的鉴定图如图10。
实施例3、PL402改善AD小鼠学习记忆能力
1、Morris水迷宫实验
选用5-6月龄的APP/PS1转基因雄性小鼠(AD小鼠)20只，按随机数字表法分为模型组及多糖给药组，PL402采用灌胃给药方式，每天给药(50mg/kg)，同时用非转基因小鼠10只作为阴性对照组(不给药)，连续给药90天后，利用Morris水迷宫行为学实验来检测PL402对APP/PS1小鼠的学习，认知功能的影响。
本实验采用的是经典Morris水迷宫测试程序，包括两部分，即定位航行试验和空间探索试验实验，共进行7天，第4天和第7天加入空间探索试验。
从图1实验结果可知，此次定位航行实验，3组动物经过3天训练，其逃避潜伏期均缩短，说明各小鼠均能顺利完成水迷宫的空间学习任务。以逃避潜伏期作为检测指标。
结果显示：阴性对照组小鼠反应比较迅速，入水后能快速找到平台，随着训练次数增加，寻找平台的潜伏期时间缩短；而模型组小鼠反应迟钝，入水后沿桶壁有画圈行为，无逃避行为，人为将其引领至平台后，又跳入水中，经多次训练后，最终找到平台，但寻找平台潜伏期明显延长；给药组小鼠随着训练次数的增加，寻找平台的能力不断提高。以上3组都具有一定的空间记忆能力，模型组小鼠的潜伏期成绩差于对照组，提示模型组小鼠学习记忆能力出现下降，模型鼠较好地模拟了AD的学习记忆障碍。给药组小鼠潜伏期与模型组相比有显著差异具有统计学意义，可见PL402给药后AD小鼠学习和记忆能力有明显改善。
2、5-溴-2’-脱氧尿苷(BrdU)处理
在5-6个月大小AD小鼠的给药实验中，每只小鼠灌胃给药PL402，给予100l，给药浓度为50mg/kg小鼠体重；另设置参照组，灌胃给予100l水，每日一次，持续给药90天，而在60天开始腹腔注射50mg/kg小鼠体重的5-溴-2’-脱氧尿苷(BrdU)，每日一次，共注射7天，给药90天后将小鼠麻醉后多聚甲醛(PFA)灌流，取全脑进行检测。
实施例4、PL402抑制神经炎症
AD大脑中的神经炎症是造成认知能力下降的原因之一。小胶质细胞是介导神经炎症关键细胞。本发明人通过检测BV-2细胞上炎症因子的表达，探究 PL402是否具有抑制神经炎症的作用。
小鼠胶质瘤细胞BV-2培养及刺激：BV-2细胞培养在DMEM中，铺至24孔板培养24小时后，加入PL402(用量0、10、30、100、300μM)和LPS(300ng/ml)，加药后共孵育24小时，Trizol抽提RNA，并通过QPCR检测相关的炎症因子的表达。
结果显示，PL402处理能显著抑制炎症因子IL-6和IL-1β的表达，如图2。
实施例5、PL402减少Aβ生成
Aβ是AD的主要致病蛋白。本发明人通过检测SK-N-SH细胞(自身能分泌产生Aβ)中Aβ的水平，探究PL402是否具有抑制减少Aβ生成的作用。
神经母细胞瘤细胞SK-N-SH培养及Aβ检测：SK-N-SH细胞培养在DMEM中，铺至24孔板培养24小时后，加入PL402(用量0、10、30、100、300μM)，加药后共孵育24小时，取出上清，并通过ELISA检测总Aβ的蛋白水平。
结果显示，PL402处理能显著抑制Aβ生成，如图3，其中100μM效果较理想。
实施例6、PL404对动物学习记忆能力的影响
采用与前述实施例3相同的方法选择动物以及进行“Morris水迷宫实验”，检测PL404对动物学习记忆能力的影响。
结果如图4，给药组小鼠潜伏期与模型组相比有显著差异，这种差异具有统计学意义。
因此，PL404给药后AD小鼠学习和记忆能力有明显改善。
实施例7、PL404对人源神经干细胞增殖的影响
本发明人通过检测人源神经干细胞(人源iPSC分化)EdU的掺入，探究PL404是否具有促进增殖的作用。PL404用量：0，1，3，10，30，100μM。
结果如图5。结果显示，PL404处理能显著促进人源神经干细胞增殖。与不以PL404处理的对照组相比，人源神经干细胞量增加约30％。
实施例8、PL405对人源神经干细胞增殖的影响
采用与实施例7接近的方法，不同点在于将化合物由PL404替换为PL405，通过检测人源神经干细胞EdU的掺入，探究PL405是否具有促进增殖的作用。
结果如图6。结果显示，PL405处理能显著促进人源神经干细胞增殖。与不以PL405处理的对照组相比，人源神经干细胞量增加约60％。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (22)

  1. 式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐，
    Figure PCTCN2019073777-appb-100001
    其中，
    Figure PCTCN2019073777-appb-100002
    为六元杂环，X为O；
    R1～R4独立地选自：氢、羟基、C1-C4烷基、C2-C4链烯基、C2-C4链炔基、卤素，或R1～R4中相邻两个基团相互连接、并与母环共同构成环结构；
    R1’～R3’独立地选自：氢、羟基、C1-C4烷基、C2-C4链烯基、C2-C4链炔基、卤素，或R1’～R3’中相邻两个基团相互连接、与母环构成环结构。
  2. 如权利要求1所述的式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐，其特征在于，
    Figure PCTCN2019073777-appb-100003
    包括选自下组的环结构：
    Figure PCTCN2019073777-appb-100004
  3. 如权利要求1所述的式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐，其特征在于，
    Figure PCTCN2019073777-appb-100005
    包括环结构：
    Figure PCTCN2019073777-appb-100006
