WO2017220028A1 - Composé de médicament antiviral précurseur de nucléoside cyclo-phosphate à base de distribution du foie et son utilisation - Google Patents

Composé de médicament antiviral précurseur de nucléoside cyclo-phosphate à base de distribution du foie et son utilisation Download PDF

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WO2017220028A1
WO2017220028A1 PCT/CN2017/089850 CN2017089850W WO2017220028A1 WO 2017220028 A1 WO2017220028 A1 WO 2017220028A1 CN 2017089850 W CN2017089850 W CN 2017089850W WO 2017220028 A1 WO2017220028 A1 WO 2017220028A1
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compound
formula
substituted
unsubstituted
group
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PCT/CN2017/089850
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English (en)
Chinese (zh)
Inventor
席志坚
徐华强
陆春平
伍中山
孙锋
张振伟
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浙江柏拉阿图医药科技有限公司
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Priority claimed from CN201710254377.3A external-priority patent/CN107540710B/zh
Priority to EP17814766.6A priority Critical patent/EP3476854B1/fr
Priority to SG11201811516QA priority patent/SG11201811516QA/en
Priority to JP2019520191A priority patent/JP6980779B2/ja
Priority to ES17814766T priority patent/ES2880391T3/es
Priority to PL17814766T priority patent/PL3476854T3/pl
Application filed by 浙江柏拉阿图医药科技有限公司 filed Critical 浙江柏拉阿图医药科技有限公司
Priority to RS20210867A priority patent/RS62144B1/sr
Priority to KR1020187037490A priority patent/KR102434764B1/ko
Publication of WO2017220028A1 publication Critical patent/WO2017220028A1/fr
Priority to ZA2018/08616A priority patent/ZA201808616B/en
Priority to PH12018502735A priority patent/PH12018502735A1/en
Priority to US16/231,497 priority patent/US10668090B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/6574—Esters of oxyacids of phosphorus

Definitions

  • the present invention relates to an antiviral prodrug based on liver specific delivery (LSD), a preparation and application of a nucleoside cyclic phosphate compound, or an optical isomer, a hydrate thereof, a solvent Compounds, pharmaceutically acceptable salts, and pharmaceutical compositions.
  • LSD liver specific delivery
  • hepatitis B virus HBV
  • HDV hepatitis D virus
  • HAV human immunodeficiency virus
  • WHO World Health Organization
  • Anti-hepatitis B virus drugs the main one is nucleotides, such as: adefovir dipivoxil, tenofovir (TDF), tenofovir alafenamide (TAF), entecavir, pull Mivudine, telbivudine, etc., its mechanism of action is to activate into a triphosphate metabolite in the cell, inhibit the DNA or RNA polymerase activity of the virus, prevent DNA or RNA synthesis, and inhibit the replication of the virus.
  • nucleotides such as: adefovir dipivoxil, tenofovir (TDF), tenofovir alafenamide (TAF), entecavir, pull Mivudine, telbivudine, etc.
  • nucleotide compounds such as adefovir, tenofovir, etc.
  • Some nucleotide compounds are highly electronegative at physiological pH. Therefore, oral administration, poor transmembrane ability, low bioavailability; at the same time, increased toxic side effects of the gastrointestinal tract and kidney.
  • esterification and modification to form ester prodrugs such as adefovir dipivoxil, tenofovir, etc., can improve bioavailability and tissue distribution.
  • the ester hydrolase is widely distributed in the body, and most of the drugs are hydrolyzed into negatively charged bioactive components (adefovir, tenofovir, etc.) before the drug reaches the liver cells, and the component does not easily enter the liver cells.
  • the proximal tubule that is actively transported to the kidney is prone to nephrotoxicity.
  • the cyclic phosphate (4-aryl-2-oxo-1,3,2-dioxaphosphane) precursor structure has good liver-specific delivery properties, and the mechanism is very clear, as shown in Figure 1.
  • the 4-aryl substitution position is specifically catalyzed by CYP3A in the cytochrome P450 isozyme family in hepatocytes to form a hydroxyl group, which is then opened to form a negatively charged phosphate intermediate, which is not readily present through the cell membrane.
  • a nucleoside monophosphate compound is formed, and a nucleotide triphosphate compound is continuously produced under the action of a nucleotide kinase, and at the same time,
  • the metabolic by-product aryl vinyl ketone can be removed by a 1,4-addition reaction with abundant antioxidant and free radical glutathione in hepatocytes, and no side effects of the addition product have been reported.
