WO2023142729A1 - Use of ribofuranosyl pyridine derivative for prevention or treatment of epilepsy or convulsions - Google Patents

Abstract

The present invention relates to the use of a ribofuranosyl pyridine derivative for the prevention or treatment of epilepsy or convulsions, which belongs to the field of medicine. The drug of the present invention can improve the convulsion situation of epileptic seizures and improve the Racine grading score, which is of great significance for the prevention or treatment of such diseases or conditions.

Description

Use of ribofuranosylpyridine derivatives for preventing or treating epilepsy or convulsions

The present invention claims to enjoy the rights of the prior application submitted to the State Intellectual Property Office of China on January 27, 2022, the patent application number is 202210101550.7, and the title is "Use of Ribofuranosylpyridine Derivatives for the Prevention or Treatment of Epilepsy or Convulsions" priority. The entirety of this prior application is incorporated herein by reference.

technical field

The invention relates to the use of ribofuranosyl pyridine derivatives for preventing or treating epilepsy or convulsions, and belongs to the field of medicines.

Background technique

Epilepsy, commonly known as "shorn wind" or "epilepsy", is a chronic disease in which the sudden abnormal discharge of brain neurons leads to transient brain dysfunction. According to the latest epidemiological data in China, the overall prevalence rate of epilepsy in China is 7.0‰, the annual incidence rate is 28.8/100,000, and the prevalence rate of active epilepsy with seizures within one year is 4.6‰. Based on this, it is estimated that there are about 9 million epilepsy patients in China, of which 5 to 6 million are active epilepsy patients, and about 400,000 new epilepsy patients are added every year. In China, epilepsy has become the second most common disease in neurology after headache. sick. Epilepsy can occur in all age groups. The incidence of epilepsy in children is higher than that in adults, and the incidence of epilepsy decreases with age. In old age (after the age of 65), the incidence of epilepsy increases again due to the increase of cerebrovascular disease, senile dementia and degenerative diseases of the nervous system.

At present, the treatment of epilepsy at home and abroad is mainly based on drug therapy. After formal antiepileptic drug treatment, about 70% of patients with epilepsy are expected to have their seizures under control, and 50% to 60% of them are expected to recover after 2 to 5 years of treatment, and they can even work and live like normal people. Therefore, reasonable and formal antiepileptic drug treatment is the key, and it is necessary to develop more effective drugs for the prevention or treatment of epilepsy.

Contents of the invention

In order to improve the above-mentioned technical problems, the present invention provides the compound shown in formula I, its racemate, stereoisomer, tautomer, isotope label, solvate or its prodrug in the purposes of preparing medicine, so The above medicines are used to prevent and/or treat epilepsy or convulsions:

Wherein, R ₁ , R ₂ , and R ₃ are the same or different, and are independently selected from C _1-22 alkyl or C _2-22 alkenyl, preferably, at least one of R ₁ , R ₂ , and R ₃ is C _{7 -22} alkyl or C _7-22 alkenyl, such as C _7-12 alkyl, C _20-22 alkyl, C _7-12 alkenyl or C _20-22 alkenyl;

A ^- is selected from pharmaceutically acceptable anions, such as R ₄ COO ^- or halogen anions;

R ₄ is selected from C _1-22 alkyl or C _2-22 alkenyl, preferably C _7-22 alkyl or C _7-22 alkenyl, such as C _7-12 alkyl, C _20-22 alkyl, C _{7 -12} alkenyl or C _20-22 alkenyl.

According to an embodiment of the present invention, R ₁ , R ₂ , _and R ₃ in the compound represented by formula I are the same or different, and are independently selected from C _7-22 alkyl; for example, C _7-12 alkyl or C _{20 -22} alkyl; preferably, at least one of R ₁ , R ₂ , R ₃ is C _7-12 alkyl or C _20-22 alkyl; A ^- is selected from R ₄ COO ^- or halogen anion, wherein R ₄ is selected from From C _7-12 alkyl or C _20-22 alkenyl.

According to an embodiment of the present invention, R ₁ , R ₂ , _and R ₃ in the compound represented by formula I are the same or different, and are independently selected from C _7-14 alkyl groups, such as heptyl, octyl, nonyl, and decyl base, undecyl, dodecyl, tridecyl or tetradecyl.

According to an embodiment of the present invention, at least one of R ₁ , R ₂ , and R ₃ in the compound represented by formula I, more preferably two or three groups are selected from decyl.

According to the exemplary technical scheme of the present invention, A ^- in the compound shown in formula I is selected from R ₄ COO ^- or Cl ^- ; preferably, R ₄ is selected from C _7-14 alkyl, such as heptyl, octyl, Nonyl, Decyl, Undecyl, Dodecyl, Tridecyl or Tetradecyl.

