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WO2023104039A1 - Dérivé de ribofuranosyl pyridine, composition pharmaceutique de celui-ci et utilisation associée - Google Patents

Dérivé de ribofuranosyl pyridine, composition pharmaceutique de celui-ci et utilisation associée Download PDF

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WO2023104039A1
WO2023104039A1 PCT/CN2022/136963 CN2022136963W WO2023104039A1 WO 2023104039 A1 WO2023104039 A1 WO 2023104039A1 CN 2022136963 W CN2022136963 W CN 2022136963W WO 2023104039 A1 WO2023104039 A1 WO 2023104039A1
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alkyl
compound
acid
alkenyl
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朱新法
朱然
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Ningbo Xijian Pharmaceutical Technology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/048—Pyridine radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the invention belongs to the field of medicines, and in particular relates to ribofuranosylpyridine derivatives and pharmaceutical compositions and applications thereof.
  • Nicotinamide ribose is a derivative of vitamin B3, which can form nicotinamide adenine dinucleotide (NAD, also known as coenzyme I) and nicotinamide adenine dinucleotide phosphate (NADP) with phosphoric acid and adenine , also known as coenzyme II), is a precursor of the main coenzyme NAD+. Nicotinamide adenine dinucleotide is a coenzyme that transfers protons.
  • NAD nicotinamide adenine dinucleotide
  • NADP nicotinamide adenine dinucleotide phosphate
  • nicotinamide riboside and its derivatives are currently one of the hotspots in biological and medical research, and they are protective in diseases such as obesity, hearing loss, and senile neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. It can improve cognitive decline, and nicotinamide riboside is used in the preparation of drugs for the treatment of non-alcoholic steatohepatitis, which can effectively reduce the liver lipid content and liver inflammation in animal models.
  • the present invention provides a compound represented by the following formula I, its racemate, stereoisomer, tautomer, isotope label, solvate or its prodrug:
  • 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.
  • R 1 , R 2 , and R 3 are the same or different, and are independently selected from C 7-22 alkyl groups; for example, C 7-12 alkyl groups or C 20-22 alkyl groups; preferably, At least one of R 1 , R 2 , and 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.
  • 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, decyl, undecyl, deca Dialkyl, Tridecyl or Tetradecyl.
  • At least one, more preferably two or three of R 1 , R 2 , R 3 are selected from decyl.
  • a - 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 Alkyl, dodecyl, tridecyl or tetradecyl.
  • the compound shown in formula I has the structure shown in the following formula II:
  • R 1 , R 2 , R 3 , A - independently have the above definitions.
  • the compound shown in formula I has the structure shown in the following formula III:
  • the present invention also provides the compound shown in formula I, the preparation method of its racemate, stereoisomer, tautomer, isotope label, solvate or its prodrug, comprising the following steps: the compound shown in formula a Reaction with R 1 -C(O)-Y, R 2 -C(O)-Y and/or R 3 -C(O)-Y to obtain the compound shown in formula I;
  • R 1 , R 2 , R 3 , A - independently have the above definitions;
  • Y is selected from leaving groups such as halogen.
  • the reaction can be carried out in the presence of an organic base;
  • the organic base can be selected from at least one of triethylamine, pyridine, DIPEA, DMAP, and DBU.
  • the present invention also provides a pharmaceutical composition, which comprises at least one of the compound represented by formula I, its racemate, stereoisomer, tautomer, isotope label, solvate or its prodrug compound kind.
  • the present invention also provides a pharmaceutical composition, which comprises a therapeutically effective amount of the compound represented by formula I, its racemate, stereoisomer, tautomer, isotope label, solvate or its prodrug compound at least one of the
  • the pharmaceutical composition further includes at least one pharmaceutically acceptable excipient.
  • compositions 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
  • 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 desirable.
  • the active ingredient is usually mixed with excipients, diluted by excipients or filled into such carriers in the form of eg capsules, sachets, paper or other containers.
  • excipients 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.
  • the pharmaceutical composition may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or in liquid vehicles); ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders containing, for example, up to 10% by weight of the active compound.
  • 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.
  • lubricants such as talc, sodium stearate, magnesium stearate, sodium oleate, sodium benzoate, sodium acetate, sodium chloride and mineral oil
  • wetting agents such as talc, sodium stearate, magnesium stearate, sodium oleate, sodium benzoate, sodium acetate, sodium chloride and mineral oil
  • wetting agents such as talc, sodium stearate, magnesium stearate, sodium oleate, sodium benzoate, sodium acetate, sodium chloride and mineral oil
  • Preservatives such as methyl benzoate and hydroxypropy
  • compositions may be formulated in unit dosage form, each dose containing from about 5 to 1000 mg, more usually from about 100 to 500 mg, of the active ingredient.