  • Adefovir is used as the active ingredient, through the modification of the substituents on the aryl group, monosubstituted, disubstituted, different substituents and other dozens of combined compounds, and finally found the inter-chloro-substituted aromatic ring, Pradefovir, under the action of CYP3A enzyme
  • the rate of metabolism to adefovir is the highest, nearly five times that of 3,5-dichloroaryl (US200707214668 B2).
  • the present invention synthesizes a cyclic phosphate of an antiviral nucleotide drug, and then further modifies its aromatic ring substituent to obtain a class of prodrugs having a liver-specific delivery (liver delivery) effect, thereby making the therapeutic effect more effective. High, less toxic side effects.
  • R 1 is selected from hydrogen, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1- a C6 alkylamino group; wherein said substitution has one or more substituents selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, nitro, hydroxy, amino, cyano;
  • n 0, 1, 2, 3, 4, 5;
  • Each R 2 is independently selected from halogen, nitro, hydroxy, amino, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkane Oxy, substituted or unsubstituted C1-C6 alkylamino, substituted or unsubstituted C1-C6 carboxyl, substituted or unsubstituted C1-C6 ester, substituted or unsubstituted C2-C6 alkanoyl, substituted or not Substituted C2-C6 alkanoamide group;
  • substitution has one or more substituents selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, nitro, hydroxy, amino, cyano;
  • each chiral center is an R type or an S type.
  • P2 and its 4-aryl group are cis, and P2 is R and C4 is S.
  • said R 1 is selected from the group consisting of H, C1-C3 alkyl, and cyclopropyl.
  • said R 1 is selected from the group consisting of H, methyl, and cyclopropyl.
  • the compound is selected from the group consisting of:
  • the compound of formula II is a compound of formula II-a.
  • the compound has the structure shown below:
  • R 3 and R 5 are halogen
  • n 0, 1, 2, 3.
  • the compound is a compound of formula I-a and formula III-a.
  • R 3 is halogen
  • R 5 is F, Br, or I
  • R 3 ⁇ R 5 is halogen
  • R 3 is Cl and R 5 is F.
  • the compound is selected from the group consisting of:
  • the salt of the compound of Formula I, Formula II and Formula III is a pharmaceutically acceptable salt of a compound of Formula I, Formula II and Formula III with an inorganic or organic acid.
  • a salt of the compound of the formula I, formula II and formula III is a pharmaceutically acceptable salt formed by reacting a compound of formula I, formula II and formula III with a base.
  • the compound of the formula I, the formula II and the formula III or a salt thereof is an amorphous substance or a crystal.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound as described in the first aspect of the invention, or an optical isomer thereof, a pharmaceutically acceptable salt thereof a hydrate or solvate; and a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a third aspect of the invention provides a use of a compound according to the first aspect of the invention, or an optical isomer, pharmaceutically acceptable salt, hydrate or solvate thereof, or as in the second aspect of the invention
  • Use of the pharmaceutical composition for the preparation of a pharmaceutical composition for treating and/or preventing acute or chronic diseases associated with hepatitis B virus (HBV), hepatitis D virus (HDV) or human immunodeficiency virus (HIV) infection .
  • HBV hepatitis B virus
  • HDV hepatitis D virus
  • HAV human immunodeficiency virus
  • the acute or chronic disease associated with hepatitis B virus (HBV), hepatitis D virus (HDV) or human immunodeficiency virus (HIV) infection is selected from the group consisting of hepatitis B, hepatitis D or AIDS.
  • step i the reaction is carried out in the presence of a condensing agent.
  • the condensing agent is selected from the group consisting of dicyclohexylcarbodiimide (DCC).
  • the condensation reaction is carried out at 60 to 100 ° C (about 80 ° C).
  • the condensation reaction has a reaction time of from 1 to 72 hours, preferably from 3 to 48 hours, more preferably from 6 to 24 hours.
  • the inert solvent is selected from the group consisting of N,N-dimethylformamide, pyridine, or a combination thereof; preferably 20:1 of N,N-dimethylformamide and pyridine A mixed solvent of 1:5 (v/v) (preferably 10:1 to 1:2 (v/v)).