According to an embodiment of the present invention, the compound shown in formula I has the structure shown in the following formula II:

Wherein, R ₁ , R ₂ , R ₃ , A ^- independently have the above definitions.

According to an exemplary embodiment of the present invention, the compound represented by formula I has the structure represented by the following formula III, which is also referred to as NRTDA in this specification:

According to an embodiment of the present invention, the medicament may also optionally contain other active ingredients selected from autophagy modulators (Autophagy Modulator or AM).

According to an embodiment of the present invention, the other active ingredients can be selected from selective autophagy modulator (Selective Autophagy Modulator or AM), more preferably autophagy inducer (Autophagy Inducer) or selective autophagy inducer (Selective Autophagy Inducer ), for example, the other active ingredients can be selected from one or more of the following, or pharmaceutically acceptable salts, prodrugs (such as pharmaceutically acceptable carboxylates or phosphates), solvates :

ATP synthase inhibitors, such as: α-helical basic peptide inhibitors, angiostatin, enterostatin, tentoxin, tentoxin analogs, leucinostatins, efrapeptin ), stilbenes, flavones, isoflavones, steroidal estradiol, estrogen metabolites, polyketide inhibitors (such as macrolides), organotin compounds, α-pyrone and its derivatives, etc.; Preferably, the macrolide can be selected from oligomycin, Peliomycin, Venturicidin, Ossamycin, Apoptolidin and Cytovaricin ;

TOR inhibitors, such as: rapamycin (Rapamycin, may be referred to as RAP in this manual), rapamycin derivatives (such as sirolimus, temsirolimus, everolimus, etc.), dartori Coxib (Dactolisib), GSK2126458, XL765, AZD8055, INK128/MLN0128.OSI027, RapaLink, etc.;

AMPK activators, such as: indirect AMPK activators, biguanides (such as metformin), thiazolidinediones, polyphenols, ginsenosides, alpha-lipoic acid, direct AMPK activators, such as 5-aminoimidazole-4-carbazine Amide ribonucleotide, thienopyridone, benzimidazole, salicylate, PT-1, MT 63-78, thienopyridone and its derivatives, benzimidazole and its derivatives, 5-(5 -Hydroxy-isoxazol-3-yl)-furan-2-phosphonic acid (C-2), etc.;

TOR-independent autophagy enhancers, such as: N-allyl-6-bromoquinazolin-4-amine (SMER28), chloroquine or 3-methyladenine (3-MA), etc.

According to an embodiment of the present invention, the medicament further comprises at least one pharmaceutically acceptable excipient.

These drugs can be prepared in manners well known in the art of pharmacy and can be administered by a variety of routes depending upon whether local or systemic treatment is desired and the area to be treated. Topical (e.g., transdermal, dermal, ocular, and mucous membranes, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powder or aerosol, including by nebulizer; intratracheal, intranasal), Oral or parenteral administration. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, eg, intrathecal or intracerebroventricular, administration. Administration can be parenteral in the form of a bolus, or it can be administered, for example, by means of a continuous infusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, powders and powders. Conventional pharmaceutical carriers, water, powder or oily bases, thickening agents and the like may be necessary or desired.

In preparing the medicaments of the present invention, the active ingredient is usually mixed with excipients, diluted by excipients or enclosed within such a carrier in the form of eg a capsule, sachet, paper or other container. When an excipient is used as a diluent, it can be a solid, semi-solid or liquid substance, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the pharmaceutical composition may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or dissolved in a liquid vehicle); containing, for example, up to 10% by weight of a compound represented by formula I, its racemate, stereoisomer, tautomer, isotope label, solvate or its prodrug ointment, Soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone , Cellulose, Water, Syrup and Methylcellulose. The excipients can also be selected from: lubricants such as talc, sodium stearate, magnesium stearate, sodium oleate, sodium benzoate, sodium acetate, sodium chloride and mineral oil; wetting agents; emulsifying agents and suspending agents; Preservatives such as methyl benzoate and hydroxypropyl benzoate; sweeteners and flavorings. The compositions of the present invention can be formulated so as to provide immediate, sustained or delayed release of the active ingredient after administration to the patient by employing methods known in the art.

The medicament may be formulated in unit dosage form, the active ingredient in each dose being independently selected from about 1 to 1000 mg, more usually about 100 to 500 mg. The term "unit dosage form" means physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect, in admixture with a suitable pharmaceutical excipient. substance.

The effective dose of the active ingredient can vary widely, and is usually administered in a pharmaceutically effective amount. However, it is understood that the amount of active ingredient actually administered will generally be at the discretion of the physician based on relevant circumstances, which include the condition being treated, the route of administration chosen, the actual active ingredient administered; the age, weight, and response of the individual patient; the patient's severity of symptoms, etc.

