WO2011069322A1 - Dérivé de nucléoside phosphonate acyclique et son utilisation médicale - Google Patents

Dérivé de nucléoside phosphonate acyclique et son utilisation médicale Download PDF

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WO2011069322A1
WO2011069322A1 PCT/CN2010/000902 CN2010000902W WO2011069322A1 WO 2011069322 A1 WO2011069322 A1 WO 2011069322A1 CN 2010000902 W CN2010000902 W CN 2010000902W WO 2011069322 A1 WO2011069322 A1 WO 2011069322A1
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Prior art keywords
bis
amino
methoxyphenylthio
oxime
ethyl
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PCT/CN2010/000902
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English (en)
Chinese (zh)
Inventor
仲伯华
何新华
王勇广
刘河
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中国人民解放军军事医学科学院毒物药物研究所
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Priority to JP2012542339A priority Critical patent/JP2013513552A/ja
Priority to EP10835359.0A priority patent/EP2511281A4/fr
Priority to US13/514,749 priority patent/US9187507B2/en
Publication of WO2011069322A1 publication Critical patent/WO2011069322A1/fr

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    • 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 Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • 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

Definitions

  • the present invention relates to an acyclic nucleoside phosphonate derivative having potent antiviral such as hepatitis B virus activity and lower cytotoxicity, a process for the preparation thereof and use thereof for the preparation of a medicament for treating a viral infection such as hepatitis B virus infection.
  • Viral hepatitis such as hepatitis B is a serious disease that threatens people's lives and health.
  • the fundamental way to treat hepatitis B is antiviral therapy.
  • clinically effective anti-hepatitis B virus drugs are mainly interferon and lamivudine.
  • the effective rate of interferon therapy is only 30-50%, and it has dose-limiting side effects.
  • Lamivudine has an exact anti-HBV effect, but long-term use is prone to drug resistance. After 2 years of continuous drug use, the incidence of drug resistance is as high as 40-50%, which can cause serious consequences such as acute exacerbation of hepatitis. .
  • Nucleotide analogs do not require phosphorylation in cells, thus overcoming the resistance of lamivudine and not producing resistance by itself. Its representative drug, adefovir dipivoxil, has been approved for marketing in Europe and the United States. However, adefovir dipivoxil has certain cytotoxicity and can produce renal toxicity in clinical applications. Moreover, similar to lamivudine, adefovir dipivoxil treatment may cause rebound of hepatitis B virus replication after stopping the drug. Recurrence of hepatitis B.
  • COCKTAIL therapy can effectively overcome drug resistance and accelerate virus clearance.
  • the number of people infected with hepatitis B is more than 10 times that of HIV infection, but there are only a few clinically effective anti-hepatitis B virus drugs compared with anti-HIV drugs.
  • European Patent EP 0 785 208 discloses a series of acyclic nucleoside phosphinate compounds having the following structure:
  • R represents a monosubstituted group such as an alkoxy group or an alkyl group; represents hydrogen or an alkyl group, and R 3 and R 4 represent a hydrogen atom, an alkyl group or the like.
  • R represents a monosubstituted group such as an alkoxy group or an alkyl group
  • R 3 and R 4 represent a hydrogen atom, an alkyl group or the like.
  • MCC-478 is a new class of nucleotides of the anti-hepatitis B virus.
  • chemical structure unlike the currently known nucleoside anti-hepatitis B drugs, in addition to the modification of the glycosyl structure, the MCC-478 molecule is substituted with a phenylthio group at the 6 position of the nucleobase nucleus;
  • MCC-478 also exhibits different properties from other anti-HB V drugs, inhibiting viral replication by inhibiting the initiation and assembly reactions of protein synthesis (Clark Chan, et al. Clinical Pharmacokinetics of Alamifovir and Its Metabolites.
  • MCC-478 also inhibits lamivudine-resistant HBV-resistant strains (Suzane Kioko Ono-Nita, Ono-Nita SK, et al. Novel Nucleos Ide analogue MCC-478 (LY582563) is effective against wild-type or lamivudine-resistant hepatitis B virus. Antimicrob Agents Chemother 2002;46:2602-2605).
