Libramycin derivative and application thereof in nervous system diseases

Abstract

The invention relates to the technical field of medicinal chemistry, in particular to a ribramycin derivative and application thereof in nervous system diseases. According to the present invention, the treatment activity of the nervous system is improved by modifying the 18-site hydroxyl group of the ribramycin, and the fat solubility of the compound can be improved especially when the 18-site hydroxyl group is replaced with the methyl group so as to improve the brain passing efficiency.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and in particular to a libramycin derivative and application thereof in treating nervous system diseases. Background Art

[0002] Excitotoxicity is a common pathological phenomenon in many brain diseases. It is widely present in diseases such as epilepsy, Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). It is characterized by the accumulation of large amounts of excitatory neurotransmitters, mainly glutamate, which cause toxic damage to neurons and trigger a series of neuropathological changes1, including: (1) causing abnormal discharges in neurons, which in extreme cases can induce epilepsy; (2) overactivating nucleases and proteases in neurons, causing neurons to lose homeostasis; (3) causing oxidative stress damage to neurons; and (4) directly inducing apoptosis or autophagy of neurons in severe cases.

[0003] Excitotoxicity plays an important role in the pathogenesis of many neurological diseases and is considered to be one of the key factors that destroy normal brain function and cause neurodegenerative diseases. In the past, researchers mainly focused on the repair strategies that neurons may adopt after suffering excitotoxic damage: alleviating or reversing the pathological phenotype of the disease through drugs or molecular interventions, cell therapy and other methods. For example, in recent years, there have been many reports on neural stem cell transplantation and methods to inhibit neural apoptosis, which have brought hope for the treatment of diseases such as ALS, AD, and PD. However, there are also some problems with the above measures, such as the low survival rate of stem cells in cell transplantation therapy and the difficulty of integrating transplanted neurons into existing neural networks.

[0004] There is a speculation that the limited effectiveness of such treatments is due to their failure to prevent the "strike mechanism" that always exists during the disease process. If the strike mechanism can be addressed upstream of the disease, better treatment results may be achieved.

[0005] Astrocytes can maintain normal glutamate levels in the neural microenvironment by taking up and releasing glutamate, among which the glutamate transporter GLT1 (Glutamate transporter 1; also known as excitatory amino acid transporter 2, Excitatory amino acid transporter 2, EAAT2) plays the most important role in glutamate clearance3. GLT1 is a membrane integral protein specifically expressed by astrocytes. It transports glutamate from the extracellular to the intracellular by active transport, so that the glutamate concentration in the neural microenvironment is maintained within the normal range. Intracellular glutamate is converted into glutamine by the action of glutamine synthetase (GS) and enters the metabolic pathway. GLT1 can also prevent excessive neuronal excitation by quickly clearing glutamate from receptors on the postsynaptic membrane. Reports show that under the action of GLT1, the difference in glutamate concentration inside and outside the cell can be as high as 10,000 times. Studies have confirmed that GLT1 is the most important inward transporter of glutamate in the brain, responsible for nearly 80% of glutamate clearance.

[0006] Evidence shows that GLT1 is abnormally downregulated in a variety of neurological diseases, causing astrocytes to severely lose their glutamate clearance ability, which may be an important cause of abnormal glutamate accumulation. Studies on patients with refractory temporal lobe epilepsy found that both GLT1 mRNA and protein were downregulated in the patient's epileptogenic focus (sclerotic hippocampal tissue). AD and epilepsy have certain comorbidities. Many studies have confirmed that AD patients also have neuronal damage caused by excitotoxicity in their brains. At the same time, GLT1 protein levels were found to be significantly decreased in autopsy brain tissue of AD patients. Studies on autopsy brain tissue of ALS patients found that the loss of GLT1 protein was as high as 90%. Subsequent functional studies have shown that abnormal internalization and protein degradation of GLT1 under pathological conditions may be an important cause of its insufficient protein amount. In addition, researchers have also observed the phenomenon of GLT1 downregulation in model mice of tuberous sclerosis.

[0007] Functional studies at the animal level provide conclusive evidence for the relationship between the loss of GLT1 and the disease phenotype. First, GLT1 transgenic mice have the ability to resist epileptic seizures, which is manifested by the reduction of the death rate of hippocampal neurons in GLT1 transgenic mice under the induction of epilepsy-inducing drugs (pilocarpine, an agonist of muscarinic acetylcholine receptors, can be used to establish a rodent model of epilepsy by intraperitoneal injection), the degree of mossy fiber sprouting and other pathological phenotypes related to hippocampal sclerosis are alleviated, and the number of spontaneous chronic epileptic seizures in GLT1 transgenic mice is also reduced by about 50%. On the contrary, inhibiting the expression of GLT1 by injecting antisense RNA can lead to a large accumulation of glutamate in the mouse brain, induce neurodegenerative lesions, and gradually paralyze the mice. These studies show that astrocytes play an important neuroprotective function through their specifically expressed GLT1 molecules, and the loss of GLT1 is sufficient to cause excitotoxic damage to the nervous system.

[0008] In summary, abnormal downregulation of GLT1 protein may be an important reason for excessive accumulation of glutamate in the brain of patients with epilepsy, AD, ALS, etc. In recent years, some researchers have proposed the hypothesis of excessive degradation of GLT1 protein and found that HSP90 protein promotes 20S proteasome-dependent GLT1 protein degradation by recruiting GLT1 to proteasome. On the other hand, reactive astrocyte proliferation is a common pathological phenomenon in almost all brain diseases, and this process itself is accompanied by increased expression of HSP90 molecules. Therefore, HSP90 inhibitor treatment can increase the level of GLT1 protein in brain diseases such as temporal lobe epilepsy and AD. In terms of therapeutic effect, in mice with chronic temporal lobe epilepsy induced by kainate, two HSP90 inhibitors 17AAG and NVP-HSP990 can relieve epileptic seizures; in AD mouse models, NVP-HSP990 can reduce epileptic discharges in the brain and alleviate cognitive decline. Interestingly, since the expression level of HSP90 in astrocytes is much lower than that in neurons, and the overall expression level of HSP90 in the brain is comparable to that in other tissues and organs, the dosage of HSP90 inhibitors used in the treatment of brain diseases is much lower than the dosage used in anti-tumor treatment, which can increase the level of GLT1 protein and exert anti-epileptic and anti-AD effects. 18 These research results show that HSP90 inhibitors can have therapeutic effects on brain diseases with neuroexcitotoxicity such as epilepsy and AD at low doses.

[0009] However, existing HSP90 inhibitors have certain problems. For example, 17AAG and NVP-HSP990 have their own shortcomings: 17AAG has poor drugability (low water solubility, low bioavailability, and toxicity); NVP-990 has been reported to have optic neurotoxicity in clinical trials; (2) More importantly, HSP90 inhibitors have great limitations in treating brain diseases (such as blood-brain barrier permeability). Therefore, it is necessary to further optimize and transform them for the goal of "treating brain diseases."

[0010] Reblastatin is a type of aniline mycin, and its structural formula is as follows:

[0011]

[0012] Compared with 17AAG, the benzoquinone structure on the benzene ring of this compound is replaced by a phenol structure, so its toxicity is reduced. However, its disadvantage is that its brain-penetrating efficiency is extremely low, so it is necessary to modify its compound structure to improve its brain-penetrating efficiency. Summary of the invention

[0013] The purpose of the present invention is to provide a libramycin derivative and its use in nervous system diseases. By modifying the hydroxyl group at position 18 of libramycin, the nervous system therapeutic activity is improved, and at the same time, especially when replaced with a methyl group, the fat solubility of the compound can be increased, thereby improving the brain-passing efficiency.