  • the compound of formula Vc (preferably a chiral 1,3-propanediol derivative) is prepared by the following method:
  • amphoteric solvents such as EtOH
  • a reducing agent such as NaBH4
  • Reaction eg 1-5h
  • the It is prepared by any one of methods 1-3 selected from the group consisting of:
  • Figure 1 shows a schematic diagram of the mechanism of action of liver delivery compounds.
  • Figure 2 shows the ratio of each liver-delivering compound (racemate) metabolized to an active molecule by the action of the CYP3A4 enzyme.
  • the compound names are shown in Table 1.
  • the active metabolic molecule corresponding to all compounds is PMPA.
  • Figure 3 shows the ratio of liver delivery compounds (S configuration cis) metabolized to active molecules by the action of the CYP3A4 enzyme.
  • the compound names are shown in Table 1. Wherein, the compound 6-cis corresponding active metabolic molecule is PMPA, and the active metabolic molecule corresponding to compound 9 (Pradefovir) is PMEA.
  • Figure 4 is a graph showing the concentration-time columnar distribution of the metabolically released active molecule PMPA in plasma, liver and kidney after intragastric administration of 30 mg/kg of PA1010 in rats.
  • the compound names are shown in Table 1.
  • Figure 5 is a graph showing the concentration-time columnar distribution of the metabolically released active molecule PMPA in plasma, liver and kidney after intragastric administration of 30 mg/kg of PA1007 in rats.
  • the compound names are shown in Table 1.
  • Figure 6 is a graph showing the concentration-time columnar distribution of the metabolically released active molecule PMPA in plasma, liver and kidney after intragastric administration of 30 mg/kg of TAF in rats.
  • Figure 7 is a graph showing the concentration-time columnar distribution of the metabolically released active molecule PMPA in plasma, liver and kidney after intragastric administration of 30 mg/kg of TDF in rats.
  • the present inventors After long-term and intensive research, the present inventors have discovered for the first time through a screening study of a large number of compounds: a class of compounds of formula I and formula III having a specific structure (for example, the 3 and 5 positions of the benzene ring moiety are different halogens, or The 2- and 5-positions of the phenyl ring moiety are different halogens, surprisingly having very excellent antiviral activity, significantly improved liver-specific delivery (liver delivery), and significantly reduced toxic side effects. Based on the above findings, the inventors completed the present invention.
  • C1-C6 alkyl refers to a straight or branched alkyl group having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, A sec-butyl group, a tert-butyl group, or the like.
  • C2-C6 alkanoyl refers to a substituent of the structure “linear or branched alkyl-carbonyl having 1 to 6 carbon atoms", such as acetyl, propionyl, butyryl, or Similar group.
  • C1-C6 alkylamino refers to a substituent of the form “linear or branched alkyl-amino" having 1 to 6 carbon atoms, such as methylamino, dimethylamino. , ethylamino, propylamino, diethylamino, or the like.
  • halogen refers to F, Cl, Br and I.
  • the terms "containing”, “comprising” or “including” mean that the various ingredients may be used together in the mixture or composition of the present invention. Therefore, the terms “consisting essentially of” and “consisting of” are encompassed by the term “contains.”
  • the term "pharmaceutically acceptable” ingredient means a substance which is suitable for use in humans and/or animals without excessive adverse side effects (such as toxicity, irritation, and allergic reaction), that is, a reasonable benefit/risk ratio.
  • the term "effective amount" means an amount of a therapeutic agent that treats, alleviates or prevents a target disease or condition, or an amount that exhibits a detectable therapeutic or prophylactic effect.
  • the precise effective amount for a subject will depend on the size and health of the subject, the nature and extent of the condition, and the combination of therapeutic and/or therapeutic agents selected for administration. Therefore, it is useless to specify an accurate effective amount in advance. However, for a given condition, routine experimentation can be used to determine the effective amount that the clinician can determine.
  • substituted means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, nitrate Base, hydroxyl, amino, cyano group.
  • each of the chiral carbon atoms may be optionally in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
  • compound of the invention refers to a compound of formula II.
  • the term also encompasses various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of Formula II.
  • the term "pharmaceutically acceptable salt” refers to a salt of the compound of the invention formed with an acid or base suitable for use as a medicament.
  • Pharmaceutically acceptable salts include inorganic and organic salts.
  • a preferred class of salts are the salts of the compounds of the invention with acids.
  • the acid forming the salt includes, but is not limited to, mineral acid such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzoic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.