  • MCC-478 As a prodrug of nucleotide analogues, MCC-478 enters the body and hydrolyzes to release free acid (602076) to exert antiviral effect; however, pharmacokinetic studies show that the main metabolite of MCC-478 in human body is nuclear. Glycosyl monoester (602074), The free acid 602076 has a plasma concentration of only 1/10 of the monoester 602074 (Clark Chan, et al. Clinical Pharmaco-kinetics of Alamifovir and Its Metabolites.
  • the present inventors have discovered a novel class of compounds which not only have good antiviral activity, but also have surprisingly excellent in vivo behavior.
  • the present invention has been completed based on the above findings.
  • the first aspect of the present invention provides an acyclic nucleoside phosphonate derivative represented by the following formula I or a pharmaceutically, isomer, hydrate or solvate thereof:
  • Ri is selected from H or methyl
  • Each R 2 is independently selected from -R 3 or -OR 3 ;
  • Each R 3 is independently selected from the group consisting of CrC 8 alkyl groups and C 3 -C 8 cycloalkyl groups.
  • acyclic nucleoside phosphonate derivative according to any one of the first aspects of the present invention, or a pharmaceutically acceptable salt, isomer, hydrate or solvate thereof, wherein H.
  • acyclic nucleoside phosphonate derivative according to any one of the first aspects of the invention, or a pharmaceutically acceptable salt, isomer, hydrate or solvate thereof, wherein R is a methyl group.
  • R 2 is the same.
  • R 2 is different.
  • acyclic nucleoside phosphonate derivative according to any one of the first aspects of the present invention, or a pharmaceutically acceptable salt, isomer, hydrate or solvate thereof, wherein R 2 is -R 3 .
  • acyclic nucleoside phosphonate derivative according to any one of the first aspects of the invention, or a pharmaceutically acceptable salt, isomer, hydrate or solvate thereof, wherein R 2 is -OR 3 .
  • R 2 is -R 3 and the other R 2 is -OR 3 .
  • acyclic nucleoside phosphonate derivative according to any one of the first aspects of the present invention, or a pharmaceutically acceptable salt, isomer, 7J or solvate thereof, wherein each occurrence of R 3 are each independently selected from C r C 6 alkyl or C 3 -C 6 cycloalkyl.
  • acyclic nucleoside phosphonate derivative according to any one of the first aspects of the present invention, or a pharmaceutically acceptable salt, isomer, hydrate or solvate thereof, wherein each occurrence of R 3 is independently It is selected from a C 2 -C 6 alkyl group or a C 4 -C 6 cycloalkyl group.
  • acyclic nucleoside phosphonate derivative according to any one of the first aspects of the present invention, or a pharmaceutically acceptable salt, isomer, hydrate or solvate thereof, wherein the alkyl group (for example, d -Cs alkyl) is a specified number of straight or branched alkyl groups (e.g., alkyl groups containing from 1 to 8 carbon atoms).
  • acycloalkyl group e.g., c 3 -c 8 cycloalkyl
  • a cycloalkyl group is a cycloalkyl group having a specified number of cycloalkyl or cycloalkylalkyl groups (e.g., having 3-8 carbon atoms; or, for example, containing 3 a cycloalkylalkyl group of -8 carbon atoms, such as cyclopropylmethyl or cyclohexylmethyl).
  • acyclic nucleoside phosphonate derivative according to any one of the first aspects of the present invention, or a pharmaceutically acceptable salt, isomer, hydrate or solvate thereof, wherein each occurrence of R 3 is independently Selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, cyclopropyl, cyclobutyl , cyclopentyl, cyclohexyl, -CH(CH 2 CH 3 ) 2 and the like.
  • acyclic nucleoside phosphonate derivative according to any one of the first aspects of the present invention, or a pharmaceutically acceptable salt, isomer, hydrate or solvate thereof, wherein each occurrence of R 3 is independently It is selected from the group consisting of ethyl, propyl, isopropyl, butyl, isobutyl, isopentyl, neopentyl, cyclopentyl, cyclohexyl, -CH(CH 2 CH 3 ) 2 and the like.