[0014] To achieve the above-mentioned purpose of the invention, the technical solution of the present invention is as follows:

[0015] In a first aspect, the present invention provides a use of a libramycin derivative or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, pharmaceutically acceptable salts or prodrugs in the preparation of a method for treating and / or preventing a nervous system disease.

[0016] The structural formula of the libramycin derivative is shown in Formula I:

[0017]

[0018] Wherein, R is selected from H; halogen; amino; substituted or unsubstituted C1-5 alkyl, C1-5 alkoxy, C3-10 cycloalkyl, C1-5 ester, aryl, amine, heterocyclic group, and the substituted substituent is selected from at least one of C1-C5 alkyl, carbonyl, hydroxyl, C1-C5 alkyl, halogen, amine, aryl, heterocyclic group.

[0019] Preferably, R is selected from substituted or unsubstituted C1-5 alkyl, C1-5 alkoxy, C3-10 cycloalkyl, ester, aryl, amine, and heterocyclic group, and the substituted substituent is selected from at least one of C1-C5 alkyl, carbonyl, hydroxyl, C1-C5 alkyl, halogen, amine, aryl, and heterocyclic group.

[0020] Further preferably, the R is selected from substituted or unsubstituted C1-5 alkyl, C1-5 ester, heterocyclic group, the substituted substituent is selected from at least one of carbonyl, hydroxyl, C1-C5 alkyl, halogen, amine, aryl, heterocyclic group; the heteroatom in the heterocyclic group is selected from at least one of N, S, B, O.

[0021] More preferably, R is selected from substituted or unsubstituted C1-3 alkyl, C1-5 ester, heterocyclic group, the substituted substituent is selected from at least one of C1-C5 alkyl, amine, heterocyclic group; the heteroatom in the heterocyclic group is selected from at least one of N, S, B, O.

[0022] More preferably, the R is selected from C1-3 alkyl, -OCO-Ra, and a substituted heterocyclic group; the Ra and the substituted substituent are each independently selected from at least one of a C1-C3 alkyl, an amine group, and a heterocyclic group; and the heteroatom in the heterocyclic group is selected from at least one of N, S, B, and O.

[0023] More preferably, the R is selected from C1-3 alkyl, -OCO-Ra, substituted heterocyclic group, the Ra is selected from at least one of amino group and heterocyclic group; the substituted substituent is selected from C1-C3 alkyl, and the heteroatom in the heterocyclic group is selected from at least one of N, B and O.

[0024] More preferably, the R is selected from C1-3 alkyl, -OCO-Ra, at least one C1-3 alkyl-substituted pentacyclic heterocyclic group containing B and O, and the Ra is selected from at least one of an amino group and a N-containing six-membered heterocyclic group.

[0025] More preferably, the R is selected from methyl, -OCO-Ra, at least one C1-3 alkyl-substituted pentacyclic heterocyclic group containing B and O, and the Ra is selected from at least one of a C1-3 alkyl-substituted amine, a piperazinyl, and a C1-3 alkyl-substituted piperazinyl.

[0026] More preferably, the R is selected from methyl, -OCO-Ra, at least one methyl-substituted pentacyclic heterocyclic group containing B and O, and the Ra is selected from at least one of dimethylamino, methylethylamino, diethylamino, piperazinyl and methyl-substituted piperazinyl.

[0027] More preferably, the R is selected from methyl, -OCO-Ra, The Ra is selected from dimethylamino,

[0028] Most preferably, said R is methyl.

[0029] Preferably, the neurological disease is a brain disease.

[0030] Preferably, the nervous system disease is selected from at least one of epilepsy, Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis.

[0031] More preferably, it is at least one of epilepsy and Parkinson's disease.

[0032] In a second aspect, the present invention provides a libramycin derivative or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, the structural formula of which is shown in Formula I:

[0033]

[0034] The R is selected from methyl, -OCO-Ra, and a substituted heterocyclic group; the Ra and the substituted substituent are each independently selected from at least one of a C1-C3 alkyl group, an amine group, and a heterocyclic group; the heteroatom in the heterocyclic group is selected from at least one of N, S, B, and O.

[0035] Preferably, the R is selected from C1-3 alkyl, -OCO-Ra, substituted heterocyclic group, the Ra is selected from at least one of amino group and heterocyclic group; the substituted substituent is selected from C1-C3 alkyl, and the heteroatom in the heterocyclic group is selected from at least one of N, B and O.

[0036] Further preferably, the R is selected from C1-3 alkyl, -OCO-Ra, at least one C1-3 alkyl-substituted pentacyclic heterocyclic group containing B and O, and the Ra is selected from at least one of an amino group and a N-containing six-membered heterocyclic group.

[0037] More preferably, the R is selected from methyl, -OCO-Ra, at least one C1-3 alkyl-substituted pentacyclic heterocyclic group containing B and O, and the Ra is selected from at least one of a C1-3 alkyl-substituted amine, a piperazinyl, and a C1-3 alkyl-substituted piperazinyl.

[0038] More preferably, the R is selected from methyl, -OCO-Ra, at least one methyl-substituted pentacyclic heterocyclic group containing B and O, and the Ra is selected from at least one of dimethylamino, methylethylamino, diethylamino, piperazinyl and methyl-substituted piperazinyl.

[0039] More preferably, the R is selected from methyl, -OCO-Ra, The Ra is selected from dimethylamino,

[0040] Most preferably, said R is methyl.

[0041] In a third aspect, the present invention provides a method for preparing the above-mentioned libramycin derivative, which is selected from the following methods:

[0042]

[0043] Wherein, R has the same definition as above.

[0044] Preferably, when R is methyl or substituted heterocyclic group, the preparation method is:

[0045]

[0046] When R is -OCO-Ra, the preparation method is:

[0047]

[0048] In a fourth aspect, the present invention provides a pharmaceutical composition comprising the aforementioned libramycin derivative or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, and a pharmaceutically acceptable carrier or excipient.

[0049] The phrase "carrier" is art-recognized and includes pharmaceutically acceptable materials, components or vehicles that are suitable for administering the compounds of the present invention to mammals. Carriers include liquid or solid fillers, diluents, excipients, solvents or encapsulating materials that participate in carrying or transporting the subject substance from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation or not injurious to the subject. Some examples of materials that can serve as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium methyl cellulose, ethyl cellulose and cellulose acetate; tragacanth, malt, gelatin, talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol, polyols such as glycerol, behenyl alcohol, glycerol ... Sorbitol, mannitol, and polyethylene glycol, esters such as ethyl oleate and ethyl laurate, agar, buffers such as magnesium hydroxide and aluminum hydroxide, alginic acid, pyrogenic water, isotonic saline, ethanol, phosphate buffer, and other nontoxic compatible substances used in pharmaceutical preparations, wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate and stearic acid esters, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may also be present in the composition.

[0050] Examples of pharmaceutically acceptable antioxidants include: water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; oil-soluble antioxidants, such as ascorbyl palmitate, butylated benzoic acid (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and metal compounds, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0051] Suitable pharmaceutically acceptable carriers include, but are not limited to, water, salt solutions (e.g., NaCl), alcohol, gum arabic, vegetable oils, benzyl alcohol, polyethylene glycol, gelatin, sugars (e.g., lactose, amylose or starch), polyethylene glycol, magnesium stearate, talc, silicic acid, viscous paraffin, essential oils, fatty acid esters, methylcellulose, polyvinylpyrrolidone, etc. The pharmaceutical composition may be sterilized and, if desired, may be mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salt buffers that affect osmotic pressure, colorants, flavorings and / or aromatic substances, etc., which do not deleteriously react with the active compounds.