For the preparation of solid compositions such as tablets, the compound represented by formula I, its racemate, stereoisomer, tautomer, isotopic label, solvate or prodrug thereof is mixed with a pharmaceutical excipient, A solid preformulation composition comprising a compound represented by formula I, a homogeneous mixture of its racemate, stereoisomer, tautomer, isotope label, solvate or prodrug thereof is formed. When these preformulation compositions are referred to as homogeneous, it is meant that the active ingredient is generally uniformly distributed throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

The tablets or pills of the present invention may be coated or compounded to obtain dosage forms which provide the advantage of prolonged action. For example, a tablet or pill contains an inner dose and an outer dose component, the latter being a coated form of the former. The two components can be separated by an enteric layer, which is used to prevent disintegration in the stomach, allowing the inner component to pass through the duodenum intact or to delay release. A variety of materials can be used for such enteric layers or coatings, such materials including various polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

According to an embodiment of the present invention, the medicament of the present invention may be incorporated, and liquid forms for oral or injectable administration include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions; and edible oils such as cottonseed oil , sesame, coconut, or peanut oil flavored emulsions; and elixirs and similar pharmaceutical vehicles.

Drugs for inhalation or insufflation include solutions, suspensions, and powders dissolved in pharmaceutically acceptable water or organic solvents or mixtures thereof. Liquid or solid medicaments may contain suitable pharmaceutically acceptable excipients as described above. In certain embodiments, the pharmaceutical composition is administered by the oral or nasal respiratory route for local or systemic effect. Compositions can be nebulized by use of inert gases. The nebulized solution can be inhaled directly from the nebulizing device, or the nebulizing device can be connected to a face mask or intermittent positive pressure breathing machine. The drug may be administered in solution, suspension or powder form orally or nasally from devices that deliver the formulation in an appropriate manner.

The amount of drug administered to a patient is not fixed, depending on the drug administered, the purpose of administration such as prophylaxis or treatment; the state of the patient, the manner of administration, and the like. In therapeutic applications, an amount of the composition sufficient to cure or at least partially suppress the symptoms of the disease and its complications may be administered to a patient already suffering from the disease. Effective doses will depend on the disease state being treated and on the judgment of the attending clinician which will depend on factors such as the severity of the disease, the age, weight and general condition of the patient.

The drug administered to the patient may be in the above-mentioned pharmaceutical forms. These drugs can be sterilized by conventional sterilization techniques or filterable sterilization. Aqueous solutions can be used as received as packaged, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the pharmaceutical preparation is usually 3-11, more preferably 5-9, most preferably 7-8. It will be appreciated that the use of certain of the foregoing excipients, carriers or stabilizers will result in the formation of pharmaceutical salts.

Therapeutic dosages of the agents of the invention may depend, for example, on the particular use for the treatment, the mode of administration of the agent, the health and state of the patient, and the judgment of the prescribing physician. For the compound represented by formula I of the present invention, the ratio or concentration of its racemate, stereoisomer, tautomer, isotope label, solvate or its prodrug in the drug may not be fixed, depending on various factors , which include dosage, chemical properties (eg, hydrophobicity), and route of administration.

The present invention also provides a method for treating and/or preventing epilepsy or convulsions, comprising administering to patients a therapeutically or preventively effective dose of the compound represented by formula I, its racemate, stereoisomer, tautomer, isotope label , a solvate or a prodrug thereof.

According to an embodiment of the invention, said epilepsy is selected from primary or secondary epilepsy.

Definition and Explanation of Terms

Unless otherwise stated, the definitions of groups and terms recorded in the specification and claims of this application include their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples etc., can be arbitrarily combined and combined with each other. Such combinations and combined group definitions and compound structures should be understood as falling within the scope of the specification and/or claims of the present application.

Unless otherwise stated, the numerical ranges described in the specification and claims are equivalent to at least recording each specific integer value therein. For example, the numerical range "1-100" is equivalent to recording every integer value in the numerical range "1-100", that is, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20..., 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 and 100, and at least Each decimal value in intervals of 0.1.

Unless otherwise stated, when the "active ingredient" is mentioned in the context of this specification, it means the compound shown in formula I, its racemate, stereoisomer, tautomer, isotope label, solvate or its prodrugs.

The term "halogen" denotes fluorine, chlorine, bromine and iodine.