  • acyclic nucleoside phosphonate derivative according to any one of the first aspects of the present invention, or a pharmaceutically acceptable salt, isomer, hydrate or solvate thereof, which is selected from the group consisting of:
  • a second aspect of the present invention provides a method of producing the acyclic nucleoside phosphonate derivative according to any one of the first aspects of the present invention, or a pharmaceutically acceptable salt, isomer, hydrate or solvate thereof. Includes the following steps:
  • a suitable solvent eg DMF
  • suitable reagents eg DBU (ie Bicyclic amidine), especially when hydrogen
  • potassium carbonate especially when methyl
  • a third aspect of the invention provides a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of the acyclic nucleoside phosphonate derivative according to any one of the first aspects of the invention.
  • the pharmaceutical composition of the present invention may be a solution, a tablet, a capsule or an injection; these pharmaceutical compositions may be administered by injection or orally.
  • the compound of formula I of the invention, or a pharmaceutical composition thereof is preferably administered orally.
  • a fourth aspect of the present invention provides the acyclic nucleoside phosphonate derivative according to any one of the first aspects of the present invention, or a pharmaceutically acceptable salt, isomer, sulphate or solvate thereof, or the present invention
  • Use according to any of the fourth aspects of the invention, wherein the virus is a hepatitis virus, such as hepatitis B virus.
  • the use according to any of the fourth aspects of the invention, wherein the disease associated with the viral infection is hepatitis, such as hepatitis B.
  • a fifth aspect of the invention provides a method of treating and/or preventing a disease associated with a viral infection in a mammal in need thereof, the method comprising administering to the mammal in need thereof a therapeutically and/or prophylactically effective amount of the invention
  • the virus is a hepatitis virus, such as hepatitis B virus.
  • the method according to the fifth aspect of the invention, wherein the disease associated with viral infection is hepatitis, such as hepatitis B.
  • a sixth aspect of the invention relates to a compound for use in the treatment and/or prevention of a disease associated with a viral infection, said compound being as described in any one of the first aspects of the invention.
  • the virus is a hepatitis virus, such as hepatitis B virus.
  • the disease associated with the viral infection is hepatitis, such as hepatitis B.
  • halo refers to fluoro, chloro, bromo, and hydrazine.
  • alkyl alkenyl
  • alkynyl straight or branched hydrocarbyl groups such as, but not limited to, methyl, B.
  • Base propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, allyl, propenyl, propynyl, etc., and said "alkyl”, “alkenyl” and “alkyne”
  • bases may be collectively referred to as “hydrocarbyl groups,” or “chain hydrocarbyl groups.”
  • CVC 8 alkyl refers to a substituted or unsubstituted alkyl group having the indicated number of carbon atoms, and which may include a subset of alkyl with 7 _ e.g., Ci_6 pit group, Ci-5 An alkyl group, a Ci-4 group, a Ci-3 pit group, a C2-7 pit group, a C2-6 alkyl group, a ⁇ : 2-5 alkyl group, etc., may also include a specific group thereof, such as but not limited to: ⁇ Base, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, neopentyl.
  • C 3 -C 8 cycloalkyl refers to a substituted or unsubstituted cyclic alkyl group having the indicated number of carbon atoms, and which may include a subset thereof e.g. c 3 _ 7 alkyl, C 3 - 6 fluorenyl, C 4 - 7 alkyl, (: 4 -6 alkyl, etc., may also include a specific group thereof such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.
  • the target compound of formula I when RfH, can be prepared according to an exemplary synthetic route as shown below:
  • An exemplary synthetic step is to dissolve 2-amino-6-chloro-indole and bis-(isopropyl)-phosphorylethyl chloride in DMF and stir the reaction at 80 ° C to 100 ° C under the action of DBU.
  • the target compound of formula I can be prepared according to an exemplary synthetic route as shown below:
  • the various starting materials used in the reaction can be prepared by those skilled in the art based on prior knowledge, or can be obtained by methods well known in the literature, or can be commercially obtained. of.
  • the intermediates, raw materials, reagents, reaction conditions and the like used in the above reaction schemes can be appropriately changed according to the knowledge of those skilled in the art.
  • one skilled in the art can also synthesize other compounds of formula I not specifically enumerated herein in accordance with the method of the second aspect of the invention.
  • the compounds of the formula I according to the invention can be used either as such or in the form of their pharmaceutically acceptable salts or solvates.