[0052] Composition can also contain the wetting agent, emulsifier or pH buffer of minor amount.Composition can be liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release preparation or powder.Composition can be formulated into suppository with conventional adhesive and carrier (such as triglyceride).Oral preparation can comprise standard carrier such as pharmaceutical grade mannitol, lactose, magnesium stearate, polyvinylpyrrolidone, saccharin sodium, cellulose, magnesium carbonate etc.

[0053] According to ordinary methods, the composition can be formulated into a pharmaceutical composition suitable for human intravenous administration. When needed, the composition may also include a stabilizer and a local anesthetic to alleviate the pain at the injection site. Generally, the composition is supplied separately or mixed together in a unit dosage form, for example, in a sealed container such as an ampoule or a sachet showing the amount of the active agent as a dry freeze-dried powder or anhydrous concentrate. When the composition is administered by infusion, it can be dispersed with an infusion bottle containing pharmaceutical grade sterile water, saline or glucose water. When the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the composition can be mixed before administration.

[0054] The pharmaceutical compositions of the present invention may also include an agent that controls the release of the compound of the present invention, thereby providing a timed or sustained release composition.

[0055] The pharmaceutical compositions of the present invention include compositions suitable for oral, rectal, topical, vaginal and parenteral (including subcutaneous, intramuscular and intravenous) administration, although the most suitable route in any particular case depends on the nature and severity of the condition to which the active ingredient is administered. The pharmaceutical compositions can be prepared by any method known in the art of pharmacy.

[0056] The active ingredient can be administered orally in a solid dosage form or a liquid dosage form, such as capsules, tablets, lozenges, lozenges, granules and powders, and the liquid dosage form is such as elixirs, syrups, emulsions, dispersions and suspensions. The active ingredient can also be administered parenterally in a sterile liquid dosage form such as a dispersion, suspension or solution. Other dosage forms that can be used to administer the active ingredient include ointments, creams, drops, transdermal patches or powders for topical administration; ophthalmic solutions or suspension forms for eye administration, i.e., eye drops; sprays or powder compositions for inhalation or intranasal administration, or creams, ointments, sprays or suppositories for rectal or vaginal administration. Gelatin capsules contain active ingredients and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc. Similar diluents can be used to prepare compressed tablets. Both tablets and capsules can be prepared as sustained-release products to provide sustained release of drugs over several hours. Compressed tablets can be coated with sugar or film to cover any unpleasant taste and protect the tablet from air, or can be enteric coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration can include coloring agents and flavoring agents to increase the patient's acceptance. Generally speaking, water, suitable oil, saline, dextrose (glucose) aqueous solution and related sugar solution and glycols such as propylene glycol or polyethylene glycol are suitable carriers of parenteral solutions. The solution for parenteral administration preferably includes water-soluble salts of active ingredients, suitable stabilizers and buffer substances used as required. Antioxidants such as sodium bisulfite, sodium sulfite or ascorbic acid alone or in combination are suitable stabilizers. Citric acid and its salts and sodium EDTA can also be used. In addition, parenteral solutions can also include preservatives, such as benzalkonium chloride, methylparaben or propylparaben and chlorobutanol.

[0057] For inhalation administration, the compound of the present invention can be conveniently delivered in the form of a spray from a pressurized package or a nebulizer. The compound can also be delivered in the form of a powder for preparation, and the powder composition can be inhaled with the help of a powder inhaler device. The preferred delivery system for inhalation is a metered dose inhalation (MDI) aerosol, which can be formulated into a suspension or solution of the compound of formula I in a suitable propellant, such as a fluorocarbon or a hydrocarbon. For eye administration, ophthalmic preparations can be prepared with a solution or suspension of a suitable weight percentage of the compound of formula I in a suitable ophthalmic carrier, thereby keeping the compound in contact with the surface of the eye for enough time to allow the compound to penetrate into the cornea and the inner area of ​​the eye.

[0058] Useful pharmaceutical dosage forms for administering the pharmaceutical compositions of the present invention include, but are not limited to, hard and soft gelatin capsules, tablets, parenteral injection solutions, and oral suspensions.

[0059] In a fifth aspect, the present invention provides a method for treating a nervous system disease, comprising administering an effective amount of the above-mentioned libramycin derivative or its stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the above-mentioned pharmaceutical composition to an individual. The method can be used in vivo or in vitro. The individual can be a mammal, such as a human.

[0060] When the compounds of the present invention are administered stepwise or in combination with other therapeutic agents, the same dosage forms as described above may be used. When the drugs are administered in physical combination, the dosage form and route of administration should be selected based on the compatibility of the combined drugs. The compounds of the present invention may be administered as the sole active ingredient or in combination with a second active ingredient, including active ingredients known to be useful for treating related diseases.

[0061] In some embodiments, the amount of the compound is in the range of about 0.001 mg / kg body weight / day to about 1000 mg / kg body weight / day. In other embodiments, the amount of the compound ranges from about 0.5 mg / kg body weight / day to about 50 mg / kg body weight / day. In some embodiments, the amount of the compound is about 0.001 g / day to about 7 g / day. In other embodiments, the amount of the compound is about 0.002 g / day to about 6 g / day. In other embodiments, the amount of the compound is about 0.005 g / day to about 5 g / day. In other embodiments, the amount of the compound is about 0.01 g / day to about 5 g / day. In other embodiments, the amount of the compound is about 0.02 g / day to about 5 g / day. In other embodiments, the amount of the compound is about 0.05 g / day to about 2.5 g / day. In other embodiments, the amount of the compound is about 0.1 g / day to about 1 g / day. In other embodiments, dosage levels below the lower limit of the above range may be sufficient. In other embodiments, dosage levels above the upper limit of the above range may be required. In some embodiments, the compound is administered in a single dose, once a day. In other embodiments, the compound is administered in multiple doses, more than once a day. In some embodiments, the compound is administered twice a day. In other embodiments, the compound is administered three times a day. In other embodiments, the compound is administered four times a day. In other embodiments, the compound is administered more than four times a day. In some embodiments, the individual to whom the pharmaceutical composition is administered is a mammal. In other embodiments, the mammal is a human.

[0062] Preferably, the nervous system disease is selected from at least one of epilepsy, Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis.

[0063] More preferably, it is at least one of epilepsy and Parkinson's disease.

[0064] Terminology Note:

[0065] Unless otherwise defined, all technical terms used herein have the same meanings as those commonly understood by those skilled in the art. Unless otherwise indicated, all patents, patent inventions, and public materials cited herein are incorporated herein by reference in their entirety. If there are multiple definitions of a term in this article, the definition in this chapter shall prevail.

[0066] It should be understood that the above brief description and the following detailed description are exemplary and are only used for explanation, and do not limit the subject matter of the present invention in any way. In the present invention, unless otherwise specifically stated, the use of the singular also includes the plural. It should also be noted that unless otherwise stated, the use of "or" and "or" means "and / or". In addition, the use of the term "including" and other forms, such as "including", "containing" and "containing" are not restrictive.