  • 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 compound can vary widely and is usually administered in a pharmaceutically effective amount. However, it is understood that the amount of compound actually administered will generally be determined by the physician based on relevant circumstances, which include the condition being treated, the route of administration chosen, the actual compound being administered; the age, weight and response of the individual patient; the severity of the patient's symptoms; severity etc.
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of the compounds of the invention.
  • 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 solid preformulation is then subdivided into unit dosage forms of the type described above containing, for example, about 0.1 to 1000 mg of the active ingredient of the invention.
  • the tablets or pills of the present invention may be coated or compounded to obtain dosage forms which provide the advantage of prolonged action.
  • 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.
  • 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.
  • liquid forms for oral or parenteral administration include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions; and edible oils such as cottonseed oil, sesame oil, coconut or peanut oil flavored emulsions; and elixirs and similar pharmaceutical vehicles.
  • compositions for inhalation or insufflation include solutions, suspensions, and powders dissolved in pharmaceutically acceptable water or organic solvents or mixtures thereof.
  • Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above.
  • 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.
  • Pharmaceutical compositions in solution, suspension or powder form can be administered orally or nasally from devices that deliver the formulation in an appropriate manner.
  • the amount of the compound or pharmaceutical composition administered to a patient is not fixed and depends 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.
  • 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 pharmaceutical composition administered to the patient may be in the form of the pharmaceutical composition described above.
  • These compositions can be sterilized by conventional sterilization techniques or by filter 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 compound 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 compounds of this invention will depend, for example, on the particular use for the treatment, the mode of administration of the compound, the health and state of the patient, and the judgment of the prescribing physician.
  • the ratio or concentration of the compounds of the invention in the pharmaceutical compositions may vary and depend on a variety of factors including dosage, chemical properties (eg, hydrophobicity) and route of administration.
  • a compound of the invention may be provided for parenteral administration as an aqueous physiologically buffered solution containing about 0.1-10% (w/v) of the compound.
  • Some typical dosages range from about 1 ⁇ g/kg to about 1 g/kg body weight per day.
  • the dosage range is about 1 mg/kg to about 2000 mg/kg body weight/day, preferably about 50 mg/kg to about 500 mg/kg body weight/day.
  • the dosage will likely depend on such variables as the type and extent of the disease or condition, the general health of the particular patient, the relative biological potency of the compound selected, the formulation of the excipient and its route of administration. Effective doses may be obtained by extrapolation from dose-response curves derived from in vitro or animal model test systems.
  • the present invention also provides the use of the compound represented by formula I, its racemate, stereoisomer, tautomer, isotope label, solvate or its prodrug compound in the preparation of medicine.
  • the medicament is used for preventing and/or treating tumors.
  • the tumor may be cancer, such as glioma, breast cancer, liver cancer or lung cancer, examples of which may be selected from glioma cell U87MG, small cell lung cancer cell NCI-H69, breast cancer cell MDA- MB-468, breast cancer cell MCF-7, liver cancer cell HuH7, triple-negative breast cancer cell MM231.
  • cancer such as glioma, breast cancer, liver cancer or lung cancer, examples of which may be selected from glioma cell U87MG, small cell lung cancer cell NCI-H69, breast cancer cell MDA- MB-468, breast cancer cell MCF-7, liver cancer cell HuH7, triple-negative breast cancer cell MM231.
  • the present invention also provides the use of the compound represented by formula I, its racemate, stereoisomer, tautomer, isotope label, solvate or its prodrug compound in treating and/or preventing tumors.
  • the present invention also provides a method for treating and/or preventing tumor diseases, comprising administering to a patient an effective amount of the compound represented by formula I, its racemate, stereoisomer, tautomer, isotope label, At least one of a solvate or a prodrug compound thereof.
  • the numerical ranges described in the specification and claims are equivalent to at least recording each specific integer value therein.
  • the numerical range “1-20” is equivalent to recording every integer value in the numerical range “1-20", that is, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20.
  • halogen denotes fluorine, chlorine, bromine and iodine.
  • C 1-22 alkyl should be understood to mean a linear or branched saturated monovalent hydrocarbon group with 1 to 20 carbon atoms, which may also be referred to as a "straight or branched C 1-22 alkyl” .
  • straight or branched C 1-22 alkyl 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-