The term "C _1-22 alkyl" should be understood to mean a straight-chain or branched saturated monovalent hydrocarbon group with 1 to 20 carbon atoms, which can also be referred to as "straight-chain or branched C _1-22 alkyl" . For example, means having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 1, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 carbon atoms straight-chain and branched-chain alkyl groups. "C _8-12 alkyl" means straight and branched chain alkyl having 8, 9, 10, 11 or 12 carbon atoms. The alkyl group is for example methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, Tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, isopropyl, isobutyl, sec-butyl, tert-butyl , isopentyl, 2-methylnonyl, 1-methylnonyl, 1-ethyloctyl, 1,2-dimethyloctyl, neopentyl, 1,1-dimethyloctyl, 4-methylnonyl, 3-methylnonyl, 2-ethyloctyl, 3,3-dimethyloctyl, 2,2-dimethyloctyl, 2,3-dimethyloctyl Or 1,3-dimethyloctyl, etc. or their isomers.

The term "C _2-22 alkenyl" is understood to preferably mean a linear or branched monovalent hydrocarbon group containing one or more double bonds and having 2 to 22 carbon atoms, preferably "C _2-10 alkenyl" . "C _2-10 alkenyl" is understood to preferably denote a straight-chain or branched monovalent hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, for example, having 2, 3, 4, 5 or 6 carbon atoms (ie, _C2-6 alkenyl), having 2 or 3 carbon atoms (ie, _C2-3 alkenyl). It is understood that where the alkenyl group contains more than one double bond, the double bonds may be separated from each other or conjugated. The alkenyl is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)- But-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z) -pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-pent-1-enyl Base, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3- Alkenyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl , 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, ( Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methyl But-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2- Alkenyl, (Z)-1-methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E )-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methyl 1-butylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.

The active ingredients according to the invention may exist in the form of solvates, such as hydrates, wherein the active ingredients according to the invention comprise polar solvents, such as in particular water, methanol or ethanol, as structural elements of the crystal lattice of the compound. The amount of polar solvent, especially water, may be present in stoichiometric or non-stoichiometric ratios.

Depending on their molecular structure, the active ingredients of the invention may be chiral and thus may exist in various enantiomeric forms. These active ingredients may thus exist in racemic or optically active form. The active ingredient of the present invention covers isomers whose chiral carbons are in R or S configuration or their mixtures and racemates. The active ingredients of the present invention can be separated into enantiomeric compounds by chemical or physical methods well known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, the diastereomers are prepared from the mixture by reaction with an optically active resolving reagent. Examples of suitable resolving agents are optically active acids such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g. N- benzoylproline or N-benzenesulfonylproline) or various optically active camphorsulfonic acids. With the aid of optically active resolving agents (such as dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chirally derivatized methacrylate polymers immobilized on silica gel), it is also possible to Chromatographic enantiomeric resolution is advantageously performed. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, eg hexane/isopropanol/acetonitrile. The corresponding stable isomers can be separated according to known methods, eg by extraction, filtration or column chromatography.

The term "pharmaceutically acceptable anion" includes suitable acid groups or anions thereof, such as acid groups or anions selected from the group consisting of inorganic acids, such as mineral acids, such as hydrohalic acids (such as hydrochloric acid, hydrobromic acid and hydroiodic acid) , sulfuric acid, phosphosulfate, hydrogensulfate, hemisulfate, thiocyanate, persulfate and sulfonic acid; organic carboxylic acids, such as with substituted (for example, by halogen) or unsubstituted 1 to 22 carbons Atomic linear or branched chain alkyl carboxylic acids, such as acetic acid, propionic acid, butyric acid, pentanoic acid, caproic acid, octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, dodecanoic acid, tridecanoic acid , tetradecanoic acid or pentadecanoic acid; carboxylic acids with substituted (for example, by halogen) or unsubstituted straight-chain or branched alkenyl groups of 2 to 22 carbon atoms, such as acrylic acid, crotonic acid, pentadecanoic acid, Acenoic, hexenoic, octenoic, nonenoic, decenoic, undecenoic, dodecenoic, tridecenoic, tetradecenoic, or pentadecenoic acids; saturated or unsaturated dicarboxylic acids Acids such as oxalic, malonic, succinic, maleic, fumaric, phthalic or tetraphthalic acids; hydroxycarboxylic acids such as ascorbic, glycolic, lactic, malic, tartaric or citric; With amino acids, such as aspartic acid or glutamic acid; benzoic acid; or organic sulfonic acids, such as substituted (for example, by halogen substitution) or unsubstituted (C ₁ -C ₄ )-alkyl- or aryl-sulfonic acids Acids such as methane- or p-toluenesulfonic acid.