[0067] Definitions of standard chemical terms can be found in references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4THED." Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise stated, conventional methods within the technical scope of the art, such as mass spectrometry, NMR, IR and UV / Vis spectroscopy and pharmacological methods, are used. Unless specifically defined, the terms used herein in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and drugs and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and in the treatment of patients. For example, the manufacturer's instructions for the use of the kit can be used, or the reaction and purification can be carried out in a manner known in the art or in accordance with the description of the present invention. The above-mentioned techniques and methods can usually be implemented according to the descriptions in a plurality of summary and more specific documents cited and discussed in this specification, according to conventional methods well known in the art. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural parts and compounds.

[0068] When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents that would result if the formula were written from right to left. For example, CH2O is equivalent to OCH2.

[0069] Unless otherwise indicated, the general chemical terms used, such as but not limited to, "alkyl", "amine", "aryl" are equivalent to their optionally substituted forms. For example, "alkyl" as used herein includes optionally substituted alkyl.

[0070] The term "optional / arbitrary" or "optionally / arbitrarily" means that the event or situation described subsequently may or may not occur, and the description includes the occurrence of the event or situation and the non-occurrence of the event or situation. For example, according to the definition below, "substituted or unsubstituted" means "unsubstituted" (not substituted by a substituent) or "substituted alkyl" (substituted by a substituent).

[0071] This article uses C 1-n Including C 1-2 , C 1-3 , ...C1-n For example, the "C1-C5" group means that the moiety has 1-5 carbon atoms, i.e., the group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. Thus, for example, "C 1-4 "Alkyl" refers to an alkyl group having 1 to 4 carbon atoms, i.e., the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Numerical ranges herein, such as "1-10" refers to each integer in the given range, such as "1-10 carbon atoms" means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.

[0072] The term "alkyl" used herein, alone or in combination, refers to an optionally substituted straight chain or optionally substituted branched saturated aliphatic hydrocarbon. The "alkyl" herein preferably may have 1 to about 20 carbon atoms, for example, 1 to about 10 carbon atoms, 1 to about 8 carbon atoms, or 1 to about 6 carbon atoms, or 1 to about 4 carbon atoms, or 1 to about 3 carbon atoms. Examples of alkyl groups herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and hexyl, as well as longer alkyl groups such as heptyl and octyl, etc. When a group as defined herein, such as "alkyl" appears in a numerical range, for example, "C1-C6 alkyl" or "C1-C6 alkyl" 1-6 The term "alkyl" refers to an alkyl group which may be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms. The alkyl group herein also includes the case where no numerical range is specified.

[0073] The "alkyl" used in combination herein includes alkyl groups linked to other groups, such as the alkyl group in alkoxy, the alkyl group in alkylthio, the hydroxyalkyl group, the haloalkyl group, the cyanoalkyl group, the monoalkylamino group, the dialkylamino group, and the like.

[0074] The term "alkoxy" as used herein, alone or in combination, refers to an alkyl ether group (O-alkyl). Non-limiting examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.

[0075] The term "aromatic group / aryl" used herein alone or in combination refers to an optionally substituted aromatic hydrocarbon group having 6 to about 20, such as 6 to 12 or 6 to 10 ring-forming carbon atoms, which can be a monocyclic aromatic group, a bicyclic aromatic group or a polycyclic aromatic group. A bicyclic aromatic group or a polycyclic aromatic group can be a monocyclic aromatic group fused with other independent rings, such as an alicyclic ring, a heterocyclic ring, an aromatic ring, or an aromatic heterocyclic ring. Non-limiting examples of monocyclic aromatic groups include monocyclic aromatic groups having 6 to about 12, 6 to about 10, or 6 to about 8 ring-forming carbon atoms, such as phenyl; bicyclic aromatic groups are, for example, naphthyl; polycyclic aromatic groups are, for example, phenanthrenyl, anthracenyl, and azulenyl.

[0076] The term "heteroaryl" used herein alone or in combination refers to an arbitrarily substituted heteroaryl group containing about 5 to about 20, such as 5 to 12 or 5 to 10 skeleton ring atoms, wherein at least one (such as 1-4, 1-3, 1-2) ring atom is a heteroatom, and the heteroatom is independently selected from the heteroatoms in oxygen, nitrogen, sulfur, phosphorus, silicon, selenium and tin, but is not limited thereto. The ring of the group does not contain two adjacent O or S atoms. Heteroaryl includes monocyclic heteroaryl (having one ring), bicyclic heteroaryl (having two rings) or polycyclic heteroaryl (having more than two rings). In embodiments where two or more heteroatoms appear in the ring, the two or more heteroatoms may be the same as each other, or some or all of the two or more heteroatoms may be different from each other. Bicyclic heteroaryl or more cyclic heteroaryl may be a monocyclic heteroaryl fused with other independent rings, such as alicyclic, heterocyclic, aromatic, aromatic heterocyclic (collectively referred to as fused ring heteroaryl). Non-limiting examples of monocyclic heteroaryl groups include monocyclic heteroaryl groups having 5 to about 12, 5 to about 10, 5 to about 7 or 6 backbone ring atoms, for example, non-limiting examples thereof include pyridinyl; fused ring heteroaryl groups include benzimidazolyl, quinolinyl, acridinyl. Other examples of heteroaryl groups include, but are not limited to, pyridine, pyrimidine, pyrazine, pyridazine, triazine, furan, thiophene, imidazole, triazole, tetrazole, thiazole, isothiazole, 1,2,4-thiadiazole, pyrrole, pyrazole, oxazole, isoxazole, oxadiazole, benzofuran, benzothiophene, benzothiazole, indole, indazole, quinoline, isoquinoline, purine, carbazole, benzimidazole, pyrrolopyridine, pyrrolopyrimidine, pyrazolopyridine, pyrazolopyrimidine, and the like; acridinyl, phenazinyl, benzoxazolyl, benzothiadiazolyl, benzoxadiazolyl, benzotriazolyl, isoquinolinyl, indolizinyl, isothiazolyl, and the like. The invention also includes oxadiazolyl, isothiazolyl, isoindolyl, oxadiazolyl, purinyl, phthalazinyl, pteridinyl, quinazolinyl, quinoxalinyl, triazinyl and thiadiazolyl, and oxides thereof, such as pyridyl N-oxide, and the like.

[0077] The term "heterocycle" or "heterocyclyl" as used herein, alone or in combination, refers to a non-aromatic heterocycle, including a saturated heterocycle or an unsaturated heterocycle (containing an unsaturated bond). One or more (e.g., 1-4, 1-3, 1-2) of the atoms forming the ring are heteroatoms, such as oxygen, nitrogen or sulfur atoms. The heterocycle may include a monocyclic heterocycle (having one ring) or a bicyclic heterocycle (having two bridged rings) or a polycyclic heterocycle (having more than two bridged rings); spirocycles are also included. The heterocyclic group may have 3 to about 20, such as 3 to about 10, 3 to about 8, 4 to 8, 4 to 7, 5 to about 8 or 5 to about 6 ring-forming atoms. Non-limiting examples of heterocyclic groups include azinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithiocyclohex ... The term also includes saccharides such as thiazolinyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl, and quinolizinyl. The term also includes all cyclic forms of saccharides, including but not limited to monosaccharides, disaccharides, and oligosaccharides. Examples also include, but are not limited to, aziridine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, oxazolidine, thiazolidine, imidazolidine, isoxazolidine, isothiazolidine, pyrazolidine, morpholine, thiomorpholine, piperazine, piperidinyl, and the like.Heterocyclic groups also include heterocyclic rings with one or more aromatic rings fused (i.e., having a common bond), such as 2,3-dihydrobenzofuran, 1,3-benzodioxolane, benzo-1,4-dioxane, phthalimide, and naphthalimide. Heterocyclic groups with one or more aromatic fusions can be connected to other groups through aromatic rings or non-aromatic rings. It should be noted that heterocyclic groups include substituted heterocyclic groups, i.e., other groups can be combined with heterocyclic rings through heteroatoms or carbon atoms (i.e., heterocyclic rings are connected to the parent molecule or further substituted).