  • Pharmaceutically acceptable salts of the compounds of formula I include the conventional salts formed with pharmaceutically acceptable inorganic or organic acids, or inorganic or organic bases. Examples of suitable acid addition salts include with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succinic acid, glycolic acid, formic acid, lactic acid, maleic acid, tartaric acid.
  • citric acid citric acid, malonic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, a salt formed from benzenesulfonic acid, hydroxynaphthoic acid, hydroiodic acid, malic acid, citric acid or the like.
  • Pharmaceutically acceptable salts include inorganic or organic acid salts thereof including, but not limited to, hydroiodide, hydrogen sulfate, hydrogen phosphate, butyrate, oxalate, trimethylacetate, adipate, Alginate, picrate, aspartate, gluconate, ethanesulfonate, p-toluenesulfonate, pamoate, pyruvate, glycolate, trifluoroacetate, Para-aminosalicylate, picoate and ascorbate.
  • hydroiodide hydrogen sulfate, hydrogen phosphate, butyrate, oxalate, trimethylacetate, adipate, Alginate, picrate, aspartate, gluconate, ethanesulfonate, p-toluenesulfonate, pamoate, pyruvate, glycolate, trifluoroacetate, Para-aminosalicylate, picoate and ascorbate
  • Suitable base addition salts include sodium, lithium, potassium, magnesium, aluminum, calcium, zinc, strontium, barium, -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, B. Salt formed by diamine, guanidine-methylglucamine and procaine.
  • a compound of formula I, and pharmaceutically acceptable salts or solvates thereof are included.
  • the free base forms of the compounds of the invention and their respective salt forms are in certain physical properties (e.g., solubility in polar solvents) Slightly different, but for the purposes of the present invention, each acid salt is equivalent to their respective free base forms.
  • the compound of the present invention may be Solvates, such as hydrates, alcoholates, and the like, are formed.
  • the compound of the formula I of the present invention can be used for the preparation of a medicament for treating a hepatitis virus (e.g., hepatitis B virus) infection.
  • a hepatitis virus e.g., hepatitis B virus
  • composition as used herein is meant to include a product comprising specified amounts of each of the specified ingredients, as well as any product produced directly or indirectly from a specified amount of each specified combination of ingredients. According to the invention, the term “composition” means "pharmaceutical composition”.
  • the compounds of the formula I according to the invention also include the isomers, racemates, enantiomers, diastereomers, enantiomeric enrichments, solvates, and esters thereof, the compounds of the formula I according to the invention and the isomers thereof
  • the racemates, enantiomers, diastereomers, enantiomeric enrichments, solvates, and esters may also form solvates such as hydrates, alcoholates, and the like.
  • the above compounds may also be in the form of a prodrug or a release of the active ingredient after metabolic changes in the body.
  • suitable prodrug derivatives are well known to those skilled in the art.
  • solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, are equivalent to the unsolvated forms.
  • each active ingredient in the pharmaceutical compositions of the present invention can be varied so that the resulting amount of active compound is effective to provide the desired therapeutic response to the particular patient, composition, and mode of administration.
  • the dosage level will be selected based on the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and past medical history of the patient to be treated. However, it is the practice in the art that the dosage of the compound be started from a level lower than that required to achieve the desired therapeutic effect, and the dosage is gradually increased until the desired effect is obtained.
  • a therapeutically and/or prophylactically effective amount of a compound of the invention may be administered in pure form or in the form of a pharmaceutically acceptable ester or prodrug (in the presence of In the case of these forms) application.
  • the compound can be administered in a pharmaceutical composition comprising the compound of interest and one or more pharmaceutically acceptable excipients.
  • the invention of the word "therapeutic and / or preventive effective amount" 00902 A compound refers to a sufficient amount of a compound to treat a disorder with a reasonable effect/risk ratio applicable to any medical treatment and/or prevention.
  • the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level will depend on a number of factors, including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the particular combination employed. The age, weight, general health, sex and diet of the patient; the time of administration, the route of administration and the rate of excretion of the particular compound employed; duration of treatment; in combination with or in combination with the particular compound employed Drugs; and similar factors well known in the medical field.
  • the dosage of the compound be started from a level lower than that required to achieve the desired therapeutic effect, and the dosage is gradually increased until the desired effect is obtained.