Preferred acid radicals or anions may be selected from the acid radicals or anions of the following acids: for example acetic acid, propanoic acid, butyric acid, valeric acid, hexanoic acid, octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, dodecanoic acid, decanoic acid, Tridecanoic acid, myristic or pentadecanoic acid, trifluoroacetic acid, lactic acid, gluconic acid, citric acid, tartaric acid, maleic acid, malic acid, pantothenic acid, adipic acid, alginic acid, aspartic acid, benzene Formic Acid, Butyric Acid, Digluconic Acid, Cyclopentanoic Acid, Glucoheptonic Acid, Glycerophosphoric Acid, Oxalic Acid, Heptanoic Acid, Caproic Acid, Fumaric Acid, Nicotinic Acid, Palmitate, Pectic Acid, 3-Phenylpropane acid, picric acid, pivalic acid, propionic acid, tartaric acid, lactobionic acid, pivotate, camphoric acid and succinic acid, organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, camphorsulfonic acid, 2 -naphthalenesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid and p-toluenesulfonic acid; and inorganic acids such as acid, hydrobromic acid, hydroiodic acid, sulfuric acid, hydrogen sulfate, hemisulfuric acid, thiocyanic acid, persulfuric acid, phosphoric acid and sulfonic acid.

The term "pharmaceutically acceptable salt" includes suitable acid addition or base salts thereof. See J Pharm Sci, 66, 199, 1977, Berge et al. for suitable pharmaceutical salts. For example, with strong mineral acids, such as mineral acids, such as hydrohalic acids (such as hydrochloric acid, hydrobromic acid and hydroiodic acid), sulfuric acid, phosphoric acid sulfate, hydrogen sulfate, hemisulfate, thiocyanate, persulfate and Sulfonic acids; with strong organic carboxylic acids, such as unsubstituted or substituted (for example, by halogen) alkanecarboxylic acids of 1 to 4 carbon atoms, such as acetic acid; with saturated or unsaturated dicarboxylic acids, such as oxalic acid, propane acid, succinic, maleic, fumaric, phthalic or tetraphthalic acids; with hydroxycarboxylic acids such as ascorbic, glycolic, lactic, malic, tartaric or citric acids; with amino acids such as aspartame amino acid or glutamic acid; with benzoic acid; or with organic sulfonic acids, such as unsubstituted or substituted (for example, by halogen) (C ₁ -C ₄ )-alkyl- or aryl-sulfonic acids, such as methane- Or p-toluenesulfonic acid, to form salts.

Preferred salts include, for example, acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, adipate, algal Salt, Aspartate, Benzoate, Butyrate, Digluconate, Cypopentanoate, Glucoheptonate, Glycerophosphate, Oxalate, Heptanoate, Hexanoate , fumarate, niacinate, palmitate, pectate, 3-phenylpropionate, picrate, pivalate, propionate, tartrate, lactobionate, pivotate, camphor salt, undecanoate and succinate, organic sulfonic acids such as methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, camphorsulfonate, 2-naphthalenesulfonate, benzenesulfonic acid salts, p-chlorobenzenesulfonate and p-toluenesulfonate; and inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, hydrogen sulfate, hemisulfuric acid, thiocyanic acid, persulfuric acid, phosphoric acid and sulfonic acid.

The term "prodrug compound" means a covalently bonded compound that releases the active ingredient in vivo. Such prodrugs are typically compounds of the invention in which one or more appropriate groups have been modified such that the modification may be reversed upon administration to a human or mammalian subject. Reversion is usually by enzymes naturally present in such subjects, although it is possible to administer a second agent with this prodrug to effect reversal in vivo. Examples of such modifications include the pharmaceutically acceptable esters described above, wherein such reversal can be performed by esterases and the like.

The term "pharmaceutically acceptable ester" refers to the use of an organic acid or alcohol/hydroxide to form an ester with a functional group in the structure of the compound of the present invention that can be esterified. Organic acids include carboxylic acids, such as unsubstituted or substituted (for example, by halogen) alkanecarboxylic acids of 1 to 12 carbon atoms, such as acetic acid; saturated or unsaturated dicarboxylic acids, such as oxalic acid, malonic acid, succinic acid acid, maleic acid, fumaric acid, phthalic acid or tetraphthalic acid; with hydroxycarboxylic acids such as ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid or citric acid; with amino acids such as aspartic acid or Glutamic acid; with benzoic acid; or with organic sulfonic acids, such as unsubstituted or substituted (eg, by halogen) (C ₁ -C ₄ )-alkyl- or aryl-sulfonic acids, such as methane- or p-toluene sulfonic acid. Suitable hydroxides include inorganic hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide. Alcohols include alkanols of 1-12 carbon atoms which may be unsubstituted or substituted (eg, by halogen).

The term "isotopic label" means that at least one atom in the compound of the present invention is replaced by an isotope. Examples of said isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as corresponding ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ³¹ P , ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl. Substitution with isotopes such as deuterium (ie ² H) may afford certain therapeutic advantages resulting from greater metabolic stability, eg increased in vivo half-life or reduced dosage requirements, and thus may be preferred in certain circumstances. For example, the invention includes compounds of formula I wherein any hydrogen atom is replaced by a deuterium atom.