[0078] "Halogen" refers to fluorine, chlorine, bromine, and iodine. Fluorine, chlorine, and bromine are preferred. Cyano refers to "-CN"; hydroxyl refers to "-OH"; mercapto refers to "-SH"; and amino refers to "-NH2".

[0079] The term "ester group" has two connection forms, including R1-OCO-R2 and R1-COO-R2, wherein R1 and R2 refer to the substituents on both sides respectively, and R1 and R2 may be the same or different.

[0080] The term "substituted" means that one or more hydrogens on a specified atom are replaced with the specified radicals and if the normal valency of the specified atom is not exceeded under existing conditions, the substitution results in a stable compound.

[0081] Unless explicitly stated, all ranges listed herein are inclusive. For example, "the value of n is an integer between 0 and 2" means that n can be 0, 1 or 2.

[0082] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid. When the compound of the present invention is acidic, its corresponding salt can be easily prepared from an inorganic base or an organic base. Salts derived from such inorganic bases include salts of aluminum, ammonium, calcium, copper (copper and cuprous), iron, ferrous, lithium, magnesium, manganese (manganese and manganous), potassium, sodium, zinc, etc. Preferred are salts of ammonium, calcium, magnesium, potassium and sodium. Salts prepared from organic bases include primary, secondary and tertiary amines derived from natural and synthetic sources. Pharmaceutically acceptable organic non-toxic bases that can form salts include arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, dicyclohexylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When the compound of the present invention is basic, its corresponding salt can be easily prepared from inorganic or organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and the like.

[0083] The term "solvate" refers to a complex of variable stoichiometry formed by a solute (i.e., a compound of Formula I) or a pharmaceutically acceptable salt thereof and a solvent that does not interfere with the biological activity of the solute. Examples of solvents include, but are not limited to, water, ethanol, and acetic acid. When the solvent is water, the solvate is referred to as a hydrate. Hydrates include, but are not limited to, hemihydrates, monohydrates, one and a half hydrates, dihydrates, and trihydrates.

[0084] The term "prodrug" is a functional derivative of a compound of the invention that is easily converted into the desired compound in vivo. Various prodrug forms are well known in the art. See, for a discussion of prodrugs, Pro-drugs as Novel Delivery Systems (1987) Vol. 14 of the ACSSymposium Series, by T. Higuchi and V. Stella, Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association, and Pergamon Press. Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol. 42, p. 309-396; Bundgaard, H. "Design and Application of Prodrugs" in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, pp. 113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38, the above documents are incorporated herein by reference.

[0085] "Subject", "patient" or "individual" refers to an individual suffering from a disease, disorder or condition, etc., including mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals, such as rabbits, dogs and cats; laboratory animals, including rodents, such as rats, mice and guinea pigs, etc. Examples of non-human mammals include, but are not limited to, birds and fish, etc. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[0086] The term "treating and / or preventing" and other similar synonyms include alleviating, reducing or ameliorating symptoms of a disease or condition, preventing other symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting a disease or condition, such as preventing the development of a disease or condition, alleviating a disease or condition, making a disease or condition better, alleviating symptoms caused by a disease or condition, or stopping symptoms of a disease or condition, and in addition, the term includes the purpose of prevention. The term also includes obtaining a therapeutic effect and / or a prophylactic effect. The therapeutic effect refers to the cure or improvement of the underlying disease being treated. In addition, the cure or improvement of one or more physiological symptoms associated with the underlying disease is also a therapeutic effect, for example, although the patient may still be affected by the underlying disease, the patient's condition is observed to improve. In terms of a prophylactic effect, the composition can be administered to a patient at risk for a particular disease, or even if a diagnosis of the disease has not yet been made, the composition can be administered to a patient who has one or more physiological symptoms of the disease.

[0087] As used herein, the term "effective amount", "therapeutically effective amount" or "pharmaceutically effective amount" refers to an amount of at least one agent or compound sufficient to relieve to some extent one or more symptoms of the disease or condition being treated after administration. The result can be a reduction and / or alleviation of signs, symptoms or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant symptom alleviation effect. Techniques such as dose escalation trials can be used to determine the effective amount appropriate for any individual case.

[0088] As used herein, the terms "administering", "administering", "dosing", etc. refer to methods that can deliver a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical and rectal administration. Those skilled in the art are familiar with administration techniques that can be used for the compounds and methods described herein, such as those discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, currented.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In a preferred embodiment, the compounds and compositions discussed herein are administered orally.

[0089] The term "acceptable" with respect to a formulation, composition or ingredient, as used herein, means having no long-term detrimental effect on the general health of the subject being treated.

[0090] The term "pharmaceutically acceptable" as used herein refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, that is, the substance can be administered to a subject without causing adverse biological reactions or interacting in an adverse manner with any components contained in the composition.

[0091] The term "pharmaceutical composition" refers to a biologically active compound optionally mixed with at least one pharmaceutically acceptable chemical component, including but not limited to carriers, stabilizers, diluents, dispersants, suspending agents, thickeners and / or excipients.

[0092] The term "carrier" refers to relatively nontoxic chemical compounds or agents that facilitate the introduction of a compound into cells or tissues.

[0093] The term "neurological disease" refers to diseases occurring in the central nervous system, peripheral nervous system, and autonomic nervous system, with sensory, motor, consciousness, and autonomic dysfunction as the main manifestations.

[0094] The beneficial effects of the present invention are as follows: the present invention provides a libramycin derivative and its use in nervous system diseases, expanding the application of libramycin derivatives. At the same time, for brain nervous system diseases, the present invention designs a compound with a new structure, which has excellent brain-penetrating performance, overcomes the problem of low brain-penetrating efficiency of current drugs, and shows greater advantages in the treatment of brain nervous system diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0095] Figure 1 It is the mass spectrum detection diagram of compound I of the present invention.

[0096] Figure 2 It is the mass spectrum detection diagram of compound I-2 of the present invention.

[0097] Figure 3 It is the mass spectrum detection diagram of compound I-3 of the present invention.

[0098] Figure 4 It is the mass spectrum detection diagram of compound I-4 of the present invention.

[0099] Figure 5 This is a statistical analysis chart of IC50 after HepG2 cells were treated with different concentrations of 18-Me-Reblastatin and 17AAG.

[0100] Figure 6 The diagram shows the cytotoxicity results of I-2, I-3, and I-4.

[0101] Figure 7 Figure 2. Experimental results for increasing the level of GLT1 protein in primary cultured astrocytes.

[0102] Figure 8 This is the GLT1 detection result diagram. The left side of the figure shows the Western blotting analysis results of mouse hippocampal tissue homogenate after 18-Me-Reblastatin injection. The target protein GLT1 and the internal reference protein Actin were detected respectively. The right side shows the statistical analysis results of the relative level changes of GLT1 protein.

[0103] Fig. 9 This is a graph showing PTZ-induced acute epilepsy and the protective effect of 18-Me-reblastatin, in which the data are combined from the results of two animal experiments.