  • mineral acid such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid,
  • Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid, citric
  • solvates of the present invention include stoichiometric solvates such as hydrates and the like, as well as compounds containing variable amounts of water formed upon preparation by low pressure sublimation drying.
  • thermodynamically stable isomers may be present after preparation of the compounds of the invention, such as tautomers, conformers, meso compounds, and optical isomers having enantiomeric or diastereomeric relationships.
  • tautomers such as tautomers, conformers, meso compounds, and optical isomers having enantiomeric or diastereomeric relationships.
  • R 1 is selected from hydrogen, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1- a C6 alkylamino group; wherein said substitution has one or more substituents selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, nitro, hydroxy, amino, cyano;
  • n 0, 1, 2, 3, 4, 5;
  • Each R 2 is independently selected from halogen, nitro, hydroxy, amino, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkane Oxy, substituted or unsubstituted C1-C6 alkylamino, substituted or unsubstituted C1-C6 carboxyl, substituted or unsubstituted C1-C6 ester, substituted or unsubstituted C2-C6 alkanoyl, substituted or not Substituted C2-C6 alkanoamide group;
  • substitution has one or more substituents selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, nitro, hydroxy, amino, cyano;
  • each chiral center is an R type or an S type.
  • a preferred class of compounds of formula II have the structure of formula I below:
  • the compound of formula I is a compound of formula I-a.
  • the P2 and the 4-position aromatic groups in the phosphate ring structure are cis to each other, and P2 is an R type, and C4 is an S type.
  • said R 1 is selected from the group consisting of H, C1-C3 alkyl, and cyclopropyl.
  • said R 1 is selected from the group consisting of H, methyl, and cyclopropyl.
  • R 3 is Cl and R 5 is F; or R 3 is Cl and R 5 is Br; or R 3 is Cl and R 5 is Cl.
  • the optical isomers include tautomers, cis and trans isomers, conformational isomers, meso compounds, and optical isomers having enantiomeric or diastereomeric relationships. .
  • the compound is selected from the group consisting of:
  • the compound of formula III is a compound of formula III-a.
  • the P2 and the aromatic group at the 4-position in the phosphate ring structure are cis to each other, and P2 is an R type, and C4 is an S type.
  • said R 1 is selected from the group consisting of H, C1-C3 alkyl, and cyclopropyl.
  • said R 1 is selected from the group consisting of H, methyl, and cyclopropyl.
  • R 3 is Cl and R 5 is F; or R 3 is Cl and R 5 is Br; or R 3 is Cl and R 5 is Cl.
  • the optical isomers include tautomers, cis and trans isomers, conformational isomers, meso compounds, and optical isomers having enantiomeric or diastereomeric relationships. .
  • the compound is selected from the group consisting of:
  • each of the reactants may be commercially available or may be prepared by a conventional method in the art using commercially available raw materials.
  • the 1,3-propanediol derivative Vd (preferably a chiral 1,3-propanediol derivative) is prepared by the following method:
  • the It is prepared by any one of methods 1-3 selected from the group consisting of:
  • the compound of the present invention has excellent inhibitory activity against hepatitis B virus (hepatitis B virus), the compound of the present invention and various crystal forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and
  • the pharmaceutical composition of the present invention as a main active ingredient can be used for the treatment, prevention, and alleviation of diseases caused by hepatitis B virus.
  • the compounds of the present invention are useful for the treatment of diseases caused by infections such as HBV, HDV and HIV.
  • compositions of the present invention comprise a safe or effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  • safe and effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical compositions contain from 0.1 to 1000 mg of the compound/agent of the invention, more preferably from 0.5 to 500 mg of the compound/agent of the invention.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By “compatibility” it is meant herein that the components of the composition are capable of intermingling with the compounds of the invention and with each other without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
  • magnesium stearate magnesium stearate
  • calcium sulfate vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as ), a wetting agent (such as sodium lauryl sulfate), a coloring agent, a flavoring agent, a stabilizer, an antioxidant, a preservative, a pyrogen-free water, and the like.
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
  • a particularly preferred mode of administration is oral.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) Absorbing accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethyl
  • compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and flavoring agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and flavoring agents.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for the compounds of the invention for topical administration include ointments, powders, patches, propellants and inhalants.