  • the dosage of the compound of the formula I according to the invention for use in mammals, especially humans may range from 0.001 to 1000 mg/kg body weight per day, for example between 0.01 and 100 mg/k body weight per day, for example between 0.01 and 10 11 ⁇ /13 ⁇ 4 weight/day.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof can be administered alone or in the form of a pharmaceutical composition.
  • the pharmaceutical composition of the present invention can be formulated into various suitable dosage forms depending on the route of administration.
  • the use of one or more physiologically acceptable carriers, including excipients and auxiliaries, facilitates processing of the active compounds into preparations which may be employed in pharmaceutical compositions.
  • the appropriate form of preparation will depend on the route of administration chosen and can be made according to common general knowledge in the art.
  • compositions containing a therapeutically effective amount of a compound of the invention can be prepared using pharmaceutical carriers that are well known to those skilled in the art.
  • the invention therefore also provides a pharmaceutical composition comprising a compound of the invention formulated together with one or more non-toxic pharmaceutically acceptable carriers.
  • the pharmaceutical compositions may be specially formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration.
  • the route of administration may be oral, parenteral or topical, preferably oral and injectable.
  • Pharmaceutical preparations which can be orally administered include capsules and tablets and the like. When the patient has difficulty swallowing, it can also be administered by sublingual tablets or other non-swallowing methods.
  • the compounds of the invention may also be formulated for parenteral administration or transdermal administration or transmucosal administration. Those skilled in the art will appreciate that the compounds of the invention may employ a suitable drug delivery system (DDS) to achieve a more advantageous effect.
  • DDS drug delivery system
  • the pharmaceutical composition of the present invention can be administered orally, rectally, parenterally, intrapool, intravaginally, intraperitoneally, topically (e.g., by powder, ointment or drops), to humans and other mammals, or It is administered as an oral spray or a nasal spray.
  • parenteral refers to administrations that include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, and intra-articular injections and infusions.
  • compositions suitable for parenteral injection may include physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for the preparation of sterile injectable solutions or dispersions.
  • suitable aqueous or nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), vegetable oils (such as olive oil), injectable organic esters such as oleic acid. Ethyl esters and suitable mixtures thereof.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms is ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid and the like. It is also desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of materials which delay absorption, such as aluminum monostearate and gelatin.
  • Suspensions may contain suspending agents in addition to the active compound, such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and polyoxyethylene sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite , agar and tragacanth or a mixture of these substances.
  • suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and polyoxyethylene sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite , agar and tragacanth or a mixture of these substances.
  • the rate of absorption of the drug depends on its rate of dissolution, which in turn depends on crystal size and crystal form.
  • delayed absorption of the pharmaceutical form for parenteral administration is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms can be obtained by biodegradable polymers such as polylactide
  • Injectable Depot formulations can also be prepared by embedding the drug in liposomes or microemulsions that are compatible with body tissues.
  • the injectable preparation can be sterilized, for example, by filtration with a bacteriophage or by incorporating a sterilizing agent in the form of a sterile solid composition which can be dissolved or dispersed in sterile water or other sterilized form before use. Injectable medium.
  • the compound of the present invention or a composition thereof can be administered orally or parenterally.
  • Oral administration may be a tablet, a capsule, a coating, and an enteral preparation such as an injection or a suppository.
  • enteral preparation such as an injection or a suppository.
  • These formulations are prepared according to methods familiar to those skilled in the art.
  • the excipients used in the manufacture of tablets, capsules, and coatings are conventional excipients such as starch, gelatin, gum arabic, silica, polyethylene glycol, solvents used in liquid dosage forms such as water, ethanol, propylene glycol, vegetable oils (eg Corn oil, peanut oil, olive oil, etc.).
  • the dose of the compound of the formula I of the present invention in tablets, capsules, coatings, injections and suppositories is calculated as the amount of the compound present in the unit dosage form.
  • excipients such as surfactants, lubricants, disintegrants, preservatives, flavoring agents and pigments.
  • the I compound is generally present in an amount of from 1 to 5000 mg, the preferred unit dosage form contains from 10 to 500 mg, and more preferably the unit dosage form contains from 20 to 300 mg.
  • the solid dosage form for oral administration which can be provided by the present invention includes a capsule, a tablet. Agents, pills, powders and granules.