[0104] Fig.10 This is a statistical graph of epileptic seizure frequency in male APP / PS1 mice.

[0105] Fig.11 This is a graph showing the results of the mouse climbing pole and turning test. DETAILED DESCRIPTION

[0106] The following non-limiting examples can enable those skilled in the art to more fully understand the present invention, but do not limit the present invention in any way. The following content is only an exemplary description of the scope of the present invention, and those skilled in the art can make various changes and modifications to the invention of the present invention based on the disclosed content, and they should also fall within the scope of the present application.

[0107] The present invention is further described below by way of specific examples. The various chemical reagents used in the examples of the present invention are obtained through conventional commercial channels unless otherwise specified. Unless otherwise specified, the contents described below are all weight contents. Unless otherwise specified, it is understood that the process is carried out at room temperature.

[0108] The compounds of the present invention having the various formulas described herein can be prepared from commercially available starting materials or starting materials that can be prepared using literature processes according to the processes described in the following general synthetic routes. The variables (e.g., R) in each general synthetic route are as defined herein. One of ordinary skill in the art will note that in the reaction procedures and synthetic schemes described herein, the order of certain steps may vary, such as the introduction and removal of protecting groups.

[0109] In the present invention, 18-Me-Reb and 18-Me-Reblastatin both refer to Compound I.

[0110] Compound preparation

[0111] Example 118 - Preparation of Me-Reblastatin (Compound I)

[0112]

[0113] (1) Preparation of 18-OTf-Reblastatin (Compound III)

[0114] Compound II (274.3 mg) was dissolved in anhydrous DMF (2 mL), and DIPEA (0.26 mL), Tf2NPh (268 mg) and DMAP (7 mg) were added. The reaction flask was then placed in a 40°C oil bath for heating and reaction for 5 hours. TLC monitoring revealed that the raw material spot disappeared. The reaction solution was cooled to room temperature, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound III (301 mg, yield 88%).

[0115] ESI (m / z): 703.72 [M+Na] +

[0116] (2) Preparation of 18-Me-Reblastatin (Compound I)

[0117] Compound III (301 mg), K3PO4 (280 mg), and Pd(PPh3)4 (31 mg) were added to a single-mouth round-bottom flask, and argon protection was replaced. Then, dioxane (10 mL) was added, and ultrasonic degassing was performed. Then, a TMB solution in THF (3.5 M, 151 μL) was added, and then the reaction bottle was placed in an oil bath and heated to react (100° C.) for 4 hours. After the reaction was completed by TLC monitoring, the reaction solution was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain the target compound I (200 mg, yield 83%).

[0118] ESI (m / z): 569.32 [M+Na] +

[0119] Example 2 Preparation of Compound I-2

[0120]

[0121] Compound III (14 mg), KOAc (8 mg) and Pd(dppf)2Cl2 (2 mg) were added to a round-bottom flask, the atmosphere was changed to argon protection, dioxane (1 mL) was added, and ultrasonic degassing was performed. The reaction solution was then placed in an oil bath and heated to react (100°C). The reaction was continued for 1 hour, the reaction solution was cooled to room temperature, diluted with ethyl acetate, the reaction was quenched with water, the liquids were separated, and the extraction was performed with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain the target compound I-2 (7 mg, yield 52%).

[0122] ESI (m / z): 681.39 [M+Na] +

[0123] Example 3 Preparation of Compound I-3

[0124]

[0125] Compound I-3 (20 mg) was added to a round-bottom flask, and the argon protection was changed. DMF (2 mL) was added, and then the reaction solution was placed in an ice-water bath to cool down, potassium carbonate (10 mg) was added, and then acid chloride (5 μL) was added, and then the temperature was raised to room temperature for 1 hour. After the reaction was completed, ethyl acetate was added to dilute, water was added to separate, and ethyl acetate was extracted. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain the target compound I-3 (8 mg, yield 35%), and part of the raw materials (10 mg, recovery rate 50%) were recovered.

[0126] ESI (m / z): 620.20 [M+Na] +

[0127] Example 4 Preparation of Compound I-4

[0128]

[0129] Compound I-3 (5 mg) was added to a round-bottom flask, and the argon atmosphere was changed to protect the flask. DMF (0.5 mL) was added, and then the reaction solution was placed in an ice-water bath to cool down. Potassium carbonate (3 mg) was added, and then acid chloride (2 mg) was added.

[0130] ), and then warmed to room temperature for 1 hour. After the reaction was completed, ethyl acetate was added to dilute, water was added to separate, and ethyl acetate was used for extraction. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain the target compound I-4 (4 mg, yield 65%).

[0131] ESI (m / z): 698.23 [M+Na] +

[0132] Effect detection

[0133] 1. Cytotoxicity assay

[0134] We used HepG2 cells to carry out CTG (CELL TITER-GLO) luminescence method cell proliferation inhibition rate detection. We conducted a screening experiment for 10 compounds. The compound screening concentrations were 0.005, 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 20, and 50 μM, respectively. The cells were cultured in a cell culture incubator at 37°C and 5% CO2 for 2 days, and then CTG detection was carried out. IC50 was calculated, and the results are as follows: Figure 5 As shown, it can be seen that the IC50 of 17AAG is 0.017 μM and the toxicity of 18-Me-Reb is 0.349 μM, which is much lower than the toxicity of 17AAG (19.5 times).

[0135] At the same time, we also evaluated the cytotoxicity of I-2, I-3, and I-4. Figure 6 , and the IC50 values ​​were found to be 0.301μM, 0.238μM, and 0.347μM, respectively, which were similar to those of 18-Me-Reb and were much lower than the toxicity of 17AAG.

[0136] 2. Experiment on increasing the level of GLT1 protein in primary cultured astrocytes

[0137] In order to detect whether the above four compounds can increase the expression level of GLT1. We cultured primary astrocytes and treated them with the above four compounds on the 14th day after culture. The treatment doses were 0, 20, 50, 100, 200, and 400 nM, respectively. After 48 hours of compound treatment, astrocytes were collected for Western blotting to detect the levels of GLT1 and Actin proteins. The results are shown in Figure 7 As shown, the results showed that all four compounds could increase the level of GLT1 protein.

[0138] 2. Experiment on increasing GLT1 protein level in mouse hippocampal tissue by 18-Me-reblastatin

[0139] Nine-week-old C57 / BL6j mice, 20 males and females, 4 mice in each dose group (half males and half females), were injected intraperitoneally with 0, 1, 2, 4, and 8 mg / kg doses. After injection on the 1st, 3rd, and 5th day, the hippocampal brain tissue of the mice was obtained on the morning of the 6th day, and the tissue was homogenized. 10 μl (20 μg) of protein was taken for Western blotting analysis, and the statistical method was One-way ANOVA. Figure 8 As shown, the results showed that the protein level of GLT1 gradually increased in a dose-dependent manner and reached the maximum at 4 mg / kg injection.

[0140] 3. Blood-brain barrier permeability test

[0141] 3.1 Blood-brain barrier permeability test of compound I

[0142] First, the blood drug concentration of mice was tested at a dose of 4 mg / kg after intraperitoneal injection, and the relevant pharmacokinetic parameters and the brain-blood ratio of the compound were calculated. The peak time of blood drug concentration after injection was 0.14 hours, and the half-life (T1 / 2) of the compound was 2.07 hours. By detecting the compound concentration in plasma and brain at 0.083, 0.167 and 0.5 hours after injection, the brain-blood ratios at these three time points were 0.35, 0.52 and 0.54, respectively, which means that about half of the compound can pass through the brain and achieve the properties of a central nervous system drug.