  • the active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or, if necessary, propellants.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight
  • the dose to be administered is usually 0.2 to 1000 mg, preferably 0.5 to 500 mg.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
  • Liver-specific delivery technology (liver delivery) is strong, and compounds can only be specifically catalyzed by CYP3A in the cytochrome P450 isozyme family in hepatocytes to produce active molecules with high negative charge, no It is easy to excrete from the liver, so it has a higher concentration in the liver and achieves a specific delivery effect.
  • Pillar CHIRALPAK ADH
  • Pillar CHIRALPAK ADH
  • PA1010 refers to PA1010-cis
  • PA1007 refers to PA1007-cis.
  • the efficiency of metabolism into active molecules (PMPA or PMEA) by the determination of a prodrug at a concentration of 0.1 ⁇ M at a concentration of 1 mg/ml of human recombinant CYP3A4 enzyme (CYPEX) was evaluated.
  • the enzymatic reaction was carried out in a volume of 500 ⁇ l, a 0.1 M solution of pH 7.4 in Tris-HCl buffer solution containing 5 mM magnesium chloride and 1 mM NADPH.
  • the reaction mixture was incubated in a constant temperature shaking water bath at 37 ° C for 0, 7, 17, 30 minutes, and the reaction was stopped by adding 1.5 volumes of methanol. Centrifuge for 20 minutes at a maximum speed of 13,600 rpm using an Eppendorf bench top centrifuge.
  • Compound 2 was resolved to give a S-configuration cis (compound 6-cis) metabolic ratio of 27.36%, which is higher than its corresponding S-form racemate (Compound 2).
  • the compound 2 of the present invention is about 50% to 1300% higher than the compounds of other structures.
  • the activity of the present compound 2 (different halogens Cl and F at the 3 and 5 positions) was about 13 times higher than that of the compound 8 in which both the 3 and 5 positions were Cl.
  • the most active compound 2 was resolved to obtain the cis-form 6-cis, the resolved S-configuration cis compound and the same type of compound Pradefovir (compound 9, S configuration cis) that has entered clinical research.
  • the activity of the compound 6-cis of the present invention is also about 57.5% higher.
  • the human liver microsomes used in this test were purchased from In Vitro Technologies (IVT), batch number SSP X008070, which is a mixed liver microsome extracted from the liver tissue of 150 donors. The batch of liver microparticles was recorded in the product description.
  • the metabolic activity of CYP3A4 is 1.734 nmol/mg/min (the rate at which testosterone is metabolized to produce 6-beta testosterone).
  • the test compound was synthesized by Zhejiang Plato Pharmaceutical Technology Co., Ltd., and dissolved in methanol to prepare a storage solution having a concentration of 25 mM.
  • the enzymatic reaction was carried out in 100 ⁇ l of a reaction solution (100 mM Tris-HCl, 5 mM MgCl 2 , pH 7.4) at a test compound concentration of 25 ⁇ M, a human liver microsome concentration of 2 mg/ml, and a reaction was initiated by adding NADPH (final concentration 2 mM). After reacting for 5 min in a constant temperature shaking water bath, 1.5 times the volume of acetonitrile was quickly added to terminate the reaction. Centrifuge for 20 minutes at a maximum speed of 13,600 rpm using an Eppendorf bench top centrifuge.
  • HLM is the English abbreviation for human liver microsomes.
  • Compound 2 was resolved to obtain the S configuration cis (compound 6-cis), which metabolized to produce PMPA at a rate of 75.8 pmol/min/mg HLM, higher than its corresponding S configuration racemate (compound) 2).
  • Male SD rats weighing 180-300 g were provided by Shanghai Xipuer-Beikai Experimental Animal Co., Ltd. Male animals adapted to the environment for more than 3 days, and fasted for 12 hours in the evening before the experiment.
  • a solution (physiological saline) of PA1010 (4-cis compound), PA1007 (6-cis compound), TAF and TDF was prepared. Before the administration, the animal weight was checked to meet the experimental requirements. Twelve rats were selected for grouping, and 2 rats in each group were given a drug solution of 30 mg/kg by gavage. Rats were euthanized with carbon dioxide gas at 0.5 h, 1 h, 3 h, 6 h, 12 h, and 24 h, respectively.
  • Samples were taken by cardiac extraction, stored in heparin anticoagulant tubes, centrifuged at 6000 rpm for 5 min at 4 ° C, and supernatants were taken.