  • the active compound may be mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or the following: a) filler or extender such as starch , lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; c) humectants such as glycerol; d) Decomposing agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarders such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g ) humectants such as whales Wax alcohol and glycerol monostearate; h) adsorbents such as kaolin and bentonite and i)
  • Solid compositions of a similar type may be employed as fillers in soft and hard gelatin using excipients such as lactose and high molecular weight polyethylene glycols and the like.
  • excipients such as lactose and high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other materials well known in the art of pharmaceutical preparations.
  • These dosage forms may optionally contain opacifying agents and may be of a composition such that they merely or preferentially release the active ingredient in a certain portion of the intestinal tract in a delayed manner.
  • the embedding composition that can be used include high molecular substances and waxes. If appropriate, the active compounds may also be formulated in microquine form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage form may contain, in addition to the active compound, an inert diluent commonly used in the art, such as water or other solvents, solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate.
  • the oral compositions may contain, in addition to inert diluents, excipients such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and flavoring agents.
  • compositions for rectal or vaginal administration are preferably suppositories.
  • Suppositories can be prepared by mixing a compound of the invention with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or suppository wax, which are solid at room temperature but liquid at body temperature, thus It can be melted in the rectal or vaginal cavity to release the active compound.
  • the compounds of the invention and compositions thereof are also contemplated for topical administration.
  • Dosage forms for topical administration of a compound of the invention include powders, sprays, ointments and inhalants.
  • the active compound is admixed under sterile conditions with apharmaceutically acceptable carrier and any of the required preservative, buffer or propellant.
  • Ophthalmic formulations, ocular cartilage agents, powders and solutions are also contemplated as being within the scope of the invention.
  • the compounds of the invention may also be administered in the form of liposomes.
  • liposomes are typically prepared using phospholipids or other lipid materials. Liposomes are formed from single or multiple layers of hydrated liquid crystal dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
  • the composition of the present invention in the form of a liposome may contain, in addition to the compound of the present invention, a stabilizer, a preservative, an excipient or the like.
  • Preferred lipids are natural and synthetic phospholipids and phosphatidylcholines (lecithins), which may be used alone or together. Methods of forming liposomes are well known in the art. Reference See, for example, Prescott, Ed “Methods in Cell Biology, Volume XIV, Academic Press, New York, NY (1976), p.
  • the present inventors have surprisingly found that the acyclic nucleoside phosphonate derivatives of the formula I have good antiviral activity such as anti-hepatitis virus, particularly against hepatitis B virus, and have surprising in vivo behavioral characteristics.
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the filter cake was washed with dimethylformamide ( 2 ⁇ 30 mL), and the filtrate was evaporated, and the solvent (45 ° C, 2-5 mmHg) was evaporated under reduced pressure on a rotary evaporator. After the residue was cooled, 250 mL of ethyl acetate and 100 mL of saturated brine were added and stirred to dissolve. The mixture was transferred to a separating funnel and the layers were separated. The oil layer was washed with saturated brine ( 2 ⁇ 50 mL). The oil layer was dried over anhydrous sodium sulfate and filtered. Evaporate the solvent under reduced pressure.
  • II 2 was used instead of II i to react with methoxy thiophenol under the action of triethylamine, and separated by silica gel column chromatography to obtain R-2-amino-6-(4-methoxy group.
  • chloromethyl cyclohexanoate was used in place of chlorodecyl propionate to react with IVi, and the reaction product was subjected to silica gel column chromatography to give 1 4 (yield: 35%).
  • chloromethyl-(3-pentyl)-carbonate was used instead of chloromethylethyl carbonate to react with IVi, and the reaction product was separated by silica gel column chromatography to obtain I u , yield 15%. .
  • chloromethylcyclohexyl carbonate was used in place of chloromethylethyl carbonate to react with IVi, and the reaction product was separated by silica gel column chromatography to give 1 12 , yield 24%.
  • the inhibitory effect and cytotoxicity of the target compound on HBV DNA were determined by Hep G 2.2.15 cell in vitro assay.