[0143] Table 1. Blood drug concentration detection at different time points after 1 intraperitoneal injection of 18-Me-Reblastatin

[0144]

[0145] In Tables 3-8, Mean: mean, SD: standard deviation, CV: coefficient of variation, BLQ: below limit of quantitation (not detected), NA: not available.

[0146] Table 2. Pharmacokinetic parameters of 18-Me-Reblastatin

[0147]

[0148] In Table 2, IP: intraperitoneal injection, Mean: mean, SD: standard deviation, HL-Lambda-Z: half-life, AUC: area under the concentration-time curve, which represents the bioavailability of the drug (the degree to which the drug is absorbed and utilized in the human body). A larger AUC means higher bioavailability, and vice versa. (0-t) : AUC from time 0 to the final quantifiable time point, AUC (0-∞) : AUC from 0 to infinity, T max : Time for drug concentration to reach peak, C max : Peak concentration of the drug, AUClast: AUC from the start of dosing to the last point, AUCINF-obs: AUC from the start of dosing to the theoretically extrapolated infinite time, MRTlast: Average residence time from dosing to the last quantifiable concentration time, MRTINF-obs: Average residence time of the drug from the start of dosing to the theoretically extrapolated infinite time, T 1 / 2 : Drug half-life, MRT (0-t): The average residence time of the drug from time 0 to the final quantifiable time point, MRT (0-∞) : The average residence time of the drug from 0 to infinity.

[0149] Table 3. Brain concentration of 18-Me-Reblastatin 0.083 hours after intraperitoneal injection

[0150]

[0151] Table 4. Brain-to-blood ratio 0.083 hours after intraperitoneal injection of 18-Me-Reblastatin

[0152]

[0153] Table 5. Brain concentration of 18-Me-Reblastatin 0.167 hours after intraperitoneal injection

[0154]

[0155] Table 6. Brain-to-blood ratio 0.167 hours after intraperitoneal injection of 18-Me-Reblastatin

[0156]

[0157] Table 7. Brain concentration of 18-Me-Reblastatin 0.5 hours after intraperitoneal injection

[0158]

[0159] Table 8. Brain-to-blood ratio 0.5 hours after intraperitoneal injection of 18-Me-Reblastatin

[0160]

[0161] In Table 3-8, Mean: mean, SD: standard deviation, CV: coefficient of variation.

[0162] 3.2 Blood-brain barrier permeability test of Reblastatin

[0163] The plasma and brain tissue concentrations of Reblastatin after intraperitoneal injection of mice were detected according to the above method, and it was found that Reblastatin was almost undetectable in the brain. No concentration of the compound was detected in the brain 0.5 hours after intraperitoneal injection, indicating that its brain-penetrating efficiency was low.

[0164] Table 9. Blood concentration and brain tissue concentration of Reblastatin

[0165]

[0166] In Table 9, IP: intraperitoneal injection, Mean: mean, SD: standard deviation, CV: coefficient of variation, BLQ: below limit of quantitation (not detected), NA: not available.

[0167] 4. Protective effect of compound I in acute epilepsy induced by pentetrazodone (PTZ)

[0168] PTZ is a central nervous system stimulant that induces epileptic seizures primarily by acting as a noncompetitive antagonist of GABA receptors. This inhibition reduces GABA-mediated inhibitory neurotransmission, leading to an imbalance between excitatory and inhibitory signals in the brain. As a result, neuronal excitability increases, inducing acute epileptic seizures. The PTZ-induced acute epilepsy model is often used for rapid screening of anti-epileptic and anti-neuroexcitatory compounds.

[0169] Nine-week-old male C57 / BL6j mice were used. There were 18 mice in the control group and 15 mice in the 18-Me-Reblastatin group. On the 1st, 3rd, and 5th days of the experiment, 4 mg / kg of the compound dissolved in DMSO or the solvent control group were intraperitoneally injected in a volume of 100 μl. At noon on the 6th day, PTZ was intraperitoneally injected at a dose of 55 mg / kg to induce epileptic seizures. The time of the first epileptic seizure after PTZ injection and the Racine scale of the maximum level of epileptic seizure were detected.

[0170] Racine Rating Standards:

[0171] 0) No seizure behavior;

[0172] 1) The behavior suddenly stops and the patient stares motionlessly;

[0173] 2) whisker tremors and / or facial and neck twitching;

[0174] 3) Orthoplastic seizures;

[0175] 4) Tonic-clonic seizure (prone);

[0176] 5) Tonic-clonic seizures (lying on the side, loss of postural control) or violent jumping.

[0177] The statistical method is Student's t test, and the results are as follows Fig. 9From the statistical results, it can be seen that the average onset time of epileptic seizures in the solvent control group was 80 seconds, while the average onset time of epileptic seizures in the 18-Me-Reblastatin treatment group was 98 seconds. In terms of Racine score, the average score of the solvent control group was 3.8 points, while the average score of the 18-Me-Reblastatin treatment group was 2.9 points. In summary, pretreatment with 18-Me-Reblastatin resulted in a prolonged onset time of PTZ-induced epileptic seizures and a milder severity of seizures. This indicates that 18-Me-Reblastatin has a protective effect on acute epilepsy induced by PTZ.

[0178] 5. Anti-epileptic and cognitive improvement effects of compound I in AD mouse model (APP / PS1)

[0179] Eight-month-old male APP / PS1 mice (carrying both APP695swe / PS1-dE9 mutations; Jacksonlab strain number 034832) were used. In the EEG test, there were 8 mice in each of the control group and the experimental group. After the electrodes were implanted, the baseline EEG recording was first monitored continuously for 24h×14 days. From the 15th day, the solvent control group or 18-Me-Reblastatin (4mg / kg) was intraperitoneally injected every other day for 7 consecutive times. Finally, the EEG recording was terminated on the 14th day after the first injection. The effect of the compound was analyzed by comparing the baseline period and the epileptic seizures after administration. Fig.10 As shown, the results showed that the solvent (DMSO) control group had no significant effect on the frequency of epileptic seizures, with a baseline of 1.08 times / day and a seizure frequency of 1.11 times / day after solvent injection. In the experimental group, the baseline of epileptic seizures was 0.96 times / day, and after 18-Me-Reblastatin treatment, it was 0.16 times per day, with an average decrease of 83%.

[0180] 6. Protective effect of compound I in MPTP-induced PD model

[0181] In order to detect the therapeutic effect on Parkinson's mouse model. We selected 37 8-week-old male c57 mice and randomly divided them into three groups, namely the control group (n=8), MPTP modeling group (n=11) and 18Me administration group (n=18). The administration group was pre-administered with 18-Me-Reblastatin (4 mg / kg, ip) twice, and then the MPTP subacute PD model was established. MPTP was intraperitoneally injected into mice at a dose of 30 mg / kg, and the control group was injected with an equal amount of saline, once a day, for a total of 14 days; during this period, the mice in the administration group were simultaneously injected with 18-Me-Reblastatin (4 mg / kg) intraperitoneally, once every other day, and the control group and the modeling group were injected with an equal amount of DMSO. Behavioral tests were performed two weeks later.