  • 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 mean 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-eny
  • the compounds of the invention may exist in the form of solvates, such as hydrates, wherein the compounds of the invention comprise a polar solvent, such as water, methanol or ethanol in particular, as a structural element of the crystal lattice of the compound.
  • a polar solvent such as water, methanol or ethanol in particular, as a structural element of the crystal lattice of the compound.
  • the amount of polar solvent, especially water, may be present in stoichiometric or non-stoichiometric ratios.
  • the compounds of the present invention may be chiral and thus may exist in various enantiomeric forms. These compounds may thus exist in racemic or optically active forms.
  • the compounds of the present invention cover isomers whose chiral carbons are in R or S configuration or their mixtures and racemates.
  • the compounds of the present invention or their intermediates can be separated into enantiomer compounds by chemical or physical methods well known to those skilled in the art, or used in the synthesis in this form. In the case of racemic amines, the diastereomers are prepared from the mixture by reaction with an optically active resolving reagent.
  • 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.
  • optically active resolving agents such as dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chirally derivatized methacrylate polymers immobilized on silica gel
  • 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.
  • 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, valeric acid, caproic acid, octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, dodecanoic acid, tridecanoic acid , tetradecanoic acid or pentadecanoic acid; carboxylic acids with
  • 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, caprylic 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-Phenylprop
  • isotopic label means that at least one atom in the compound of the present invention is replaced by an isotope.
  • 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.
  • 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.
  • the invention includes compounds of formula I wherein any hydrogen atom is replaced by a deuterium atom.
  • patient refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, most preferably humans.
  • terapéuticaally effective amount refers to the amount of an active compound or drug that a researcher, veterinarian, physician, or other clinician is seeking to elicit a biological or medical response in a tissue, system, animal, individual, or human, and includes any of the following 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.
  • 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.
  • 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 .
  • the compound of the present invention can be used for treating/preventing tumor diseases, and preparing antitumor drugs.
  • the compound has excellent antitumor activity and is of great significance for treating tumor diseases.
  • Fig. 1 is the 1 H NMR spectrum of the compound NRTDA in Example 1.
  • the inhibitory rate figure of the compound NRTDA of different concentrations in Fig. 4 embodiment 2 to different cancer cells (a) is the inhibitory rate figure to U87MG; (b) is the inhibitory rate figure to NCI-H69; (c) is to MDA - The inhibition rate graph of MB-468; (d) is the inhibition rate graph for MCF-7.
  • Figure 5 is a diagram of the inhibition rate of different concentrations of compound NR on different cancer cells in Example 2: (a) the inhibition rate diagram of MDA-MB-468; (b) the inhibition rate diagram of MCF-7.
  • Compound NRTDA, NR and SD of different concentrations in Fig. 6 embodiment 2 are respectively to the OD of HuH7 or MM231 490nm place absorbance figure (*P ⁇ 0.05 compares with the control group; **P ⁇ 0.01 compares with the control in different action time) group comparison; ***P ⁇ 0.001 compared with the control group; ****P ⁇ 0.0001 compared with the control group).
  • 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.
  • Embodiment 2 cell viability test
  • NRTDA sodium caprate
  • NR and/or sodium caprate were tested against glioma cell U87MG, small cell lung cancer cell NCI-H69, breast cancer cell MDA-MB-468, breast cancer cell MCF-7, liver cancer Inhibition rates of HuH7 cells and triple-negative breast cancer cells MM231.
  • the concentration gradient set by NRTDA is: 5 ⁇ M, 10 ⁇ M, 20 ⁇ M, 40 ⁇ M, 80 ⁇ M, 160 ⁇ M, 320 ⁇ M;
  • NR+SD the concentration gradient set by NR is: 0, 100 ⁇ M, 200 ⁇ M, 400 ⁇ M and 800 ⁇ M
  • the concentration gradient set by SD is: 0 , 300 ⁇ M, 600 ⁇ M and 1200 ⁇ M.
  • Test group the inhibition rate of compound NRTDA on U87MG, NCI-H69, MDA-MB-468 and MCF-7 respectively, the results are shown in Figure 4;
  • Control group the inhibitory rate of compound NR to MDA-MB-468 and MCF-7, the results are shown in Figure 5; the compounds NRTDA, NR and SD respectively to HuH7 or MM231 OD 490nm absorbance value map, the results are shown in Figure 6 Shown; The combination of compound NR and SD is to the OD of HuH7 Absorbance at 490nm, the results are shown in Figure 7.
  • NRTDA has obvious inhibitory effect on various tumor cells under appropriate concentration conditions; NR has no toxic effect on liver cancer cell HuH7 at 100-800 ⁇ M; SD has no toxic effect on liver cancer cell HuH7 at 200-1200 ⁇ M; NR Combination with SD has no obvious killing effect on liver cancer cells HuH7. Therefore, NRTDA has very obvious anti-tumor activity, which is of great significance for the treatment of tumor diseases.