The term "patient" refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, most preferably humans.

The term "therapeutically effective amount" refers to the amount of an active ingredient or drug combination that a researcher, veterinarian, physician or other clinician is looking for in a tissue, system, animal, individual or human to elicit a biological or medical response, and it includes the following: One or more: (1) Preventing a disease: eg, preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but has not yet experienced or developed disease pathology or symptoms. (2) Inhibiting a disease: For example, inhibiting a disease, disorder or condition (ie preventing further development of the pathology and/or symptoms) in an individual experiencing or developing pathology or symptoms of the disease, disorder or condition. (3) Alleviating disease: For example, alleviating a disease, disorder or condition (ie reversing the pathology and/or symptoms) in an individual experiencing or developing the pathology or symptoms of the disease, disorder or condition. Therapeutically effective amounts can be estimated initially from cell culture assays, or initial doses can be estimated from in vivo data. Using these preliminary guidelines, one of ordinary skill in the art can determine effective doses in humans. In addition, toxicity and therapeutic efficacy of the compounds described herein can also be determined by standard pharmaceutical procedures in cell culture or experimental animals, eg, by determining the _LD50 and _ED50 .

Beneficial effect

The inventors have discovered unexpectedly that the compound shown in formula I, its racemate, stereoisomer, tautomer, isotope label, solvate or its prodrug can improve the convulsions of epileptic seizures, and improve Racine Grading score, which is of great significance for the prevention or treatment of such diseases or conditions.

Detailed ways

The technical solutions of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following examples are only for illustrating and explaining the present invention, and should not be construed as limiting the protection scope of the present invention. All technologies realized based on the above contents of the present invention are covered within the scope of protection intended by the present invention.

Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

Example 1: 1-((2R,3R,4S,5R)-3,4-Didecanoyloxy-5-(decanoyloxymethyl)tetrahydrofuran-2-yl)-3-carbamoylpyridine- Preparation of 1-onium chloride (NRTDA)

Decanoyloxy (150g, 786.54mmol, 163.22mL, 3.27eq) was added dropwise to a solution of nicotinamide ribose chloride (compound NR, 70g, 240.80mmol, 1eq) in pyridine (1L) at 10-15°C. After stirring at room temperature for 4 hours, the reaction solution was directly filtered and concentrated under reduced pressure. The obtained residue was separated and purified by flash silica gel column chromatography (eluent: 0-5% methanol/dichloromethane) to obtain 1-((2R,3R,4S,5R)-3,4-didecyl Acyloxy-5-(decanoyloxymethyl)tetrahydrofuran-2-yl)-3-carbamoylpyridin-1-ium chloride (compound NRTDA, 32g, 41.52mmol, yield 17.24%, purity 97.77%) It is an orange solid.

MS m/z(ESI):717.7;

¹ H NMR: EB5107-1-P1A(400MHz,DMSO-d6)δ9.62(s,1H),9.18-9.37(m,2H),9.02(s,1H),8.37-8.49(m,1H), 8.24(s,1H),6.69(d,J=3.38Hz,1H),5.67(dd,J=3.75,5.50Hz,1H),5.47(t,J=5.88Hz,1H),4.63-4.72(m , 1H), 4.39-4.57(m, 2H), 2.23-2.46(m, 6H), 1.49-1.58(m, 6H), 1.15-1.35(m, 36H), 0.80-0.91(m, 9H).

Embodiment 2: Experimental research on the therapeutic effect of the drug combination of the present invention on rat epilepsy

1. Test product

NRTDA, prepared from Example 1, uses Tween 80 to increase dissolution.

2. Positive control substance

Name: Valproic acid (VPA), trade name: Debakin, manufacturer: Sanofi Pharmaceutical Co., Ltd., batch number: BHG0505, specification: 0.5g/tablet, storage conditions: sealed, dry storage below 25°C, expiration date: 2024 January, Preparation: Prepared with ultrapure water.

3. Experimental animals

Male Wistar rats, with a weight range of 180-200g when grouped, were provided by the Experimental Animal Center of Henan Province. They were raised in a breeding room in an IVC environment. The reference standard was GB 14925-2001. Rats were given food once a day in the morning, free to ingest and drink water .

4. Grouping and identification of experimental animals

4.1 Animal identification method

Quarantine period: Use a black oil-based pen to mark and distinguish animals (No. 1/2/3/4).

Administration observation period: rats used for administration were marked with picric acid, and each caged animal (4 rats) was distinguished in order of head, back, tail and white.