[0182] Test 1: Pole climbing test. The motor coordination ability of mice was evaluated by observing their ability to grasp and descend a vertical pole. The experimental apparatus consisted of a wooden pole with a diameter of 1 cm and a length of 50 cm, with a wooden ball with a diameter of 2.5 cm fixed on the top. Gauze was wrapped around the vertical wooden pole to prevent the mouse from slipping. During the test, the wooden pole was at a 90° angle to the ground. The mouse was placed on the top wooden ball, and the time it took the mouse to spontaneously climb from the top to the bottom was recorded. Each mouse was tested three times, with at least 30 minutes between each experiment, and the three results were averaged.

[0183] Test 2: Rotarod test. Used to evaluate the coordinated movement and balance ability of mice. Before all experiments, each mouse was pre-trained for three days, with the speed set to 8rpm, 12rpm and 16rpm for 5 minutes. During the formal experiment, the rotarod instrument was set to a uniform acceleration process from 4rpm to 40rpm for 10 minutes, and the time when the mouse fell from the rotating rod was recorded. Each mouse was tested three times, with at least 30 minutes between each experiment, and the three results were averaged.

[0184] The results are as follows Fig.11 The results showed that 18-Me-Reblastatin can significantly alleviate the motor impairment caused by MPTP, suggesting that 18-Me-Reblastatin also has a protective effect on PD.

[0185] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. Use of a libramycin derivative or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, pharmaceutically acceptable salts or prodrugs in the preparation of a drug for treating and / or preventing a nervous system disease, The structural formula of the libramycin derivative is shown in Formula I: in, R is selected from H; halogen; amino; substituted or unsubstituted C1-5 alkyl, C1-5 alkoxy, C3-10 cycloalkyl, C1-5 ester, aryl, amine, heterocyclic group, and the substituted substituent is selected from at least one of C1-C5 alkyl, carbonyl, hydroxyl, C1-C5 alkyl, halogen, amine, aryl, heterocyclic group.

2. The use according to claim 1, characterized in that The R is selected from substituted or unsubstituted C1-5 alkyl, C1-5 alkoxy, C3-10 cycloalkyl, ester, aryl, amine, and heterocyclic groups, and the substituted substituent is selected from at least one of C1-C5 alkyl, carbonyl, hydroxyl, C1-C5 alkyl, halogen, amine, aryl, and heterocyclic groups.

3. The use according to claim 2, characterized in that: The R is selected from substituted or unsubstituted C1-5 alkyl, C1-5 ester, and heterocyclic group; the substituted substituent is selected from at least one of carbonyl, hydroxyl, C1-C5 alkyl, halogen, amine, aryl, and heterocyclic group; the heteroatom in the heterocyclic group is selected from at least one of N, S, B, and O.

4. The use according to claim 3, characterized in that The R is selected from substituted or unsubstituted C1-3 alkyl, C1-5 ester, and heterocyclic group; the substituted substituent is selected from at least one of C1-C5 alkyl, amine, and heterocyclic group; the heteroatom in the heterocyclic group is selected from at least one of N, S, B, and O.

5. The use according to claim 4, characterized in that The R is selected from C1-3 alkyl, -OCO-Ra, and substituted heterocyclic group; the Ra and the substituted substituent are each independently selected from at least one of C1-C3 alkyl, amine, and heterocyclic group; the heteroatom in the heterocyclic group is selected from at least one of N, S, B, and O.

6. The use according to claim 5, characterized in that The R is selected from C1-3 alkyl, -OCO-Ra, substituted heterocyclic group, and the Ra is selected from at least one of amino group and heterocyclic group; the substituted substituent is selected from C1-C3 alkyl, and the heteroatom in the heterocyclic group is selected from at least one of N, B, and O.

7. The use according to claim 6, characterized in that The R is selected from C1-3 alkyl, -OCO-Ra, at least one C1-3 alkyl-substituted five-ring heterocyclic group containing B and O, and the Ra is selected from at least one of an amino group and a six-membered heterocyclic group containing N.

8. The use according to claim 7, characterized in that The R is selected from methyl, -OCO-Ra, at least one C1-3 alkyl-substituted pentacyclic heterocyclic group containing B and O, and the Ra is selected from at least one of a C1-3 alkyl-substituted amine, a piperazinyl, and a C1-3 alkyl-substituted piperazinyl.

9. The use according to claim 8, characterized in that The R is selected from methyl, -OCO-Ra, at least one methyl-substituted pentacyclic heterocyclic group containing B and O, and the Ra is selected from at least one of dimethylamino, methylethylamino, diethylamino, piperazinyl, and methyl-substituted piperazinyl.

10. The use according to claim 9, characterized in that The R is selected from methyl, -OCO-Ra, The Ra is selected from dimethylamino, 11. The use according to claim 10, characterized in that The R is a methyl group.

12. The use according to any one of claims 1 to 11, characterized in that The nervous system disease is a brain disease.

13. The use according to claim 12, characterized in that The nervous system disease is selected from at least one of epilepsy, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.

14. The use according to claim 13, characterized in that The nervous system disease is selected from at least one of epilepsy and Parkinson's disease.

15. A libramycin derivative or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, characterized in that: The structural formula of the libramycin derivative is shown in Formula I: The R is selected from methyl, -OCO-Ra, and a substituted heterocyclic group; the Ra and the substituted substituent are each independently selected from at least one of a C1-C3 alkyl group, an amine group, and a heterocyclic group; the heteroatom in the heterocyclic group is selected from at least one of N, S, B, and O.

16. The libramycin derivative or its stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug according to claim 15, characterized in that: The R is selected from C1-3 alkyl, -OCO-Ra, substituted heterocyclic group, and the Ra is selected from at least one of amino group and heterocyclic group; the substituted substituent is selected from C1-C3 alkyl, and the heteroatom in the heterocyclic group is selected from at least one of N, B, and O.

17. The libramycin derivative or its stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug according to claim 16, characterized in that: The R is selected from C1-3 alkyl, -OCO-Ra, at least one C1-3 alkyl-substituted five-ring heterocyclic group containing B and O, and the Ra is selected from at least one of an amino group and a six-membered heterocyclic group containing N.

18. The libramycin derivative or its stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug according to claim 17, characterized in that: The R is selected from methyl, -OCO-Ra, at least one C1-3 alkyl-substituted pentacyclic heterocyclic group containing B and O, and the Ra is selected from at least one of a C1-3 alkyl-substituted amine, a piperazinyl, and a C1-3 alkyl-substituted piperazinyl.

19. The libramycin derivative or its stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug according to claim 18, characterized in that: The R is selected from methyl, -OCO-Ra, at least one methyl-substituted pentacyclic heterocyclic group containing B and O, and the Ra is selected from at least one of dimethylamino, methylethylamino, diethylamino, piperazinyl, and methyl-substituted piperazinyl.

20. The libramycin derivative or its stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug according to claim 19, characterized in that: The R is selected from methyl, -OCO-Ra, The Ra is selected from dimethylamino, 21. The libramycin derivative or its stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug according to claim 20, characterized in that: The R is a methyl group.

22. The method for preparing the libramycin derivative according to any one of claims 15 to 21, characterized in that: Select from the following methods: Wherein, R has the same definition as described in any one of claims 15-21.

23. The preparation method according to claim 20, characterized in that: When R is methyl or substituted heterocyclic group, the preparation method is: When R is -OCO-Ra, the preparation method is:

24. A pharmaceutical composition, characterized in that The invention comprises the libramycin derivative according to any one of claims 15 to 21 or its stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug, and a pharmaceutically acceptable carrier or excipient.

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