  • the plasma was stored in ice; the kidney and liver tissues of the rats were collected and washed with 4 ° C pre-cooled saline, and the water was drained. Store in ice. After the experiment, the samples were stored in a -80 ° C refrigerator.
  • LC-MS/MS-AJ Triple Quad 5500, AB SCIEX
  • Mobile phase A 0.1% aqueous formic acid
  • mobile phase B acetonitrile solution. The sample was separated by gradient elution and the procedure is shown in Table 4.
  • ESI electrospray ionization
  • MRM multiple reaction monitoring
  • the tissue concentration-time curve area (AUC0-t) of PMPA was fitted using the log-linear trapezoidal method in the non-compartmental model of WinNonLin 6.2.1 (Pharsight, CA).
  • the ratio of liver to kidney to hepatic blood of PMPA is their AUC0-t ratio.
  • the distribution of liver tissue showed that the active molecule PMPA released by PA1010 was significantly higher than the TAF and TDF at the corresponding time points (p ⁇ 0.01, Figures 4, 6 and 7).
  • WinNonLin6.2.1 to fit the area under the curve of the drug, according to Table 5, the liver exposure of PMPA released by each test drug was compared: PA1010>TAF>PA1007>TDF, and the PMPA released by PA1010 was 1.5 times of TAF. 222692h ⁇ ng/g vs. 148407h ⁇ ng/g) and TDF 2.9 times (222692h ⁇ ng/g vs.

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Abstract

L'invention concerne un composé de médicament antiviral précurseur nucléoside cyclo-phosphate basé sur la technologie de distribution spécifique du foie (LSD) et son utilisation, et en particulier, l'invention concerne un composé de formule II et un isomère, un sel pharmaceutiquement acceptable, un hydrate, un solvate de celui-ci, et la composition pharmaceutique correspondante. L'invention concerne également l'utilisation des composés seuls ou en combinaison avec d'autres médicaments antiviraux dans le traitement du virus de l'hépatite B (HBV), le virus de l'hépatite D (HDV) et le virus de l'immunodéficience humaine (HIV) et des maladies causées de la même façon.
PCT/CN2017/089850 2016-06-24 2017-06-23 Composé de médicament antiviral précurseur de nucléoside cyclo-phosphate à base de distribution du foie et son utilisation WO2017220028A1 (fr)

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KR1020187037490A KR102434764B1 (ko) 2016-06-24 2017-06-23 간 전송 항바이러스 전구체 약물 뉴클레오시드 시클로 포스페이트 에스테르 화합물 및 응용
SG11201811516QA SG11201811516QA (en) 2016-06-24 2017-06-23 Liver delivery-based antiviral precursor drug nucleoside cyclophosphate compound and use thereof
JP2019520191A JP6980779B2 (ja) 2016-06-24 2017-06-23 肝臓送達に基づく抗ウイルス性プロドラッグであるヌクレオシド環状リン酸エステル化合物およびその使用
ES17814766T ES2880391T3 (es) 2016-06-24 2017-06-23 Compuesto de ciclofosfato de nucleósido de fármaco precursor antivírico y uso del mismo
PL17814766T PL3476854T3 (pl) 2016-06-24 2017-06-23 Związek cyklofosforanu nukleozydu stanowiący przeciwwirusowy lek prekursorowy oraz jego zastosowanie
EP17814766.6A EP3476854B1 (fr) 2016-06-24 2017-06-23 Composé de médicament antiviral précurseur de nucléoside cyclo-phosphate et son utilisation
RS20210867A RS62144B1 (sr) 2016-06-24 2017-06-23 Jedinjenje leka antivirusnog prekursora nukleozida ciklofosfata i njegova primena
ZA2018/08616A ZA201808616B (en) 2016-06-24 2018-12-20 Liver delivery-based antiviral precursor drug nucleoside cyclophosphate compound and use thereof
PH12018502735A PH12018502735A1 (en) 2016-06-24 2018-12-21 Liver delivery-based antiviral precursor drug nucleoside cyclophosphate compound and use thereof
US16/231,497 US10668090B2 (en) 2016-06-24 2018-12-22 Liver specific delivery-based antiviral prodrug nucleoside cyclophosphate compound and uses thereof

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
WO2021074443A1 (fr) 2019-10-17 2021-04-22 Ai-Biopharma Médicaments antiviraux et ciblés sur le foie

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