Grouping of experimental animals: After the quarantine period is over, the rats used will be modeled and administered according to the proposed plan, and divided into the pentylenetetrazolium (PTZ) model experimental group according to the model. Each model group is divided into:

(1) Model group

(2) Positive drug group (valproic acid)

(3) NRTDA group (200mg)

4.2 Administration method, frequency, dosage and duration of administration of the test article and reference article

Administration method: normal saline, positive drug sodium valproate, and the test substance are administered by oral gavage.

Medication period: The pentylenetetrazole (PTZ) model experimental group began to be administered on the day of modeling, once a day for the first 3 days, and then changed to once every other day. Administration for 28 days.

Dosing frequency: NRTDA group was given twice a day, once in the morning and in the afternoon.

4.3 Dosage design of the test product and reference product

Positive drug group: sodium valproate (100mg·kg ^-1 ·d ^-1 )

Test product group: NRTDA group (200mg).

Body weight was weighed once a week, and the dosage was calculated based on the latest body weight.

Administration solvent: 1ml/200g.

5. Experimental method

5.1 PTZ model 24 rats (180±20g) were randomly divided into three groups: model group, positive drug group and treatment group. Drugs were given to each group in the first three days: the model group was orally administered normal saline 5ml·kg ^-1 d ^-1 , and the positive drug group was orally administered 5ml·kg -1 ^{d -1 sodium} valproate (100mg·kg ^-1 d ^-1 ), the treatment group was orally gavaged with the test substance according to the planned dose, and 30 minutes after administration on the fourth day, the modeling agent was given: the normal group was injected with normal saline 3ml·kg ^-1 d ^-1 , the rest of the group After intraperitoneal injection of pentylenetetrazole 35 mg·kg ^{- 1} d ^-1 (concentration 1%), rats were evaluated for convulsions every 7 days according to the Racine ^[1] grading method. Intervention drugs were co-administered for 4 weeks (the time refers to the behavior rating of rats in the model group), and the modeling agent was administered for 3 weeks. After the second pentylenetetrazol ignition test was given at the 4th week, the rats were evaluated for convulsions according to the Racine grading method. Afterwards, the rats were sacrificed, and the brains were removed, and the number of c-fos and c-jun protein-positive cells in rat brain tissue was determined by immunohistochemical SP two-step method ^[2] .

5.2 Detection indicators: rat body weight and general state; Racine grading scoring method for scoring convulsions in rats, c-fos, c-jun protein positive cell numbers and brain tissue neuron activity.

6. Data statistical processing method

data usage

Said that the data were analyzed by one-way ANOVA (one-way ANOVA test), and the LSD method was used to compare between groups, and the test level was α=0.05.

7. Experimental results

7.1 Body weight and general condition

During the experiment, the weight of the rats in each group increased, and the weight of the rats in the NRTDA group increased slowly. At the end of the experiment, the weight of the rats in the two groups was significantly different from that of the model group, P<0.05; the general state of the rats in each group during the experiment There was no significant difference, the results are shown in Table 1.

Table 1 Body weight of rats in each group

group	Quarantine weight	first week weight	second week weight	Weight in the third week	Week 4 weight
model group	203.4±5.28	206.5±23.54	220.2±30.01	304±11.31	343.8±12.46
positive group	216.3±7.4	257.2±9.33	274.5±11.5	325.5±15.5	349.5±11.5
NRDTA (200mg)	201.8±7.46	218.8±4.15	251.3±10.06	282.3±11.30	299±9.41*

^* Compared with the model group on the same day, P<0.05.

7.2 Seizure latency and seizure duration

After the rats in each group were given pentylenetetrazole, they all developed epileptic symptoms within 3 minutes, and the seizures lasted for 3-5 minutes. No significant difference was observed between the groups.

7.3 Rats in each group were scored by Racine grading scoring method

Racine grading method: grade 0, normal behavior, without any seizures; grade Ⅰ (grade 1), facial muscle twitching, chewing; grade Ⅱ (grade 2), forelimb clonus, but no upright position; grade Ⅲ (grade 3 ), forelimb-clonic seizures with upright position; grade IV (grade 4), generalized tonic-clonic seizures; grade V (grade 5), generalized tonic-clonic seizures with falls. Effective ignition standard: Anyone who has 5 consecutive convulsions of grade 2 or above, or 2 convulsions of grade 5 or above, shall meet the ignition standard.

The experimental results are shown in Table 2.

Table 2 Racine grading score results of rats in each group

^* Compared with the model group on the same day, P<0.05.

The results showed that the rats in the NRDTA group had milder seizures than those in the model group (lower Racine score), P<0.05.

The exemplary embodiments of the present invention have been described above. However, the protection scope of the present invention is not limited to the above exemplary embodiments. It should be understood that within the spirit and principles of the present invention, any modifications, equivalent replacements, improvements, etc. made by those skilled in the art shall be included within the protection scope of the claims of the present application.