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Abstract

La présente invention relève du domaine des médicaments, et concerne en particulier un dérivé de ribofuranosyl pyridine, une composition pharmaceutique de celui-ci et une utilisation associée. La présente invention concerne un composé tel que représenté dans la formule I ci-dessous, et un racémate, un stéréoisomère, un tautomère, une étiquette isotopique, un solvate ou un promédicament de celui-ci, qui ont une très excellente activité antitumorale et qui ont une grande importance pour traiter des maladies tumorales.
PCT/CN2022/136963 2021-12-06 2022-12-06 Dérivé de ribofuranosyl pyridine, composition pharmaceutique de celui-ci et utilisation associée Ceased WO2023104039A1 (fr)

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CN115232184B (zh) * 2021-12-06 2024-07-05 宁波熙健医药科技有限公司 呋喃核糖基吡啶衍生物及其药物组合物和用途
CN115400140B (zh) * 2022-01-27 2024-02-20 宁波熙健医药科技有限公司 呋喃核糖基吡啶衍生物用于预防或治疗癫痫或惊厥的用途

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106715455A (zh) * 2014-06-06 2017-05-24 葛兰素史密斯克莱知识产权（第2 号）有限公司 烟酰胺核苷类似物及其药物组合物和用途
CN107531738A (zh) * 2015-03-16 2018-01-02 可劳迈戴斯有限公司 烟酸核苷或烟酰胺核苷组合物、其还原衍生物及其用途
WO2020191359A1 (fr) * 2019-03-21 2020-09-24 Fred Hutchinson Cancer Research Center Polythérapies anticancéreuses utilisant un inhibiteur de nicotinamide phosphoribosyltransférase en combinaison avec un précurseur de la voie de récupération du nicotinamide adénine dinucléotide
CN111909229A (zh) * 2020-08-12 2020-11-10 福建瑞博奥科技有限公司 一种β-烟酰胺核糖氯化物的制备方法
WO2021013795A2 (fr) * 2019-07-19 2021-01-28 Biosynth Ag Procédé de fabrication de sels de nicotinamide ribofuranoside, sels de nicotinamide ribofuranoside en tant que tels, et leurs utilisations
CN113727987A (zh) * 2019-02-21 2021-11-30 可劳迈戴斯有限公司 烟酰胺核苷、烟酸核苷、还原型烟酰基核苷化合物和烟酰基核苷化合物衍生物在制品的用途
CN115232184A (zh) * 2021-12-06 2022-10-25 宁波熙健医药科技有限公司 呋喃核糖基吡啶衍生物及其药物组合物和用途
CN115400140A (zh) * 2022-01-27 2022-11-29 宁波熙健医药科技有限公司 呋喃核糖基吡啶衍生物用于预防或治疗癫痫或惊厥的用途

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017079195A1 (fr) * 2015-11-02 2017-05-11 Mitobridge, Inc. Nicotinamide riboside et dérivés de nicotinamide mononucléotidique utiles dans les traitements de maladies associées aux mitochondries
EP3642214A2 (fr) * 2017-06-19 2020-04-29 Gangadhara Ganapati Dérivés de nicotinamide riboside et leurs utilisations

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106715455A (zh) * 2014-06-06 2017-05-24 葛兰素史密斯克莱知识产权（第2 号）有限公司 烟酰胺核苷类似物及其药物组合物和用途
CN107531738A (zh) * 2015-03-16 2018-01-02 可劳迈戴斯有限公司 烟酸核苷或烟酰胺核苷组合物、其还原衍生物及其用途
CN113727987A (zh) * 2019-02-21 2021-11-30 可劳迈戴斯有限公司 烟酰胺核苷、烟酸核苷、还原型烟酰基核苷化合物和烟酰基核苷化合物衍生物在制品的用途
WO2020191359A1 (fr) * 2019-03-21 2020-09-24 Fred Hutchinson Cancer Research Center Polythérapies anticancéreuses utilisant un inhibiteur de nicotinamide phosphoribosyltransférase en combinaison avec un précurseur de la voie de récupération du nicotinamide adénine dinucléotide
WO2021013795A2 (fr) * 2019-07-19 2021-01-28 Biosynth Ag Procédé de fabrication de sels de nicotinamide ribofuranoside, sels de nicotinamide ribofuranoside en tant que tels, et leurs utilisations
CN111909229A (zh) * 2020-08-12 2020-11-10 福建瑞博奥科技有限公司 一种β-烟酰胺核糖氯化物的制备方法
CN115232184A (zh) * 2021-12-06 2022-10-25 宁波熙健医药科技有限公司 呋喃核糖基吡啶衍生物及其药物组合物和用途
CN115400140A (zh) * 2022-01-27 2022-11-29 宁波熙健医药科技有限公司 呋喃核糖基吡啶衍生物用于预防或治疗癫痫或惊厥的用途

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE Registry 18 February 2021 (2021-02-18), ANONYMOUS : "INDEX NAME NOT YET ASSIGNED ", XP093071503, retrieved from STN Database accession no. 2591503-94-3 *
MAKAROV, M. V. ET AL.: "Scalable Syntheses of Traceable Ribosylated NAD+ Precursors", ORG. BIOMOL. CHEM., 13 September 2019 (2019-09-13), XP055812690 *

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