  • the inhibition of HBV DNA by the target compound was determined by quantitative real-time fluorescent PCR: Hep G 2.2.15 cells were cultured in DMEM medium containing 10% calf serum and incubated in a 5% CO 2 incubator. Then, the cells were seeded in a 96-well plate, the number of cells was 3 ⁇ 10 4 , and the culture was continued. When the cell density reached about 80%, the old culture solution was discarded, and a new culture solution containing different concentrations of the drug was added to set three parallel holes; The culture solution was changed 2 days. On the 10th day after the administration, the supernatant of ⁇ was taken, and the content of HBV DNA was determined by quantitative PCR to calculate the 50% inhibitory concentration, which is the IC 5 o value.
  • cytotoxicity of target compounds by MTT assay Hep G 2 cells were cultured in DMEM containing 10% calf serum in 5% CO 2 incubator Incubate. Then, the cells were seeded in a 96-well plate, the number of cells was 5 ⁇ 10 4 , the culture was continued for 3 days, and a new culture solution containing different concentrations of the drug was added to set three parallel wells; on the third day after the administration, MTT was added to 7.5 mg/ Ml, continue to culture for 2 hours, discard the supernatant, add 10% Tween X-100 isopropanol, 120 ⁇ 1/well, add 0.4 ⁇ 1/well, measure the absorption at 540nm by enzyme-linked instrument, calculate 50% inhibition The concentration is the CC S0 value. The results are shown in Table 1.
  • the sample to be tested is formulated into a suspension of 1% sodium carboxymethyl cellulose at a concentration of 10 mg/ml, and administered intragastrically at a dose equivalent to 20 g/kg of 2-amino-6-(4-A Oxyphenylthio)-9-(2-phosphonomethoxyethyl)-indole (IVi, 602076); 602076 is formulated into a 10 mg/ml physiological saline solution, administered by tail vein injection, dose 10 Mg/kg.
  • the plasma concentration-time data was input into the computer, the pharmacokinetic parameters were calculated using the non-compartmental model method, and the AUC was calculated by the trapezoidal method.
  • the value of .oo was calculated from the oral administration of the test sample and the area under the mean blood concentration-time curve (AUC._ ⁇ ) of 602076 measured after intravenous injection of 602076, respectively, to calculate the oral administration of each precursor compound in rats.

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Abstract

La présente invention concerne un dérivé de nucléoside phosphonate acyclique et son utilisation médicale. L'invention concerne, plus précisément, un dérivé de nucléoside phosphonate acyclique de formule I, présentant une puissante activité antivirale (par exemple contre le virus de l'hépatite B) et une faible cytotoxicité, ainsi que des isomères, des hydrates, des solvates ou des sels pharmaceutiquement acceptables de celui-ci. Dans la formule 1, R1 est choisi parmi H ou le méthyle; chaque R2 est choisi, indépendamment des autres, parmi -R3 ou -OR3 ; et chaque R3 est choisi, indépendamment des autres, parmi un alkyle en C1-C8 ou un cycloalkyle en C3-C8. L'invention concerne également un procédé de préparation de ces composés de formule I, une composition pharmaceutique contenant lesdits composés et leur application médicale. Ce dérivé de nucléoside phosphonate acyclique est un antivirus efficace, en particulier contre le virus de l'hépatite B, et est caractérisé par un bon comportement in vivo.
PCT/CN2010/000902 2009-12-10 2010-06-21 Dérivé de nucléoside phosphonate acyclique et son utilisation médicale WO2011069322A1 (fr)

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EP10835359.0A EP2511281A4 (fr) 2009-12-10 2010-06-21 Dérivé de nucléoside phosphonate acyclique et son utilisation médicale
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CN102816184B (zh) * 2012-09-07 2015-11-18 山东大学 (2-(2-氧基-4-硫代嘧啶)乙氧基)甲基膦酸酯类衍生物及其制备与应用

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US9593137B2 (en) 2011-12-22 2017-03-14 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
US10035814B2 (en) 2011-12-22 2018-07-31 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
US10562926B2 (en) 2011-12-22 2020-02-18 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
US11279720B2 (en) 2011-12-22 2022-03-22 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors

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CN102093422B (zh) 2015-02-25
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JP2013513552A (ja) 2013-04-22
EP2511281A4 (fr) 2013-05-29
US9187507B2 (en) 2015-11-17

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