Claims (9)

1. The compound represented by formula I, its racemate, stereoisomer, tautomer, isotopic label, solvate or its prodrug in the purposes of preparation medicine, described medicine is used for prevention and/or treatment Seizures or seizures:

   

   Wherein, R ₁ , R ₂ , and R ₃ are the same or different, and are independently selected from C _1-22 alkyl or C _2-22 alkenyl, preferably, at least one of R ₁ , R ₂ , and R ₃ is C _{7 -22} alkyl or C _7-22 alkenyl, such as C _7-12 alkyl, C _20-22 alkyl, C _7-12 alkenyl or C _20-22 alkenyl;

   A ^- is selected from pharmaceutically acceptable anions, such as R ₄ COO ^- or halogen anions;

   R ₄ is selected from C _1-22 alkyl or C _2-22 alkenyl, preferably C _7-22 alkyl or C _7-22 alkenyl, such as C _7-12 alkyl, C _20-22 alkyl, C _{7 -12} alkenyl or C _20-22 alkenyl.
2. The use according to claim 1, characterized in that R ₁ , R ₂ , and R ₃ are the same or different, and are independently selected from C _7-22 alkyl; for example, C _7-12 alkyl or C _20-22 Alkyl; preferably, at least one of R ₁ , R ₂ , R ₃ is C _7-12 alkyl or C _20-22 alkyl; A ^- is selected from R ₄ COO ^- or halogen anion, wherein R ₄ is selected from C _7-12 alkyl or C _20-22 alkenyl.
3. The use according to claim 1 or 2, characterized in that R ₁ , R ₂ , and R ₃ are the same or different, and are independently selected from C _7-14 alkyl groups, such as heptyl, octyl, nonyl, and decyl base, undecyl, dodecyl, tridecyl or tetradecyl.
4. The use according to claim 1 or 2, characterized in that at least one of R ₁ , R ₂ , R ₃ , more preferably two or three groups are selected from decyl.
5. The use according to any one of claims 1-4, wherein A ^- is selected from R ₄ COO ^- or Cl ^- ;

   Preferably, R _is selected from C _7-14 alkyl groups such as heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl or tetradecyl.
6. The use according to any one of claims 1-5, wherein the compound shown in formula I has a structure shown in formula II below:

   

   Wherein, R ₁ , R ₂ , R ₃ , A ^- independently have the definition described in any one of claims 1-5;
7. purposes as claimed in claim 1, is characterized in that, the compound shown in formula I has the structure shown in following formula III:

   
8. The use according to any one of claims 1-7, wherein the medicament optionally further comprises other active ingredients, the other active ingredients include but not limited to autophagy regulators;

   Preferably, the other active ingredients are selected from selective autophagy regulators, more preferably autophagy inducers or selective autophagy inducers, for example, the other active ingredients can be selected from one or more of the following, Or its pharmaceutically acceptable salt, prodrug (such as pharmaceutically acceptable carboxylate or phosphate), solvate:

   ATP synthase inhibitors, such as: α-helical basic peptide inhibitors, angiostatin, enterostatin, tentoxin, tentoxin analogs, leucinostatins, efrapeptin ), stilbenes, flavones, isoflavones, steroidal estradiol, estrogen metabolites, polyketide inhibitors (such as macrolides), organotin compounds, α-pyrone and its derivatives, etc.; Preferably, the macrolide can be selected from oligomycin, Peliomycin, Venturicidin, Ossamycin, Apoptolidin and Cytovaricin ;

   TOR inhibitors, such as: rapamycin (Rapamycin, may be referred to as RAP in this manual), rapamycin derivatives (such as sirolimus, temsirolimus, everolimus, etc.), dartori Coxib (Dactolisib), GSK2126458, XL765, AZD8055, INK128/MLN0128.OSI027, RapaLink, etc.;

   AMPK activators, such as: indirect AMPK activators, biguanides (such as metformin), thiazolidinediones, polyphenols, ginsenosides, alpha-lipoic acid, direct AMPK activators, such as 5-aminoimidazole-4-carbazine Amide ribonucleotide, thienopyridone, benzimidazole, salicylate, PT-1, MT 63-78, thienopyridone and its derivatives, benzimidazole and its derivatives, 5-(5 -Hydroxy-isoxazol-3-yl)-furan-2-phosphonic acid (C-2), etc.;

   TOR-independent autophagy enhancers, such as: N-allyl-6-bromoquinazolin-4-amine (SMER28), chloroquine or 3-methyladenine (3-MA), etc.
9. The use according to any one of claims 1-8, characterized in that the epilepsy is selected from primary or secondary epilepsy.