  4. 如权利要求1所述的式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐，其特征在于，
    R1～R4独立地选自：氢、羟基、C1-C2烷基，或R1～R4中相邻两个基团相互连接、与母环构成五元环；
    R1’～R3’独立地选自：氢、羟基、C1-C2烷基，或R1’～R3’中相邻两个基团相互连接、与母环构成五元环。
  5. 如权利要求4所述的式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐，其特征在于，所述的五元环为含O杂环；较佳地，所述的五元环含有两个O。
  6. 如权利要求1所述的式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐，其特征在于，所述的化合物包括：
    Figure PCTCN2019073777-appb-100007
  7. 权利要求1～6任一所述的式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐的用途，用于制备预防、缓解或治疗神经退行性疾病、抑郁症或中风的药物或药盒。
  8. 如权利要求7所述的用途，其特征在于，神经退行性疾病是：
    以脑内发生神经炎症为特征的神经退行性疾病；或
    以Aβ生成显著性增加为特征的神经退行性疾病；或
    以学习记忆能力显著性下降为特征的神经退行性疾病；或
    以神经干细胞显著减少为特征的神经退行性疾病。
  9. 如权利要求8所述的用途，其特征在于，所述的神经退行性疾病包括：阿尔茨海默症，帕金森症，路易体痴呆，亨廷顿病、肌萎缩侧索硬化症。
  10. 权利要求1～6任一所述的式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐的用途，用于制备抑制神经炎症的组合物、试剂 盒或药盒。
  11. 权利要求1～6任一所述的式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐的用途，用于制备促进神经干细胞生成的组合物、试剂盒或药盒。
  12. 权利要求1～6任一所述的式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐的用途，用于制备降低Aβ生成的组合物、试剂盒或药盒。
  13. 一种药物组合物，其特征在于，所述的药物组合物包含：
    权利要求1～6任一所述的式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐；和
    药学上可接受的载体。
  14. 如权利要求13所述的药物组合物，其特征在于，所述的药物组合物的剂型包括：粉剂、散剂、片剂、丸剂、胶囊剂、缓释剂、控速释剂、注射剂、输液剂、混悬剂。
  15. 一种药盒，其特征在于，所述的药盒中包括：权利要求1～6任一所述的式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐；或
    权利要求13或14任一所述的药物组合物。
  16. 一种预防、缓解或治疗神经退行性疾病、抑郁症或中风的方法，其特征在于，所述方法包括：给予需要治疗的对象有效量的权利要求1～4任一所述的式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐。
  17. 一种如式(II)所示的化合物的制备方法，其特征在于，所述方法包括步骤：使吡喃鼠李糖苷(二糖)与四丁基氟化铵反应，得到结构如(II)所示的化合物；
    Figure PCTCN2019073777-appb-100008
  18. 如权利要求17所述的制备方法，其特征在于，所述吡喃鼠李糖苷(二糖)是通过将吡喃鼠李糖硫苷(二糖)与(4-O-叔丁基二甲基甲硅烷基)-阿魏酸反应而得到。
  19. 如权利要求18所述的制备方法，其特征在于，所述吡喃鼠李糖硫苷(二糖)是通过将吡喃鼠李糖硫苷(单糖)与1-O-三氯乙酰亚胺-2,3,4-O-三乙酰基鼠李糖反应而得到。
  20. 一种如式(III)或(IV)所示的化合物的制备方法，其特征在于，所述方法包括步骤：
    将化合物
    Figure PCTCN2019073777-appb-100009
    进行还原反应(更特别地为去除邻二醇丙叉保护的反应)，获得式(III)或(IV)所示的化合物。
  21. 如权利要求20所述的方法，其特征在于，所述化合物
    Figure PCTCN2019073777-appb-100010
    通过包括将化合物
    Figure PCTCN2019073777-appb-100011
    与化合物
    Figure PCTCN2019073777-appb-100012
    缩合的步骤来获得；
    其中P为H或保护基团；较佳地所述保护基团包括选自下组的基团：AII，Boc，TBS，Ac，Bn，PMB，Cbz；所述的保护基团可被还原为H。
  22. 如权利要求21所述的方法，其特征在于，所述化合物
    Figure PCTCN2019073777-appb-100013
    通过包括将化合物
    Figure PCTCN2019073777-appb-100014
    与化合物
    Figure PCTCN2019073777-appb-100015
    加成以及邻二醇丙叉保护反应的步骤来获得。
PCT/CN2019/073777 2018-02-06 2019-01-29 用于防治神经退行性疾病的新化合物及其应用 WO2019154196A1 (zh)

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